Jadelson Andrade - Fausto Pinto - Donna Arnett (Eds.) - Prevention of Cardiovascular Diseases - From Current Evidence To Clinical Practice-Springer International Publishing (2015)

Prevention of
Cardiovascular
Diseases
From Current Evidence
to Clinical Practice
Jadelson P. Andrade
Fausto J. Pinto
Donna K. Arnett
Editors
123
Prevention of Cardiovascular Diseases
Jadelson P. Andrade Fausto J. Pinto

Donna K. Arnett
Editors
Prevention of Cardiovascular
Diseases
From Current Evidence to Clinical Practice
Editors
Jadelson P. Andrade, M.D.
Director, Hospital da Bahia
Salvador, Bahia, Brazil
Donna K. Arnett, M.S.P.H., Ph.D.
Professor and Chair of the Department
of Epidemiology
School of Public Health
University of Alabama School of Medicine
Birmingham, AL, USA
Fausto J. Pinto, M.D., Ph.D.

Head of Cardiology Department
University Hospital of Santa Maria
Faculty of Medicine
University of Lisbon
Lisbon, Portugal
Originally published in Portuguese

With the title Tratado de Preveno Cardiovascular Um Desao Global
Published by Atheneu, 2014
ISBN 978-3-319-22356-8
ISBN 978-3-319-22357-5
DOI 10.1007/978-3-319-22357-5
(eBook)
Library of Congress Control Number: 2015945957

Springer Cham Heidelberg New York Dordrecht London
Springer International Publishing Switzerland 2015
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microlms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specic statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.
Printed on acid-free paper
Springer International Publishing AG Switzerland is part of Springer Science+Business Media
(www.springer.com)
Preface by Jadelson P. Andrade
According to data released by the World Health Organization (WHO), 56.9 million
deaths were reported worldwide in 2008, and of these about 17 million were caused
by cardiovascular diseases.
From this alarming reported epidemiological reality, the WHO began to encourage all countries of the world to embrace the banner of cardiovascular prevention,
proposing an alliance between the nations, governments, civil society, and private
sectors to team up in your face.
The WHO proposal has the primary objective to promote working together to
modify these serious epidemiological data and the gloomy future outlook projected
for the following 30 years.
In line with the WHO global project, the Brazilian Society of Cardiology proposed an international partnership with the European Society of Cardiology and the
American Heart Association to prepare the book Cardiovascular Prevention A
Global Challenge. Three editors were invited, Jadelson P. Andrade, Donna
K. Arnett, and Fausto J. Pinto, then president and president-elect of the aforementioned institutions.
The work was developed in 28 chapters addressing different themes of cardiovascular prevention with the original version in Portuguese and this edition in
English with the title: Prevention of Cardiovascular Diseases: From Current
Evidence to Clinical Practice. The authors of the chapters were distributed among
Brazilian, European, and American experts, all with relevant scientic contributions
on the subject.
The ultimate purpose of the editors, in line with the recent proposal from WHO,
is to make available to the international medical community a valuable reference
tool for proper addressing the alarming epidemiological index.
Salvador, Brazil
Jadelson P. Andrade, MD, FACC, FESC
Preface by Fausto J. Pinto
Cardiovascular diseases represent the main cause of mortality worldwide, accounting

for 36 % of all deaths in the European Union in 2010 according to the latest available statistics published in the last OECD report. They cover a range of diseases
related to the circulatory system, including ischemic heart disease (IHD) and cerebro-vascular disease, which together comprise 60 % of all cardiovascular deaths,
and caused more than one-fth of all deaths in EU member states.
The occurrence of several risk factors, such as hypertension, diabetes, dyslipidemia, obesity, smoking, and others, accounts for an increase in the prevalence and
severity of cardiovascular disease. The uprising of some of these risk factors in
some regions more than other may explain partially the differences observed among
the different regions in the globe and even within the same continent. There are
underlying risk factors, such as diet, which may explain differences in IHD mortality across countries. For instance, on average across EU member states, IHD mortality rates in 2010 were nearly two times greater for men. The disparity was greatest
in Cyprus, France, and Luxembourg, with male rates two-to three times higher, and
least in Malta, Romania, and the Slovak Republic, at 60 % higher.
The success of different strategies in the treatment of cardiovascular disease has
resulted in a decrease in IHD mortality rates in nearly all countries in Europe and
the USA. The decline has been most remarkable in Denmark, Ireland, the
Netherlands, and the United Kingdom. Estonia and Norway also saw IHD mortality
rates cut by one-half or more, although rates in Estonia are still high. Declining
tobacco consumption contributed signicantly to reducing the incidence of IHD,
and consequently to reducing mortality rates.
However, the impact of treatment improvement should not undermine the absolute need to improve healthy lifestyles and reduce the weight of the different risk
factors, particularly the ones who can be easily prevented if appropriate steps are
taken (e.g., smoking, overweight-obesity, diabetes, hypertension, dyslipidemia).
The relationship of prevention strategies with cardiovascular events and death
rates is clearly established through different scientic studies. Therefore, the efcacy of primary prevention programs in patients with recognized, treatable risk factors such as hypercholesterolemia, hypertension, diabetes, and smoking should be a
vii
viii
Preface by Fausto J. Pinto
priority across the different countries. It is also important to recognize the need of a
tailored approach considering the differences among different countries, which
reinforces the importance of putting in place surveillance systems in place that may
be able to monitor properly the need and implementation of preventable measures.
This is of crucial importance for a successful ght against inequalities to access
to appropriate health care among the different countries. The role of scientic societies in the dissemination of information as well as in the promotion of different
activities towards the populations as well as the decision makers can ll in an important gap in this regard. This Book on Prevention, being a joint enterprise between
the Brazilian Society of Cardiology, European Society of Cardiology and American
Heart Association, will certainly t into this common goal of improving Prevention
of Cardiovascular Disease worldwide.
Cardiology Department, CCUL, CAML
University of Lisbon, Lisbon, Portugal
Fausto J. Pinto, MD, PhD, FESCC, FACC

faustopinto@medicina.ulisboa.pt
Preface by Donna K. Arnett
For those of us who have devoted our lives to studying and treating cardiovascular
disease (CVD), the idea that CVD prevention is critical is so obvious that further
exposition on the subject may seem gratuitous. It is decidedly not. The successes
that clinicians and public health practitioners have had in the realm of CVD prevention are not only reasons to exult, but also cause for redoubling our efforts with
some assurance that prevention is eminently possible and further progress can be
made. And although some of the more alarming trends observed in some parts of the
world (rising prevalence of obesity, for example) are cause for deep concern, they
are also cause for increased and improved preventive action. It is precisely this
changing landscape of CVD and its risk factors that makes continued assessment
and discussion of CVD-prevention strategies so critically important. Programs in
the USA such as the Centers for Disease Control and Preventions Million Hearts
Initiative and the American Heart Associations 2020 Impact Goal (to improve cardiovascular health by 20 % by 2020 while reducing CVD and stroke mortality by
20 %) and analogous efforts in other countries are tangible representations of population evaluation, goal setting, policy making, and program development that drive
progress in this realm. Each of the chapters in this book represents a primer in CVD
and its prevention. With its calculated mix of CVD and risk factor fundamentals and
trenchant foresight, this volume will be welcomed by all those around the globe
who aim to rise to the challenge of CVD prevention.
Birmingham, AL, USA
Donna K. Arnett, MSPH, PhD
ix
Contents
Global Burden of Non-Communicable, Chronic Diseases ..........................

Mark D. Huffman and Sidney C. Smith Jr.
Cardiovascular Disease Worldwide: A Global Challenge ...........................

Jadelson P. Andrade, Marianna D. Andrade, and Luiz Alberto Mattos
13
Value of Primordial and Primary Prevention for Cardiovascular

Diseases: A Global Perspective ......................................................................
Armin Barekatain, Sandra Weiss, and William S. Weintraub
21
How to Estimate Cardiovascular Risk ..........................................................

Protsio L. da Luz and Renata Caruso Fialdini
29
Tobacco and Alcohol Control: Preventable Risk Factors ...........................

Aloyzio Chechella Achutti
41
Physical Inactivity: Preventable Risk Factor

of Cardiovascular Disease ..............................................................................
Evangelista Rocha
49
Diet and Cardiovascular Health: Global Challenges

and Opportunities ...........................................................................................
Cheryl A.M. Anderson and Amanda R. Ratigan
59
Raised Blood Cholesterol: Preventable Risk Factor

for Cardiovascular Disease.............................................................................
Lale Tokgozoglu
69
Hypertension: Primary Health Care Approach ...........................................

Evgeny Shlyakhto
81
Diabetes: A Primary Health Care Approach ...............................................

Meltem Zeytinoglu and Elbert S. Huang
91
Risk Factors in Childhood and Youth ........................................................... 101

Joep Perk
xi
xii
Contents
Other Determinants of Cardiovascular Diseases:

Social, Globalization, and Urbanization ....................................................... 109
Dalton Bertolim Prcoma, Jorge Ilha Guimares,
and Antonio Felipe Simo
Genetics of Cardiovascular Disease............................................................... 117
Steven A. Claas, Stella Aslibekyan, and Donna K. Arnett
Cardiovascular Disease in Women: An Update ........................................... 129
Helen C. Huang, Puja K. Mehta, and C. Noel Bairey Merz
Rheumatic Heart Disease: A Neglected Heart Disease ................................ 143
Marcia de Melo Barbosa, Maria do Carmo Pereira Nunes,
and Regina Mller
Chagas Disease: A Neglected Disease ............................................................ 159
Jos Antonio Marin-Neto, Anis Rassi Jr., Andra Silvestre de Sousa,
Joo Carlos Pinto Dias, and Anis Rassi
Prevention and Control of Cardiovascular Diseases:
Policies, Strategies, and Interventions........................................................... 183
lvaro Avezum Jr. and Gabriel Pelegrineti Targueta
Prevention and Control of Cardiovascular Diseases
Focusing on Low- and Middle-Income Countries ........................................ 195
Gilson S. Feitosa
Prevention and Control of Cardiovascular Diseases: What Works? ......... 207
Dan Gaita and Laurence Sperling
Prevention and Control of Cardiovascular Diseases:
Integrated and Complimentary Strategies ................................................... 219
Roberto Ferrari, Lina Marcantoni, and Gabriele Guardigli
Posttraumatic Stress Disorder and Cardiovascular Disease ....................... 227
Donald Edmondson, David Hiti, and Ian Kronish
Individual Interventions for Prevention and Control of CVDs .................. 237
Pantaleo Giannuzzi
Social Mobilization for Cardiovascular Disease
Prevention and Control .................................................................................. 245
Carlos Alberto Machado
Frugal Innovation: Solutions for Sustainable Global
Cardiovascular Health.................................................................................... 251
Donna K. Arnett and Steven A. Claas
Atrial Fibrillation and Stroke Prevention..................................................... 261
Antonio Carlos Camargo de Carvalho, Renato D. Lopes,
and Angelo A.V. de Paola
Contents
xiii
A Global Alliance for Cardiovascular Disease Prevention

in Clinical Practice .......................................................................................... 277
David A. Wood
Priority Areas for CVD Research .................................................................. 289
Stephan Gielen
Evidence for Preventing Cardiovascular Disease ........................................ 301
Ian M. Graham and Marie-Therese Cooney
Advisory Board
Angelo Amato Vincenzo de Paola Full professor and chief of the discipline of
Cardiology; chief of the Arrhythmia and Electrophysiology Sector Federal
University of So Paulo (UNIFESP), Brazil. President of the Brazilian Society of
Cardiology (20142015)
Antonio Carlos de Carvalho Full professor of Cardiology Federal University of
So Paulo (UNIFESP)
Luiz Alberto Piva e Mattos Coordenator of hemodynamics and Cardiovascular
Intervention Rede DOr Hospitals, Brazil. Professor of the Port-Graduate Program
in Tecnology and Intevention in Cardiology Dante Pazzanese Cardiology Institute,
So Paulo, Brazil
Marcia de Melo Barbosa Director of Ecocenter, Hospital Socor Belo Horizonte,
Brazil. President of the Interamerican Society of Cardiology. PhD in Cardiology by
the University of So Paulo (USP), Brazil
xv
Contributors
Aloyzio Chechella Achutti, M.D., Ph.D. School of Medicine, Federal University

from Rio Grande do Sul, Porto Alegre, Brazil
Department of Social Medicine, School of Medicine, Federal University from Rio
Grande do Sul, Porto Alegre, Brazil
Cheryl A. M Anderson, M.P.H., Ph.D. University of California San Diego School
Medicine, La Jolla, CA, USA
Marianna D. Andrade, M.D., Ph.D. Intensive Care Unit from the Hospital da
Bahia, Salvador, Brazil
Research and Educational Institute from the Hospital da Bahia, Salvador, Brazil
Stella Aslibekyan, Ph.D. Department of Epidemiology, University of Alabama at
Birmingham, Birmingham, AL, USA
Alvaro Avezum Jr., M.D., Ph.D. Instituto Dante Pazzanese of Cardiology, Sao
Paulo, Brazil
University of Sao Paulo, Sao Paulo, Brazil
Population Health Research Institute, Mc Master University, Hamilton, ON, Canada
Armin Barekatain, M.D. Internal Medicine, Houston, TX, USA
Steven A. Claas, M.S. Department of Epidemiology, School of Public Health,
University of Alabama at Birmingham, Birmingham, AL, USA
Marie-Therese Cooney, MB, BCH, NUI, MRCPI, PhD. Department of AgeRelated Health Care, St Vincents Hospital, Dublin, Ireland
Protazio L. da Luz, M.D., Ph.D. CardiologyHeart Institute from the School of
Medicine, University of Sao Paulo, Sao Paulo, Brazil
Antonio Carlos Camargo de Carvalho, M.D., Ph.D. Paulista School of Medicine,
Federal University of Sao Paulo, Sao Paulo, Brazil
xvii
xviii
Contributors
Marcia de Melo Barbosa, M.D., Ph.D. ECO Center, Hospital Socor, Belo
Horizonte, Brazil
Interamerican Society of Cardiology
Angelo A. V. de Paola, M.D., Ph.D. Paulista School of Medicine, Federal
University of So Paulo, So Paulo, Brazil
Arrhythmia Department of the Paulista School of Medicine, Federal University of
So Paulo, So Paulo, Brazil
Brazilian Society of Cardiology, Rio de Janeiro, Brazil
Andra Silvestre de Sousa, M.D., Ph.D. Federal University of Rio de Janeiro,
Rio de Janeiro, Brazil
Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
Joo Carlos Pinto Dias, M.D., Ph.D. School of Medicine, Federal University of
Minas Gerais, Belo Horizonte, Brazil
Neglected Diseases Committee of the World Health Organization, Geneva,
Switzerland
Maria do Carmo Pereira Nunes, M.D. School of Medicine, Federal University of
Minas Gerais, Belo Horizonte, Brazil
Donald Edmondson, M.P.H., Ph.D. Center for Behavioral Cardiovascular Health,
Columbia University Medical Center, New York, NY, USA
Gilson S. Feitosa, M.D., Ph.D. Bahia School of Medicine and Public Health,
Salvador, Brazil
Hospital Santa Isabel/Santa Casa da Bahia, Salvador, Brazil
Roberto Ferrari, M.D. Department of Cardiology, LTTA Centre, University
Hospital of Ferrara and Maria Cecilia Hospital, GVM Care et Research, E. S. Health
Science Foundation, Cotignola, Italy
Renata Caruso Fialdini, M.D. University of Sao Paulo, Sao Paulo, Brazil
Dan Gaita, M.D. Cardiology inn Romanian, Bucharest, RomaniaRomanian Heart
Foundation, Bucharest, Romania
Pantaleo Giannuzzi, M.D. Cardiac Rehabilitation Department, Salvatori Maugeri
FoundationIRCCS, Scientic Institute of Veruno, Veruno, Italy
Stephan Gielen, M.D. University Hospital, Martin-Luther-University of Halle/
Wittenberg, Halle, Germany
Department of Internal Medicine III, University Hospital, Martin-Luther
University of Halle/Wittenberg, Halle, Germany
Contributors
xix
Ian M. Graham, M.D. Cardiovascular Medicine, Trinity College Dublin, Dublin,

Ireland
Cardiology Emeritus, Royal College of Surgeons in Ireland, Dublin, Ireland
Gabriele Guardigli, M.D. Department of Cardiology, University Hospital of
Ferrara, Ferrara, Italy
Jorge Ilha Guimares, M.D. Brazilian Society of Cardiology, Rio de Janeiro,
Brazil
David Hiti, M.D. Columbia University, New York, NY, USA
Elbert S. Huang, M.P.H., Ph.D. Medicine University of Chicago, Chicago, IL,
USA
Helen C. Huang, M.D. Barbra Streisand Womens Heart Center, Cedars-Sinai
Heart Institute, Los Angeles, CA, USA
Mark D. Huffman, M.P.H., M.D. Department of Preventive Medicine, Feinberg
of Northwestern University, Chicago, IL, USA
Ian Kronish, M.P.H., M.D. Mount Sinai School of Medicine, New York, NY,
USA
Renato D. Lopes, M.D., Ph.D. Division of Cardiology, Duke University Medical
Center, Durham, NC, USA
Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil
Brazilian Institute of Clinical Research, Sao Paulo, Brazil
Carlos Alberto Machado, M.D. Cardiovascular Health Promotion from the
Jos Antonio Marin-Neto, M.D., Ph.D. Cardiology and Pneumology from the
Interventional Cardiology from the Hospital das Clinicas, Ribeirao Preto Medical
School, Sao Paulo, Brazil
Luiz Alberto Mattos, M.D., Ph.D. Interventional Cardiology from Rede Dor
Hospitals, Sao Paulo, Rio de Janeiro and Recife, Sao Paulo, Brazil
Puja K. Mehta, M.D. Cedars-Sinai Medical Center, Los Angeles, CA,
USAWomens Heart Center in the Division of Cardiology in the Cedars-Sinai Heart
Institute, Los Angeles, CA, USA
Lina Mercantoni, M.D. Department of Cardiology, University of Ferrara,
Ferrara, Italy
xx
Contributors
C. Noel Bairey Merz, M.D. Barbara Streisand Womens Heart Center, Preventive
and Rehabilitative Cardiac Center, Womens Guild Chair in Womens Health,
Los Angeles, CA, USA
Regina Mller, M.D., Ph.D. Working Group on Rheumatic Fever from the World
Heart Federation, Geneva, Switzerland
National Heart Institute of Rio de Janeiro, Rio de Janeiro, Brazil
Joep Perk, M.D., Ph.D. Linnaeus University, Kalmar, Sweden
Dalton Bertolim Prcoma, M.D., Ph.D. Catholic University of Parana, Curitiba,
Brazil
Anis Rassi, M.D., Ph.D. Faculty of Medicine, Federal University of Goias,
Goiania, Goias, Brazil
Anis Rassi Jr. M.D., Ph.D. Anis Rassi Hospital, Goiania, Goias, Brazil
Amanda R. Ratigan, M.S. Joint Doctoral Program in Public Health Epidemiology,
University of California San Diego State University, San Diego, CA, USA
Department of Defense HIV/AIDS Prevention Program, Naval Research Center,
San Diego, CA, USA
Master of Public Health, Epidemiology, San Diego State University, San Diego,
CA, USA
Evangelista Rocha, M.D., Ph.D. Faculty of Medicine, Institute of Preventive
Medicine and Public Health, University of Lisbon, Lisbon, Portugal
Evgeny Shlyakhto, M.D., Ph.D. Federal Almazov Medical Research Center,
Saint-Petersburg, Russia
Russian Society of Cardiology, Moscow, Russia
Antonio Felipe Simo, M.D. Institute of Cardiology from Santa Catarina,
Florianpolis, Brazil
Sidney C. SmithJr. M.D. Department of Medicine, University of North Carolina
at Chapel Hill School of Medicine, Chapel Hill, USA
Laurence Sperling, M.D. Emory University School of Medicine, Atlanta,
GA, USA
Gabriel Pelegrineti Targueta, M.D. Instituto Dante Pazzanese of Cardiology,
Federal University of Sao Paulo, Sao Paulo, Brazil
Lale Tokgzoglu, M.D. Hacettepe University in Ankara, Ankara, Turkey
Contributors
xxi
William S. Weintraub, M.D. Center for Outcomes Research, One of Four

Research Centers Comprising the Value Institute at Christiana Care Health Center,
Newark, DE, USA
Sandra Weiss, M.D. Christiana Care Center for Heart et Vascular Health from the
University of Chicago Medical Center, Newark, DE, USA
David A. Wood, M.D., Ph.D. Foundation Gareld Weston of Cardiovascular
Medicine, International Centre for Circulatory Health, National Heart and Lung,
Imperial College London, London, UK
Meltem Zeytinoglu, M.D. Endocrinology and Metabolism, Chicago, IL, USA
Global Burden of Non-Communicable,

Chronic Diseases
Mark D. Huffman and Sidney C. Smith Jr.
Measuring Burden of Disease

Reliable, contemporary data about the distribution, determinants, and trends in
global morbidity and mortality are fundamental to understanding and improving
global health. The estimation of the worlds disease burden in the modern era
was heralded by the publication of the Global Burden of Disease report in 1990 [1].
The World Bank initially commissioned the report in collaboration with researchers
at the Harvard School of Public Health. The Institute for Health Metrics and
Evaluation at the University of Washington (Seattle, USA) and Imperial College
London (London, UK) serve as the current host centers for the Global Burden of
Disease and Metabolic Risk Factors, respectively. The Global Burden of Disease
underwent periodic updates until the release of its 2010 report in a 2012 Lancet
series, which represented its most comprehensive overhaul since its inception [2].
The next generation of the Global Burden of Disease aims to provide annual updates,
starting with 2013 data that will be published in 2014.
The study of disease burden initially led to fundamental questions about how
best to measure burden. Counting numbers of deaths, such as in wartime or epidemics,
or describing death rates have been common methods that are relatively straightforward to interpret. Researchers within the Global Burden of Disease project
have measured the cumulative effect of premature deaths through the Years of Life
M.D. Huffman, MD, MPH (*)

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine,
680 North Lake Shore Drive, Suite 1400, Chicago, IL 60611, USA
e-mail: m-huffman@northwestern.edu
S.C. Smith, Jr., MD
Department of Medicine, University of North Carolina at Chapel Hill School of Medicine,
CB# 7075, 6031 Burnett Womack, 160 Dental Circle, Chapel Hill, NC 27599-7075, USA
e-mail: scs@med.unc.edu
J.P. Andrade et al. (eds.), Prevention of Cardiovascular Diseases,
DOI 10.1007/978-3-319-22357-5_1
M.D. Huffman and S.C. Smith Jr.
Lost (YLL) metric, which measures differences from the same potential life length
across populations to estimate burden, usually taken as the global mean life expectancy [3]. However, these measures do not account for the age- and sex-characteristics of different countries. Therefore, age-adjustment or -standardization to a global
population have been basic strategies to account for a populations age structure to
improve comparability across populations. Data are usually stratied by sex to
account for differences in the proportion of men and women among different
countries.
However, these approaches do not account for any measure of health during the
lifecourse. To overcome this limitation, the Global Burden of Disease team developed the Disability Adjusted Life Year (DALY) metric, which is equal to the sum of
Years of Life Lost (YLL) and Years Lived with Disability (YLD), or:
Disability Adjusted LifeYear = Years of Life Lost + Years Lived with Disability
The DALY metric was founded on the principles that: (1) everyone in the world has
right to best life expectancy, and (2) differences in the rating of a death or disability
should be due to age and sex and not to income, culture, location, social class.
It is also important to understand how Years Lived with Disability (YLD) is
dened, by whom, and at what time in the disease course [4]. First, disability represents an objective alteration of behavior or performance at the individual level.
Disability falls between impairment, which is dened by symptoms at an organ
level, and handicap, which is dened by changed interactions with others at the
social or environmental level due to disability. To illustrate, if an individual suffers
from a stroke, s/he might have symptoms of unilateral arm and leg weakness
(impairment), which limits her/his ability to walk independently (disability) and
her/his ability to work in a job that requires walking (handicap). Second, researchers
have typically surveyed medical professionals and public health experts to rank
symptom states to quantitatively estimate YLD for myriad disease states. Other
individuals, including but not limited to patients, families, caregivers, general public, insurance companies, and legal experts, might offer complementary perspectives on how YLDs should be estimated yet have not been incorporated in these
estimates to date. Third, YLD estimates can be sensitive to the time course of the
disease, particularly for non-communicable, chronic diseases, which can have long
periods of minimal to no symptoms followed by acute shocks and gradual recovery
to or near baseline. In the stroke example, the immediate post-stroke disability can
be substantially different than 3, 6, or 12 months later and can be dependent upon
access to rehabilitation and medical therapy. As such, YLD estimates may be susceptible to reporting bias by experts based on their previous clinical or health
experiences.
Newer estimates of disease burden incorporate costs and nancial risk through
measures such as catastrophic health spending (based on the proportion of health
spending relative to non-food expenditures) and distress nancing (based on risky
nancial activities to pay for health, including borrowing money or selling assets)
[5]. These complementary measures of nancial protection, or lack thereof, are
Global Burden of Non-Communicable, Chronic Diseases
associated with individuals and families falling into poverty. Because health systems
are evaluated in terms of quality, access, and nancial protection [6], these measures
of disease burden will likely gain more attention.
Using the International Classification of Diseases framework, the Global
Burden of Disease project employed systematic searched published and unpublished data on causes of death through a variety of sources, including the World
Health Organization mortality database, national vital registration systems, verbal
autopsy-based sample registration systems, demographic surveillance systems,
cancer registers, crime reports, mortuary data, among others [3]. In the case of socalled garbage codes that have been deemed implausible causes of death, available data were used to reclassify the causes of death [1]. The project team then
incorporated these best available data into advanced, multi-level statistical models
and imputation methods to estimate the causes of death among all countries from
1980 through 2010.
The Global Burden of Disease project is not without its critics who express concern about the complex analytic methods and frequent use of imputation to estimate
data for countries that do not have accurate, updated mortality data. Some fear that
the Global Burden of Disease, which is largely funded by the Bill & Melinda Gates
Foundation, a private non-governmental organization, may lead to reduced public
investments in vital registration systems, a basic public health function that currently covers less than half of the worlds population [7]. Nevertheless, the Global
Burden of Disease project represents the most comprehensive and accessible summary of contemporary global disease burden, including providing estimates for
non-communicable, chronic diseases.

Based on data from the Global Burden of Disease project, non-communicable,
chronic diseases (NCDs) accounted for 34.5 million (65.5 % of total) deaths globally in 2010, compared with 13.2 million (24.9 % of total) deaths due to maternal,
neonatal, and nutritional diseases, and 5.1 (9.6 % of total) deaths due to injuries
during the same year (Table 1) [3]. While there was an increase of approximately 8
million deaths due to NCDs (30 % relative increase) since 1990, there was also a
32 % decrease in the age- and sex-specic death rate from NCDs over the same time
period from 645.9 (95 % uncertainty interval: 629.9, 662.9) per 100,000 in 1990 to
520.4 (95 % UI: 499.5, 532.0) per 100,000 in 2010 (19 % decrease). Population
aging contributed substantially (39 %) to the increases in NCD deaths since 1990,
which primarily explains this difference between increasing numbers of deaths and
declining rates [3].
Similarly, the number of disability adjusted life years (DALYs) for all NCDs
increased from 1075 million (95 % UI: 1000, 1160) DALYs in 1990 compared with
1343 million (95 % UI: 1240, 1457) in 2010, which represents a 25 % increase,
while the rate of DALYs per 100,000 decreased by 3.8 % from 20,283 (95 % UI:
Table 1 All-cause and non-communicable, chronic disease (NCD)-specic deaths and death rates
in 1990 and 2010 estimated by the Global Burden of Disease Study [3]
1990 deaths
Deaths expected with 1990 population, 2010 population age structure,
1990 death rates
Deaths expected with 2010 population, 2010 population age structure,
1990 death rates
2010 deaths
Percentage change from 1990 due to population growth
Percentage change from 1990 due to population aging
Percentage change from 1990 due to change in death rates
Percentage change from 1990 to 2010
All causes
46,511,000
61,307,000
NCDs
26,560,000
32,647,000
70,316,000
43,062,000
52,770,000
31.8 %
19.4 %
37.7 %
13.5 %
34,540,000
22.9 %
39.2 %
32.1 %
30.0 %
Table 2 Global Burden of Disease 2010 estimates of deaths and age-standardized death rates per
100,000 in 1990 and 2010 across non-communicable, chronic diseases
All ages deaths (thousands)
1990
2010
All non26,560.3
34,539.9
communicable,
(25,843.4,
(33,164.7,
chronic diseases
27,249.3)
35,313.0)
Cardiovascular and 11,903.7
15,616.1
circulatory diseases (11,329.4,
(14,542.2,
12,589.3)
16,315.1)
Neoplasms
5779.1
7977.9
(5415.9,
(7337.1,
6201.9)
8403.8)
Chronic lung
3986.3
3776.3
diseases
(3914.3,
(3648.2,
4063.8)
3934.1)
Diabetes
1544.3
2726.2
(1420.0,
(2447.1,
1804.0)
2999.1)
Mental and
138.1 (95.2, 231.9 (176.3,
behavioral disorders 188.0)
329.1)
Musculoskeletal
69.5 (46.2, 153.5 (110.7,
disorders
89.6)
214.8)
Age-standardized death rates

per 100,000
% change 1990
2010
% change
30.0
645.9
520.4
19.4
(629.9, (499.5,
662.9)
532.0)
31.2
298.1
234.8
21.2
(283.9, (218.7,
314.9)
245.2)
38.0
140.8
121.4
13.8
(131.9, (111.6,
151.4)
127.9)
5.3
98.2
57.0
41.9
(96.4,
(55.1,
100.1)
59.4)
76.5
36.1
41.0
13.8
(33.4,
(36.8,
41.6)
45.1)
68.0
3.2 (2.2, 3.5 (2.6, 9.3
4.3)
4.9)
121.0
1.7 (1.1, 2.3 (1.7, 37.8
2.2)
3.2)
Data abstracted from Lozano et al. [3]
18,893, 21,874) per 100,000 in 1990 to 19,502 (95 % UI: 17,997, 21,143) per
100,000 in 2010.
The death and disability burdens of specic NCDs are outlined below with
supporting data presented in Tables 2 and 3.
Table 3 Global Burden of Disease 2010 estimates of disability adjusted life years and disability
adjusted life years lost per 100,000 in 1990 and 2010 across non-communicable, chronic diseases
All noncommunicable,
chronic diseases
Cardiovascular
and circulatory
diseases
Neoplasms
Chronic lung
diseases
Diabetes
Mental and
behavioral
disorders
Musculoskeletal
disorders
All disability adjusted life years

(thousands)
1990
2010
% change
1,075,297
1,343,973
25.0
(1,001,607, (1,239,973,
1,159,673)
1,456,773)
240,667
295,036
22.6
(227,084,
(273,061,
257,718)
309,562)
148,078
188,487
27.3
(136,775,
(174,452,
158,256)
199,037)
119,153
117,945
1.0
(107,917,
(102,924,
132,391)
135,608)
85,084
122,437
43.9
(73,638,
(107,437,
102,489)
143,387)
134,598
185,190
37.6
(112,138,
(154,647,
159,316)
218,496)
116,554
169,624
45.5
(88,684,
(129,771,
147,285)
212,734)
Disability adjusted life years per

100,000
1990
2010
% change
20,283
19,502
3.8
(18,893, (17,997,
21,874)
21,143)
4540
4282
5.7
(4283,
(3963,
4861)
4493)
2793
2736
2.1
(2580,
(2532,
2985)
2889)
2248
1712
23.8
(2036,
(1494,
2497)
1968)
1605
1777
10.7
(1389,
(1559,
1933)
2081)
2539
2668
5.9
(2115,
(2245,
3005)
3171)
2198
2462
12.0
(1673,
(1883,
2778)
3088)
Data abstracted from Murray et al. [2]
Cardiovascular Diseases
Global cardiovascular disease deaths increased from 11.9 million (95 % UI: 11.2,
12.6) in 1990 to 15.6 million (95 % UI: 14.5, 16.3) in 2010, which represents a 31 %
increase. Age- and sex-adjusted rates of cardiovascular disease deaths decreased
from 298.1 (95 % UI: 283.9, 314.9) per 100,000 in 1990 to 234.8 (95 % UI: 218.7,
245.2) per 100,000 in 2010, which represents a 21 % decrease [3]. Ischemic heart
disease was the leading cause of cardiovascular deaths during both time periods.
The number of deaths increased from 5.2 million (95 % UI: 5.0, 5.6) ischemic heart
disease deaths in 1990 to 7.0 million (95 % UI: 6.6, 7.4), which represents a 35 %
increase. Age- and sex-adjusted death rates due to ischemic heart disease decreased
from 131.3 (95 % UI: 126.4, 142.2) per 100,000 to 105.7 (95 % UI: 98.8, 111.9) per
100,000 in 2010, which represents a 20 % decrease.
The number of disability adjusted life years (DALYs) due to cardiovascular
diseases increased from 240,667 (95 % UI: 227,084, 257,718) DALYs in 1990 compared with 295,036 (95 % UI: 273,061, 309,562) in 2010, which represents a 23 %
increase, while the rate of DALYs per 100,000 due to cardiovascular diseases
decreased by 6 % from 4540 (95 % UI: 4283, 4861) per 100,000 in 1990 to 4282
(95 % UI: 3963, 4493) per 100,000 in 2010.
Cancer
Global cancer deaths increased from 5.8 million (95 % UI: 5.4, 6.2) in 1990 to 8.0 million (95 % UI: 7.3, 8.4) in 2010, which represents a 38 % increase. Similar to other
cardiovascular diseases, age- and sex-adjusted rates of cancer deaths decreased from
140.8 (95 % UI: 131.0, 151.5) per 100,000 in 1990 to 121.4 (95 % UI: 111.6, 127.9)
per 100,000 in 2010, which represents a 14 % decrease [3]. Cancers of the trachea,
bronchus, and lungs were the leading cause of cancer deaths during both time periods.
The number of deaths increased from 1.0 million (95 % UI: 0.8, 1.3) cancers of the
trachea, bronchus, and lung in 1990 to 1.5 million (95 % UI: 1.1, 1.8), which represents
a 47 % increase. Age- and sex-adjusted death rates due to cancers of the trachea,
bronchus, and lung modestly decreased from 25.5 (95 % UI: 20.4. 32.4) per 100,000 to
23.4 (95 % UI: 17.3, 27.3) per 100,000 in 2010, which represents an 8 % decrease.
The number of disability adjusted life years (DALYs) due to cancer increased from
148,078 (95 % UI: 136,775, 158,256) DALYs in 1990 compared with 188,487 (95 %
UI: 174,452, 199,037) in 2010, which represents a 27 % increase, while the rate of
DALYs per 100,000 due to cancer decreased by 2 % from 2793 (95 % UI: 2580, 2985)
per 100,000 in 1990 to 2736 (95 % UI: 2532, 2889) per 100,000 in 2010.
Chronic Lung Diseases

Global chronic lung disease deaths decreased from 4.0 million (95 % UI: 3.9, 4.1)
in 1990 to 3.8 million (95 % UI: 3.6, 3.9) in 2010, which represents a 5 % decrease.
Age- and sex-adjusted rates of chronic lung disease deaths increased from 98.2
(95 % UI: 96.4, 100.1) per 100,000 in 1990 to 57.0 (95 % UI: 55.1, 59.4) per
100,000 in 2010, which represents a 42 % decrease [3].
The number of disability adjusted life years (DALYs) due to chronic lung diseases
was similar at 119,153 (95 % UI: 107,917, 132,391) DALYs in 1990 compared with
117,945 (95 % UI: 102,924, 135,608) in 2010, while the rate of DALYs per 100,000
due to chronic lung diseases decreased by 24 % from 2248 (95 % UI: 2036, 2497) per
100,000 in 1990 to 1712 (95 % UI: 1494, 1968) per 100,000 in 2010.
Diabetes
Global diabetes deaths increased from 665,000 (95 % UI: 593,300, 757,500) in
1990 to 1.3 million (95 % UI: 1.1, 1.3) in 2010, which represents a 93 % increase.
Unlike cardiovascular diseases, cancer, and chronic lung disease, age- and
sex-adjusted rates of diabetes deaths increased from 16.3 (95 % UI: 14.5, 18.6)
per 100,000 in 1990 to 19.5 (95 % UI: 16.2, 20.5) per 100,000 in 2010, which
represents a 20 % increase.
The number of disability adjusted life years (DALYs) due to diabetes increased
from 85,084 (95 % UI: 73,638, 102,489) DALYs in 1990 compared with 122,437
(95 % UI: 107,437, 143,387) in 2010, which represents a 44 % increase, while the rate
of DALYs per 100,000 due to diabetes increased by 11 % from 1605 (95 % UI: 1389,
1933) per 100,000 in 1990 to 1777 (95 % UI: 1559, 2081) per 100,000 in 2010.
Mental and Behavioral Disorders

Global mental and behavioral disorder related deaths increased from 138,100 (95 %
UI: 95,200, 188,000) in 1990 to 231,900 (95 % UI: 176,300, 329,100) in 2010, which
represents a 68 % increase. Age- and sex-adjusted rates of mental and behavioral
disorder related deaths increased from 3.2 (95 % UI: 2.2, 4.3) per 100,000 in 1990 to
3.5 (95 % UI: 2.6, 4.9) per 100,000 in 2010, which represents a 9 % increase [3].
The number of disability adjusted life years (DALYs) due to mental and behavioral
disorder increased from 138.1 (95 % UI: 95.2, 188.0) DALYs in 1990 compared
with 231.9 (95 % UI: 176.3, 329.1) in 2010, which represents a 68 % increase, while
the rate of DALYs per 100,000 due to mental and behavioral disorder increased
by 9 % from 3.2 (95 % UI: 2.2, 4.3) per 100,000 in 1990 to 3.5 (95 % UI: 2.6, 4.9)
per 100,000 in 2010.
Shared Risk Factors for Non-Communicable,

Chronic Diseases
Non-communicable, chronic diseases (NCDs) share causal risk factors, which
suggests that strategies to reduce the burden of these risk factors will have multiplicative benets. Common risk factors can be behavioral (tobacco use, unhealthy diet,
and physical inactivity), physiologic (body mass index, blood pressure, blood cholesterol, and blood glucose), and social (stress, socioeconomic position). While
these risk factors are generally considered modiable, prevention of abnormal risk
factor development, also known as primordial prevention [8], leads to more favorable health outcomes than even treatment of risk factors. Prevalence estimates and
attributable burdens of disease for behavioral risk factors are outlined below.
Tobacco
Smoking prevalence has decreased from 41 % (95 % UI: 40, 43) in 1980 to 31 %
(95 % UI: 30, 32) in 2012 for men >15 years and from 11 % (95 % UI: 10, 11) to
6 % (95 % UI: 6, 6) for women >15 years [9]. However, due to population growth
and aging as well as the inherent lag time between tobacco exposure and diseases
such as cancer, the number of deaths attributable to tobacco increased from 5.3
million (95 % UI: 4.8, 6.0) in 1990 to 6.3 million (95 % UI: 5.4, 7.0) in 2010 [10].
If recent trends continue, there will be an estimated 1 billion tobacco-related deaths
in the twenty-rst century, most of which will occur in low- and middle-income
countries and half of which will occur before age 70 years [11].
Unhealthy Diet
Global increases in body mass index from 1980 to 2010 (0.4 mg/kg2 per decade
(95 % UI: 0.2, 0.6) for men and 0.5 mg/kg2 per decade (95 % UI: 0.3, 0.7) for
women) [12] suggest that access to calories has increased. However, global trends
in diet quality are difcult to assess not only because of the inherent complexity in
comparing different dietary patterns across the world but also because of the limitations in instruments for dietary data collection. The Global Burden of Disease project evaluates the effects of 14 dietary variables (fruit intake, vegetable, whole grains,
nuts and seeds, milk, red meat, processed meat, sugar sweetened beverages, ber,
calcium, omega-3 containing seafood, polyunsaturated fats, trans fats, and sodium).
The investigators estimate the number of attributable deaths due to unhealthy diet
increased from 8.5 million (95 % UI: 7.9, 9.2) in 1990 to 12.5 million (95 % UI:
11.7, 13.3) in 2010, with the greatest proportion coming from diets low in fruits (4.9
million [95 % UI: 3.8, 5.9]), low in nuts/seeds (2.5 million [95 % UI: 1.6, 3.2]), and
low in vegetables (1.8 million [95 % UI: 1.2, 2.4]) [10].
Physical Inactivity
Major changes in migration, transportation, and mechanization over the past century
have undoubtedly led to declines in global physical activity [13]. However, like diet,
global physical activity estimates and time trends are difcult to obtain because of:
(1) limited number of global physical inactivity surveys; (2) limitations in survey
instruments that rely upon self-reporting of physical activity; and (3) historical reliance on leisure-time physical activity estimates, rather than inclusion of transport,
occupational, and domestic activity domains, which may overestimate physical
inactivity prevalence. These limitations notwithstanding, global physical inactivity
prevalence in 2010 has been estimated to be 28 and 34 % for men and women,
respectively [14]. In 2010, the Global Burden of Disease project estimated that the
number of attributable deaths due to physical inactivity was 3.2 million (95 %
UI: 2.7, 3.7) [10]. The Lancets Physical Activity Series Working Group produced
a higher estimate of deaths due to inactivity for 2008 (5.3 million, a 65 % higher
estimate), which reects the uncertainty in creating such estimates of attributable
disease burden [15].
Future Projections
Despite reductions in age-adjusted mortality from non-communicable, chronic
diseases (NCDs) overall, the burden of NCDs will continue to grow in absolute
terms because of the inexorable effects of population growth and aging. For example, if the 2010 death rates due to cardiovascular diseases, cancer, chronic lung
diseases, and diabetes remained unchanged until 2025, the annual numbers of
deaths would increase from 28.3 million to 38.8 million [16]. To galvanize global
action and momentum in reducing the burden of NCDs, member states of the World
Health Organization have adopted nine voluntary targets to reduce the burden of
NCDs and their risk factors (Box) [17]. The primary, equity-based target is to reduce
the risk of premature death, between the ages of 30 and 69 years, from NCDs by
25 % by 2025, or the so-called 25 25 target.
Box: Nine Voluntary Targets Adopted by Member States of the World

Health Organization to Reduce the Burden of Non-Communicable,
Chronic Diseases [17]
1. 25 % relative reduction in risk of premature mortality from cardiovascular
diseases, cancer, diabetes, or chronic lung diseases.
2. At least 10 % relative reduction in the harmful use of alcohol, as appropriate, within the national context.
3. A 10 % relative reduction in the prevalence of insufcient physical
activity.
4. A 30 % relative reduction in mean population intake of salt/sodium.
5. A 30 % relative reduction in prevalence of current tobacco use in persons
aged 15+ years.
6. A 25 % relative reduction in the prevalence of raised blood pressure or
contain the prevalence of raised blood pressure, according to national
circumstances.
7. Halt the rise in diabetes and obesity.
8. At least 50 % of eligible people receive drug therapy and counseling
(including glycemic control) to prevent heart attacks and strokes.
9. An 80 % availability of the affordable basic technologies and essential
medicines, including generics, required to treat major noncommunicable
diseases in both public and private facilities.
Kontis et al. estimated the effect of achieving six of the eight risk factor targets
(tobacco, alcohol, salt intake, obesity, raised blood pressure, raised glucose/diabetes)
on the 25 25 mortality target overall and on specic NCD subtypes, stratied by
sex and country, compared with business as usual trends [16]. These projections
suggest that, if these six risk factor targets were achieved, the risk of premature
10
deaths from NCDs would decrease by 22 % for men and 19 % for women between
2010 and 2025. These estimates compare favorably with projected decreases in the
risk of premature mortality from NCDs by 11 % for men and 10 % for women under
the business as usual scenario where recent declines in NCD mortality rates continue to 2025. Achieving these six risk factor targets would not only prevent or
postpone 16.1 million NCD-related deaths among individuals 3069 years old over
the 15 year period (20102025) but would also prevent or postpone an additional
21.4 million deaths among individuals 70 years and greater. The majority (70 %) of
these premature deaths prevented or postponed would be from cardiovascular
disease (11.4 million), followed by cancer (2.4 million), chronic lung diseases
(1.2 million) and diabetes (1.1 million). Because low- and middle-income countries
have a higher burden of NCD-related deaths and death rates compared with highincome countries, these countries would experience far greater progress toward the
25 25 mortality target if the risk factor targets were achieved.
Conclusions
Non-communicable chronic diseases (NCDs), including cardiovascular diseases,
cancer, chronic lung diseases, diabetes, and mental and behavioral disorders, are the
leading causes of death and disability worldwide. While global age-adjusted death
rates from NCDs have been falling over the past two decades, population growth
and aging have led to absolute and ongoing increases in NCD-related deaths and
disability adjusted life years (DALYs). Low- and middle-income countries are projected to bear even greater proportions of the global burden of NCDs in the coming
decades due, at least in part to their younger demographics, unless comprehensive,
sustainable, and intersectoral action is taken to prevent, detect, treat, and control
NCDs and their shared risk factors.
References
1. Murray CJL, Lopez AD. Estimating causes of death: new methods and global and regional
application for 1990. In: Murray CJL, Lopez AD, editors. The global burden of disease: a
comprehensive assessment of mortality and disability from diseases, injuries, and risk factors
in 1990 and projected to 2020. Boston: Harvard School of Public Health, on behalf of the
World Health Organization and the World Bank; 1996. p. 117200.
2. Murray CJ, Vos T, Lozano R, Naghavi M, Flaxman AD, Michaud C, et al. Disability-adjusted
life years (DALYs) for 291 diseases and injuries in 21 regions, 19902010: a systematic analysis
for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2197223.
3. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional
mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis
for the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095128.
4. Salomon JA, Vos T, Hogan DR, Gagnon M, Naghavi M, Mokdad A, et al. Common values in
assessing health outcomes from disease and injury: disability weights measurement study for
the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):212943.
11
5. Huffman MD, Rao KD, Pichon-Riviere A, Zhao D, Harikrishnan S, Ramaiya K, et al. A crosssectional study of the microeconomic impact of cardiovascular disease hospitalization in four
low- and middle-income countries. PLoS One. 2011;6(6), e20821.
6. Reinhardt UE, Cheng T-M. The world health report 2000-Health systems: improving performance. Bull World Health Organ. 2000;78(8):1064.
7. Byass P, de Courten M, Graham WJ, Laamme L, McCaw-Binns A, Sankoh OA, et al. Reections
on the Global Burden of Disease 2010 estimates. PLoS Med. 2013;10(7), e1001477.
8. Strasser T. Reections on cardiovascular diseases. Interdiscip Sci Rev. 1978;3(3):22530.
9. Ng M, Freeman MK, Fleming TD, Robinson M, Dwyer-Lindgren L, Thomson B, et al.
Smoking prevalence and cigarette consumption in 187 countries, 19802012. JAMA.
2014;311(2):183.
10. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, et al. A comparative risk
assessment of burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions, 19902010: a systematic analysis for the Global Burden of Disease Study
2010. Lancet. 2012;380(9859):222460.
11. Jha P, Peto R. Global effects of smoking, of quitting, and of taxing tobacco. N Engl J Med.
2013;370(1):608.
12. Finucane M, Stevens GA, Cowan MJ, Danaei G, Lin JK, Paciorek C, et al. National, regional,
and global trends in body-mass index since 1980: systematic analysis of health examination
surveys and epidemiological studies with 960 country-years and 9 1 million participants.
Lancet. 2011;377(9765):55767.
13. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: Part I: general
considerations, the epidemiologic transition, risk factors, and impact of urbanization.
Circulation. 2001;104(22):274653.
14. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U, Lancet Physical Activity
Series Working Group. Global physical activity levels: surveillance progress, pitfalls, and
prospects. Lancet. 2012;380(9838):24757.
15. Lee IM, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical Activity
Series Working Group. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet. 2012;380(9838):21929.
16. Kontis V, Mathers CD, Rehm J, Stevens GA, Shield KD, Bonita R, et al. Contribution of six
risk factors to achieving the 25 25 non-communicable disease mortality reduction target: a
modelling study. Lancet. 2014;384:42737.
17. World Health Organization. Global action plan for the prevention and control of noncommunicable diseases 20132020. World Health Organization; 2013.
Cardiovascular Disease Worldwide: A Global

Challenge
Jadelson P. Andrade, Marianna D. Andrade, and Luiz Alberto Mattos
At the beginning of this century, cardiovascular diseases (CVD) showed an

epidemiological behavior very similar to those of the great endemics of past centuries and were responsible for high mortality rates worldwide.
This current epidemiological prole of CVD is evident in data from the World
Health Organization (WHO), which show that of the 56.9 million total deaths
reported worldwide, approximately 30.5 % or 17 million people had CVD listed as
the cause of death [1, 2].
An important epidemiological fact that needs to be considered is the uneven
geographic distribution of CVD deaths. Lower mortality rates are observed in developed countries and much of Latin America, and higher rates are observed in lower
income countries, such as Eastern European countries [1].
Data released by the WHO in 2008 indicate that of the total number of CVD
deaths worldwide, approximately 80.1 % occurred in low- and middle-income
countries, and only 19.9 % occurred in high-income countries.
If this global scenario is already alarming at the beginning of this new century,
the expectations for the future are even more troubling; it is estimated that if concrete
J.P. Andrade, M.D. (*)

Hospital da Bahia, Salvador, Brazil
e-mail: jadelson@hospitaldabahia.com.br
M.D. Andrade, M.D., Ph.D.
Intensive Care Unit from the Hospital da Bahia, Salvador, Brazil
Research and Educational Institute from the Hospital da Bahia, Salvador, Brazil
e-mail: madeway@hotmail.com
L.A. Mattos, M.D., Ph.D.
Interventional Cardiology from Rede Dor Hospitals, Sao Paulo,
Rio de Janeiro and Recife, Sao Paulo, Brazil
DOI 10.1007/978-3-319-22357-5_2
13
14
J.P. Andrade et al.
actions are not implemented, by the year 2030, seven out of ten deaths will be due
to non-communicable diseases (NCDs), and CVD will account for the highest
percentage of these deaths [1, 3].
However, although the CVD mortality rates in developed countries have been
declining in recent decades, as previously mentioned, the rates in most developing
countries are still increasing. This is due, among other factors, to the increased economic power of developing countries. Rising incomes per capita have led to
improvement in the health and basic living conditions of these populations, resulting
in a signicant reduction in the incidence of and mortality from infectious and parasitic diseases, with a proportional increase in the number of deaths caused by NCDs.
In addition, the lifestyle adopted by urban populations in developing countries has
signicantly increased the prevalence of risk factors for cardiovascular diseases
such as obesity, physical inactivity, tobacco use, high blood pressure, excessive salt
intake, dyslipidemia, and diabetes [4, 5].
Risk Factors for CVD

At the end of the 1940s, important epidemiological studies, such as the pioneering
study by Framingham, began to identify predictive risk factors for the development
of CVD. The primary factors listed were systemic hypertension, dyslipidemia,
tobacco use, obesity, physical inactivity, excessive salt intake, and mental/emotional
stress [6, 7]. The identication of these and other risk factors in populations in both
developed and developing countries indicated the steps that should be followed to
counter this epidemiological challenge.
At rst, population programs were developed and applied in developed countries,
including some European countries, the USA, Canada, Australia, and Japan. These
programs were designed to establish some type of epidemiological control over
these risk factors in their populations. Analyses of the results of these programs
have shown a signicant reduction in CVD mortality rates where and when they
were applied. The Framingham Heart Study, the North Karelia Project, and the
Stanford Project are some of the more notable programs implemented [5, 7, 8].
In Finland, for example, efforts to implement well-organized cardiovascular
prevention programs have been rewarded with a reduction in CVD risk factors and
CVD mortality rates. The combined efforts of governments, health professionals,
food companies, universities, and non-governmental organizations have resulted in
effective actions [8]. The results of these actions have led to the consumption of
healthier diets with reduced levels of sodium and saturated fats and adecreased prevalence of tobacco use and physical inactivity. Between 1972 and 2007, in Finland, there
was a signicant reduction in cholesterol levels by approximately 21 %, systolic blood
pressure by 10.1 mmHg, and the prevalence of tobacco use by 51 % [9].
The implementation of this program model would surely bring potential benets
to developing countries such as Brazil, which has a high CVD mortality rate.
According to data published by the Ministry of Health (Ministrio da SadeMS)
of Brazil and obtained from a telephone survey conducted in 2010 in major Brazilian
Cardiovascular Disease Worldwide: A Global Challenge
15
cities (Surveillance of Risk and Protective Factors for Chronic Diseases Telephone
SurveyVIGITEL), 15 % of adults 18 years and older are smokers, only 30 %
regularly consume fruits and vegetables, whereas 34 % reported consuming meat
with excess fat, and only 30 % practice physical activity regularly (including leisure
activities and commuting to work) [10, 11].
According to the 2012 European Guidelines on Cardiovascular Prevention, there
are eight reasons to promote cardiovascular prevention [12]:
1. Atherosclerotic CVD, especially coronary artery disease, is the leading cause of
premature death worldwide;
2. CVD affects men and women equally;
3. CVD mortality rates are declining in many European countries but remain high
in Eastern Europe;
4. More than half of the observed decrease in the CVD rate is related to changes in
risk factors, and 40 % is due to improved treatments;
5. Preventive efforts should be applied throughout life, from birth to old age;
6. Preventive approaches limited to high-risk individuals are less effective, and
education programs for the entire population are needed;
7. Despite gaps in knowledge, there is ample evidence to justify intensive efforts
related to public health and individual prevention;
8. There is still room for improvement in the control of risk factors, even in high-risk
individuals.
Prevention of Risk Factors, Early Diagnosis

and Treatment of CVD
The evolution and improvement of diagnostic methods and the therapeutic arsenal
for CVD have created a valuable tool for reducing cardiovascular mortality. Some
epidemiological studies still attribute a greater impact on reducing cardiovascular
morbidity and mortality to treatment rather than to prevention. More recent studies,
however, reveal a balance between preventive and therapeutic actions in the ght
against CVD. In 2007, an epidemiological analysis was published that used the validated IMPACT mortality model, and it showed a signicant decrease in mortality
rates due to coronary heart disease in both men and women in the USA between
1980 and 2000. Furthermore, the authors concluded that approximately 44 % of this
decrease was due to the control of several cardiovascular risk factors, while 47 %
resulted from therapeutic actions. Preventive actions that contributed to this result
included reductions in total cholesterol (24 %), systolic blood pressure (24 %), the
prevalence of tobacco use (12 %) and physical inactivity (5 %) [13, 14]. This result
was counterbalanced by the signicant increase in the prevalence of obesity and
diabetes in this population.
Figure 1 summarizes the main epidemiological studies that have been published
in recent decades evaluating the impact of treatments and preventive actions on
reducing cardiovascular mortality.
16
J.P. Andrade et al.

Treatments
Risk factors
No Explication
United States 68-76
40
54
New Zealand 74-81
40
60
Netherlands 78-85
46
44
10
United States 80-90
43
50
Finland 72-92
24
76
IMPACT New Zealand 82-93
35
60
IMPACT Scotland 75-94
35
55
10
IMPACT England and Wales 81-00
38
52
10
IMPACT Italy 80-00
40
55
IMPACT United States 80-00
47
44
IMPACT Finland 82-97
23
53
24
IMPACT Sweden 86-02
36
55
0%
50%
100%
Fig. 1 Percent decrease in the number of deaths from coronary heart disease attributed to changes
in treatment and risk factors in different populations. (Adapted from Di Chiara and Vanuzzo [13])
Global Targets for the Prevention and Control of CVD

The data presented here reinforce the importance of a new strategy for combating
CVD, which will require a combination of cardiovascular prevention actions and
earlier and more accurate diagnosis methods, as well as increased availability of
effective treatments. The balance of these actions will result in signicant reductions
in the current epidemiological indices and also a change in future prospects.
During the World Health Assembly in 2012, the WHO initiated the campaign
Unite in the Fight against NCDs, setting a global target to reduce premature
mortality rates due to NCDs by 25 % by the year 2025 [15]. The campaign was
based on well-dened principles and supported by all recent scientic evidence
related to the prevention of NCDs. The pillars of this campaign are the following:
Accelerate tobacco control;

Reduce salt intake;
Implement appropriate treatment of high-risk CVD;
Reduce alcohol consumption;
Reduce physical inactivity.
The WHO has encouraged all countries to unite around this banner of cardiovascular disease prevention, proposing an alliance between the United Nations,
governments, civil society, and private sectors.
The goal of the WHO is to promote a collaborative effort to change the serious
epidemiological reality of CVD and the future prospects that have been projected
for the next 30 years [15, 16].
17
The Letter from Rio de Janeiro

In line with the WHO proposal, the Brazilian Society of Cardiology (Sociedade
Brasileira de CardiologiaSBC) gathered a committee formed by the presidents of
ve of the most important cardiology societies in the world in 2013 in the city of
Rio de Janeiro: the World Heart Federation, American Heart Association, European
Society of Cardiology, Interamerican Society of Cardiology, and Brazilian Society
of Cardiology. In conjunction with specialists in global cardiovascular prevention, a
document was prepared containing targets for the prevention and control of NCDs
[16]. The document, called the Letter from Rio, was ratied by the presidents of
the participating societies and aims to provide an overall view of CVD and propose
strategic actions to reduce the prevalence of the risk factors contributing to the high
CVD mortality [17, 18]. The letter conrms the global target of a 25 % reduction in
early mortality due to NCDs by the year 2025. The following are included in the
resolutions contained in the Letter from Rio:
Work together in defense of global targets for achieving a 25 % reduction in
mortality from NCDs by the year 2025;
Implement public policies for the prevention and control of NCDs in the general
population and specic groups;
Act on social determinants that contribute to the occurrence of CVD through
government policies;
Interact with health policy makers to develop cardiovascular prevention programs
and methods for evaluating their results;
Mobilize the media to continuously disseminate information on the importance
of CVD, its major risk factors, and means of prevention.
Targets from the Letter from Rio for the Prevention and Control of NCDs
25 % reduction in mortality rates from NCDs;
10 % reduction in the prevalence of physical inactivity among adults;
25 % reduction in the prevalence of hypertension (dened as a systolic
blood pressure 140 mmHg and a diastolic pressure 90 mmHg);
Reduction in the average intake of salt in the adult population to 5 g/day
(2000 mg sodium);
30 % reduction in the prevalence of tobacco use;
15 % reduction in the intake of saturated fatty acids to achieve the recommended level of <10 % of the daily fat requirements;
Reduction in the prevalence of obesity;
10 % reduction in excessive alcohol consumption;
20 % reduction in hypercholesterolemia;
50 % of eligible individuals should receive counseling and drug therapy to
prevent heart attacks and strokes;
Make available essential technologies and drugs, including generics, to 80 %
of the population suffering from NCDs in both the public and private sectors.
18
J.P. Andrade et al.
Conclusion
The recognition that CVD is responsible for 30 % of all deaths worldwide, together
with the alarming projections for the coming years, indicate that CVD should be
the target of actions against it that involve governments, trade associations, and
civil society.
The identication of the main factors responsible for the occurrence of CVD
and the signicant technological and scientic advancements in the diagnostic and
therapeutic arsenal against NCDs have created valuable tools for intervention in this
context. An analysis of the results of cardiovascular prevention programs implemented in some developed countries, using the triad of reduction of cardiovascular
risk factors, early diagnosis, and proper treatment, has shown signicant reductions
in CVD mortality and has indicated the paths to be followed in the future.
References
1. WHO Statistical Information Center. World Health Statistics 2009 En-WHS 2009.
2. Buttler D. Un targets top killers. Nature. 2011;477(7364):2601.
3. Beaglehole R. International trends in coronary heart disease mortality and incidence rates.
J Cariovasc Risk. 1999;6(2):638.
4. Beaglehole R, Bonita R. Global public health: a score-card. Lancet. 2008;372(9654):
198896.
5. World Health Organization, World Heart Federation, World Stroke Organization. Global atlas
on cardio-vascular disease prevention and control: policies, strategies, and interventions. 2011.
http://www.who.int/cardiovascular_dis-eases/publications/atlas_cvd/en/.
6. Dawber TR, Meadors GF, Moore Jr FE. Epidemiological approaches to heart disease: The
Framingham Study. Am J Public Health. 1951;41(3):27981.
7. Capewell S, Morrison CE, McMurray JJ. Contribution of modern cardiovascular treatment
and risk fac-tor changes to the decline in coronary heart disease mortality in Scotland between
1975 and 1994. Heart. 1999;81(4):3806.
8. Laatikainen T, Critchley J, Vartiainen E, Salomaa V, Ketonen M, Capewell S. Explaining the
decline in coronary heart disease mortality in Finland between 1982 and 1997. Am J Epidemiol.
2005;162(8):76473.
9. Thirty-ve-year trends in cardiovascular risk factors in Finland. Int J Epidemiol. 2010;
39(2):50418.
10. Vigitel Brasil 2012: vigilncia de fatores de risco e proteo para doenas crnicas por
inqurito telefni-co/Ministrio da Sade, Secretaria de Vigilncia em Sade, Departamento
de Vigilncia de Doenas e AgravosnoTransmissveis e Promoo de Sade. Braslia:
Ministrio da Sade, 2013.
11. Brasil. Ministrio da Sade. Secretaria de Vigilncia em Sade. Departamento de Anlise de
Situao de Sade. Plano de aes estratgicas para o enfrentamento das doenas crnicas no
transmissveis (DCNT) no Brasil 2011-2022/Ministrio da Sade. Secretaria de Vigilncia em
Sade.
12. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European Guidelines
on cardio-vascular disease prevention in clinical practice (version 2012). The Fifth Joint Task
Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice (constituted by representatives of nine societies and by invited
experts). Eur Heart J. 2012;33(13):1635701.
19
13. Di Chiara A, Vanuzzo D. Does surveillance impact on cardiovascular prevention? Eur Heart
J. 2009;30:10279.
14. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, et al. Explaining the
decrease in U.S. deaths from coronary disease, 19802000. Explaining the decrease in U.S.
deaths from coronary disease, 19802000. N Engl J Med. 2007;356(23):238898.
15. World Health Organization. Revised [third] WHO discussion paper on the development of a
comprehensive global monitoring framework, including indicators, and a set of voluntary
global targets for the prevention and control of NCDs. July 2012. http://www.who.int/nmh/
events/2012/ncd_discussion_paper/en/index.html.
16. World Health Organization. 65th World Health Assembly document A65/54: Second report of
Committee A. 25 May 2012. http://apps.who.int/gb/ebwha/pdf_les/WHA65/A65_54-en.pdf.
17. Andrade JP, Arnett DK, Pinto F, Pieiro D, Smith Jr SC, Mattos LAP, et al. Sociedade Brasileira
de Cardi-ologia Carta do Rio de Janeiro. Arq Bras Cardiol. 2013;100(1):35.
18. Simo AF, Prcoma DB, Andrade JP, Correa Filho H, Saraiva JFK, Oliveira GMM, et al.
Sociedade Brasile-ira de Cardiologia. I Diretriz Brasileira de Preveno Cardiovascular. Arq
Bras Cardiol 2013:101(6 Suppl 2):163.
Value of Primordial and Primary Prevention

for Cardiovascular Diseases: A Global
Perspective
Armin Barekatain, Sandra Weiss, and William S. Weintraub
Global Burden of Cardiovascular Disease

Worldwide, cardiovascular disease (CVD) is estimated to be the leading cause of
death and loss of disability-adjusted life years. Although age-adjusted cardiovascular
death rates have declined in several developed countries in past decades, rates of
cardiovascular disease have risen greatly in low-income and middle-income countries [1]. CVD is now the leading cause of death in all developing regions, with the
exception of sub-Saharan Africa [1]. It causes twice as many deaths as HIV, malaria,
and tuberculosis combined. Furthermore, due to the increasing prevalence of risk
factors and lack of appropriate preventive measures, a relatively younger population
is affected by CVD in these countries [2]. This leads to the loss of many potential
years of productive life and places a huge economic burden on these countries.
Hence, efforts to produce even modest reductions in age-specic disease rates could
have a very large economic impact.
A. Barekatain, M.D. (*)

Internal Medicine, Houston, Texas, USA
e-mail: armin.b@gmail.com
S. Weiss, M.D.
Christiana Care Center for Heart et Vascular Health from the University of Chicago
Medical Center, Newark, DE, USA
e-mail: sandra.weiss@ucsf.edu
W.S. Weintraub, M.D.
Center for Outcomes Research, One of Four Research Centers Comprising the Value Institute
at Christiana Care Health Center, Newark, DE, USA
e-mail: wweintraub@christianacare.org
DOI 10.1007/978-3-319-22357-5_3
21
22
A. Barekatain et al.
Risk Factors for Cardiovascular Disease

Epidemiologic research ndings from the Framingham Heart Study and many others
have established high blood pressure, high blood cholesterol, smoking, obesity,
diabetes, and physical inactivity as major risk factors for CVD [3]. These risk factors
have been shown in other studies to apply almost universally among racial and
ethnic groups [4]. In INTERHEART, a casecontrol study of 19,470 people from
52 countries, nine modiable risk factors were found to have a globally consistent
association with myocardial infarction (MI) in both sexes and at all ages and in all
regions: abnormal lipids, smoking, hypertension, diabetes, abdominal obesity,
psychosocial factors, dietary factors, physical exercise, and alcohol consumption,
with the two most important risk factors being smoking and abnormal lipids [5].
The levels of these risk factors have increased in most non-Western countries
over the past two decades [1]. Social and economic changes have driven these
trends. The epidemiologic transition is a term used to describe the observation that
people are living longer, and those who live longer have greater exposure to risk
factors. Westernized diets and patterns of physical inactivity result in elevations in
blood pressure, body weight, blood sugar levels, and lipid concentrations. Moreover,
the global expansion of the tobacco trade has led to large increases in the rate of
smoking [6].
Is Cardiovascular Disease Preventable?

While clinical trials have provided us with evidence that treatment of people with
elevated risk factors is efcacious in preventing CVD, it is less well known that lowering the levels of or eliminating risk factors in communities is effective in reducing
the rate of CVD at the population level. The rst line of evidence that CVD can be
prevented at the population level comes from studying its trends in several highincome countries. For example, in the United States, the CVD mortality rate peaked
during the 1960s then reversed direction and has generally steadily fallen since then.
Reduction in the CVD mortality rate started before powerful modern medical treatments entered mainstream medical practice [7]. In addition, modeling studies have
demonstrated that almost half of the decline in the rate of coronary heart disease in
the US between 1980 and 2000 is attributable to the reductions in major risk factors.
These signify that improvements in risk factors, primarily smoking, total cholesterol,
and blood pressure, were key elements to initiate the decline [8].
Another line of evidence that population-based interventions can be effective in
lowering the burden of CVD in the community comes from several epidemiologic
studies, as mentioned bellow.
The Stanford Three-Community Study began in 1972 and studied the effects of
mass-media educational campaigns to promote knowledge and awareness of
CVD and their risk factors as well as the specic measures which may reduce
Value of Primordial and Primary Prevention for Cardiovascular Diseases
23
risk. A statistically signicant reduction of 2530 % was achieved in the composite risk score for cardiovascular disease as a result of signicant declines in
blood pressure, smoking, and cholesterol levels [9].
In the Stanford Five-City Project, a reduction in cholesterol level (about 2 %),
blood pressure (about 4 %), and smoking rate (13 %) was achieved in a 5-year,
low-cost, comprehensive educational and organizational programs by utilizing
about 26 h of exposure to multichannel and multifactor education. These risk
factor changes resulted in important decreases in composite total mortality risk
scores (15 %) and coronary heart disease risk scores (16 %) [10].
The North Karelia project offers a powerful lesson in successful populationbased interventions. This project was launched in 1972 to lower CVD rates by
improving the three cardinal risk factors for CHD: smoking, total cholesterol,
and blood pressure. Information was obtained about socioeconomic status, medical history, smoking, diet, alcohol consumption, physical activity, as well as
height, weight, skinfold thicknesses, blood pressure, and serum cholesterol.
Practical means were developed to modify risk factors by mass media, by training volunteers and community leaders, and through environmental changes such
as smoking restrictions, use of low-fat dairy and meat products. These interventions resulted in reduced rates of smoking, high total cholesterol and high blood
pressure. As a result, the CHD mortality rate among males aged 3564 years in
North Karelia decreased by 2.9 % per year between 1969 and 1978, signicantly
more than the national mortality rate (1.0 % per year) [11]. These experiences
suggest that population-based approaches to reduce risk factors could be effective
even in the absence of extensive medical treatments.
Primordial and Primary Prevention of Cardiovascular Disease

Primordial prevention is dened as prevention of the development of risk factors in
the rst place, and primary prevention are dened as interventions designed to modify adverse levels of risk factors once present with the goal of preventing an initial
CVD event. Although no multi-decade, population-based, longitudinal studies have
been conducted linking absolute levels of risk factors in childhood to incident clinical CVD events in adult life, several lines of evidence support the need for and value
of prevention beginning early in life.
Barker et al., have suggested a developmental model for the origin of chronic
non-communicable disease and suggested that people who develop cardiovascular
disease or type 2 diabetes grew differently than other people in their early life. They
tend to grow slowly in utero and in the rst 2 years after birth, followed by a rapid
compensatory growth later in life. Therefore, variations in fetoplacental and infant
development appear to be linked to later chronic non-communicable disease [12].
Moreover, studies have shown that high maternal weight and adiposity are associated with the development of insulin deciency, type 2 diabetes, and coronary heart
disease in the offspring [13, 14]. Therefore, prevention efforts started early in life
may have a lasting impact later or even from one generation to the next.
24
Additional evidence supporting the need for primordial and primary prevention
beginning early in life comes from epidemiological studies indicating that major
risk factors for CVD in adulthood, including cigarette smoking, dyslipidemia, elevated blood pressure, physical inactivity, and obesity, are prevalent in childhood and
adolescence [15, 16], and are potentially modiable [17, 18]. Furthermore, noninvasive imaging studies demonstrated that adverse levels of major risk factors for CVD
measured in childhood and adolescence are associated with a signicant subclinical
atherosclerosis [19]. Risk factor exposures in 12- to 18-year-old adolescents predict
increased carotid intima-media thickness in adulthood independently of the risk factors for CVD present in adulthood [20]. Children with type 2 diabetes mellitus have
signicantly greater carotid intima-media thickness and stiffer carotid arteries than
their healthy counterparts [21]. Moreover, a combined data analysis from 4 cohorts
comprising 4380 patients showed that risk factors from 9 years of age were predictive
of carotid intima-media thickness in adulthood [22].
The efcacy and safety of modifying major CVD risk factors in early life with
therapeutic lifestyle change and pharmacologic interventions have also been demonstrated. Lowering dietary intake of total fat, saturated fat, and cholesterol in prepubertal boys and girls aged 810 years resulted in signicant reduction in low-density
lipoprotein cholesterol levels [23]. Other studies have shown that 2 years of pravastatin therapy induced a signicant regression of carotid atherosclerosis in children
with familial hypercholesterolemia, with no adverse effects on growth, sexual maturation, hormone levels, or liver or muscle tissue [24]. School-based prevention interventions, including nutrition and physical activity components, led to signicant decrease
in weight and blood pressures, particularly among girls [25]. Finally, favorable risk
factor levels in middle age are associated with a lower lifetime risk for CVD mortality,
increased survival, and improved quality of life. Framingham Heart Study participants
who were free of CVD at 50 years of age had very low lifetime risk for CVD and
markedly longer survival [26]. Collectively, these results should promote efforts
aimed at preventing development of risk factors in young individuals.
The Cost-Effectiveness and Value of Prevention

The economic impact of CVD comes both in direct costs to the health care system
and indirectly in losses to the economy through work loss. This is particularly of
importance in developing countries where CVD more frequently affects those of
working age, and therefore leads to the loss of potential years of healthy life [3].
Hence, efforts to produce even modest reductions in age-specic disease rates could
have very large economic impacts. For example, a 2 % annual reduction in cardiovascular death rates, as proposed by the World Health Organization (WHO) in 2005,
may avert the loss of $8.1 billion over a decade, including $1.36 billion in China,
$1.64 billion in India, and $1.49 billion in Russia [7]. There is no legal standard
or regulation for what is cost-effective and this may vary among the countries.
The WHO Commission on Macroeconomics and Health recommended choosing
25
interventions that were less than three times a countrys growth national income
(GNI) per capita [27]. The strategies reviewed below are generally acceptable in all
developing regions, particularly since many are cost- saving interventions.
Cardiovascular disease burden can be lowered through both population-based as
well as individual-based interventions. When high-income countries brought CVD
under control, they used these preventive approaches in combination. Declines in CVD
mortality have run in parallel with decades of decreasing consumption of animal fat,
decreasing tobacco consumption, and growing community awareness about CVD
risk factors and heart health consciousness. In addition, medical and surgical treatments have improved in efcacy. These range from pharmaceuticals that lower
blood pressure and cholesterol to surgical interventions. Most estimates of the
effects of these interventions conclude that half of the declining CVD mortality is
due to community-based prevention and half to treatment [8, 28].
The focus of population-based primordial and primary prevention is life style
modication including tobacco cessation, physical activity, diet, and obesity. These
interventions have been found to be cost effective in all regions of the world [29].
Educational programs should be implemented to raise awareness of CVD in the
society and promote the important need for behavioral and life style modications
starting at early ages.
Smoking cessation is the most cost-effective intervention for prevention of cardiovascular disease [27]. There are more than one billion smokers worldwide, 80 % of
whom reside in developing countries. Current smoking increases the risk of acute
MI with an odds ratio (OR) of 2.95. The OR associated with former smoking falls
to 1.87 within 3 years of quitting [30]. Strategies should include interventions
to both quit smoking and prevent its initiation. Other public measures that are
non-price-related, such as restrictions on smoking in public places, public health
education, and advertising bans would also be highly cost-effective.
The centerpiece of a healthy lifestyle is a diet and physical activity pattern that
follows the evidence-based recommendations. The protective effects of regular
exercise and cardiorespiratory and general physical tness have been very well
documented. Similarly, numerous clinical trials have demonstrated the benets
of reduced sodium intake and the benets of healthy eating patterns such as the
Mediterranean-style diet [31].
Governmental policies on food production, processing, and marketing should be
focused on reducing salt and fat content of processed foods as well as nutrition and
cooking at schools. Urban planning policies such as city design that encourages
physical interaction with the environment should be implemented to promote physical activity. Educational programs including media projects should be set up to raise
the awareness of the society to the following subjects: risks of smoking, the causes
of high blood pressure and the benets of control strategies, the causes of hyperlipidaemia and dietary recommendations, the dangers of obesity and warnings about
diabetes, the importance of good nutrition and physical exercise in weight control.
As risk factors accumulate and become more prominent in the population, CVD
prevention must shift to be more individualized and medical. This entails delivering
26
proven and affordable preventive care to those at high risk of fatal or catastrophic
events. As in high-income countries, an effective and affordable primary health care
system for targeted screening for the identication of individuals at very high risk of
a fatal or disabling cardiovascular event and the provision of cost-effective, evidencebased preventive care is essential for the prevention and control of CVD. Primary
health care services should be organized such that core interventions can be delivered
by non-physician health care workers, ideally working under the supervision of a
physician, to enable the most efcient use of scarce resources. Various risk prediction
tools, such as the Framingham risk prediction tool, have been developed to calculate
cardiovascular risk and tailor clinical management according to the level of risk. The
most appropriate screening tools for use in resource-poor settings should involve simple methods focused on medical history and physical measurements such as blood
pressure and body mass, without reliance on laboratory test results. Cost effectiveness
generally increases at higher risk thresholds for treatment.
Treatment regimens should be simple to administer and not require extensive
titration. In this regard, the concept of a CVD polypill for disease prevention is
attractive where combination of aspirin, a statin, and 1 or more blood pressurelowering drugs at low dose is cost-effective and well tolerated. This has been shown
in studies to be associated with a 20 % reduction in the blood cholesterol level, 28 %
reduction in difference in BP between 115 and current and 18 % reduction absolute
risk for CVD [32]. It is estimated that a 5060 % reduction in cardiovascular disease
would occur if all patients with a 10-year risk greater than 5 % were treated with
these regimens of four drugs, which are currently available and widely assessed in
clinical trials with event reductions. The incremental cost-effectiveness ratios (ICER)
remain at $3001300/QALY (quality adjusted life year) gained in all the regions
studied [29]. Other cost-effective strategies could include nicotine-replacement
therapy and low-dose, xed-combination blood pressure-lowering therapy for those
with moderate to severe hypertension. Use of these regimens would range between
$310 and 1220 per QALY gained across the developing regions, depending on the
risk level of those taking them for primary prevention [29].
Therefore, a concerted public health response must integrate population-based
prevention strategies and cost-effective clinical care, since the health systems of
developing countries can not afford the demands of technology-intensive treatments.
The population approach is more rewarding and sustainable in the medium and long
term, since even small reductions in each risk factor can add up to huge reductions in
the rate of cardiovascular events. And if healthy behavior is established as a desirable
norm in a society, it can have a multigenerational effect.
Conclusion
Cardiovascular disease remains the most common cause of death in all countries,
excluding sub-Saharan Africa, where it is the second. A high proportion of CVD
burden occurs earlier among working-age adults in developing countries and has a
27
huge social and economic impact in such countries. Therefore, prevention of premature
deaths due to CVD and reduction of related-health care costs should be the priority
of health policy makers. The risk factors for CVD are global and are becoming more
prevalent among children and adolescents. Prevention efforts started early in life may
have a lasting impact later or even from one generation to the next.
Reductions in CVD mortality in the United States and several other developed
countries are believed to be the result of both improvements in risk factorsprimarily
smoking, total cholesterol, and blood pressureand introduction of pharmacologic
treatments. Because the risk factors are the same, we can assume the same reductions in developing countries. The focus of population-based prevention should be
life style modication including tobacco cessation, physical activity, diet, and obesity. These interventions are cost effective in all regions of the world. Pharmacological
interventions offer further reductions in CVD mortality. Effective and inexpensive
treatments are available in developing countries but often underused despite the
proven benets. This problem is partly due to a belief that the treatments are too
expensive. Yet we have shown above that there are prevention regimens which are
cost-effective across the developing regions.
In sum, primordial and primary prevention of cardiovascular disease should be
the major goal of medicine. A multilevel approach that integrates policy actions,
health education, and efcient health care delivery systems should be the mission of
public health.
References
1. Gaziano TA, Bitton A, et al. Growing epidemic of coronary heart disease in low- and middleincome countries. Curr Probl Cardiol. 2010;35(2):72115.
2. Gaziano TA. Reducing the growing burden of cardiovascular disease in the developing world.
Health Aff (Millwood). 2007;26(1):1324.
3. Kannel WB, Dawber TR, et al. Factors of risk in the development of coronary heart disease
six year follow-up experience. The Framingham Study. Ann Intern Med. 1961;55:3350.
4. American Heart Association. Heart Disease and Stroke Statistics2004 Update. http://www.
americanheart.org/downloadable/heart/1072969766940HSStats2004Update.pdf. Accessed 1
Dec 2004.
5. Yusuf S, Hawken S, et al. Effect of potentially modiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): casecontrol study. Lancet.
2004;364(9438):93752.
6. Joshi R, Jan S, Wu Y, et al. Global inequalities in access to cardiovascular health care: our
greatest challenge. J Am Coll Cardiol. 2008;52(23):181725.
7. Ford ES, Capewell S. Proportion of the decline in cardiovascular mortality disease due to
prevention versus treatment: public health versus clinical care. Annu Rev Public Health.
2011;32:522.
8. Ford ES, Ajani UA, et al. Explaining the decrease in U.S. deaths from coronary disease, 1980
2000. N Engl J Med. 2007;356(23):238898.
9. Fortmann SP, Williams PT, et al. Effect of health education on dietary behavior: the Stanford
Three Community Study. Am J Clin Nutr. 1981;34(10):20308.
10. Fortmann SP, Taylor CB, et al. Effect of community health education on plasma cholesterol
levels and diet: the Stanford Five-City Project. Am J Epidemiol. 1993;137(10):103955.
28
11. Puska P, Nissinen A, et al. The community-based strategy to prevent coronary heart disease:
conclusions from the ten years of the North Karelia project. Annu Rev Public Health.
1985;6:14793.
12. Barker DJ. Sir Richard Doll Lecture. Developmental origins of chronic disease. Public Health.
2012;126(3):1859.
13. Forse T, Eriksson JG, et al. Mothers weight in pregnancy and coronary heart disease in a
cohort of Finnish men: follow up study. BMJ. 1997;315:83740.
14. Fall CHD, Stein CE, et al. Size at birth, maternal weight, and type 2 diabetes in south India.
Diabet Med. 1998;15:220e7.
15. Centers for Disease Control and Prevention (CDC). Prevalence of abnormal lipid levels among
youths: United States, 19992006. MMWR Morb Mortal Wkly Rep. 2010;59:2933.
16. Din-Dzietham R, Liu Y, et al. High blood pressure trends in children and adolescents in
national surveys, 1963 to 2002. Circulation. 2007;116:148896.
17. Savoye M, Shaw M, et al. Effects of a weight management program on body composition and
metabolic parameters in overweight children: a randomized controlled trial. JAMA.
2007;297:2697704.
18. Foster GD, Linder B, et al. A school-based intervention for diabetes risk reduction. N Engl J
Med. 2010;363:44353.
19. Li S, Chen W, et al. Childhood cardiovascular risk factors and carotid vascular changes in
adulthood: the Bogalusa Heart Study. JAMA. 2003;290:22716.
20. McGill Jr HC, McMahan CA, et al. Effects of nonlipid risk factors on atherosclerosis in youth
with a favorable lipoprotein prole. Circulation. 2001;103:154650.
21. Urbina EM, Kimball TR, et al. Youth with obesity and obesity-related type 2 diabetes mellitus
demonstrate abnormalities in carotid structure and function. Circulation. 2009;119:29139.
22. Juonala M, Magnussen CG, et al. Inuence of age on associations between childhood risk factors and carotid intima-media thickness in adulthood: the Cardiovascular Risk in Young Finns
Study, the Childhood Determinants of Adult Health Study, the Bogalusa Heart Study, and the
Muscatine Study for the International Childhood Cardiovascular Cohort (i3C) Consortium.
Circulation. 2010;122:251420.
23. Efcacy and safety of lowering dietary intake of fat and cholesterol in children with elevated
low-density lipoprotein cholesterol. The Dietary Intervention Study in Children (DISC). The
Writing Group for the DISC Collaborative Research Group. JAMA. 1995;273(18):142935.
24. Wiegman A, Hutten BA, et al. Efcacy and safety of statin therapy in children with familial
hypercholesterolemia: a randomized controlled trial. JAMA. 2004;292:3317.
25. Hollar D, Messiah SE, et al. Healthier options for public schoolchildren program improves
weight and blood pressure in 6- to 13-year-olds. J Am Diet Assoc. 2010;110:2617.
26. Lloyd-Jones DM, Leip EP, et al. Prediction of lifetime risk for cardiovascular disease by risk
factor burden at 50 years of age. Circulation. 2006;113:7918.
27. Gaziano TA. Cardiovascular disease in the developing world and its cost-effective management. Circulation. 2005;112(23):354753.
28. Hunter DJ, Reddy KS. Noncommunicable diseases. N Engl J Med. 2013;369(14):133643.
29. Shrou A, Chowdhury R, et al. Cost effective interventions for the prevention of cardiovascular disease in low and middle income countries: a systematic review. BMC Public Health.
2013;13:285.
30. Teo KK, Ounpuu S, et al. Tobacco use and risk of myocardial infarction in 52 countries in the
INTERHEART study: a casecontrol study. Lancet. 2006;368(9536):64758.
31. Weintraub WS, Daniels SR, et al. Value of primordial and primary prevention for cardiovascular disease: a policy statement from the American Heart Association. Circulation.
2011;124(8):96790.
32. Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a multidrug
regimen in the developing world: a cost-effectiveness analysis. Lancet. 2006;368(9536):67986.
How to Estimate Cardiovascular Risk

Protsio L. da Luz and Renata Caruso Fialdini
Introduction
Estimation of individual cardiovascular risk is essential to guide patient counseling
as well as for patients adherence to physicians recommendations. A particular difculty regarding patients adherence is that risk is, most of the time, conferred by
factors which by themselves do not cause symptoms. Further, risk modication
involves lifestyle changes or the use of medications. Neither are easily accepted
unless patients thoroughly understand the magnitude and long-term meaning of
risk stratication. Several attempts have been made to develop algorithms that
allow risk assessment. In this chapter we present a brief summary of such scores
focusing specically on practical issues.
Framingham Risk Score (FRS) [1] is a classic tool for CHD risk evaluation
also used to guide treatment. FRS classies patients into three categories over a
10 years period. High risk = >20 % + 2 or more risk factors (RF); Moderate/high
risk = between 10 and 20 % + 2 or more RF; Moderate risk = <10 % + 2 or more
RF. Low risk = 0 or 1 RF. RF include cigarette smoking, hypertension (blood pressure 140/90 mmHg or patients on antihypertensive medication), low high-density lipoprotein cholesterol (<40 mg/dL), family history of premature CHD (CHD
P.L. da Luz, MD (*)

Departament of Cardiopneumologia, InCor/FMUSP,
Avenida Dr. Enias de Carvalho Aguiar, n44, 5 andar Bloco II sala 08, So Paulo, Brazil
e-mail: protasio.luz@incor.usp.br
R.C. Fialdini, MD
InCor/FMUSP, So Paulo, Brazil
e-mail: rcarusoalni@gmail.com
DOI 10.1007/978-3-319-22357-5_4
29
30
P.L. da Luz and R.C. Fialdini

500
6 year incidence (per 1000)
500
400
300
204
200
143
103
72
100
36
80
40
32
17
Overall
One
Two
None
Number of factors
Women
Three
Men
Fig. 1 Risk of CHD according to elevated blood pressure (BP), elevated cholesterol, and left
ventricular hypertrophy: Framingham cohort 6-year follow-up. Elevated BP = 160/95; elevated
cholesterol = 260 mg/dl (DAgostinho et al. [16] with permission)
in male rst-degree relative <55 years of age; CHD in female rst-degree relative
<65 years of age), and age (men 45 years; women 55 years). Figure 1 illustrates the cumulative nature of RF.
FRS has limitations since it does not include family history, activity level or
tness, obesity, the presence and magnitude of RF overtime. Moreover, low-risk
individuals were overestimated and high-risk underestimated by algorithms from
FRS over a xed time of 10 years. Ten years is indeed too short a period for a life
long disease as atherosclerosis.
Ridker et al. [2] developed the Reynolds Risk Score (RRS), especially for women
based on participants of the Womens Heart Study. To FRS they added novel
biomarkers: hs-CRP and premature familiar history (<60 years old). This score prediction reclassied 4050 % of women at intermediate risk based on the Adult Treatment
Panel III, into higher or lower-risk categories [2]. An 18 % improvement in risk prediction also was demonstrated in male population from Physicians Health Study II [3].
Despite these scores a recent review showed that for practicing clinicians risk
assessment by calculators is still inconsistent.
Clinical History
Detailed clinical history is essential. Information regarding diet, exercise, previous
cardiac events, smoking, marital status, stress, sleep apnea and general complaints
are decisive. In a multinational study [4] of 14,000 patients with suspected of CAD
subjected to coronary computed tomographic angiography, typical angina was
31
associated with highest prevalence of 50 % stenosis, compared to other categories,

but the prevalence was lower than predicted by previous guidelines. The highest
prevalence were in older male patients with typical angina.
Family history of premature heart disease among sibilings is an independent
RF. The risk of CHD in siblings of victims of premature CHD is approximately
50 % higher for men and less for women [5]. In comparison with a population without family history, the risk of dying from CHD is 5.2 times higher compared to
those with positive family history.
In the General Cardiovascular Risk Prole (GCRP) of the MESA study a
CAC > 300 was considered high risk [6]. In that study Scheuner et al demonstrated
that when family history was added to GCRP it permitted reclassication into low,
intermediate and high risk of having CAC >300. Furthermore, in a casecontrol
study of MI patients without established CAD, a detailed family history predicted
primary ventricular brillation (VF); 43.1 % had histories of parents with familial
sudden death versus 25.1 % of controls [7].
A recent review analyzed health-behavior changes when a strong CAD family
history was present. That information, by itself, was not sufcient to promote personal health-related changes [8]. In contrast, 99 % of the individuals diagnosed with
Familial Hypercholesteromia by DNA testing adhered to the proposed treatment
[9]. Hence, perception of cardiovascular risk by single polymorphism was deemed
more reliable to those individuals.
Physical Exam
Hypertension is one of the major modiable RF for CVD. In the Prospective Studies
Trialists Collaboration [10] an increment of 20 mmHg in SBP or 10 mmHg in DBP,
in middle-aged and elderly persons, increased by twofold the risk of CHD and
stroke mortality [10]. Children with prehypertension associated to overweight, obesity and positive family history had increased risk by about twofold 11]. In the
CARDIA study [12], FRS predicted hypertension risk in young individuals.
Adiposity measures and ethnicity were related in the prediction of hypertension risk
observed in the TOPS study [11]. Although African-Americans showed no inuence of adiposity in their hypertension risk, among Caucasian greater adiposity in
the neck and waist led to increased risk in 30 % to 56 %, respectively. Even in lean
or overweighted elderly, increased abdominal adiposity was strongly associated to
higher hypertension risk when compared with control without central obesity [13].
In the Strong Heart Study [14], in American Indians, the positive association
among age, obesity and ethnicity to hypertension development was conrmed. In that
study, microalbuminuria and macroalbuminuria elevated the risk to hypertension in
3.47 and 1.72 times, respectively; therefore albuminuria was considered a relevant
risk factor for hypertension.
32
A meta-analysis of observational studies involving more than 1 million individuals

without prior histories of stroke or heart disease carried out by the Prospective
Studies Trialists Collaboration [10] demonstrated that death from CAD and stroke
increases continuously and linearly from SBP levels as low as 115 mmHg systolic
and 75 mmHg DBP.
Metabolic Syndrome and Diabetes

Metabolic Syndrome (MS) consists in the presence of 3 of 5 factors: abdominal
obesity, elevated triglyceride, reduced HDL-c, elevated blood pressure, elevated
plasma fasting glucose or diabetes [15]. Patients with MS are twice as likely to
develop CVD in the next 510 years compared with no MS. Type 2 diabetes
increases risk by about vefold [16].
Serum Biomarkers
Lipids-high LDL and triglycerides and low HDL are traditional RF [17]. We also
demonstrated that an elevated triglyderides/HDL ratio is associated with premature
CAD [17]. However, 1520 % of patients with acute cardiac events had no major
RFs. Hence, more than 20 new biomarkers have been proposed. Among those,
inflammatory markers such as high-sensitivity C-Reactive Protein (hsCRP), have
been especially considered in acute and chronic situations as well. The role of
hsCRP was emphasized in The JUPITER study [18] which included individuals
with low to normal LDL-C who were at increased CV risk as identied by elevated
hsCRP above 2 mg/L and who did not require statin treatment based on current
guidelines. In the group treated with Rosuvastatin, 20 mg/day, 44 % reduction in the
primary endpoint of major cardiovascular events and a 20 % in total mortality in the
statins group versus placebo were noted (p < 0.00001).
Yet, hsCRP has not been adopted uniformly in guidelines. That is due to the fact
that its power to predict absolute risk is low and it is a nonspecic marker, being
extremely high in other systemic infections or vessel injuries due to trauma.
Increments in several cytokines plasma concentrations, such as Interleukin-6 (IL-6)
have been correlated with plaque instabilization [19]. The TNF and CD40/ families,
are linked to immunemodulation and trombogenicity. Although their participation in
plaque instability is indisputable, lack of specicity makes them inappropriate for routine use in clinical practice. The same occurs with endothelial markers, the family of
ICAM (inter-cellular adhesion molecule) and VCAM (vascular cell adhesion molecule), E-selectin, PAI-I (plasminogen activator inhibitor) and others [20].
Results of the SIESTA study [21] suggest that the association of NT-proBNP and
brinogen could be a marker to predict acute events. Fibrinogen besides hsCRP,
higher plasma PAI-1 and serum aldosterone had also a strong correlation in MS
development [15].
33
Another extensively studied biomarker is Liprotein-associated phospholipase A2

(Lp-PLA) [2], a proinammatory enzyme that degrades phospholipids into low density liprotein cholesterol (LDL-C). The WOSCOPS [22] and ARIC [23] studies
demonstrated an association of Lp-PLA2 and CHD. Recently, 66 healthy individuals and 111 patients with stable angina and at least one vessel with >50 % stenosis
were classied according to the number of affected vessels: no disease, 1, 2, or 3
vessels disease. Except for lower age in the control group, smoking, hypertension
and diabetes were similar in all participants. Mieloperoxidase, hsCRP and Lp-PLA2
also were analyzed. Lp-PLA 2 was elevated in all individuals and positively correlated with RF but not with the number of vessels disease; hsCRP was increased in
all coronary patients, independently of RF or the affected vessels. There was no
signicance difference in mieloperoxidase between the groups [20]. Oxidation biomarkers [24] such as oxidized phospholipids in plasma also have been shown to
correlate with risk of peripheral arterial disease.
Genetic biomarkers are of great interest. Atherosclerosis is a typical polygenic
disease. Indeed CAD is determined by multiple genes, each one with modest inuence. The rst genetic variant for CAD, 9p21, was identied in 2007. Since then the
CARDIoGRAMplusCAD Consortium [25] conrmed the association of 36 genetic
variants with CAD in sample size of 190,000 participants, in independent populations. Most of the SNPs (single nucleotide polymorphisms) mediate their risk
independent of conventional RF. Yet 10 of the variants act through cholesterol,
hypertension and ABO. Furthermore, most SNPs signaling risk variant are found in
non-coding protein regions. Despite considerable efforts, genetic prediction remains
elusive, and have not yet been incorporated in the guidelines. Emotional and social
RFs are also recognized. CAD has been related to ve specic psychological
factors: anxiety, depression, character traits and personality, social isolation and
chronic life stress [26]. For instance, different forms of stresses may affect the cardiovascular system through direct stimulation of neuroendocrine pathways or indirectly by unhealthy behaviors: diet, smoking, lack of exercise, and excessive
drinking (Fig. 2). In the Whitehall II Study [26] work stress was associated with
poor diet (eating less fruits and vegetables), less physical activity, metabolic syndrome, lower heart rate variability, and elevated morning cortisol, Greater reports of
work stress were associated with higher risk of CVD, i.e., fatal events, MI and denite angina. The InterHeart Study [27] also documented the role of social/emotional
factors upon MI incidence.
Imaging Methods
Identication of incipient disease before clinical manifestations is a crucial step in
prevention. Since atherosclerosis has a long course before causing vessel obstruction,
identifying these early stages offers opportunity to halt progression. It is germane to
consider that RFs are dangerous primarily because they induce vascular damage, not
by themselves. The one exception is diabetes, which is a disease in its own.
34
Fig. 2 Pathways by which emotional stresses can lead to atherosclerosis development (da Luz
et al. [26] with permission)
Since risk assessment through RF is inaccurate the next step is the use of
noninvasive image methods. Despite access restriction and doubts in relation to
radiation and cancer, the benets can be justied by reclassication of low and
intermediate risk individuals and better individual therapeutic strategies. Moreover
an objective detection of disease makes acceptance of lifestyle behavior changes
and adherence to long-term treatment more appealing.
The Carotid Intima Media Thickness

Ultrasonic measurements of carotid intima-media thickness (CIMT) is widely used to
detect atherosclerosis. A meta-analyses [28] of 37,197 subjects, adjusted for age and
sex, showed that a difference of 0.1 mm in CIMT increases the risk of future of MI
by 1015 %, and the stroke risk increases by 1318 % [28]. In the large multicenter
European Carotid Intima Media Thickness and IMPROVE studies [29] conrmed
the positive correlation between increased risk and increased CIMT. Finally, a stronger relation with the prediction of stroke and IMCT was evidenced in numerous studies (Rotterdam, Malmo Diet and Cancer, ARIC, Cardiovascular Health Study). The
presence of a plaque confers special risk. Easiness to perform, great availability and
low costs are characteristics that make this technique attractive.
35
Coronary Calcium Score

Coronary calcium (CAC) detection by Computerized Tomography (CT) is a safe,
easy and powerful method to estimate cardiovascular risk. In the MESA [6] study
6814 white, black, hispanic, and Chinese individuals, of both sexes, aged 4584
years, without previous CVD were studied. Cumulative incidence of major coronary events was about 5 percentage points higher among individuals with CAC > 300,
compared to 0 score over 5 years; considering any coronary event, the increment
was about 10 percentage points. Reclassication in patients initially classied by
FRS, based on CAC, was observed in 4129 subjects of the HNR study [30], investigated for subclinical coronary atherosclerosis; high net reclassication rates of
21.7 % and even 30.6 % in participants at intermediate risk were achieved; correct
down-reclassication occurred in 21 % and 46 % and incorrect up-classication in
4.4 % and 6 % of 4036 individuals with no events.
The SHAPE initiative [31] recommended CAC screening for men over age 45
and women over age 55 with at least one additional RF. Berman et al. [32], studied
2119 asymptomatic patients who based on FRS, would not need statins according to
NCEP; however, after CAC determination, a large number of them qualied for
statin treatment (Fig. 3).
Fig. 3 Comparison of recommendations for statin therapy according to the NCEP and the
SHAPE. SHAPE incorporates CAC and therefore increases the number of individuals who should
receive statins (Berman et al., AHA 2007, with permission)
36
In the EISNER Trial [32], Rozanski et al. suggested that CAC scanning improved
RFs at 4 years prole due to greater reduction in SBP, LDL-C, waist circumference
and weight. Moreover, the degree of RF modication increased as CAC score
increased [30]. It is worth remembering that recommendations to repeat testing
are for 0 score, each 5 years and for any other score, between 3 and 5 years.
Stress Tests
EKG, echocardiogram and radioisotopes, under physical or pharmacological
stresses, are powerful tools to detect and quantify ischemia, myocardial viability or
brosis; all factors profoundly inuence outcomes and therapeutic decisions. There
are differences in sensitivity and accuracy among the tests; hence, their use should
be individualized according to local expertises and patient characteristics, taking
into special consideration the principles of the Bayes theorem. Both short and long
term prognosis can be predicted with considerable accuracy with these tests.
Coronary Computed Tomography Angiography (CCTA)

CCTA is a relatively new technique that allows non-invasive evaluation of coronaries, thus representing an alternative to conventional angiography to clarify potential
individuals at risk for CHD events. It is even more powerful than left ventricular
ejection function (LVEF) to predict all cause death. In the Conrm Registry [4],
in a large population without known CHD and without chest pain, a comparative
analyses between CAC score, CCTA and FRS were carried out to predict mortality
and outcomes. Inclusion of CACS over the FRS improved all-cause mortality prediction by AUC (0,620,71 and from 0,59 to 0,71 for the composite outcome), but
no incremental risk were observed by the additional CCTA [4]. Adding CAC to the
model improved accuracy from 0.62 to 0.71.
Global Risk
Framingham Risk Score [1] for CHD, which included coronary death, myocardial
infarction, coronary insufciency and angina is validated in US and with recalibrations were exported for different regions worldwide. However, to predict a global
risk for CVD, it was necessary to add the risk-estimate of cerebrovascular events,
namely ischemic stroke, hemorrhagic stroke, and transient ischemic attack, peripheral artery disease, and heart failure. A new algorithm (Framingham Website) based
in FRS produces an absolute risk to global CVD (i.e., idea of unity risk to the individual) and could estimate the risk of each component of CVD. The model included
37
Fig. 4 Suggested principal items to be considered in risk assessment. In a particular patient not all
items need to be fullled. For instance, non-invasive testing may not be necessary in a patient with
typical angina, multiple risk factors and advanced age. Straight angiography may be preferable
the variables mean of age, Total-Cholesterol, HDL-C, SBP, use of antihypertensives,

diabetes, smoking and number of incident CVD events adapting sex-specic CVD
functions discrimination and general calibration CVD risk score and also introduced the concept of heart age meaning vascular age [25]. Simplication of risk
prediction by a general CVD prediction could encourage their application for the
physician at least in primary prevention [6]. In Fig. 4 we suggest key steps to be
followed in risk stratication.
Conclusions
We can summarize the ndings above as follows: (1) Risk is incremental in an
exponential manner according to the number of RF; (2) Men and women have
distinct clinical proles; (3) Increased risk may be identied at early age (family
history, dyslipidemia); (4) Non-invasive detection of premature atherosclerosis
is an incentive to implement preventive measures in asymptomatic individuals;
(5) Global risk assessment is the desirable strategy; (6) Risk assessment must be
individualized.
38
Several factors must be considered in assessing CV risk, as shown in Fig. 4.

Decision as to how to proceed on the course of investigation depends on specic
patients. Clearly, not all methods need to be used to establish individual risk.
The use of guidelines is recommended for clinical practice; information should be
simple and preferentially automated.
References
1. DAgostino GR, et al. General cardiovascular risk prole for use in primary care: the
Framingham Heart Study. Circulation. 2008;117:74353.
2. Ridker PM, et al. Development and validation of improved algorithms for the assessment of
global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:6119.
3. Ridker PM, et al. C-reactive protein and parental history improve global cardiovascular risk
prediction: the Reynolds Risk Score for men. Circulation. 2008;118:224351.
4. Cheng VY, et al. Performance of the traditional age, sex, and angina typicality-based approach
for estimating pretest probability of angiographically signicant coronary artery disease in
patients undergoing coronary computed tomographic angiography. Results from the multinational coronary CT angiography evaluation for clinical outcomes: an International Multicenter
Registry (CONFIRM). Circulation. 2011;124:242332.
5. Rissanen AM, et al. Familial occurrence of coronary heart disease: effect of age at diagnosis.
Am J Cardiol. 1979;44:606.
6. Scheuner MT, et al. The general cardiovascular risk prole identies advanced coronary artery
calcium and is improved by family history. The Multi-Ethnic Study of Atherosclerosis. Circ
Cardiovasc Genet. 2010;3:97105.
7. Dekker LRC, et al. Familial sudden death is an important risk factor for primary ventricular
brillation: a casecontrol study in acute myocardial infarction patients. Circulation. 2006;
114:11405.
8. Imes CC, et al. Family history of cardiovascular disease, perceived cardiovascular disease risk,
and health-related behavior: a review of the literature. J Cardiovasc Nurs. 2014;29:10829.
9. Claassen L, et al. Being at risk for cardiovascular disease: perceptions and preventive behavior
in people with and without a known genetic predisposition. Psychol Health Med. 2012;
17:51121.
10. Turnbull F, et al. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed
overviews of randomized trials (Blood Pressure Lowering Treatment Trialists Collaboration).
Arch Intern Med. 2005;165:14109.
11. McAuley PA, et al. General and regional adiposity and hypertension risk in a multi-ethnic
community cohort of men and women: The Take off the Pressure Study (TOPS). Circulation.
2012;125:AP385.
12. Carson AP, et al. Evaluating hypertension risk prediction models in young adults: the Coronary
Artery Risk Development in Young Adults (CARDIA) study. Circulation. 2012;125, AMP049.
13. Mello RB, et al. Central obesity is a risk factor for hypertension independent of body mass
index in elderly individuals: results of a population-based study. Circulation. 2011;124,
A12691.
14. Wang W, et al. A longitudinal study of hypertension risk factors and their relation to cardiovascular disease. The Strong Heart Study. Hypertension. 2006;47:4039.
15. Ingelsson E, et al. Multimarker approach to evaluate the incidence of the metabolic syndrome
and longitudinal changes in metabolic risk factors. The Framingham Offspring Study.
Circulation. 2007;116:98492.
39
16. DAgostinho RB, et al. Cardiovascular disease risk assessment: insights from Framingham.
Glob Heart. 2013;8:1123.
17. Da Luz PL, et al. High ratio of triglycerides to HDL-cholesterol predicts extensive coronary
disease. Clinics. 2008;64:42732.
18. Ridker PM, et al. Rosuvastatin to prevent vascular events in patients with elevated C-reactive
protein JUPITER study group. N Engl J Med. 2008;359:2195207.
19. Gabay C, et al. Acute-phase proteins and other systemic responses to inammation. N Engl J
Med. 1999;340:44854.
20. Uydu HA, et al. Comparison of inammatory biomarkers for detection of coronary stenosis in
patients with stable coronary artery disease. Eur Rev Med Pharmacol Sci. 2013;17:1128.
21. Sauter C, et al. The assessment of vigilance: normative data on the SIESTA sustained attention
test. Sleep Med. 2013;14:5428.
22. Sheperd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995;
16:13017.
23. The Atherosclerosis Risk in Communities (ARIC) study: design and objectives. The ARIC
investigators. Am J Epidemiol. 1989;129:687702.
24. Bertoia ML, et al. Oxidation-specic biomarkers and risk of peripheral artery disease. J Am
Coll Cardiol. 2013;61:216979.
25. Roberts R, et al. Genomics in cardiovascular disease. J Am Coll Cardiol. 2013;61:202937.
26. da Luz PL, et al. Drugs and lifestyle for the treatment and prevention of coronary artery disease: comparative analysis of the scientic basis. Braz J Med Biol Res. 2011;44:97391.
27. Yusuf S, et al. Effect of potentially modiable risk factors associated with myocardial infarction in 52 countries (The INTERHEART study): casecontrol study. Lancet. 2004;364:
93752.
28. Lorenz MW, et al. Prediction of clinical cardiovascular events with carotid intima-media thickness. A systematic review and meta-analysis. Circulation. 2007;115:45967.
29. Bots ML, et al. Should we indeed measure carotid intima-media thickness for improving
prediction of cardiovascular events after IMPROVE? J Am Coll Cardiol. 2012;16:15002.
30. Erbel R, et al. Coronary risk stratication, discrimination, and reclassication improvement
based on quantication of subclinical coronary atherosclerosis. The Heinz Nixdorf Recall
Study. J Am Coll Cardiol. 2010;56:1397406.
31. Naghavi M, et al. From vulnerable plaque to vulnerable patientPart III: executive summary
of the Screening for Heart Attack Prevention and Education (SHAPE) task force report. Am J
Cardiol. 2006;98:2H15.
32. Rozanski A, et al. Impact of coronary artery calcium scanning on coronary risk factors and
downstream testing: The EISNER (Early Identication of Subclinical Atherosclerosis by
Noninvasive Imaging Research) Prospective Randomized Trial. J Am Coll Cardiol. 2011;
57:162232.
Tobacco and Alcohol Control: Preventable

Risk Factors
Aloyzio Chechella Achutti
Nicotine and Alcohol: Psychoactive Substances

That Are Dependent on Neither Traffickers Nor Prescription
Psychoactive substances are used throughout the world, at all times, irrespective of
geography, ethnicity, culture, or religion. They are substances that modulate the
central nervous system, preferentially operating on the limbic system in the reward
circuitry, which may lead to chemical and psychological dependence. This system,
present in all mammals as a result of evolution and adaptation, is related to the preservation of the species and acts by strengthening potentially benecial behaviors.
This is the largest and most difcult challenge to any attempt to control abuse
because it is a function that is fundamentally essential for survival.
The second challenge is to develop a preventive attitude as a future investment.
There is no immediate pleasure or gain, and it requires effort, reasoning, and even
some sacrice, especially when the alternative is accompanied by pleasure, as is
usually the case with stimulation of the brains reward circuitry.
Controlling tobacco and alcohol as preventable risk factors thus requires behavior and intention to change an immediate pleasure into a future gain. In economic
terms, it is the same as avoiding consumption to save and invest in the future.
To negotiate and make decisions, information and knowledge regarding behavioral consequences are essential, as is a condent outlook toward the future when
A.C. Achutti, M.D., Ph.D. (*)

School of Medicine, Federal University from Rio Grande do Sul,
Porto Alegre, Brazil
Department of Social Medicine, School of Medicine, Federal University
from Rio Grande do Sul, Porto Alegre, Brazil
e-mail: aloyzio.achutti@terra.com.br
DOI 10.1007/978-3-319-22357-5_5
41
42
A.C. Achutti
one can enjoy what was saved today. Education provides access to information and
enables the formation of a positive attitude, and the prevailing culture or dominant
collective behavior consolidate and also facilitate the adoption of healthy habits or
behavioral changes when undesirable deviations occur.
The goal of achieving a world free of tobacco and alcohol should be considered a
direction to follow and a slogan to promote, but it cannot be considered an achievable goal in the short term, as there are so many other evils throughout the world,
such as social inequalities, frustration, violence, and prot-related interests involving
a captive clientele (dependent).
Other abusive behaviors have factors in common with and should also be considered as additional risks for the phenomenon of dependence, including overeating to
the point of obesity, sexual obsession, abuse of other drugs, gambling, violence,
whether practiced or assisted, and disregard for the environment.
The distance from the goal or the difculties of the journey cannot be a disincentive to a professional approach to every patient treated.
As the eminent cardiologist and epidemiologist Geoffrey Rose said, physicians
are not responsible for the choices that society makes, but need to be aware of their
responsibility to denounce, and of their role as societys counselors and mentors.
The World Health Organization, academia, governments and scientic societies
have shown concern regarding this subject by producing extensive literature that
has accumulated over the course of half a century. The majority of this information
is available and accessible from several reliable sources, including the Internet, with
periodic updates [16]. Currently, there is little point discussing what is already
consolidated; it is more important to try to understand why the abuse is still frequent
and how to confront it.
Among the national bibliography, two topical references are recommended:
The Brazilian Cardiology Society Smoking Guidelines (Diretrizes da Sociedade
Brasileira de Cardiologia sobre Tabagismo) (now in press but will soon be available
through the SBC portal) and the chapters on smoking and problems concerning
alcohol intake in the book titled Ambulatory Medicine: evidence-based primary
care conduct (Medicina Ambulatorial: condutas de ateno primria baseadas em
evidncias). The authors of the latter have proposed to maintain updated references
available on the Internet. Among the international literature, reports from the World
Health Organization, World Heart Federation, American Heart Association, US
Centers for Disease Control and Prevention, and European Society of Cardiology
contain a great deal of information regarding the epidemiology, physiopathology
and treatment of these conditions, as previously discussed.
Cardiology societies joined the movement to control substances after some delay
[7] and today, no longer accept simply promoting the treatment of currently existing
injuries and their complications. The cardiologists professional prestige makes a
difference in terms of mobilizing politicians and governments to adopt appropriate
public health policies. In this sense, with respect to tobacco control, our country and
the SBC have been exemplary.
It is important to stress the ability of the physician to inuence their patients.
If cardiologists were to give the removal of preventable risk factors the same dedication
Tobacco and Alcohol Control: Preventable Risk Factors
43
they give to the prescription of treatments for hypertension and dyslipidemia or to indicating invasive tests or cardiovascular surgery, the success rate would be even greater.
Expected Behavior of Health Professionals with Respect to Removable Risk
Factors
Not to drink in excess and not to smoke;
If smoking or using alcohol, not doing so in health care settings and taking into
account the responsibilities of a social model;
To ask for an anamnesis of current and past exposure to alcohol and active and
passive smoking and its intensity and duration, among other risk factors;
To record the responses on the medical record and give priority to high-risk
patients;
To determine possible complications related to these risk factors, taking advantage
of the opportunity to express professional concern regarding the consequences
inherent in abuse;
To recommend smoking and alcohol cessation as well as necessary measures to
prevent consequential damage via passive exposure of the individual and that of
bystanders;
To provide necessary support to the patient by monitoring the abandonment process using counseling strategies and techniques;
To keep themselves updated on existing therapeutic resources, prescribing these
therapies, or referring the patient to skilled professionals and services;
To cooperate with community activities and control campaigns.
With Regard to Both Risk Factors, Particular Attention Should Be Paid
to the Following High-Risk Groups
Children and the young, due to organic fragility and increased susceptibility to
injury and dependence;
Adolescents, due to the psychological characteristics of rebellion, experimentation irrespective of risk, and frequent anxiety in the discovery of new stages of
adulthood, leading them to pursue reward;
Pregnant women, due to the increased risk of damage to fetal development;
Women using birth control with a potential risk of thromboembolism;
Patients exposed to other risk factors;
Patients with heart disease or patients with other chronic diseases;
Patients belonging to socially marginalized groups;
Patients with other psychological problems or mental illness (both smoking and
alcoholism may be classied as mental disorders).
Summary Data on the Magnitude of the Problem and Trends

In 2005, the average annual consumption of pure alcohol per capita per year was
estimated at 6.13 L in the population aged 15 or older, which includes approximately two billion people. In Brazil, approximately 52 % of people aged 18 and
44
A.C. Achutti
older use alcohol at least once a year. This abuse is excessive in 28 % of cases,
harmful in 3 % of cases, and dependency occurs in 9 % of cases [8].
According to the WHO criteria, for men, an intake of over 21 units of 10 g
of alcohol per week is considered excessive. For women, this limit is reduced to
14 units.
A glass of wine on average is equivalent to one unit, spirits are twice that amount,
and beer (a 350 mL can) is approximately one and a half units.
It should also be noted that approximately 3.8 % of all deaths from all causes are
associated with alcohol use, as well as 4.5 % of the disability adjusted life years
(DALYS) [8].
Alcohol and tobacco abuse may be considered as indicators of ego fragility
and a chronic stress risk, which is also involved in the genesis of cardiovascular
diseases. It is possible, however, that together with biochemical mechanisms, the
moderate use of alcoholic beverages can explain the lower cardiovascular risk
observed in relation to abstinent individuals and those who drink to excess [911].
Brazil has one of the highest abusive alcohol consumption rates. The consequences can be easily observed when monitoring the news of accidents and trafc
fatalities. Young drivers under the inuence of alcohol are involved in the majority
of these deaths and in the demand for traumatology treatment. The depressant and
euphoric effects of alcohol reduce the awareness of immediate risk; therefore, driving under such conditions is equivalent to risking sudden death. Individuals who do
not take immediate risk into account do not have the sensitivity to prevent future
problems.
In addition to education and more restrictive legislation, control of advertising
and motorists conditions are essential for developing cultural awareness regarding
avoiding death or killing others due to external causes before we can move on to
other causal factors that promote cardiovascular diseases.
Cigarette consumption (the most frequent exposure method for burning tobacco)
is approximately 1200 units per year worldwide, per capita. It involves approximately 25 % of the adult population, half of whom are likely to die from problems
related to smoking and experience the loss of approximately 15 years of life. The
estimated worldwide mortality associated with smoking is six million and is just
over half a million by inhalation of passive smoke.
Brazil is a good example of the feasibility of smoking prevention. In the state of
Rio Grande do Sul, the countrys largest tobacco producer, the prevalence of smoking among men over 20 years old in the 1970s was higher than 60 %. Today, it has
dropped to less than half of that gure [12]. It takes time to have an effect on a
culture, but it is possible. The fact that our economic wealth was predicated on
something causing illness and death could have led to the guilt that gave rise to a
regional and then national awareness movement. Success was brought about initially via schoolchildren, with directed counter-propaganda, and then by a combination of organizations and activists and the law itself. The author of this article was
active at the time of these changes, both in the Department of Health and Environment
(Secretaria da Sade e do Meio Ambiente) and the Medical Association of Rio
Grande do Sul (Associao Mdica do Rio Grande do Sul). It was possible to wit-
45
ness the implementation of the rst Public Health Cardiovascular Disease Prevention
program in the country, and as a second step, it became evident that something had
to be done to control smoking as a major and preventable risk factor, despite going
against current economic state interests. One cannot fail to pay tribute to countryman Professor Mrio Rigatto (former president of the SBC) in this regard, who
recruited doctors sensitive to this subject throughout the country, as exemplied by
Professor Jos Rosemberg. Support from the WHO, PAHO, and the American
Cancer Society have been important to progress, and these initiatives have been able
to eliminate resistance and insensitivity, not only from the government but also from
scientic societies.
Astonishingly, people smoked during our conferences and the World Heart
Federation conferences and at the PAHO ofces and hospitals. A Smoke Free
Conference was declared, but the SBC General Assembly unanimously did not
adopt a declaratory motion to combat smoking until the year 2000.
To not focus solely on disease, death, and adverse outcomes, it is worth remembering the success achieved due to the joint effort of many people, typied by two
colleagues who have been fundamental to that success: Professor Antnio Pedro
Mirra of So Paulo, who has, from the beginning, advocated tobacco control within
the Brazilian Medical Association (Associao Mdica Brasileira), and Dra. Vera
Luiza da Costa e Silva, who, via the Ministry of Health, the National Cancer Institute
(Instituto Nacional do Cncer), and later, the WHO has been able to establish the
rst international treaty involving the production, processing, and trade of tobacco
products.
The nicotine in tobacco has an immediate stimulating and euphoric effect,
and alcohol has an opposite calming and depressing effect. It is likely that these
two characteristics, which to some extent are antagonistic, partially explain their
concomitant use in achieving a ne tuning of the mood.
Mass consumption and patronage have aroused many economic interests surrounding the production, processing, marketing, and commercialization of tobacco
products and alcoholic drinks.
The possibility of acquiring both alcohol and tobacco in a relatively free, culturally
accepted, and frequently glamorized manner is related to the extent of its use.
Governments have attempted to control use with tax increases in the commercialization of these products, which, however, has also made those governments dependent
on this new source of revenue.
Smokers inhale thousands of other substances when lighting a cigarette in addition to the nicotine that they crave, including carbon monoxide, which is mostly
responsible for damage to the endothelium. This is important in cardiovascular
disease. Bystander exposure to smoke (passive smoking) is also not negligible,
especially in indoor environments. Alcohol, in turn, also entails passive risk in the
form of trafc accidents and other types of violence.
Distortions resulting from misuse of the reward mechanism are frequent and not
only limited to the abuse of alcohol and nicotine. Reward can reinforce any behavior, and in general, this stimulus is accompanied by the pleasure of repetition or the
simple realization that the path was re-established (doing it again).
46
A.C. Achutti
Genetic characteristics, psychological problems, and both happy and unhappy

life experiences can make individuals more likely to stimulate the reward circuitry.
Frustration, overpopulation, urban crowding, and social conict often cause
individuals to look for an escape and follow the wrong path.
When considering phenomena on a population scale, it must be taken into
account that small deviations from normality can have a large impact if they are
very common. The tendency is to value the larger deviations observed in isolated
individuals, such as the smoker who consumes several packs of cigarettes a day, and
the stubborn drunk. The same is true of hypertension, where the highest number of
deaths and complications in a population are not associated with the most exaggerated blood pressure levels (less frequent) but those closer to normality that occur in
greater numbers. In addition, smaller deviations from normality are often accompanied by the illusion of harmlessness, allowing the accumulation of various risk
factors, with an end result that is exponential.
Biology evolves, but at a very slow pace, so the achievements made by the
various species are not lost. The reward mechanism is extremely important but vulnerable and subject to distortion if life does not evolve in the manner intended. The
abuse of this mechanism should be seen as a desperate search for compensation;
unfortunately, in this case, it has disastrous consequences. Nonetheless, alcohol and
tobacco can still be acquired without the need for trafckers (unless one includes in
this category everyone who prots from these risk factors) or a medical prescription. cultural evolution, which arises at an increasingly faster rate, prevents biological adjustments from occurring. Meanwhile, nature possibly responds by selectively
eliminating those who cannot nd the healthiest path [1316].
It is up to doctors to guide better choices.
This text was completed when (December 11, 2013) the LENAD IINational
Survey on Alcohol and Drugs data were released [1719]. The INPAD (National
Institute of Public Policies on Alcohol and Other DrugsInstituto Nacional de
Polticas Pblicas do lcool e Outras Drogas) and UNIFESP (Federal University of
So PauloUniversidade Federal de So Paulo), funded by the CNPq (National
Council for Scientic and Technological DevelopmentConselho Nacional de
Desenvolvimento Cientco e Tecnolgico) and by the State of So Paulo Research
Foundation (Fundao de Amparo Pesquisa do Estado de So PauloFAPESP),
developed their rst survey in 2006. The second was performed in 2012 and gathered
information on the consumption of alcohol and tobacco to produce a trend analysis.
All phenomena of population dimensions are dynamic and vary over time. They
are impacted not only by economic, cultural, and historical inuences but also by
the results of public health intervention programs and individual professional educative action within the doctor-patient relationship. It is therefore important to add
recent information to keep the professional perspective current and also to evaluate
the effectiveness of interventions that, hopefully, will show favorable trends in other
research and future studies. Cardiologists may not work directly in public health
organizations, but using epidemiological data, they can maintain a vision of what
demands them in their practice and the hospital. They will no doubt see that the
concentration of alcoholics and smokers will be higher due to the risks to which
47
they have been exposed. More details can be obtained by accessing the constantly
updated electronic addresses of the references.
A total of 4607 individuals aged 14 and older were interviewed in their homes in
the last phase of LENADs random probability sampling, which is representative of
the Brazilian population.
INPADs mission is to coordinate a set of actions of a preventive nature, including care, research, and community and public interventions, that will contribute to
the denition of policies concerning dependency control and the harmful use of
alcohol and other drugs in Brazil.
Regarding alcohol consumption, an increase was observed between 2006 and
2012, particularly in frequent drinkers (one or more times per week), from 45 to
54 %, especially among women (from 29 % in 2006 to 39 % in 2012). Two out of
10 drinkers do so in a harmful manner, as abusive or dependent drinkers.
Regarding smoking, the data indicate a reduction in prevalence of 20 % (from
19.3 to 15.6 %) between 2006 and 2012; the largest reduction was among adolescents (from 6.2 to 3.4 %). The study estimated the total number of smokers in the
country at 40 million, with 70 million passive smokers (taking into account an average of 4.5 people per smokers household).
The prevalence was reduced among men, but it is still higher than in women.
The southern region has the largest proportion of smokers, but there was a greater
decrease in prevalence in this region. Across the country, the average number of
cigarettes smoked per day by smokers increased from 12.9 to 14.1, likely due to the
effect of selection, with the overall decline in prevalence resulting from those who
smoke more and who have a greater degree of dependency remaining in the sample.
The number of former smokers is approximately 11.3 % of the population [20].
References
1. Achutti A, Lantieri CJ, Issa JS, Ismael SC, Alencar Filho AC. Diretriz da SBC Tabagismo.
No prelo. http://publicacoes.cardiol.br/consenso/.
2. Duncan BB, Schmidt MI, Giuliani ERJ, Duncan MS, Giugliani C. Medicina Ambulatorial:
condutas de ateno primria baseadas em evidncias. 4a edio. Captulo LX sobre tabagismo por Juliana DP dos Santos, Aloyzio Achutti e Paula Guths. Captulo LXI Problemas
relacionados ao consumo de lcool, por Mauro Soibelman, Thiago BM Rocha e Lisia von Die
men. Porto Alegre: Artmed, 2013.
3. Medicina Ambulatorial: http://www.grupoa.com.br/uploads/imagensExtra/legado/D/DUNCAN_
Bruce_B/Medicina_Ambulatorial_4Ed/Lib/hot/ref/05/Cap_60.pdf.
4. Medicina Ambulatorial: http://www.grupoa.com.br/uploads/imagensExtra/legado/D/DUNCAN_
Bruce_B/Medicina_Ambulatorial_4Ed/Lib/hot/ref/05/Cap_61.pdf.
5. WHO report on the global tobacco epidemic, 2013. http://www.who.int/tobacco/global_
report/2013/en/index.html.
6. WHO Global Status Report on Alcohol and Health 2011 http://www.who.int/substance_
abuse/publications/global_alcohol_report/en/index.html http://wwwwho.int/substance_abuse/
publications/global_alco hol_report/msbgsruproles.pdf.
7. Jabbour SK, Reddy S, Muna WFT, Achutti A. Cardio vascular disease and the global tobacco
epidemic: a wake-up call for cardiologists. Int J Cardiol. 2002;86(23):18592.
48
A.C. Achutti
8. World Heart Federation Cardiovascular Diseases Risk Factors: Alcohol. http://www.world-heartfederation.org/cardiovascular-health/cardiovascular-disease-risk-factors/diet/.

9. World Heart Federation code of practice on tobacco control. Genebra, 2004. http://www.
world-heart-federation.org/leadmin/user_upload/documents/ tobacco-code-practice.pdf. Accessed 02/07/2013.
10. WHO: Fact sheet N 339 on Tobacco (Updated July 2013) http://www.who.int/mediacentre/
factsheets/fs339/en/index.html.
11. American Heart Association; Alcoholic Beverages and Cardiovascular Disease: http://www.
heart.org/HEARTORG/GettingHealthy/NutritionCenter/Alcoholic-Beverages-andCardiovascular-Disease_UCM_305864_Article.jsp.
12. Achutti A, Achutti VR. Fatores de risco para atero sclerose. Elementos para Descrio da
Situao no Rio Grande do Sul. Arq Bras Cardiol. 1994;63:42731 http://www.arquivosonline.
com.br/pesquisartigos/Pdfs/1994/V63N5/63050017.pdf.
13. Ministrio da Sade amplia acesso a tratamentos para deixar de fumar (Portal da Sade)
http://www2.inca.gov.br/wps/wcm/connect/agencianoticias/site/home/noticias/2013/
atualizada_diretrizes_atendimento_tabagista.
14. Surgeon Generals Report on Smoking and Health 1992: http://www.cdc.gov/mmwr/preview/
mmwrhtml/00016297.htm.
15. Surgeon General Report Preventing Tobacco Use Among Youth and Young Adults 2012 http://
www.surgeongeneral.gov/library/reports/preventing-youth-tobacco-use/full-report.pdf.
16. CDC: Alcohol and Public Health http://www.cdc.gov/alcohol/.
17. UNIFESP, CNPq, FAPESP: II LENAD Levantamento Nacional sobre Alcool e Drogas.
http://inpad.org.br/.
18. http://inpad.org.br/wp-content/uploads/2013/12/Press LENAD_Tabaco.pdf.
19. http://inpad.org.br/wp-content/uploads/2013/04/LENAD_PressRelease_Alcohol_RVW.pdf.
20. http://inpad.org.br/wp-content/uploads/2013/12/Resultados_Preliminares_Tabaco.pdf.
Physical Inactivity: Preventable Risk Factor

of Cardiovascular Disease
Evangelista Rocha
Acronyms/Abbreviations
ACSM
AHA
BSC
CABG
CDC
CHD
CR
CVDs
DALYs
ESC
HF
LTPA
METs
MI
NCDs
NIH
PA
PCI
RC
USA
WHO
YLL
American College of Sports Medicine

American Heart Association
Brazilian Society of Cardiology
Coronary artery bypass graft
Centers for Disease Control and Prevention
Coronary heart disease
Exercise-based cardiac rehabilitation/cardiac rehabilitation
Cardiovascular diseases
Disability adjusted life years
European Society of Cardiology
Heart failure
Leisure time physical activity
Metabolic equivalents
Myocardial infarction
Non-communicable diseases
National Institutes of Health
Physical activity
Percutaneous transluminal coronary angioplasty
Rehabilitation Centers
United States of America
World Health Organization
Years of life lost
E. Rocha, M.D., Ph.D. (*)

Faculty of Medicine, Institute of Preventive Medicine and Public Health,
University of Lisbon, Lisbon, Portugal
e-mail: evangelistarocha@hotmail.com
DOI 10.1007/978-3-319-22357-5_6
49
50
E. Rocha
Introduction
A sedentary behavior is one of the major risk factors for cardiovascular diseases
(CVDs). Regular physical activity (PA) and aerobic exercise training are related to a
reduced risk of fatal and non fatal cardiovascular events in healthy individuals, in high
risk individuals (subjects with hypertension, glucose intolerance/diabetes, dyslipidemia,
overweight/obesity), and cardiac patients. It is a very important non-pharmacological
tool for primary and secondary cardiovascular prevention [1]. Moreover, there is substantial evidence that physical inactivity is a major contributor to death and disability
from CVDs and other non-communicable diseases (NCDs) worldwide, identied by
the United Nations as threats to global health (diabetes, breast and colon cancer). This
modiable lifestyle has been identied as the fourth leading risk factor for global mortality, causing an estimated 3.2 million deaths globally, and the main cause for approximately 30 % of ischemic heart disease burden [2].
By the 1990s, health care agencies and organizations have issued position statements regarding benets and recommendations on PA for health (CDC, AHA, NIH,
Surgeon General, ACSM, WHO, ESC, BSC and other medical societies and national
healthcare authorities worldwide). Notwithstanding scientic knowledge outlining
the benets of exercise both for primary and secondary cardiovascular prevention,
the society and patients with known CVDs remain sedentary [3]. In view of the
prevalence and distribution, and health effects with cardiovascular and global
impact (mortality, YLLs and DALYs lost), physical inactivity should be addressed
as pandemic and a public health challenge [4]. Although the global ght against
CVDs has been very successful, due to the growing prevalence of metabolic disorders such as obesity and diabetes, poor exercise regimens, high fat and sugar diets,
alcohol and tobacco consumption, especially in the younger population, and the
ageing population, the incidence of atherosclerosis-related CVDs is expected to
increase in future. It means that CVDs should remain by far the leading cause of
death. It urges to take effective preventive interventions (healthful diet and PA) to
ght against the expected increase in CVDs, particularly coronary heart disease
(CHD) whose reduction was responsible for the largest increase in life expectancy
between 1970 and 2000 [5]. It has been estimated that elimination of physical
inactivity would increase the life expectancy of the worlds population by 0.68
(0.410.95) years [6].
Mechanisms
The evidence that a sedentary lifestyle leads to CHD, and particularly myocardial
infarction (MI) or sudden death, is based on observational studies in the general
population and in specic groups, on experimental studies that compare a sedentary
group with one doing more exercise. There is evidence that regular PA, together
with other risk reduction behaviors, can help prevent rst cardiac and stroke events,
Physical Inactivity: Preventable Risk Factor of Cardiovascular Disease
51
reduces the risk of their recurrence and helps patients recover after MI, surgical
revascularization or coronary angioplasty (PCI). In relation to CHD, biological
mechanisms have been identied through which PA and exercise training may contribute to primary and secondary prevention: it maintains or increases myocardial
oxygen supply, decreases myocardial work and reduces cardiac work and oxygen
demand, increases myocardial function and electrical stability of myocardium by a
favorable modulation of autonomic balanceinduces ischemic pre-conditioning of
the myocardium, increasing their tolerance to more ischemic stress. The underlying
cardioprotective mechanisms involve changes in the coronary arteries, myocardial
heat shock proteins and cyclooxygenase-2 activity, endoplasmic reticulum stress
proteins, nitric oxide, sarcolemmal and/or mitochondrial adenosine triphosphate
(ATP)-sensitive potassium channels and myocardial antioxidant capacity, antioxidant enzymes, mitochondrial phenotype that protect against apoptotic stimuli [7].
At another level, PA has a positive effect on established risk factors for CVDs, leading
to improvements in blood pressure, glucose intolerance, diabetes, dyslipidemia, and
obesity. Specically, it helps to control body weight, prevents or delays the development of hypertension in normotensive subjects and reduces blood pressure in hypertensive patients, improves lipoprotein proleincreases HDL cholesterol levels,
improves carbohydrate metabolism, the bodys use of insulinlowering the risk of
developing type 2 diabetes mellitus, particularly in those at high risk of diabetes,
improves glycemic control and reduces type 2 diabetes medications and increases
exercise capacity [1, 8]. In short, antiatherogenic effects of PA and exercise training
are well documented by changes on the body fat mass, lipoprotein metabolism,
carbohydrate intolerance, regression of coronary lesions, vascular reactivity and
structure, and neurohormonal modulation [9].
Physical Inactivity and Cardiovascular Risk

The rst studies to examine the relationship between CHD and PA were based on
occupational activities. It all began with the Morriss landmark study, the rst rigorous epidemiological study in the eld of PA, showing that men in physically
demanding occupations (bus conductors and postmen) had a signicantly lower risk
of heart disease than individuals who worked in less demanding jobs (bus drivers
and ofce workers). Since then, many investigations have focused on occupational
activity and leisure-time physical activity (LTPA), although with different qualitative and quantitative assessments. The procedures to assessing PA in epidemiological research are critical both for understanding the relation between PA, or opposite
physical inactivity, and measures of health as for comparability of data around the
world. Nevertheless, the research to date has been consistent and compelling: regular PA reduces markedly the risk for CVDs and has other documented benets.
Indeed, there is strong evidence that PA is associated with healthier body mass and
composition, increased cardio-respiratory tness, reduced rates of high blood pressure, metabolic syndrome, type 2 diabetes, CHD, and stroke [2, 10].
52
E. Rocha
Worldwide, the relative risk (95 % CI) associated with physical inactivity,
activity level insufcient to meet WHO recommendations [2], adjusted for confounders, for incidence of CHD and diabetes is, respectively, 1.16 (1.041.30) and
1.20 (1.101.33) [6]. These numbers are consistent with ndings from INTERHEART
study, a casecontrol study conducted in 52 countries throughout Africa, Asia,
Australia, Europe, Middle East, and North and South America, in which the adjusted
OR for MI associated with physical inactivity was 1.16 (1.031.32) [11].
Numerous reviews or meta-analyses strengthened the evidence that PA has an
independent role in primary prevention of CHD, with a 2030 % lower risk of CHD
[10]. A meta-analysis of prospective cohort studies of occupational and LTPA and
CVDs (CHD and stroke), with follow-up 5 years, exploring the doseresponse
relationship, shows that high level of LTPA and moderate level of occupational PA
reduces the risk of incidental events of CHD and stroke among men and women by
2030 % and 1020 %, respectively [12]. On the other hand, the reduction in risk of
all-cause and cardiovascular mortality derived from systematic review is signicant,
3040 % [10] to 2030 % [1], with a stronger doseresponse gradient for tness
than for PA [13]. Fitness has direct doseresponse relations between intensity, frequency, duration and volume for CVDs and CHD. The weaker relation of PA than
cardiorespiratory tness with health benet may result from bias in the measurement method (objectively versus self-reports) and resultant misclassication. The
procedures to assessing PA in epidemiological research are critical both for understanding the relation between PA, or opposite physical inactivity, and measures of
health as for comparability of data around the world. Recent technological advances
(accelerometers and heart rate monitors) will increase in the future the accuracy of
the PA assessment.
The-Lancet-Series-Physical-Activity highlights global burden of physical inactivity
and suggests that its responsible for 5.8 % of the burden of CHD worldwide, ranging
from 3.2 % in Southeast Asia to 7.8 % in the Eastern Mediterranean. In addition, physical inactivity accounts for 11.9 % of the burden of CHD in the Cook Islands and Malta,
11.4 % in Swaziland and Saudi Arabia, 11.3 % in Argentina, 10.5 % in the UK, 6.7 %
in the US, and 5.6 % in Canada. Similarly, the burden of diabetes attributable to physical inactivity is 7.2 % worldwide, ranging from 3.9 % in Southeast Asia to 9.6 % in the
Eastern Mediterranean [6].
Dose Response Between Physical Activity and Risk Of CVDs

In the meta-analysis which quantied the amount of PA in relation with the magnitude of benet to CHD risk, individuals who engaged in the equivalent of 150 min/
week of moderate-intensity LTPA had a 14 % lower CHD risk (RR 0.86; 95 %CI
0.770.96) compared with those without LTPA. Those engaged in the equivalent of
300 min/week had a 20 % lower risk (RR 0.80; 95 % CI 0.740.88). At higher levels
of PA, RRs were modestly lower, while people physically active but at levels
lower than the minimum recommended had signicant lower risk of CHD.
53
This association was stronger among women than men [14]. Some PA is better
than none. Other authors concluded that risk reductions routinely occur at levels of
150 min/week of at least moderate-intensity activity [2]. Specifying, the benets of
moderate-intensity PA or aerobic exercise training (common daily activities and
sport-related activities) in all-cause and cardiovascular mortality ranges from 2.5 to
5 h/week [10] equivalent to perform 11.5 h/week of vigorous-intensity PA/aerobic
exercise training. A moderate-intensity PA is an activity performed at 4059 % of
VO2 or at a rate of perceived exertion of 56 in the Borg CR 10 scale and a absolute
energy expenditure of 4.87.1 METs (1 MET = 3.5 ml/min/kg) in the young, 4.05.9
METs in the middle-aged, 3.24.7 METs in the old, and 2.02.9 METS in the very
old [15]. These results support European and American guidelines on physical
activity [1, 10].
Patients with Known CVDs

In patients with documented CVDs, men and women referred to specialized preventive centers/exercise-based cardiac rehabilitation (CR), cardiac available research is
based in cardiovascular tness measurements. However, the effects of exercise
alone in cardiovascular risk is not easily discernible because CR represent more
than an exercise program. It includes components that aim risk reduction, healthy
behaviors, reduce disability, and promote an active lifestyle for patients. The effectiveness of exercise only or exercise as part of a comprehensive CR has been
measured in a systematic review, searching electronic databases of randomised controlled trials, with men and women of all ages, in hospital or community settings,
who have had MI, coronary artery bypass graft (CABG) or PCI, or who have angina
pectoris or CHD dened by angiography. The estimated pool effect for total mortality for the exercise alone intervention shows a 27 % reduction in all cause mortality
(OR 0.73; 95 % CI 0.540.98) and 31 % reduction in total cardiac mortality (OR
0.69; 95 % CI 0.510.94). Neither intervention had any effect on the occurrence of
non-fatal MI [16]. A systematic review of 47 studies randomising 10,794 patients to
exercise-based CR or usual care, predominantly male, middle aged and low risk,
following MI, PCI, CABG, or who had known CHD showed in medium to longer
term (12 or more months follow-up) a 26 % reduction in cardiovascular mortality, a
13 % reduction in all-cause mortality, and a 31 % reduction in hospital admissions
in the shorter term (<12 months follow-up). Exercise-based CR was not effective in
reducing total MI or revascularization (CABG or PCI) [17]. Nevertheless, in the
GOSPEL study, a continued reinforced intervention up to 3 years after CR following MI was effective in decreasing the risk of cardiovascular outcomes: cardiovascular mortality, nonfatal infarction, although the overall effect is small, and nonfatal
stroke, and cardiac death and nonfatal infarction.
CR has a well-documented scientic evidence of beneting patients with CHD
but the research in preventive cardiology over the last years has fostered the evolution of CR programmes. The role of exercise training has been evaluated in clinical
54
E. Rocha
trials involving patients with heart failure (HF), diabetes, peripheral arterial disease
(PAD), pulmonary arterial hypertension, and congenital heart disease [18].
Even though the wealth of evidence supporting the scientic statements and
guidelines directed toward increasing referral and participation rates for CR, the
underutilization of CR is general worldwide. Recent surveys in USA reported referrals in the order of 20 %, averaging between 10 % and 30 % [19], and in Europe
fewer than half of eligible cardiovascular patients are advised to follow cardiac
prevention or rehabilitation programme [3, 20]. Beside, the enrollment rate varied
greatly between countries, e.g., in Portugal is less than 4 % [21]. So why isnt there
greater participation and referral for CR? Some of the reasons are identied (coverage and resources for outpatient CR services, lack of accessibility to formal
programs, etc.).
Effectiveness of Interventions to Promote Physical Activity

Heath and colleagues did a systematic review of reviews of representative studies of
PA interventions in children, adolescents, or adults without established disease, published in the last decade, evaluating the effectiveness of approaches to increase PA
according to domains established by the Guide to Community Preventive Services
[22]. In the domain of campaigns and informational approaches, were effective:
mass media campaigns and links to community programming (e.g., the VERB campaign targeted tweens in USA); messages about PA at key community sites (workplaces, centers for senior citizens, and community centers) to inform, instruct
and motivate people, developed in Brazil and Latin America; point-of-decision
prompts, using specic signage (use stairs); community-wide campaigns (using
multicomponent, multisector, and multisite interventions), directed mainly to specic populations, in countries of middle to high income (e.g., the Stanford heart
disease prevention programme) [23]. In behavioral and social approaches, the
interventions can be individually adapted through a health provider, the formation of
walking or other PA support groups, and community-based supervised intervention
(community PA classes). Brazil is an example of a country of effective policyapproaches to promote PA, wherein the central role was played by the local, regional
and national governments, with important strategies for reducing health disparities
among vulnerable populations such as older adults, women and low-income individuals. First, Brazilian government funded community interventions to promote
PA, particularly PA classes in community settings, in more than 1000 cities.
The success of this programme led to their integration into the national plan to tackle
NCDs, in partnership with the CDC (economic and technical support) and universities in Brazil and USA as well as other countries in Latin America (Mexico, Chile,
Colombia). The progress and evidence lent support to the launch of the Health
Academy programme, integrated in primary care. The objective is to overcome
structural barriers to PA, especially among vulnerable populations. The program
offers physical activity classes (e.g., aerobics, yoga, tai chi, dance, stretching) and it
55
is expected that this intervention will benet 4000 municipalities by 2015 [24, 25].
Various studies in middle-income and high-income countries have shown that
school-based interventions reduce CVDs risk factors. Enhanced reporting of external validity elements will inform the translation of research into practice [26].
Concerning policy and environmental approaches, were effective: provision of
tness zone equipment (e.g., 12 parks in Los Angeles); urban environments friendly
to pedestrians (undertaken in the USA, Canada and outside North America); urban
environment improvements based in redesigning of streets and pavements, creation
of bike lanes and paths; travel interventions to increase active transport; communitywide policies to promote PA in conjunction with information (e.g., Ciclovias also
known as open streets initiatives, a program that started in Bogota and had many
replications in the Americas) [22].
Physical Inactivity Prevalence

To estimate PA levels internationally, surveys were carried using the validated
International PA Questionnaire (IPAQ) and the same dimensions and concepts of
physical inactivity. According to the pooled analysis of studies conducted between
2002 and 2004 in 76 countries, the crude worldwide prevalence of physical inactivity was 21.4 % (23.7 % among women and 18.9 % among men), ranging from 2.6 %
(in Comoros) to 62.3 % (Mauritania). There was a positive association between
human development index and prevalence of physical inactivity [27].
The Lancet PA Series Working Group describe PA levels worldwide with data
for adults (15 years or older) from 122 countries and for adolescents (1315 years
old) from 105 countries. Worldwide, 31.1 % (95 % CI: 30.931.2) of adults are
physically inactive, with proportions ranging from 17.0 % (16.817.2) in southeast
Asia to about 43 % in the Americas and the eastern Mediterranean. Inactivity rises
with age, and women are more inactive (34 %) than men (28 %) and is increased
in high-income countries. The frequency of inactivity varied greatly between WHO
regions: 27.5 % in Africa, 43.3 % in the Americas, 43.2 % in the eastern
Mediterranean, 34.8 % in Europe, 17 % in southeast Asia, and 33.7 % in the western
Pacic. Larger differences exist between countries, e.g., the proportion of inactive
individuals of both sexes was 4.7 % in Bangladesh and 71.9 % in Malta. The proportion of 1315 year olds doing fewer than 60 min of PA of moderate to vigorous
intensity per day is 80.3 % (80.180.5); boys are more active than girls. Continued
improvement in monitoring of PA will help to guide development of policies and
programmes to increase activity levels and to reduce the burden of NCDs [4].
Physical inactivity, in view of the prevalence, health effects, economic, environmental, and social consequences has been identied as one of the biggest public
health problem of the twenty-rst century [28]. In spite of the robust evidence, there
is a huge discrepancy between the importance of maintaining regular PA throughout
life and practice in public health, missing translation of knowledge into action.
56
E. Rocha
Physical Activity Challenges

Physical activity is not a panacea but a very important tool in the prevention of
CVDs or to delay its manifestation, and due to other health benets integrates
Global Action Plan on NCDs [29]. Its a need to nd solutions to overcome
common barriers to increase physical activity/tness:
Personal: lack of time; lack of energy; lack of resources; fear of injury; lack of
family support; lack of skill; lack of self-motivation; low self-efcacy; etc.
Doctors and healthcare authorities/governments: undervalued prescription of
PA and not address physical inactivity as a public health prioritya neglected
dimension of prevention.
Approaches to increase physical activity: For a number of reasons, existing
approaches to mobilize large segments of the population to do even minimal
levels of PA are just not working or have a small effect. The PA must be done by
the individual but, as the review of reviews shows, efforts beyond the health sector through social and environmental change will be necessary to see greater
uptake of this health behavior in peoples lives. Probably there is a need to rethink
our approach to PA with the perspective that its a cultural challenge [30]
Research to dene whether: prognostic gains can be achieved with less (duration/intensity) PA, in groups that are not able to meet the recommendations
(elderly, patients with advanced chronic HF); the doseresponse relationship
between cardiorespiratory tness and reduction in cardiovascular risk observed
in primary prevention also holds in the secondary prevention setting; regular PA
yields a long-term prognostic gain in patients with chronic HF; high-intensity
interval training is superior to moderate-intensity continuous training in improving functional capacity and inducing favourable left ventricular remodelling in
chronic HF patient [1].
References
1. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, et al. European guidelines
on cardiovascular disease prevention in clinical practice: fth joint task force of European and
other societies on cardiovascular disease prevention in clinical practice. Eur Heart J. 2012;
33(13):1635701.
2. WHO. Global recommendations on physical activity for health. Geneva: World Health
Organization; 2010.
3. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U. EUROASPIRE III: a
survey on the lifestyle, risk factors and use of cardioprotective drug therapies in coronary
patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16:12137.
4. Hallal PC, Andersen LB, Bull FC, Guthold R, Haskell W, Ekelund U, Lancet Physical Activity
Series Working Group. Global physical activity levels: surveillance progress, pitfalls, and
prospects. Lancet. 2012;380:24757.
5. Lenfant C. Clinical research to clinical practice-lost in translation? N Engl J Med. 2003;
349:86874.
57
6. Lee I-M, Shiroma EJ, Lobelo F, Puska P, Blair SN, Katzmarzyk PT, Lancet Physical Activity
Series Working Group. Effect of physical inactivity on major non-communicable diseases
worldwide: an analysis of burden of disease and life expectancy. Lancet. 2012;380:21929.
www.thelancet.com. Physical Activity. July 2012.
7. Kavazis AN. Exercise preconditioning of the myocardium. Sports Med. 2009;39:92335.
8. Marwick TH, Hordern MD, Miller T, Chyun DA, Bertoni AG, Blumenthal RS, et al., On
behalf of the American Heart Association Exercise, Cardiac Rehabilitation, and Prevention
Committee of the Council on Clinical Cardiology; Council on Cardiovascular Disease in the
Young; Council on Cardiovascular Nursing; Council on Nutrition, Physical Activity, and
Metabolism; Interdisciplinary Council on Quality of Care and Outcomes Research. Exercise
training for type 2 diabetes mellitus. Circulation 2009;119(25):324462.
9. Niebauer J, Cooke JP. Cardiovascular effects of exercise: role of endothelial shear stress. J Am
Coll Cardiol. 1996;28:165260.
10. US Department of Health and Human Services. Physical Activity Guidelines for Americans.
2008. http://www.health.gov/paguidelines/pdf/paguide.pdf.
11. Yusuf S, Hawken S, unpuu S, Dans T, Avezum A, Lanas F, et al. On behalf of the
INTERHEART Study Investigators. Effect of potentially modiable risk factors associated
with myocardial infarction in 52 countries (the INTERHEART study): casecontrol study.
Lancet. 2004;364(9438):93752.
12. Li J, Siegrist J. Int J Environ Res Public Health. 2012;9(2):391407.
13. Williams PT. Physical tness and activity as separate heart disease risk factors: a metaanalysis. Med Sci Sports Exerc. 2001;33:75461.
14. Sattelmair J, Pertman J, Ding EL, Kohl III HW, Haskell W, Lee I-M. Dose response between
physical activity and risk of coronary heart disease a meta-analysis. Circulation. 2011;
124:78995.
15. Kodama S, Saito K, Tanaka S, Maki M, Yachi Y, Asumi M, et al. Cardiorespiratory tness as
a quantitative predictor of all-cause mortality and cardiovascular events in healthy men and
women: a meta-analysis. JAMA. 2009;301(19):202435.
16. Jolliffe JA, Rees K, Taylor RS, Thompson D, Oldridge N, Ebrahim S. Exercise-based rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2001;1:CD001800.
17. Heran BS, Chen JM, Ebrahim S, Moxham T, Oldridge N, Rees K, et al. Exercise-based cardiac
rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2011;7:CD001800.
18. Kwan G, Balady GJ. Cardiac rehabilitation-advancing the eld through emerging science.
Circulation. 2012;125(7):e36973.
19. Boyden T, Rubenre M, Franklin B. Will increasing referral to cardiac rehabilitation improve
participation? Prev Cardiol. 2010;13:198202.
20. Bjarnason-Wehrensa B, McGeeb H, Zwislerc A-D, Piepolid MF, Benzere W, Schmidf J-P,
et al. on behalf of the Cardiac Rehabilitation Section European Association of Cardiovascular
Prevention and Rehabilitation. Cardiac rehabilitation in Europe: results from the European
Cardiac Rehabilitation Inventory Survey. Eur J Cardiovasc Prev Rehabil. 2010;17:4108.
21. Abreu A, Bettencourt N, Fontes P. Overview of cardiac rehabilitation in Portugal 20072009.
Rev Port Cardiol. 2010;29:5458.
22. Heath GW, Parra DC, Sarmiento OL, Andersen LB, Owen N, Goenka S, Lancet Physical
Activity Series Working Group, et al. Evidence-based intervention in physical activity: lessons
from around the world. Lancet. 2012;380(9838):27281.
23. Kahn EB, Ramsey LT, Brownson RC, Heath GW, Howze EH, Powell KE, et al. The effectiveness of interventions to increase physical activity: a systematic review. Am J Prev Med. 2002;
22:73107.
24. Knuth AG, Simes EJ, Reis RS, et al. Atividade Fsica no Brasil: uma reviso de evidncias
em experincias selecionadas. In: Sade M, editor. Sade Brasil 2010: uma anlise da situao
de sade e de evidncias selecionadas de impacto de aes de vigilncia em sade. Brasilia:
Brazilian Ministry of Health; 2011.
58
E. Rocha
25. Hoehner CM, Ribeiro IC, Parra DC, Reis RS, Azevedo MR, Hino AA, et al. Physical activity
interventions in Latin America: expanding and classifying the evidence. Am J Prev Med.
2013;44(3):e3140. doi:10.1016/j.amepre.2012.10.026.
26. Malta DC, Silva JB. Policies to promote physical activity in Brazil. Lancet. 2012;380:1956.
27. Dumith SC, Hallal PC, Reis RS, Kohl III HW. World prevalence of physical inactivity and its
association with human development index in 76 countries. Prev Med. 2011;53:248.
28. Blair SN. Physical inactivity: the biggest public health problem of the 21st century. Br J Sports
Med. 2009;43:12.
29. 66th World Health Assembly in May 2013. NCD Action Plan 20132020: Final Draft of the
Global NCD Action Plan 20132020.
30. Das P, Horton R. Rethinking our approach to physical activity. Lancet. 2012;380(9838):
18990.
Diet and Cardiovascular Health: Global

Challenges and Opportunities
Cheryl A.M. Anderson and Amanda R. Ratigan
Introduction
A healthy diet is the cornerstone of cardiovascular health, and individual behavior
and environmental level factors work together to inuence healthful dietary intake.
Across the world, correlations can be seen between cardiovascular health and
healthful food environments. Further, evidence from a large body of research studies shows that dietary intake is related to risk factors for cardiovascular disease and
stroke [1]. One framework for thinking about dietary intake is the socioecological
model which shows the dynamic inter-relations among various personal and environmental factors (Fig. 1) [2]. This framework for prevention highlights the complex
interplay amongst multiple levels of factors that inuence public health problems.
Individual level factors include genetics, sex, age, education, race, ethnicity, culture, socioeconomic status, health behavior, and occupation. Relationship factors
include family, peers, intimate partners, religious and social groups. Community
factors include neighborhood, schools, workplace, and geographical placement.
Societal factors include health care system, educational and economic policies,
politics, justice system, and the natural and built environment. All of these factors
must be considered in efforts to promote diets for optimal cardiovascular health.
Dietary intake across the world is inuenced by the level of modernization of the
society, and many populations are experiencing changes in diet that often do not
support the current recommendations for cardiovascular health. Currently, some
parts of the world struggle with the adverse impacts on cardiovascular health that
accompany modernization while other parts of the world are experiencing an epidemiologic transition (Table 1) [3]. To enhance success, public health efforts that are
C.A.M. Anderson (*) A.R. Ratigan

Department of Family and Preventive Medicine, University of California San Diego,
9500 Gilman Drive, MC 0725, La Jolla, CA 92093-0725, USA
e-mail: c1anderson@ucsd.edu; ajrondin@ucsd.edu
DOI 10.1007/978-3-319-22357-5_7
59
60
C.A.M. Anderson and A.R. Ratigan
Community
Societal
Relationship
Individual
Fig. 1 The socio-ecological model showing the complex interplay amongst multiple levels of
factors that inuence public health problems. Figure adapted from: Dahlberg LL, Krug EG.
Violence a global public health problem
Table 1 Stages of the epidemiologic transition

Stage 1
Stage 2
Stage 3
Stage 4
Malnutrition and infectious diseases are the leading causes of mortality and
morbidity
Improved nutrition and public health leads to increase in non-communicable
diseases (NCDs)
Increased fat and caloric intake, widespread tobacco use, NCD deaths surpass
deaths from infections and malnutrition
CVD and cancer are the leading causes of morbidity and mortality; primary
and secondary prevention efforts lead to declines in age-adjusted CVD
devoted to optimizing cardiovascular health should evaluate and recognize nutrition

and activity changes that occur with epidemiologic transitions. For example, regions
that have diets that are high in complex carbohydrates and ber may change to more
varied diets with higher proportions of fat, saturated fats and sugars. This could be
related to the introduction of western foods that are less healthy and these foods
replacing more healthful, traditional foods.
In this chapter, we discuss how healthful dietary patterns and various components of the diet can promote or interfere with optimal cardiovascular health,
emphasizing global challenges and opportunities.
Dietary Patterns
Dietary patterns can be dened as combinations of foods and nutrients that are typically eaten together. Dietary patterns are gaining popularity because of a growing
body of research on patterns, and increased recognition that we do not eat foods or
nutrients in isolation. Although dietary patterns vary across the world, there are
commonalities amongst them that are related to cardiovascular health. At the heart
of the current lifestyle recommendations from the American Heart Association/
Diet and Cardiovascular Health: Global Challenges and Opportunities
61
Table 2 Lifestyle recommendations about blood pressure and LDL-cholesterol from the AHA/
ACC for individuals
Advise adults who would benefit from blood pressure lowering to:
1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains;
includes low-fat dairy products, poultry, sh, legumes, non-tropical vegetable oils and nuts;
and limits intake of sweets, sugar-sweetened beverages and red meats.
(a) Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food
preferences, and nutrition therapy for other medical conditions (including diabetes
mellitus).
(b) Achieve this pattern by following plans such as the DASH dietary pattern, the USDA food
pattern, or the AHA diet.
2. Lower sodium intake.
3. Advise adults to consume no more than 2400 mg of sodium/day and that a further reduction
of sodium intake to 1500 mg/day can result in even greater reduction in BP. Even without
achieving these goals, reducing sodium intake by at least 1000 mg/day lowers BP.
4. Combine the DASH dietary pattern with lower sodium intake.
Advise adults who would benefit from LDL-cholesterol lowering to:
1. Consume a dietary pattern that emphasizes intake of vegetables, fruits, and whole grains;
includes low-fat dairy products, poultry, sh, legumes, non-tropical vegetable oils and nuts;
and limits intake of sweets, sugar-sweetened beverages and red meats.
(a) Adapt this dietary pattern to appropriate calorie requirements, personal and cultural food
preferences, and nutrition therapy for other medical conditions (including diabetes
mellitus).
(b) Achieve this pattern by following plans such as the DASH dietary pattern, the USDA food
pattern, or the AHA diet.
2. Aim for a dietary pattern that achieves 56 % of calories from saturated fat.
3. Reduce percent of calories from saturated fat.
4. Reduce percent of calories from trans fat.
American College of Cardiology (AHA/ACC) is the recommendation to consume a

dietary pattern that emphasizes intake of vegetables, fruits, and whole grains;
includes low-fat dairy products, poultry, sh, legumes, non-tropical vegetable oils
and nuts; and limits intake of sweets, sugar-sweetened beverages and red meats
(Table 2) [4]. There are additional nutrient-specic recommendations for those with
high blood pressure and those with high LDL-cholesterol. Given the differing needs
of populations, these patterns should be adapted to appropriate calorie requirements, personal and cultural food preferences, and nutrition therapy for certain
medical conditions.
Several eating plans or patterns can be used to achieve cardiovascular health.
These include the Dietary Approaches to Stop Hypertension (DASH) dietary
pattern, the United States Department of Agriculture (USDA) Food Pattern, and
the AHA Diet. Although an overall healthful dietary pattern that is high quality is
the goal, there has been a lot of interest in various components of the diets such
as kilocalorie intake, sodium, fats and cholesterol, and carbohydrates and added
sugars.
62
Excess Kilocalorie Intake

The preponderance of readily available, inexpensive, high-kilocalorie (Calorie)
foods that do not have a lot of nutrients has landed some societies in the midst of an
obesity epidemic. For example in the United States, 33 % of adults are classied as
overweight (body mass index (BMI) of 2529.9) and 36 % are obese (BMI 30)
[5]. The American health care system is overburdened from the excess disease that
is due to obesity. While obesity is known to be independently associated with cardiovascular disease (CVD), it is also associated with decreased life expectancy, and
various comorbid conditions including hypertension, dyslipidemia, type 2 diabetes
and metabolic syndrome [6]. Remarkably, morbidity due to these conditions can be
prevented or reduced with as little as 510 % weight loss [7].
It is known that weight gain results from an energy imbalance where calories
consumed from food and beverages are greater than the bodys energy expenditure
[8]. Caloric intake and subsequent weight gain is inuenced by the quality of the
diet. Energy density is a marker of diet quality and refers to the amount of calories
per unit weight (e.g., kcal/g) of a particular food, and studies have found that diets
with high energy density signicantly contribute to increased total caloric intake,
overall BMI, and decreased nutritional quality [9].
Moreover, the habit of eating larger portions of foods and beverages is fueling
the obesity epidemic. The portion size of pre-packaged foods overwhelmingly
exceeds standards set forth by the US Food and Drug Administration (FDA) and
USDA sometimes by as much as 700 % [10]. With increased portion sizes there has
been substantial increase in calorie consumption. One experimental study found
that a 50 % increase in portion size lead to an increase in daily calorie consumption
of 25 % in women and 14 % in men, and an average increase of more than 4600 cal
over a period of 11 days [11].
Although signicant barriers exist, in order to reduce the rates of obesity, behavioral and environmental modications must be made to ensure that those who desire
to reduce total caloric intake can nd environments that provide nutrient-rich, low
energy dense food options, and smaller portion sizes.
Dietary Sodium
Evidence from around the world shows that excessive sodium intake is linked to the
epidemics of pre-hypertension, hypertension, cardiovascular disease and stroke.
In the United States, 97 % of the population consumes more than the recommended
daily sodium intake [12, 13]. Data from the National Health and Nutrition
Examination Surveys (NHANES) shows that adults 20 years and older had a median
daily sodium intake of 3371 mg excluding table salt (i.e., sodium chloride) [13].
Hypertension is the most prevalent modiable risk factor for CVD with approximately 34 % of the US adult population affected [14], and contributing to 62 % of
stroke and 49 % of coronary heart disease [15]. There is strong evidence indicating
63
a direct relationship between increased sodium consumption and elevated blood

pressure [16]. Reducing sodium consumption has been found to reduce blood pressure among individuals with and without hypertension. A meta-analysis examining
modest salt reduction on blood pressure found that among studies where participants were followed for at least 4 weeks, reducing sodium intake by 4.6 g/day
reduced systolic blood pressure by 5 mmHg and 2 mmHg among hypertensive and
normotensive cohorts, respectively [17].
In addition to being a risk factor for hypertension and its associated health consequences, evidence indicates that excess sodium intake is independently associated
with CVD. It has been estimated that a daily reduction of 3 g of sodium chloride
would result in an annual reduction of up to 120,000 new cases of CHD, 66,000 new
cases of stroke and 99,000 new cases of myocardial infarction [18]. Current dietary
guidelines recommend that individuals who would benet from blood pressure lowering should eat a healthful pattern and lower sodium intake [4], and further advise
adults to consume no more than 2400 mg of sodium/day and that a further reduction
of sodium intake to 1500 mg/day can result in even greater reduction in blood
pressure. The guidelines also emphasize that even without achieving these goals,
reducing sodium intake by at least 1000 mg/day lowers blood pressure.
Enforcing guidelines to reduce sodium consumption is challenging given that 80 %
of sodium consumption comes from prepared or processed foods sources [19]. Given
the evidence, it has been recommended that a population-level sodium reduction strategy be used, and that it includes a collaborative effort amongst food manufacturers,
food processors, and the restaurant industry [2022].
Dietary Fat and Cholesterol

Dietary fats are heterogeneous and include saturated, trans, monounsaturated and
polyunsaturated fats. Despite their diversity, for decades total fat was considered
responsible for a major burden of coronary disease, and not surprisingly, low-fat
diets were recommended for reducing CVD risk. However, more recent evidence
indicates that total fat consumption is not associated with increased risk of CVD,
but rather that its the type of fat that confers CVD risk [23]. Monounsaturated and
polyunsaturated fatty acids have been associated with both a benecial lipid prole
and decreased risk of CVD, earning the term good fats. On the other hand, saturated and trans fatty acids have been associated with unbalanced lipid proles
and an increased risk of CVD, now often referred to as bad fats. [23] Amongst a
cohort of over 80,000 women, when 5 % of energy from saturated fats and 2 % of
energy from trans fats were replaced with monounsaturated or polyunsaturated
fats, the risk of CHD decreased by approximately 50 % [23]. Furthermore, when
carbohydrates replaced 5 % of energy from saturated fat, CHD risk reduced only
10 %; but when they replaced monounsaturated or polyunsaturated, CHD risk
increased by about 17 %. Omega-3 fatty acids intake from diet and supplements has
been recommended for secondary prevention of cardiovascular disease but study
64
results have been inconsistent. A review of the literature found that omega 3 fatty
acids may reduce death from vascular diseases, but not sudden death, stroke, or
arrhythmias [24].
Dietary fat is intimately linked to cholesterol, not only because many sources
high in fat also contain cholesterol but because saturated and trans fatty acids can
lead to accelerated atherosclerosis through dyslipidemia. A meta-analysis of 60
controlled trials found that low-density lipoprotein (LDL)-cholesterol levels increased when 1 % of energy from carbohydrates were replaced with saturated or trans
fat, but decreased when replaced with monounsaturated or polyunsaturated fats,
with the largest increase seen among trans fats and the largest decrease seen among
polyunsaturated fats [25]. Additionally, saturated, monounsaturated and polyunsaturated fats slightly raised high-density lipoprotein (HDL)-cholesterol levels while
trans fats did not.
Total cholesterol level is the product of LDL-cholesterol, very low-density lipoprotein (VLDL), and HDL-cholesterol. Clinical medicine has long focused on
LDL-cholesterol as the bad cholesterol and HDL as the good cholesterol, given
multiple studies indicating that higher LDL and lower HDL levels confer increased
risk of CVD [26]. The likelihood of developing an unbalanced lipid prole, is both
a product of diet and genetic background. Dietary cholesterol intake can be lowered
by reducing intake of cholesterol-rich foods, and saturated [27, 28] and trans fats;
however there is limited and insufcient evidence to determine whether lowering
dietary cholesterol reduces LDL-C.
To improve cardiovascular health, and reduce the risk of CVD and death due to
CVD, current recommendations include eliminating trans-fatty acids completely,
reducing and substituting saturated fat with monounsaturated or polyunsaturated
fatty acid, eating cholesterol in moderation, and not using carbohydrates as a saturated fat substitute [4]. Individuals who would benet from lowering their LDLcholesterol are further advised to eat a healthful pattern and limit saturated fat and
trans fat intake [4].
Carbohydrates and Added Dietary Sugar

Carbohydrates are traditionally referred to as either being simple or complex.
Simple sugars represent mono- or disaccharides and are typically encountered as
fructose (e.g., fruits and vegetables, high fructose corn syrup), lactose (e.g., milk
products) and sucrose (e.g., sugar cane, honey, and corn syrup). Complex carbohydrates on the other hand describe larger chain carbohydrate molecules such as those
seen in starch or ber (e.g., bread, potatoes, rice and beans). Historically, complex
carbohydrates were thought to be healthier because, in theory, these should take
more time to digest and lead to lower peak serum glucose concentrations. However,
studies dating back to the 1970s demonstrated that some starches were actually
digested quite rapidly and resulted in peak glucose concentrations similar to simple
sugars. [29] Over time this reality has led to a reclassication of carbohydrates
65
according to their glycemic index (GI). According to this system, foods that cause a
greater spike in prandial glucose are assigned a higher glycemic index. Associations
have been documented between diets comprised of high GI foods and type 2 diabetes mellitus, HDL-cholesterol, high triglyceride levels, and coronary heart disease
[30, 31]. Furthermore, whole grains (grains which have not been milled and contain
the entire grain, e.g., whole-wheat our, brown rice and oatmeal) are classied as
low glycemic foods, and increased consumption has been linked to reduced risk of
weight gain [32], coronary heart disease [33] and type 2 diabetes [34].
Over the years, simple sugar sweeteners (e.g., high-fructose corn syrup, cane
sugar, beet sugar), often referred to as added sugar, have played a role in excess
carbohydrate overconsumption. Although their consumption appears to be on the
decline in the United States, they still contribute approximately 77 g of sugar and
15 % of total energy intake per day [35]. Excess consumption of added sugar, particularly in the form of sugar-sweetened beverages, has been implicated as a major
contributor to overweight and obesity [36], type 2 diabetes [37] dyslipidemia [38],
and cardiovascular disease [39].
References
1. Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S, Franch HA, et al. Diet and
lifestyle recommendations revision 2006: a scientic statement from the American Heart
Association Nutrition Committee. Circulation. 2006;114:8296.
2. Krug E, Dahlberg LL, Mercy JA, Zwi AB, Lozano R, editors. World report on violence and
health. Geneva: World Health Organization; 2002. p. 156.
3. Gaziano TA. Reducing the growing burden of cardiovascular disease in the developing world.
Health Aff. 2007;26(1):1324.
4. Eckel RH, Jakicic JM, Ard JD, Hubbard VS, de Jesus JM, Lee I, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation.
2014;129:S7699.
5. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 19992010. JAMA. 2012;307(5):4917.
6. Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology,
evaluation, and effect of weight loss an update of the 1997 American Heart Association
Scientic Statement on obesity and heart disease from the Obesity Committee of the Council
on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113(6):898918.
7. Stein DJ. Benecial health effects of modest weight loss. Int J Obes Relat Metab Disord.
1992;16(6):397415.
8. Spiegelman BM, Flier JS. Obesity and the regulation of energy balance. Cell. 2001;104(4):
53143.
9. Ledikwe JH, Blanck HM, Khan LK, et al. Dietary energy density is associated with energy
intake and weight status in US adults. Am J Clin Nutr. 2006;83(6):13628.
10. Young LR, Nestle M. The contribution of expanding portion sizes to the US obesity epidemic.
Am J Public Health. 2002;92(2):2469.
11. Rolls BJ, Roe LS, Meengs JS. The effect of large portion sizes on energy intake is sustained
for 11 days. Obesity. 2007;15(6):153543.
12. Lloyd-Jones DM, Hong YL, Labarthe D, et al. Dening and setting national goals for cardiovascular health promotion and disease reduction the American Heart Associations strategic
impact goal through 2020 and beyond. Circulation. 2010;121(4):586613.
66
13. Cogswell ME, Zhang Z, Carriquiry AL, et al. Sodium and potassium intakes among US adults:
NHANES 20032008. Am J Clin Nutr. 2012;96(3):64757.
14. World Health Organization. Reducing risks, promoting healthy life. World Health Organization,
2002. http://www.who.int/whr/2002/en/. Accessed 6 Nov 2013.
15. Roger VL, Go AS, Lloyd-Jones DM, et al. Heart disease and stroke statistics 2012 update: a
report from the American Heart Association. Circulation. 2012;125(1):e2220.
16. Sacks FM, Svetkey LP, Vollmer WM, et al. Effects on blood pressure of reduced dietary
sodium and the dietary approaches to stop hypertension (DASH) diet. N Engl J Med.
2001;344(1):310.
17. He F, MacGregor GA. Effect of modest salt reduction on blood pressure: a meta-analysis of
randomized trials. Implications for public health. J Hum Hypertens. 2002;16(11):76170.
18. Bibbins-Domingo K, Chertow GM, Coxson PG, et al. Projected effect of dietary salt reductions on future cardiovascular disease. N Engl J Med. 2010;362(7):5909.
19. Mattes RD, Donnelly D. Relative contributions of dietary sodium sources. J Am Coll Nutr.
1991;10(4):38393.
20. Appel LJ, Anderson CA. Compelling evidence for public health action to reduce salt intake.
N Engl J Med. 2010;362:6502.
21. Appel LJ, Frohlich ED, Hall JE, et al. The importance of population-wide sodium reduction as
a means to prevent cardiovascular disease and stroke: a call to action from the American Heart
Association. Circulation. 2011;123(10):113843.
22. Anderson CAM. Beyond the clinic: importance of community involvement in sodium reduction efforts. J Public Health Manag Pract. 2014;20:S68.
23. Hu FB, Stampfer MJ, Manson JE, et al. Dietary fat in-take and the risk of coronary heart disease in women. N Engl J Med. 1997;337(21):14919.
24. Kotwal S, Jun M, Sullivan D, Perkovic V, Neal B. Omega 3 fatty acids and cardiovascular
outcomes: systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes. 2012;
5:80818.
25. Mensink RP, Zock PL, Kester ADM, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins:
a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003;77(5):114655.
26. Wilson PWF, DAgostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction
of coronary heart disease using risk factor categories. Circulation. 1998;97(18):183747.
27. Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized
controlled trials. PLoS Med. 2010;7(3), e1000252.
28. Jakobsen MU, OReilly EJ, Heitmann BL, et al. Major types of dietary fat and risk of coronary
heart disease: a pooled analysis of 11 cohort studies. Am J Clin Nutr. 2009;89(5):142532.
29. Crapo PA, Reaven G, Olefsky J. Postprandial plasma-glucose and plasma-insulin responses to
different complex carbohydrates. Diabetes. 1977;26(12):117883.
30. Barclay AW, Petocz P, McMillan-Price J, et al. Glycemic index, glycemic load, and chronic
disease risk a meta-analysis of observational studies. Am J Clin Nutr. 2008;87(3):62737.
31. Abbasi F, McLaughlin T, Lamendola C, et al. High carbohydrate diets, triglyceride-rich lipoproteins, and coronary heart disease risk. Am J Cardiol. 2000;85(1):458.
32. Mozaffarian D, Hao T, Rimm EB, Willett WC, Hu FB. Changes in diet and lifestyle and longterm weight gain in women and men. N Engl J Med. 2011;364(25):2392404.
33. Liu SM, Stampfer MJ, Hu FB, et al. Whole-grain consumption and risk of coronary heart
disease: results from the Nurses Health Study. Am J Clin Nutr. 1999;70(3):4129.
34. Meyer KA, Kushi LH, Jacobs DR, Slavin J, Sellers TA, Folsom AR. Carbohydrates, dietary
ber, and incident type 2 diabetes in older women. Am J Clin Nutr. 2000;71(4):92130.
35. Welsh JA, Sharma AJ, Grellinger L, Vos MB. Consumption of added sugars is decreasing in
the United States. Am J Clin Nutr. 2011;94(3):72634.
67
36. Vartanian LR, Schwartz MB, Brownell KD. Effects of soft drink consumption on nutrition and
health: a systematic review and meta-analysis. Am J Public Health. 2007;97(4):66775.
37. Schulze MB, Manson JE, Ludwig DS, et al. Sugar-sweetened beverages, weight gain,
and incidence of type 2 diabetes in young and middle-aged women. JAMA. 2004;292(8):
92734.
38. Welsh JA, Sharma A, Abramson JL, Vaccarino V, Gillespie C, Vos MB. Caloric sweetener
consumption and dyslipidemia among US adults. JAMA. 2010;303(15):14907.
39. Fung TT, Malik V, Rexrode KM, Manson JE, Willett WC, Hu FB. Sweetened beverage
consumption and risk of coronary heart disease in women. Am J Clin Nutr. 2009;89(4):
103742.
Raised Blood Cholesterol: Preventable Risk

Factor for Cardiovascular Disease
Lale Tokgozoglu
Dyslipidemia has been proven to be one of the most important risk factors for
atherosclerotic vascular disease. It has been shown that raised serum total cholesterol causes an estimated 4.4 million deaths every year worldwide [1]. According to
the World Health Report published in 2002, it was estimated that around 8 % of all
disease burden in developed countries was caused by raised blood cholesterol and
that over 60 % of CHD and around 40 % of ischaemic stroke in developed countries
was due to elevated total blood cholesterol levels [2]. In that report, the highest rates
of raised cholesterol levels were seen in the high income countries of Northern and
Western Europe at that time. There have been major changes in the epidemiology of
risk factors since then. A systematic analysis of health examination surveys and
epidemiological studies with 321 country-years and 3.0 million participants was
performed in 2010 looking at global trends in cholesterol levels since 1980.
According to this more recent report, age-standardised mean total cholesterol
worldwide was 4.64 mmol/L for men and 4.76 mmol/L for women. Globally, mean
total cholesterol changed little between 1980 and 2008, falling by less than
0.1 mmol/L per decade in men and women. Despite converging trends, serum total
cholesterol in 2008 was highest in the high income region consisting of Australasia,
North America, and western Europe [3]. This recent report conrms that hypercholesterolemia is still an important risk factor we need to combat if we want to decrease
the epidemic of cardiovascular disease.
We know today that plasma lipids are transported in macromolecular complexes
referred to as lipoproteins so that the hydrophobic lipid constituents become soluble. Lipoproteins vary in size, density, lipid and apoprotein content. High-density
lipoprotein, VLDL, IDL, LDL, and Lp(a) are secreted primarily by the liver, while
chylomicrons carry dietary lipid. Two-thirds of the cholesterol in the plasma is
transported by LDL fraction of lipoproteins. Although the earlier clinical trials
L. Tokgozoglu, MD, FACC, FESC (*)
Hacettepe University, Ankara, Turkey
e-mail: lalet@hacettepe.edu.tr
DOI 10.1007/978-3-319-22357-5_8
69
70
L. Tokgozoglu
measured only total cholesterol levels, subsequent trials measured lipoprotein

fractions, especially LDL cholesterol levels and showed it to be the most important
lipid fraction predicting risk. Most of the epidemiologic and clinical trial data on
atherosclerotic vascular disease relate to LDL-C; but some data show that apo B
measurements may be superior to LDL-C, since all of the cholesterol in the plasma
(excluding HDL cholesterol) is carried in atherogenic, apo B-containing particles
[4, 5]. Non-HDL-C, which encompasses LDL, Lp(a), IDL, VLDL remnants, VLDL,
and chylomicron remnants is also a predictor of risk since it measures the atherogenic lipid particles.
Epidemiologic and Clinical Studies

There have been several studies showing a strong relationship between plasma
cholesterol and atherosclerotic vascular disease. The Seven Countries Study with a
25 year follow up was one of the rst major studies showing the relationship between
serum cholesterol, diet, and coronary heart disease [6]. Another landmark study was
the Framingham Heart Study which identied major risk factors for CHD, to be an
elevated serum plasma cholesterol level, high blood pressure, and cigarette smoking
[7]. Subsequent analysis of lipid and lipoprotein levels in participants in the
Framingham study found that LDL-C levels were positively correlated with CHD
risk, whereas HDL cholesterol (HDL-C) levels were inversely correlated [8].
The INTERHEART study evaluated the association of risk factors for myocardial
infarction (MI) globally, as well as in each region and among the different ethnic
groups. Evaluating more than 29,000 subjects from 262 sites across 52 countries, it
was found that the two most important risk factors worldwide for acute MI were
dyslipidemia dened as an abnormal apolipoprotein B/apolipoprotein A-1 (ApoB/
ApoA-1) ratio and cigarette smoking. Diabetes, hypertension, abdominal obesity,
psychosocial variables such as stress and depression, exercise, diet, and alcohol
intake were the other variables that predicted risk of acute MI. In this study, regardless of ethnicity, region, or gender; an abnormal ApoB/ApoA-1 ratio and current
smoking were the two strongest predictors of acute MI risk. Taken together, current
smoking and an abnormal ApoB/ApoA-1 ratio predicted 66 % of global heart
disease. Therefore, trying to lower plasma LDL-Cholesterol and raise HDL cholesterol became an important goal to slow the progression of atherosclerotic vascular
disease and prevent cardiovascular events.
When the statins were developed in 1976, it became possible to test the cholesterol hypothesis and see whether a signicant reduction in cholesterol levels would
translate into decreased cardiovascular events. The Scandinavian Simvastatin
Survival Study was a secondary prevention study involving 4444 patients who had
existing coronary artery disease and a mean cholesterol level of 272 mg/dL. In this
study, simvastatin was compared with placebo. The LDL-C of statin-treated patients
was reduced by 38 % and CHD related events in this group decreased by 34 %.
Furthermore, there was a 30 % decrease in total mortality, which demonstrated for
71
the rst time that lowering cholesterol in high-risk patients could increase survival [9].
To determine the effect of lowering cholesterol in primary prevention, several studies were conducted. The Air Force/Texas Coronary Atherosclerosis Prevention
Study (AFCAPS/TexCAPS) showed that a 5-year period, treatment with lovastatin
reduced the risk for a rst acute major coronary event by 37 % in primary prevention [10]. Another landmark study was the The Heart Protection Study (HPS) which
was a large study with over 20,000 subjects in the UK showed benet with 40 mg/day
of simvastatin regardless of baseline LDL-C level in high risk patients. The relative
risk reduction in major vascular events was 24 % in this study [11]. Further evidence of benet with statin therapy was provided by the Cholesterol Treatment
Trialists (CTT) meta-analysis which reported the results for more than 90,000 subjects treated with statins in primary and secondary prevention trials showing that for
every 1 mmol/L (39 mg/dL) reduction in LDL-C, there was a 21 % relative reduction in risk for major vascular events. An update of the CTT meta-analysis included
trials of intensive statin therapy showing a 22 % reduction in major vascular events
per 1 mmol/L reduction in LDL-C suggesting that there is no lower threshold of
benet for LDL-C reduction [12, 13].
In light of all this evidence, lowering LDL cholesterol levels became one of the
most important goals in Preventive Cardiology both for primary and secondary
prevention. The importance of knowing the lipid prole was also recognised both
by physicians and the general public.
Who Should Get a Lipid Profile ?

The 2011 ESC/EAS guidelines for the management of dyslipidemias recommends
that risk factor screening, including the lipid prole, may be considered in adult
men 40 years of age, and in women 50 years of age or postmenopausal, particularly in the presence of other risk factors. In addition, all subjects with evidence of
atherosclerosis in any vascular bed or with type 2 diabetes, Individuals with a family
history of premature CVD, patients with arterial hypertension, central obesity,
autoimmune chronic inammatory conditions, patients with CKD, clinical manifestations or family history for genetic dyslipidaemias should be screened.
The baseline lipid evaluation suggested is: TC, TG, HDL-C, and LDL-C, calculated
with the Friedewald formula unless TG are elevated (>4.5 mmol/L or greater than
400 mg/dL) [14].
Management of Dyslipidemia
All the current guidelines on the management of dyslipidemia recommend that
assessment of total cardiovascular risk is important to plan the therapy of the patient.
Dyslipidemia is only one of the risk factors therefore all the other risk factors need
72
L. Tokgozoglu
to be assessed and targeted. Higher risk patients need more aggressive therapies
therefore calculation of the patients risk of having a cardiovascular event is important.
Treatment targets of dyslipidaemia are primarily based on results from clinical trials.
In nearly all lipid-lowering trials the LDL-C level has been used as an indicator of
response to therapy. Therefore, LDL-C remains the primary target of therapy in
most strategies of dyslipidaemia management. The overall guidelines on CVD
prevention in clinical practice strongly recommend modulating the intensity of the
preventive intervention according to the level of the total CV risk. Therefore the
targets should be less demanding when the total CV risk decreases from very high
to high or moderate. The most frequently used risk prediction systems are the
SCORE and Framingham risk calculation systems [15, 16]. The SCORE system
estimates the 10 year risk of a rst fatal atherosclerotic event (heart attack, stroke,
aneurysm of the aorta or other). Most other systems estimate coronary heart disease
risk only. The ESC/EAS Guidelines recommend the use of SCORE system.
Risk can be calculated based upon new SCORE charts in which, in addition to total
cholesterol, systolic blood pressure, age, sex and smoking, and HDL-C is taken into
account (www.heartscore.org).
The ESC/EAS Dyslipidemia guidelines have dened the following levels of total
CV risk:
1. Very high risk:
Documented CVD by invasive or non-invasive testing, previous myocardial
infarction (MI), ACS, coronary revascularization (percutaneous coronary
intervention, coronary artery bypass graft and other arterial revascularization
procedures, ischaemic stroke, PAD).
Patients with type 2 diabetes, patients with type 1 diabetes with target organ
damage (such as microalbuminuria). Patients with moderate to severe CKD
[glomerular ltration rate (GFR) <60 mL/min/1.73 m2)].
A calculated 10-year risk SCORE 10 %.
2. High risk:
Markedly elevated single risk factors such as familial dyslipidaemias and
severe hypertension.
A calculated SCORE 5 % and <10 % for 10-year risk of fatal CVD.
3. Moderate risk:
Subjects are considered to be at moderate risk when their SCORE is 1 % and
<5 % at 10 years. Many middle-aged subjects belong to this risk category. This
risk is further modulated by a family history of premature CAD, abdominal obesity, physical activity pattern, HDL-C, TG, hs-CRP, Lp(a), brinogen, homocysteine, apo B, and social class.
4. Low risk:
The low risk category applies to individuals with SCORE <1 %. After determining the risk level and LDL cholesterol levels of the patient, intervention
strategies on lifestyle and pharmacotherapy are decided according to the LDL
cholesterol goal for each category. The main target of treatment is LDL cho-
73
Table 1 Intervention strategies recommended according to risk and LDL level of the patient
LDL-C levels
Total CV
risk
(SCORE)
%
<1
70 to
<100 mg/dL
<70 mg/dL
1.8
<1.8 mmol/L to < 2.5 mmol/L
No lipid
No lipid
intervention intervention
Class/level
1 to <5
I/C
Lifestyle
intervention
Class/level I/C
>5 to <10, Lifestyle
or high risk intervention,
consider
druga
Class/level
10 or
very high
risk
IIa/A
Lifestyle
intervention,
consider
druga
Class/level
IIa/A
100 to
<155 mg/dL
2.5 to
<4.0 mmol/L
Lifestyle
intervention
155 to
<190 mg/dL
4.0 to
<4.9 mmol/L
Lifestyle
intervention
>190 mg/dL
>4.9 mmol/L
Lifestyle
intervention,
consider drug
if uncontrolled
I/C
I/C
I/C
IIa/A
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention
intervention,
intervention,
intervention,
consider drug consider drug consider drug
if uncontrolled if uncontrolled if uncontrolled
I/C
IIa/A
IIa/A
I/A
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention,
intervention
intervention
intervention
consider druga
and immediate and immediate and immediate
drug
drug
drug
intervention
intervention
intervention
IIa/A
IIa/A
I/A
I/A
Lifestyle
Lifestyle
Lifestyle
Lifestyle
intervention and intervention
intervention
intervention
immediate drug and immediate and immediate and immediate
intervention
drug
drug
drug
intervention
intervention
intervention
IIa/A
I/A
I/A
I/A
Initial treatment with statins CV cardiovascular; LDL cholesterol - low-density lipoprotein

European Heart Journal 2011;32:17691818 [14]
lesterol. Table 1 shows the intervention strategies recommended according to

risk and LDL level of the patient:
Every 1.0 mmol/L (40 mg/dL) reduction in LDL-C is associated with a
corresponding 22 % reduction in CVD mortality and morbidity Extrapolating
from the available data, an absolute reduction to an LDL-C level, <1.8 mmol/L
(less than 70 mg/dL) or at least a 50 % relative reduction in LDL-C provides
the best benet in terms of CVD reduction [13]. In the majority of patients, this
is achievable with statin monotherapy. Therefore, for patients with very high
CV risk, the treatment target for LDL-C is, <1.8 mmol/L (less than 70 mg/dL)
or a 50 % reduction from baseline LDL-C. LDL-C is the primary target.
Although elevated triglyceride rich lipoproteins and low HDL are markers of
cardiovascular risk, interventional studies have resulted in conicting results.
Therefore they are not primary targets of therapy. Non HDL cholesterol or
ApoB is a secondary target of therapy in combined hyperlipidaemias, diabetes, the
metabolic syndrome or CKD.
74
L. Tokgozoglu
Table 2 Percentage reduction of LDL-C required to achieve goals as a function of starting value
Starting
LDL-C
mmol/L
>6.2
6.26.2
4.45.2
3.94.4
3.43.9
2.93.4
2.32.9
1.82.3
% Reduction to reach LDL-C

<1.8 mmol/L
~mg/dL
(~70 mg/dL)
>240
>70
200240
6570
170200
6065
150170
5560
130150
4555
110130
3545
90110
2235
7090
<22
<2.5 mmol/L
(~100 mg/dL)
>60
5060
4050
3540
2535
1025
<10
<3 mmol/L
(~115 mg/dL)
>55
4055
3045
2530
1025
<10
LDL-L low-density lipoprotein

European Hear Journal 2011;32:17691818 [14]
To make it easier for the physician, guidelines have a table to calculate the
percentage reduction of LDL-C required to achieve goals as a function of starting
value (Table 2). According to this table, treatment decisions can be made. Before
starting any treatment, it is important to exclude secondary caused such as
nephrotic syndrome, hypothyroidism, excessive alcohol consumption, pregnancy,
corticosteroid excess, anorexia, and use of immunosuppressive agents.
Lifestyle Recommendations to Lower LDL-Cholesterol

All subjects should be given lifestyle advice on diet (if possible by a dietician),
physical activity, and tobacco cessation, In overweight patients, caloric intake
should be decreased and energy expenditure increased.
Consumption of fruit, vegetables, legumes, nuts, wholegrain cereals and bread,
sh (especially oily) should be encouraged.
A fat content of <35 % of energy intake is recommended. In particular the energy
from saturated fat should be below 7 % and from trans fats to <1 % of total
energy intake
The intake of beverages and foods with added sugars should be limited, particularly for patients with high TG.
Physical activity should be encouraged aiming at regular physical exercise for at
least 30 min every day.
Smoking should be quit.
Table 3 summarises the dietary recommendations made by the EAS/ESC
guideline [14].
75
Table 3 Dietary recommendations to lower total and LDL cholesterol according to ESC/EAS
Guideline for the management of dyslipidemia
Dietary recommendations to lower TC and LDL-C
To be used with
To be preferred
moderation
Cereals
Whole grains
Rened bread, rice and
pasta, biscuits, com
akes
Vegetables
Raw and cooked
vegetables
Legumes
All (including soy
and soy protein)
Fruit
Fresh and frozen
Dried fruit, jelly, jam
fruit
canned fruit, sorbets,
popsicles
Sweets and
Non-caloric
Sucrose, honey,
sweeteners
sweeteners
fructose, glucose,
chocolate, candies
Meat and sh Lean and oil sh,
Lean cuts of beef, lamb,
poultry without
pork or veal, seafood,
skin
shellsh
Dairy food
Skimmed milk and Low fat milk, low fat
and eggs
yogurt, egg white
cheese and other milk
products
Cooking fat
Vinegar, ketchup,
Vegetable oils, soft
and dressings mustard, fat-free
margarines, salad
dressings
dressing, mayonnaise
Nuts/seeds
Cooking
procedures
Grilling, boiling,
steaming
All
Stir-frying, roasting
To be chosen occasionally in
limited amounts
Pastries, mufns, pies,
croissants
Vegetables prepared in butter
or cream
Cake, ice creams
Sausages, salami, bacon, spare

ribs, hot dogs, organ meats
Regular cheese, cream, egg
yolk, whole milk and yogurt
Butter, solid margarines, trans
fats, palm and coconut oils;
lard, bacon fat, dressings made
with egg yolks
Coconut
Frying
European Hear Journal 2011;32:17691818 [14]
Pharmacotherapy to Lower LDL-Cholesterol

When lifestyle measures are not enough, statin based therapies are the treatment of
choice to lower LDL-C levels. According to ESC/EAS Dyslipidemia Guidelines, If
drug treatment is indicated to decrease LDL-C, a statin is recommended, up to the
highest tolerable dose, to reach the target level. If the target level is not reached,
guidelines recommend statin combination with a cholesterol absorption inhibitor
or bile acid sequestrant or nicotinic acid. However, the recent AIM-HIGH study that
was published after the guidelines cast doubts about the safety of niacin for combination [17]. Therefore, until further evidence comes along, niacin can not be
76
L. Tokgozoglu
recommended for this purpose. A combination of statins with brates may also be
considered while monitoring for myopathy but the combination with gembrozil
should be avoided [18]. It is also important to note that statin-brate combination
has not been proven to decrease mortality in all patients. If the patient is intolerant
to statins, a cholesterol absorption inhibitor, alone or in combination with bile acid
sequestrants may also be considered. In general, statins have been remarkably safe.
The 2005 CTT meta-analysis showed that LDL-C reduction with statins was not
associated with increased risk for cancer, and that the 5-year excess risk for rhabdomyolysis, the primary serious adverse reaction with statins, was extremely low and
non-signicant. Myopathy and rhabdomyolysis were seen in patients who were
immunosuppressed or on immunosuppressant drugs, as well as in patients taking
both a statin and gembrozil. Changes in liver enzymes can occur, particularly at
higher doses of statins, but are almost always reversible. Recently, a slight increase
in development of diabetes in patients taking statins has been reported [19]. A metaanalysis of statin trials found a 9 % greater risk for incident diabetes equivalent to 1
extra case of diabetes per 255 patients treated with statins for 4 years [20]. The CTT
collaborators meta-analysis found that cardiovascular risk reduction with statins
was equivalent in patients both with and without diabetes, so that after 5 years of
statin therapy, 42 major vascular events would be prevented per 1000 diabetic
patients treated with a statin [21]. These should be kept in mind in starting a statin
and follow up of patients in primary prevention but should not deter from using
statin if indicated by guidelines.
Treatment of Dyslipidemia in Special Groups According

to ESC/EAS Guidelines
Elderly Patients
Treatment with statins is recommended for elderly patients with established CVD in
the same way as for younger patients. However, the starting dose should be lower
than the maximal possible dose. As for primary prevention, statin therapy may be
considered if there is at least one other risk factor besides age.
Female Patients
Treatment with statins is recommended for female patients with established CVD
in the same way as for males. As for primary prevention, statin treatment is recommended in high risk women. Lipid lowering drugs should not be given during
pregnancy or breast feeding.
77
Diabetic Patients
In people with type 1 diabetes with microalbuminuria or other target organ damage,
LDL-C lowering therapy with statins is recommended irrespective of their basal
LDL-C. In patients with type 2 diabetes and CVD or CKD and in those without
CVD who are over age of 40 years with one or more other CVD risk factor the recommended goal for LDL-C is <1.8 mmol/L (<~70 mg/dL) and the secondary goal
for non-HDL-C is, <2.6 mmol/L (<100 mg/dL) or for apo B <80 mg/dL. LDL-C
<2.5 mmol/L (<~100 mg/dL) is the primary target for all other people with type 2
diabetes and the secondary targets for non-HDL-C are <3.3 mmol/L (<100 mg/dL)
or for apo B <100 mg/dL.
Patients with Chronic Kidney Disease

CKD is acknowledged as a CAD risk equivalent and LDL-C reduction is recommended
as primary target of the therapy. Statins with minimal renal excretion should be
preferred. In moderate to severe CKD statins as monotherapy or in combination with
other drugs should be considered to achieve LDL-C <1.8 mmol/L (<~70 mg/dL).
Other Dyslipidemias
Patients with insulin resistant states such as diabetics, metabolic syndrome patients
and obese patients tend to have a state of atherogenic dyslipidemia characterised by
elevated triglyceride rich proteins, low HDL and small dense LDL particles. Statins
are effective in lowering LDL and non-HDL in these patients. An important question
is whether we can lower cardiovascular risk by targeting other non-LDL lipoproteins
in these patients to decrease residual risk. Clinical trials conducted with brates have
yielded disappointing results in terms of mortality reduction in general [22, 23].
A meta-analysis looking at the effects of brates in clinical trials showed a 10 %
decrease in cardiovascular events and microalbuminuria but no decrease in mortality
[24]. The ACCORD study evaluated the combination of brate and statin compared
to statin alone and found no signicant benet in the combination group in general
[23]. However, subgroups of these patients with high triglycerides and low HDL in
the ACCORD study did benet from addition of brates to statins. In a meta-analysis
of brate trials, the subgroup of patients with high triglycerides and low HDL had a
35 % reduction in cardiovascular events [25]. For today, LDL lowering with statin
based therapies are the standard of care for patients with high cardiometabolic risk,
but event rates are still high. There is no conclusive evidence about use of brates for
cardiovascular protection to decrease remaining risk. However, since adding brates
to statin is relatively safe, in the high risk diabetic subgroup with high TG and low
HDL, brates may be considered [26].
78
L. Tokgozoglu
References
1. Prospective Studies Collaboration, Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson
J, Halsey J, Qizilbash N, Peto R, Collins R. Blood cholesterol and vascular mortality by age,
sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with
55,000 vascular deaths. Lancet. 2007;370:182939.
2. Mutangadura GB. World health report 2002: reducing risks, promoting healthy life. Agricult
Econ. 2004;30:1702.
3. Farzadfar F, Finucane MM, Danaei G, Pelizzari PM, Cowan MJ, Paciorek CJ, Singh GM,
Lin JK, Stevens GA, Riley LM, Ezzati M, Global Burden of Metabolic Risk Factors of
Chronic Diseases Collaborating Group (Cholesterol). National, regional, and global trends
in serum total cholesterol since 1980: Systematic analysis of health examination surveys and
epidemiological studies with 321 country-years and 3.0 million participants. Lancet.
2011;377:57886.
4. Sniderman AD, Furberg CD, Keech A, van Lennep JER, Frohlich J, Jungner I, Walldius
G. Apolipoproteins versus lipids as indices of coronary risk and as targets for statin treatment.
Lancet. 2003;361:77780.
5. Grundy SM. Low-density lipoprotein, non-high-density lipoprotein, and apolipoprotein b as
targets of lipid-lowering therapy. Circulation. 2002;106:25269.
6. Verschuren WM, Jacobs DR, Bloemberg BP, Kromhout D, Menotti A, Aravanis C, Blackburn
H, Buzina R, Dontas AS, Fidanza F, et al. Serum total cholesterol and long-term coronary heart
disease mortality in different cultures. Twenty-ve-year follow-up of the seven countries
study. JAMA. 1995;274:1316.
7. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes 3rd J. Factors of risk in the development of coronary heart diseasesix year follow-up experience. The Framingham Study.
Ann Intern Med. 1961;55:3350.
8. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High-density lipoprotein as a
protective factor against coronary heart-disease Framingham Study. Am J Med.
1977;62:70714.
9. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the
Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:13839.
10. Downs JR, Cleareld M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein
EA, Kruyer W, Gotto Jr AM. Primary prevention of acute coronary events with lovastatin in
men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/
Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:161522.
11. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol
lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled
trial. Lancet. 2002;360:722.
12. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T,
Peto R, Collins R, Simes R, Cholesterol Treatment Trialists (CTT) Collaborators. Efcacy
and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056
participants in 14 randomised trials of statins. Lancet. 2005;366:126778.
13. Cholesterol Treatment Trialists (CTT) Collaborators, Baigent C, Blackwell L, Emberson J,
Holland LE, Reith C, Bhala N, Peto R, Barnes EH, Keech A, Simes J, Collins R. Efcacy and
safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000
participants in 26 randomised trials. Lancet. 2010;376:167081.
14. European Association for Cardiovascular Prevention & Rehabilitation, Reiner Z, Catapano
AL, De Backer G, Graham I, Taskinen MR, Wiklund O, Agewall S, Alegria E, Chapman MJ,
Durrington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF,
Wood D, ESC Committee for Practice Guidelines (CPG) 20082010 and 20102012
Committees. ESC/EAS guidelines for the management of dyslipidaemias: the task force for
the management of dyslipidaemias of the European Society of Cardiology (ESC) and the
European Atherosclerosis Society (EAS). Eur Heart J. 2011;32:17691818.
79
15. Conroy RM, Pyorala K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D,
Ducimetiere P, Jousilahti P, Keil U, Njolstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H,
Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM, SCORE Project Group.
Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur
Heart J. 2003;24:9871003.
16. D'Agostino RB, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, Kannel WB. General
cardiovascular risk prole for use in primary care the Framingham Heart Study. Circulation.
2008;117:74353.
17. Investigators A-H, Boden WE, Probsteld JL, Anderson T, Chaitman BR, Desvignes-Nickens
P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol
levels receiving intensive statin therapy. N Engl J Med. 2011;365:225567.
18. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with brates. Am J Cardiol.
2004;94:9358.
19. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, Koenig W, Libby
P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ,
JUPITER Study Group. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195207.
20. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de Craen AJ, Seshasai SR, McMurray
JJ, Freeman DJ, Jukema JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Shepherd
J, Davis BR, Pressel SL, Marchioli R, Marsi RM, Maggioni AP, Tavazzi L, Tognoni G,
Kjekshus J, Pedersen TR, Cook TJ, Gotto AM, Cleareld MB, Downs JR, Nakamura H,
Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and risk of incident diabetes: a collaborative
meta-analysis of randomised statin trials. Lancet. 2010;375:73542.
21. Cholesterol Treatment Trialists (CTT) Collaborators, Kearney PM, Blackwell L, Collins R,
Keech A, Simes J, Peto R, Armitage J, Baigent C. Efcacy of cholesterol-lowering therapy in
18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet.
2008;371:11725.
22. Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder P, Pillai A, Davis T,
Glasziou P, Drury P, Kesaniemi YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting M,
Ehnholm C, Laakso M, FIELD Study Investigators. Effects of long-term fenobrate therapy
on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study):
randomised controlled trial. Lancet. 2005;366:184961.
23. ACCORD Study Group, Ginsberg HN, Elam MB, Lovato LC, Crouse 3rd JR, Leiter LA, Linz
P, Friedewald WT, Buse JB, Gerstein HC, Probsteld J, Grimm RH, Ismail-Beigi F, Bigger JT,
Goff Jr DC, Cushman WC, Simons-Morton DG, Byington RP. Effects of combination lipid
therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:156374.
24. Abourbih S, Filion KB, Joseph L, Schiffrin EL, Rinfret S, Poirier P, Pilote L, Genest J,
Eisenberg MJ. Effect of brates on lipid proles and cardiovascular outcomes: a systematic
review. Am J Med. 2009;122:962 e961968.
25. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med.
2010;363:6924. author reply 694695.
26. Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F, Boren J, Catapano AL, Descamps OS,
Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray KK,
Reiner Z, Taskinen MR, Tokgozoglu L, Tybjaerg-Hansen A, Watts GF, European Atherosclerosis
Society Consensus Panel. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
Eur Heart J. 2011;32:134561.
Hypertension: Primary Health Care Approach

Evgeny Shlyakhto
Clinical, social and economical burden of arterial hypertension is still extremely

high all over the world. It stays the major cardiovascular risk factor with the prevalence of 3045 % among adults and up to 70 % in elderly population. Arterial
hypertension still accounts for the majority of cases of coronary events, strokes,
renal failure and cerebrovascular diseases including cognitive dysfunction.
Most of the patients with hypertension who take blood pressure medications fail
to reach treatment goals despite the development of new, effective and well-tolerated
antihypertensive medications. There is a strong evidence base coming from the
clinical trials for the benets of both lifestyle modication and antihypertensive
drug therapy in reducing cardiovascular morbidity and mortality. Still, there is a
lack of clarity on how to organize and deliver care for patients with hypertension in
the settings of real clinical practice and how to ll the gap between existing recommendations and blood pressure control. Many causes for poor blood pressure control exist including persistence of risk factors, sub-optimal patient medication
adherence and failure to intensify therapy (clinical inertia) by clinicians. From this
point of view, primary healthcare structures form a unique tool which could improve
the everyday hypertension management.
At the present time the strategy of antihypertensive treatment is based not only
on blood pressure levels, but mainly on the general cardiovascular risk assessment.
According to the current Guidelines for the management of arterial hypertension
([1] ESH/ESC, ACC/AHA 2003) initial evaluation of the patient with arterial hypertension should include:
1. Conrmation of the diagnosis
2. Ruling out secondary hypertension
E. Shlyakhto (*)
Federal Almazov Medical Research Center, Saint-Petersburg, Russia
Russian Society of Cardiology, Moscow, Russia
e-mail: shlyakhto@almazovcentre.ru
DOI 10.1007/978-3-319-22357-5_9
81
82
E. Shlyakhto
3. Estimation of cardiovascular risk.

Obviously all these tasks could be carried out by the primary care specialists
under adequate support provided by government and community, as most of preventive health care as well as screening for early disease and risk factors detection and
management take place in the primary health care settings. At the present time there
is a general trend all over the world of shifting focus from expensive specialized
care to primary and secondary prevention of hypertension and its consequences
provided by primary health care professionals.
In 2010 World Health Organization stated that major noncommunicable diseases
(heart disease, stroke, cancer, asthma, chronic obstructive pulmonary disease, diabetes, hypertension and other cardiovascular risk factors including tobacco) can be
addressed in primary care using cost effective interventions. Primary care is the rst
point of contact in the healthcare system of all countries, and it is usually available
for the majority of people. Primary health care facilities are ideally positioned to
provide regular contact with patients and to apply the preventive measures and continuum of care, that people need to prevent or delay disabilities resulting from chronic
health conditions.
Of course the particular characteristics of work in primary healthcare should
be taken into account. Rutten et al. [2] have compared the primary and secondary
care patients, and declared a signicant differences in both population and disease
parameters. For example, that means higher rate of non-cardiac comorbidities and
different spectrum of cardiovascular diseases. With adequate support and training
primary care practitioners form an invaluable workforce in the community to deliver
coordinated care to hypertensive patients, especially those with clinically stable
conditions, and to identify high risk subjects for referral to specialists. Working in
partnership with other healthcare professionals primary care practitioners are in a
prime position to provide patient-centered, continuing and comprehensive care.
The efforts of primary care practitioners should be aimed at:
1. Diagnosis of hypertension with appropriate individual and family medical history
and all indicated laboratory investigations in accordance with evidence-based
guidelines;
2. Risk stratication;
3. Ongoing patients education to reduce risks, to encourage adequate lifestyle
modication;
4. Medication selection based on risk stratication and presence of specic
indications;
5. Monitoring of treatment responses and adherence.
6. Treatment of comorbidities.
Primary health care system potentially can deliver a dened package of services
to prevent and control hypertension consisting of:
information,
education and communication related to healthy lifestyle and proper nutrition;
smoking control services.
83
Table 1 Recommended laboratory investigations [1]

Routine tests
Haemoglobin and/or haematocrit
Fasting plasma glucose
Serum total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol
Fasting serum triglycerides
Serum potassium and sodium
Serum uric acid
Serum creatinine (with estimation of GFR)
Urine analysis: microscopic examination; urinary protein by dipstick test; test for
microalbuminuria
12-lead ECG
Additional tests, based on history, physical examination, and findings from routine laboratory tests
Haemoglobin A1c (if fasting plasma glucose is >5.6 mmol/L (102 mg/dL) or previous diagnosis
of diabetes
Quantitative proteinuria (if dipstick test is positive); urinary potassium and sodium concentration
and their ratio
Home and 24-h ambulatory BP monitoring
Echocardiogram
Holter monitoring in case of arrhythmia
Carotid ultrasound
Peripheral artery/abdominal ultrasound
Pulse wave velocity
Ankle-brachial index
Fundoscopy
Extended evaluation
Further search for cerebral, cardiac, renal, and vascular damage, mandatory in resistant and
complicated hypertension
Search for secondary hypertension when suggested by history, physical examination, or routine
and additional tests
Primary health care facilities should be able to screen for hypertension, map
diagnosed cases, set up a community-based follow-up system, treat hypertension
and undertake relevant emergency management.
According to the hypertension guidelines primary examination should include
routine tests which are being performed in any hypertensive patient, additional tests
which are done for special indications revealed during physical examination or after
the results of routine test are obtained, and extended evaluation usually done by
specialists (Table 1).
The next step needed for appropriate treatment selection is risk stratication,
which is based not only on the level of blood pressure, but also on the presence of
other risk factors (e.g. family history, smoking, etc.), target organ damage and coexistence of cardiovascular or renal diseases.
84
E. Shlyakhto
Patient education is the cornerstone of hypertension management. The patients

should be empowered with appropriate knowledge and skills to live with the chronic
disease. Hypertensive patients must have basic knowledge about the nature, consequences and treatment of the disease as well as their rights and responsibilities in
terms of access to care, adherence to recommended treatment and self-management.
Primary care physicians and other care professionals including nurses and psychologists should help dispel misconceptions and address patients concerns about the
disease and its treatment, for example, fear for long-term medication use or sideeffects, and emphasize the positive aspects of the disease in terms of risk awareness,
adoption of a healthy lifestyle and regular surveillance by a health care team.
So main topics of patients education (schools for hypertesives) should include
at least: (1) denition of hypertension; (2) rules of blood pressure measurement;
(3) hypertension risk factors; (4) consequences of hypertension for both individual
patients and for the whole community; (5) principles of hypertension management
including lifestyle interventions and pharmacological treatment.
The educational programmes for hypertensive patients become more and more
important as the nonpharmacological methods of treatment of arterial hypertension
form the fundamental basis for successful treatment. Current hypertension guidelines state that a number of lifestyle measures that have been shown to be capable of
reducing BP. They include:
(i)
(ii)
(iii)
(iv)
(v)
(vi)
salt restriction,
moderation of alcohol consumption,
high consumption of vegetables and fruits and low-fat and other types of diet,
weight reduction and maintenance and
regular physical exercise.
Smoking cessation, which is mandatory in order to improve CV risk, and
because cigarette smoking has an acute pressor effect that may raise daytime
ambulatory BP.
Obviously all team members should participate in patients education, and the
role of nurses, nutrition specialists and psychologists can not be overestimated.
A number of randomized clinical trials have demonstrated the signicant improvement
of blood pressure control with nurse- of pharmacist-led care [3, 4]. The results of
such studies demonstrated a reduction in blood pressure to a maximum of
13/8 mmHg [5]. The Cochrane review authors conclude that an organized system
of registration, recall and regular review allied to a vigorous stepped care approach
to antihypertensive drug treatment appears the most likely way to improve the control of high BP [6]. They also have conrmed that nurse or pharmacist led care was
promising, with the majority of randomized clinical trials being associated with
improved blood pressure control and reduction in mean systolic and diastolic blood
pressure [7].
An increased amount of investigations needed for hypertensive patient, including
those aimed at detection of asymptomatic target organ damage (see Table 1),
together with the shortage of time for adult primary care rise a serious dilemma.
One of the possible solutions lies in delegating less complex activities from
85
physicians to other members of the primary care team so that the whole team, not
solely the physician, becomes responsible for the health of patients [8]. Margolius
et al. [9] have performed a qualitative research approach to determine clinicians
opinions on the Treat-to-Target study, an intervention to improve blood pressure
control. They concluded that clinicians appreciate the presence of nonclinicians on
the primary care team. In the coming era of primary care clinician shortage, clinicians can be supportive of nonprofessional team members assisting with the care of
patients with hypertension. Telemedicine, dened as the use of telecommunications
to provide medical information and service, or remote monitoring in patients homes
has been offered as a plausible solution of improving ambulatory medical care.
Concerning the primary healthcare system it means the integration of medical,
information and communication technologies in order to provide appropriate medial
consultation to the patient basing on the information received from the patients
home. From another hand, telemedicine can be helpful in getting advice from a
remote specialized medical center to primary care professionals in complicated situations. Besides delivering care to hypertensive patients telemedicine has a critical
role in educating patients, in improving their adherence to both non-pharmacological and medical therapy. In some countries and communities the role of telemedicine is especially important because of its capability to solve the problem of large
distances and access to medical assistance. The remote counseling helps avoiding
unnecessary transportation and loss of time in the physicians ofces and out-patient
department.
Today the interest to out-of-ofce blood pressure monitoring is a subject
of extreme practical and scientic interest among cardiologists. According to the
Position Paper of the European Society of Hypertension on Ambulatory Blood
Pressure monitoring (2013), ambulatory blood pressure control has a lot of advantages over ofce blood pressure:
1. It gives a larger number of readings than ofce blood pressure measurement
2. Provides a prole of blood pressure behavior in the patients usual daily
environment;
3. Allows identication of white-coat and masked hypertension phenomena;
4. Demonstrates nocturnal hypertension;
5. Assesses blood pressure variability over the 24-hours period;
6. Assesses the 24-hours efcacy of antihypertensive medications;
7. Is a stronger predictor of cardiovascular morbidity and mortality than ofce
measurement.
According to ESH/ESC guidelines on the management of arterial hypertension
there are following indications for out-of-ofce blood pressure measurement:
A. Indications for home and ambulatory blood pressure monitoring:
Suspicion of white-coat hypertension

Suspicion of masked hypertension
Identication of white-coat effect in hypertensive patients
Considerable variability of ofce blood pressure
86
E. Shlyakhto
Autonomic, postural, post-prandial, siesta- and drug-induced hypotension

Elevated ofce blood pressure of suspected pre-eclampsia in pregnant women
Identication of true and false resistant hypertension.
B. Specic indications for ambulatory blood pressure monitoring:
Marked discordance between ofce and home blood pressure
Assessment of dipping status
Suspicion of nocturnal hypertension or absence of dipping, such as in patients
with sleep apnea, CKD, or diabetes
Assessment of blood pressure variability.
Despite the fact that method of ambulatory blood pressure monitoring has some
limitations, and its routine use demands special training both for healthcare practitioners and patients and also corresponding equipment, it combination with telemedicine could become an invaluable tool for primary healthcare system. In a
randomized control trial about 800 patients with uncontrolled essential hypertension were randomized into three groups: (1) usual care, (2) home blood pressure
monitoring plus secure patient Web training, and (3) home blood pressure monitoring plus secure patient Web training plus pharmacist care management delivered
through Web communications. After one year of follow-up, a signicant increase of
the amount of patients with controlled blood pressure was demonstrated among
those assigned to the home monitoring, Web training and Web-based pharmacist
care compared with the other two groups [10, 11]. In another multicenter prospective study of 111 patients with uncontrolled hypertension the authors were evaluating the effect of self-drug titration basing of the instructions provided by telemedicine
on blood pressure treatment outcome. Overall, 58 % of patients were satised and
23 % were very satised with the program, and 78 % of the patients fully complied
with self-measurement instructions [12].
As it was mentioned above, there is strong evidence that including a nurse
and/or pharmacist as a team member in the management of hypertension improves
blood pressure control [7, 1315]. The Electronic Communications and Home
Blood Pressure Monitoring (e-BP) study [10, 11] demonstrated that team care
incorporating a pharmacist who intensied BP management strategies (e.g., medications) through secure web messaging with patients resulted in almost twice the
rate of BP control compared with usual care [10, 11]. Robins et al. [15] have
proposed the following reasonable concept of intercommunication between main
participants of the process:
1. Physician: continues his routine activities and sees patient as usually; also
performs consultations with pharmacist.
2. Pharmacist (or nurse): reviews blood pressure records; discuss ways of blood
pressure control with patient and, if possible, adjust medications; informs physician about treatment modication and performs consultations with physician if
necessary.
3. Patient: takes blood pressure at home; emails his blood pressure to pharmacist;
exchanges Web-based communication with pharmacist (nurse) or physician.
87

Table 2 Drugs to be preferred in specic conditions
Condition
Asymptomatic organ damage
Left ventricle hypertrophy
Asymptomatic atherosclerosis
Microalbuminuria
Renal dysfunction
Clinical CV event
Previous stroke
Previous myocardial infarction
Angina pectoris
Heart failure
Aortic aneurysm
Atrial brillation, prevention
Atrial brillation, ventricular rate control
ESRD/proteinuria
Peripheral artery disease
Other
Isolated systolid hypertension (elderly)
Metabolic syndrome
Diabetes mellitus
Pregnancy
Blacks
Drug
ACE inhibitor, calcium antagonist, ARB
Calcium antagonist, ACE inhibitor
ACE inhibitor, ARB
ACE inhibitor, ARB
Any agent effectively lowering BP
BB, ACE inhibitor, ARB
BB, calcium antagonist
Diuretic, BB, ACE inhibitor, ARB,
mineralocorticoid receptor antagonists
BB
Consider ARB, ACE inhibitor, BB or
mineralocorticoid receptor antagonist
BB, non-dihydropyridine calcium antagonist
ACE inhibitor, ARB
ACE inhibitor, calcium antagonist
Diuretic, calcium antagonist
ACE inhibitor, ARB, calcium antagonist
ACE inhibitor, ARB
Methyldopa, BB, calcium antagonist
Diuretic, calcium antagonist
Of course such mode of system rises a lot of concerns about the adequacy and
accuracy of patients blood pressure readings, correct use of devices, availability
and competence with information technologies particularly in elderly patients. That
kind of problems should be solved with well-established system of patients
education.
Modern International guidelines state that the choice of antihypertensive medication should be based on (1) risk level and (2) on the presence of specic clinical
conditions and on possible side-effects. It reconrm that diuretics, beta-blockers, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors and angiotensin
receptor blockers are all suitable for the initiation and maintenance of antihypertensive treatment, either as monotherapy or in some combinations (Table 2).
Today the physicians are faced a serious problem of treatment resistance and
wide prevalence of concomitant risk factors (e.g. obesity and/or diabetes mellitus).
Modern guidelines more and more tend to recommend early start of combination
therapy. When rapid blood pressure lowering is essential (e.g., in patients with high
and very high cardiovascular risk) pharmacological treatment should be started
with the combination of two drugs (Fig. 1) which, inter alia, signicantly improves
88
E. Shlyakhto
Thiazide diurecics
Beta-blockers
Angiotensin-receptor
blockers
Others
Antihypertensives
Calcium
antagoniscs
ACE inhibitors
Fig. 1 Possible combinations of antihypertensive drugs [1]
patients adherence to therapy in gives better results. Preferred combinations are

shown on the Fig. 1. It is of note that the existing evidence do not allow to perform
dual RAS blockade so far.
Another important thing is that physicians adherence to existing guidelines on
hypertension prevention and treatment is rather poor [16] that dictates the need of
additional educational activities among primary care professionals. Lack of practice
organization, coupled with failure to intensify treatment has been characterized as
clinical inertia and is implicated as a reason with a failure to achieve treatment
goals in hypertension and prevention of cardiovascular events. Recently Carrington
et al. [17] performed a retrospective analysis of electronic medical records of half a
million patients treated by more than 700 general practitioners between 2005 and
2010 in Australia. Their data Demonstrated that there was no any signicant gains
in the community control of hypertension since 2005, with average blood pressure
in patients presenting to a primary care setting for any cause showing almost no
changes over time. Frthauer et al. [18] have performed a cross-sectional study to
estimate both patients and physicians related factors affecting the adherence to current guidelines. They have concluded that physicians lack of knowledge and
patients lack of awareness account for about 70 % of non-adherence, indicating the
necessity to improve physician education, and patient involvement. In about 30 %
of the quality indicators not fullled, non-adherence is due to other reasons like
adverse drug events or patients not willing to take a recommended drug. The above
data dictate a necessity of more intensive approach to blood pressure management
in the primary care.
89
The task of translating evidence into practice is not easy, it requires investigating
real-world settings to identify the contextual variables that will inuence the implementation process. Nevertheless, today it seem impossible to improve the quality of
care for hypertensive patients without signicant changes in the primary healthcare
system [19].
References
1. European Society of Hypertension Position Paper on Ambulatory Blood Pressure Monitoring.
J Hypertens. 2013;31:173168.
2. Rutten FH, Grobbe DE, Hoes AW. Differences between general practitioners and cardiologists
in diagnosis and management of heart failure: a survey in every-day practice. Eur J Heart Fail.
2003;5:33744.
3. De Castro MS, Fuchs FD, Santos MC, et al. Pharmaceutical care program for patients with
uncontrolled hypertension. Report of a double-blind clinical trial with ambulatory blood pressure monitoring. Am J Hypertens. 2006;19(5):52833.
4. Tobe SW, Pylypchuk G, Wentworth J, et al. Effect of nurse-directed hypertension treatment
among First Nations people with existing hypertension and diabetes mellitus: the Diabetes
Risk Evaluation and Microalbuminuria (DREAM 3) randomized controlled trial. CMAJ.
2006;174(9):126771.
5. Glynn LG, Murphy AW, Smith SM, Schroeder K, Fahey T. Self-monitoring and other nonpharmacological interventions to improve the management of hypertension in primary care: a
systematic review. Br J Gen Pract. 2010. doi:10.3399/bjgp10X544113.
6. Fahey T, Schroeder K, Ebrahim S. Interventions used to improve control of blood pressure in
patients with hypertension. Cochrane Database Syst Rev. 2006;4, CD005182.
7. Carter BL, Bosworth HB, Green BB. The hypertension team: the role of the pharmacist, nurse
and teamwork in hypertension therapy. J Clin Hypertens (Greenwich). 2012;14:5165.
8. Margolius D, Bodenheimer T. Transforming primary care: from past practice to the practice of
the future. Health Aff. 2010;29:77984.
9. Margolius D, Wong J, Goldman ML, Rouse-Iniguez J, Bodenheimer T. Delegating responsibility from clinicians to nonprofessional personnel: the example of hypertension control. J Am
Board Fam Med. 2012;25:20915.
10. Green BB, Cook AJ, Ralston JD. Effectiveness of home blood pressure monitoring, web
communication, and pharmacist care on hypertension control: a randomized controlled trial.
JAMA. 2008;299:285767.
11. Green BB, Ralston JB, Fishman PA, et al. Electronic Communications and Home Blood
Pressure Monitoring (e-BP) study: design, delivery, and evaluation framework. Contemp Clin
Trials. 2008;29(3):37695.
12. Bobrie G, Postel-Vinay N, Delonca J, Corvol P. Self-measurement and self-titration in hypertension. Am J Hypertens. 2007;20:131420.
13. Walsh JM, McDonald KM, Shojania KG, et al. Quality improvement strategies for hypertension management: a systematic review. Med Care. 2006;44:64657.
14. Carter BL, Rogers M, Daly J, Zheng S, James PA. The potency of team-based care interventions for hypertension: a meta-analysis. Arch Intern Med. 2009;169:174855.
15. Robins LS, Jackson JE, Green DD, Korngiebel D, Force RW, Baldwin L-M. Barriers and
facilitators to evidence-based blood pressure control in community practice. J Am Board Fam
Med. 2013;26:53957.
16. Anchala R, Pinto MP, Shrou A, Chowdhury R, Sanderson J, Johnson L, Blanco P, Prabhakaran
D, Franco OH. The role of decision support system (DSS) in prevention of cardiovascular
disease: a systematic review and meta-analysis. PLoS One. 2012;7(10), e47064.
90
E. Shlyakhto
17. Carrington MJ, Jennings GL, Stewart S. Pressure points in primary care: blood pressure and
management of hypertension in 532 050 patients from 2005 to 2010. J Hypertens. 2013;31:
126575.
18. Frthauer J, Flamm M, Snnichsen A. Patient and physician related factors of adherence to
evidence based guidelines in diabetes mellitus type 2, cardiovascular disease and prevention:
a cross sectional study. BMC Fam Pract. 2013;14:47.
19. The Task Force for the management of arterial hypertension of the European Society of
Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertension.
2013;31:12811357.
Diabetes: A Primary Health Care Approach

Meltem Zeytinoglu and Elbert S. Huang
Introduction and Definition of the Problem

The burden of morbidity imposed by diabetes mellitus is well known to most
healthcare providers. As of 2011, in the United States alone, there were an estimated
25.8 million children and adults with diabetes and another 79 million individuals
with prediabetes [1]. Diabetes increases the risk of a wide range of conditions from
cardiovascular disease to cancer to dementia [2]. In the case of cardiovascular disease, individuals with type 2 diabetes have a 24 times higher risk of coronary
artery disease than non-diabetics, and approximately 7580 % of people with diabetes die of cardiovascular disease [3]. Diabetes is ranked as the 7th leading cause
of death in the world. In light of the aging of populations in the developed nations
and the high prevalence of obesity, we can expect the global burden of diabetes to
soar in coming decades [4].
To forestall this global burden, public health efforts to prevent the onset of
diabetes and reduce the risks of complications among those living with diabetes
have become increasingly important. Unfortunately, multiple studies have demonstrated that we are falling short in all levels of diabetes prevention, including primary prevention to prevent the disease from occurring, secondary prevention to
identify diabetes when it has occurred, and tertiary prevention to prevent and manage diabetes complications [5]. Analysis of data obtained from the National Health
and Nutrition Examination Survey and the Behavioral Risk Factor Surveillance
M. Zeytinoglu, M.D. (*)

Endocrinology and Metabolism, Chicago, IL, USA
e-mail: diabetes@uchospitals.edu
E.S. Huang, M.P.H., Ph.D.
Medicine University of Chicago, Chicago, IL, USA
e-mail: ehuang@medicine.bsd.uchicago.edu
DOI 10.1007/978-3-319-22357-5_10
91
92
M. Zeytinoglu and E.S. Huang
System, for example, showed that adults with diabetes met goals for preventive
practices such as diabetes education, vaccinations, and annual dental examinations
only 5060 % of the time [6]. Further, only 14.3 % of adult diabetics met all of
the recommended targets for glycated hemoglobin (HbA1c), blood pressure (BP),
low density lipoprotein (LDL) cholesterol, and achieved non-smoking status.
Moreover, in specific populations such as younger adults; older patients; those with
complicated co-morbidities; those with mental illness; racial and ethnic minorities;
and patients with language barriers, financial, or social hardships, the gap between
actual and desired outcomes is even greater [712].
The Role of the Primary Care Provider in Diabetes Care

In the United States and other developed nations, primary care providers (PCP)
play the leading role in preventing and managing chronic illnesses such as diabetes. In fact, 8090 % of adults with diabetes receive their care exclusively from
their PCP [13, 14]. A hallmark of primary care is the provision of broadly accessible care, which considers multiple determinants of health, and is coordinated
among the patient, family, community, and other health-care providers. During
visits with their PCPs, many processes of care including ordering proper laboratory
tests (i.e., HbA1c, lipid levels, and urine micro-albumin tests), adjustment of medications, and management of complications and behavior changes need to be fulfilled. Each of these should occur while considering individual patients
co-morbidities, preferences, and social and financial concerns. Many providers
report diabetes to be harder to treat than other conditions such as hypertension and
angina [12]. Given the complexity of providing such comprehensive diabetes care,
it is no wonder that PCPs often struggle to achieve all of these goals in a traditional
15- to 30-min patient encounter. Diabetes specialists face many of the same challenges. In fact, although endocrinologists are more likely to perform evidencebased recommended processes of care for diabetes management, studies have not
shown consistent differences in outcomes between primary care physicians and
diabetes specialists [1517]. This suggests that while individual providers can
improve their knowledge of evidence-based guidelines and address the unique
challenges that may prevent individual patients from achieving optimal diabetes
control, both PCPs and specialists are operating in a broader system that makes
improving diabetes care challenging.
Health-System Challenges and Opportunities in Diabetes Care

Historically, health-care systems have centered on individual providers reacting to
acute illnesses. As chronic diseases have become the leading causes of morbidity
and mortality, the need to shift to a more proactive, multi-disciplinary, coordinated,
93
team-based approach to care has emerged [14, 18]. Unfortunately, many individuals
living with diabetes do not experience this model of care. This was demonstrated by
the Diabetes Attitudes, Wishes, and Needs (DAWN) Study, an international survey
of randomly selected generalist and specialist physicians and nurses, and patients
with diabetes. The DAWN study revealed that the majority of patients did not
receive diabetes care with a multi-disciplinary team of providers, including a PCP
or diabetes specialist, diabetes nurse, dietitian, eye doctor, foot doctor, and behavioral specialist [19].
In addition to the DAWN Study based on patient surveys, additional research
published over the last decade and a half has helped to paint a fuller picture of the
current status of chronic disease management and diabetes care. This research has
revealed that practitioners were not following established clinical guidelines, were
not coordinating care with each other, and were not actively following patients to
ensure optimal outcomes. At the same time, this research revealed that patients were
not adequately trained to manage their own illnesses [20]. To address these deficiencies among practitioners and patients, one of the most prominent models of care has
been the Chronic Care Model (CCM), which has been extensively applied to diabetes care. The CCM system shifts care from the traditional model of health-care to
one that is proactive in managing chronic diseases. The CCM is built upon the
principle that optimal chronic disease management necessitates a health-care system composed of six connected components. It includes leadership that encourages
a culture of quality improvement and provides the resources needed to change delivery system design. Delivery systems should be planned to provide coordinated care,
structured to prevent rather than react to disease complications. The next component
is decision support, which equips providers with evidence-based guidelines that
should be considered along with patient preferences to guide care decisions. The
CCM also incorporates clinical information systems to organize patient and population data (i.e., registries) and provides reminders to patients and physicians to enable
proactive care. The next component empowers patients to play the leading role
in the management of their disease by providing education and enabling selfmanagement support. Finally, policies and community resources to improve patient
access and care should be in place [20]. Collaboratively, these six components are
designed to improve population health in a way that makes it easier and more
efficient to address individual patients needs. In 2013, a systematic review of
16 studies, in which the CCM was applied in primary care settings providing diabetes care, showed that the CCM was effective in improving diabetes care and clinical
outcomes [21]. The authors and others acknowledge that further work is needed to
determine how well the CCM is helping patients and providers manage their diabetes and how the CCM can be more easily integrated into smaller or less motivated
practices with fewer resources [22]. Nevertheless, in promoting strategies to
improve diabetes care, the American Diabetes Association has endorsed the CCM
and noted that, care should be aligned with components of the CCM to ensure
productive interactions between a prepared proactive practice team and an informed
activated patient [7].
94
A key component of the CCM is the electronic health (EHR) or medical record,
which not only enables providers to efficiently navigate through individual patient
records, but also readily allows for population-based management. Use of EHR has
been shown, across a broad range of practices, to lead to improved outcomes. In a
study of 27,207 diabetic adults seen in 46 practices, EHR practices had a 35.1 %
increase in process measures of checking HbA1c, testing for urinary micro-albumin,
prescribing angiotensin-converting-enzyme inhibitor or angiotensin-receptor blocker
medications, performing screening eye examinations, and providing a pneumococcal vaccination. Albeit slightly lower, improvement in intermediate outcomes
HbA1c, BP, LDL, body-mass index, and nonsmoking statuswas also 15.2 %
higher in EHR practices [23]. Nevertheless, even with federal incentives and
meaningful use guidelines to promote implementation of EHR, more research on
how to use EHR in an efficient manner is needed [24].
The patient-centered medical home (PCMH) has emerged as another model for
chronic disease management and prevention in primary care and been described as
a vehicle to adopt the Chronic Care Model. [25] The PCMH is built on the
principle that management of chronic care should include the following basic elements: (1) coordination and integration of care to guide the patient through the
health system; (2) a focus on quality and safety which incorporates up-to-date
guidelines, is applied consistently, and is incorporated into patient registries so that
performance can be tracked; (3) whole person orientation which focuses on primary, secondary, and tertiary prevention; (4) a personal physician who is a first
contact for the patient, is aware of individual psychosocial and cultural components
that may influence a patients health, and, among members of the health-care team,
who serves as the lead coordinator of the patients care, (5) enhanced access with
flexible scheduling and easy access to members of the team, and (6) a system where
quality improvement and care coordination is appropriately reimbursed. Practices
that are recognized as a PCMH receive a per member per month fee in addition to
regular reimbursement through fee-for-service.
PCMH interventions have been studied a great deal and more pilots are underway. In a recent study, 8 PCMH pilots, from geographically diverse settings, were
reviewed and noted to report outcomes data. All have led to variable improvement of
intermediate outcomes including improved HbA1c, BP, and LDL control, and several have shown reduced emergency room and inpatient admissions, cost savings,
and improved patient satisfaction [25]. Of note, all of these programs included a
structured role for care coordination, in most cases, through a case manager. In a
meta-analysis of quality improvement strategies and glycemic control, case management and team changes, which add additional health-care providers to the patients
care team, or expand the role of an existing nurse or pharmacist, were identified as
the two most effective strategies in improving patient outcomes [26].
There have been a few large prospective studies designed to evaluate the
effectiveness of similar multi-component system change models. The Translating
Research Into Action For Diabetes (TRIAD) Study was a multi-center study which
gathered a cohort of 180,000 demographically and geographically diverse diabetic
individuals from 10 different health plansincluding for-profit, not-for-profit,
95
Medicare, and Medicaid plansand 68 provider groups delivering primary and

specialty care. TRIAD investigators found that performance feedback, physician
reminders, and structured care management were each strongly associated with better care processes (periodic HbA1c testing, lipid testing, micro-albuminuria testing,
retinal examinations, foot examinations, smoking cessation counseling, aspirin
prescription). However, process of care rankings were completely unrelated to
rankings for actual health outcomes, specifically HbA1c and BP control. The data
also showed that patients with co-payments or co-insurance had lower rates of
self-monitoring of blood glucose and were less likely to use recommended medications. In fact, those patients who cited that out-of pocket costs were a barrier to
self-management had significantly less control of HbA1c, BP, and LDL [8].
The TRANSLATE trial was a randomized clinical trial conducted in 24 primary
care practices and included over 8000 patients. The intervention began with identifying high-risk individuals and included an electronic diabetes registry, visit reminders, patient-specific physician alerts, a site coordinator who managed clinic
operations and planning, and monthly performance review with a local physician
champion. This study was notable in that not only did process measures improve,
but so did intermediate clinical outcomes which included significantly decreased
HbA1c, BP, and LDL in intervention patients [13].
Data on the cost-effectiveness of quality improvement and system redesign initiatives such as the Chronic Care Model are still emerging. Nevertheless, there is a
growing body of literature to support the notion that efforts aimed at primary, secondary, and tertiary prevention of diabetes outcomes are cost-effective [27]. One study,
which looked at the cost-effectiveness of the Health Disparities Collaborativea
national collaborative quality improvement program conducted in community health
centersfound that the collaborative resulted in incremental prevention of end stage
complications of diabetes (blindness, end-stage renal disease, coronary artery disease). The reduced risk of these complications was shown to be cost-effective [28].
Especially when considering that preventive efforts aimed at improving diabetes care
are likely to reduce risk for other diseases, data on cost-effectiveness of such measures will likely continue to emerge. Cost-effectiveness data also may also provide
support for improving access to diabetes care and addressing payment reform.
In addition to changing the structure of diabetes care, improving diabetes prevention and control in an increasingly aging and overweight population requires
policies to improve access to PCPs and diabetes specialists. Currently, it has been
estimated that there are only half of the needed endocrinologists in the United
States and that by 2020 there will be an estimated shortage of at least 20,000 primary care physicians [29, 30]. In addition to strengthening medical education
training to prepare trainees to manage chronic diseases and improve incentives for
choosing specialties like primary care and endocrinology, improved access may
also be achieved through increased use of midlevel practitioners including nurse
practitioners and physician assistants. One model, which has been proposed to
improve access to diabetes care, is the group visit or shared medical appointment.
It has shown, across multiple studies, to improve processes of care, adherence to
established diabetes guidelines, intermediate outcomes such as HbA1c, BP, and
96
lipid control, and patient satisfaction [31, 32]. Group visits may also facilitate
improved care coordination and efficiency if multiple providers are able to see the
patient and address different needs including medication issues, self-management
support, lifestyle and behavioral counseling, and ophthalmologic and foot evaluations in the same visit. One major impediment to restructuring care around teambased visits has been payment. Traditional payment models have not addressed
the time spent to coordinate care among members of the chronic care team.
Provisions of the Affordable Care Act, including increased Medicare reimbursement for primary care services, grants for development of patient-centered medical homes and coordinated care, and improving access to health insurance
coverage, which can improve self-reported health and lead to future reductions in
health care use and spending, are a first step towards improving outcomes from a
systems perspective [33, 34].
Conclusion
Despite all of these struggles, using an evidence-based approach, and through the
unique relationship built from continuity of care with patients, PCPs can empower
and assist their patients in improving diabetes prevention and reducing cardiometabolic risk. Approximately 7.0 million Americans have diabetes that has not been
diagnosed [1]. PCPs play a critical role in secondary prevention and should be
familiar with evidence-based screening guidelines in order to proactively diagnose
and treat diabetes. Similarly, there is now evidence, from multiple prospective trials, demonstrating sustainable interventions that are effective at preventing or
delaying diabetes [35]. The Diabetes Prevention Program (DPP), for example,
showed that a dietary intervention with a low-calorie low-fat diet leading to a 7 %
weight loss, and moderate intensity physical activity for 150 min/week lead to a
58 % reduction in type 2 diabetes risk over a mean of 2.8 years. The DPP also
showed that metformin use resulted in a 31 % risk reduction compared with placebo. The Diabetes Prevention Program Outcomes Study (DPPOS) followed these
patients for 10 years from initial randomization and also demonstrated that these
changes were sustainable [35]. Recently, the Look AHEAD (Action for Health in
Diabetes) research group published their findings that overweight/obese adults
with type 2 diabetes randomized to intensive lifestyle counseling achieved and sustained weight loss significantly more, over 8 years, than compared to patients
assigned to the usual care of diabetes support and education [36]. Taken together,
these findings further support the need to design diabetes care systems in a way that
enables such preventive programs.
Primary care providers can champion initiatives to improve diabetes care by
helping to create and engaging in the type of system that has been described.
Individual providers can build a framework for diabetes care by familiarizing themselves with the established, up-to-date, evidence base and guidelines such as the
97
American Diabetes Association Standards of Medical Care in Diabetes and relevant

guidelines for associated co-morbidities such as obesity, hypertension, and cardiovascular disease. Then, through continuity, which enables a trusting relationship to
be established with the patient over multiple visits, PCPs should identify the unique
determinants of health that may affect the outcomes in the individual diabetic
patients. These factors include the patients demographics, ethnic and cultural
background, education and health literacy, medical and psychological co-morbidities,
and socioeconomic status. All of these should be considered, such that evidencebased guidelines can be followed in a way that addresses and does not conflict with
challenges from any of these factors.
Given the complexity of the disease and the magnitude of the diabetes epidemic,
PCPs, should be ready to participate in multi-disciplinary teams and facilitate
collaboration and integration of care with other providers. A meta-analysis of five
studies looking at interactive communications such as joint patient consultations,
specialist attendance at primary care team meetings, scheduled telephone discussions, and shared electronic progress notes between collaborating endocrinologists
and primary care physicians showed an additional 1.4 % reduction in HbA1c in
individuals whose care included interactive communications [37]. Evidence has
also shown that sustained improvement in processes of care and health outcomes
requires ongoing performance measurement and feedback to clinicians [38].
To ease the access problem, primary care physicians can work with nurse practitioners, physician assistants, pharmacists, and nurse case managers to coordinate
care. This care will need to be highly structured with embedded evidence-based
decision support and include comprehensive electronic health records from which
different providers can easily obtain data and an understanding of the primary care
physicians treatment objectives and plans for the individual patient. This has the
potential to increase efficiency and ultimately yield sustained improvements in outcomes [18, 39].
With the number of diabetics expected to rise to over 592 million in the next
25 years, the International Diabetes Federation, has made the following sobering
assessment: the battle to protect people from diabetes and its disabling, life threatening complications is being lost. [5] Of the estimated 347371 million individuals
who have diabetes globally, the largest burden of diabetes morbidity and mortality
is imposed upon low- and middle-income countries, where 80 % of diabetics
live and where resources for are significantly more limited. Nevertheless, efforts to
improve regional screening efforts, access to glucose monitoring supplies and medications; educate and strengthen local community resources; and increase access to
appropriately trained health-care providers will be imperative to combat and prevent the growing global burden of morbidity and mortality related to diabetes [3].
Broad and extensive, national and international, public health and care-delivery
programs will be imperative to improving this burden, enabling the primary care
provider to continue to be the champions of their patients health, and shift the diabetes battle to a winning war of prevention.
98
References
1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: national estimates
and general information on diabetes and prediabetes in the United States, 2011. Atlanta, GA:
U.S. Department of Health and Human Services, Centers for Disease Control and Prevention;
2011.
2. Biessels GJ, Staekenborg S, Brunner E, Brayne C, Scheltens P. Risk of dementia in diabetes
mellitus: a systematic review. Lancet Neurol. 2006;5(1):6474.
3. Alberti KGMM, Zimmet P, Shaw J. International Diabetes Federation: a consensus on Type 2
diabetes prevention. Diabet Med. 2007;24:45163.
4. Huang ES, Basu A, O'Grady M, Capretta JC. Projecting the future diabetes population size and
related costs for the U.S. Diabetes Care. 2009;32(12):22259.
5. International Diabetes Federation. IDF Atlas, 6th edn. Brussels, Belgium: International
Diabetes Federation, 2013. http://www.idf.org/diabetesatlas.
6. Ali MK, Bullard KM, Saaddine JB, et al. Achievement of goals in U.S. diabetes care, 1999
2010. N Engl J Med. 2013;368:161324.
7. American Diabetes Association. Standards of medical care in diabetes 2014. Diabetes Care.
2014;37 Suppl 1:S1480.
8. TRIAD Study Group. Health systems, patient factors, and quality of care for diabetes. A synthesis of findings from the TRIAD Study. Diabetes Care. 2010;33:94047.
9. Huang ES, Laiteerapong N, Liu JY, et al. Rates of complications and mortality in older patients
with diabetes mellitus. The Diabetes and Aging Study. JAMA Intern Med. 2014;174:2518.
10. Frayne SM, Halanych JH, Miller DR, et al. Disparities in diabetes care. Impact of mental
illness. Arch Intern Med. 2005;165:26318.
11. Peek ME, Cargill A, Huang ES. Diabetes health disparities: a systematic review of health care
interventions. Med Care Res Rev. 2007;64 Suppl 5:S10156.
12. Nam S, Chesla C, Stotts NA, Kroon L, Janson SL. Barriers to diabetes management: patient
and provider factors. Diabetes Res Clin Pract. 2011;93:19.
13. Peterson KA, Radosevich DM, OConnor PJ, et al. Improving diabetes care in practice.
Findings from the TRANSLATE trial. Diabetes Care. 2008;31:223843.
14. Rothman AA, Wagner EH. Chronic illness management: what is the role of primary care? Ann
Intern Med. 2003;138:25661.
15. Post PN, Wittenberg J, Burgers JS. Do specialized centers and specialists produce better outcomes for patients with chronic diseases than primary care generalists? A systematic review.
Int J Qual Health Care. 2009;21:38796.
16. McAlister FA, Majumdar SR, Eurich DT, Johnson JA. The effect of specialist care within the
first year on subsequent outcomes in 24,232 adults with new onset-diabetes mellitus:
population-based cohort study. Qual Saf Health Care. 2007;16:611.
17. Shah BR, Hux JE, Laupacis A, Zinman B, Zwarenstein M. Deficiencies in the quality of diabetes care. Comparing specialist with generalist care misses the point. J Gen Intern Med.
2007;22:2759.
18. National Diabetes Education Program, National Institutes of Health. Redesigning the Health
Care Team: Diabetes Prevention and Lifelong Management. Bethesda, MD: U.S. Department
of Health and Human Services; 2011.
19. Funnell MM. The Diabetes Attitudes, Wishes, and Needs (DAWN) Study. Clin Diabet.
2006;24:1545.
20. Wagner EH, Austin BT, Davis C, Hindmarsh M, Schaefer J, Bonomi A. Improving chronic
illness care: translating evidence into action. Health Aff. 2001;20:6478.
21. Stellefson M, Dipnarine K, Stopka C. The Chronic Care Model and diabetes management in
US primary care settings: a systematic review. Prev Chronic Dis. 2013;10:120180. doi:10.5888/
pcd10.120180.
99
22. Coleman K, Austin BT, Brach C, Wagner EH. Evidence on the chronic care model in the new
millennium. Health Aff. 2009;28:7585.
23. Cebul RD, Love TE, Jain AK, Hebert CJ. Electronic health records and quality of diabetes
care. N Engl J Med. 2011;365:82533.
24. Blumenthal D. A tale of two angels. Ann Intern Med. 2013;158:48990.
25. Bojadzievski T, Gabbay RA. Patient-Centered Medical Home and diabetes. Diabetes Care.
2011;34:104753.
26. Shojania KG, Ranji SR, McDonald KM, et al. Effects of quality improvement strategies for
type 2 diabetes on glycemic control. JAMA. 2006;296:42840.
27. Li R, Zhang P, Barker LE, Chowdhury FM, Zhang X. Cost-effectiveness of interventions to
prevent and control diabetes mellitus: a systematic review. Diabetes Care. 2010;33:187294.
28. Huang ES, Zhang Q, Brown SE, et al. The cost-effectiveness of improving diabetes care in
U.S. federally qualified community health centers. Health Serv Res. 2007;42:217493.
29. Stewart AF. The United States endocrinology workforce: a supply-demand mismatch. J Clin
Endocrinol Metab. 2008;93:11646.
30. U.S. Department of Health and Human Services, Health Resources and Services Administration,
National Center for Health Workforce Analysis. Projecting the Supply and Demand for
Primary Care Practitioners Through 2020. Rockville, MD: U.S. Department of Health and
Human Services; 2013.
31. Davis AM, Sawyer DR, Vinci LM. The potential of group visits in diabetes care. Clin Diabet.
2008;26:5862.
32. Housden L, Wong ST, Dawes M. Effectiveness of group medical visits for improving diabetes
care: a systematic review and meta-analysis. CMAJ. 2013;185:E63544.
33. McWilliams JM, Meara E, Zaslavsky AM, Avanian JZ. Use of health services by previously
uninsured Medicare beneficiaries. N Engl J Med. 2007;357:14353.
34. McWilliams JM, Meara E, Zaslavsky AM, Avanian JZ. Health of previously uninsured adults
after acquiring Medicare coverage. JAMA. 2007;298:288694.
35. Tuomilehto J, Schwarz P, Lindstrom J. Long-term benefits from lifestyle interventions for type
2 diabetes prevention. Time to expand the efforts. Diabetes Care. 2011;34 Suppl 2:S2104.
36. The Look Ahead Research Group. Eight-year weight losses with an intensive lifestyle intervention: The Look AHEAD Study. Obesity. 2014;22:513.
37. Foy R, Hempel S, Rubenstein L, et al. Meta-analysis: effect of interactive communication
between collaborating primary care physicians and specialists. Ann Intern Med. 2010;152:
24758.
38. OConnor PJ, Bodkin NL, Fradkin J, et al. Diabetes performance measures: current status and
future directions. Diabetes Care. 2011;34:16519.
39. Morrison F, Shubina M, Goldberg SI, Turchin A. Performance of primary care physicians and
other providers on key process measures in the treatment of diabetes. Diabetes Care. 2013;
36:114752.
Risk Factors in Childhood and Youth

Joep Perk
Background
In recent decades a shift in the epidemiology of cardiovascular diseases (CVD)
from high to middle and low income countries has been observed. CVD mortality is
declining in the high income regions but it still remains a major cause of premature
death and presently >80 % of all CVD mortality occurs in the remaining part of the
world. As atherosclerotic disease is a chronic disorder developing early in life and
progressing over decades before symptoms occur factors that influence its onset
should be sought as early as in childhood.
The change in pediatric epidemiology is impressive: soon one may observe
globally more children to be overweight or adipose than children suffering from
with underweight and malnutrition. With increasing socioeconomic affluence the
access to high caloric food such as sweetened drinks and fast food may contribute
to childhood obesity. TV, video and other computer games increase the risk of a
sedentary lifestyle with significant lack of physical activity. The option of mobile
telephone communication on most hours of the day and night might interfere with
healthy sleeping habits and thereby add to a lifestyle that may be harmful for the
health of the growing child and may lead to the early onset of atherosclerosis.
Cardiovascular risk factors can be detected in childhood and may predict the risk
of CVD later in life [1, 2]. Autopsy studies have shown the influence of CVD
risk factors on the development of the early atherosclerotic lesion, the lipid loaded
subendothelial plaque, which can be observed in as early as in childhood [3]. Crosssectional studies have demonstrated an increasing trend in carotid artery intimamedia thickness (IMT) related to a number of risk factors in asymptomatic healthy
young adults [4, 5]. Data from the Bogalusa Heart Study indicated that low-density
J. Perk, MD, FESC (*)

School of Health and Caring Sciences, Linnaeus University, 391 82 Kalmar, Sweden
e-mail: joep.perk@lnu.se
DOI 10.1007/978-3-319-22357-5_11
101
102
J. Perk
lipoprotein cholesterol (LDL-C) levels, measured either in childhood or adulthood

or as a long-term cumulative burden since childhood, and BMI in childhood both
predicted adult carotid IMT. Thus, both LDL-C and BMI may be used in CVD risk
assessment in childhood [6].
Should screening all children for CVD risk factors be recommended, not just
children of parents with known CVD or high risk factors as recently recommended
by an expert panel? [7]. In the Princeton LRC follow-up study Morrison et al. could
show that risk factors for CVD and type 2 diabetes mellitus retained from childhood
predict adult outcomes: those who had elevated triglyceride levels and retained these
high levels as adults had increased CVD events as adults, while children who had a
normal body mass index (BMI) and retained a normal BMI as adults had reduced
CVD events in adulthood. They even observed that children who had high blood
pressure or high triglycerides and retained these as adults had an increased incidence
of type 2 diabetes later in life. Thus, the argument for screening is strengthening as
behavioural and pharmacologic intervention in childhood-adolescence might prevent development of CVD or Type 2 diabetes in young adulthood [8].
What is the role of lifestyle changes between youth and adulthood? Does it have
an effect on blood lipid and lipoprotein levels later in life? Adopting a heart-healthy
lifestyle in the early years of life will lower CVD risk but, as shown in an Australian
study, even youths with low CVD risk who increased their BMI and waist circumference are more likely to have high-risk levels of triglycerides and LDL-C in adulthood [9]. Therefore, screening may be of importance but likewise important are
preventive programs including cessation of smoking, weight control and increasing
physical activity aimed at those young persons who do not have a high risk profile.
This is needed if the proportion of adults with high-risk levels is to be reduced.
The main risk factors for premature coronary heart disease are smoking,
adiposity, a lack of physical activity, hypertension and less frequent hereditary
familial hyperlipidemi.
Obesity
Prevention of childhood obesity should be a global public health priority due to
the significant impact of obesity on acute and chronic diseases, general health,
development and quality of life. The importance of childhood obesity for CVD
development later in life has been convincingly demonstrated in a Danish study
where height and weight data collected from 276,835 Danish individuals when they
were children were related to data on CVD when they were adults. Here it was
shown that the risk for any CVD event was positively and linearly associated with
body mass index (BMI) for boys aged 713 years and girls aged 1013 years, with
a greater risk as age increased for both boys and girls [10].
Obesity as early as at the age of 5 years may lead to an increased prevalence of
both type 1 and 2 diabetes mellitus at the age of 21 which was reported from a
group of 2639 Australian young adult participants of the Mater-University study of
103
pregnancy. The odds ratio for diabetes if there was overweight at 5 years amounted
to 2.60 [11]. In addition, teenagers and young adults who are already obese or have
type 2 diabetes have an increased carotid artery intima-media thickness and arterial
stiffness [12]. Participants in this US study were more likely than the lean individuals to have other cardiovascular risk factors. Their risk factors correlated with both
carotid IMT and stiffness but group was reported to be an independent predictor
of common carotid artery IMT and for the beta stiffness index. Additional effects of
type 2 diabetes and obesity appear to influence changes in the carotid structure and
function beyond traditional risk factors.
Several direct and indirect methods of assessing overweight in children and adolescents have been proposed but body mass index and waist circumference can be
recommended as the best measures for estimating adverse levels of blood lipids and
blood. Mller and co-workers found that among children and adolescents with an
elevated obesity index 2030 % also had elevated levels in blood pressure and blood
lipids. Their data did not support the statement that direct measures of fat mass or
waist circumference exceed the value of BMI [13].
Are interventions aimed to improve diet or physical activity effective at preventing obesity in children? An updated analysis of a Cochrane Review included
55 childhood obesity prevention studiesan additional 36 from the previous
Cochrane reviewall with a duration of 12 weeks or more [14]. In this review
strong evidence was found to support beneficial effects of child obesity prevention
programs on BMI, particularly for programmes targeted to children aged 612 years.
The review included 55 childhood obesity studiesan additional 36 from the previous reviewall with a focus on prevention and a duration of 12 weeks or more. The
team conducted a meta-analysis using available BMI or standardized BMI (zBMI)
score data and subgroup analyses were performed by age group (05, 612, and
1318 years). The interventions were generally effective at reducing adiposity; the
overall mean reduction in adiposity (measured as BMI or zBMI) was 0.15 kg/m2,
with the largest reduction occurring among children aged 612 years. Thus there
is nowadays sufficient scientific support for conducting prevention targeted programmes for childhood obesity.
Over the years the public awareness of nutrition high in saturated fat has resulted
in an unfortunate increased use of high caloric carbohydrates. Many children and
adolescents consume significant amounts of sweetened soft drinks. These are generally both cheap and everywhere accessible. The deleterious effects of a chronic caloric
overload have become a major public health hazard. Welsh and co-workers found that
adolescents who consume high amounts of added sugars have blood lipid levels that
place them at a clearly increased risk for future CVD: increased dyslipidemia was
observed among adolescents who had a high intake of added sugars, regardless of
body size, as well as increased levels of insulin resistance among those who were
overweight or obese. Therefore minimizing the consumption of added sugars in the
young population is an important task both for parents as for society as a whole [15].
It is known that the maturing of the human brain takes mainly place in the first
two decades of life. Could unhealthy nutritional habits influence this process, especially as diet supplies the nutrients needed for the development of brain tissues in
104
J. Perk
early life? A study from Australia investigated the impact of diet on the intelligence
quotient (IQ) by assessing data from 7097 children from the Avon Longitudinal
Study of Parents and Children. They examined dietary patterns for the children
using parental questionnaires completed at 6, 15, and 24 months of age and when
the children were aged 8 years, the Wechsler Intelligence Scale for Children was
used to measure IQ. A small but significantly higher IQ at 8 years was found when
a healthy diet had been provided during the first 2 years of life [16].
Physical Inactivity
With the growing access to electronic communication devices, smart phones etc,
there is a tendency among children to become less active. Instead, children should
be encouraged to increase their participation in physical activity, rather than reducing their time spent sedentary, to improve their cardiovascular health. Ekelund et al.
pooled data from 14 studies involving more than 20,000 children (aged 418 years)
and found that higher time spent on moderate to vigorous activity spent by children
and adolescents was associated with better cardiometabolic risk factors regardless
of the amount of sedentary time. They recommend to increase daily activity at this
intensity level by participating in activities such as brisk walking, jogging, cycling,
playing soccer, and other team sports [17].
Even maintaining a high level of fitness plays an important role as children and
adolescents with higher levels of cardiorespiratory fitness (CRF) have reduced clustering of cardiometabolic risk factors. After assessing CRF and physical activity
levels in 100 children and adolescents (aged 1014 years) using a maximal cycle
ergometer test and accelerometry, Bauley et al. used a clustered risk score. They
found in comparing between fit and unfit participants, according to previously proposed health-related thresholds, that the fit group had a significantly lower mean
clustered risk score than those in the unfit group (0.74 vs 2.22, respectively) [18].
Keeping up physical activity and fitness may reduce the risk of type 2 diabetes
mellitus as children grow into adulthood. A prospective Australian cohort study followed 647 adults who had participated in the Australian Schools Health and Fitness
Survey in 1985 when they were aged 915 years and followed up in 20042006.
The study showed that the decline in fitness and in physical activity which often can
be seen in many teenagers is a stronger predictor of adult obesity and insulin resistance than low levels of fitness in childhood. Thus, efforts aimed at maintaining high
childhood physical activity levels into adulthood may have a potential to reduce the
burden of obesity and type 2 diabetes in adults [19].
Not all video and computer games seem to be hazardous, as has been considered
previously. A research team from New Zealand randomized 322 overweight and
obese children aged 1014 years, who were current users of sedentary video games,
to receive either an active video game upgrade or to have no change. After 24 weeks
the active video game intervention had a small but significant effect on BMI and
105
body composition in the overweight and obese children. As it is a challenge for

many parents to protect children from an overdose of electronic toys it may be
prudent to choose games that actually promote physical activity [20].
Over the years recommendations for physical activity have varied and in practice
1 h of moderate physical activity has been used in many countries. This has recently
been questioned and age- and gender-specific guidelines may be needed: in a study
in BMC Medicine it is proposed that boys <6 years old need more than 70 min of
moderate-to-vigorous exercise a day, whereas older boys need at least 80 min. Girls
of all ages need around an hour of exercise [21].
Hypertension
Hypertension in childhood has been considered a rare condition but data from the
Healthcare Cost and Utilization Project Kids Inpatient Database (USA) may have
changed this common belief: it has now been observed that hypertension-related
hospitalizations in the age group 218 years almost doubled between 1997 and
2006 from 12,661 to 24,602 cases annually. As a child with high blood pressure is
at increased risk for maintaining high blood pressure (BP) in adulthood this will
result in increased CVD later in life. Therefore there is a need to invest in early
detection, prevention, and treatment of elevated blood pressure in children [22].
What does predict the development of high BP in childhood? This question has
been addressed in the largest reported contemporary cohort of healthy, prepubertal
children. It appeared that the strongest anthropometric association with BP at 10 years
was weight gain after infancy. Even effects of the babys size at birth and of early postnatal growth were noticed but their magnitude was substantially smaller than weight
gain in a later phase. Greater reductions in BP at population level may be expected
from strategies that reduce the development of adiposity from infancy onwards than
merely emphasizing the nutrition and weight of mothers and infants [23].
Current salt intake remains high in children. This is likely to predispose to
develop hypertension. A recent meta-analysis showed that even modest reductions
in salt intake could lessen age-related BP increases, which will result in major
reductions in CVD. Feng et al. carried out a meta-analysis of ten trials, including
966 children and adolescents, aged 816 years, in which the effects of reducing salt
intake were investigated. The study showed that salt intake was reduced by 42 %,
with significant reductions in both systolic (by on average 1.2 mmHg) and diastolic
(1.3 mmHg) BP. In a separate, analysis of three trials, including 551 infants, a 54 %
reduction in salt intake was associated with a significant 2.5 mmHg reduction in
systolic BP. This first meta-analysis of salt reduction in children shows that a modest reduction in salt intake will lead to immediate falls in BP and, if continued, may
probably attenuate a subsequent rise in BP with age [24]. Experts now recommend
that children should consume <2300 mg of sodium per day.
106
J. Perk
Smoking
Smoking rates have fallen in several countries over the past years, however smoking
among adolescents remain a substantial public health problem, especially among
teenage girls. The so-called passive smoking contributes to an increased CVD
risk. In a cross sectional surveys of nationally representative samples of secondary
school children carried out between 1988 and 1998, in England, showed that exposure to passive smoking among children had approximately halved since the late
1980s. This reduction was partly explained by the fall in the percentage of parents
who smoke and may also likely reflect reductions of smoking in public places [25].
Parental smoking can raise the blood pressure (BP) levels of healthy children
under the age of 5 years, according to findings among Swiss children. Here, smoking
was reported by 28.5 % of fathers, 20.7 % of mothers, and 11.9 % of parent sets (both
parents). This led to a slightly higher BP among children exposed to parental smoking than those with no parental smoking exposure, with mean systolic and diastolic
BP levels of 100 versus 101 mmHg and 62 versus 62.5 mmHg, respectively [26].
New studies have clarified the vascular and metabolic consequences of smoking in
young age. In a study on 2273 subjects 1219 years of age from the National Health
and Nutrition Examination Survey III (NHANES III, 19881994) the relation between the prevalence of the metabolic syndrome and exposure to smoking has been
investigated, showing a doseresponse, cotinine-confirmed relationship between
tobacco smoke and metabolic syndrome among adolescents with a threefold increase
for passive smoking and a up to fivefold increase among active smokers [27].
Kallio and co-workers investigated the effect of exposure to tobacco smoke on
the arterial wall in healthy 13-year-old adolescents from the atherosclerosis prevention trial STRIP. They showed an independent association with exposure and
preclinical atherosclerosis as seen in the effect of smoking on maximum carotid
and aortic intima-media thickness and brachial artery flow-mediated dilation [28].
Clearly the rationale for a complete tobacco smoke free environment for the young
generation is increasingly convincing!
Hyperlipidemia
The main lipid disorder in childhood and adolescence is familial hypercholesterolaemia (FH), a common genetic disorder affecting approximately 30 children per
100,000 persons. The disorder leads to a marked elevation in LDL-C levels that
predisposes to premature CVD in adult life. The majority of children and adolescents with FH remain undiagnosed, as the clinical symptoms develop after decades.
Once a family member with FH has been diagnosed screening is the recommended
approach that allows the diagnosis of FH to be made in the young, before significant
atherosclerosis develops. With the availability of effective lipid lowering drugs,
these children should be referred to a paediatrician for specialist management and
follow-up, thus improving the prognosis for these children [29].
107
Summary
Prevention of CVD in childhood and adolescence remains a challenge that calls for
high priority among many stakeholders: politicians, health care providers, schools,
parents, sport clubs etc. The targets for preventive programmes are creating a
tobacco-free environment, combating the childhood obesity pandemic and promoting regular physical activity on most days of the week. Promising policies and strategies can be a school curriculum that includes healthy eating, physical activity and
body image. Improvements in nutritional quality of the food supply in schools, environments and cultural practices that support children eating healthier foods and
being active throughout each day are needed. Parent support and home activities
that encourage children to be more active, eat more nutritious foods and spend less
time in screen based activities are invaluable for an effective CVD prevention [14].
References
1. Akerblom HK, Uhari M, Pesonen E, et al. Cardiovascular risk in young Finns. Ann Med.
1991;23:359.
2. Berenson GS. Childhood risk factors predict adult risk associated with subclinical cardiovascular disease: the Bogalusa Heart Study. Am J Cardiol. 2002;90(suppl):3L7.
3. McGill Jr HC, McMahan CA, Malcom GT, Oalmann MC, Strong JP. Effects of serum lipoproteins and smoking on atherosclerosis in young men and women: the Pathobiological
Determinants of Atherosclerosis in Youth (PDAY) Research Group. Arterioscler Thromb Vasc
Biol. 1997;17:95106.
4. Urbina EM, Srinivasan SR, Tang R, Bond MG, Kieltyka L, Berenson GS. Impact of multiple
coronary risk factors on the intima-media thickness of different segments of carotid artery in
healthy young adults (the Bogalusa Heart Study). Am J Cardiol. 2002;90:9538.
5. Juonala M, Magnussen CG, Venn A, Dwyer T, Burns TL, Davis PH, et al. Influence of age on
associations between childhood risk factors and carotid intima-media thickness in adulthood:
the Cardiovascular Risk in Young Finns Study, the Childhood Determinants of Adult Health
Study, the Bogalusa Heart Study, and the Muscatine Study for the International Childhood
Cardiovascular Cohort (i3C) Consortium. Circulation. 2010;122:251420.
6. Li S, Chen W, Srinivasan SR, Bond G, Tang R, Urbina EM, Berenson GS. Childhood cardiovascular risk factors and carotid vascular changes in adulthood, the Bogalusa Heart Study.
JAMA. 2003;290:22716.
7. Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in
Children and Adolescents; National Heart, Lung, and Blood Institute. Expert panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents:
summary report. Pediatrics 2011;128(Suppl 5):S21356. doi:10.1542/peds.2009-2107C. Epub
2011 Nov 14.
8. Morrison JA, Glueck CJ, Woo JG, Wang P. Risk factors for cardiovascular disease and type 2
diabetes retained from childhood to adulthood predict adult outcomes: the Princeton LRC
Follow-up Study. Int J Pediatr Endocrinol. 2012;2012(1):6. doi:10.1186/1687-9856-2012-6.
9. Magnussen CG, Thomso R, Cleland VJ, Ukoumunne OC, Dwyer T, Venn A. Factors affecting
the stability of blood lipid and lipoprotein levels from youth to adulthood evidence from
the childhood determinants of adult health study. Arch Pediatr Adolesc Med. 2011;165(1):
6876.
108
J. Perk
10. Baker JL, Olsen LW, Srensen TIA. Childhood body-mass index and the risk of coronary heart
disease in adulthood. N Engl J Med. 2007;357:232937.
11. Al Mamun A, Cramb SM, OCallaghan MJ, Williams GM, Najman JM. Childhood overweight
status predicts diabetes at age 21 years: a follow-up study. Obesity. 2009;17:125561.
12. Urbina EM, Kimball TR, McCoy CE, Khoury PR, Daniels SR, Dolan LM. Youth with obesity
and obesity-related type 2 diabetes mellitus demonstrate abnormalities in carotid structure and
function. Circulation. 2009;119:29139.
13. Plachta-Danielzik S, Landsberg B, Johannsen M, Lange D, Muller MJ. Association of different obesity indices with blood pressure and blood lipids in children and adolescents. Br J Nutr.
2008;100:20818.
14. Waters E, de Silva-Sanigorski A, Burford BJ, Brown T, Campbell KJ, Gao Y, et al. Interventions
for preventing obesity in children. Cochrane Database Syst Rev. 2011;(12). Art. No:CD001871.
doi:10.1002/14651858.CD001871.pub3.
15. Welsh JA, Sharma A, Cunningham SA, Vos MB. Consumption of added sugars and indicators
of cardiovascular disease risk among US adolescents. Circulation. 2011;123:24957.
16. Smithers LG, Golley RK, Mittinty MN, Brazionis L, Northstone K, et al. Dietary patterns at 6, 15
and 24 months of age are associated with IQ at 8 years of age. Eur J Epidemiol. 2012;27:52535.
17. Ekelund U, Luan Ja, Sherar LB, Esliger DW, Griew P, Cooper A. Moderate to vigorous physical activity and sedentary time and cardiometabolic risk factors in children and adolescents.
JAMA. 2012;307(7):70412.
18. Bailey DP, Boddy LM, Savory LA, Denton SJ, Kerr CJ. Associations between cardiorespiratory fitness, physical activity and clustered cardiometabolic risk in children and adolescents:
the HAPPY study. Eur J Pediatr. 2012;171:131723.
19. Dwyer T, Magnussen CG, Schmidt MD, Ukoumunne OC, Ponsonby A-L, et al. Decline in
physical fitness from childhood to adulthood associated with increased obesity and insulin
resistance in adults. Diabetes Care. 2009;32:6837.
20. Maddison R, Foley L, Mhurchu CN, Jiang Y, Jull A, Prapavessis H, Hohepa M, Rodgers
A. Effects of active video games on body composition: a randomized controlled trial. Am J
Clin Nutr. doi:10.3945/ajcn.110.009142.
21. Jimnez-Pavn D, Konstabel K, Bergman P, Ahrens W, Pohlabeln H, Hadjigeorgiou C, et al.
Physical activity and clustered cardiovascular disease risk factors in young children:
a cross-sectional study (the IDEFICS study). BMC Med. 2013;11:172. doi:10.1186/
1741-7015-11-172.
22. Tran CL, Ehrmann BJ, Messer KL, Herreshoff E, Kroeker A. Recent trends in healthcare utilization among children and adolescents with hypertension in the United States. Hypertension.
2012;60:296302.
23. Jones A, Charakida M, Falaschetti E, Hingorani AD, Finer N, Masi S, Donald AE, Lawlor DA,
Smith GD, Deanfield JE. Adipose and height growth through childhood and blood pressure
status in a large prospective cohort study. Hypertension. 2012;59:91925.
24. He FJ, MacGregor GA. Importance of salt in determining blood pressure in children, metaanalysis of controlled trials. Hypertension. 2006;48:8619.
25. Jarvis MJ, Goddard E, Higgins V, Feyerabend C, Bryant A, Cook DG. Childrens exposure to
passive smoking in England since the 1980s: cotinine evidence from population surveys. BMJ.
2000;321:3435.
26. Simonetti GD, Schwertz R, Klett M, Hoffmann GF, Schaefer F, Whl E. Determinants of blood
pressure in preschool children. The role of parental smoking. Circulation. 2011;123:2928.
27. Weitzman M, Cook S, Auinger P, Florin TA, Daniels S, Nguyen M, Winickoff JP. Tobacco
smoke exposure is associated with the metabolic syndrome in adolescents. Circulation.
2005;112:8629.
28. Kallio K, Jokinen E, Saarinen M, Hmlinen M, Volanen I, Kaitosaari T, et al. Arterial intimamedia thickness, endothelial function, and apolipoproteins in adolescents frequently exposed
to tobacco smoke. Circ Cardiovasc Qual Outcomes. 2010;3:196203.
29. Martin AC, Coakley J, Forbes DA, Sullivan DR, Watts GF. Familial hypercholesterolaemia in
children and adolescents: a new paediatric model of care. J Paediatr Child Health. 2013;
49(4):E26372.
Other Determinants of Cardiovascular

Diseases: Social, Globalization,
and Urbanization
Dalton Bertolim Prcoma, Jorge Ilha Guimares, and Antonio Felipe Simo
Introduction
Cardiovascular diseases (CVD) are responsible for 30 % of the annual worldwide
mortality. There is a trend toward decreased mortality rates in developed countries
but increased rates in countries with lower socioeconomic levels, particularly the
socialist and emerging third world countries. India, China, and Latin America have
the worst predictions of growth of cardiovascular mortality [1]. In 2010, Brazil
accounted for one third of all deaths and nearly 30 % of all deaths in the age group
of 2059 years, which affected the economically active adult population [2].
All developed and developing countries have experienced large reductions in
mortality rates over the past century, and the pattern of epidemiological transition
in these countries suggests that the main causes of mortality have changed from
transmissible diseasesespecially those prevalent among children and the young
D.B. Prcoma, M.D., Ph.D. (*)

Catholic University of Parana, Curitiba, Brazil
e-mail: daltonprecoma@gmail.com
J.I. Guimares, M.D.
e-mail: guimass@terra.com.br
A.F. Simo, M.D.
Institute of Cardiology from Santa Catarina, Florianpolis, Brazil
e-mail: afsimao@matrix.com.br
DOI 10.1007/978-3-319-22357-5_12
109
110
D.B. Prcoma et al.
populationto problems resulting from chronic degenerative diseases at older ages.

The prevalence of classic risk factors has increased in recent decades, with the
exception of smoking, and cannot explain the observed decreases in mortality rates.
Therefore, other factors could explain this decrease; including the social determinants of health [3]. The World Bank classifies countries according to their economy
into high-income, middle-income, and low-income. These categories are widely used
in the context of the implementation of global actions for health promotion [4]. Noncommunicable diseases (NCDs) accounted for 35 million deaths in 2005 (60 % of
the total) worldwide, and 80 % of these deaths occurred in low- and middle-income
countries, with the expectation of a 20 % increase between 2006 and 2015 [4].
A major problem in emerging and third world countries is the low investment in
healthcare, particularly for the prevention of chronic diseases. This scenario has
improved in many countries, including Brazil, with respect to communicable
diseases, including AIDS, rheumatic fever, and Chagas disease [2].
Another aspect to be considered is the demographic transition of the world
population, which involves population aging, particularly in developing countries.
This transition will bring profound changes in the epidemiological planning of the
population as well as in government welfare actions and disease prevention and
healthcare programs [45].
Social Determinants
Since the establishment of the World Health Organization in 1948, health has been
defined as a state of complete physical, mental, and social development and not
merely the absence of disease [4].
In the first International Conference for the Promotion of Health conducted on
November 21, 1986 in Ottawa, a letter of intent known as the Ottawa Charter was
drafted with the aim to promote improvement of the health of the worlds population. This letter stressed that the improvement of health conditions would require
the allocation of core resources to health, including those for the promotion of
peace, shelter, education, food, income, stable ecosystems, sustainable resources,
social justice, and equity [4].
Subsequently, a Commission of Social Determinants of Health was established
by the WHO in 2005 to address the social factors responsible for inequalities in
health. The main objective was to draw the attention of governments and society to
the development of better social conditions for health, especially for those populations living in vulnerable conditions [4].
These actions are focused on the key risk factors that can significantly decrease
the incidence of atherosclerotic diseases and other non-communicable diseases. The
target risk factors were tobacco use, high blood pressure, increased cholesterol levels,
and diabetes mellitus, whose incidence has increased significantly in recent years
because of populational aging and the increased prevalence of obesity [6]. Other
contributing factors include low socioeconomic status, physical inactivity, poor diet,
obesity, insulin resistance, and family history of early coronary disease [7].
Other Determinants of Cardiovascular Diseases: Social, Globalization, and Urbanization
111
Other diseases, including Chagas disease and rheumatic heart disease, are closely
associated with the socioeconomic level of the country and with the uncontrolled
urbanization of major urban centers, leading to poverty, malnutrition, improper
housing, and overcrowding, among other problems [8, 9].
Social and economic determinants not only affect the occurrence and distribution
of traditional risk factors but also directly influence the biological mechanisms
closely associated with cardiovascular pathogenesis (e.g., low birth weight and the
chronic impairment of neuroinflammatory processes). Due to the limited knowledge of the relationship between social sciences and neuropsychology and how
these determinants interact in the regionalization of biological vulnerability to
diseases, the advancements in this field have been limited [10].
One of the most important determinants that should be addressed for the
prevention of cardiovascular diseases is social inequality, considering the internal
socioeconomic differences in certain countries. The socioeconomic status (SES)
has four main characteristics, which were described by Link and Phelan [11]: influence of multiple diseases, influence of SES on disease outcomes through multiple
risk factors, access to resources (or loss of resources) that can prevent risks and
disease outcomes, and the association between the fundamental cause of healthrelated problems and health conditions, which, over time, may be replaced by
predisposing factors (lifestyle, behavior, and strategies aimed to minimize social
inequalities).
The migration of knowledge from individual-based determinants of disease to
determinants based on socioeconomic indicators, particularly low socioeconomic
status, poverty, and loss of benefits from social interaction, was achieved by understanding how these determinants affect prevalence, morbidity, and disease outcomes, particularly mortality, because this understanding is essential for resource
allocation for disease prevention, treatment, and longevity in multiple population
groups [12].
Phelan et al. observed that the incorporation of new knowledge of the risk factors
that affect multiple non-communicable diseases, including the effect of smoking on
cardiovascular and neoplastic diseases, and the incorporation of new technologies,
including antiretroviral therapy and surgical procedures for the treatment of ischemic heart disease, produced the most benefits for the reduction of mortality and
morbidity among the population groups with higher socioeconomic status [13].
A systematic review of 20 studies published between 1998 and 2010 on social
inequalities in health and disease prevention in Germany showed a significant association between morbidity, mortality, horizontal inequalities (age, gender, marital
status, and nationality), and vertical inequalities (occupation, education, and
income) [14]. The INTERHEART study analyzed the association between risk factors and myocardial infarction in men and women and indicated that psychosocial
factors, together with diabetes, dyslipidemia, smoking, obesity, and high blood
pressure, were the major causes of myocardial infarction [15].
A review on social determinants in India confirmed the association between low
socioeconomic status and increased morbidity and mortality from cardiovascular
diseases and diabetes. It also highlighted that 52 % of deaths from CVD occurred
112
D.B. Prcoma et al.
among individuals younger than 70 years and that the population groups with lower
educational levels living in urban communities were the most vulnerable. The
authors emphasize the importance of changing the paradigm from the biological
model to the populational model together with intervention, in addition to improvements in the health sector, with joint planning by the education, agriculture, economy, trade, urbanization, and transportation sectors [16].
In a study conducted in 73 districts of Porto Alegre, Brazil, Bassanesi et al.
showed that more than 50 % of the cases of mortality from CVD in the age group
below 65 years can be attributed to poverty; therefore, investments in socioeconomic development of the population are necessary [17]. Strong correlations were
found between decreased infant mortality, increased gross domestic product (GDP)
per capita, and increased levels of education, with reductions in mortality from
cardiovascular diseases in adults since 1980 in the state of Rio de Janeiro [3].
A document published by the WHO indicates that social injustice is the main
determinant of the inequalities that affect cardiovascular disease outcomes. This
document emphasizes that the primary approach should be based on the implementation of key actions, including balanced investment between prevention and cure
with a focus on vulnerable population groups, intersectoral collaborations led by the
public sector, and increased awareness of cardiovascular risk factors and their social
determinants. The document concludes that further studies are needed to elucidate
the mechanisms by which social determinants contribute to the social stratification
of cardiovascular diseases [18].
Urbanization
Most researchers use the urbanrural dichotomy, considered an inadequate division,
for the assessment of urbanicity. There is also variation of the factors involved in this
problem. To address this issue, Dahly and Adair constructed an urbanicity scale using
different methods to validate the performance against the urbanrural dichotomy and
evaluated the best relationship between urbanization and health. These determinants
included population size, demographic density, communication (presence of telephone service, e-mail, newspapers, internet, cable TV, and mobile phones), transportation (density of paved roads and availability of public transport), presence of
educational establishments and institutions (including secondary schools, universities,
and vocational schools), and healthcare services (hospitals, medical clinics, maternal
health clinics, family planning clinics, and community healthcare centers) as well as
the presence of markets, pharmacies, retail stores, supermarkets, and gas stations.
Each of these seven items was assigned a score between 0 and 10, for a maximum of
70 points. This scale allowed better understanding of the differences between urban
and rural areas [19].
The comparison studies that evaluate urban and rural areas have important limitations because of the concept of rurality. The concepts found in the literature are
diverse and do not allow more accurate analyses, and regional and cultural differ-
113
ences greatly influence these interpretations. In Brazil, with its large territorial
dimension, rural areas suffer from a lack of care resources. Despite this problem, it
is important to highlight the predisposition of genetic factors and lifestyle habits
present in rural areas, which may be inserted in the family environment. Giroldo
et al. evaluated adolescents living in a city with one of the lowest human development index (HDI) scores in the state of Paran and showed that children of parents
with coronary risk factors had the highest incidence of hypertension, obesity, and
dyslipidemia compared to adolescents of healthy parents [20].
The association between urbanization and the risk of CVD is determined by
lifestyle changes, particularly smoking, sedentary lifestyle, air pollution, poor
diet, and excessive use of alcohol and illicit drugs [21]. A systematic literature
review conducted by Holmboe-Ottesen and Wandel demonstrated that inadequate
carbohydrate-rich diets showed a strong association with obesity, diabetes, and cardiovascular risk among individuals who migrated from southern Africa to Europe [22].
India has experienced an increase in the number of cases of CVD in both urban
and rural areas. Coronary artery disease (CAD) cases have increased more than
fourfold in the last 40 years, and in rural areas, where over 700 million people live,
the incidence has doubled in the last 30 years and has even surpassed the incidence
of infectious diseases [23].
Globalization
The world population is rapidly increasing, with an estimated 9.3 billion people by
2050 [24]. To better understand globalization, one must understand the determinants
of populational health involving the institutional, economic, sociocultural, and environmental sectors. In the institutional sector, the most important factors include the
government structure, legislation, environmental policies, and regulatory systems.
In the economic sector, the occupational structure and tributary and marketing systems should be considered. In the sociocultural sector, the role of religion, customs
system, populational aspects (size and geographic distribution), and social infrastructure (social organization, knowledge development, social security, insurance
system, mobility, and communication) are important. In the environmental sector,
the ecosystem and climate should be considered [25].
Rapid globalization has generated trends that are influencing human health patterns. The many changes observed on global, socioeconomic, sociodemographic,
and environmental scales, particularly climate changes, are involved in the increased
prevalence of obesity, regional changes in food production, emergence of infectious
diseases, increased use of tobacco, and persistence of health inequalities [26].
The determinants of populational health that affect the planet have a cumulative
effect with regard to the emission of pollutants and climate change and may lead to
the decreased availability of drinking water, changes in soil properties, and food
shortages. Because of this population growth, other factors can affect the globaliza-
114
D.B. Prcoma et al.
tion of health, including technological, sociocultural, economic, and environmental

development [27].
Globalization increases interpopulational connectivity, resulting in further demographic, economic, and environmental changes. Demographic changes, including
rapid population growth, increased population density in urban centers, increased
longevity, and changes in family structure due to social changes, influence economic
activities, such as capital mobility, working conditions, and allocation of resources
to health, and will dictate patterns of disease prevalence and mortality. These diseases, in turn, are also influenced by environmental degradation due to globalization, with the rupture of biogeophysical ecosystems [28].
All these factors should be considered when providing primary prevention with
the aim to reduce the health risks stemming from global influences, pursue knowledge of causality, and implement novel prevention strategies based on the concept of
modification of the risk factors for cardiovascular diseases, including socioeconomic
factors, urbanization, and globalization. These actions should involve joint planning
by the sectors responsible for education, agriculture, economy, trade, urbanization,
and transportation, among others, to provide adequate health conditions to the population and teach it how to live sustainably in the long term [29].
References
1. World Health Organization. The 10 leading causes of death by broad income group (2008).
Available from: www.who.int. Accessed on Oct 2013.
2. Ministrio da Sade. Secretaria Executiva. Datasus. Informaes de Sade. Morbidade e
informaes ep-idemiolgicasConsultaeletrnica. Available from http://www.datasus.gov.br.
Accessed on Oct 2013.
3. Soares GP, Brum JD, Oliveira GMM, Klein CH, Silva NAS. Evoluo de IndicadoresSocioeconmicos e da Mortalidade Cardiovascular emtrsEstados do Brasil. Arq Bras
Cardiol. 2013;100(2):14756.
4. Lopez AD, Mathers CD, Ezzati M, et al., editors. Global burden of diseases and risk factors.
Oxford/Washington, DC: Oxford University Press/The World Bank; 2006.
5. Centers for Disease Control and Prevention. Public health and aging. MVMR 2003;52(96):
1016.
6. Smith SC, Greenland P, Grundy SM. Prevention Conference V: beyond secondary prevention.
Identifying the high risk patient for primary prevention: executive summary. Circulation.
2003;101:1116.
7. Lindholm LH, Mendis S. Prevention of cardiovascular disease in developing countries. Lancet.
2007;370(9589):7202.
8. World Health Organization. Rheumatic fever and rheumatic heart disease. WHO Technical
Report 923. World Health Organization, Geneva, 2001.
9. World Health Organization. Control of Chagas disease. WHO Technical Report 811. Geneva,
World Health Organization, 1991.
10. Achutti A, Azambuja MIR. Interessa saber e discutirsobre as causas das DCV? Revista da
Sociedade de Cardiologia do Estado Rio Grande do Sul. Ano XVIII no 20 Set/Out/Nov/Dez.
2010.
11. Link BG, Phelan JC. Social conditions as fundamental causes of disease. J Health Soc Behav.
1995;35:8094.
115
12. Flaskerud JH, DeLilly CR. Social determinants of health status. Issues Ment Health Nurs.
2012;33(7):4947.
13. Phelan JC, Link BG, Tehranifar P. Social conditions as fundamental causes of health inequalities: theory evidence, and policy implications. J Health Soc Behav. 2010;5(suppl 1):S2840.
14. Janen C, Sauter S, Christoph K. The influence of social determinants on the use of prevention
and health promotion services: results of a systematic literature review. GMS Psychosoc Med.
2012;9:112.
15. Yusuf S, Hawken S, Ounpuu S, on behalf of the INTERHEART Study Investigators. Effect of
potentially modifiable risk factors associated with myocardial infarction in 52 countries (the
INTERHEART study): casecontrol study. Lancet. 2004;364:93752.
16. Jeemon P, Reddy KS. Social determinants of cardio-vascular disease outcomes in Indians.
Indian J Med Res. 2010;132(5):61722.
17. Bassanesi SL, Azambuja MI, Achutti A. Premature mortality due to cardiovascular disease
and social inequalities in Porto Alegre: from evidence to action. Arq Bras Cardiol. 2008;
90(6):3709.
18. Blas E, Kurup AS (eds). Equity, social determinants and public health programmes. World
Health Organization, Printed in Switzerland; 2010.
19. Dahly DL, Adair LS. Quantifying the urban environment: a scale measure of urbanicity
outperforms the urbanrural dichotomy. Soc Sci Med. 2007;64(7):140719.
20. da Luz Giroldo M et al. Household cardiovascular screening in adolescents from high-risk
families. Atherosclerosis. 2013;226(1):28690.
21. De Cock KM, Simone PM, Davison V, Slutsker L. The new global health. Emerg Infect Dis.
2013;19(8):11927.
22. Holmboe-Ottesen G, Wandel M. Changes in dietary habits after migration and consequences
for health: a focus on South Asians in Europe. Food Nutr Res. 2012;56(56).
23. Reddy KS. India wakes up to the threat of cardiovascular diseases. J Am Coll Cardiol.
2007;50:13702.
24. World population prospects, the 2010 revision. New York: United Nations Department of
Economic and Social Affairs, 2011. http://esa.un.org/unpd/wpp/index.htm.
25. Huynen MM, Martens P, Hilderink HB. The health impacts of globalization: a conceptual
framework. Global Health. 2005;1:14.
26. Murray SF, Bisht R, Baru R, Pitchforth E. Understanding health systems, health economies
and globalization: the need for social science perspectives. Global Health. 2012;8:30.
27. Labont R, Mohindra K, Schrecker T. The growing impact of globalization on health and
public health practice. Annu Rev Public Health. 2011;32:26383.
28. McMichael AJ. Globalization, climate change, and human health. N Engl J Med. 2013;
368:133543.
29. De Cock KM, Simone PM, Davison V, Slutsker L. The new global health. Emerg Infect Dis.
2013;19(8):11927. www.cdc.gov/eid.
Genetics of Cardiovascular Disease

Steven A. Claas, Stella Aslibekyan, and Donna K. Arnett
Cardiovascular diseases (CVD) remain a major source of mortality and morbidity

worldwide, and considerable effort has been applied to identifying modifiable environmental factors such as diet, exercise, weight control, smoking, and drug therapy
that can reduce the risk of CVD. Many CVDs have a strong familial component,
however, and at least some of this is attributable to genetic factors. Over the past
decades, our understanding of monogenic CVD (sometimes referred to as simple
or Mendelian diseases, such as familial hypercholesterolemia and hypertrophic
cardiomyopathy) has increased dramatically. Monogenetic disorders are typically
caused by relatively rare variants in single genes that have a large phenotypic effect
in individuals and high penetrance. Consequently, these forms of CVD account for
a small proportion of the total population CVD burden. In contrast, complex genetic
diseases (sometimes referred to as common diseases, such as atherosclerosis)
may be influenced by multiple (and interacting) sequence variants, epigenetics, and
gene x environment interactions. The genetic component of complex diseases is
S.A. Claas, M.S. (*)

Department of Epidemiology, School of Public Health,
e-mail: sclass@uab.edu
S. Aslibekyan, Ph.D.
Department of Epidemiology, University of Alabama
at Birmingham, Birmingham, AL, USA
e-mail: saslibek@uab.edu
D.K. Arnett, M.S.P.H., Ph.D.
Department of Epidemiology, School of Public Health, University of Alabama School
of Medicine, Birmingham, AL, USA
American Heart Association, Dallas, TX, USA
e-mail: arnett@uab.edu
DOI 10.1007/978-3-319-22357-5_13
117
118
S.A. Claas et al.
possibly the aggregate of multiple small effects. The relatively small phenotypic
variation (compared to monogenic traits) of intermediate CVD traits (such as hypertension) disposes individuals toward disease development. For these reasons, genetics (the study of the function of individual genes) and genomics (the study of the
function of the entire genome, i.e., genes, non-protein-coding stretches of DNA,
genegene interactions, etc.) play a potentially important part in our evolving understanding of CVDs, including risk prediction, discovery and functional explorations
of susceptibility loci, and ultimately identification of new therapeutic targets.
This chapter will review the current state of CVD genetics and genomics research,
with some attention given to monogenic disease but a more detailed discussion of
the flourishing arena of complex CVD genomics. Given the number of studies and
the rapidly evolving research front in this discipline, we cannot hope to be
comprehensive. This survey, however, should supply interested readers with the
fundamental terms and methods of genetic and genomics, the areas of CV health
and disease that have been most robustly explored, and the existing and potential
clinical implications of this work.
Monogenic Cardiovascular Traits and Diseases

Dyslipidemias
Population-based studies and large clinical trials have demonstrated that elevated
low density lipoprotein cholesterol (LDL-C) and reduced high density lipoprotein
cholesterol (HDL-C) are CVD risk factors [1]. Because at least half of the variation
in cholesterol and other lipids can be explained by genetic factors [2], understanding
the genetic pathogenesis of hypercholesterolemia and other lipid abnormalities has
long been a priority. A number of cholesterol metabolism phenotypes influenced by
single genes have been documented. Studies of these monogenic conditions have
helped establish the connection between hypercholesterolemia and atherosclerosis
and the elucidation of these regulatory pathways have been instrumental in the
development of drugs used to treat dyslipidemias [3]. As a group, these monogenic
diseases are referred to as autosomal dominant hypercholesterolemia (ADH). The
most common and potentially severe form of ADH is familial hypercholesterolemia
(FH), which results in elevated serum LDL-C concentrations. FH results from any of
some 1000 known mutations in the low-density lipoprotein receptor gene (LDLR)
[4, 5]. Individuals homozygous (i.e., carry two copies of the mutation) for LDLR
mutations are unresponsive to dietary and drug interventions and often develop clinical CVD before reaching age 30 years [6]. Heterozygotes (i.e., those with one copy
of the mutation) have somewhat less elevated LDL-C and are more responsive to
treatment interventions [7]. ADH stemming from variants in other genes have also
been documented. For example, some mutations in the proprotein convertase, subtilisin/kexin-type, 9 gene (PCSK9) present symptoms similar to that of heterozygous
119
FH [8]; interestingly, other mutations in this gene can lower LDL-C and be cardioprotective [9]. The study of the functional effects of PCSK9 mutations have lead, in
part, to the development of a number of therapeutic agents that inhibit PCSK9 to
reduce LDL-C [10]. Population studies estimate that 553 % of individuals with clinical ADH phenotypes do not have mutations in any of the known ADH genes [11].
This diagnostic gap suggests other forms of ADH remain to be discovered.
Hypertrophic Cardiomyopathy
Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy
without dilation or any obvious systemic causes (e.g., aortic stenosis, hypertension).
In individuals with HCM, the normal alignment of myocytes is disrupted and electrical functions of the heart can be impeded. HCM is the most common cause of sudden
death in young athletes, and it is an important contributor to heart failure and stroke
[12]. The 0.2 % prevalence of HCM in the general population is considered high for a
monogenic disease [13]. Some 1400 mutations in 20 genes have been identified in
HCM [14], the majority of which are in sarcomere- and myofilament-related genes.
About 70 % of HCM patients have mutations in either the -myosin heavy chain gene
(MYH7) or the myosin-binding protein C gene (MYBPC3) [12]. Although HCM traditionally falls within the realm of monogenic disorders, genetic dissection of this
disease has complicated the simple-complex disease dichotomy: a number of modifier genetic variants have been identified (e.g., END1 [15]) that add to or interact with
the implicated Mendelian variants. Given that HCM can go undiagnosed until after
the occurrence of a severe clinical event, it would seem an obvious candidate for
genetic testing. However, given that the number of potentially pathogenic mutations
(nearly all families with HCM in their pedigree have a different mutation) and that
pathogenic mutations can be identified in 50 % of clinically affected individuals, it
is likely that HCM-causing mutations would go unrecognized in a significant number
of those tested. Thus, HCM illustrates the challenges of translating even detailed
genetic knowledge of a monogenic disorder into fruitful clinical tools.
Other Monogenic CVDs

ADH and HCM are not the only examples of monogenic CVDs: at least some forms
of Brugada syndrome, Marfan syndrome, long QT syndrome, and other conditions
can also be traced to single-gene mutations. As noted above, although populationlevel screening may be of questionable value for some monogenic CVDs, identifying a potentially causal mutation in the proband of a family can aid in diagnosis in
other family members, identification of silent carriers, reproductive risk assessment,
and, in some cases, prognosis and treatment decisions.
120
S.A. Claas et al.
Complex Genetic Cardiovascular Diseases

The history of the study of common genetic diseases has been driven by evolving
technologies available for measuring genetic variation. Early studies used restriction fragment length polymorphism (RFLP)/electrophoresis techniques to genotype
candidate genesgenes that were, a priori, hypothesized to play a role in the disease
or phenotype of interest. In contrast to these hypothesis-testing experiments, genetic
linkage studies are agnostic in their assumptions and are capable of scanning the
entire genome for loci that may be associated with a trait of interest. These familybased studies are capable of identifying loci not previously known or suspected to
be involved in the trait or disease of interest. Although each of these methods has
their merits, both proved limited in their abilities. The genotyping methods of candidate gene studies could not be efficiently applied to interrogate a large selection of
variants across the genome in large study samples. The micro-satellite genotyping
techniques frequently used in linkage studies often provided poor localization, that
is, they could identify only a broad region of the genome where the causal variant
was likely to lie. The development of genotyping microarrays (gene chips) capable of interrogating millions of single-nucleotide polymorphisms (SNPs) throughout the genome (with the possibility of predicting millions more through statistical
imputation) merged the association methods of candidate gene studies with the
agnostic, hypothesis-generating methods of whole-genome linkage methods. These
gene chips gave rise to the genome-wide association study (GWAS). Importantly, as
we will discuss below, the design of the gene chips used in GWAS was predicated
upon the common disease/common variant hypothesis: the idea that common disease-causing variants will be found in all populations with a high burden of disease.
Therefore, the variants typed by GWAS arrays are relatively common in populations, usually with minor allele frequencies 5 %. Because the influence of any
single genetic variant on disease development may be quite small, large sample
populations are necessary to find statistically significant results. For this reason,
many of the most compelling findings from the GWAS era come
from meta-analyses of multiple studies that have investigated the same trait in different populations that sometimes total hundreds of thousands of participants, as
described below.
Coronary Artery Disease

Coronary artery disease (CAD) is a complex genetic disease with heritability
(i.e., proportion of inter-individual differences in a trait that is attributable to genetic
differences) of about 40 % [16]. Genetic loci associated with CAD have been identified via GWAS and GWAS consortia in recent years. For example, individually,
combined, and with follow-up replication using the Metabochip genotyping array
(Illumina Inc), the CARDIoGRAM [17] and C4D [18] consortia have leveraged
121
data from over 200,000 individuals of European and South Asian ancestry to identify and replicate more than 30 novel loci for CAD susceptibility [19]. About a
quarter of the variants with validated CAD associations in these studies were also
significantly associated with lipid traits (e.g., LDL-C and triglycerides (TG), data
from the Global Lipids Genetics Consortium) and about 10 % were also significantly associated with blood pressure (data from the International Consortium of
Blood Pressure), reinforcing the causal link between these risk factors and CAD
risk [19]. Although findings from these studies suggest that many CAD-associated
loci are important for both sexes and across racial and groups, data for blacks and
other non-Caucasian groups is limited. Studies of CAD illustrate a number of critical themes that, as will become apparent, have emerged in studies of other complex
diseases and phenotypes. First, genetic associations were generally stronger for hard
endpoints (e.g., MI, angiographically-diagnosed CAD) rather than intermediate
phenotypes like lipids [20]. Although endpoint phenotypes may not be the best
choice for all complex diseases, studies of CAD underscore the importance of judicious phenotype selection and measurement in genetic studies. Second, the effect
sizes of genetic variation in CAD studies were often modest (i.e., with odds ratios
typically <1.2). It appears the common variants interrogated by GWAS assays
explain only a small proportion of CAD heritability.
Blood Lipids, Lipoproteins, and Related Phenotypes

The monogenic lipid disorders described above account for only a small portion of
the total population variation in blood lipids, and LDL-C concentrations considerably lower than those observed in some forms of ADH can still be a significant
contributor to CVD, as can elevated TG and low HDL-C concentrations. Common
genetic variation is believed to influence lipid trait variability. Given the explosive
growth of our understanding of lipid chemistry, metabolism, and genetic underpinnings of some monogenic lipodystrophies since the middle of the last century, its
not surprising that lipid traits have been frequently studied using candidate gene
approaches. These hypothesis-driven studies were among the first to investigate the
role of common variants in complex disease phenotypes. They also demonstrated
the difficulty of making generalizations about genotype-phenotype associations
across study populations. For example, a variant (rs670) in the promoter region of
the gene (APOA1) encoding the main apolipoprotein component in HDL-C and an
important actor in cholesterol excretion was associated with elevated plasma apo
A-1 in Chinese male never-smokers (but not associated in male ever-smokers or
females) [21]; in a European population, similar associations were found in females,
but no significant associations between this variant and HDL-C were found in
Canadian [22], Hispanic [23], Finnish [24], or Japanese populations [25]. Many of
the common variants studied in candidate genes have been significantly associated
with lipid phenotypes in GWAS, but uncertainties often remain regarding possible
interacting factors and genetic heterogeneity across populations.
122
S.A. Claas et al.
As of this writing, the GWAS catalog maintained by the US National Human

Genome Research Institutes Division of Genomic Medicines included 75 studies
of more than 20 lipid-related traits with over 600 significant or suggestive genetic
associations across the genome. Genes known or suspected to be involved in lipid
metabolism (e.g., LDLR, genes in the apolipoprotein (APOA/APOC3) cluster on
chromosome 11, and the cholesterol ester transfer protein gene (CETP)), have been
reported in GWAS findings. Such confirmatory findings are important because,
although the gene products may be known to play a role in lipid metabolism, identifying the variants associated with interindividual variation of a trait may provide
insights into disease etiology, molecular mechanisms, and novel interventions.
Many replicated GWAS findings have also pointed to novel genes not previously
suspected to play a role in lipid metabolism. Lipid trait GWAS (and meta-analyses)
reported that ~4060 % of their significant associations with total cholesterol, LDLC, HDL-C, or TG were novel [26, 27].
Hypertension
Blood pressure (BP) is a quantitative trait with 3060 % heritability in humans [28].
As in the realm of lipid genetics, the study of the complex traits of BP and essential
hypertension has often been influenced by earlier work on more severe monogenic
forms of hypertension and hypotension. This earlier research identified functional
mutations influencing mineralocorticoid activity, renal sodium reabsorption, and
the renin-angiotensin-aldosterone system, which subsequently cause physiological
imbalances presenting as abnormal BP. As with lipids, however, these rare syndromes account for only a small fraction of the population burden of hypertension,
and studies of the genes associated with these Mendelian forms suggest that they
contribute little to population hypertension risk [29]. Given the complexity of BP
homeostasis, it is likely that genes influencing the central nervous system, endocrine system, vasculature, and blood also play a role in the phenotype. Early studies
of common variants on BP-related traits were plagued by low statistical power, and
heterogeneous ascertainment, comorbidities, treatment, and phenotype definitions
(e.g., office BP, ambulatory BP, hypertension defined with different cutpoints, etc.)
that made comparison, replication, and meta-analysis difficult. More recently, GWAS
with sufficient statistical power and comparable phenotypes have found significant
associations between common variants and BP-related traits. Two large GWAS consortia joined forces to form the International Consortium for Blood Pressure to perform a mega-meta-analysis on a discovery-phase sample of >79,000 individuals
of European decent with follow up replication in >200,000 individuals from diverse
ancestral populations [30]. Twenty-nine loci were associated with SBP, DBP, and
hypertension. However, these statistically significant associations illustrate dramatically a conundrum that has been called the problem of missing heritability: the
29 BP loci discovered in the mega-meta-analysis account for less than 1 % of
the trait variance, leaving unexplained the remaining 2959 % of variation
123
attributable to genetic factors. This is a phenomenon that has been widely reported
in studies of common genetic variation (i.e., GWAS) of most presumed polygenic
traits.
The majority of successful BP and hypertension genetic association studies have
been conducted in cohorts of European origin. GWAS in non-European populations
have also been conducted; however, fewer significantly-associated loci have been
discovered, probably because of much smaller sample sizes [31]. Many of the genes
identified in studies of BP-related traits in non-European populations point to an
important role of natriuretic factors and their precursors (e.g., NPPA, NPPB,
GUCY1A3, etc,) and novel renal genes (e.g., PLCE1, SLC4A7) [32].
Cardiovascular Pharmacogenetics
The field of pharmacogenetics concerns itself with interactions between drug therapies
and genetic variants that result in interindividual variation in response to a drug.
This variability of response is of interest with respect to both safety and efficacy.
Because the variant-drug interactions that result in adverse reactions typically have
large effect sizes, pharmacogenetic GWAS of drug safety can often be conducted with
considerably smaller samples than the complex disease phenotypes discussed above.
These variants are more likely to be rare, and because the drugs have only recently
been used in large populations, natural selection hasnt yet had an impact on them.
Pharmacogenetic biomarkers have been identified for adverse reactions to a number
of cardiovascular drugs. To date, pharmacogenetic research on the antithrombotic
drugs clopidogrel and warfarin has had the greatest translational impact. Clopidogrel
is a prodrug that requires enzymatic activation by cytochrome P450 2C19 (encoded
by CYP2C19) [33]. A number of loss-of-function variants in CYP2C19 can lead to
reduced production of the drugs active form with a consequent reduction in its antiplatelet effects. Up to 70 % of individuals with Asian ancestry and approximately
2530 % of those with European and African ancestry carry at least one CYP2C19
allele that is non-functional [33]. In 2010, relying on internal and published literature,
the US Food and Drug Administration (FDA) issued a black box warning on the
clopidogrel product label informing clinicians of potentially reduced efficacy of the
drug as function of CYP2C19 genotype. The label does not mandate genetic testing,
but it does outline risks associated with particular variants. Subsequent research on
clopidogrel pharmacogenetics called into question the value of genotype-guided
dosing: one meta-analysis found associations between clopidogrel CYP2C19 lossof-function alleles and responsiveness to the drug but found no significant association
between genotype and cardiovascular events [34]. A recent update of therapeutic recommendations issued by the Clinical Pharmacogenetics Implementation Consortium
acknowledged that there was an absence of randomized clinical trial evidence that
CYP2C19 genotyping improves outcomes. However, this group also acknowledged
that genotype-guided therapy was an option for clinicians. In general, this group
recommended that standard clopidogrel dosing be used for those with extensive or
124
S.A. Claas et al.
ultrarapid metabolizer genotypes and that alternative antiplatelet drugs (prasugrel,

ticagrelor) be used for intermediate or poor metabolizer genotypes, except for cases
where these alternative drugs were contraindicated [35].
Warfarin has a narrow therapeutic index, and there is considerable interindividual variation in response among those treated with the drug. This is an unfortunate
combination of characteristics: under-dosing can increase the risk of potentially
fatal clotting; over-dosing can increase the risk of fatal hemorrhagic complications.
Variants in CYP2C9 and VKORC1 have been implicatedfirst via candidate gene
studies and later in GWASas important contributors to the variable response to
warfarin [36, 37]. As with clopidogrel, the US FDA has mandated labeling requirements for warfarin formulations, including information about the influence of
CYP2C9 and VKORC1 variants and a table with dosing recommendations as a function of genotype. Physicians can also use dosing algorithms that incorporate both
clinical as well as genotype data to predict stable dose requirements. These algorithms were shown to be more effective than standard dosing or that guided by the
FDA genotype table [38]. Like in the case of clopidogrel, initial enthusiasm about
the translation of warfarin pharmacogenetics to the clinical setting has been somewhat tempered by recent studies that have offered mixed evidence regarding the
relative value of genotype-guided dosing [39, 40]. These recent studies, however,
looked primarily at the time patients spent in the therapeutic range; they did not
collect data on adverse clinical outcomes such as thromboembolisms or bleeding.
Some studies have also provided evidence that the value of genotype-guided dosing
may vary among racial groups [39].
Efficacy studies of other drugs used to treat cardiovascular disease (e.g., hypertension [41], lipodystrophies [42, 43]) have produced significant associations, but
translation to clinical utility has proven difficult. In 2005, the Evaluation of Genomic
Applications in Practice and Prevention (EGAPP) working group was formed to,
among other functions, develop systematic guidelines to assess the analytic validity,
clinical validity, and clinical utility of genetic tests, including those that might be
used to inform treatment decisions. To date they have published eight recommendation statements, two of which are relevant to cardiovascular practice [44]. In the
case of genomic profiling to assess overall cardiovascular risk, the working group
found insufficient evidence of clinical utility above that of traditional risk factors
[45]. In the case of genetic testing of adults with venous thromboembolism (and
their family members), the group found insufficient evidence of clinical utility
and a potential increase for net harm with genotype-guided treatment [46].
The Future of Cardiovascular Genetics: Clinical and Public

Health Implications
The accumulation of genotype-phenotype associations in the realm of cardiovascular
health and disease has grown enormously in the past decades. These findings have
increased our understanding of the mechanisms and pathways of cardiovascular
125
disease and associated risk factors. In some cases, the findings of genetics researchers have been translated into improved clinical care. It should be evident from the
above discussion, however, that the promises of personalized medicine have yet to be
fully realized. In many cases, the aggregate contributions of the genetic associations
reported to date explain only small fraction of the trait variability; this has made
translation to clinical utility difficult. But every obstacle encountered in the journey
from bench to bedside represents a net gain in our more general understanding of
disease genetics: the common disease/common variant hypothesis has been problematized; our understanding of the relative importance of coding and non-coding
regions of DNA has been refined; our consideration of epigenetics, mitochondrial
DNA, and other factors that lie outside the classic genetic paradigm has blossomed;
the care with which disease phenotypes are defined and measured has increased, the
importance of gene-environment interactions has been underscored; and the necessity of careful coordination among studies has become apparent. We are poised on
the cusp of the next methodological revolution in the field: soon our gaze will extend
beyond the mere millions of variants typed with genotyping arrays and limited
sequencing to billions of nucleotides as whole-genome sequencing becomes economically feasible in large study populations. This deluge of data will no doubt present both logistical and statistical challenges, but it will also offer unprecedented
opportunities for the study of cardiovascular disease.
The American Heart Association recently issued a list of recommendations to
be put into practice now to foster discovery and optimize patient care [32]. These
included:
Basic research: Foster continued research that characterizes genetic associations
with CVD, with attention paid to ancestry/race, gene-environment (including
drug) interactions, and functional follow up studies.
Translational research: Foster research that accelerates the translation of genetic
discoveries to prevention and treatment of CVD.
Implementation research: Foster research that anticipates clinical genetic screening, including research that establishes effective screening triggers, sets appropriate
genetic laboratory oversight, and assesses the potential cost effectiveness of genetic
screening programs.
Education: Train clinicians to understand genetic testing and its use; train
researchers in genetics, computational biology, and statistical genetics.
References
1. Castelli WP, Doyle JT, Gordon T, et al. HDL cholesterol and other lipids in coronary heart
disease. The cooperative lipoprotein phenotyping study. Circulation. 1977;55:76772.
2. Knoblauch H, Bauerfeind A, Toliat MR, et al. Haplotypes and SNPs in 13 lipid-relevant genes
explain most of the genetic variance in high-density lipoprotein and low-density lipoprotein
cholesterol. Hum Mol Genet. 2004;13:9931004.
3. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest. 2003;111:1795803.
126
S.A. Claas et al.
4. Jensen HK. The molecular genetic basis and diagnosis of familial hypercholesterolemia in
Denmark. Dan Med Bull. 2002;49:31845.
5. De Castro-Oros I, Pocovi M, Civeira F. The genetic basis of familial hypercholesterolemia:
inheritance, linkage, and mutations. Appl Clin Genet. 2010;3:5364.
6. Goldstein J, Hobbs H, Brown M. Familial hypercholesterolemia. In: Beaudet A, Sly W, Valle
D, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill;
2001. p. 2863913.
7. Robinson JG. Management of familial hypercholesterolemia: a review of the recommendations from the National Lipid Association Expert Panel on familial hypercholesterolemia.
J Manag Care Pharm. 2013;19:13949.
8. Horton JD, Cohen JC, Hobbs HH. PCSK9: a convertase that coordinates LDL catabolism.
J Lipid Res. 2009;50 Suppl:S1727.
9. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African
descent resulting from frequent nonsense mutations in PCSK9. Nat Genet. 2005;37:1615.
10. Wierzbicki AS, Hardman TC, Viljoen A. Inhibition of pro-protein convertase subtilisin kexin
9 [corrected] (PCSK-9) as a treatment for hyperlipidaemia. Expert Opin Investig Drugs.
2012;21:66776.
11. Ahmad Z, Adams-Huet B, Chen C, et al. Low prevalence of mutations in known loci for autosomal dominant hypercholesterolemia in a multiethnic patient cohort. Circ Cardiovasc Genet.
2012;5:66675.
12. Maron BJ, Maron MS. Hypertrophic cardiomyopathy. Lancet. 2013;381:24255.
13. Subasic K. Hypertrophic cardiomyopathy. Nurs Clin North Am. 2013;48:57184.
14. Yingchoncharoen T, Tang WW. Recent advances in hypertrophic cardiomyopathy. F1000Prime
Rep. 2014;6:12.
15. Brugada R, Kelsey W, Lechin M, et al. Role of candidate modifier genes on the phenotypic
expression of hypertrophy in patients with hypertrophic cardiomyopathy. J Investig Med.
1997;45:54251.
16. Lloyd-Jones DM, Nam BH, DAgostino Sr RB, et al. Parental cardiovascular disease as a risk
factor for cardiovascular disease in middle-aged adults: a prospective study of parents and
offspring. JAMA. 2004;291:220411.
17. Preuss M, Konig IR, Thompson JR, et al. Design of the Coronary ARtery DIsease GenomeWide Replication And Meta-Analysis (CARDIoGRAM) study: a Genome-wide association
meta-analysis involving more than 22 000 cases and 60 000 controls. Circ Cardiovasc Genet.
2010;3:47583.
18. Consortium CADCDG. A genome-wide association study in Europeans and South Asians
identifies five new loci for coronary artery disease. Nat Genet. 2011;43:33944.
19. Deloukas P, Kanoni S, Willenborg C, et al. Large-scale association analysis identifies new risk
loci for coronary artery disease. Nat Genet. 2013;45:2533.
20. Schunkert H, Konig IR, Kathiresan S, et al. Large-scale association analysis identifies 13 new
susceptibility loci for coronary artery disease. Nat Genet. 2011;43:3338.
21. Saha N, Tay JS, Low PS, et al. Guanidine to adenine (G/A) substitution in the promoter region
of the apolipoprotein AI gene is associated with elevated serum apolipoprotein AI levels in
Chinese non-smokers. Genet Epidemiol. 1994;11:25564.
22. Minnich A, DeLangavant G, Lavigne J, et al. GA substitution at position 75 of the apolipoprotein A-I gene promoter. Evidence against a direct effect on HDL cholesterol levels.
Arterioscler Thromb Vasc Biol. 1995;15:17405.
23. Barre DE, Guerra R, Verstraete R, et al. Genetic analysis of a polymorphism in the human
apolipoprotein A-I gene promoter: effect on plasma HDL-cholesterol levels. J Lipid Res.
1994;35:12926.
24. Miettinen HE, Korpela K, Hamalainen L, et al. Polymorphisms of the apolipoprotein and
angiotensin converting enzyme genes in young North Karelian patients with coronary heart
disease. Hum Genet. 1994;94:18992.
25. Akita H, Chiba H, Tsuji M, et al. Evaluation of G-to-A substitution in the apolipoprotein A-I
gene promoter as a determinant of high-density lipoprotein cholesterol level in subjects with
and without cholesteryl ester transfer protein deficiency. Hum Genet. 1995;96:5216.
127
26. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of
95 loci for blood lipids. Nature. 2010;466:70713.
27. Kathiresan S, Willer CJ, Peloso GM, et al. Common variants at 30 loci contribute to polygenic
dyslipidemia. Nat Genet. 2009;41:5665.
28. Williams RR, Hunt SC, Hasstedt SJ, et al. Genetics of hypertension: what we know and dont
know. Clin Exp Hypertens A. 1990;12:86576.
29. Ji W, Foo JN, ORoak BJ, et al. Rare independent mutations in renal salt handling genes contribute to blood pressure variation. Nat Genet. 2008;40:5929.
30. Ehret GB, Munroe PB, Rice KM, et al. Genetic variants in novel pathways influence blood
pressure and cardiovascular disease risk. Nature. 2011;478:1039.
31. Kato N, Takeuchi F, Tabara Y, et al. Meta-analysis of genome-wide association studies identifies common variants associated with blood pressure variation in east Asians. Nat Genet.
2011;43:5318.
32. Ganesh SK, Arnett DK, Assimes TL, et al. Genetics and genomics for the prevention and treatment of cardiovascular disease: update: a scientific statement from the American Heart
Association. Circulation. 2013;128:281351.
33. Mega JL, Close SL, Wiviott SD, et al. Cytochrome P450 genetic polymorphisms and the
response to prasugrel: relationship to pharmacokinetic, pharmacodynamic, and clinical outcomes. Circulation. 2009;119:255360.
34. Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet
function, and cardiovascular events: a systematic review and meta-analysis. JAMA. 2011;
306:270414.
35. Scott SA, Sangkuhl K, Stein CM, et al. Clinical Pharmacogenetics Implementation Consortium
guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol
Ther. 2013;94:31723.
36. Rettie AE, Wienkers LC, Gonzalez FJ, et al. Impaired (S)-warfarin metabolism catalysed by
the R144C allelic variant of CYP2C9. Pharmacogenetics. 1994;4:3942.
37. Limdi NA, McGwin G, Goldstein JA, et al. Influence of CYP2C9 and VKORC1 1173C/T
genotype on the risk of hemorrhagic complications in African-American and EuropeanAmerican patients on warfarin. Clin Pharmacol Ther. 2008;83:31221.
38. Finkelman BS, Gage BF, Johnson JA, et al. Genetic warfarin dosing: tables versus algorithms.
J Am Coll Cardiol. 2011;57:6128.
39. Kimmel SE, French B, Kasner SE, et al. A pharmacogenetic versus a clinical algorithm for
warfarin dosing. N Engl J Med. 2013;369:228393.
40. Pirmohamed M, Burnside G, Eriksson N, et al. A randomized trial of genotype-guided dosing
of warfarin. N Engl J Med. 2013;369:2294303.
41. Lynch AI, Boerwinkle E, Davis BR, et al. Pharmacogenetic association of the NPPA T2238C
genetic variant with cardiovascular disease outcomes in patients with hypertension. JAMA.
2008;299:296307.
42. Barber MJ, Mangravite LM, Hyde CL, et al. Genome-wide association of lipid-lowering
response to statins in combined study populations. PLoS One. 2010;5, e9763.
43. Frazier-Wood AC, Aslibekyan S, Borecki IB, et al. Genome-wide association study indicates
variants associated with insulin signaling and inflammation mediate lipoprotein responses to
fenofibrate. Pharmacogenet Genomics. 2012;22:7507.
44. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group. EGAPP
Working Group Recommendations. 2009. http://www.egappreviews.org/recommendations/index.
htm. Accessed 18 Mar 2014.
45. Recommendations from the EGAPP Working Group: genomic profiling to assess cardiovascular risk to improve cardiovascular health. Genet Med. 2010;12:83943.
46. Recommendations from the EGAPP Working Group: routine testing for Factor V Leiden
(R506Q) and prothrombin (20210G>A) mutations in adults with a history of idiopathic venous
thromboembolism and their adult family members. Genet Med. 2011;13:6776.
Cardiovascular Disease in Women: An Update

Helen C. Huang, Puja K. Mehta, and C. Noel Bairey Merz
Introduction
CVD ranks number one in all-cause mortality in women around the world annually
[1]. According to the World Health Organization (WHO) 2008 data, one-third of
women died from heart attacks due to ischemic heart disease (IHD) and strokes
globally. Although men and women share similar health challenges, the presentation of CVD in women deserves additional attention. Emerging studies have shown
that women do not present or respond the same way as men do. Unfortunately,
though public awareness of CVD in men has increased over the years, women
remain understudied and under-promoted. The presentation of CVD in women
warrants further study due to its growing incidence and prevalence in the aging
female population around the world.
H.C. Huang, M.D.

Barbra Streisand Womens Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA, USA
P.K. Mehta, M.D.
Cedars-Sinai Medical Center, Los Angeles, CA, USA
Womens Heart Center in the Division of Cardiology in the Cedars-Sinai Heart Institute,
Los Angeles, CA, USA
e-mail: puja.mehta@cshs.org
C.N.B. Merz, M.D., F.A.C.C., F.A.H.A. (*)
Barbra Streisand Womens Heart Center, Preventive and Rehabilitative Cardiac Center,
Womens Guild Chair in Womens Health, Los Angeles, CA, USA
e-mail: noel.baireymerz@cshs.org
DOI 10.1007/978-3-319-22357-5_14
129
130
H.C. Huang et al.
Risk Factors
There are numerous non-modifiable risk factors of CVD, such as age, race, and
genetic factors. However, 90 % of CVD in women is attributable to modifiable risk
factors, which stratifies women into three risk categories: at high risk, denoting a
10-year predicted risk for CVD >20 % based on documented CVD, diabetes mellitus, or end-stage or chronic kidney disease; at risk based one or more CVD risk
factors, metabolic syndrome, or poor exercise tolerance on treadmill testing or
evidence of subclinical atherosclerotic disease; and at optimal risk, denoting the
absence of CVD risk factors or a healthy lifestyle in the setting of a Framingham
risk score <10 % [2]. Modifiable CVD risk factors include dyslipidemia, hypertension, smoking, diabetes, obesity, physical inactivity, stress, diet, alcohol consumption,
pregnancy-related complications, and most recently autoimmune disorders, such as
systemic lupus erythematosus and rheumatoid arthritis [2, 3].
Hypertension
Hypertension is a well-established risk factor that contributes to CVD in both men
and women, and numerous studies have demonstrated that treatment of hypertension leads to improved CVD outcomes. In a prospective study among 13,740 Dutch
women, those with SBP >185 were 3 times more likely to develop CVD compared
to women with SBP <135 [4]. In the Womens Health Initiative (WHI) study, 17 %
of women were noted to have isolated elevated systolic BP, of which treatment in
the elderly showed a profound reduction in the risk of hemorrhagic stroke within the
first year and ischemic stroke in the second year of treatment of hypertension [5].
The JNC 8 (Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure) recommends the goal BP <150/90 for elderly
patients age 60 years or older without diabetes mellitus or chronic kidney disease
(CKD) and goal BP <140/90 in younger patients without major co-morbidities or in
elderly patients who have diabetes mellitus or CKD [6].
Dyslipidemia
Dyslipidemia also remains a known high-risk contributor to IHD in both men and
women. Even though a high LDL predisposes both males and females to high incidence of CVD, a follow-up study from the Lipid Research Clinic showed that low
HDL is actually the most significant predictor of death in IHD in women [7]. In addition, the Atherosclerosis Risk in Communities (ARIC) study showed that elevated
triglyceride levels greater than 400 mg/dL increases the risk of CVD specifically
in older women, but not in men [8]. However, current guidelines by the National
Cholesterol Education Program (NCEP) do not include hypertriglyceridemia as a
131
primary risk factor for CVD. Surprisingly, the ARIC study did not reveal significant
findings with dyslipidemia and its association with incidence of ischemic stroke,
though it did show a decreased risk of an event in women with high HDL [9]. Recent
guidelines released from the ACC/AHA recommend moderate to high intensity
statin for patients with clinical atherosclerotic cardiovascular disease (ASCVD),
with LDL-C >190 mg/dL. or with diabetes mellitus (aged 4075 years) and 10-year
ASCVD risk score of >7.5 %, based on pooled cohort equations [10].
Diabetes
Diabetes is the strongest risk factor for CVD in women. CVD mortality in diabetic
women is 35 times higher than their non-diabetic peers compared to 23 times in
diabetic men when compared to non-diabetic peers [11]. In addition, diabetic women
are more likely to develop CVD and subsequent heart failure than diabetic men.
Unfortunately, a significant 43 % relative reduction in CVD mortality in diabetic
males has not been the same for diabetic females in the last 30 years [12]. Diabetic
females are treated less aggressively in terms of achieving goal HgbA1c and are at
increased risk for hypertension, low HDL, and elevated triglycerides than diabetic
males [13]. Women with gestational diabetes are at increased risk of developing
diabetes later in life and warrant routine screening.
Obesity and Metabolic Syndrome

Lifestyle risk factors of CVD include obesity and level of physical inactivity. Thirty
percent of women are overweight, while 27 % are obese worldwide. The Nurses
Health Study (NHS) demonstrated that non-smoking women with a body mass
index (BMI) 32 had a 4.1 relative risk of death from CVD compared to that of
women with BMI <19 [14]. A sedentary lifestyle is associated with an increased risk
of myocardial infarction (MI) and stroke by 4.7-fold than an active lifestyle [15].
The AHA defines metabolic syndrome as having three or more of the following
criteria in women: as abdominal obesity (ie., waist circumference >35 in.), hypertriglyceridemia, HDL <50 mg/dL, BP >130/85 mmHg, and elevated fasting glucose [16].
Metabolic syndrome is associated with a threefold risk for CVD [17].
Smoking
In addition, the NHS also noted that an increasing daily number of cigarettes is associated with an increased risk of CVD, in which 15 cigarettes daily were associated
with a two- to threefold increase, while 20 cigarettes daily with a sixfold increase [18].
132
H.C. Huang et al.
Similarly, smoking is associated with a twofold increase with ischemic stroke and 7.2
times increase in risk when used with oral contraceptives [19]. Surprisingly, CVD
mortality is decreased by 24 % within 2 years of tobacco cessation and essentially the
same as non-smokers after 1014 years.
Psychosocial Risk Factors

Psychosocial factors have also been implicated in CVD. Depression is more prevalent in women who have experienced an MI, as high as 40 % in women at or under
the age of 60 compared to 22 % of their male counterparts [20]. A prospective study
of Vietnam-era male twins found that the incidence of CVD was more than twice as
likely in twins with post-traumatic stress disorder (PTSD) than in those without
PTSD [21]. In addition, marital stress is associated with an increased risk in CVD
in women and worsened prognosis [22]. Low socioeconomic status is associated
with a two- to threefold increase in CVD in women compared to one- to twofold
increase in men [23].
Autoimmune Diseases
In the Effectiveness-Based Guidelines for the Prevention of Cardiovascular Disease
in Women2011 Update, autoimmune collagen-vascular disorders, such as systemic lupus erythematosus and rheumatoid arthritis, were added as risk factors for
CVD risk in women [2]. In addition to accelerated atherosclerosis due to underlying
inflammation and possibly due to chronic steroid use, women with systemic autoimmune disorders are also at risk of electrical disturbances including sinus tachycardia, transient atrial fibrillation, complete heart block, and ventricular arrhythmias
[24]. Fibromuscular dysplasia, antiphospholipid antibodies syndrome, Takayasu
arteritis, and SICRET (Small Infarcts of the Cochlear, Retinal, and Encephalic
Tissues) syndrome all contribute to stroke risk in younger women.
Pregnancy-Related Complications
Pregnancy-related complications are associated with increased risk of CVD.
Peripartum cardiomyopathy, though rare in Western society (occurring 1 in 2500 to
4000 live births) is much more common in developing countries (1 in 1000 live
births in South Africa and 1 in 300 in Haiti). It usually occurs within 3 months of
delivery and only half of those patients recover normal heart function. Though pregnancy is not associated with an increased risk of stroke, etiologies include eclampsia
(24 % pregnant women with cerebral infarction and 14 % with intracerebral hemorrhage), choriocarcinoma, peripartum cardiomyopathy, and amniotic fluid embolism.
133
The postpartum period, however, is a particularly hypercoagulable state, in which

the relative risk is 5.4 for cerebral infarction, 18.2 for intracerebral hemorrhage, and
7.9 for all strokes [25]. Adverse pregnancy outcomes (APOs) such as pregnancyinduced hypertension, eclampsia, and gestational diabetes are considered a CVD
risk factor for future development of CVD in women [2].
Highly Sensitive C-Reactive Protein (hs-CRP)

High-sensitivity CRP (hsCRP) appears to be an independent risk factor for CVD
and is associated with a twofold risk in CVA. This inflammatory marker is higher in
women than in men as early as puberty [26]. Increasing levels of hsCRP are associated with increased risk in the development of CVD, suggesting an inflammatorymediated component. The randomized, placebo-controlled JUPITER (Justification
for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating
Rosuvastatin) trial demonstrated that rosuvastatin decreased the incidence of CVD
events in study participants with elevated hs-CRP despite having lipid levels that
were below the threshold for treatment per prevention guidelines [27].
Menopause
The incidence of CVD in postmenopausal women is comparable to age-matched
men. Estrogen deficiency is associated with worsening of CVD risk factors, including a shift to adverse lipid profile, coagulability, and increased arterial stiffness [28].
However, exogenous supplementation with hormone therapy in post-menopausal
women has not been shown to be beneficial. The Womens Health Initiative (WHI),
a 15-year study sponsored by the National Institute of Health (NIH), revealed that
the use of combined hormone replacement therapy (HRT)conjugated equine
estrogens, 0.625 mg/day, and medroxyprogesterone acetate, 2.5 mg/dayin menopausal women increased the incidence of MI by 29 % and CVD by 22 % in comparison those who did not receive hormones [29]. Similarly, the use of combined
HRT was associated with a hazard ratio of 1.44 for ischemic stroke and 0.82 for
hemorrhagic stroke. It also increased the risk of dementia and mild cognitive impairment. Results of the more recently conducted randomized controlled trial in healthy
women with no established CVD showed that hormone therapy may be safe if
started early in menopause for treatment of symptoms.
Presentation
Men and women can present with both typical and atypical symptoms of IHD. While
men present with typical severe radiating sub-sternal chest pressure associated with
nausea, many women experience more atypical symptoms such as mild chest pain,
134
H.C. Huang et al.
fatigue, nausea, shortness of breath, upper back pain, feelings of anxiety, or loss of
appetite. Interestingly, in a recall study of 515 women, 47 % of women who experienced a myocardial infarction did not experience any episodes of chest pain prior to
the ischemic event [30]. Unfortunately, a national survey conducted on 1000 women
revealed that although more than two-thirds of women were aware of the classic
signs of a heart attack (chest pain or tightness with radiation to arm or jaw associated with shortness of breath), only 10 % knew of the symptoms more likely to
affect women (light-headedness, nausea, and fatigue). It should also be noted that
women with persistent chest pain and non-specific chest pain are also at higher risk
of MI [31, 32].
A condition that can mimic the presentation of MI is Takotsubo cardiomyopathy
(ie., Broken Heart Syndrome or stress cardiomyopathy). Patients often present with
chest symptoms with troponin leak and a spectrum of EKG changes. However, there
is an absence of obstructive CAD on angiography and is primarily characterized by
apical wall ballooning, although wall motion abnormalities at base and midventricular have also been described. It is often associated with a high emotional
stress, catecholamine-excess state. In majority of cases, the left ventricular dysfunction is transient and resolves over 3 to 6 months [33].
Gender differences are present in cerebrovascular disease (Table 1). Women tend
to have more pre-stroke comorbidities than men do, since they typically present
with an older age at onset (an average of 4 years) and are more likely to have hypertension and atrial fibrillation. In the WHI, 18.7 % of all strokes were hemorrhagic;
the ARIC Study found that the 30-day age and race-adjusted case-fatality in women
was increased in hemorrhagic stroke by 4.7 times when compared to ischemic
stroke. In addition, several studies have found that women have a higher incidence
of cardioembolic stroke than men have, likely due to increased prevalence of atrial
fibrillation in older women. Stroke is characterized by the sudden onset of symptoms such as unilateral numbness or weakness, confusion, trouble seeing in one or
both eyes, loss of balance or coordination, or severe headache with no known cause.
Diagnostic Testing
Exercise Treadmill Testing (ETT)
An ETT is usually recommended as the first test for IHD to assessment. The current
ACC/AHA guidelines recommend ETT for evaluation of chest symptoms in patients
at risk for CAD (Class IIb) and vasospastic angina (Class IIa). However, it can be of
a lower utility in women because of its lower specificity and sensitivity in detecting
obstructive coronary artery disease (CAD) in women compared to men. This may
be due to lower prevalence of obstructive CAD in women, increased frequency of
non-specific ST changes in baseline EKGs compared to men (32 % versus 23 %,
respectively), and inability to achieve maximal functional capacity secondary to
increased prevalence of obesity and osteoarthritis in women [34].
135

Table 1 Differences in CVD in women and men
Condition
Spontaneous coronary artery dissection
Autoimmune-related cardiovascular disease
Heart failure with preserved ejection fraction
Takotsubo cardiomyopathy
Benefit from cardiac resynchronization therapy
Sudden cardiac death
Pulseless electrical activity
Ventricular tachycardia/ventricular fibrillation
Sudden cardiac death with structurally normal heart
Myocardial infarction due to erosions and microemboli
Myocardial infarction due to plaque rupture
Acute coronary syndrome with no obstructive coronary artery
disease
Bleeding from anti-coagulation for atrial fibrillation
Bleeding complications post percutaneous coronary angioplasty
Mortality in younger age groups from CVD
Mortality after coronary artery bypass grafting
Mortality from stroke
Women
More
More
More
More
Greater
Men
More
More
More
More
More
More
More
More
More
Greater
Greater
More
Non-Invasive Imaging
Stress-induced changes in non-invasive cardiac imaging are better markers in
assessing for IHD in women. In a study with more than a 1000 women with suspected obstructive CAD, stress echocardiography had a high sensitivity (8189 %)
and high specificity (86 %) in patients with multi-vessel CAD in its ability of
predict IHD [35]. In addition, a stress echo can be conducted in various ways, such
as a treadmill, bicycle, and pharmacologically. Exercise stress testing is encouraged
as it can also assess the patients functional capacity and exercise tolerance. The
WOMEN (What is the Optimal Method for Ischemia Evaluation in Women?) trial,
in which 824 symptomatic women with suspected obstructive CAD were randomized to ETT or exercise myocardial perfusion imaging (MPI), found at 2 years that
there was no significant difference in major cardiac events predicted by either
modality [36].
Myocardial gated single-photon emission computed tomography (SPECT) is
recommended for both men and women with CVD risk factors, and allows for
visualization of global or regional perfusion defects. The accuracy of the MPI is
comparable between women and men, and is advantageous in patients who have
poor exercise tolerance. However, limitations in the MPI include high rate of
false positives in global perfusion defects, patients with small hearts, and breast
tissue artifact.
136
H.C. Huang et al.
Cardiac computed tomography (CT) and magnetic resonance imaging (MRI) are
newer imaging modalities that assess cardiac ischemia different from coronary
angiography. Cardiac MRI can assess for subendocardial ischemia, one of the initial
manifestations of cardiac ischemia, and can explain the etiology of chest pain in the
setting of non-obstructive CAD. Coronary computed tomography angiography
(CCTA) assesses coronary atherosclerosis, and is often used in the place of invasive
coronary angiography. In a large, multicenter prospective international cohort study,
the CONFIRM trial demonstrated that CCTA improves the ability to predict mortality
and non-fatal MI in symptomatic patients with suspected obstructive CAD [37].
Multiple studies have shown that CCTA can detect significant stenosis in smaller
coronary arteries and side branches with 8694 % sensitivity and 9397 % specificity, such that it can rule out the presence of hemodynamically significant CAD [38].
However, while the CCTA is an excellent tool to detect anatomic CAD severity, it is
unable to assess whether a lesion causes ischemia [31, 32]. To help with risk stratification in primary prevention, very low dose radiation testing with electron beam
CT (EBCT) can assess the amount of calcium in coronary arteries, in which a
calcium score between 100 and 400 is associated with increased obstructive CAD.
Invasive Coronary Angiography

Coronary angiography or cardiac catheterization remains the gold standard in the
detection of significant, obstructive CAD. The use of fractional flow reserve (FFR)
to determine the hemodynamic significance of a lesion and to guide percutaneous
coronary intervention (PCI) with stenting is recommended in both men and women
[31, 32]. Although PCI is equally effective in men and women, there is an increased
bleeding risk in women, like secondary to the lack of dose adjustment in glycoprotein IIb/IIIa inhibitor according to body size and renal function [39]. Women are
treated less aggressively than men are when first presenting with acute coronary
syndrome (ACS). Women are also more likely to undergo stress testing than cardiac
catheterization in evaluation of their ischemia, and are subsequently likely to experience a delay in cardiac catheterization.
Many women who do have not have obstructive CAD on diagnostic testing are
falsely reassured that they do not have IHD. In the WISE (Womens Ischemia
Syndrome Evaluation) study, approximately one-half of symptomatic women without obstructive CAD have coronary microvascular dysfunction (CMD), which is
associated with higher CVD risk than asymptomatic women are. In fact, patients
with unstable angina in the absence of obstructive CAD have a 2 % risk of CVD and
death at 30 days [40]. Furthermore, the 5-year event rates for CVD events in women
with persistent chest pain with non-obstructive CAD (i.e., lesions <50 % stenosis in
coronary arteries) were 16 % compared to WISE women with normal coronary
arteries (i.e., 0 % stenosis in all coronary arteries) at 7.9 % compared to asymptomatic women with normal coronary arteries at 2.4 % [41]. CMD is detected by
137
invasive coronary reactivity testing to assess endothelial and non-endothelial micro

and macrovascular responses vasoactive substances, including adenosine, acetylcholine, and nitroglycerin [42].
Stroke Diagnostics
On arrival to the hospital with stroke symptoms, women have longer door-to-scan
times than men. A European study revealed that after age-adjustment, women are
less likely than men are to receive imaging of brain, carotid ultrasound, or echocardiograms [43].
Treatment
Medical Therapy
Women are less likely to be medically optimized after MI or stroke compared to
men. Aspirin use is associated with a reduction in future events in women with a
history of CVD, such as unstable angina and acute MI, and stroke. It is recommended for primary prevention for MI in women after age 65 and for stroke prevention after age 50 [44]. However, women are less likely to be discharged on
dual antiplatelet therapy, ACE-inhibitor, or statins after an acute event, such as a
stroke of MI.
Many CVD medications found to be life-saving have not been adequately tested
in women likely due to the under-representation of women in most trials. Betablockers have been found to reduce the risk of subsequent MI by 25 % in both
women and men (though not statistically significant in women, likely due to the
small sample size) [45]. Similarly, the Heart Outcomes Prevention trial demonstrated a reduction in death, MI, and stroke equally in women and men with vascular
disease or diabetes with the ACE inhibitor or ARB therapy. If an ACE-inhibitor is
used in a woman of child-bearing age, a discussion regarding its teratogenic effects
is warranted.
HMG-CoA reductase inhibitors (or statins) are commonly prescribed for dyslipidemia though their pleotropic effects have been found to extend beyond lowering
the cholesterol. Statins have been observed to improve endothelial dysfunction and
myocardial perfusion, in which treatment for 612 weeks of fluvastatin was shown
to significantly improve myocardial perfusion in ischemic segments [46]. In addition, long-term therapy with statin in the CARE trial lowered hs-CRP levels in postinfarction patients though the effects have not been shown to correlate with LDL-C
levels [34]. The Heart Protection Trial Study (HPS) demonstrated that statins led to
a prominent reduction in all-cause mortality in women and a 24 % reduction in
vascular events [4].
138
H.C. Huang et al.
Percutaneous Coronary Intervention

Advances in coronary revascularization appear to have provided benefit in women
and men. Women who receive invasive coronary revascularization are older, have
more comorbidities (e.g., diabetes, hypertension, peripheral arterial disease, dyslipidemia), have unstable angina, and more severe angina compared to men. Women make
up only one-third of cardiac catheterizations even though there is mortality benefit
with intervention in those with obstructive CAD. In addition, physicians are less
likely to use heparin, ACE-inhibitors, and glycoprotein IIb/IIIa inhibitors in women,
and less likely to discharge them with ACE-inhibitors, statins, beta-blockers and
aspirin [28]. A meta-analysis of eight ACS trials revealed that women and men both
benefited from an invasive therapy, with a 1927 % relative risk reduction in death,
MI, or repeat ACS. However, biomarker-positive women had a 33 % lower risk
reduction than biomarker-negative women, which was not seen in men [47]. In addition, there are more associated complications in women younger than age 55, such as
coronary vascular injury likely due to smaller vessels and bleeding complications
when compared to men.
Coronary Artery Bypass Graft

Coronary artery bypass graft (CABG) surgery is associated with increased operative
mortality in women compared to men (ie., 4.5 % in women versus 1.9 % in men)
[48]. This may be because women who undergo CABG have a higher pre-operative
risk due to increased comorbidities and smaller anatomy than men. In addition,
there is also an increase in complications in women compared to men, including
atrial fibrillation, pneumonia, sternal reclosure, leg wounds, and prolonged mechanical ventilation. Women were also found to have fewer internal mammary artery
conduits than men, which can be associated with increased incidence of incomplete
revascularization in women.
Stroke Interventions
Interestingly, in a study by Patrick et al. of patients hospitalized for ischemic stroke,
women underwent fewer cerebral angiography (7.2 %) and carotid endarterectomy
(5.7 %) than did men (11.8 % and 10.6 %, respectively), but the differences were not
significant after the increased prevalence of carotid disease in men were adjusted
[49]. Both men and women benefit equally from carotid endarterectomy. In addition, most studies show that women were less likely to receive alteplase than men.
An analysis of a Michigan registry study of ischemic stroke patients revealed that
the adjusted odds ratio for alteplase treatment in women was 0.56 (95 % CI 0.40.9)
compared to men [50].
139
Conclusion
In the setting of the growing prevalence of cardiovascular disease in women globally, gender differences in the presentation, evaluation and treatment of CVD are
notable and warrant more extensive studies. Women are often overlooked in diagnostic studies and interventions when presenting with symptoms compared to men.
Promoting public awareness and education of the CVD in women are crucial for
prevention and timely treatment.
Acknowledgement This work was supported by contracts from the National Heart, Lung
and Blood Institutes, nos. N01-HV-68161, N01-HV-68162, N01-HV-68163, N01-HV-68164,
K23HL105787, grants U0164829, U01 HL649141, U01 HL649241, T32HL69751, R01-HL090957,
1R03AG032631 from the National Institute on Aging, GCRC grant MO1-RR00425 from the
National Center for Research Resources and grants from the Gustavus and Louis Pfeiffer Research
Foundation, Danville, NJ, The Womens Guild of Cedars-Sinai Medical Center, Los Angeles, CA,
The Ladies Hospital Aid Society of Western Pennsylvania, Pittsburgh, PA, and QMED, Inc.,
Laurence Harbor, NJ, the Edythe L. Broad Womens Heart Research Fellowship, Cedars-Sinai
Medical Center, Los Angeles, California, the Barbra Streisand Womens Cardiovascular Research
and Education Program, Cedars-Sinai Medical Center, Los Angeles, The Society for Womens
Health Research (SWHR), Washington, D.C., and the Linda Joy Pollin Womens Heart Health
Program, Los Angeles, C.A.
References
1. World Health Organization. Ten leading causes of death in females by age and country income
group. 2008.
2. Mosca L, Benjamin EJ, Berra K, et al. Effectiveness-based guidelines for the prevention of
CVD in women: 2011 update. J Am Coll Cardiol. 2011;57:140423.
3. Schenck-Gustafsson K. Risk factors for CVD in women. Maturitas. 2009;63:18690.
4. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol
lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo controlled
trial. Lancet 2002;360(9326):7.
5. Shep CRG. Prevention of stroke by antihypertensive drug treatment in older persons with
isolated systolic hypertension. Final results of the systolic hypertension in the elderly program
(SHEP). JAMA. 1991;265:3255e64.
6. James PA, Oparil S, Carter B, et al. 2014 Evidence-based guideline for the management of
high blood pressure in adults. JAMA. 2014;311(5):50720.
7. Jacobs DR, Mebane IL, Bangdiwala SI, et al. High density lipoprotein cholesterol as a predictor of CVD mortality in men and women: the follow up study of the lipid research clinics
prevalence study. Am J Epidemiol. 1990;131:132.
8. Sharrett AR, Ballantyne CM, Coady SL, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL
density subfractions: the Atherosclerosis Risk in Communities (ARIC) study. Circulation.
2001;104:110813.
9. Shahar E, Chambless E, Rosamond WD, et al. Plasma lipid profile and incident ischemic
stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2003;34(3):62331.
10. Stone NJ, Robinson J, Lichtenstein AH, Bairey Merz CN, Lloyd-Jones DM, Blum CB,
McBride P, Eckel RH, Schwartz JS, Goldberg AC, Shero ST, Gordon D, Smith Jr SC, Levy D,
Watson K, Wilson PWF. 2013 ACC/AHA guideline on the treatment of blood cholesterol to
140
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
H.C. Huang et al.

reduce atherosclerotic cardiovascular risk in adults. Circulation. 2013. doi:10.1161/01.cir.
0000437738.63853.7a.
Kannel WB. The Framingham Study: historical insight on the impact of cardiovascular risk
factors in men versus women. J Gend Specif Med. 2002;5:2737.
Gregg EW, Gu Q, Cheng YJ, Narayan KM, Cowie CC. Mortality trends in men and women
with diabetes. Ann Intern Med. 2007;147:14955.
Legato MJ, Gelzer A, Goland R, et al. Gender-specific care of the patient with diabetes: review
and recommendations. Gend Med. 2006;3(2):13158.
Manson JE, Willet WC, Stampfer MJ, et al. Body weight and mortality among women. N Engl
J Med. 1995;333:677.
Blair SN, Kohl HW, Paffenbarger RS, et al. Physical fitness and all cause mortality: a prospective study of healthy men and women. JAMA. 1989;262:2395.
Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute scientific
statement. Circulation. 2005;112(17):273552.
Isomoaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and mortality associated with
metabolic syndrome. Diabetes Care. 2001;24(4):6839.
Sarna L, Bialous SA, Jun HJ, Wewers ME, Cooley ME, Feskanich D. Smoking trends in the
Nurses Health Study (19762003). Nurs Res. 2008;57(6):37482.
Ischaemic stroke and combined oral contraceptives: results of an international, multicentre,
case control study. WHO Collaborative Study of CVD and Steroid Hormone Contraception.
Lancet. 1996;348(9026):498505.
Mallik S, Spertus JA, Reid KJ, et al. Depressive symptoms after acute myocardial infarction:
evidence for higher rates in younger women. Arch Intern Med. 2006;166:87683.
Vaccarino V, Goldberg J, et al. Post-traumatic stress disorder and incidence of coronary heart
disease: a twin study. J Am Coll Cardiol. 2013;62(11):9708.
Orth-Gomr K, Wamala SP, Horsten M, et al. Marital stress worsens prognosis in women with
coronary heart disease: The Stockholm Female Coronary Risk Study Circulation. JAMA.
2000;284(23):300814.
Morrison C, Woodward M, Leslie W, et al. Effect of socioeconomic group on incidence of,
management of, and survival after myocardial infarction and coronary death: analysis of community coronary event register. BMJ. 1997;314:5416.
Seferovic PM, Ristic AD, Mastimovic R, et al. Cardiac arrhythmias and conduction disturbances in autoimmune rheumatic diseases. Rheumatology (Oxford). 2006;45 Suppl 4:iv3942.
Kittner SJ, Stern BJ, Feeser BR, Hebel JR, Nagey DA, Buchholtz DW, Earley CJ, Johnson CJ,
Macko RF, Sloan MA, Wityk RJ, Wozniak M. Pregnancy and the risk of stroke. N Engl J Med.
1996;335:76874.
Wong ND, Pio J, Valencia R, Thakal G. Distribution of C-reactive protein and its relation to
risk factors and coronary heart disease risk estimation in the National Health and Nutrition
Examination Survey (NHANES) III. Prev Cardiol. 2001;4:10914.
Ridker PM, Danielson E, Fonseca FA. Rosuvastatin to prevent vascular events in men and
women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195207.
McGrath BP, Liang YL, Teede H, et al. Age-related deterioration in arterial structure and function in postmenopausal women: impact of hormone replacement therapy. Arterioscler Thromb
Vasc Biol. 1998;18:114956.
Writing Group for the Womens Health Initiative Investigators. Risks and benefits of estrogen
plus progestin in healthy postmenopausal women: principal results from the womens health
initiative randomized controlled trial. JAMA. 2002;288:32133.
McSweeney JC, Marisue C, OSullivan P, Elberson K, Moser DK, Garvin BJ. Womens early
warning symptoms of acute myocardial infarction. Circulation. 2003;108:261923.
Robinson J. Cardiovascular risk in women with non-specific chest pain. Am J Cardiol.
2008;102:6939.
Johnson BD, Shaw LJ, Pepine CJ, Reis SE, Kelsey SF, Sopko G, Rogers WJ, Mankad S,
Sharaf BL, Bittner V, Bairey Merz CN. Persistent chest pain predicts cardiovascular events in
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
141
women without obstructive coronary artery disease: results from the NIH-NHLBI-sponsored
Women's Ischaemia Syndrome Evaluation (WISE) study. Eur Heart J. 2006;27:140815.
Sharkey S, Lesser J, Maron B. Cardiology Patient Page. Takotsubo (stress) cardiomyopathy.
Circulation. 2011;124:e4602.
Dey S, Flather MD, Devlin G, et al. Sex-related differences in the presentation, treatment
and outcomes among patients with acute coronary syndromes: the Global Registry of Acute
Coronary Events. Heart. 2009;95:206.
Picano E. Stress echocardiography: a historical perspective. Am J Med. 2003;114:12630.
Shaw LJ, Mieres JH, et al. Comparative effectiveness of exercise electrocardiography with or
without myocardial perfusion single photon emission computed tomography in women with
suspected coronary artery disease: results from the What Is the Optimal Method for Ischemia
Evaluation in Women (WOMEN) trial. Circulation. 2011;124(11):123949.
Al-Mallah M, Qureshi W, Lin F, et al. Does coronary CT angiography improve risk stratification over coronary calcium scoring in symptomatic patients with suspected coronary artery
disease? Results from the prospective multicenter international CONFIRM registry. Eur Heart
J Cardiovasc Imaging. 2014;15:26774.
Hoffman U, Ferencik M, Cury RC, Pena AJ. Coronary CT angiography. J Nucl Med. 2006;
47:797806.
Cho L, Topol EJ, Balog C, et al. Clinical benefit of glycoprotein IIb/IIIa blockade with abciximab is independent of gender: pooled analysis from EPIC, EPILOG and EPISTENT trials.
Evaluation of 7E3 for the Prevention of Ischemic Complications. Evaluation in Percutaneous
Transluminal Coronary Angioplasty to Improve Long-Term Outcome with Abciximab GP IIb/
IIIa blockade. Evaluation of Platelet IIb/IIIa Inhibitor for Stent. J Am Coll Cardiol. 2000;
36:3816.
Diver DJ, Bier JD, Ferreira PE, et al. Clinical and arteriographic characterization of patients
with unstable angina without critical coronary arterial narrowing (from the TIMI-IIIA Trial).
Am J Cardiol. 1994;74:5317.
Gulati M, Cooper-DeHoff RM, McClure C, et al. Adverse cardiovascular outcomes in women
with nonobstructive coronary artery disease: a report from the Womens Ischemia Syndrome
Evaluation Study and the St James Women Take Heart Project. Arch Intern Med. 2009;
169(9):84350.
Wei J, Mehta PK, et al. Safety of coronary reactivity testing in women with no obstructive
coronary artery disease: results from the NHLBI-sponsored WISE (Womens Ischemia
Syndrome Evaluation) study. JACC Cardiovasc Interv. 2012;5(6):64653.
Di Carlo A, Lamassa M, Baldereschi M, et al. Sex differences in the clinical presentation,
resource use, and 3-month outcome of acute stroke in Europe: data from a multicenter multinational hospital based registry. Stroke. 2003;34:11149.
Smith Jr SC, Benjamin EJ, et al. AHA/ACCF secondary prevention and risk reduction therapy
for patients with coronary and other atherosclerotic vascular disease: 2011 Update. Circulation.
2011;124(22):245873.
Olsson G, Ogden A, Johansson I, et al. Prognosis after withdrawal of chronic postinfarction
metoprolol treatment: a 27 year follow-up. Eur Heart J. 1988;9:36572.
Davignon J. Beneficial cardiovascular pleiotropic effects of statins. Circulation. 2004;109:
III3943.
ODonoghue M, Boden WE, Braunwald E, et al. Early invasive vs conservative treatment
strategies in women and men with unstable angina and non-ST-segment elevation myocardial
infarction: a meta-analysis. JAMA. 2008;300:7180.
Kennedy JW, Killip T, Fisher LD, et al. The clinical spectrum of coronary artery disease
and its surgical and medical management, 19741979. The Coronary Artery Surgery study.
Circulation. 1982;66:III1623.
Patrick SJ, Concato J, Viscoli C, Chyatte D, Brass LM. Sex differences in the management of
patients hospitalized with ischemic cerebrovascular disease. Stroke. 1995;26:57780.
Gargano JW, Reeves MJ. Sex differences in stroke recovery and stroke-specific quality of life:
results from a statewide stroke registry. Stroke. 2007;38:25418.
Rheumatic Heart Disease: A Neglected Heart

Disease
Marcia de Melo Barbosa, Maria do Carmo Pereira Nunes, and Regina Mller
Acute Rheumatic fever (ARF) and its chronic sequel, rheumatic heart disease
(RHD) result from an autoimmune disease that starts with an infection caused by
Streptococcus pyogenes (Group A streptococciGAS) and remain the most common cause of preventable childhood heart disease worldwide. It follows a nontreated throat infection in susceptible children and teenagers (3- to 19-years old); and
strongly relates to socioeconomic and environmental determinants, such as overcrowding, poor standard of living, poor access to medical care and inadequate
expertise of health-care teams [1, 2].
Epidemiology
Despite being considered today as virtually eliminated [3] after a documented
decrease in the incidence of ARF in developed countries during the past 6 decades,
RHD remains a medical and public health problem, especially in low and middleincome countries and in indigenous populations, where it causes disability and
M. de Melo Barbosa, M.D., Ph.D. (*)

ECO Center, Hospital Socor, Belo Horizonte, Brazil
Interamerican Society of Cardiology
e-mail: marciambarbosa@terra.com.br
M. do Carmo Pereira Nunes, M.D.
School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
e-mail: mcarmo@waymail.com.br
R. Mller, M.D., Ph.D.
Working Group on Rheumatic Fever from the World Heart Federation, Geneva, Switzerland
National Heart Institute of Rio de Janeiro, Rio de Janeiro, Brazil
e-mail: reginamuller@globo.com
DOI 10.1007/978-3-319-22357-5_15
143
144
M. de Melo Barbosa et al.
premature death in children and young adults in their most productive years [1].
As stated recently, RHD does not get the same attention as cancer as a chronic noncommunicable disease (NCD) because it is a disease of the bottom billion of the
poorest people in the worldone of the most neglected of the neglected diseases [2].
In 2005, the World Health Organization (WHO) estimated a prevalence of at least
15.6 million cases of RHD worldwide, with 282,000 new cases (ARF) and 233,000
deaths related to RHD each year. The burden of stroke due to RHD in less developed countries was also considered: 144,000360,000 new strokes each year [4].
However, these are conservative assumptions, and future incoming-data will show
these figures to be dramatically underestimated [5].
In Brazil, estimates based on WHO epidemiological model and data from the last
Census in 2010, appointed to around 30,000 new cases of ARF each year, of which
around 12,800 can develop RHD [1, 6]. Brazilian official figures have shown a significant reduction in the number of hospitalizations due to ARF and RHD in the last
10 years, however, in 2012, 2713 ARF and 4268 RHD hospital admissions were still
reported [7], since, similar to other countries, Brazil has not yet implemented a
national register system and a RHD control program. Underreporting of cases and
difficulties in access to hospital admission, especially for adolescents and young
adults, are very common.
In a recent linkage study with 53,210 Brazilian in-hospital children and adolescents admitted for heart failure (HF) from 2001 to 2007 the survival analysis for the
ARF/RHD patients showed only 61 %, 55 % and 36 % survival rate at 1, 2 and
7 years, respectively, with a hazard ratio observed for RHD patients death of 15.5.
These poor results were strongly related to social conditions measured by human
development index (HDI) of the patients residence [8].
Another Brazilian study with 100 RHD low-income patients in Sao Paulo analyzing the entire course of the disease concluded that costs of ARF/RHD amounted to
approximately 1.3 % of the annual family income in this population. Direct and
indirect costs, such as school failure rate of 22 %, 23 % parents work absenteeism,
about 5 % lost jobs, and the intangible costs associated with RHD, resulting from
premature disability and death, and loss of intellectual opportunities, with its adverse
effects on the socioeconomic family and society development. The estimated annual
cost of RF for society in Brazil was estimated in 2001 as US$ 51,144,347.00 [9].
More recently, advocacy groups, including the World Heart Federation (WHF),
have put greater efforts into rectifying this neglect disease [2]. In April 2013, the
WHF issued a statement of commitment to the strategic objective of a 25 % reduction in premature deaths from ARF and RHD among individuals aged <25 years by
the year 2025. To achieve the objective of controlling RHD and eliminating ARF,
five strategic targets have been identified: (1) Comprehensive register-based control
programs; (2) Global access to Benzathine penicillin G; (3) Identification and development of public figures as RHD champions; (4) Expansion of RHD training
hubs; and (5) Support for vaccine development [10].
A recent editorial about RHD discussed that the challenge regarding RHD does
not relate to knowledge of the disease, but to the implementation of measures to
control the disease globally [5], which depends on the political will of the governments and inclusion of ARF in public health policies. It requires advocacy, awareness, commitment, coordination, and resources [5].
Rheumatic Heart Disease: A Neglected Heart Disease
145
Pathogenesis
The pathogenesis of ARF/RHD is complex and both environmental and genetic
factors contribute to its etiology, but still remains incompletely understood [11].
Streptococcus, in the appropriate condition, triggers the pathogenic sequence that
starts with pharyngitis, leading, in a small percentage of cases (1 to 5 % of susceptible
children), to ARF which, in about 60 % of the cases, will develop life-threatening
valve lesions characteristic of RHD [2].
Several genes associated with RHD have been described, related to both the
innate and adaptive immune responses. The susceptibility of developing ARF/RHD
is associated with some alleles of HLA (human leukocytes antigens) class II genes
(DRB1, DQB and DQA), as well as with TNF- gene which are all located on
human chromosome 6. HLA alleles are involved in antigen recognition by T lymphocytes through the T cell receptor (TCR). TNF- gene encodes the inflammatory
TNF alpha protein, which is involved in the inflammatory process mediating hearttissue lesions in RHD. Several other associations have been established through
single nucleotide polymorphisms (SNPs) for genes code for other proteins also
involved with the immune response (innate and adaptive pathways) [11].
Molecular mimicry between streptococcal antigens and human proteins is central to RHD pathogenesis, and mainly cardiac myosin epitopes and vimentin seem
to be the major target antigens. Autoreactive T cells (CD4+) migrate from the
peripheral blood to the heart and proliferate in the valves in response to stimulation
with specific cytokines. High TNF alpha, interferon gamma, and low IL4 are found
in the rheumatic valve. IL-4+ cells are found in the myocardium; however, these
cells are very scarce in the valve lesions of RHD patients. IL-4 is a Th2-type cytokine and plays a regulatory role in the inflammatory response mediated by Th1
cytokines. These findings indicate that the Th1/Th2 cytokine balance has a role in
healing myocarditis, while the low numbers of IL-4-producing cells in the valves
probably induce progressive and permanent valve damage [11].
Diagnosis
The diagnosis of ARF is essentially clinical and laboratory exams are not pathognomonic of the disease, only contributing to confirm the inflammatory process and the
streptococcal infection. Clinical diagnosis of carditis is usually made by the auscultation of a pathological mitral regurgitation (MR) murmur. Jones criteria [12] created in 1944, are characterized in major and minor, and represent the gold standard
for the diagnosis of the first attack. They are an epidemiological and not clinical tool
for the initial attack and have been revised, modified and updated by the American
Heart Association [13, 14] and by the WHO [1] (Tables 1 and 2).
For the initial attack, the presence of two major manifestations or of one major
and two minor manifestations supported by the evidence of a preceding GAS
infection indicates high probability of ARF. For the diagnosis of recurrences in a
146
Table 1 Modified Jones
criteria for the diagnosis of
rheumatic fever (1992)

Major criteria
Carditis
Arthritis
Chorea
Eritema marginatum
Subcutaneous nodulous
Minor criteria
Fever
Arthralgia
Elevation of inflammatory markers
(ESR, CRP)
Prolonged PR interval in the ECG
Evidence of GAS infection

Adapted from Dajani et al., Jones criteria 1992 UpdateAHA
ESR erythrocyte sedimentation rate, CRP C-reactive protein
Table 2 WHO Criteria (2004) for the diagnosis of the first attack, recurrence and RHD (based on
the modified Jones criteria)
Diagnostic category
First episode of ARF
Recurrence of ARF in patients without established

RHD
Recurrence of ARF in patients with established
RHD
Sydenham Chorea
Insidious rheumatic carditis
Chronic valve lesions of the RHD: pure MS or MS
and MR diagnosis and/or aortic valve lesion with
characteristic rheumatic involvement
Criteria
2 major criteria or 1 major and 2 minor +
evidence of previous streptococcus
infection
2 major criteria or 1 major and 2 minor +
evidence of previous streptococcus
infection
2 major criteria + evidence of previous
streptococcus infection
No other major criteria or evidence of
previous streptococcus infection is
required
No additional criteria for the diagnosis
of RHD is necessary
Source: WHO 2004
patient with established RHD, just two minor criteria plus evidence of preceding
GAS infection is sufficient. The presence of chorea, insidious carditis and chronic
valve lesions are exception and do not require any other criteria to be considered as
having rheumatic fever [1].
Subclinical carditis (SCC) is also a major concern, since 16.827 % may have it.
In endemic areas, strict adherence to the revised Jones criteria can result in underdiagnosis of ARF [15]. Failure to diagnose these patients can lead to severe adverse
consequences since prophylaxis will not be started [16, 17]. In Australia, diagnosis
rates increased significantly when monoarthritis and SCC were included as major
criteria and low-grade fever (37.5) as a minor criterion [17].
The disease usually presents with an acute febrile onset, with variable combinations of arthritis, carditis, chorea and skin manifestations. Published criteria are
useful for epidemiological purposes, but clinical judgment should prevail, especially in areas of the world where RHD is still common.
147
Evidence of previous GAS infection is demonstrated by increased or rising antistreptolisin O titer or other antibodies or a positive throat swab for GAS. Inflammatory
markers, such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)
are usually elevated. Though unspecific, they can add in monitoring the inflammatory process and its remission.
Major Clinical Manifestations

Arthritis
The classical presentation is that of migratory and asymmetric polyarthritis involving large joints, especially in the legs, and than migrating to other joints with some
overlapping of joints involvement. It occurs in approximately 75 % of the cases and
should be differentiated from arthralgia (no inflammatory signs). When associated
with carditis, there seems to be an inverse correlation between the severity of the
two findings [1]. It responds rapidly to anti-inflammatories and thus, self-medication
may mask the typical presentation.
Carditis
It is the most serious manifestation of the disease, and the only one that leaves
sequelae. Clinically, it is present in 4070 % of the cases, however the percentage is
much higher when the diagnosis is made by echocardiography [18, 19]. Although
there is a pancarditis (endocardial, myocardial and pericardial involvement), valve
lesions are the ones responsible for the clinical presentation and prognosis.
Myocarditis can be diagnosed by histology, but it does not cause HF and systolic
function is usually preserved at the initial presentation. Pericardium involvement is
not common, does not happen in isolation and does not lead to constriction, but the
presence of a pericardial effusion may help confirm the diagnosis [20].
The most common valve lesion is MR and its pan-systolic murmur does not
indicate permanent lesion. Aortic regurgitation (AR) is less common and stenotic
lesions do not happen in the early stage of the disease. Tricuspid regurgitation may
occur in acute carditis secondary to pulmonary hypertension.
The severity of carditis can vary from SCC to a fulminant form. In SCC, cardiovascular exam, X Ray and ECG are normal (except for a prolonged PR). Doppler
echocardiogram is essential for its diagnosis, as it can detect pathological mild MR
and/or AR [21]. Mild carditis is present when there is tachycardia disproportional to
the degree of fever, diminished S1 and MR systolic murmur. Chest X Ray and ECG
are normal (except for a prolonged PR), but Doppler echocardiogram shows mild or
moderate regurgitations and a normal-sized left ventricle (LV). In the moderate
148
form, cardiovascular exam is abnormal, with signs of incipient HF, abnormal

chest X Ray and ECG, and more severe regurgitations in the echocardiogram, with
enlarged LV. Finally, in the severe form, cardiovascular signs are more important,
the patient presents in HF, with murmurs related to more severe degrees of regurgitation, arrhythmias, pericarditis, and several abnormalities on the ECG, chest X Ray
and Doppler echocardiogram [20].
Chorea
Sydenhams chorea may occur in association with other manifestations, but it may
also be the sole expression. It is a neurological disorder characterized by rapid and
involuntary movements, which are more common during stress and cease during
sleep. Its incidence varies from 5 to 36 % and it occurs predominantly in female
children and adolescents [20].
Eritema Marginatum
It is a rare skin manifestation (415 % of the patients), generally occurring at the
beginning of the disease. It is usually associated with carditis, but not with its severity, being characterized by a non-itchy pink-red lesion, which predominantly affects
the trunk and spares the face. It may disappear within hours and it is difficult to
detect in dark-skin patients [20].
Subcutaneous Nodules
They are firm and painless, varying greatly in size, and representing a rare manifestation (25 %) of the disease. The overlying skin is not inflamed and they are usually located over bones surfaces or tendons and best detected by palpation and not
inspection. Their presence is strongly associated with severe carditis [20].
Minor Manifestations
They are unspecific and only when associated with major criteria and evidence of
previous GAS infection help to establish the diagnosis. Fever and tachycardia out of
proportion to the fever are usually present. Fever is usually of low grade when there
is carditis without arthritis, and absent in isolated chorea [20].
149
After recovery from the initial episode, 72 % of patients will develop valve heart
diseases [18]. Recurrence of the disease can lead to progression of valve lesions
with all its consequences, as HF, atrial fibrillation, stroke, infective endocarditis and
pregnancy-related complications. With progression of the disease, cardiac surgery
becomes mandatory and, if not performed, premature death from RHD and its complications is frequent, with some countries presenting the unacceptable mean age of
death <25 years [22, 23]. Otherwise, patients under regular secondary prophylaxis
may present recovery on the severity of valve lesions.
ECG
ECG is unspecific, since it can be normal in the presence of carditis. A prolonged PR
interval (minor sign) can be present in the absence of carditis. Sinus tachycardia, ST-T
abnormalities, low QRS and T amplitude in the frontal leads can be present [20].
Echocardiogram
Although echocardiogram has been shown to be much more sensitive in the diagnosis
of rheumatic lesions, screening by echocardiography is not always feasible, especially in low-income countries, where the disease is usually more prevalent. Besides,
physiological regurgitations in normal individual can be interpreted as secondary to
RHD. To avoid this misclassification, regurgitation should be considered abnormal
only in the presence of morphological valve abnormalities [21] (Table 3).
Since secondary prevention can avoid adverse outcomes, early echocardiographicbased diagnosis of valve lesions by active surveillance strategies has been shown in
several countries to be of major importance [2427].
MR is the most frequent lesion in ARF, being present in up to 94 % of the cases.
Valve thickening and focal nodules in the distal portion of the leaflets are frequent
and disappear in the follow-up [28]. AR is not a frequent lesion in ARF, but in males
it can occasionally be an isolated lesion. Stenosis is a late finding. LV dilation may
be present and both cardiomegaly and valve regurgitation can disappear. Systolic
function is usually preserved and HF, when present, is considered nowadays to
occur due to valve lesion and not to myocardium involvement.
In patients with chronic RHD, recurrence is always associated with carditis,
which can be expressed as pericarditis, new or worsening of a pre-existing valve
regurgitation, increase in cardiac silhouette and HF. Size and function of cardiac
chambers, left valve abnormalities (stenosis and regurgitation), tricuspid lesion
(much less frequent) and associated pulmonary hypertension can all be adequately
detected by echocardiography in RHD.
Features in the AV
Irregular or focal thickening
Coaptation defect
Restricted leaflet motion
Prolapse
Pathological aortic regurgitation

Seen in 2 views
In at least 1 view, jet length 1 cm
Velocity 3 m/s in early diastole
Pan-diastolic jet in at least 1 envelope
Source: WHF criteria for echocardiographic diagnosis of RHD

AMVL anterior mitral valve leaflet, AR aortic regurgitation, AV aortic valve, MR mitral regurgitation, MS mitral stenosis, MV mitral valve, RHD
rheumatic heart disease
a
All four Doppler echocardiographic criteria must be met
Definite RHD (either A, B, C, or D)

A) Pathological MR and at least 2 morphological features of RHD of the MV
B) MS mean gradient 4 mmHg
C) Pathological AR and at least 2 morphological features of RHD of the AV
D) Borderline disease of both the AV and MV
Borderline RHD (either A, B, or C)
A) At least 2 morphological features of RHD of the MV without pathological MR or MS
B) Pathological MR
C) Pathological AR
Criteria for pathological regurgitation
Pathological mitral regurgitation
Seen in 2 views
In at least 1 view, jet length 2 cm
Velocity 3 m/s for 1 complete envelope
Pan-systolic jet in at least 1 envelope
Morphological features of RHD
Features in the MV
AMVL thickeninga 3 mm (age-specific)
Chordal thickening
Restricted leaflet motion
Excessive leaflet tip motion during systole
Table 3 Echocardiographic criteria for individuals aged 20 years
150
151
Treatment
General Measures
Treatment aims to suppress the acute inflammatory process, minimizing clinical
repercussions on the heart, joints and central nervous system, in addition to eradicating GAS infection and promoting relief of main symptoms [20, 29].
Absolute bed rest is no longer recommended, except in the presence of carditis,
when bed rest, at least during the symptomatic stage, is recommended. Return to
normal activities should be gradual depending on the improvement of symptoms
and normalization or marked reduction of inflammatory activity tests.
In cases of high temperature, paracetamol is recommended as a first option, and
dipyrone as a second. Anti-inflammatory drugs, including acid acetylsalicylic, are
not indicated before the diagnosis of ARF is confirmed [20].
Anti-inflammatory and Corticosteroids

The first lines of symptomatic therapy are anti-inflammatory agents, ranging from
salicylates to steroids [27, 30, 31]. Salicylates markedly reduce fever and relieve joint
pain and swelling, but they have no effect on the natural course of the disease. Adults
may require large doses of aspirin, 0.60.9 g every 4 h, while children are treated with
lower doses. Corticosteroids are not frequently used because they offer no therapeutic
benefits and may mask the presence of other illnesses causing arthritis [20, 29].
Therapeutic Modalities
Acute carditis has generally been treated with steroids even though they have
no effect on the progression of RHD. Nevertheless, in the setting of severe, potentially life-threatening HF, steroid administration is largely employed [20, 2931].
Treatment of cardiac manifestations follows established guidelines, including management of HF and severe valve regurgitation. Digitalis can be used but with special
attention because of the risk of development of heart block. Cardiac surgery should
be avoided whenever possible during ARF, being indicated only in the presence of
severe valve regurgitation with HF refractory to drug therapy [20, 29, 31].
Treatment for chorea is indicated only in severe forms, when uncoordinated
movements interfere with usual activity of the patients. Drugs used to control chorea symptoms are haloperidol, valproic acid, and carbamazepine. Small series have
studied corticosteroids, along with plasmapheresis and intravenous immunoglobulin,
to assess their influence on the severity and time course of symptoms, but there is
not enough evidence for the indication of these therapies [20, 29].
152
Prophylaxis for Rheumatic Fever

Primary Prevention
The initial episode of ARF can usually be prevented by early treatment of streptococcal pharyngitis. Patients with evident bacterial pharyngitis and positive test
results for GAS should be treated as early as possible in the suppurative phase.
Effective prevention of ARF is obtained even when antibiotics are started until
9 days after the onset of the infection [20, 29]. Early treatment of streptococcal
pharyngitis is especially recommended in countries with a high prevalence of ARF
to avoid the development of new cases of the disease, since the transmission rate in
untreated patients is approximately 35 % in close contacts (families, schools, or
other agglomerations). It is noteworthy that 24 h after beginning treatment with
penicillin, patient becomes minimally contagious [20].
Intramuscular Benzathine penicillin G and oral V penicillin are the recommended
for the treatment of streptococcal pharyngitis, except in individuals with history of
penicillin allergy (Table 4). Benzathine penicillin remains the drug of choice
because it is cost-effective, has a narrow spectrum of activity, long-standing proven
efficacy, low incidence of side effects, and good adherence to the regimen imposed.
Furthermore, to date, penicillin-resistant GAS has not been registered.
The oral antibiotics of choice are V penicillin and amoxicillin (Table 4). All
patients should continue to take penicillin regularly for an entire 10-day period,
even though they likely become asymptomatic after the first few days. Oral cephalosporin, indicated for penicillin-allergic patients, have been used in shorter than
10-day courses, with high compliance, bacterial elimination and clinical response
that may be superior to penicillin treatment. However, evidence is insufficient to
recommend this treatment regimen in endemic areas. Azithromycin can be used in
shorter treatment regimen (35 days) [20, 29], however, proven resistance to GAS
has been reported. Aggressive antibiotic therapy for primary prevention is essential
in areas where RF is prevalent and may represent the best hope for decreasing the
overall health care burden of RHD [32]. In contrast, in populations where ARF is
rare, antibiotic use results in modest therapeutic benefit, and the risk-benefit ratio
has been called into question.
Certain antimicrobials are not recommended for treatment of GAS upper
respiratory tract infections [29]. Tetracyclines should not be used because of the
high prevalence of resistant strains. Sulfonamides and trimethoprim-sulfamethoxazole do not eradicate GAS in patients with pharyngitis. Older fluoroquinolones (eg, ciprofloxacin) have limited activity against GAS and newer
fluoroquinolones (eg, levofloxacin, moxifloxacin) are active in vitro against GAS
but are expensive and have an unnecessarily broad spectrum of activity, and
therefore, they are not recommended for routine treatment of streptococcal pharyngitis [29].
Varies by drug
300 mg PO
500 mg PO day 1
250 mg PO days 25
250 mg PO
Dose
<20 kg: 600,000 U IM
20 kg: 1,200,000 U IM
500 mg PO
500 mg PO
100 mg/kg/day PO
Sources: Arq Bras Cardiol.2009;93 (3 supl.4):118

Circulation. 2009 24; 119(11):154151
*
In case of allergy to penicillin and erythromycin [20, 29]
Clarithromycin
Penicillin V
Amoxicillin
Ampicilin
Penicillin allergic
Narrow-spectrum cephalosporins
Clindamycin*
Azithromycin
Antibiotic
Benzathine penicillin G
Table 4 Primary prevention of rheumatic fever
Twice
daily
Varies by drug
Twice daily
Daily
2 or 3 times daily
Thrice daily
Thrice daily
Frequency
1 time
10
days
10 days
10 days
5 days
10 days
10 days
10 days
Duration
Acutely only

153
154
Secondary Prevention
Prevention of recurrent episodes of GAS pharyngitis is the most effective method to
prevent the development of severe RHD [20, 29]. Recurrences of ARF are most
common in patients who have had carditis during their initial episode. A recurrent
attack can be associated with worsening of the severity of RHD that developed after
a first attack, or less frequently with the new onset of RHD in individuals who did
not develop cardiac manifestations during the first attack.
For these reasons, prevention of recurrent ARF requires continuous antimicrobial
prophylaxis. The preferred method of prophylaxis is with Benzathine penicillin G,
1.2 million units intramuscularly every 3 weeks (Table 5) [20, 30].
Successful oral prophylaxis depends primarily on patient adherence to prescribed
regimens. The recommended oral agent is V penicillin. The dosage for children and
adults is 250 mg twice daily (Table 5). There are no published data about the use of
other penicillins, macrolides, azalides, or cephalosporins for the secondary prevention of rheumatic fever. If the patient is allergic to penicillin, sulfadiazine is recommended. Although sulfonamides are not effective in the eradication of GAS, they
prevent infection. For the patient who is allergic to both penicillin and sulfadiazine,
an oral macrolide (erythromycin or clarithromycin) [20, 29].
Recurrences are uncommon after 5 years following the first episode and in
patients over 25 years of age. Prophylaxis is usually discontinued after these times,
except in groups with a high risk of streptococcal infection, such as parents or teachers of young children, nurses, military recruits, etc.
Secondary prevention of RF depends on whether carditis has occurred (Table 6).
If there is no evidence of carditis, preventive therapy can be stopped at age 21.
If carditis has occurred but there is no residual valve disease, it can be stopped at
10 years after the first episode. If carditis has occurred with residual valve involvement,
it should be continued for 10 years after the last episode or until the age of 40 years,
if the patient is in a situation in which re-exposure would be expected [29]. Lifelong
prophylaxis should be considered in high-risk patients according to the severity of
valve heart disease and exposure to group A streptococcus, in a situation in which
Table 5 Secondary prevention of rheumatic fever

Antibiotic
Benzathine
penicillin G
Penicillin V
Penicillin allergic
Sulfadiazine
Penicillin and sulfadiazine allergic
Erythromycin
Dose
<20 kg: 600,000 U IM
20 kg: 1,200,000 U IM
250 mg PO
Twice
1g
Daily
PO
250 mg

Circulation. 2009 24; 119(11):154151
PO
Frequency
Every 3 weeks
Twice
daily
daily
155
Table 6 Duration of secondary rheumatic fever prophylaxis

Category
Rheumatic fever with carditis and
residual heart diseasea
Rheumatic fever with carditis, but
no residual heart disease
Rheumatic fever without carditis
Duration after last attack

10 years or until 40 years of age (whichever is longer),
sometimes lifelong prophylaxis
10 years or until 21 years of age (whichever is longer)
5 years or until 21 years of age (whichever is longer)

Circulation. 2009 24; 119(11):154151
a
Patients at high risk for repeated episodes of rheumatic fever, such as those at significant risk of
recurrent exposure to group A streptococcus infection, should be considered for life-long antibiotic
prophylaxis
reexposure would be expected. The decision to discontinue prophylaxis should be

made after discussion with the patient of the potential risks and benefits, considering the epidemiological risk factors.
In summary, RHD remains a major public health problem in many countries
throughout the world, with the unfair profile of affecting children and young adults
of poor and developing countries, with devastating personal and economical burden
for this already sacrificed population. Low- or middle-income countries still do not
have coordinated, national control programs [5]. A remarkable transformation leading to increased advocacy for the establishment of comprehensive approaches to
RF/RHD control, encompassing primary and secondary prevention, treatment of
established RHD, broad education and health promotion strategies, is highly necessary [32]. RF vaccine is still a future possibility [5], but its development will bring
new hope to this difficult scenario [20].
References
1. World Health Organization. Rheumatic fever and rheumatic heart disease: report of a WHO
expert consultation on rheumatic fever and rheumatic heart disease. World Heart Organization.
Geneva, 2001 October 29November 1. Geneva: WHO 2004.
2. Maurice J. Rheumatic heart disease back in the limelight. Lancet. 2013;382:10856.
3. Braunwald, E. Introduction to heart failure compendium. In: Research advances in heart failure:
a compendium. Circul Res, published online July 25, 2013. doi:10.1161/CIRCRESAHA.
113.3022541.
4. Carapetis JR, Steer AC, Mulholland EK, Weber M. The global burden of group A streptococcal
disease. Lancet Infect Dis. 2005;5:68594.
5. Carapetis JR, Zhlke L, Taubert K, Narula J. Continued challenge of rheumatic heart disease:
the gap of understanding or the gap of implementation? Glob Heart. 2013;8(3):1856.
6. Mller RE. Cardiopatia reumtica com leso valvar em crianas e adolescentes: fatores associados ao tempo at a teraputica cirrgica. [Tese de Doutorado]. Rio de Janeiro: Doutorado
em Sade da Criana e da Mulher, Instituto Fernandes Figueira, Fundao Oswaldo Cruz;
2011. [Thesis in Portuguese].
7. DATASUS. Ministrio da Sade - Sistema de Informaes Hospitalares do SUS (SIH/SUS).
Disponvel em http://www.datasus.gov.br/ Acesso em 27/10/2013. [Data in Portuguese].
156
8. Azevedo VMP, Kaufman R, Chaves RBM, Santos MA, Kuschnir MCC, Santos B, Santos
AMR, Xavier RMA. Survival analysis in the real world of 53,210 children and adolescents
hospitalized for heart failure between 2001 and 2007 in a developing country using probabilistic linkage of databases. Circulation. 2012;125(19):e334.
9. Terreri MT, Ferraz MB, Goldenberg J, Len C, Hilrio MO. Resource utilization and cost of
rheumatic fever. J Rheumatol. 2001;28(6):13947.
10. Remenyi B, Carapetis J, Wyber R, Taubert K, Mayosi BM. Position statement of the World
Heart Federation on the prevention and control of rheumatic heart disease. Nat Rev Cardiol.
2013;10:28492.
11. Guilherme L, Khler K, Kalil J. Rheumatic Heart Disease: mediation by complex immune
events. Adv Clin Chem. 2011;53:3150.
12. Jones TD. The diagnosis of rheumatic fever. JAMA. 1944;126:4814.
13. Dajani AS, Ayoub E, Bierman FZ. Guidelines for diagnosis of rheumatic fever: Jones criteria,
1992 updated. Circulation. 1993;87:3027.
14. Ferrieri P, Baddour L, Bolger A, Dajani A, Pallasch T, Tani L, et al. Proceedings of Jones
Criteria Workshop (AHA Scientific Statement). Committee on Rheumatic Fever, Endocarditis,
and Kawasaki Disease of the Council on Cardiovascular Disease in the Young of the American
Heart Association. Circulation. 2002;106:25213.
15. Walsh W, Al B, Carapetis J. The diagnosis and management of chronic rheumatic heart
diseasean Australian Guideline. Heart Lung Circ. 2008;17:27189.
16. Tubridy-Clark M, Carapetis JR. Subclinical carditis in rheumatic fever: a systematic review.
Int J Cardiol. 2007;119:548.
17. Cann MP, Sive AA, Norton RE, McBride WJH, Ketheesan N. Clinical presentation of rheumatic fever in an endemic area. Arch Dis Child. 2010;95:4557.
18. Meira ZM, Goulart EM, Colosimo EA, Mota CC. Long term follow up of rheumatic fever and
predictors of severe rheumatic valvar disease in Brazilian children and adolescents. Heart.
2005;91:101922.
19. Juneja R, Tandon R. Rheumatic carditis: a reappraisal. Indian Heart J. 2004;56(3):2525.
20. Barbosa PJB, Mller RE, Latado AL, Achutti AC, Ramos AIO, Weksler C, et al. Diretrizes
Brasileiras para Diagnstico, Tratamento e Preveno da Febre Reumtica da Sociedade
Brasileira de Cardiologia, da Sociedade Brasileira de Pediatria e da Sociedade Brasileira de
Reumatologia. Arq Bras Cardiol. 2009;93 (3 supl.4):118 [Article in Portuguese].
21. Remenyi B, Wilson N, Steer A, Ferreira B, Kado J, Kumar K, et al. World Heart Federation
criteria for echocardiographic diagnosis of rheumatic heart diseasean evidence-based guideline. Nat Rev Cardiol. 2012;9:297309.
22. Gunther G, Asmera J, Parry E. Death from rheumatic heart disease in rural Ethiopia. Lancet.
2006;367:391.
23. Kumar R, Raizada A, Aggarwal AK, Ganguly NK. A community-based rheumatic fever/
rheumatic heart disease cohort: twelve-year experience. Indian Heart J. 2002;54:548.
24. Marijon E, Ou P, Celermajer DS, Ferreira B, Mocumbi AO, Jani D, Paquet C, Jacob S, Sidi D,
Xavier J. Prevalence of rheumatic heart disease detected by echocardiographic screening. N
Engl J Med. 2007;357:4706.
25. Carapetis JR, Hardy M, Fakakovikaetau T, et al. Evaluation a screening protocol using auscultation and portable echocadiography to detect asymptomatic rheumatic heart disease in Tongan
schoolchildren. Nat Clin Pract Cardiovasc Med. 2008;5:4117.
26. Marijon E, Ou P, Celermajer DS, et al. Echocardiographic screening for rheumatic heart
disease. Bull World Health Organ. 2008;86:84.
27. Marijon E, Mirabel M, Celermajer DS, Jouven X. Rheumatic heart disease. Lancet. 2012;
379:95364.
28. Vasan R, Shirivastava S, Vijayakumar M, Narang N, Lister B, Narula J. Echocardiographic
evaluation of patients with acute rheumatic fever and rheumatic carditis. Circulation. 1996;
94:7382.
29. Gerber MA, Baltimore RS, Eaton CB, Gewitz M, Rowley AH, Shulman ST, Taubert
KA. Prevention of rheumatic fever and diagnosis and treatment of acute Streptococcal pharyn-
157
gitis: a scientific statement from the American Heart Association Rheumatic Fever,
Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in
the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology,
and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the
American Academy of Pediatrics. Circulation. 2009;119(11):154151.
30. Raju BS, Turi ZG. Rheumatic fever. In: Bonow RO, Mann DL, Zippes DP, Libby P, editors.
Braunwalds heart disease: a textbook of cardiovascular medicine. 9th ed. Philadelphia:
Elsevier-Saunders; 2012. p. 186974.
31. Bonow RO, Carabello BA, Chatterjee K, de Leon Jr AC, Faxon DP, Freed MD, Gaasch WH,
Lytle BW, Nishimura RA, OGara PT, ORourke RA, Otto CM, Shah PM, Shanewise JS, 2006
Writing Committee Members, American College of Cardiology/American Heart Association
Task Force. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the
management of patients with valvular heart disease: a report of the American College
of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing
Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart
Disease): endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation.
2008;118(15):e523661.
32. Karthikeyan G, Mayosi BM. Is primary prevention of rheumatic fever the missing link in the
control of rheumatic heart disease in Africa? Circulation. 2009;120:70913.
Chagas Disease: A Neglected Disease

Jos Antonio Marin-Neto, Anis Rassi Jr., Andra Silvestre de Sousa,
Joo Carlos Pinto Dias, and Anis Rassi
Introduction
In 1909, the Brazilian physician Carlos Chagas reported to the scientific community
the discovery of a new pathogenic agent, Trypanosoma cruzi (T. cruzi) and the previously unknown illness it caused [1]. Far from being rare, it was soon noted that the
new disease affected millions of people across nearly the entire Latin American
subcontinent. The recovery of T. cruzi genetic material from South American
J.A. Marin-Neto, M.D., Ph.D. (*)

Cardiology and Pneumology from the University of Sao Paulo, Sao Paulo, Brazil
Interventional Cardiology from the Hospital das Clinicas, Ribeiro Preto Medical School,
Sao Paulo, Brazil
e-mail: marin_neto@yahoo.com
A. Rassi Jr., M.D., Ph.D.
Anis Rassi Hospital, Goiania, Goias, Brazil
e-mail: arassijr@terra.com.br
A.S. de Sousa, M.D., Ph.D.
Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
Oswaldo Cruz Foundation, Rio de Janeiro, Brazil
e-mail: andrea.silvestre@globo.com
J.C.P. Dias, M.D., Ph.D.
School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Brazil
Neglected Diseases Committee of the World Health Organization, Genve, Switzerland
e-mail: jcpdias@cpqrr.fiocruz.br
A. Rassi , M.D.
Faculty of Medicine, Federal University of Goias, Goiania, Goias, Brazil
DOI 10.1007/978-3-319-22357-5_16
159
160
J.A. Marin-Neto et al.
mummies in paleoparasitological studies provided evidence that Chagas disease

had already affected human beings at least 9000 years ago [2].
A few years later, Carlos Chagas and a group of collaboratorsBelisrio Penna,
Eurico Villela, and Ezequiel Dias, among otherssucceeded in characterizing the
main clinical manifestations of the disease in the cardiovascular system [3]. The
chief mode of disease transmission between humans, involving hematophagous
mosquitos of the family Triatominae, was described soon afterwards.
Despite the unassailable success and distinction of the aforementioned research,
Chagas disease endured periods of complete oblivion during the twentieth century,
in the words of pathologist Fritz Kberle, in addition to an early continuous relative
neglect by a segment of the medical and scientific communities. As a result, undeniable gaps remain in the elucidation of the pathogenesis of the cardiovascular
involvement, as well as some uncertainty regarding the clinical management of the
disease.
In the present chapter, aspects that remain unclear relative to the pathogenesis of
Chagas heart disease (CHD) and its overlooked prevention at the primary, secondary and tertiary levels are reviewed.
Etiopathogenesis of CHD
The pathogenetic mechanisms that underlie the development of the chronic stage of
CHD have not yet been fully elucidated.
Fundamentally, CHD is an inflammatory form of dilated cardiomyopathy often
accompanied by low-intensity, although effectively relentless myocardial damage,
resulting in reactive and reparative fibrosis and progressive ventricular dysfunction [4].
Among various other particular pathophysiological characteristics germane to
CHD, several investigators have independently observed destruction of the neurons
of the cardiac intramural ganglia, particularly those of the parasympathetic subtype,
with consequent dysregulation of autonomic circulatory control. The cardiac dysautonomia observed in patients with CHD results in abolition of the overall vagal
inhibition of the sinoatrial node and also deprives such patients of the mechanism of
rapid adjustment of the heart rate to transient variations of the systemic arterial pressure and venous return. Based on those changes in the intrinsic cardiac nervous
system, characterized by the (non-exclusive) predominance of parasympathetic
denervation, the so-called neurogenic theory of CHD postulated that autonomic
imbalance accounted for a true heart disease induced by excessive adrenergic stimulation [5]. However, this theory could not be validated due to the lack of correlation
between the degree of parasympathetic denervation and the extent of myocardial
injury, among other factors [4]. Nevertheless, the hypothesis that cardiac dysautonomia may contribute to the occurrence of malignant arrhythmias and sudden death
as well as to the development of disorders of coronary microcirculation regulation,
remains attractive [4].
161
Indeed, various microcirculatory abnormalities were described in experimental

models of T. cruzi infection and in human individuals with CHD, including thrombosis, spasm and endothelial dysfunction associated with amplified platelet activity
[6]. Such disorders might be due to the tissue inflammatory changes induced by
infection with T. cruzi, or to the immune reactions consequent to infection. Together,
these microcirculatory abnormalities might cause ischemic myocardial injury and
superimposed fibrosis [7]. These disorders might play a role in the genesis of symptoms, such as atypical angina, which is common among individuals with CHD, and
might cause the myocardial perfusion defects that are frequently observed. Although
the coronary arteries of CHD patients are normal on angiography, abnormal
responses to vasodilator and vasoconstrictor stimuli at subepicardial levels have also
been reported. The hypothesis that microcirculatory abnormalities participate in the
formation of the characteristic fibrotic and aneurysmal lesions found in most patients
with CHD, particularly in the apical and inferoposterior regions of the left ventricle,
namely, vascular areas of relative separation among the various territories of coronary distribution (watershed) is quite plausible [8]. Chest pain is possibly the most
neglected among the symptoms commonly exhibited by CHD patients, and its clinical treatment only recently became the specific target of a study still in progress [9].
Several convincing clues suggest that autoimmune mechanisms participate in the
pathogenesis of CHD, as cardiac injury was found to occur after immunization with
T. cruzi antigens and the passive transfer of lymphocytes from infected animals,
whereas chronic myocarditis was attenuated once the animals became tolerant to
myocardial antigens [10]. The immune response to parasitic infection, involving
polyclonal activation or molecular mimicry, might itself represent a mechanism of
aggression to the myocardium [11].
Nevertheless, the actual role of autoimmunity in the pathogenesis of the lesions
characteristic of the chronic stage of disease is rather poorly established. Yet, the
hypothesis that the nature and intensity of the hosts immune response to the presence of parasites in the tissues might behave as a true doubled-edged sword
remains plausible. When the immune system is depressed by disease (e.g., by coinfection with the human immunodeficiency virusHIV) or iatrogenically (e.g., in
transplanted patients to avoid rejection), infection with T. cruzi is patently exacerbated. This fact indicates that before being suppressed, the immune system seeks to
prevent infection with the parasite, and thus it is an inherently protective factor. In
accord with that theory, a persistently well-modulated immune response might represent the primary mechanism by which most patients with chronic T. cruzi infection remain with the indeterminate form of Chagas disease for life (i.e., without
clinical manifestations of heart disease or gastrointestinal disordersmegas).
The impression resulting from the aforementioned considerations on ambivalent
(beneficial or harmful) immune mechanisms in CHD notwithstanding, a growing
consensus holds that the persistence of the parasite in the tissues is the fundamental
pathogenic factor in the myocardial affliction characteristic of the chronic disease
stage [4, 1214]. The evidence supporting that consensus derive from multiple
sources, including both experimental research and human studies as discussed
162
below, together with the all-important issue regarding the prevention of CHD development in patients with chronic T. cruzi infection.
To summarize, several crucial aspects of the etiopathogenesis of CHD have not
yet been definitively elucidated [15]. Whereas the available pathogenetic hypotheses and theories are reasonable to some extent, they lack firm support in conclusive
studies. Thus, in the course of one century of research, some negligence in the
approach to CHD pathogenesis appears to have been unavoidable. Such relative
negligence appears obvious, for example, in the fact that over one decade, some
studies and investigators insisted repeatedly in asserting certain aspects of the
pathophysiology of CHD instead of seeking to investigate more objectively and
persistently the consequences of those disorders to elucidate the prognostic meaning of the abnormalities that were already exhaustively demonstrated [16].
Prevention of CHD
Vector-borne transmission remains the main route of human infection with T. cruzi
and is usually associated with the vectors blood meals. Indeed, the hematophagous
insects defecate while sucking the hosts blood, and thus the parasites enter the
bloodstream through the skin disruption caused by the sting, or even through intact
mucous membranes close to the sting site. The insects also played a role, albeit
passive, in recently reported outbreaks of infection via the intake of contaminated
food, that is, during the preparation of food (usually during the grinding of sugarcane, aa palm, etc.) [17, 18]. As a result of the interventions that led to the eradication of the main vectors in Latin America, the oral route of transmission became the
most common route in several countries, including Brazil. The second most frequent route of transmission of infection with T. cruzi is via blood transfusions, the
prevalence of which is most likely underestimated due to poor reporting within the
medical sector [19]. This is the most pertinent route of transmission of infection in
countries where Chagas disease is not endemic, due to the lack of efficacious serologic control and the increasing number of infected immigrants from Latin America,
particularly in Europe and the United States.
The incidence of vertical mother-to-child transmission of infection through the
transplacental route is estimated to vary from 1 % in Brazil to 7 % in some areas of
Bolivia and Paraguay, depending on factors such as parasite strain, the mothers
immune status and the diagnostic technique used to detect infection [20]. Transmission
is less often due to transplantation of organs donated by infected individuals or to
laboratory accidents. Most of the cases of transmission via transplanted organs occur
in countries where Chagas disease is not endemic and are due to the lack of efficacious and validated serologic techniques, lack of familiarity with the manifestations
of acute disease and the presence of Latin American donors, many of whom have
dual citizenship, which may make the identification of high-risk donors difficult.
Among the parasitic diseases, only malaria and schistosomiasis are more significant from an epidemiological point of view than Chagas disease [21]. Chagas
disease was historically confined to rural areas with very low levels of social develop-

Prevention level
Target population
Strategies
Responsible entities
Intervention
aims
163
Primary prevention
Secondary prevention
Individuals
at risk
Early/asymptomatic
stage of disease
Tertiary prevention
Established
disease
Vector control
Prevention of
of transmission
via blood transfusions
Prevention of
transmission
via organ transplantation
Care in
laboratory
handling ofT. cruzi
Screening
Detection of infected
individuals
Early intervention
Antiparasitic
treatment
Periodic health exams
Antiparasitic disease
(selected cases)
Pharmacological and
non-pharmacological
interventions
Symptomatic treatment
Management of
complications
Permanent care
Public health
Primary care
Other
Primary care
Public health
Specialized services
Hospital units
Prevent transmission
of Chagas disease
Avoid progression of
the indeterminate form
to the clinical forms
of disease
To limit the morbidity
Chagas disease
absent
Indeterminate
form
and mortality of
disease
manifestations
Cardiac and
digestive forms
Disease progression
Fig. 1 Strategies for prevention of Chagas disease [28]
ment in nearly all of the continental Latin American countries. That scenario changed
quite recently, as the epidemiological significance of Chagas disease in those countries was greatly reduced [22]. In global terms, 810 million people are currently
estimated to be infected [23, 24] versus 1618 million in the 1990s [25]. In parallel,
as a function of migration circuits involving infected individuals from endemic countries, Chagas disease became a public health problem in the United States and other
countries, such as Spain, Belgium, France, England, Japan and Australia [26]. Such
epidemiological transitions in non-endemic countries accentuated the concern
regarding the possible transmission of infection via blood transfusions, solid organ
donation and the transplacental route. Additionally, the search for diagnostic and
clinical treatment methods for infected individuals was intensified in those countries,
which also targeted the prevention of transmission to other people [27].
The methods available to reduce the medical and social impact of Chagas disease
are based on three levels of prevention, primary, secondary and tertiary, and are
discussed next [28] (Fig. 1).
Primary prevention seeks to avoid the occurrence of new infections, i.e., to eliminate the risk of infection of exposed individuals and to interrupt the chain of
transmission. Those goals are mainly achieved by means of strategies focusing on
the control of both vector- and non-vector-borne transmission. However, in the case
of the vertical route, it should be borne in mind that there is no procedure available
to reliably impede mother-to-child transmission.
Secondary prevention consists of the screening and detection of individuals
infected with T. cruzi in the early stages of disease. This strategy is essential in acute
cases. In chronic cases, and more particularly those with the indeterminate form of
164
Chagas disease, particularly asymptomatic individuals who are often unaware of

being infected, the aim of secondary prevention is to provide etiological treatment.
Eradication or reduction of the parasite load may in principle avoid or delay the
progression of disease into the determinate chronic forms and contributes to interrupting the infections epidemiological chain of transmission.
Tertiary prevention consists of the clinical interventions performed to limit the
morbidity and mortality of established disease in a special manner as concerns CHD.
Primary Prevention of Chagas Disease

Since the era of Carlos Chagas and colleagues, the belief has been held that the
control of infection could be more easily attained by means of primary prevention.
Currently, primary prevention is still centered on the control of vectors by chemical
means, in addition to the screening of blood donors using sensitive and specific
serologic methods. Such measures must be continuously supported by strategies
targeting basic health education, effective participation of the community in programs, improvement of housing conditions and constant epidemiological
surveillance. The reward for such strategies is immediate when they are rigorously
implemented, as the number of new vector-borne infections is reduced. The rate of
infection through blood transfusions decreases soon afterwards. In areas where
vector-borne and blood transfusion transmission are controlled, the number of
infected pregnant women is progressively reduced, whereby vertical transmission
exhibits a significant tendency towards reduction. The early detection of infection in
fetuses allows for specific treatment of the affected children [29, 30]. Moreover,
primary prevention strategies targeting care in the laboratory handling of T. cruzi are
quite effective by avoiding work accidents. Similarly effective is the adequate
screening of organ donors through the application of universal serologic techniques
in locations where the seroprevalence is high, or also the use of serologic tests combined with specific epidemiological investigation.
Alternatively, the opportunities to diagnose infection with T. cruzi and to provide
etiological treatment before women become pregnant to prevent vertical transmission are rare. Additionally, the prevention of infection by the oral route is practically
impossible. Therefore, in both instances, the most effective strategy to control
infection consists of early detection and trypanosomicidal treatment.
Preventive immunization by means of a safe and effective vaccine is not yet
available, partially as a function of the theoretical risk of adverse immune reactions
[31]. Another hindrance is represented by the multiple molecular variants of T. cruzi
[32], which confounds the search for an adequate vaccine by a rather indefinite
antigenic target [33].
The implementation of control programs depends on three essential factors:
acknowledgment of the medical significance of the disease; definition of its social
impact; and the availability of resources and minimal strategies aimed at control.
Following the most characteristic period of oblivion to Chagas disease, the modern
165
era of combat against the disease began between 1945 and 1955, when residual
insecticides were used to combat the vectors and pathologic, serologic and clinical
studies became systematized [34]. Beginning in the 1960s, national programs of
vector control were launched; serologic screening for T. cruzi in blood banks became
mandatory in the 1980s, parallel to the measures established for the control of the
emerging HIV pandemic [19, 34].
Control of Vectors
Vector control is essential under conditions of domiciliary and peridomiciliary
infestation, by means of continuous and regular application of residual insecticides
also followed, in principle, by continuous and sustained epidemiological surveillance. Synthetic pyrethroids derived from chrysanthemic acid (deltamethrin,
lambda-cyhalothrin, cyfluthrin, etc.) are currently the most effective insecticides. In
cases of resistance to those agents, which seldom occurs, organochlorine or carbamate compounds may be alternatively used [34].
The perception that population-based educational campaigns and active
participation of the community in strategies for vector control are an essential part
of epidemiological surveillance is universally accepted. Improvement of housing
conditions is also quite effective; however, except for rare exceptions (such as the
2001 experience in Venezuela), this has never been properly prioritized in national
programs [35].
It should be noted that eradication, namely, complete interruption of Chagas disease transmission, is practically an unattainable epidemiological target. Even in
places where that goal could be partially achieved, such as the extinction of transmission by Triatoma infestans in countries such as Uruguay, Chile and Brazil,
entomological surveillance must be maintained for many years. The proposal that
infection with T. cruzi evolved from a primitive type of zoonosis to a true and highly
spread anthropozoonosis is currently very clear. Moreover, the parasite is currently
disseminated across many sylvatic areas, in which its ecotopes are being increasingly altered by human activity (e.g., indiscriminate deforestation) such as in the
Amazon region, where the incidence of autochthonous cases is increasing [36].
Evidence also exists for the presence of several secondary vectors, namely, triatomine insects potentially susceptible to domiciliation, as well as that of vector
resistance to the most commonly used insecticides.
Control of Transmission via Transfusions

Although less rigorous, this strategy was applied as early as the 1990s, through the
serologic detection and chemoprophylaxis of suspected blood, and intensified in parallel with the establishment of measures against infection with HIV. Ideally, two
166
highly accurate serologic tests based on two different techniques (e.g., indirect immunofluorescence and ELISA) should be employed for the screening of blood donors.
However, starting in 2002, the World Health Organization (WHO) recommends
performing only one test (ELISA) to detect blood donors infected with T. cruzi [20].
Likely due to technical inadequacies in the performance of the serologic tests, this
recommendation led to a significant reduction in the sensitivity of detecting infected
blood and organ donors, the consequences of which are only beginning to be understood. For example, acute Chagas infection was detected in one individual without
Chagas disease who received the transplanted liver of an allegedly non-infected donor
in Brazil, which is an endemic country [37]. The challenge is heightened by the fact
that a large fraction of the donors and recipients are transfused with large amounts of
blood components on the occasion of the event leading to death or in the perioperative
period of heart transplantation, respectively. Under such circumstances, high-sensitivity serologic control of hemodiluted sera, with sufficient specificity so as not to reject
viable organs should be mandatory. The need to improve the methods for serologic
detection of T. cruzi infection in endemic and non-endemic areas is reinforced by the
recent description of a series of patients with chest pain and segmental wall-motion
abnormalities of the left ventricle (such as apical aneurysm) highly suggestive of
CHD, but who had negative results by the immunofluorescence serologic test [38].
Prevention of Infection Through Solid Organ Donation

The most common scenario of infection via solid organ donation is the case of a
seropositive donor and a seronegative recipient. However, just as in the case cited
above [37], the transmission of Chagas infection through organ transplantation
(heart, kidneys, bone marrow, liver) was also reported relative to allegedly seronegative donors, even in non-endemic countries.
In the absence of more conclusive and informative evidence, the consensus of
specialists converges towards the following prophylactic guidelines based on the
serologic status of organ donors and recipients before transplantation [39, 40].
When the donor is seronegative and the recipient is seropositive, the latters postoperative recovery should be closely monitored for the early detection of possible
infection reactivation, which might occur as a function of the immune modulation
regimen required to prevent graft rejection. If parasitemia intensifies or if clinical
indicators consistent with reactivation appear, etiological treatment should be initiated. Prophylactic treatment of recipients with trypanosomicidal agents before
transplantation is a less favored approach, although it is a reasonable option within
the context of heart transplantation [41]. Notably, not even qualitative polymerase
chain reaction (PCR) techniques for the detection of parasitemia have sufficient
sensitivity to define the presence of reactivation, although their negative predictive
value is adequate to rule it out. Quantitative PCR techniques (real-time PCR) are
currently used only for research purposes. However, it is safe to assume that once
cutoff points are established, this method will be used for the indication of preemptive treatment in cases with high parasitemia levels.
167
The same principles apply when both donor and recipient are seropositive; as a
rule, specific treatment is recommended for the donor before transplant surgery
[28]. Relative to heart transplantation, which is not allowed when the donor is seropositive, relative to other organs, prior specific consent is required.
Finally, the situation of a seropositive potential donor and a seronegative recipient (in the case of living donors) is a particular cause of concern because
transplantation is a priority that cannot be bypassed. In such cases, it is recommended to administer antitrypanosomal treatment to the donor for at least 10 days
(60 days ideally) to reduce or eliminate the parasitemia as well as to the recipient
along with treatment for 10 days after surgery to minimize the odds of parasite invasion and multiplication in his/her body. If the recipient becomes seropositive,
standard trypanosomicidal treatment for 6090 days is recommended [28].
Prevention of Laboratory and Hospital Accidents

Training in and compliance with the universally accepted basic principles for work
in environments in which professionals work with people or materials that are
potentially contaminated with T. cruzi are the core of the prevention of transmission
through this route. Ideally, the professionals should be subjected to serologic testing
upon being hired by institutions in which they may be exposed to unintentional risk.
If contamination is suspected, the following procedures should be adopted: immediate disinfection of the eyes or skin lesions using alcohol; start prophylactic etiological treatment with the usual dose for 10 days; notify the head of the laboratory or
hospital unit in which the incident occurred to avoid repetitions; and perform serological testing 30 days after the event. In cases of seroconversion, standard
etiological treatment for 6090 days is recommended [28].
Preventive Treatment for Cases of Congenital Transmission

Preventive etiological treatment using the currently available drugs is contraindicated for seropositive pregnant women. Pregnant women without a previous diagnosis of Chagas disease should be subjected to serological testing. Incases of
positive results, the early detection of transmission to and treatment of the infected
newborn infants are the basic measures [29, 40]. Newborn infants from mothers
with known or highly suspected infection by T. cruzi should be carefully examined
for signs of acute Chagas disease. Additionally, parasitemia should be investigated
particularly by direct examination of the umbilical cord and the infants blood.
The conventional serologic tests (based on the detection of IgG antibodies) are not
indicated in this stage because the maternal antibodies remain in the infant for
approximately 6 months after birth. In contrast, serological tests that investigate
IgM antibodies might contribute to the diagnosis because the latter are indicative
of active infection.
168
In confirmed cases of congenital transmission, etiological treatment should be

started immediately, which is usually well tolerated by infants.
In the absence of clinical or laboratory evidence of infection, the infants should
be subjected to conventional serologic testing (investigating IgG antibodies) at age
68 months; only positive cases should be administered etiological treatment. The
infants should be then subjected to clinical and laboratory assessments once per
year. Persistently negative serologic results are indicative of cure of infection, which
usually occurs about one year after the onset of treatment. In contrast, positive
results denote therapeutic failure and the infants should be treated again, preferably
with a different trypanosomicidal drug [28].
Oral Transmission
Being unpredictable, primary prevention of transmission by the oral route is unfeasible; only progressive improvement of the populations educational and hygienic
levels will allow the control of this mechanism of Chagas disease transmission.
Because the parasitic load is usually high, and because the mucosa of the digestive
tract is highly permeable to T. cruzi, the mortality in the acute stage of infection may
be quite high. Healthcare professionals should develop a high degree of diagnostic
suspicion, as atypical cases with gastrointestinal bleeding and myopericarditis with
large pericardial effusions are often described, to achieve effective parasitological
confirmation and to begin etiological treatment immediately. Similarly, epidemiological surveillance should be established later on, also including the people in
contact with patients infected with T. cruzi per the oral route [40].
Secondary Prevention of Chagas Disease

Independent of the route of transmission, human exposure to T. cruzi exhibits three
main scenarios. The first, that of no infection, is based on the assumption that a
quick and efficient immune response might prevent the settlement of the parasite in
the human body. Infection does occur in the other two scenarios, but it may be clinically unapparent (scenario two) or it may manifest the signs and symptoms of the
acute stage of Chagas disease (Fig. 2).
Following vector-borne exposure to T. cruzi, the usual incubation period of the
acute stage is 12 weeks (being variable in other routes of transmission), during
which the parasites in trypomastigote (flagellate) form are detectable in the bloodstream by microscopic methods. The acute stage lasts approximately 12 weeks,
with most patients being asymptomatic or oligosymptomatic; because the actual
cause of infection passes unnoticed, the few (unspecific) symptoms are attributed to
other and trivial diseases, such as the flu.
The acute stage of Chagas disease is diagnosed in a very small number of
patients, who exhibit signs and symptoms compatible with myocarditis or severe
169
Acute stage
Other
exposure
routes
Chronic stage
No infection
4050%
Human
Infected
triatomine insects
exposed to
T. cruzi
Acute
asymptomatic
infection
Acute
Chagas
disease
Time interval
1-2 weeks
Parasitemia
Diagnosis
Etiological treatment
% cure
Indeterminate
chronic form
Determinate
chronic forms
cardiac
digestive
mixed
Remission
Death
4-12 weeks
high
detection of parasites
mandatory
50-80
20-30 years
Lifelong
low intensity, but continuous

detection of antibodies (IgG)
mandatory
40-60
recommended
optional
to be
established
Fig. 2 Progression of Chagas disease: clinical, diagnostic and therapeutic aspects [28]
meningoencephalitis. Under such circumstances, the patients are at risk of death

(which occurs in 510 % of the cases, particularly among small children or when
infection is transmitted per the oral route and the parasitic load is intrinsically high).
Once the acute stage ends, the parasitemia becomes practically undetectable by
direct examination, even when specific treatment is not administered, as a function
of the protective action of the immune system. Then, the chronic stage of CHD
begins, with most patients remaining asymptomatic for decades, which characterizes the indeterminate form of the disease. As previously noted, 4050 % of the
patients characteristically develop signs and symptoms of organ involvement 2030
years after the acute stage of disease, corresponding to the cardiac, digestive or
mixed types of CHD [42].
Secondary prevention especially targets the second and third aforementioned
scenarios to hinder the progression of the indeterminate form of disease into the
clinically determined types. In practical terms, the aim is to avoid the manifestation
of CHD, to wit, the most formidable and frequent expression of the disease.
The basic strategy to achieve that goal is to provide etiological treatment to the
infected individuals, its applicability depending on the active identification of the
largest possible number of such patients.
Etiological Treatment
Although specific treatment is the cornerstone of the secondary prevention of Chagas
disease, only two compounds admittedly active against T. cruzi are available for
clinical use, that is, benznidazole and nifurtimox. Both were developed 40 years ago,
170
and thus, the lack of further investigation of additional drugs bears witness to the
neglect of Chagas disease by the medical and scientific community and society at
large, in this case represented by governmental agencies and the industrial sector.
Both available drugs have trypanosomicidal activity against the amastigote and
more intensively against the circulating trypomastigote forms [43]. Those agents
were tested for the treatment of patients in the acute stage of infection, inducing
clinical remission and parasitological and serological negative conversion (delayed)
in up to 80 % of the cases [44]. Based on such evidence and in the absence of more
definitive studies, there is essentially universal agreement that etiological treatment should be indicated in all patients diagnosed with acute Chagas disease,
independent of the route of transmission [41]. That indication is also unanimously
accepted relative to episodes of reactivation in patients in the chronic stage of disease, who usually exhibit natural or iatrogenic immunosuppression.
However, the most propitious scenario of secondary prevention is not represented by the patients diagnosed in the acute stage of disease but by the much larger
number of patients with the indeterminate form of chronic disease. That crucial
epidemiological fact notwithstanding, the indication for trypanosomicidal treatment
in patients in the chronic stage of Chagas disease [45] has been repeatedly discredited and called into question, to the point that consensus is nonexistent in this regard,
although it is an essential component of secondary prevention [41]. This position,
which is not justified under the current knowledge, is largely due to an erroneous
concept, according to which the main pathogenetic mechanism in Chagas disease is
autoimmunity, in disregard of the fact that this was challenged long ago [46]. Further
arguments for that unfounded position derive from the personal experience of some
physicians with the more advanced stages of diseasewhen, indeed, trypanosomicidal treatment has little to contributewho refuse to acknowledge the evidence
that, although not definitive, reasonably supports the fundamental notion that
Chagas disease is, in essence, an infectious disease, the etiological agent of which
remains in the human body, where it is the direct cause of a low-intensity although
practically incessant inflammatory state in some tissues, such as the myocardium.
Multiple and an increasing number of studies indicate that parasite persistence is
the essential mechanism that accounts for the establishment of inflammatory tissue
lesions either directly or mediated by the immune system. Such lesions damage the
contractile myocardium and the specialized system generating and conducting cardiac electrical activity, causing cell necrosis and intensive reactive and reparative
fibrosis [4, 47]. Thus, it is natural to speculate that antitrypanosomal treatment in the
non-advanced chronic stage of CHD may favorably modify the natural history of
the disease [48]. The underlying hypothesis is that elimination, or at least reduction,
of the parasitic load may attenuate and/or delay the progression of myocarditis in
the chronic stage of CHD. That basic notion reflects the theory that autoimmune
aggression (disregarding the presence of parasites in the tissues) is not the decisive
mechanism in the pathogenesis of CHD [49].
Although still a controversial subject, etiological treatment should be administered, as a rule, to most patients with the indeterminate and the cardiac and digestive
forms of disease in the non-advanced stages [48, 49]. In some South American
171
countries, this indication became official public health policy. This recommendation
is also considered fundamental in the United States, based on studies, seminars and
a systematic literature review conducted by investigators at the Centers for Disease
Control and Prevention (CDC) and Latin American collaborators [50]. This position
is supported by a systematic review with meta-analysis of the few randomized studies performed with asymptomatic infected patientspresumably most of them with
the indeterminate form of disease. The results indicated that etiological treatment
(particularly with benznidazole) is beneficial in as much as it improves the hostparasite relationship, resulting in negative conversion of the xenodiagnosis and the
reduction of circulating anti-T. cruzi antibodies, as demonstrated by the serologic
tests [51, 52]. The two most conclusive studies included in that meta-analysis were
performed in children; the results demonstrated seroconversion and cure of infection in approximately 60 % of the participants after follow-up of 34 years [53, 54].
Children characteristically tolerate trypanosomicidal treatment better than adults.
Relative to infected individuals with clinical and laboratory abnormalities demonstrating established CHD, many investigators consider that specific treatment
should still be offered, except in cases of highly advanced myocardial injury. That
position is based on several lines of evidence that taken together tip the balance in
favor of this strategy:
evidence resulting from experimental models of infection with T. cruzi collected
by different groups of investigators, according to which etiological treatment
attenuates the progression of heart disease, although complete eradication of the
parasite was not attained (the parasitic load was merely reduced) [5557];
the side effects of either available trypanosomicidal agent occur less frequently
and are better tolerated than was previously believed; moreover, such undesirable effectsgastrointestinal and skin reactions, polyneuropathy, leukopenia
might be considered as tolerable and reversible, thus contrasting with the
beneficial potential of short-term treatment (23 months) [5859];
the results of several observational studies that assessed the effect of etiological
treatment in patients with heart disease and applied clinically relevant outcome
measures point to a true positive effect, with favorable modification of the natural history of the disease [6064];
a meta-analysis that included three randomized and six observational studies
concluded that the patients treated with benznidazole exhibited significant risk
reduction of presenting clinical events over time compared to the patients not
subjected to etiological treatment (odds ratio: 0.29; 95 % confidence interval:
0.160.53) [65].
To summarize, based on the actions and individual positions of many investigators [58, 66, 67], and on official statements by agencies responsible for developing
health policies, an emergent current convergence favors the position that etiological
treatment should be made available to most infected patients in the chronic stage of
Chagas disease [25, 40, 50, 68]. This perspective is based on the concept that as a
function of the currently available knowledge and while still awaiting the conclusive
evidence of the BENEFIT randomized study [69], the risk of incurring an alpha error
172
(not to apply a promising therapeutic intervention with tolerable side effects) is

much less acceptable than incurring a beta error (not to adopt something that might
prove futile in the future) [41]. In fact, even to basic researchers, the indifference of
doctors that precludes them from even considering the possibility of indicating etiological treatment for their patients is questionable from an ethical standpoint [70].
The implementation of effective secondary prevention measures at the population level must include active screening of children of infected mothers, relatives
and other individuals exposed to infection in endemic areas. Additionally, the diagnostic opportunities provided by screening in blood banks, organ donations and job
hiring processes should be maximized.
New trypanosomicidal drugs may possibly become available for clinical use in
the near future, whether prescribed alone or in combination with the two agents
known to be effective. Some of the drugs found promising in preclinical trials
include posaconazole [71], ravuconazole [72] and fexinidazole [57]. However, itraconazole and allopurinol are not promising, due to the lack of sufficient favorable
evidence or clearly negative results [73].
Finally, one should hope that the supply of benznidazole and nifurtimox does not
become jeopardized by management problems among the industrial suppliers [74].
Tertiary Prevention of Chagas Disease

The fundamental issue in the tertiary prevention of Chagas disease is to reduce its
inherent mortality, which is the outcome exhibited by 4050 % of the individuals
infected with T. cruzi. Those are the patients who, in the chronic stage, progress to
the determined cardiac, digestive and mixed forms of the disease [48, 49]. The
digestive form manifests as megaesophagus and/or megacolon in 1520 % of the
cases, independent of an association with cardiovascular involvement. There are no
data on the mortality, specifically attributable to the involvement of the digestive
tract, with no fully effective clinical or surgical treatment for symptoms such as
dysphagia, odynophagia, constipation and malnutrition.
The cardiac form is the most severe and frequent clinical manifestation of Chagas
disease by far, affecting 3040 % of the infected individuals during the many
decades of progression of the chronic disease stage. It is the most prevalent cardiomyopathy in Latin America and the first cause of cardiovascular mortality among
individuals aged 3050 years in endemic areas [42].
The manifestations of cardiovascular involvement in the chronic stage of Chagas
disease correspond to three clinical syndromes that often coexist in one and the
same patient: ventricular dysfunction progressing to heart failure, rhythm disorders,
and systemic and pulmonary thromboembolic complications. Whereas all three
syndromes contribute to the high mortality associated with Chagas disease, sudden
death, which has particular clinical relevance, is significantly related to arrhythmias
that cause bradycardia and/or tachycardia, which frequently coexist in one and the
same individual.

STAGE I
Asymptomatic
Unspecific
electrocardiographic
abnormalities : incomplete
RBBB,
LAFB , mild bradycardia,
st
1 degree AVB , discrete ST -T
abnormalities
Chest x-ray: normal
2D echo: normal
24-h Holter: absence of
complex VAs
173
STAGE II
STAGE III
Asymptomatic or
mild symptoms
NYHA class I/II
ECG: complete RBBB+LAFB,
monomorphic VEs,
primary T-wave
abnormalities,
nd
rd
2 and 3 degree AVB
Chest x-ray: normal
2D echo: contractility
segmental
abnormalities, apical
aneurysm
24-h Holter: complex VAs
ECG*: Q waves,
polymorphic VEs,
considerable bradycardia,
low QRS
voltage
Chest x-ray: mild
cardiomegaly
2D echo: mild-to-moderate
global LV dysfunction
24-h Holter: complex VAs
STAGE IV
Classes II/III/IV per NYHA

ECG*: atrial fibrillation/
flutter
Chest x-ray: moderate-toConsiderable cardiomegaly
2D echo: severe global
LV dysfunction
24-h Holter: complex
VAs
Sudden cardiac death

CHF
Stroke
Causes of death
*in addition to the electrocardiographic abnormalities characteristic of the previous stages
2D echo= two-dimensional Doppler echocardiogram; VAs= ventricular arrhythmias; AVB= atrioventricular block;
RBBB= right bundle branch block; LAFB = left anterior fascicular block; ECG= conventional electrocardiogram;
VEs= ventricular extrasystoles; CHF= congestive heart failure; LV= left ventricle.
Fig. 3 Stages and causes of death in Chagas heart disease (CHD) [28]
The progression of CHD might schematically be described as four sequential

stages (Fig. 3).
In stage one, the patients are asymptomatic, as they were during the indeterminate form, whereas the presence of cardiomyopathy is usually revealed by a few
relevant electrocardiographic (ECG) abnormalities: sinus bradycardia, first-degree
atrioventricular block, incomplete right bundle branch block and nonspecific ventricular repolarization abnormalities. In a small proportion of cases, the ECG is
completely normal, whereas diagnostic imaging tests disclose discrete segmental
wall-motion abnormalities of the left and/or right ventricle, with the left ventricular
global systolic function being preserved [75]. Other possible functional changes
include ventricular diastolic dysfunctionmost likely caused by sparse areas of
fibrosison the echocardiogram [76] and parasympathetic denervation on Holter
monitoring or other autonomic tests [77]. In many cases, during this stage, the
patients are characteristically able to undergo intense physical exertion, manifesting
vague symptoms only.
In stage two, the most typical ECG abnormalities are commoncomplete right
bundle branch block and left anterior fascicular block, whereas segmental wallmotion abnormalities most commonly affect the apical, inferoapical and inferoposterior wall of the left ventricle. Mural thrombosis of the apical aneurysm occurs in
some cases.
Beginning in stage three, the ECG abnormalities become more severe, including
more intense bradycardia, low QRS voltage in the frontal plane leads, pathologic Q
waves or the loss of the R wave in the horizontal plane leads and atrial fibrillation.
174
The heart chambers undergo progressive global dilatation, the functional class
becomes gradually worse, and in the more advanced stages, significant biventricular
systolic dysfunction develops, which is followed by heart failure in which the signs
and symptoms of congestion are sometimes clearly predominant over the pulmonary signs and symptoms. Perfusion defects might be detected in patients with chest
pain, being initially ischemic with progression to irreversible abnormalities, which
denote the presence of fibrotic areas [78].
Although ventricular arrhythmias often manifest in the early stages of disease,
they become typically exacerbated parallel to the progression of the heart affliction,
being somewhat associated with the aggravation of the ventricular dysfunction.
Complex and multiform ventricular ectopic rhythms are a common finding, appearing in pairs or as episodes of non-sustained ventricular tachycardia, being most
evident on Holter monitoring. Another characteristic manifestation of CHD is sustained ventricular tachycardia, which might cause presyncope and syncope and
progress into ventricular fibrillation with sudden death [79]. This form of arrhythmia usually originates in reentrant micro- or macro-circuits due to the presence of
fibrosis in the lateral inferoposterior area of the left ventricle and might be
reproduced in the laboratory in most patients who manifest it on electrophysiology
studies with programmed ventricular stimulation [80].
Similarly, systemic and pulmonary thromboembolic events may occur, which are
often found only at necropsy [81]. Such events account for approximately 10 % of
CHD deaths. Stroke is the most frequent complication, with Chagas disease being
an acknowledged independent risk factor for cerebral embolism in areas where disease is endemic [82].
It should be emphasized that the prognosis of heart failure due to CHD is poorer
compared to other causes of this condition [83]. Congestive heart failure, which is a
typical occurrence in stage four, causes 25 % of the deaths by CHD. Nevertheless, sudden death is the most conspicuous threat posed by CHD, as it accounts for more than
60 % of the mortality associated with this condition. As a rule, sudden death occurs in
the course of some physical exertion, sometimes in patients previously asymptomatic,
but more often in stages two and three (Fig. 3). More than 90 % of deaths are due to
ventricular fibrillation, with the remainder of sudden deaths occurring during the state
of asystole, sometimes preceded by complete atrioventricular block.
Tertiary prevention of CHD, namely, death, may now be based on the application
of a risk score that was developed and validated, also externally, in a multivariate
analysis study conducted with 424 non-selected patients who were followed up for
approximately 8 years on average. Among other advantages, Rassis score includes
just six variables that proved to behave as independent predictors of mortality in
CHD and are assessed by means of simple clinical methods, such as 24-hour Holter
monitoring, exercise testing, two-dimensional transthoracic echocardiogram, chest
radiographs and conventional ECG. Those variables, which are weighted to compound the final score, are as follows: male gender, low QRS voltage, NYHA functional class III or IV, cardiomegaly, left ventricular dysfunction on echocardiogram
and non-sustained ventricular tachycardia on Holter monitoring. Based on that
175
score, 60 % of the patients are classified as at low risk of death, 20 % as high risk
and 20 % as intermediate risk [884].
Diagnostic Assessment of Patients with CHD

Different from the individuals infected with T. cruzi who exhibit the indeterminate
form of disease, in whom the performance of one ECG test every one or two years is
recommended, the patients with signs, symptoms or ECG abnormalities indicative
of CHD should be assessed by means of a detailed clinical interview and examination, chest radiographs, two-dimensional echocardiogram, 24-hour Holter monitoring and/or ergometric stress testing. The results are used to estimate their risk of
death by means of Rassis score. Particularly in the case of patients with presyncope
or syncope, 24-hour Holter monitoring might be complemented with ergometric
stress testing to investigate the presence of exercise-induced arrhythmias, assessment of the functional capacity and the physiological chronotropic response. In
cases of syncope of unknown cause, seven-day Holter monitoring and intracardiac
electrophysiology studies might be considered, following the aforementioned initial
investigation. In patients with angina, the detection of perfusion defects on myocardial perfusion scintigraphy is not a mandatory indication for cardiac catheterization
with coronary angiography, as the coronary arteries are shown to be normal in the
vast majority of the cases, whereas the clinical manifestations are, as a rule, too
atypical to suggest the presence of coronary stenosis at the subepicardial level.
Tertiary Prevention Therapeutic Measures

Therapy essentially aims at the prevention of the severe complications of disease,
including death, refractory heart failure and disabling embolic events (e.g., embolic
stroke). Additionally, patients with CHD must be treated to avoid exacerbation of
the ventricular dysfunction, heart rhythm disorders and the tendency towards intracavitary or systemic venous thrombosis.
Treatment of Ventricular Dysfunction and Heart Failure

Apparently inducing satisfactory clinical results, the treatment of evident heart
failure in individuals with CHD is empirical by consensus, being based on evidence
of its benefit in heart failure due to other causes. However, in the cases that exhibit
the atypical type of ventricular dysfunction found in CHD, characterized by regional
dyssynergia and preservation of global systolic function, no consensus exists as to
176
the need for treatment with angiotensin-converting enzyme inhibitors or betablockers to eventually prevent the development of heart failure.
Other peculiarities of the pathogenesis and pathophysiology of CHD pose additional challenges to the treatment of heart failure to impede or delay the progression
of ventricular dysfunction and its inherent mortality. Thus, it is often necessary to
administer higher doses of diuretics, either loop or thiazide, to manage the signs and
symptoms of systemic and pulmonary congestion. Beta-blockers tend to be less
well tolerated, particularly when used concomitantly with digoxin and amiodarone,
as a function of the aggravation of the heart electrical generation and conduction
disorders, and with full doses of angiotensin-enzyme converting inhibitors, due to
the greater tendency to arterial hypotension. Although the extrapolation of the
highly significant results obtained in the treatment of heart failure by other causes is
attractive, neither the efficacy nor the effectiveness of beta-adrenergic blockers to
modify the natural history of heart failure due to CHD have been demonstrated; the
results of the single randomized study specifically performed for that purpose have
not yet been communicated [85].
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are
liberally used; however, without confirmation of their efficacy. In turn, spironolactone, an aldosterone inhibitor, is used based on the results of a study that demonstrated reduction of mortality among patients with heart failure by several causes,
including a few dozen cases with CHD [86]. Although subgroup analysis according
to cause was not performed, one further rationale underlying the empirical use of
spironolactone is based on the assumption that because aldosterone blockers inhibit
fibrosis formation, they may play a relevant role in CHD, especially, in this cause of
heart failure that induces most fibrosis.
Cardiac resynchronization therapy was empirically used in small observational,
case series studies; however, the results do not appear promising for patients with
CHD because in this condition, prolonged QRS occurs more often compared to
right bundle branch block.
Heart transplantation represents the last alternative for many patients in very
advanced stages of heart failure. The results obtained in a series of patients with CHD
thusly treated are particularly encouraging in comparison with other etiologies due to
several reasons, and notwithstanding the previous misgivings regarding the induction
of immunosuppression in individuals with a chronic infectious disease [41].
Treatment of Heart Rhythm Disorders and Prevention

of Sudden Death
A frequent idiosyncratic occurrence in patients with CHD is the alternation of episodes of bradycardia-causing disorders with periods of sustained and more often
non-sustained ventricular tachycardia. In addition to the sudden death spectrum that
occurs in many cases, the symptoms of presyncope, syncope, angina, dyspnea and
palpitations occur that require adequate treatment. Severe bradycardia is often
177
caused by sinus node dysfunction and atrioventricular block and less often by atrial
fibrillation with a slow ventricular response. The standard treatment consists of permanent pacemaker implantation, which is empirically based on the results of case
series reported in the literature. Ventricular tachyarrhythmias are treated with amiodarone or an automatic implantable cardioverter defibrillator (AICD).
Electrophysiological mapping followed by radiofrequency catheter ablation has
been described as sporadically used in patients with refractory malignant arrhythmias such as arrhythmic storm and incessant ventricular tachycardia; however, there
is no sound evidence confirming its efficacy [80, 87, 88].
The empirical use of amiodarone is recommended as first-choice therapy in
patients with non-sustained tachycardia or even the sustained variety without serious hemodynamic repercussions (as a rule, while the global systolic function of the
left ventricle is still preserved). In the absence of evidence from randomized studies,
the indication of amiodarone is supported by the results of observational studies that
suggest that it might increase the survival of patients with CHD at high risk of death
by arrhythmia [79, 89, 90].
Adequate evidence for AICD implantation is also lacking; it is recommended
also empirically for patients with sustained ventricular tachycardia and serious
hemodynamic repercussions, as well as for cases of recovery from sudden death
[89]. The discrepancy among the results of a few observational series of patients
with implanted AICDs demonstrates that the singular pathophysiology of CHD
poses an additional challenge to the treatment of these potentially fatal arrhythmias.
Additionally, it points to the need for rigorous scientific studies instead of the mere
extrapolation of evidence gathered from patients with arrhythmias due to other
causes [91]. The concomitant use of amiodarone is mandatory in many cases with
implanted AICDs to minimize the number of appropriate electric shocks and their
deleterious consequences for myocardial contractility. One randomized study comparing treatment with AICD or amiodarone for patients with CHD at moderate and
high risk of death according to Rassis score and with non-sustained ventricular
tachycardia by Holter monitoring is currently in progress [92].
Prevention of Thromboembolic Complications

Oral anticoagulants, such as warfarin, are especially recommended for patients with
CHD at high risk of developing mural or thrombi in veins that have become stagnant
as a consequence of heart failure. Moreover, just as in other heart diseases, they are
recommended for patients with atrial fibrillation, mural thrombi and a past history
of embolic events. Due to the high emboligenic potential of CHD, a cardioembolic
stroke risk score using simple clinical variables was tested in a large series of
patients [93]. Based on that score, patients are categorized and treated with warfarin
or acetylsalicylic acid. Acetylsalicylic acid is a viable option for patients at high
medical and social risk of bleeding.
178
Antitrypanosomal Therapy to Delay or Avoid the Progression

of Established CHD
The aforementioned medical and scientific arguments that support antitrypanosomal therapy at the secondary prevention level also partially apply to tertiary prevention. Evidently, those principles do not apply to the advanced stages of CHD, as
trypanosomicidal drugs are no longer efficacious to halt the natural progression of
the disease, in addition to causing side effects. However, the recommendation for
their use in many patients in less advanced stages of CHD is logical [48, 50].
However, it should be observed that a study currently in progress, meant to demonstrate that etiological therapy is beneficial for patients in the chronic stage of Chagas
disease, for logistic reasons had to focus on the population infected with T. cruzi that
already exhibits clinically manifest CHD [69]. Any study assessing individuals with
the indeterminate form of disease to test the hypothesis as formulated to explore the
prevention of clinically relevant outcomes would be practically unfeasible, as a function of the small number of clinical events in that patient subpopulation.
To summarize, although ideal tertiary prevention of CHD remains an elusive and
remote target, it is plausible to speculate that also that preventive modality contributed at least partially to the remarkable reduction in the morbidity and mortality
associated with Chagas disease in the past decades [94].
References
1. Chagas C. Nouvelle espce de trypanosomiase hu-maine. Bull Soc Path Exotique. 1909;Tome
II,6:814.
2. Aufderheide AC, Salo W, Madden M, Streitz J, Buiks-tra J, Guhl F, et al. A 9,000-year record
of Chagas disease. Proc Natl Acad Sci U S A. 2004;101(7):20349.
3. Chagas C, Vilella E. Cardiac form of American trypanosomiasis. Mem Inst Oswaldo Cruz.
1922;14:561.
4. Marin-Neto JA, Cunha-Neto E, Maciel BC, Simes MV. Pathogenesis of chronic Chagas heart
disease. Circulation. 2007;115:110923.
5. Kberle F. Chagas heart disease and Chagas syndromes: the pathology of American trypanosomiasis. Adv Parasitol. 1968;6:63116.
6. Rossi MA, Tanowitz HB, Malvestio LM, Celes MR, Campos EC, Blefari V, et al. Coronary
microvascular disease in chronic Chagas cardiomyopathy including an overview on history,
pathology, and other proposed pathogenic mechanisms. PLoS Negl Trop Dis. 2010; 4(8):e674.
7. Marin-Neto JA, Simoes MV, Rassi Junior A. Patho-genesis of chronic Chagas cardiomyopathy: the role of coronary microvascular derangements. Rev Soc Bras Med Trop.
2013;46(5):53641.
8. Higuchi ML, Brito T, Parzianello LC, Fukasawa S, Ramires JA. Severe arteriolar dilatation
and ischemic lesions in chronic Chagas cardiopathy: a 3D confocal laser microscopic study. J
Am Coll Cardiol. 1998;31:382.
9. Macedo LGR, Lemos DC, Lago IM, Figueiredo GL, Lima Filho MO, Schmidt A, et al. Base
racional e plano de estudo prospectivo para avaliar o efeito de teraputica antiplaquetria e
vasodilatadora micro-circulatria em pacientes com cardiopatia chagsica crnica e distrbios
microvasculares coronrios. Rev Bras Cardiol Invasiva. 2012;20:828.
179
10. Cunha-Neto E, Teixeira PC, Nogueira LG, Kalil J. Autoimmunity. Adv Parasitol.
2011;76:12952.
11. Dutra WO, Gollob KJ. Current concepts in immuno-regulation and pathology of human
Chagas disease. Curr Opin Infect Dis. 2008;21:28792.
12. Kierszenbaum F. Mechanisms of pathogenesis in Chagas disease. Acta Parasitologica.
2007;52:112.
13. Bonney KM, Engman DM. Chagas heart disease pathogenesis: one mechanism or many? Curr
Mol Med. 2008;8:5108.
14. Tanowitz HB, Machado FS, Jelicks LA, Shirani J, Carvalho ACC, Spray DC, et al. Perspectives
on Trypanosoma cruzi-induced heart disease (Chagas disease). Prog Cardiovasc Dis.
2009;51(6):52439.
15. Rassi Jr A, Rassi A, Marin-Neto JA. Chagas heart disease: pathophysiologic mechanisms,
prognostic factors and risk stratification. Mem Inst Oswaldo Cruz. 2009;104 Suppl 1:1528.
16. Marin-Neto JA, Rassi Jr A. Update on Chagas heart disease on the first centenary of its discovery. Rev Esp Cardiol. 2009;62(11):12116.
17. de Souza-Lima RC, Vale Barbosa MD, Coura JR, Lima Arcanjo AR, da Silva Nascimento A,
Barbosa Ferreira JM, et al. Outbreak of acute Chagas disease associated with oral transmission
in the Rio Negro region, Brazilian Amazon. Rev Soc Bras Med Trop. 2013;46(4):5104.
18. Marques J, Mendoza I, Noya B, Acquatella H, Pala-cios I, Marques-Mejias M. ECG manifestations of the biggest outbreak of Chagas disease due to oral Infection in Latin-America. Arq
Bras Cardiol. 2013;101(3):24954.
19. Wendel S, Dias JCP. Transfusion transmitted Chagas disease. In: Wendel S, Brener Z, Camargo
ME, et al., editors. Chagas disease (American trypanosomiasis): its impact on transfusion and
clinical medicine. So Paulo: ISBT; 1992. p. 10334.
20. World Health Organization. Control of Chagas disease. Second report of the WHO Expert
Committee. WHO Technical Report Series 905. Geneva, 2002.
21. World Bank. World Development Report 1993. Investing in health. New York: Oxford
University Press; 1993.
22. Moncayo A. Chagas disease: current epidemiological trends after the interruption of vectorial
and transfusional transmission in the Southern Cone countries. Mem Inst Oswaldo Cruz.
2003;98:57791.
23. Organizacion Panamericana de la Salud. Estima-cion cuantitativa de la enfermedad de Chagas
en las Americas. Montevideo, Uruguay: Organizacion Pana-mericana de la Salud, 2006.
24. Remme JHF, Feenstra P, Lever PR, et al. Tropical diseases targeted for elimination: Chagas
disease, lymphatic filariasis, onchocerciasis, and leprosy. In: Jamison DT, Breman JG,
Measham AR, et al., editors. Disease control priorities in developing countries. New York: The
World Bank and Oxford University Press; 2006. p. 43349.
25. World Health Organization. Control of Chagas disease. Report of a WHO Expert Committee.
WHO Technical Report Series 811. Geneva, 1991.
26. Schmunis GA. Epidemiology of Chagas disease in non-endemic countries: the role of international migration. Mem Inst Oswaldo Cruz. 2007;102 Suppl 1:7585.
27. Kessler DA, Shi PA, Avecilla ST, Shaz BH. Results of lookback for Chagas disease since the
inception of donor screening at New York Blood Center. Transfusion. 2013;53(5):10837.
28. Rassi Jr A, Dias JC, Marin-Neto JA, Rassi A. Challenges and opportunities for primary, secondary, and tertiary prevention of Chagas disease. Heart. 2009;95(7):52434.
29. Carlier Y, Dias JCP, Luquetti AO, et al. Trypanosomiase amricaine ou maladie de Chagas.
Enciclopdie Mdico Chirurgicale. 2002;8:50520.
30. Dias JCP, Schofield CJ. Control of Chagas disease. In: Maudlin I, Holmes PH, Miles MA,
editors. The trypanosomes. London: CABI Publishing; 2004. p. 54764.
31. Garg N, Bhatia V. Current status and future prospects for a vaccine against American trypanosomiasis. Expert Rev Vaccines. 2005;4:86780.
32. Ramrez JD, Guhl F, Rendn LM, Rosas F, Marin-Neto JA, Morillo CA. Chagas cardiomyopathy manifestations and Trypanosoma cruzi genotypes circulating in chronic Chagasic patients.
PLoS Negl Trop Dis. 2010;4(11), e899.
180
33. Beaumier CM, Gillespie PM, Hotez PJ, Bottazzi ME. New vaccines for neglected parasitic
diseases and dengue. Transl Res. 2013;162(3):14455.
34. Dias JCP, Schofield CJ. The evolution of Chagas disease (American trypanosomiasis) control after
90 years since Carlos Chagas discovery. Mem Inst Oswaldo Cruz. 1999;94(Suppl I):10321.
35. Ach A, Matos AJ. Interrupting Chagas disease transmission in Venezuela. Rev Inst Med Trop
Sao Paulo. 2001;43:3743.
36. Pinto AYN, Valente SA, Valente VC, Ferreira-Junior AG, Coura JR. Acute phase of Chagas
disease in the Brazilian Amazon region: study of 233 cases from Par, Amap and Maranho
observed between 1988 and 2005. Rev Soc Bras Med Trop. 2008;41(6):60214.
37. Souza FF, Castro-E-Silva O, Marin Neto JA, Sankarankutty AK, Teixeira AC, Martinelli AL,
et al. Acute Chagasic myocardiopathy after orthotopic liver transplantation with donor and
recipient serologically negative for Trypanosoma cruzi: a case report. Transplant Proc.
2008;40(3):8758.
38. Pavo RB, Moreira HT, Macedo LGR, Novaes GC, Lemos DC, Lago IM, et al. Los exmenes
serolgicos habituales subestiman la prevalencia de la enferme-dad de Chagas en enfermos sometidos a cinecoro-nariografia por dolor precordial. Rev Argent Cardiol. 2013;160:354 (abstract).
39. Dias JCP, Macedo VO. Doena de Chagas. In Coura JR (Organ.) Dinmica das doenas infecciosas e par-asitrias. Rio de Janeiro: Guanabara Koogan; 2005: p. 55794.
40. Ministrio da Sade do Brasil. Brazilian Consensus on Chagas disease [in Portuguese]. Rev
Soc Bras Med Trop. 2005;38(Suppl3):729.
41. Andrade JP, Marin-Neto JA, Paola AA, Vilas-Boas F, Oliveira GM, Bacal F et al; [I Latin
American guidelines for the diagnosis and treatment of Chagas cardiomyopathy]. Sociedade
Brasileira de Cardiologia. I Diretriz Latino Americana para o Diagnstico e Trat-amento da
Cardiopatia Chagsica. Arq Bras Cardiol. 2011;97(2 Suppl 3):148.
42. Rassi Jr A, Rassi A, Little WC. Chagas heart disease. Clin Cardiol. 2000;23:8839.
43. Rodriques Coura J, de Castro SL. A critical review on Chagas disease chemotherapy. Mem Inst
Oswaldo Cruz. 2002;97:324.
44. Rassi A, Rassi A Jr., Rassi GG. Fase Aguda. In Trypanosoma cruzi e doena de Chagas (2a.
Edio). Brener Z, Andrade ZA, Barral Neto M (orgs.). Rio de Janeiro, Brazil: Guanabara
Koogan; 2000: p. 23145.
45. Brener. Recent advances in the chemotherapy of Chagas disease. Mem Inst Oswaldo Cruz.
1984;79:14955(Suppl).
46. Kierszenbaum F. Autoimmunity in Chagas disease. J Parasitol. 1986;72:20111.
47. Tarleton RL, Zhang L. Chagas disease etiology: autoimmunity or parasite persistence?
Parasitol Today. 1999;15:949.
48. Rassi Jr A, Rassi A, Marin-Neto JA. Chagas disease. Lancet. 2010;375(9723):1388402.
49. Marin-Neto JA, Rassi Jr A, Maciel BC, Simes MV, Schmidt A. Chagas heart disease. In:
Yusuf S, Cairns J, Camm J, Fallen EL, Gersh BJ, editors. Evidence-based cardiology. 3rd ed.
London: BMJ Books/Wiley Blackwell; 2010. p. 82341.
50. Bern C, Montgomery SP, Herwaldt BL, Rassi Jr A, Marin Neto J, Dantas RO, et al. Evaluation and
treatment of Chagas disease in United States: a systemic review. JAMA. 2007;298(18):217181.
51. Villar JC, Villar LA, Marin-Neto JA, Ebrahim S, Yusuf S. Efficacy of trypanocidal therapy
for chronic asymptomatic Trypanosoma cruzi infection: a meta-analysis. JACC. 2002;
39(9-Suppl.B):417B.
52. Villar JC, Marin-Neto JA, Ebrahim S, Yusuf S. Trypanodical drugs for chronic asymptomatic
Trypanosoma cruzim infection. Cochrane Database Syst Rev. 2002;1, CD003463. Review.
53. Andrade AL, Zicker F, Oliveira RM, Silva AS, Luquetti AO, Travassos LR, et al. Randomised
trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet.
1996;348(9039):140713.
54. Sosa-Estani S, Segura EL, Ruiz AM, Velasquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas disease.
Am J Trop Med Hyg. 1998;59:5269.
55. Andrade SG, Stocker-Guerret S, Pimentel AS, Grimaud JA. Reversibility of cardiac fibrosis in
mice chronically infected with Trypanosoma cruzi, under specific chemotherapy. Mem Inst
Oswaldo Cruz. 1991;86:187200.
181
56. Garcia S, Ramos CO, Senra JF, Vilas-Boas F, Rodrigues MM, Campos-de-Carvalho AC, et al.
Treatment with benznidazole during the chronic phase of experimental Chagas disease
decreases cardiac alterations. Antimicrob Agents Chemother. 2005;49(4):15218.
57. Bahia MT, de Andrade IM, Martins TA, do Nascimento AF, Diniz Lde F, Caldas IS, et al.
Fexinidazole: a potential new drug candidate for Chagas disease. PLoS Negl Trop Dis.
2012;6(11), e1870.
58. Rassi A, Luquetti AO. Specific treatment for Trypanosoma cruzi infection (Chagas disease).
In: Tyler KM, Miles MA, editors. American trypanosomiasis. Boston, MA: Kluwer Academic
Publishers; 2003. p. 11725.
59. Viotti R, Vigliano C, Lococo B, Alvarez MA, Petti M, Bertocchi G, et al. Side effects of
benznidazole as treatment in chronic Chagas disease: fears and realities. Expert Rev Anti
Infect Ther. 2009;2:15763.
60. Fragata Filho AA, Silva MAD, Boainain E. Trata-mento etiolgico da doena de Chagas na
fase agu-da e crnica. Rev Soc Cardiol Estado de So Paulo. 1994;4:1927.
61. Fragata Filho AA, Correia EB, Borges Filho R. Tratamento parasiticida na forma indeterminada da doena de Chagas previne o aparecimento de cardiopatia. Rev Soc Cardiol Estado de
So Paulo. 2005;15(5 Suppl B):44.
62. Fabbro DL, Streiger ML, Arias ED, Bizai ML, del Barco M, Amicone NA. Trypanocide treatment among adults with chronic Chagas disease living in Santa Fe city (Argentina), over a
mean follow-up of 21 years: parasitological, serological and clinical evolution. Rev Soc Bras
Med Trop. 2007;40(1):110.
63. Canado JR. Long term evaluation of etiological treatment of Chagas disease with benznidazole. Rev Inst Med Trop Sao Paulo. 2002;44(1):2937.
64. Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, et al. Long-term cardiac
outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006;144(10):72434.
65. Prez-Molina JA, Prez-Ayala A, Moreno S, Fernn-dez-Gonzlez MC, Zamora J, LpezVelez R. Use of benznidazole to treat chronic Chagas disease: a systematic review with a
meta-analysis. J Antimicrob Chemother. 2009;64(6):113947.
66. Canado JR. Tratamento especfico da doena de Chagas nas fases aguda e crnica. In: Coura
JR, ed. Dinmica das doenas infecciosas e parasitrias. Rio de Janeiro, Brazil: Guanabara
Koogan; 2005: p. 66776.
67. Fragata Filho AA. Tratamento etiolgico da doena de Chagas. Rev Soc Cardiol Estado de So
Paulo. 2009;19(1):25.
68. OPAS/OMS 1998. Tratamiento etiolgico de la en-fermedad de Chagas: conclusiones de una
consulta tcnica, OPC/HPC/HCT/140/99. 32 p. Rev Patol Trop 1999;28:24779.
69. Marin-Neto JA, Rassi Jr A, Morillo CA, et al. Rationale and design of a randomized placebo
controlled trial assessing the effects of etiologic treatment in Chagas cardiomyopathy: the
BENznidazole Evaluation For Interrupting Trypanosomiasis (BENEFIT). Am Heart
J. 2008;156:3743.
70. Tarleton RL, Reithinger R, Urbina JA, et al. The challenges of Chagas diseasegrim outlook
or glimmer of hope? PLoS Med. 2007;4, e332.
71. Diniz Lde F, Urbina JA, de Andrade IM, Mazzeti AL, Martins TA, Caldas IS, et al. Benznidazole
and posaconazole in experimental Chagas disease: positive interaction in concomitant and
sequential treatments. PLoS Negl Trop Dis. 2013;7(8), e2367.
72. Urbina JA, Payares G, Sanoja C, et al. In vitro and in vivo activities of ravuconazole on
Trypanosoma cruzi, the causative agent of Chagas disease. Int J Antimicrob Agents.
2003;21:2738.
73. Rassi A, Luquetti AO, Rassi Jr A, et al. Specific treatment for Trypanosoma cruzi: lack of
efficacy of allopurinol in the human chronic phase of Chagas disease. Am J Trop Med Hyg.
2007;76:5861.
74. Navarro M, Norman FF, Prez-Molina JA, Lpez-Vlez R. Benznidazole shortage makes
Chagas disease a neglected tropical disease in developed countries: data from Spain.
Am J Trop Med Hyg. 2012;87(3):48990.
182
75. Marin-Neto JA, Marzulo P, Sousa ACS, et al. Radio-nuclide angiographic evidence for early
predominant right ventricular involvement in patients with Chagas disease. Can J Cardiol.
1988;4:2316.
76. Lima MM, Nunes MC, Rocha MO, Beloti FR, Alencar MC, Ribeiro AL. Left ventricular diastolic function and exercise capacity in patients with Chagas cardiomyopathy. Echocardiography.
2010;27(5):51924.
77. Marin-Neto JA, Bromberg-Marin G, Pazin-Filho A, et al. Cardiac autonomic impairment and
early myocardial damage involving the right ventricle are independent phenomena in Chagas
disease. Int J Cardiol. 1998;65:2619.
78. Hiss FC, Lascala TF, Maciel BC et al. Changes in myocardial perfusion correlate with deterioration of left ventricular systolic function in chronic Chagas cardiomyopathy. JACC Cardiovasc
Imaging. 2009;2(2):16472.
79. Rassi Jnior A, Gabriel Rassi A, Gabriel Rassi S, et al. Ventricular arrhythmia in Chagas disease. Diagnostic, prognostic, and therapeutic features. Arq Bras Cardiol. 1995;65:37787.
80. Sosa E, Scanavacca M, dAvila A, et al. Endocardial and epicardial ablation guided by nonsurgical transthoracic epicardial mapping to treat recurrent ventricular tachycardia. J Cardiovasc
Electrophysiol. 1998;9:22939.
81. Oliveira JSM, Araujo RRC, Navarro MA, et al. Cardiac thrombosis and thromboembolism in
chronic Chagas heart disease. Am J Cardiol. 1983;52:14751.
82. Carod-Artal FJ, Vargas AP, Horan TA, et al. Chagasic cardiomyopathy is independently associated with ischemic stroke in Chagas disease. Stroke. 2005;36:96570.
83. Freitas HF, Chizzola PR, Paes AT, et al. Risk stratification in a Brazilian hospital based cohort
of 1220 outpatients with heart failure: role of Chagas heart disease. Int J Cardiol.
2005;102:23947.
84. Rassi Jr A, Rassi A, Little WC, et al. Development and validation of a risk score for predicting
death in Chagas heart disease. N Engl J Med. 2006;355:799808.
85. Quiros FR, Morillo CA, Casas JP, et al. CHARITY: Chagas cardiomyopathy bisoprolol intervention study: a randomized double-blind placebo force-titration controlled study with
Bisoprolol in patients with chronic heart failure secondary to Chagas cardiomyopathy
[NCT00323973]. Trials. 2006;7:21.
86. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in
patients with severe heart failure. N Engl J Med. 1999;341:70917.
87. Sosa E, Scanavacca M, DAvila A, et al. Radiofrequency catheter ablation of ventricular tachycardia guided by nonsurgical epicardial mapping in chronic Chagasic heart disease. Pacing
Clin Electrophysiol. 1999;22:12830.
88. Henz BD, do Nascimento TA, Dietrich CO, Dalegrave C, Hernandes V, Mesas CE, et al.
Simultaneous epicardial and endocardial substrate mapping and radiofrequency catheter ablation as first-line treatment for ventricular tachycardia and frequent ICD shocks in chronic
Chagasic cardiomyopathy. J Interv Card Electrophysiol. 2009;26(3):195205.
89. Rassi Jr A, Rassi SG, Rassi AG, et al. Sudden death in Chagas disease. Arq Bras Cardiol.
2001;76:7596.
90. Scanavacca MI, Sosa EA, Lee JH, et al. Empiric therapy with amiodarone in patients with
chronic Chagas cardiomyopathy and sustained ventricular tachycardia. Arq Bras Cardiol.
1990;54:36771.
91. Rassi Jr A. Implantable cardioverter-defibrillators in patients with Chagas heart disease:
misperceptions, many questions and the urgent need for a randomized clinical trial.
J Cardiovasc Electrophysiol. 2007;18:12413.
92. Martinelli M, Rassi Jr A, Marin-Neto JA, et al. Chagasics Group of Investigators. Chronic use
of amiodarone against implantable cardioverter-defibrillator therapy for primary prevention of
death in patients with Chagas cardiomyopathy Study: rationale and design of a randomized
clinical trial. Am Heart J. 2013;166(6):97682.
93. Sousa AS, Xavier SS, Freitas GR. Hasslocher-More-no. Prevention strategies of cardioembolic ischemic stroke in Chagas disease. Arq Bras Cardiol. 2008;91(5):30610.
94. Dias JC, Prata A, Correia D. Problems and perspectives for Chagas disease control: in search
of a realistic analysis. Rev Soc Bras Med Trop. 2008;41:1936.
Prevention and Control of Cardiovascular

Diseases: Policies, Strategies,
and Interventions
lvaro Avezum Jr. and Gabriel Pelegrineti Targueta
The epidemiological transition characterized by the increased social and economic

impact of non-communicable diseases at the expense of communicable, maternalfetal, and nutritional diseases was described by Murray and Lopez in 1997 [1]. The
recent publication of the updated results of the Global Burden of Disease (GBD2010) [2] study confirms this trend. Since the first study in 1990 [3], ischemic heart
disease and cerebrovascular disease have been responsible for one in four deaths in
2010 and a 1728 % increase in the years of life lost from premature death due to
these conditions was observed. In the U.S., the mortality rate from cardiovascular
diseases (CVD) decreased by 32.7 % between 1999 and 2009. However, one in
three deaths are still caused by CVD, with an estimated cost of USD 312.6 billion
in 2009 [4]. In South America, in addition to the aging population, increased urbanization has also played an important role in this transition. The increase in population size in large cities increases the prevalence of traditional cardiovascular risk
factors, including obesity, smoking, hypertension, and diabetes [5]. These data are
alarming when considering the vast scientific knowledge available for primary prevention and treatment of these diseases; therefore, these data should stimulate the
formulation of comprehensive and effective public policies and population-based
strategies.
. Avezum, Jr., M.D.

Instituto Dante Pazzanese of Cardiology, Sao Paulo, Brazil
Population Health Research Institute, Mc Master University, Hamilton, Canada
e-mail: aavezumjr@gmail.com
G.P. Targueta, M.D. (*)
Instituto Dante Pazzanese of Cardiology, Federal University of Sao Paulo, Sao Paulo, Brazil
e-mail: gptargueta@gmail.com
DOI 10.1007/978-3-319-22357-5_17
183
184
G.P. Targueta and . Avezum
Clinical Relevance of Cardiovascular Risk Factors

Strategic planning for the prevention of CVD should be initiated after the establishment of investment priorities. Different risk factors affect the various social groups
around the world differently. The population-attributable risk (PAR) is a variable
that reflects the excess morbidity/mortality attributable only to the presence of a
specific risk factor; therefore, it is an important tool for the development of prevention strategies. This variable is calculated by subtracting the incidence of the disease
among individuals exposed to the factor under study from the incidence among
individuals not exposed.
The INTERHEART [6] is a large international casecontrol study involving
patients from all continents and ethnic groups that evaluated the importance of risk
factors for coronary heart disease worldwide. A total of 15,152 patients were evaluated for the presence of certain clinical or laboratory signs at the time of their first
acute myocardial infarction and were compared with 14,820 controls. Nine factors
were closely associated with acute myocardial infarction, with consistent effects
between men and women and among patients of different ethnicities and from different regions of the world. These factors are detailed in Table 1, with their respective adjusted odds ratio (OR) and PAR. Dyslipidemia, characterized by an abnormal
Apo-B/ApoA-1 ratio, and tobacco use were the most important factors. Together,
these factors accounted for more than two-thirds of the PAR, whereas the nine major
risk factors identified accounted for more than 90 % of the PAR. The INTERHEART
study revealed that a diet containing daily servings of fruits and vegetables, in addition to physical activity and alcohol consumption, were protective factors.
Another important finding of the INTERHEART study was the importance of
family history as a risk factor for myocardial infarction (MI). After statistical analysis, its risk factor status was confirmed, with an OR of 1.45 (1.311.60). However,
the PAR increased only slightly, from 90.4 to 91.4 %, after adding family history to
the remaining nine factors evaluated. These findings indicate that most of the risk
attributable to family history is associated with other risk factors evaluated.
Table 1 Risk of myocardial infraction associated with risk factorsINTERHEART study [6]
Risk factor
Apo-B/ApoA-1
Smoking
Diabetes
Hypertension
Abdominal obesity
Psychosocial stress
Daily intake of vegetables and fruits
Physical activity
Alcohol consumption
All combined
OR (CI 99 %)
3.25 (2.813.76)
2.87 (2.583.19)
2.37 (2.072.71)
1.91 (1.742.10)
1.62 (1.45180)
2.67 (2.213.22)
0.7 (0.620.79)
0.86 (0.760.97)
0.91 (0.821.02)
129.2 (90.2185.0)
PAR (99 % CI)

49.2 (43.854.5)
35.7 (32.539.1)
9.9 (8.511.5)
17.9 (15.720.4)
20.1 (15.326.0)
32.5 (25.140.8)
13.7 (9.918.6)
12.2 (5.525.1)
6.7 (2.020.2)
90.4 (88.192.4)
Prevention and Control of Cardiovascular Diseases: Policies, Strategies, and Interventions
185
Table 2 PAR values associated wit risk factors for strokeINTERSTROKE study [7]
Risk factor
Hypertension
Smoking
Abdominal obesity
Diet (risk score)
Physical activity
Diabetes
Alcohol consumption
Psychosocial stress
Depression
Cardiac causes
Apo B/Apo-A1
PAR (99 % CI)

34.6 % (30.439.1)
18.9 % (15.323.1)
26.5 % (18.836.0)
18.8 % (11.229.7)
28.5 % (14.548.5)
5.0 % (2.69.5)
3.8 % (0.914.4)
4.6 % (2.19.6)
5.2 % (2.79.8)
6.7 % (4.89.1)
24.9 % (15.737.1)
With a proposal similar to INTERHEART, the INTERSTROKE study is underway and aims at assessing risk factors and their weight in the incidence of ischemic
and hemorrhagic stroke. This international casecontrol study will also evaluate
patients from all continents and ethnic groups. The patients are selected at the time
of their first stroke and are compared with controls. The INTERSTROKE study [7]
has already evaluated 3000 affected patients and 3000 controls, and its preliminary
results (Phase 1) showed a risk factor profile similar to that reported for myocardial
infarction in the INTERHEART study. Hypertension was the most important risk
factor for both stroke subtypes, with a more prominent effect on hemorrhagic stroke.
When associated with active smoking, abdominal obesity, diet, and sedentary
behavior, the PAR reached 80 % of the overall risk of stroke. The analysis of these
five risk factors together with the effects of diabetes, alcohol consumption, psychosocial factors, cardiac causes, and the Apo-B/Apo A1 ratio yielded a list of 10 risk
factors, which accounted for 90.3 % of the PAR. Diets with greater consumption of
fish and fruits (components of the Mediterranean diet) and physical activity were
protective factors. The interaction between alcohol consumption and risk of stroke
in INTERSTROKE was complex, suggesting a J-curve relationship for ischemic
stroke and a gradual increase of the risk for hemorrhagic stroke as alcohol consumption increased. The risk factors with significant associations with stroke and their
respective PAR values are shown in Table 2.
Available Evidence for Primary Prevention

Evaluating the efficacy of preventive measures in apparently healthy individuals is
not an easy task, considering that the period elapsed until the development of diseases can be very long. Determining the efficiency of these measures is also difficult
because the savings resulting from primary prevention are achieved only in the long
term. Therefore, the cost-effectiveness of preventive measures is often determined
based on mathematical and statistical models [8].
186
Lifestyle Changes
Lifestyle changes consist primarily of the control of tobacco and obesity, regular
physical activity, and proper diet and have a significant impact on the primary prevention of CVD in a cost-effective manner. The Quality Adjusted Life Years (QALY)
indicator is an important tool for the quantification of the impact of a disease or
intervention because it combines quantity and quality of life in a single score.
Eriksson et al. [9] showed that a lifestyle intervention program based on physical
activity and dietary guidance had a cost ranging from USD 1668 to USD 4813 per
QALY, a value compatible with a cost-effective measure. A prospective cohort study
with 43,685 men and 71,243 women [10] demonstrated that a low-risk lifestyle
involving an adequate diet, body mass index (BMI) < 25 kg/m2, no smoking, regular
physical activity, and moderate alcohol consumption can reduce the risk of stroke,
especially ischemic. In the U.S., between 1985 and 2003, there was a linear and
independent relationship between total expenditure on government programs for
tobacco control and the decrease in smoking prevalence [11].
Pharmacological Treatment
The effective treatment of diabetes can decrease the number of macrovascular outcomes, according to a meta-analysis that combined the results of the ACCORD,
ADVANCE, UKPDS, and VADT studies [12]. A total of 27,049 patients were evaluated, and the results indicated that the risk of myocardial infarction decreased by
15 % (hazard ratio [HR] 0.85, 95 % confidence interval [CI] 0.760.94) in the intensive glycemic control group. With regard to the role of statins in the primary prevention of cardiovascular disease, a recent meta-analysis of the Cholesterol Treatment
Trialists (CTT) collaboration [13] involving 27 clinical trials demonstrated that the
use of these drugs could reduce disease outcomes in patients with low estimated risk
of adverse events (<10 % in five years). This study reported decreases in the number
of major coronary events, stroke, need for revascularization, and major vascular
events regardless of the presence of previously diagnosed vascular disease. The use
of statins as recommended by current guidelines would cost USD 42,000 per QALY,
considering the cost of USD 2.11 per tablet (this value is above the market), which
is also a cost-effective strategy [8]. The emerging concept of the polypill can also
have important future implications in public health policies. A mathematical analysis of the TIPS study, which evaluated the control of blood pressure, lipid level,
heart rate, and antiplatelet effect of aspirin in patients with no history of cardiovascular disease (CVD) with at least one risk factor, reported that the use of polypills
could potentially decrease the rate of CVD by 62 % and of stroke by 48 % [14].
Subsequently, Bautista et al. [15] reported that the strategy of the TIPS study is costeffective in Latin American countries, even among those countries with lower per
capita incomes.
187
Global Proposal for Cardiovascular Prevention

Despite the available knowledge on the impact of cardiovascular risk factors and on
the existence of effective primary prevention strategies, the adoption of healthy habits by the population is still very low. An evaluation of 153,996 participants of the
Prospective Urban Rural Epidemiology (PURE) study [16] living in urban and rural
communities in 17 countries from all continents showed that tobacco use, physical
inactivity, and improper diet were highly prevalent, even among individuals who
had a previous diagnosis of coronary disease or stroke. In general, the prevalence of
a healthy lifestyle was correlated with the patients level of education and with
income per capita in the countries evaluated and reached levels as low as 4.3 %
when the three habits were adopted simultaneously.
After recognizing the political and cultural difficulties for the implementation of
the changes necessary to reduce the impact of CVD, the World Health Organization
(WHO), during its 66th World Health Assembly in Geneva (May 2012), set as a
global target a 25 % reduction in premature mortality from non-communicable diseases by 2025. This resolution included the control of CVD, cancer, diabetes, and
chronic respiratory diseases [17]. Based on this resolution, the World Heart
Federation (WHF) determined as its primary focus a 25 % reduction in premature
mortality from CVD only. For this purpose, cardiologists and healthcare professionals were urged to promote evidence-based good practices for secondary prevention
and treatment of cardiac and cerebrovascular diseases; journalists were invited to
disseminate the preventive nature of these diseases and to influence state policies;
and emerging leaders were encouraged to guide the global agenda on CVD, to promote the adoption of best practices, to guide state policies, and to mediate the
responses of health systems.
The means to achieve this audacious goal involved a focus on the main factors
with high PAR values, as illustrated in Fig. 1, and consisted of actions that would
promote healthy habits and ensure access to healthcare and adequate treatment of
hypertension and, specially, of diabetes.
The general principles of the global action proposed are: [18]
Life-course approach;
Empowerment of individuals and communities;
Evidence-based strategies;
Universal healthcare coverage;
Management of real, perceived or potential conflicts of interest;
Protection of human rights;
Equity-based approach;
National action and international cooperation and solidarity; and
Multisectoral actions.
With regard to financial matters, according to estimates, the cost of action would
be considerably outweighed by the cost of inaction. The total costs of implementing
the measures proposed in relation to the current spending on health are approximately
188
GLOBAL TARGET 2525

A 25% relative reduction in overall mortality from cardiovascular disease, cancer,
diabetes, and chronic respiratory diseases
OBJECTIVE of the WHF

A 25% reduction in mortality from
cardiovascular diseases by 2025
10% relative
0% Increases in
reduction
10% relative
of the harmful use

reduction in
of alcohol
physical inactivity
30% Relative
reduction in
sodium/salt intake
30% reduction in
50% of the eligible individuals receiving drug therapy
25% reduction in
hypertension
the prevalence
rates of diabetes
and obesity
tobacco use
80% availability of essential medicationsc

and basic technology for treatment of
cardiovascular and non-communicable diseases
and counseling to prevent

myocardial infarction and stroke
2025
Fig. 1 Adapted from the 65th World Health Assembly (WHO) [18]
4 % in low-income countries, 2 % in middle-income countries, and less than 1 % in

the richest countries. The estimated spending between 2013 and 2020 is USD
940.2 million, whereas the cumulative cost of non-communicable diseases without
proper management would reach USD 47 trillion (75 % of the global gross domestic
product [GDP] in 2010). Therefore, spending should be considered as an investment
for all countries. One possible source of revenue is the deduction of taxes from
products that are harmful to health, including alcohol and tobacco, a strategy that
has already been implemented in Jamaica and Thailand [19].
The strategies planned for tobacco control, promotion of a healthy diet, promotion of physical activity, and reduction of alcohol abuse, according to the political
statement made in the 66th World Health Assembly, are detailed below [18].
Tobacco Control
The goal for tobacco control is a 30 % relative reduction in the prevalence of tobacco
use among individuals aged 15 years or older. For this purpose, it is important to:
Protect tobacco control policies from commercial interests of the tobacco
industry;
Ensure that all indoor environments and other public places are completely
smoke-free.
Develop mass media campaigns to alert the population about the dangers of
tobacco use;
189
Ban tobacco promotion, sponsorship, and advertising, when appropriate;

Provide assistance to individuals who desire to quit smoking, particularly pregnant women;
Regulate the contents and emissions of tobacco products; and
Increase taxes on all tobacco products.
Promotion of Healthy Diet

This item refers to the target to reduce by 30 % the average intake of sodium, to
prevent increases in the prevalence rates of diabetes and obesity, and to reduce by
25 % the prevalence of high blood pressure. For this purpose, it is necessary to:
Promote exclusive breast feeding up to six months of age and continued breastfeeding until the age of two years;
Decrease the amount of sodium added to prepared or processed food products;
Increase the availability, affordability, and consumption of fruits and
vegetables;
Decrease the intake of saturated fatty acids and trans fat, substituting them for
unsaturated fatty acids;
Decrease the sugar content in beverages;
Reduce the sizes of food portions and limit excess caloric intake;
Promote the availability of healthy food products in all public institutions;
Develop policies in cooperation with farmers;
Conduct evidence-informed public campaigns; and
Promote international standard labeling for processed foods.
Promotion of Physical Activity

The measures intended for the promotion of physical activity are aimed at a 10 %
relative reduction in the prevalence of sedentary lifestyle or insufficient physical
activity, in addition to the control of obesity, diabetes, and hypertension.
Said measures aim to:
Adopt and implement national guidelines for physical activity;
Establish a multisectoral committee and engage all stakeholders, including governments, nongovernmental organizations (NGOs), civil society, and sponsors
for the active implementation of actions aimed at increasing physical activity in
all age groups;
Stimulate cycling and walking in cities;
Ensure access to physical education in schools;
Ensure adequate infrastructure; and
Conduct evidence-informed mass media campaigns.
190
Decrease the Harmful Use of Alcohol

The aim of this strategy is a 10 % relative reduction in harmful use of alcohol, in
addition to the objectives for the control of blood pressure mentioned previously.
Harmful use of alcohol is defined by the WHO as a behavior that leads to harmful
social or health consequences to the individual, friends and family, and society in
general. The 10 main goals are:
Commitment, awareness, and leadership;

Health services response;
Community action;
Countermeasures to drinking and driving;
Availability of alcohol;
Marketing of alcoholic beverages;
Pricing policies;
Reducing the negative consequences of alcohol intoxication;
Reducing the impact of the use of illicit and informally produced alcohol on
public health; and
Monitoring and surveillance.
The Lancet NCD Action Group recently published a detailed step-by-step strategy for the implementation of the aforementioned measures in lower-income countries [19]. Figure 2 lists the suggested steps and what each step encompasses.
STEP 1 - PLANNING AND RAISING AN ACTION MULTISECTORAL

Prepare the stage for the action and communicate public and partners
Ensuring national leadership and coordination mechanisms
Promote involvement of civil society and, where appropriate, the private sector
Develop a national plan based on clear policies with appropriate goals and targets
Strengthen the capacity for change: human, financial and regulatory
STEP 2 - IMPLEMENTING THE INTERVENTION PRIORITY

Tobacco control measures
Reduce salt diet to reduce blood pressure
Treatment for people at high cardiovascular risk
Other insusceptible costing and cost-effective interventions, as resources permit
STEP 3 - DOCUMENT THE PROGRESS

Monitor progress: leadership, results and resources
Review, evaluate and report progress
Take steps to accelerate progress
Fig. 2 Steps suggested by The Lancet BCD Action Group for the implementation of the target
proposed by the WHO [19]
191
Table 3 Restructuring of healthcare systems (adapted from Travis et al. [20])

Restrictions
Distance to the healthcare units
Poorly trained staff
Unmotivated staff
Poor planning and management
Lack of partnership and intersectoral
action
Poor quality of the private sector
Responses
Construction of new units
Reform of the medical curriculum
Reassessment of salary structures and career plans
Restructuring of Health Ministries
Decentralization of administrations with representation
from various sectors
Development of accreditation and regulation systems
Policies for Healthcare Systems

In addition to the aforementioned interventions, the restructuring of healthcare systems is also essential to achieve the successful prevention of cardiovascular diseases
on a global scale. Particularly in lower-income countries, the problems in healthcare
systems include physical structure, human resources, and lack of strategic planning.
Table 3 summarizes the limitations of the healthcare systems and the effective measures to solve these problems.
The Hypertension Detection and Follow-up Program Cooperative Group (HDFP)
study [21] provided sufficient evidence to justify investments in the structure and
organization of healthcare systems. Initiated in the 1970s, when alternative therapies for hypertension were fewer and less effective than they are today, this clinical
trial showed that decreased mortality could be achieved with the organization and
systematization of healthcare to hypertensive patients. The individuals randomly
allocated to the intervention group were treated in special healthcare units at no cost
for patients with regard to consultations, transport, and purchase of medications,
with the aim to stimulate treatment adherence, and drug therapy was guided by a
standardized protocol for the sequential use of antihypertensive drugs.
The control group received standard care in community healthcare centers. At
the end of five years, all-cause mortality decreased by 17 % in the intervention
group [22].
Another topic of interest in the planning of healthcare systems is the availability
of essential medications for the treatment of non-communicable diseases. A list
with drugs considered essential for public health is released every two years by the
WHO since 1977; its last version was made available in April 2013 [23]. Table 4
lists the medications for the treatment of CVD included in the updated list. The goal
in 2025 is to reach an 80 % availability of these medications.
However, global access to these medications is still very low. In poorer countries,
the probability of patients receiving at least a suitable medication for the secondary
prevention of CVD is 19.8 %. In contrast, in countries with higher income per capita, the situation is different but not less alarming: this probability reaches only
54.9 % [24]. The recommendations from Table 5 should be followed to achieve the
target proposed for 2025 [25]. The adequate management of conflicts of interest
192
Table 4 List of essential medications for treatment of CVD [23]

Antiplatelet
Acetylsalicylic acid
Antianginal
Bisoprolol
Isosorbide dinitrate
Verapamil
Antiarrhythmics
Antihypertensives and diuretics

Amlodipine
Enalapril
Hydralazine
Hydrochlorothiazide
Methyldopa
Furosemide
Digoxin
Amiodarone
Lipid-lowering
Simvastatin
Antidiabetic
Gliclazide
Metformin
NPH insulin
Regular Insulin
Anti-smoking therapies
Nicotine replacement therapy
(Gum or transdermal)
Amiloride
Table 5 Policies for increasing availability and access to essential medications

Increase efficiency of selection and
inventory, promoting access within
the budget available
Generic
Rational selection
Ensure quality
Monitor availability
Rational use
Increase funding for medications

through local funds or
international aid
New initiatives to promote
treatment adherence
Implement policies that promote the purchase of

generic drugs
Prioritize the drugs available in the list of essential
drugs from the WHO
Follow quality-control policies already adopted for
drugs against HIV, malaria, and tuberculosis
Use of novel technologies to prevent stock depletion
Promote national guidelines for the prescription,
training, and information to prescribers and patients
Create taxes or mandatory health insurance to promote
equity at a low cost per patient
Maintain an international fund for poorer countries
Restructure healthcare services, including
decentralization; increase the availability of counselors
to promote treatment adherence, nursing care
Patient-centered healthcare
Polypill
with the pharmaceutical industry and the monitoring of the results of interventions
are other important strategies.
Based on the above considerations, it is clear that the knowledge necessary to
establish priorities and to initiate actions for CVD prevention is available. Political
will and the involvement of healthcare professionals and civil society is essential to
achieve the targets proposed by the WHO and to decrease the major impacts of noncommunicable diseases worldwide.
193
References
1. Lopez A, Murray C. The global burden of disease, 19902020. Nat Med. 1998;4(11):12413.
2. Lozano R. Global and regional mortality from 235 causes of death for 20 age groups in 1990
and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet.
2012;380(9859):2095128.
3. Murray C, Lopez A. The global burden of disease. A comprehensive assessment of mortality
and disability from diseases, injuries and risk factors in 1990 and projected to 2020. GBD
series vol I. Cambridge, MA: Harvard School of Public Health on behalf of the World Health
Organization and the World Bank; 1996.
4. Go A. Heart disease and stroke statistics-2013 update: a report from the American Heart
Association. Circulation. 2013;127(1):e6245.
5. Avezum A, Braga J, Santos I, Guimares H, Marin-Neto J, Piegas L. Cardiovascular disease in
South America: current status and opportunities for prevention. Heart. 2009;95(18):147582.
6. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART
study): casecontrol study. Lancet. 2004;364(9438):93752.
7. ODonnell M, Xavier D, Liu L, Zhang H, Chin S, Rao-Melacini P, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a
casecontrol study. Lancet. 2010;376(9735):11223.
8. Weintraub W, Daniels S, Burke L, Franklin B, Goff DJ, Hayman L, et al. Value of primordial
and primary prevention for cardiovascular disease: a policy statement from the American Heart
Association. Circulation. 2011;124(8):96790.
9. Eriksson M, Hagberg L, Lindholm L, Malmgren-Olsson E, Osterlind J, Eliasson M. Quality of
life and cost-effectiveness of a 3-year trial of lifestyle intervention in primary health care. Arch
Intern Med. 2010;170(16):14709.
10. Chiuve S, Rexrode K, Spiegelman D. Primary prevention of stroke by healthy lifestyle.
Circulation. 2008;118:947.
11. Farrelly M, Pechacek T, Thomas K, Nelson D. The impact of tobacco control programs on
adult smoking. Am J Public Health. 2008;98(2):3049.
12. Turnbull F, Abraira C, Anderson R, Byington R, Chalmers J, Duckworth W, et al. Intensive
glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia.
2009;52:228898.
13. Cholesterol Treatment Trialists (CTT) Collaborators. The effects of lowering LDL cholesterol
with statin therapy in people at low risk of vascular disease: meta-analysis of individual data
from 27 randomised trials. Lancet. 2012;2012(380):581.
14. Yusuf S, Pais P, Afzal R. Indian Polycap Study (TIPS). Effects of a polypill (Polycap) on risk
factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, doubleblind, randomised trial. Lancet. 2009;373:134151.
15. Bautista L, Vera-Cala L, Ferrante D, et al. A polypill aimed at preventing cardiovascular
disease could prove highly cost-effective for use in Latin America. Health Aff.
2013;32(1):15564.
16. Teo K, Lear S, Islam S, et al. Prevalence of a healthy lifestyle among individuals with cardiovascular disease in high-, middle- and low-income countries: the Prospective Urban Rural
Epidemiology (PURE) study. JAMA. 2013;309(15):161321.
17. 65th World Health Assembly closes with new global health measures. 2012. http://www.who.
int/mediacentre/news/releases/2012/wha65_closes_20120526/en/index.html. Cited 2013 10th
October.
18. Sixty-sixth World Health Assembly. Follow-up to the political declaration of the high-level
meeting of the general assembly on the prevention and control of non-communicable diseases. 2013. http://apps.who.int/gb/ebwha/pdf_files/WHA66/A66_R10-en.pdf: World Health
Organization (WHO). Cited 2013 10th October.
194
19. The Lancet NCD Action Group. Country actions to meet UN commitments on noncommunicable diseases: a stepwise approach. Lancet. 2013;381:57584.
20. Travis P, Bennett S, Haines A, Pang T, Bhutta Z, Hyder A, et al. Overcoming health-systems
constraints to achieve the millennium development goals. Lancet. 2004;364(9437):9006.
21. Glynn L, Murphy A, Smith S, Schroeder K, Fahey T. Interventions used to improve control of
blood pressure in patients with hypertension. Cochrane Database Syst Rev. 2010;3:CD005182.
doi:10.1002/14651858.CD005182.pub4.
22. Glynn L, Murphy A, Smith S, Schroeder K, Fahey T. Interventions used to improve control of
blood pressure in patients with hypertension. Cochrane Database Syst Rev. 2010;3:CD005182.
doi:10.1002/14651858.CD005182.pub4.
23. WHO. WHO model list of essential medicines. 18th list. April 2013. http://www.who.int/
Cited
medicines/publications/essentialmedicines/18th_EML_Final_web_8Jul13.pdf2013.
2013 13th October.
24. Yusuf S, Islam S, Chow C. Use of secondary prevention drugs for cardiovascular disease in the
community in high income, middle-income, and low-income countries (the PURE Study): a
prospective epidemiological survey. Lancet. 2011;378:123143.
25. The Lancet NCD Action Group. Promotion of access to essential medicines for noncommunicable diseases: practical implications of the UN political declaration. Lancet.
2013;381:6809.

Diseases Focusing on Low- and MiddleIncome Countries
Gilson S. Feitosa
General Considerations
The role of cardiovascular diseases as the main cause of death in the socioeconomically developed world has long been recognized [1].
There is mounting epidemiological evidence indicating the increasing role of
these diseases as causes of mortality in developing countries, as well as in those
with a lower development index and reduced financial resources [2].
Determinants of that phenomenon have been correlated with progressive urbanization, the consequent epidemiological transition resulting from exposure to risk
factors in the industrialized world, physical inactivity, and psychosocial stress [3].
In addition, there is reduced government funding for enabling the implementation of health policies aimed at achieving the best control of the disease with effective prevention, diagnosis, and treatment measures.
Epidemiological Transition in Developing or Low-Income

Countries
Progressive urbanization, such as internal migration from rural areas to cities, is a
highly relevant sociological phenomenon observed in the contemporary world
(Table 1) [5, 6].
G.S. Feitosa (*)

Bahia School of Medicine and Public Health, Salvador, Brazil
Hospital Santa Isabel/Santa Casa da Bahia, Salvador, Brazil
Brazilian Society of Cardiology, Rio de Janeiro, USA
e-mail: gilson-feitosa@uol.com.br
DOI 10.1007/978-3-319-22357-5_18
195
196
G.S. Feitosa
Table 1 Impact of the epidemiological transition [4]

Potential impact of the transition in risk factors for cardiovascular diseases in the population
Transition
Changes in the risk
Possible metabolic
Development of
profile for
responses (which
CVD
cardiovascular
may vary between
diseases
populations)
Mortality from infectious
Tobacco use
Obesity
parasitic diseases
Life expectancy
Physical activity
Dyslipidemia
Urbanization
Dietary changes (i.e., Hypertension
fat, calories)
Stress
Diabetes mellitus
Coagulation
abnormalities (i.e.,
fibrinolytic activity)
Such conditions coincide with the improved control of infectious and parasitic
diseases, improved access to healthcare, and increased adult survival rates.
However, a whole new population group has been exposed to the conditions of
an increasingly industrialized world. The inevitable consequences of that fact
include increased daily intake of salt and saturated animal fats, higher dietary content of trans fats, increased tobacco use, and significant physical inactivity.
Consequently, the incidence of hypertension, obesity, and diabetes mellitus has
worsened.
Hypertension has shown increasing prevalence, and its future numbers are projected to be even more striking, particularly in less developed regions (Fig. 1).
These conditions have contributed to the progressive manifestation of atherosclerosis at an epidemic scale across the contemporary world. Most notably, the
disease has reached, in absolute terms, less developed and more numerous populations [8] without easy access to education on the subject or even access to modern
resources that mitigate the problem in more developed countries.
It is estimated that approximately nine million people died from cardiovascular
diseases in developing countries and that five million died in developed countries in
1990, and the estimates for 2020 are six and 19 million people, respectively.
This prediction undoubtedly reiterates the widespread epidemic threat of cardiovascular disease in the contemporary world, especially in developing countries.
Although the entire transition process occurred in the early twentieth century,
much time had elapsed until one could recognize the impact caused by noncommunicable diseases in the underdeveloped or developing world, particularly
cardiovascular diseases, as subsequently noted.
The World Health Organization began to warn about the problem in the midtwentieth century.
The overview of socioeconomic disparities between areas affected by hunger
and poverty and affluent regions, per se, has already hindered the establishment of
uniform measures. The emergence of AIDS/HIV has worsened the situation.
197
Prevention and Control of Cardiovascular Diseases Focusing on Low-

2000
Men
50
37.4
Hypertension Prevalence %
40
37.2
35.3
40.7
39.1
30
Women
34.8
22
20.6 20.9
20
23.7
22.6
26.9 28.3
19.7
17
14.5
10
0
2025
50
45.9
41.6 42.5
44.5
39.1
40
30
40.2
24
22.9 23.6
27
27.7 27
27
18.8
20
28.2
17.1
10
fric
a
s
-Sa
har
Sub
trie
sa
nd
un
Oth
er
Co
an
A
Isla
nd
ina
Ch
ast
in t
nt
sce
Cre
rica
me
in A
he
and
Mi
Car
dd
ibb
le E
ean
ia
Ind
st E
Old
Soc
iali
Lat
Est
abl
ish
ed
Ma
rke
tE
con
con
om
i
om
i
es
es
Fig. 1 Global prevention of hypertension 20002025 [7]
Recently (2000), such events prompted a WHO policy, expressed in the

Millennium Declaration [9], that prioritized measures against extreme poverty and
hunger and aimed to promote universal primary education, protection of women,
child mortality reduction, and control of HIV/AIDS, malaria, tuberculosis, and
other diseases. Non-communicable diseases, including cardiovascular diseases,
were not mentioned as a primary focus of attention.
Only in subsequent years, especially after the widely cited study conducted by
Leeder et al. [10] has the focus shifted toward the prevention of cardiovascular diseases
in less developed countries, which has affected global measures for health promotion
and disease prevention, including two complementary actions for that purpose [11].
Current Status of Cardiovascular Diseases in Low-Income

Countries
Considering the substantial number of inhabitants of underdeveloped areas worldwide, the contribution of these regions to global mortality is significant in absolute
numbers, both in terms of non-communicable and communicable diseases, especially cardiovascular diseases.
198
G.S. Feitosa
Considering these diseases and using the mortality rate per 100,000 inhabitants
as the only indicator, a value of more than 200 is obtained. The mortality rate of
developing countries ranges from 200 to 300/100,000, while almost all underdeveloped countries remain above 300/100,000 in habitants for both men and women
(Figs. 2 and 3).
The other relevant epidemiological indices, including disability-adjusted life
years (DALY), among others, are equally impressive (Fig. 4).
Some cardiovascular diseases, including Chagas disease in South America and
rheumatic fever in Africa and some regions of the Americas, among other less common types, including endomyocardial fibrosis, occur in some underdeveloped or
developing regions.
Chagas disease, caused by the protozoan Trypanosoma cruzi, and transmitted by
the insect Triatoma infestans(commonly known as the barber bug), among other
insects, is a disease autochthonous to South America that affects approximately
1618 million people, including 5 million in Brazil (Table 2).
A quarter of the people affected with Chagas disease present or will present with
severe forms of myocardiopathy.
Successful campaigns against the transmission agent have prevented the appearance of new cases, and some of the regions affected have been recognized as
disease-free by the WHO.
Cardiovascular diseases and diabetes, age-standardized mortality rates per 100.000 inhabitants,Women,
2008
Mortality rates per 100,000

inhabitants
200
201-300
301-400
401-500
> 500
Data not available Not
applicable
Fig. 2 Mortality of women from cardiovascular diseases worldwide. Modified from the WHO
[11]. Source: World Health Organization. Map: Public Health Information and Geographic
Information Systems (GIS) World Health Organization. WHO 2011.
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country,
territory, city or area or of its authorities or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full
agreement
199
Cardiovascular diseases and diabetes, age-standardized mortality rates per 100.000 inhabitants,
Men, 2008
Mortality rates per 100,000

inhabitants
200
201-300
301-400
401-500
> 500
Data not available
Not applicable
Fig. 3 Mortality in men from cardiovascular diseases worldwide. Modified from the WHO [11].
Source: World Health Organization. Map: Public Health Information and Geographic Information
Systems (GIS) World Health Organization. WHO 2011.
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the WHO concerning the legal status of any country,
territory, city or area or of its authorities or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full
agreement
Age-standardized DALY per 1,000 inhabitants
Age-standardized DALY for non-communicable diseases grouped by

leading cause, gender, and country income in 2004
160
140
Other non-communicable diseases
120
Sensory disorders
100
Neuropsychiatric disorders
80
Chronic respiratory diseases
60
Cancer
40
Cardiovascular diseases
20
0
Men Women
High
income
Men Women
Men Women
Medium-high
income
Medium-low
income
Men Women
Low
income
Fig. 4 Disability-adjusted life years (DALY). Modified from the WHO 2004
200
G.S. Feitosa
Table 2 Chagas disease in Latin America [12]

Chagas disease status
In Latin America
1618 million infected individuals
In Brazil
5 million infected individuals
25 % developed Chagas heart disease within 10 years
Table 3 Mortality from cardiovascular diseases in South America [13]

Country
Argentina
Bolivia
Brazil
Chile
Colombia
Equator
Guiana
Paraguay
Peru
Suriname
Uruguay
Venezuela
Population (millions)
2005
32.6
9.2
186.4
16.3
45.6
13.2
0.7
6.2
28.0
0.4
3.5
26.6
Age-standardized mortality rate from

cardiovascular disease (per 100,000 inhabitants)
2012
260
341
165
240
244
526
291
190
421
208
241
Rheumatic heart disease still significantly contributes to morbidity and mortality

from cardiovascular diseases in some parts of the developing world and has already
been eradicated in many parts of the developed world.
This is a poverty-related disease, resulting from the crowding of children in precarious homes with few hygiene resources.
Improved housing and hygiene conditions are responsible for its eradication
more than any other medical measure.
Ischemic heart disease and stroke are the leading causes of death worldwide in
less developed regions.
The scenario is noticeably serious, especially in South America, and Brazil
shows alarming rates (Table 3).
The aforementioned epidemiological transition phenomenon and the lack of care
for those already affected by the disease contribute to its severity.
The risk factors for the establishment of atherosclerotic disease in less developed
countries are the same as those in developed countries, as demonstrated in the
INTERHEART [14] study and in the INTERSTROKE study [15].
201
The INTERHEART study shows that 90 % of individuals who experienced acute

myocardial infarction showed at least one of nine factors considered related to lifestyle or established risk factors, including reduced dietary intake of fruits and
vegetables, reduced physical exercise, tobacco use, alcohol use, dyslipidemia,
hypertension, obesity, diabetes, and psychosocial stress.
That study involved approximately 30,000 cases and controls for myocardial
infarction in 52 countries and found somewhat similar results in different parts of
the world, as shown in Tables 4 and 5.
The INTERSTROKE study reported the same results using a similar analysis
model, wherein 10 risk factors were evaluated in 22 countries, showing the importance of hypertension for all types of strokes, especially hemorrhagic stroke.
Cardiovascular Prevention Prospects in Low-Income

Countries
The global goal of reducing the prevalence and incidence of cardiovascular events
is noticeable. In the USA, the 20/20 target (a 20 % reduction of cardiovascular diseases by 2020) and in Europe the 25/25 project (reducing cardiovascular diseases by
25 % by 2025) are expanding worldwide with the support of the World Heart
Federation (WHF).
Political and governmental awareness should be emphasized globally in countries with lower levels of development and reduced resources for investment in
health expenditure (as is the case of Brazil), aiming to reverse the current unfavorable situation shown in Table 6.
Table 4 Risk attributable to hygiene and dietary factors in the world population by region [14]
Region
Western Europe
Central and Eastern
Europe
Middle East
Africa
North Asia
China
South and East Asia
Australia/New Zealand
South America
North America
Global
Hygienic and dietary factors

Tobacco
Fruits and
use
vegetables
% exercise
28.9
12.9
38.8
30.2
10.2
11.3
% alcohol
18.9
12.9
All risk
factors
67.8
49.6
44.8
38.0
37.5
35.8
36.2
44.7
38.5
26.3
35.7
4.4
27.3
5.3
5.3
27.9
18.5
3.1
25.3
6.7
45.5
63.2
55.2
62.4
69.9
65.8
56.9
59.8
54.6
8.1
3.8
18.4
17.8
11.2
10.7
6.7
19.8
13.7
4.0
11.1
24.3
21.1
31.4
23.8
27.2
25.3
12.2
202
G.S. Feitosa
Table 5 Established risk factors [14]

Region
Western Europe
Central and Eastern
Europe
Middle East
Africa
North Asia
China
South and East Asia
Australia/New Zealand
South America
North America
Global
HTN
%
22.0
24.5
DM %
14.9
9.1
Obesity
63.6
28.0
Psychosocial
stress %
38.9
4.9
Lipids
%
44.6
35.0
9 risk
factors
94.0
72.5
9.7
29.9
19.4
22.1
38.4
22.8
32.8
18.9
17.9
15.5
17.1
12.1
10.0
21.0
7.2
12.8
7.9
9.9
26.7
58.3
37.0
5.5
58.0
61.6
45.4
59.6
20.1
41.6
40.0
15.9
35.6
26.7
28.9
35.6
51.4
32.5
70.5
74.1
58.7
43.8
67.7
43.4
47.6
50.5
49.2
95.0
97.4
89.4
89.9
93.7
89.5
89.4
98.7
90.4
Table 6 Expenditure on health and life expectancy statistics of some countries selected2009
[16, 17]
Countries
Argentina
Brazil
Canada
USA
France
Japan
UK
Total expenditure
on Health per
capita (USD)
1322
837
3900
7285
3709
2696
2992
% of government
expenditure on
health
50.8
41.6
70.0
45.5
79.0
81.3
81.8
% of expenditure on
health (GDPgross
domestic product)
10.0
8.4
10.1
15.7
11.0
8.0
8.4
Life
expectancy at
birth
76.6
72.0
81.2
78.1
80.9
82.1
79.0
USD united states dolars
The relationship between resource distribution and human development

inequalities is clearly noticeable, as shown in Fig. 5.
Other measures to be implemented aim to promote health, on the one hand, and
correct risk factors already present, on the other hand.
In a recent study, the Institute of Medicine [19] proposed, among others, the following measures:
Recognizing the importance of non-communicable diseases as a priority;

Improving local data collection;
Implementing cardiovascular health-promoting policies;
Training national coordinators for chronic diseases;
Conducting local studies for testing better solutions for different regions;

CV
expenditure
per capita
USD
< 2.17
2.17-3.7
3.7-5.2
5.2-6.7
> 6.7
203
Human development
index
< 0.682
0.682-0.705
0.705-0.746
0.746-0.776
0.776-0.844
Fig. 5 Regional CV healthcare disparities in Brazil [18]. CV cardiovascular diseases
Disseminating information and measures between countries with similar

characteristics;
Improving dietary patterns;
Improving access to diagnostic and therapeutic resources for cardiovascular
diseases;
Defining necessary resources;
Intensifying the anti-smoking campaign, increasing tobacco taxes, and banning
smoking in public places;
Preventing alcohol abuse;
Reducing the salt content in foods;
Banning trans fats;
Promoting physical activity;
Promoting the use of evidence-based medications in appropriate situations.
Accordingly, the World Health Organization proposed seven lines of action: [11]
An approach of cardiovascular disease prevention beginning in childhood;

Joint government, civil society, and private sector involvement;
Detection and monitoring of recognized morbidity and mortality indicators;
Adequate funding, especially for primary prevention;
Cost-effective applications;
Recognition that cardiovascular disease control is an integral part of poverty
eradication resulting from the improved use of the workforce;
Society as an element of constant surveillance of the adequate application of
resources.
204
G.S. Feitosa
Conclusions
Along with the developed world diseases, including ischemic heart disease and
cerebrovascular diseases, developing and low-income countries face a challenging
reality of diseases that have already been eradicated in first world countries, namely,
rheumatic heart disease, and other diseases typical in those countries, including
Chagas disease in South America and beriberi, which is still recorded in some
African countries.
The burden of cardiovascular diseases not only results in reduced life expectancy
but also entails a significant reduction in the productive work force in those regions
because most people affected by those conditions are fit to work.
Thus, the challenge for those regions is enormous and relies on the civic spirit,
humanism, integrity, commitment, and political will of governments and society in
general toward promoting changes in education, leading to the improved use of
human resources and to disciplined, selfless, and honest actions to assist those at
risk of developing infectious and deficiency diseases, non-communicable diseases,
and especially cardiovascular diseases.
References
1. Losano R, et al. Global and regional mortality from 235 causes of death for 20 age groups in
1990 and 2010: a systematic analysis for the global burden of disease study 2010. Lancet.
2012;380:2095128.
2. Kim SA, Johnston SC. Global variation in the relative burden of stroke and ischemic heart
disease. Circulation. 2011;124:31423.
3. Yusuf S, Reddy S, Ounpuu S, Anand S. Global burden of cardiovascular diseases: part I: general considerations, the epidemiologic transition, risk factors, and impact of urbanization.
Circulation. 2001;104:274653.
4. unpuu S, Anand S, Yusuf S. Eur Heart J. 2000;21:8803.
5. Tyroler HA, Cassel J. Health consequences of culture change-II: the effect of urbanization on
coronary heart mortality in rural residents. J Chronic Dis. 1964;17:16777.
6. Omran AR. The epidemiologic transition. A theory of the epidemiology of population change.
Milbank Mem Fund Q. 1971;49(4):50938.
7. Kearney PM, Whelton M, Reynolds K, Muntner P, Whelton PK. Global burden of hypertension: analysis of world-wide data. Lancet. 2005;365:21723.
8. Reddy KS. Cardiovascular disease in non-western countries. N Engl J Med. 2004;350:
243840.
9. United Nations General Assembly. Resolution adopted by the General Assembly: United
Nations Millennium Declaration, A/RES/55/2. New York: United Nations; 18 September
2000.
10. Leeder S, Raymond S, Greenberg H. A race against time: the challenge of cardiovascular disease in developing countries. New York: Trustees of Columbia University in the City of
New York; 2004.
11. World Health Organization. Global status report on noncommunicable diseases 2010: description of the global burden of NCDs, their risk factors and determinants. Geneva: World Health
Organization; April 2011.
205
12. Institute of Medicine. Promoting cardiovascular health in the developing world: a critical
challenge to achieve global health. Washington: National Academies Press; 2010.
13. Feitosa GS. Cardiology in South America. J Am Coll Cardiol. 2007;50:6436.
14. Yusuf S, et al. INTERHEART Study Investigators. Effect of potentially modifiable risk factors
associated with myocardial infarction in 52 countries (the INTERHEART study): case-control
study. Lancet. 2004;364:93752.
15. ODonnell MJ, et al. INTERSTROKE investigators. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study.
Lancet. 2010;376:11223.
16. http://www.who.int/gho/publications/world_health_statistics/EN_WHS09_Full.pdf. Accessed
in Feb 2014.
17. https://www.cia.gov/library/publications/download/download-2009. Accessed in Feb 2014.
18. Polanczyk CA, Ribeiro JP. Coronary artery disease in Brazil: contemporary management and
future perspectives. Heart. 2009;95:8706.
19. Ramos Jr AN, Maul CD. The various meanings of Brazils certification as free of Chagas disease. Cad Sade Pblica. 2001;17:140312.

Diseases: What Works?
Dan Gaita and Laurence Sperling
Cardiovascular disease (CVD) is the leading cause of death worldwide, despite the
growing evidence for the efficacy of primary prevention. The EURIKA study of
2010 was the first to attempt a large scale comparative assessment of primary CVD
prevention among individuals with varying degrees of CVD risk across Europe,
after the EuroAspire I, II and III trials had previously delved into secondary prevention. On both accounts, the results highlighted a generally poor control of the risk
factors [1, 2]. CVD is strongly connected to unhealthy life style, tobacco smoking,
inappropriate diet, physical inactivity and psychosocial stress. The World Health
Organization (WHO) has stated that over three quarters of CVD mortality could be
prevented with adequate changes in lifestyle. Prevention of CVD should ideally
start in utero and last until the end of life. It is defined as a coordinated set of actions,
at both public and individual levels, aimed at eradicating, eliminating or minimizing
the impact of CVDs and their related disability [3]. Comprehensive lifestyle interventions, in addition to medical therapy when indicated, are effective strategies that
can significantly impact individual and global heart disease prevention. Despite this,
the fact that there are still uncontrolled risk factors, lifestyle counseling is often not
well implemented and that there is substantial variation between countries, indicates
there is room for improvement [1].
Every child born in the new millennium has the right to live until the age of at least 65 without
suffering from avoidable cardiovascular disease (St Valentines Declaration, 14 February 2000)
D. Gaita, MD, FESC (*)
University of Medicine and Pharmacy Victor Babes, Timisoara, Romania
e-mail: dgaita@cardiologie.ro
L. Sperling, MD, FACC, FACP, FAHA
Emory University School of Medicine, Atlanta, GA, USA
e-mail: lsperli@emory.edu
DOI 10.1007/978-3-319-22357-5_19
207
208
D. Gaita and L. Sperling
Lifestyle Changes
Tobacco Smoking
Smoking is one of the most preventable causes of mortality and morbidity in
developed countries. The adverse effects of smoking are numerous, including lung
cancer, cerebrovascular disease and chronic pulmonary obstructive disease. A report
in 2000 estimated that worldwide, nearly five million premature deaths occur every
year due to tobacco smoking [4]. Moreover, there is overwhelming evidence that
there is an increase in mortality and morbidity due to passive smoking (second-hand
smoking). Thus, we can no longer consider smoking a matter of personal preference, but a health threat to everybody exposed to cigarette smoke [5].
Epidemiological evidence has confirmed without doubt that active smoking is a
risk factor for cardiovascular disease and the leading cause of preventable death.
The risk for coronary heart disease increases twofold among smokers when compared with non-smokers, two-thirds of sudden cardiac deaths due to acute coronary
thrombosis occur in cigarette smokers and smoking is associated with an 50 %
increase in the risk of stroke [6].
Non-smokers live 8.66 (men) and 7.59 (women) years longer than smokers and
more years free of cardiovascular disease: 6.22 years for males and 4.93 for females.
But non-smokers spend more years with cardiovascular disease over the life course:
2.43 years for males and 2.66 years for females [6]. The Framingham Heart Study
analyzed the cardiovascular life course of their cohort by smoking status. Their
results showed that smoking both shortens the duration of life free of cardiovascular
disease and the duration of life with cardiovascular disease [7].
A study carried out among the cadets from the General Military Academy in
Zaragoza regarding tobacco smoking, physical exercise and lipid profile showed
that smoking 10 or more cigarettes per day decreases HDL cholesterol levels and
significantly increases triglycerides levels, total cholesterol/HDL cholesterol ratio,
leucocytes, haematocrit and haemoglobin values [8].
However, clinical data gathered in the Atherosclerosis Risk in Communities
(ARIC) studies have shown that both active and passive smoking were associated
with accelerated atherosclerosis progression as assessed by the increase in the
carotid artery intimalmedial thickness [6]. Evidence shows that passive smoking
increases the risk for coronary heart disease, but also that a non-smoker living with
a smoking spouse has an estimated 30 % higher risk of CVD, while exposure in the
work place is associated with a similar increase in risk [3]. In the US more than
50,000 deaths annually from ischemic heart disease are linked to second hand
smoking [6]. Relatively low doses of toxins inhaled by passive smokers are sufficient to elicit endothelial dysfunction, platelet activation, oxidative stress and
inflammatory reactions involved in the pathogenesis of atherosclerosis. But most
importantly, passive smoking seems to be capable of precipitating atherothrombosis
and may also have a negative impact on patients who suffer acute coronary syndromes [6].
Prevention and Control of Cardiovascular Diseases: What Works?
209
Legal bans and increased taxation appear to be the most effective measures for
decreasing overall smoking, in addition to passive tobacco exposure [5]. The first
known public smoking ban was issued in 1590 by Pope Urban VII who threatened
to excommunicate anyone who took tobacco in the porchway of or inside a church,
whether it be by chewing it, smoking it with a pipe, or sniffing it in powdered form
through the nose. Quitting smoking must be encouraged in all smokers, especially
since there is no age limit to the benefits of smoking cessation [3]. Moreover, smoking reduction cannot be generally recommended as an alternative to quitting smoking since it has not been shown to enhance the probability of future smoking
cessation [3]. On the other hand the benefits of quitting smoking are amply reported:
a systematic review and meta-analysis of 20 cohort studies of smoking cessation
after myocardial infarction have demonstrated a mortality reduction of 36 % compared with continued smokers [9].
Advising individuals regarding tobacco cessation can be approached through
behavioural interventions involving limited clinical interaction (a brief advice to
stop smoking delivered in <20 min by a healthcare worker during a single consultation), individual counseling (one or more face-to-face encounters of 15 min or more
between a smoker and a trained smoking cessation counsellor not involved in routine
clinical care), group counseling (two or more behavioural therapy meetings in which
at least two smokers were present) and telephone counseling (the provision of telephone calls to aid in smoking cessation). All four of these interventions have similar
efficacy, which importantly increases when used in combination with pharmacological interventions as part of a comprehensive smoking cessation strategy [10].
Smoking, either active or passive, has been unequivocally proved as a major
cardiovascular risk factor capable of decreasing life expectancy and thus must not
be approached leniently or considered a matter of personal preference, but actively
combated through any means available.
Nutrition
The role of nutrition in preventing CVDs has long been investigated and there is
strong evidence that shows that diet may influence atherogenesis directly or through
effects on traditional risk factors such as lipid levels, blood pressure or glucose
levels.
Saturated fatty acids (SFAs) are a dietary factor with a strong impact on LDL-C
levels (0.020.04 mmol/L or 0.81.6 mg/dL of LDL-C increase for every additional
1 % energy coming from saturated fat) [11]. Partially hydrogenated fatty acids of
industrial origin represent the major source of trans fatty acids in the diet.
Quantitatively, dietary trans fatty acids have a similar raising effect on LDL-C to
that of SFAs [12].
If 1 % of the dietary energy derived from SFAs is replaced by monounsaturated
fatty acids (MUFAs), LDL-C decreases by 0.041 mmol/L (1.6 mg/dL); if replaced
by n-6 polyunsaturated fatty acids (PUFAs) the decrease would be 0.051 mmol/L
210
(2.0 mg/dL); and if replaced by carbohydrate it would be 0.032 mmol/L (1.2 mg/
dL). PUFAs of the n-3 series have no direct hypocholesterolaemic effect; however,
frequent fish consumption is associated with a reduced CV risk that is mostly independent of any effect on plasma lipids. When consumed in pharmacological doses
(>2 g/day) the effect of n-3 PUFAs on LDL-C levels is either neutral or a slight
increase with a concomitant decrease of triglycerides (TG) [12]. Dietary carbohydrate presents no effect on LDL-C; therefore, carbohydrate-rich foods represent one
of the possible options to replace saturated fat in the diet. Dietary fibre (particularly
of the soluble type), which is present in legumes, fruit, vegetables, and wholemeal
cereals, has a direct hypocholesterolaemic effect [12].
Studies have shown that every 1.0 mmol/L reduction in LDL-C is associated
with a corresponding 22 % reduction in CVD mortality and morbidity [12].
Another effect of diet is that an alimentation that includes high monounsaturated
fats also improves insulin sensitivity compared to a high saturated fat diet. This goes
along with a decrease in TG levels, especially in the post-prandial period. On the
other hand alcohol intake can have a major negative impact on TG levels [12].
Daily ingestion of phytosterols found in vegetable oils (2 g/day), which is more
common in the Mediterranean countries compared to the rest of Europe, can lower
total cholesterol and LDL-C by 710 %, with little or no effect on HDL-C and TG
levels when consumed with the main meal [12].
Available evidence is notable for a TC- and LDL-C-lowering effect of watersoluble fibre from oat bran, -glucan, and psyllium at a daily dose of 515 g/day
soluble fibre [12].
There is strong evidence of an association between high sodium intake (>5 g/
day) and CVD. However, some diets may be high in sodium content but also high in
other cardioprotective factors (e.g. salted fish and vegetables), while other diets may
be high in sodium content and low in cardioprotective factors (e.g. fast foods, some
processed foods) [13]. Epidemiological studies have also reported that increased
potassium intake is associated with a reduced risk of CVD, most notably for stroke,
but also that the association between sodium intake and CVD may be mitigated by
increased potassium intake. The ONTARGET/TRANSCEND study observed that
the lowest rate of CV events occurred in the group with moderate sodium intake and
high potassium intake [13].
A healthy diet contributing to cardiovascular disease prevention should be varied
and rich in fruits and vegetables of different types to obtain a sufficient amount and
variety of antioxidants. At least two or three portions of fish per week are recommended to the general population for the prevention of CVD, together with regular
consumption of other food sources of n-3 PUFAs (nuts, soy, and flaxseed oil); for
secondary prevention of CVD, the recommended amount of n-3 unsaturated fat
should be 1 g/day, which is not easy to derive exclusively from natural food sources,
and use of n-3 nutriceuticals and/or pharmacological supplements may be considered. Salt intake should be limited to <5 g/day, not only by reducing the amount of
salt used for food seasoning but also by reducing the consumption of foods preserved by the addition of salt [12].
211
The European Heart Network proposes a series of targets for a healthy nutrition
based on the current dietary and physical activity patterns in Europe, including what
might be aimed for in the next 510 years. Thus, total fat should constitute less than
30 % of the dietary energy, while saturated fat should represent less than 10 % and
trans fats less than 1 %. On the other hand the intake of PUFAs and MUFAs should
increase to 611 % respectively 813 % of dietary energy. The consumption of fruit
and vegetables should include 400 g/day, while added sugars should not constitute
more than 10 % of energy and sugar sweetened drinks should be avoided as much
as possible. The total intake of carbohydrates should represent more than 55 % of
the dietary energy [14].
A recent study conducted in Germany discovered that consumption of 6 g of
chocolate per day was associated with a 39 % lower risk of the combined outcome
of myocardial infarction and stroke. Chocolate consumption appears to lower CVD
risk, in part through reducing blood pressure, improving endothelial and platelet
function, as well as reducing the markers of inflammation. The flavanols in cocoa
are thought to be responsible for these effects [15].
A healthy diet is comprised of nutrientdense foods rather than energydense
foods and plays a crucial role in decreasing cardiovascular risk.
Physical Activity
The first scientific evidence concerning the beneficial effects of physical exercise
was published by Morris in 1953, after he examined the incidence of coronary
artery disease (CAD) in London bus driver teams. He observed that the incidence of
CAD was less in the middle-age conductors than in the sedentary drivers of the
same age [16]. Decades later, after the publication of many more supportive studies,
physical activity became part of the guidelines for CVD prevention (class I recommendation), recommending at least 30 min of moderate intensity aerobic activity, 7
days per week with a minimum of 5 days per week [17]. Physical activity promotes
health through many metabolic and other pathways which affect cardiovascular risk
factors. It improves the plasma lipid profile, reduces body weight, lowers blood
pressure, reduces platelet aggregation, increases fibrinolytic activity, improves cardiac function, improves cardio-respiratory fitness and lowers the resting heart rate.
Furthermore, exercise training seems to improve endothelium-dependent vasodilatation and to increase urinary sodium excretion and insulin sensitivity. Long-term
exercise may be associated with a decrease of atherogenic activity of blood mononuclear cells and with lower C-reactive protein levels [18]. Recently, Katzmarzyk
et al. reported that reducing excessive sitting to <3 h/day and excessive television
viewing to <2 h/day would result in gains in life expectancy of 2.0 and 1.4 years,
respectively [19]. Moreover, Nocon et al. published a systematic review and meta
analysis of 33 cohort studies consisting of 883,372 participants, which revealed that
physical activity was associated with 35 % risk reduction for CVD mortality and
33 % risk reduction for all-cause mortality [20]. More recently, Wen et al. [21] and
212
Sattelmair et al. [22] have reported that that even 15 min of daily exercise
(about half of the minimal level of guideline recommendation) is associated with a
significant reduction of all-cause mortality or CAD risk. This finding may support
the guidelines assertion that some physical activity is better than none. However,
one of the existing problems is patient compliance. The 2009 HF-ACTION trial
documented that during the initial period of supervised training sessions only 84 %
of the patients were compliant decreasing even to 62 % at 1 year, and to 40 % at 3
years during individual home-based exercises [23]. Suboptimal adherence is unfortunately common, particularly in home based exercise programs, where supervision
is less intensive and compliance much lower. There are many reasons why patients
elude exercise; in older patients sickness and pain are the dominant reasons given
for non-adherence, whereas younger patients usually blame economic factors and
lack of time. Most patients entering secondary prevention programs are beyond the
age of 50 years; they have often not participated in regular physical exercise for
decades since leaving school, thus long-term adherence can be challenging [16].
In order to improve physical activity on a large scale several recommendations
need to be implemented: community wide campaigns, point-of-decision prompts to
encourage using stairs, school-based physical education, social support interventions in community settings, individual adaptations promoting health behaviour
change and creation of enhanced access to places for physical activity combined
with informal outreach activities [24].
A study conducted in Finland several years ago concerning physical activity
showed that moderate levels of leisure time physical activity and occupational physical activity are associated with a reduced CVD and all-cause mortality among both
men and women. This protective effect was observed regardless of body mass index,
age, education, smoking, total cholesterol, systolic blood pressure and other forms
of physical activity [25].
Daily exercise under any given form should become the gold standard for the
entire population, the health benefits derived from it outweighing all other reservations, and it should commence as early as possible and continue throughout life.
Preventive Drug Treatment

A cumulative body of scientific evidence soundly supports cholesterol as both a
permissive and causative risk factor in coronary artery disease. Statins, depending
on potency and dose, reduce LDL-C levels by 2050 %. They also decrease plasma
concentrations of other apolipoprotein B-containing particles believed to contribute
to plaque formation. Statins used in primary CVD prevention reduce risk within
12 months of initiating treatment and this benefit persists over many years [26]. The
Atorvastatin Comparative Cholesterol Efficacy and Safety Study showed that most
CHD patients (4785 %, depending on the statin) fail to achieve their LDL-C goal
of 100 mg/dL (2.6 mmol/L) at starting statin doses [27]. The ATP III update
recommends that all high-risk patients should start on a statin dose that provides
3040 % reduction in LDL-C [28].
213
The use of statins, beta-blockers, and angiotensin-converting enzyme-inhibitors

is widely recommended for patients with symptomatic CHD, regardless of cholesterol or blood pressure levels [29].
As for antithrombotic therapy in primary prevention a risk reduction from 0.57
to 0.51 % per year of serious vascular events with aspirin therapy was noted by the
Antithrombotic Trialists Collaboration [30]. However, there was a slight increase in
haemorrhagic stroke and a reduction of ischaemic stroke. The net effect on stroke
was not statistically significant. Major gastrointestinal and extracranial bleeds
increased by 0.03 % per year. Risk of vascular mortality was not changed by treatment with aspirin. Aspirin cannot be recommended in primary prevention due to its
increased risk of major bleeding [3].
On the other hand in long-term secondary prevention after myocardial infarction,
stroke, or peripheral arterial disease (PAD), aspirin reduces total mortality by 10 %,
but was also associated with a significant excess of major bleeds; nevertheless, the
benefits of aspirin exceeded the bleeding hazards [3].
In a comparison between the HOPE study and other secondary prevention trials,
it was recommended that the indication for ACE inhibitors should be extended to
secondary prevention for coronary heart disease, patients aged >55 years with
established cardiovascular disease: coronary heart disease with or without prior
myocardial infarction; prior stroke or transient ischemic attack; peripheral atherosclerotic disease; also to older patients with diabetes mellitus with at least one of the
following risk factors: hypertension, hypercholesterolaemia, smoking, microalbuminurea [31].
Epidemiological studies conducted thus far have suggested that a lower resting
heart rate (HR) is associated with decreased cardiovascular and all-cause mortality
[32]. HR has also been reported to be an independent predictor of adverse outcomes
after myocardial infarction and a determinant of infarct size in acute myocardial
infarction [32]. A relationship between resting HR reduction mortality has also been
observed in post-MI patients with beta-blockers. A meta-regression of randomized
clinical trials was carried out to assess this relationship which reported that post-M
the benefit of drugs modifying HR is strongly related to the magnitude of reduction
in resting HR. Each 10 beats per minute reduction in resting HR is estimated to
reduce the relative risk of cardiac death by about 30 %, the risk of sudden death by
39 %, leading to a reduction in the relative risk of all-cause mortality of 20 % [33].
Following a cardiovascular event, long-term adherence to prescribed medications is of similar importance to continued lifestyle improvement in order to reduce
the risk of a recurrent ischaemic event [3].
Metabolic Disorders Related to CVDs

The rising prevalence of worldwide diabetes mellitus (DM) has reached such point
where in 2011 almost 360 million people had DM, out of which 95 % type II DM,
numbers which are expected to increase in the following years. In addition, it is
estimated that another 300 million people had features indicating future risk of
214
developing T2DM, including fasting hyperglycaemia, impaired glucose tolerance

(IGT), gestational DM and euglycaemic insulin resistance (IR). The vast majority of
these T2DM new cases occur in the context of westernized lifestyles, high-fat diets
and decreased exercise, leading to increasing levels of obesity, IR, compensatory
hyperinsulinaemia and, ultimately, beta-cell failure and T2DM [34]. The association of vascular risk with IR, often referred to as the metabolic syndrome, has led to
the belief that cardiovascular risk appears early, prior to the development of T2DM,
whilst the strong relationship between hyperglycaemia and microvascular disease
(retinopathy, nephropathy, neuropathy) indicates that this risk is not apparent until
frank hyperglycaemia appears. These concepts highlight the progressive nature of
both T2DM and associated cardiovascular risk, which pose specific challenges at
different stages of the life of an individual with DM. More than half the mortality
and a vast amount of morbidity in people with DM is associated with CVDs [34].
Preventive Strategies
The North Karelia project on cardiovascular prevention was initiated out of the need
of the Finnish people to reduce the high mortality caused by cardiovascular diseases
and through the course of 40 years it decreased dramatically, by 80 %, through the
combined intervention of environmental changes, reorganization of health services,
training of professionals as well as use of the media [35, 36]. This comes to show
that cardiovascular prevention is a matter of team work, aiming at all the risk factors
and working together with specialist across multiple fields.
Simon Capewells analysed the US CHD deaths prevented or postponed by treatments and risk factor changes between 1980 and 2000 using the Impact mortality
model. The results showed that while obesity and diabetes mellitus increased more
than expected, improving risk factors such as smoking, diet, physical activity and
blood pressure as well as primary and secondary prevention treatments had a high
negative impact on CVD mortality [37].
During the 65th World Health Assembly in May 2012, all WHO Member States
endorsed a historic target to reduce premature deaths from non-communicable diseases (which include cardiovascular diseases) by 25 % by 2025. This should be
achieved by reducing the consumption of tobacco, salt, alcohol and transfats as
well as reducing the prevalence of physical inactivity, blood pressure and obesity
and ensuring the availability of essential medicines for persons living and coping
with NCDs.
To be efficient, CVD prevention has to start earlyso, for a young adult steps
into life, there are three numbers which he must keep in mind related to the reduced
risk: 100/120/0. That means maximum 100 mg/dL for glycaemia, 100 mg/dL for
LDL cholesterol and 120 mmHg for systolic blood pressure. Of course, 0 for the
consumption of tobacco. This is the essence of primary prevention and these four
elements are the cornerstones of CVD risk but the healthy DNA has inside the
solution and the promise of a healthy life for many years to come (Fig. 1).
215
Fig. 1 Prevention and

control of CVDswhat
works?
Acknowledgements We would like to give thanks to Svetlana Mosteoru, MD, for the outstanding
help in the process of writing this chapter.
References
1. Banegas JR, Lpez-Garca E, Dallongeville J, et al. Achievement of treatment goals for
primary prevention of cardiovascular disease in clinical practice across Europe: the EURIKA
study. Eur Heart J. 2011;32(17):214352.
2. Kotseva K, Wood D, De Backer G, et al. EUROASPIRE III: a survey on the lifestyle, risk
factors and use of cardioprotective drug therapies in coronary patients from 22 European countries. Eur J Cardiovasc Prev Rehabil. 2009;16(2):12137.
3. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M et al. European Guidelines
on cardiovascular disease prevention in clinical practice. Eur Heart J. 2012;33(13):1635701.
4. Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet.
2003;362:84752.
5. Barone-Adesi F, et al. Public smoking ban: Europe on the move. Eur Heart J. 2006;27(20):
23856.
6. Raupach T, Schfer K, Konstantinides S, Andreas S. Secondhand smoke as an acute threat for
the cardiovascular system: a change in paradigm. Eur Heart J. 2006;27(4):38692.
7. Al Mamun A, Peeters A, Barendregt J, et al., NEDCOM; The Netherlands Epidermiology and
Demography Compression of Morbidity Research Group. Smoking decreases the duration of
life lived with and without cardiovascular disease: a life course analysis of the Framingham
Heart Study. Eur Heart J. 2004;25(5):40915.
216
8. Casanovas JA, la Petra A, Puzo J, et al. Tobacco, physical exercise and lipid profile. Eur Heart
J. 1992;13(4):4405.
9. Critchley J, Capewell S. Smoking cessation for the secondary prevention of coronary heart
disease. Cochrane Database Syst Rev. 2004;1:CD003041.
10. Mottillo S, Filion KB, Blisle P, et al. Behavioural interventions for smoking cessation:
a meta-analysis of randomized controlled trials. Eur Heart J. 2009;30(6):71830.
11. Mensink RP, Zock PL, Kester ADM, et al. Effects of dietary fatty acids and carbohydrates on
the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a metaanalysis of 60 controlled trials. Am J Clin Nutr. 2003;77:114655.
12. Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen MR, Wiklund O, et al. ESC/EAS
Guidelines for the management of dyslipidaemias. Eur Heart J. 2011;32(14):1769818.
13. ODonnell MJ, Mente A, Smythand A, et al. Salt intake and cardiovascular disease: why are
the data inconsistent? Eur Heart J. 2013;34(14):103440.
14. Zoghbi WA, Duncan T, Antman E, Barbosa M, Champagne B, Chen D, et al. Sustainable
Development goals and the future of cardiovascular health: a statement from the Global
Cardiovascular Disease Taskforce. Glob Heart. 2014;9(3):2734. doi:10.1016/j.gheart.2014.
09.003. Epub 2014 Sep 22.
15. Buijsse B, Weikert C, Drogan D, et al. Chocolate consumption in relation to blood pressure
and risk of cardiovascular disease in German adults. Eur Heart J. 2010;31(13):161623.
16. Schuler G, Adams V, Goto Y. Role of exercise in the prevention of cardiovascular disease:
results, mechanisms, and new perspectives. Eur Heart J. 2013;34(24):17909.
17. Haskell WL, Lee IM, Pate RR, et al. Physical activity and public health: updated recommendation for adults from the American College of Sports Medicine and the American Heart
18. Barengo NC, Hu G, Lakka TA, et al. Low physical activity as a predictor for total and cardiovascular disease mortality in middle-aged men and women in Finland. Eur Heart
J. 2004;25(24):220411.
19. Katzmarzyk PT, Lee IM. Sedentary behaviour and life expectancy in the USA: a cause-deleted
life table analysis. BMJ Open. 2012;2:e000828.
20. Nocon M, Hiemann T, Mller-Riemenschneider F, et al. Association of physical activity with
all-cause and cardiovascular mortality: a systematic review and meta-analysis. Eur J Cardiovasc
Prev Rehabil. 2008;15:23946.
21. Wen CP, Wai JP, Tsai MK, et al. Minimum amount of physical activity for reduced mortality
and extended life expectancy: a prospective cohort study. Lancet. 2011;378:124453.
22. Sattelmair J, Pertman J, Ding EL, et al. Dose response between physical activity and risk of
coronary heart disease/clinical perspective. Circulation. 2011;124:78995.
23. OConnor CM, Whellan DJ, Lee KL, et al. Efficacy and safety of exercise training in patients
with chronic heart failure: Hf-action randomized controlled trial. JAMA. 2009;301:143950.
24. Increasing physical activity. A report on recommendations of the Task Force on Community
Preventive Services. MMWR Recomm Rep. 2001;50(RR-18):114.
25. Laufs U, Weintraub WS, Packard CJ. Beyond statins: what to expect from add-on lipid regulating therapy? Eur Heart J. 2013;34(34):26605.
26. Andrews TC, Ballantyne CM, Hsia JA, et al. Achieving and maintaining National Cholesterol
Education Program low-density lipoprotein cholesterol goals with five statins. Am J Med.
2001;111:18591.
27. Grundy SM, Cleeman JI, Merz CN, et al., National Heart, Lung, and Blood Institute; American
College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110:22739.
28. Ballantyne C, Arroll B, Shepherd J. Lipids and CVD management: towards a global consensus. Eur Heart J. 2005;26(21):222431.
29. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary prevention of
vascular disease: collaborative meta-analysis of individual participant data from randomised
trials. Lancet. 2009;373:184960.
217
30. Otterstad JE, Sleight P. The HOPE study: comparison with other trials of secondary
prevention. Eur Heart J. 2001;22(15):130710.
31. Hjalmarson A. Significance of reduction in heart rate in cardiovascular disease. Clin Cardiol.
1998;21:II37.
32. Stangeland L, Grong K, Vik-Mo H, et al. Is reduced cardiac performance the only mechanism
for myocardial infarct size reduction during beta adrenergic blockade? Cardiovasc Res.
1986;20:32230.
33. Cucherat M. Quantitative relationship between resting heart rate reduction and magnitude of
clinical benefits in post-myocardial infarction: a meta-regression of randomized clinical trials.
Eur Heart J. 2007;28(24):30129.
34. Rydn L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, et al. ESC Guidelines on
diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the
EASD. Eur Heart J. 2013;34(39):303587.
35. Wagner EH. The North Karelia Project: what it tells us about the prevention of cardiovascular
disease. Am J Public Health. 1982;72(1):513.
36. Puska P. The North Karelia Project: 30 years successfully preventing chronic diseases.
Diabetes Voice 2008;53:269.
37. Capewell S, Ford ES, Croft JB, et al. Cardiovascular risk factor trends and potential for reducing coronary heart disease mortality in the United States of America. Bull World Health Organ.
2010;88:12030.

Diseases: Integrated and Complimentary
Strategies
Roberto Ferrari, Lina Marcantoni, and Gabriele Guardigli
Introduction
Over the past century, life expectancy has increased by approximately 10 years.
Although this is a remarkable achievement, cardiovascular diseases (CVDs)
remain the biggest cause of deaths worldwide. More than 17 million people died
from CVDs in 2008 alone! More than 3 million of these deaths occurred before the
age of 60 and could have been prevented [1]. The situation is further alarming
because over the last decade mortality rates have declined in many high-income
countries and astronomically increased in low-middle income countries, leading to
growing inequalities in the occurrence and outcome of CVDs between countries
and population [1].
In reality, when successful, cardiology has converted an acute disease into a
chronic one and even this result, although of paramount importance, is a mixed
blessing. There is a distinct downside to this success, mainly the dramatic inversion
of the population pyramid that is projected to take place in the not too distant future,
at least in the western part of the world. The consequences of this evolution, together
with the drop in the birth rate of western societies will have major effects in terms
of demographic changes.
The aging of the post-baby boom population means that there will not be enough
young people to ensure the sustainability of the funding of healthcare and pension
benefits for the elderly. This will have important socioeconomic consequences,
which we are already starting to have to come to grips with in the western world.
Furthermore, lifestyle, too, is undergoing sweeping changes. Major social
milestones are being crossed increasingly later in life, such as getting married,
starting a family and assuming greater work responsibilities. It is no longer posR. Ferrari (*) L. Marcantoni G. Guardigli
Department of Cardiology and LTTA Centre, University Hospital of Ferrara and Maria
Cecilia Hospital, GVM Care & Research, E.S. Health Science Foundation, Cotignola, Italy
e-mail: roberto.ferrai@unife.it
DOI 10.1007/978-3-319-22357-5_20
219
220
R. Ferrari et al.
sible to experience somebodys death at home and when this happens we are
unprepared to cope with it.
Nevertheless, lets not be too pessimistic. We should praise where praise is due.
Much to our pride, cardiologists take most of the credit for the extended life
expectancy, as we contributed to at least 7 of the 8 years in the observed increase
in life expectancy, while much less success has resulted from progress in other
specialities [2].
Prevention vs Treatment
The reduction in cardiovascular (CV) mortality is mainly due to the reduction of
atherosclerosis progression and to efficacious treatment of its clinical manifestation,
i.e. acute myocardial infarction (MI) and heart failure (HF). Unfortunately, the ultimate cause of atherosclerosis is still a mystery. Therefore, all the attention of the
cardiological community is devoted to the treatment of its sequel or to a reduction
of the modifiable risk factors such as smoking, sedentariness, nutritional imbalance,
blood pressure elevation, impaired glucose tolerance and diabetes, dyslipidaemia,
overweight and abdominal adiposity and markers of chronic inflammation.
Treatments play an important role in any strategy aimed to reduce the burden of
CVDs. The potential contribution of pharmacological treatments such as aspirin,
-blockers, statins, and angiotensin converting enzyme inhibitors is enormous,
particularly if delivered at low cost to avoid the progressive bankruptcy of national
health services. Interestingly, the more recent drugs, such as renin inhibitors and
angiotensin receptor blockers do not provide any further benefit, although they are
highly promoted to cardiologists. Equally, the most costly therapeutic interventions, although highly advocated by cardiologists contribute relatively little to the
reduction in CVDs. This is probably because these interventions in any case are
applied too late or to too few of the people at risk and are too expensive. In the US,
revascularization procedures explain only 5 % of the observed fall in CVD mortality. Even doubling the number of revascularisation procedures will make little difference. It is estimated that we can attribute between 45 and 75 % of the CVD
mortality decline to prevention and changing risk factors and the remaining
5525 % to treatment in general [3]. This is encouraging as changes in lifestyle
and diet are doubly more effective than other high-profile and expensive strategies.
It follows that the future lies in reducing risk factors in primary and secondary
prevention settings and selected intervention for high-risk patients. The various
models suggest that to decrease the global occurrence of a disease, even small
changes in population risk factors are crucial, particularly in primary prevention.
Therefore, we need to prioritise our strategy to change the disease burden of the
entire population and not only of the people at high risk or of the patients already
affected by the disease.
Prevention and Control of Cardiovascular Diseases: Integrated and Complimentary
221
Nobody Is Considered Safe

Although CV events are less likely to occur in people with low levels of risk, no
levels of risk and nobody can be considered safe. Without population-wide public
health prevention efforts, CV events will continue to occur in people with low and
moderate levels of risk, and who are the majority in any population. Furthermore,
public health approaches can effectively slow down the development of atherosclerosis (and also reduce the incidence of some cancers and chronic respiratory diseases) in young people, thereby reducing the likelihood of future epidemics of CV
events such as were seen in the period 19601990 in most high-income countries.
Population-wide strategies would also support lifestyle modification in those at high
risk. The extent to which one strategy is emphasised over the other depends on
achievable effectiveness, cost effectiveness and resource considerations. These concepts contrast with the model based on hospital care focused on the treatment of
disease, often centred around high technology hospitals that provide extensive and
efficacious treatment but for only a minority of the population. Hospitals consume
large amounts of the over-limited resources, leaving little if not nothing for large
populations of people at risk underdiagnosed and undertreated at a primary car
health level. This is worrying as premature death due to non-communicable diseases, including CVDs can be averted by primary prevention. It is worthwhile to
remember that, through the years, all of the important epidemics have been resolved
not only by drug treatments but mainly by lifestyle modifications (Fig. 1).
Fig. 1
222
R. Ferrari et al.
Global Action Is Needed

It is obvious that all of this is too much and too important to be left in the hands of
the cardiologists or of the general practitioner alone. First, because they simply do
not have the time, and, second, because they do not have the know-how to deal with
such a complex issue on their own.
It is all very well and easy to tell patients that they have to change their lifestyle
and draw up a list of dos and donts, of pleasures forbidden and burdens imposed.
Taken to the extreme, the issue becomes a philosophical one, in the sense that if we
are really in earnest about preventing CVDs, the majority (if not all) aspects of
western civilisation will have to be altered dramatically.
Changing the lifestyle of a population for the better is no easy taskironically,
getting it to deteriorate is easily done: the negative influence of subliminal messages
from consumer society (TV, movies, internet) is pervasive to the extent that even in
Italy, children now prefer burgers and chips to the traditional plate of spaghetti with
tomato and basil, which, of course, is the healthier option! Changing the lifestyle of
a population means challenging important vested economic interestssuch as the
tobacco industry, to name but one. The introduction of legislation banning smoking
in public places in Italy has been effective in reducing tobacco consumption,and
good results in terms of reduction of CVD mortality are already noticeable at a
national level [4].
Addressing CVDs requires concrete and substation action in three areas: (1) surveillance and monitoring; (2) prevention and reduction of risk factors; (3) improved
management and healthcare through early detection and timely treatment. Not only,
but the goal of halting premature death from CVDs will also require global solidarity and broad alliances beyond national, cultural and ethnic boundaries. Heads of
State and Governments will have to come together to address prevention and cultural campaigns worldwide. The 2011 high-level meeting of the United Nations
General Assembly on the prevention and control of NCDs held in September 2011
[5] is just the beginning of communal concrete action.
In the meantime, however, much lower scale projects should be encouraged and
we are pleased to report here an initiative undertaken by the Chair of Cardiology of
the University of Ferrara, named Ferrara, the City of Prevention [6, 7].
Ferrara, the City of Prevention

There were several reasons for making Ferrara (a small town of approximately
134,000 inhabitants, located in the county of Emilia Romagna in Italy) the city of
prevention. First, Ferrara is known as the city of bicycles. Being situated on a plain,
the citizens of Ferrara traditionally use their bicycles to move around town. Second,
Ferrara is surrounded by a medieval wall, approximately 9 km in circumference. On
top of the wall there is an alley that makes it the ideal place to go for a walk, a run,
223
to go by bike, or to exercise any other type of recreational activity. The city wall, or
the so-called mura, has become a sort of meeting place for the citizens of Ferrara,
where they go not only to exercise but also to meet their friends. Therefore, in
Ferrara, at least, a small degree of exercise is a must!
Furthermore, from an economic point of view, Ferrara is completely dominated
by the agriculture industry and Ferrara is famous all over Italy for its vegetable
(mainly asparagus) and fruit production (pears in particular). Therefore, it is not
difficult to obtain the recommended five portions of fruits and vegetables a day in
Ferrara. Being situated close to the flood plain of the river Po, the biggest river in
Italy, Ferrara is also famous for its fish industry and particularly for the so-called
bluefish which is very tasty, inexpensive and extremely rich in omega 3 which has
been proven, once again by two Italian studiesthe GISSI trialsto be effective in
preventing myocardial infarction and also in reducing the progression of heart failure [8, 9]. Thanks to all of these characteristics Ferrara has the basis for being a city
of prevention.
Several initiatives have been put into action to this end, some are still ongoing,
and others are in the pipeline. This is indeed a joint effort of the entire city, of its
municipality, university, Mayor, hospital local province, supermarkets, banks and
private industries, etc.
What have we achieved so far?
First of all, we launched an initiative called Ferrara-Arte e Prevenzione. Ferrara
is also known for its art exhibitions shown in marvelous historic palaces, such as the
Palazzo dei Diamanti built in 1503 and the Castello Estense built in 1385. The castle
has also become the official national site of the well-known Hermitage museum in
St Petersburg. The province kindly provided the Chair of Cardiology of the
University of Ferrara a room in the castle where doctors performed free-of-charge
calculations of the risk chart of the 4208 visitors in a period of 2 months. The project
was carried out in conjunction with the Istituto Superiore di Sanita, the Italian
Health Ministry and the region Emilia Romagna.
Two types of risk charts were used. One, which is the official chart from the Italian
Ministry of Health and of the ISS, the same one used for the project Cuore [10], and
one modified by the University of Ferrara which, in addition to the usual risk factors,
also takes into consideration the heart rate, the abdominal circumference, the body
weight and provides ideas of the degree of education and anamnestical data.
The data obtained, reported in Figs. 2, 3, 4 and 5 are astonishing. In a rather
highly educated population interested in visiting a rather sophisticated art exhibition
and motivated to have the risk chart determined 17 % were smokers, 25 % sedentary, 45 % overweight, 10 % hypertensive and 61 % had high cholesterol levels.
Heart rate was above 70 b/m in 56 % of them.
The same project and the same risk charts will be used in different types of populationfor example, in housewives doing the grocery shopping at the supermarket,
metal-mechanic industry workers and the employees of the hospital of Ferrara. The
idea is to compare the level of risk of all different population classes and to see
whether education, socioeconomic background, awareness and knowledge affect
the outcome. It will be interesting to see the data of the hospital employees!
224
R. Ferrari et al.
Fig. 2
Fig. 3
Fig. 4
Another initiative is the establishment of the Centre of Prevention where all the
residents in Ferrara as well as the patients discharged from the cardiology department of the University Hospital Ferrara can go, have their risk chart calculated and
find dedicated personnel able to provide proper recommendations and tools in terms
of lifestyle and prevention. The centre is equipped with a kitchen to run professional
225
Fig. 5
courses on how to shop for food and ways to prepare healthy recipes and to give a
proper introduction to exercise (Fig. 4).
In this way, we hope to encourage the population of Ferrara to decrease the consumption of saturated fats and equally importantly to increase the consumption of
polyunsaturated fats, fish, fruit and vegetables and, of course, to reduce smoking.
Counselling for this is also provided at the centre. In addition, proper and guided
introductions to daily exercise are provided.
One of the major problems encountered in the establishment of the centre was to
find ad hoc personnel to run it. Unfortunately, he cardiologists working at the Chair
of Cardiology as well as other doctors in general medicine did not show a real interest
towards to the centre and would not have had the necessary time to dedicate to this
project. Therefore, the University of Ferrara has launched a Master aimed at education specific non-medical personnel to obtain a degree in Prevention Professional.
The master has a duration of 6 months and its official title is: Master in Health
Prevention: focus on cardiovascular risk and will be available on-line from 2014 [11].
Acknowledgments This work was supported by a grant from Fondazione Anna Maria Sechi per
il Cuore (FASC), Italy. The funders had no role in the study design, data collection and analysis,
decision to publish or the preparation of the manuscript.
References
1. Mendis S, Puska P, Norrving B, editors. Global atlas on cardiovascular disease prevention and
control. Geneva: World Health Organization; 2011.
2. Cutler DM, McClellan M. Is technological change in medicine worth it? Health Aff (Millwood).
2001;20(5):1129.
3. Ferrari R. Preface. Eur J Cardiovasc Prev Rehabil. 2009;16 Suppl 1:S1.
4. Capewell S, OFlaherty M. What explains declining coronary mortality? Lessons and warnings. Heart. 2008;94:11058.
5. United Nationals General Assembly on the prevention and control of NCDs. September 2011.
http://www.who.int/nmh/events/un_ncd_summit2011. Accessed 13 Nov 2013.
6. Ferrra R, Guardigli G, Tavazzi L. A modern fairytale. Eur J Cardiovasc Prev Rehabil. 2009;16
Suppl 1:S657.
226
R. Ferrari et al.
7. Ferrari R. Ferrara, city of prevention, a model of the twenty-first century? CardioPulse Articles.
Eur Heart J. 2009;30:241526.
8. GISSI-Prevenzione Investigators (Gruppo Italiano per lo Studio della Sopravvivenza
nellInfarto Miocardico). Dietary supplementation with n-3 polyunsaturated fatty acids and
vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Lancet.
1999;354:44755.
9. GISSI-HF Investigators: Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini
R, et al. A randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:122330.
10. Giampaoli S, Palmieri L, Panico S, Vanuzzo D, Ferrario M, Chiodini P, et al. Favorable cardiovascular risk profile (low risk) and 10-year stroke incidence in women and men: findings on
twelve Italian population samples. Am J Epidemiol. 2006;163:893902.
11. Master sul Prevenzione della Salute: focus sul rischio cardiovascolare (www.unife.it).
Accessed 7 Mar 2014.
Posttraumatic Stress Disorder

and Cardiovascular Disease
Donald Edmondson, David Hiti, and Ian Kronish
Posttraumatic stress disorder (PTSD) is an anxiety disorder that follows exposure

to a traumatic event, such as combat, natural disaster, or sexual assault, and is characterized by symptoms such as re-experiencing (e.g., intrusive thoughts, nightmares); cognitive or behavioral avoidance of reminders of the event; negative
alterations in cognitions and mood; and physiological hyperarousal. It is associated
with abnormal amygdala, prefrontal cortex, and hippocampal function [1] as well
as abnormal neuroendocrinologic characteristics [2]. The lifetime prevalence of
PTSD in the U.S. is 78 % [3, 4]. Although the global prevalence of PTSD is difficult to estimate, a recent World Health Organization study estimated a lifetime
prevalence of 3 % based on community samples drawn from 14 countries (largely
free of conflict zones) comprising more than 20,000 respondents [5]. Prevalence
estimates are as high as 30 % in populations exposed to natural and manmade
disasters [6] and combat [7].
PTSD is a devastating mental disorder in its own right, but recent evidence suggests that it is also an independent risk factor for cardiovascular disease (CVD) [8].
The first section of this chapter will outline our current understanding of the association of PTSD with incident CVD, including potential mechanisms of that association. Further, acute cardiovascular events have been shown to elicit PTSD in
some patients, which may increase their secondary risk for cardiovascular event
recurrence. The second section of this chapter will discuss the prevalence and consequences of PTSD due to cardiovascular events.
D. Edmondson, PhD, MPH (*) D. Hiti, MA I. Kronish, MD, MPH

Department of Medicine, Center for Behavioral Cardiovascular Health,
Columbia University Medical Center, New York, NY, USA
e-mail: dee2109@cumc.columbia.edu; dth2110@columbia.edu; ik2293@cumc.clumbia.edu
DOI 10.1007/978-3-319-22357-5_21
227
228
D. Edmondson et al.
PTSD and Risk for Incident CVD/Mortality

PTSD is associated with risk for cardiovascular disease, acute coronary syndromes,
and cardiac-specific mortality. To date, 5 prospective cohort studies (total
N = 401,712) have estimated the association of PTSD with incident CVD and/or
mortality, with adjustment for numerous demographic, clinical, and psychosocial
factors. A meta-analysis of those studies estimated a 55 % increased risk for cardiac
events and mortality associated with a positive PTSD screen on validated self-report
measures of PTSD symptoms over follow-up periods of 130 years [8].
Mechanisms Linking PTSD to CVD

The association of PTSD with incident CVD appears to be independent of traditional CVD risk factors such as hypertension, diabetes, and dyslipidemia [9].
Although no studies have comprehensively evaluated the mechanisms connecting
PTSD and CVD, a number of potential biological, behavioral, and psychosocial
mechanisms have been proposed.
Biological Risk Factors

Biological mechanisms of increased CVD risk in PTSD include dysregulation of
the hypothalamicpituitaryadrenal (HPA) axis, autonomic nervous system
dysfunction, and increased inflammation [10]. In general, studies indicate that the
disruption of the HPA axis in patients with PTSD leads to lower basal cortisol secretion, but exaggerated secretion in response to psychological stressors. HPA hyperreactivity, in turn, has been implicated in the development of heart failure and
cardiac ischemia and is prospectively associated with increased CVD mortality.
Autonomic balance (i.e., the balance of sympathetic and parasympathetic activity)
may also be altered, as evidenced by an exaggerated catecholamine response to
stressful circumstances [11] and higher concentrations of circulating catecholamines [12]. Such alterations may be associated with CVD risk via increases in
blood pressure and coagulation, as elevated catecholamines have direct effects on
the heart, blood vessels, and platelets [13]. In addition, patients with PTSD demonstrate decreased heart rate variability, baroreflex dysfunction, and electrocardiogram abnormalities [12], all of which are associated with CVD risk.
Increased systemic inflammation is another potential mechanism of PTSDs
association with CVD risk. Chronic inflammation is recognized to be a major factor in the pathogenesis and progression of cardiovascular disease [14], and von
Knel and colleagues have demonstrated a doseresponse relationship between
severity of PTSD symptoms and inflammation [15]. Although some studies of
PTSD and CVD
229
PTSD and inflammation have reported conflicting results, a recent systematic

review suggested that, on the balance, participants with PTSD have higher levels of
inflammation [16].
Behavioral Risk Factors

PTSD is also associated with a number of CVD risk behaviors. Patients with PTSD
have higher rates of tobacco use and alcohol and substance dependence [4, 17] and
show increased risk of obesity in large epidemiologic studies [18]. Further, individuals with PTSD, including those with existing CVD, report lower rates of physical activity [19]. Sedentary behavior may be particularly important as it is strongly
connected to other cardiac risk factors such as blood pressure, insulin resistance,
and cholesterol levels [20]. PTSD is also associated with nonadherence to prescribed medications [21], which in turn is associated with risk for CVD events [22].
Finally, patients with PTSD experience numerous sleep disturbances, including
nightmares, difficulty falling/staying asleep, and sleep disordered breathing [23],
and such sleep disturbances are now recognized as risk factors for the development
and progression of CVD [24].
Psychosocial Risk Factors

Comorbid psychological disorders and impairments in social functioning may also
increase CVD risk in patients with PTSD. Though the association between PTSD
and CVD has remained significant after adjustment for depression in several studies, PTSD and depression are highly comorbid, and depression remains a strong risk
factor for CVD and could further increase risk of cardiac events when present [25].
PTSD is also strongly related to increased anger and hostility [26], which are, in
turn, associated with increased risk of cardiac events and greater angiographic
severity of CVD [27].
Interventions to Reduce CVD Risk Associated with PTSD

PTSD is an important, and potentially modifiable, CVD risk factor [28]. However,
PTSD is severely under-recognized in medical care settings. Indeed, a nationally
representative survey of US adults found that only 7 % of patients with PTSD
received treatment within the first year after symptom onset, and the median time
between initial symptoms and treatment was 12.1 years [29]. Even if it were recognized, no study has yet tested whether successful PTSD treatment can reduce risk
230
D. Edmondson et al.
for incident CVD or whether other types of interventions reduce CVD risk in
patients with PTSD. Such research is sorely needed.
Fortunately, multiple trials have demonstrated that the potential mechanisms of
PTSDs association with CVD can be improved with behavioral and pharmacologic
therapies [16]. For example, inflammation can be decreased with exercise interventions [30] and/or statin therapy, leading to improved cardiac risk [31]. Specifically
in PTSD patients, integration of tobacco cessation counseling in mental health care
significantly improves smoking rates [32], and both prazosin and cognitive behavioral therapy have demonstrated efficacy for sleep disturbances [33]. As research
continues to identify which of these mechanisms are most important for CVD risk
reduction, future trials of pharmacologic and behavioral treatments for PTSD should
incorporate those mechanisms and CVD events as secondary outcomes.
PTSD due to Cardiovascular Events

PTSD due to traumatic events increases subsequent risk for cardiovascular events,
but cardiovascular events themselves can be traumatic, and some CVD patients
develop PTSD after such events. Indeed, although PTSD is widely considered a
disorder of combat veterans and sexual assault survivors, acute cardiovascular disease events such as acute coronary syndromes (ACS; myocardial infarction or
unstable angina) and stroke have been shown to elicit PTSD. However, the clinical
features and behavioral correlates of PTSD due to acute medical events may differ
from those associated with PTSD due to non-medical traumas. An Enduring Somatic
Threat model of PTSD due to acute life-threatening medical events has recently
been proposed [34] to address underappreciated differences between PTSD due to
past, discrete/external traumatic events (such as combat) and PTSD due to acute
manifestations of chronic disease that are enduring/somatic in nature (such as ACS
and stroke). The differences include the external versus internal/somatic source of
the threat, the past versus present/future temporal focus of threatening cognitions,
the different types and consequences of avoidance behavior, and the different character and consequences of hyperarousal. Currently, however, PTSD due to cardiovascular events is assessed as if it were no different than PTSD due to other types of
traumatic events.
Prevalence of PTSD due to Acute Coronary Syndromes

In a systematic review and meta-analysis of 24 studies (N = 2383), we estimated that
the prevalence of ACS-induced PTSD was 12 % [35]; however, individual study
estimates varied widely. That variability may be due to a number of sampling and
research design decisions or may reflect some true demographic, clinical, or geographic variability in the susceptibility of ACS patients to PTSD.
PTSD and CVD
231
Patient-Level Factors Associated with PTSD Risk

Patient-level risk factors for ACS-induced PTSD include intense fear [36], perceived
life threat, lack of control [37], helplessness and chest pain during the ACS event
[38], dissociation during the event, acute stress disorder, depression symptoms during hospitalization [39], and history of psychiatric disorder before ACS [39], alexithymia [40], or neuroticism [41]. Demographic factors associated with ACS-induced
PTSD in some studies include younger age [42], female sex [39], ethnic minority
status, and low socioeconomic status [42]. While these scattered risk factor studies
have been useful, a unified risk stratification strategy is warranted for predicting
which patients are most likely to develop ACS-induced PTSD. It is important to note
that objective clinical severity of the ACS event is not associated with ACS-induced
PTSD, either at the study level or at the patient-level, a fact that tends to reinforce the
common belief that personality factors, previous psychiatric history, and other individual patient traits largely determine which patients will develop ACS-induced
PTSD. However, recent research suggests that external factors during ACS treatment
can significantly influence the development of ACS-induced PTSD symptoms.
Treatment Factors and Risk for PTSD

The experience of an ACS is probably universally frightening to some degree, but in
order for an individual to develop PTSD, an event generally must induce intense
fear, helplessness, and/or horror. Since a major component of the experience of an
ACS occurs in emergency departments (ED) and catheterization labs, we recently
tested the hypothesis that more stressful medical environments increase the likelihood of developing PTSD after an ACS. We recorded the initial triage time of each
of 135 ACS patients, estimated the degree of ED crowding they experienced, and
then assessed their ACS-induced PTSD symptoms 1 month later. We divided the ED
crowding variable into tertiles, and found that for every increase in ED crowding,
participants experienced a 2.5 point increase in PTSD score, after adjustment for a
number of demographic, clinical, and psychiatric covariates [43]. It may be the case
that pre-existing person-level factors may exacerbate individual patients responses
to ED crowding, but our results suggest an independent effect of ED crowding on
the development of ACS-induced PTSD.
Course of PTSD Over Time

For some of the same reasons that we are unsure of the true prevalence of ACSinduced PTSD, the true course of PTSD symptoms is unknown, and is likely
influenced by a number of demographic, clinical, and psychosocial factors. Wikman
232
D. Edmondson et al.
et al. [42] found that 12 % of 213 participants screened positive for ACS-induced
PTSD at 12 months post-ACS, and that 12.8 % of 179 of those participants screened
positive for ACS-induced PTSD at 36 months. However, while PTSD symptoms
were relatively stable, there were participants who screened positive at 12 months
who did not at 36 months, and vice versa, as 63 % of the variance in 36 month PTSD
symptoms were explained by 12 month PTSD symptoms. Ginzburg and Ein-Dor
[44] published the longest follow-up of ACS patients with measurement of ACSinduced PTSD, with multiple measurements of PTSD symptoms over multiple
years. They found that participants generally were able to be categorized into a large
resilient group who experience some psychological distress in the first 7 months
after the ACS but recover, and a much smaller group of about 6 % of participants
who still had significant ACS-induced PTSD symptoms 8 years later.
Association of ACS-Induced PTSD to ACS Recurrence/

Mortality
In the same article in which we estimated the prevalence of ACS-induced PTSD
from 24 studies, we used meta-analysis to estimate the effect size of the association
between ACS-induced PTSD and risk of adverse outcome based on estimates provided by the 3 studies that prospectively assessed this association. By combining the
three estimates, we found that a positive screen for ACS-induced PTSD is associated with an approximate doubling of the risk of adverse outcomes, even after
adjusting for depression and other important covariates (adjusted hazard ratio HR,
2.0; 95 % CI, 1.72.4) [35]. It is important to note that each of the included studies
used a cutoff on an ACS-induced PTSD symptom questionnaire rather than a clinical interview to classify PTSD status, suggesting the risk associated with PTSD
symptoms may be present at sub-diagnostic levels of PTSD.
Mechanisms
Many of the mechanisms that have been proposed to explain the association between
ACS-induced PTSD and adverse outcomes are the same as those proposed to
explain the association of PTSD to incident CVD. However, whereas the average
length of follow-up for studies that have shown an association of PTSD to incident
CVD is almost 10 years, ACS-induced PTSD seems to increase risk for recurrent
ACS and mortality within a few months or years. As such, either the mechanisms
that are thought to exert long-term cumulative effects on the cardiovascular system
work more quickly in post-ACS patients, or the more short-acting mechanisms are
the most likely candidates for mediators of the ACS-induced PTSD to ACS recurrence/mortality association.
PTSD and CVD
233
Physiological Risk Factors More Pronounced

in ACS-Induced PTSD
We know that both ACS and PTSD are associated with sympathetic activation and
elevated proinflammatory cytokines, including C-reactive protein, tumor necrosis
factor, and interleukin 1 [15]. It is likely that the additive effects of the inflammation
found in patients with PTSD may adversely affect recurrence risk [45]. Recently,
Ahmadi and colleagues [46] showed that PTSD is associated with mortality more
strongly in patients with high levels of coronary artery calcium, suggesting that
PTSD may exert greater influence on secondary risk than primary risk.
Behavioral Risk Factors

Among the behavioral risk factors mentioned above, the two most likely candidates
for mechanisms of the ACS-induced PTSD- secondary risk association are medication nonadherence and sleep disruption. Medication nonadherence may exacerbate
many of the physiological mechanisms that have been proposed. Sleep difficulties
are a common feature of PTSD [23], and are also a common complaint after
ACS. While sleep difficulties have been shown to be associated with CVD events
[24], no study has yet tested poor sleep as a mediator of the association of ACSinduced PTSD and adverse CVD outcomes.
Prevalence of PTSD due to Stroke

While most studies of the relationship between cardiovascular events and the development of PTSD have focused on the potential for PTSD due to ACS, a few studies
have assessed stroke-induced PTSD. Across the eight extant studies we reviewed in
a recent meta-analysis, prevalence estimates vary widely from 3 to 37 % [47], and
most of those studies relied on small samples assessed at various lengths of time
after the index stroke. Further, most published studies to date were conducted in
majority white populations without significant racial or ethnic diversity, although
risk for PTSD is greater in black survivors of some types of trauma. Our recent
cohort study, the largest on this topic to date, found that 18 % of 535 survivors of
mild to moderate stroke reported clinically significant PTSD symptoms a mean SD
of 1.9 1.5 years later [48]. Strikingly, in that study, we found that participants with
elevated stroke-induced PTSD symptoms were 2.7 times more likely than those
without PTSD symptoms to report medication nonadherence. However, the participants in that study were primarily from racial and ethnic minority groups with very
low socioeconomic status living in New York City, so the generalizability of that
result to the broader population of stroke survivors in the United States is unclear.
234
D. Edmondson et al.
Conclusions
Research conducted in the past decade has now accumulated such that we can confidently conclude that an association exists between PTSD and incident CVD, and
likely exists between PTSD and recurrent CVD, and that the association is independent of other known risk factors. However, we are not able to point to a single
mechanism that can explain that association. That inability likely exists for two
reasons: the studies that could pinpoint that mechanism have not been conducted,
and the association is carried by multiple mediators whose relative effects are modified by individual patient factors. Future research should focus on (1) methods for
decreasing PTSD, particularly where medical settings can be modified to decrease
PTSD due to ACS, stroke, and other life-threatening illnesses, (2) identifying modifiable mechanisms of the association of PTSD and CVD, particularly non-traditional
risk factors, and (3) determining whether PTSD treatment can offset CVD risk.
Acknowledgements This work was supported by grants HL088117 and HL117832, and in part
by Columbia Universitys CTSA grant No. UL1RR024156, from the National Institutes of Health,
Bethesda, Maryland, United States.
References
1. Shin LM, Rauch SL, Pitman RK. Amygdala, medial prefrontal cortex, and hippocampal function in PTSD. Ann N Y Acad Sci. 2006;1071:6779.
2. Yehuda R. Advances in understanding neuroendocrine alterations in PTSD and their therapeutic implications. Ann N Y Acad Sci. 2006;1071:13766.
3. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence
and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey
Replication. Arch Gen Psychiatry. 2005;62(6):593.
4. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB. Posttraumatic stress disorder in the
National Comorbidity Survey. Arch Gen Psychiatry. 1995;52(12):104860.
5. Kessler RC, Ormel J, Petukhova M, et al. Development of lifetime comorbidity in the World
Health Organization world mental health surveys. Arch Gen Psychiatry. 2011;68(1):90.
6. Galea S, Nandi A, Vlahov D. The epidemiology of post-traumatic stress disorder after disasters. Epidemiol Rev. 2005;27(1):7891.
7. Weiss DS, Marmar CR, Schlenger WE, et al. The prevalence of lifetime and partial posttraumatic stress disorder in Vietnam theater veterans. J Trauma Stress. 1992;5(3):36576.
8. Edmondson D, Kronish IM, Shaffer JA, Falzon L, Burg MM. Posttraumatic stress disorder and
risk for coronary heart disease: a meta-analytic review. Am Heart J. 2013;166(5):80614.
9. Kubzansky LD, Koenen KC, Spiro 3rd A, Vokonas PS, Sparrow D. Prospective study of posttraumatic stress disorder symptoms and coronary heart disease in the Normative Aging Study.
Arch Gen Psychiatry. 2007;64(1):10916.
10. Boscarino JA. Post-traumatic stress disorder and cardiovascular disease link: time to identify
specific pathways and interventions. Am J Cardiol. 2011;108(7):10523.
11. VanItallie TB. Stress: a risk factor for serious illness. Metab Clin Exp. 2002;51(1):405.
12. Rozanski A, Blumenthal JA, Davidson KW, Saab PG, Kubzansky L. The epidemiology, pathophysiology, and management of psychosocial risk factors in cardiac practice: the emerging
field of behavioral cardiology. J Am Coll Cardiol. 2005;45(5):63751.
PTSD and CVD
235
13. Bedi US, Arora R. Cardiovascular manifestations of posttraumatic stress disorder. J Natl Med
Assoc. 2007;99(6):6429.
14. Ridker PM. C-reactive protein, inflammation, and cardiovascular disease: clinical update. Tex
Heart Inst J. 2005;32(3):3846.
15. von Knel R, Hepp U, Kraemer B, et al. Evidence for low-grade systemic proinflammatory
activity in patients with posttraumatic stress disorder. J Psychiatr Res. 2007;41(9):74452.
16. Gill JM, Saligan L, Woods S, Page G. PTSD is associated with an excess of inflammatory
immune activities. Perspect Psychiatr Care. 2009;45(4):26277.
17. Breslau N, Davis GC, Schultz LR. Posttraumatic stress disorder and the incidence of nicotine,
alcohol, and other drug disorders in persons who have experienced trauma. Arch Gen
Psychiatry. 2003;60(3):28994.
18. Cohen BE, Marmar C, Ren L, Bertenthal D, Seal KH. Association of cardiovascular risk factors with mental health diagnoses in Iraq and Afghanistan war veterans using VA health care.
JAMA. 2009;302(5):48992.
19. Zen AL, Whooley MA, Zhao S, Cohen BE. Post-traumatic stress disorder is associated with
poor health behaviors: findings from the Heart and Soul Study. Health Psychol.
2012;31(2):194201.
20. Brock CM, King DS, Wofford MR, Harrell TK. Exercise, insulin resistance, and hypertension:
a complex relationship. Metab Syndr Relat Disord. 2005;3(1):605.
21. Kronish IM, Edmondson D, Li Y, Cohen BE. Post-traumatic stress disorder and medication
adherence: results from the Mind Your Heart study. J Psychiatr Res. 2012;46(12):15959.
22. Gehi AK, Ali S, Na B, Whooley MA. Self-reported medication adherence and cardiovascular
events in patients with stable coronary heart disease: the heart and soul study. Arch Intern Med.
2007;167(16):1798803.
23. Maher MJ, Rego SA, Asnis GM. Sleep disturbances in patients with post-traumatic stress
disorder: epidemiology, impact and approaches to management. CNS Drugs.
2006;20(7):56790.
24. Cappuccio FP, Cooper D, D'Elia L, Strazzullo P, Miller MA. Sleep duration predicts cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. Eur Heart
J. 2011;32(12):148492.
25. Whooley MA, de Jonge P, Vittinghoff E, et al. Depressive symptoms, health behaviors, and
risk of cardiovascular events in patients with coronary heart disease. JAMA.
2008;300(20):237988.
26. Orth U, Wieland E. Anger, hostility, and posttraumatic stress disorder in trauma-exposed
adults: a meta-analysis. J Consult Clin Psychol. 2006;74(4):698706.
27. Kawachi I, Sparrow D, Spiro 3rd A, Vokonas P, Weiss ST. A prospective study of anger and
coronary heart disease. The Normative Aging Study. Circulation. 1996;94(9):20905.
28. Dimsdale JE. Psychological stress and cardiovascular disease. J Am Coll Cardiol.
2008;51(13):123746.
29. Wang PS, Berglund P, Olfson M, Pincus HA, Wells KB, Kessler RC. Failure and delay in initial treatment contact after first onset of mental disorders in the National Comorbidity Survey
Replication. Arch Gen Psychiatry. 2005;62(6):60313.
30. Pullen PR, Nagamia SH, Mehta PK, et al. Effects of yoga on inflammation and exercise capacity in patients with chronic heart failure. J Card Fail. 2008;14(5):40713.
31. Kinlay S, Schwartz GG, Olsson AG, et al. Inflammation, statin therapy, and risk of stroke after
an acute coronary syndrome in the MIRACL study. Arterioscler Thromb Vasc Biol.
2008;28(1):1427.
32. McFall M, Saxon AJ, Malte CA, et al. Integrating tobacco cessation into mental health care for
posttraumatic stress disorder: a randomized controlled trial. JAMA. 2010;304(22):248593.
33. Germain A, Richardson R, Moul DE, et al. Placebo-controlled comparison of prazosin and
cognitive-behavioral treatments for sleep disturbances in US Military Veterans. J Psychosom
Res. 2012;72(2):8996.
236
D. Edmondson et al.
34. Edmondson D. An enduring somatic threat model of posttraumatic stress disorder due to acute
life-threatening medical events. Soc Personal Psychol Compass. Invited Article.
35. Edmondson D, Richardson S, Falzon L, Davidson KW, Mills MA, Neria Y. Posttraumatic
stress disorder prevalence and risk of recurrence in acute coronary syndrome patients: a metaanalytic review. PLoS One. 2012;7(6), e38915.
36. Bennett P, Owen RL, Koutsakis S, Bisson J. Personality, social context and cognitive predictors of post-traumatic stress disorder in myocardial infarction patients. Psychol Health.
2002;17(4):489500.
37. Doerfler LA, Paraskos JA, Piniarski L. Relationship of quality of life and perceived control
with posttraumatic stress disorder symptoms 3 to 6 months after myocardial infarction.
J Cardiopulm Rehabil. 2005;25(3):16672.
38. Wiedemar L, Schmid J-P, Muller J, et al. Prevalence and predictors of posttraumatic stress
disorder in patients with acute myocardial infarction. Heart Lung. 2008;37(2):11321.
39. Roberge M-A, Dupuis G, Marchand A. Post-traumatic stress disorder following myocardial
infarction: prevalence and risk factors. Can J Cardiol. 2010;26(5):e1705.
40. Bennett P, Brooke S. Intrusive memories, post-traumatic stress disorder and myocardial infarction. Br J Clin Psychol. 1999;38(Pt 4):4116.
41. Pedersen SS, Middel B, Larsen ML. Posttraumatic stress disorder in first-time myocardial
infarction patients. Heart Lung. 2003;32(5):3007.
42. Wikman A, Bhattacharyya M, Perkins-Porras L, Steptoe A. Persistence of posttraumatic stress
symptoms 12 and 36 months after acute coronary syndrome. Psychosom Med.
2008;70(7):76472.
43. Edmondson D, Shimbo D, Ye S, Wyer P, Davidson KW. The association of emergency department crowding during treatment for acute coronary syndrome with subsequent posttraumatic
stress disorder symptoms. JAMA Intern Med. 2013;173(6):4724.
44. Ginzburg K, Ein-Dor T. Posttraumatic stress syndromes and health-related quality of life following myocardial infarction: 8-year follow-up. Gen Hosp Psychiatry. 2011;33(6):56571.
45. Kubzansky LD, Koenen KC. Is posttraumatic stress disorder related to development of heart
disease? An update. Cleve Clin J Med. 2009;76 Suppl 2:S605.
46. Ahmadi N, Hajsadeghi F, Mirshkarlo HB, Budoff M, Yehuda R, Ebrahimi R. Post-traumatic
stress disorder, coronary atherosclerosis, and mortality. Am J Cardiol. 2011;108(1):2933.
47. Edmondson D, Richardson S, Fausett JK, Falzon L, Howard VJ, Kronish IM. Prevalence of
PTSD in survivors of stroke and transient ischemic attack: a meta-analytic review. PLoS One.
2013;8(6), e66435.
48. Goldfinger JZ, Edmondson D, Kronish IM, Fei K, Balakrishnan R, Tuhrim S, et al. Correlates
of post-traumatic stress disorder in stroke survivors. J Stroke Cerebrovasc Dis. 2014;23(5):
1099105.
Individual Interventions for Prevention

and Control of CVDs
Pantaleo Giannuzzi
Introduction
Noncommunicable diseases (NCDs) are the leading causes of death globally, killing
more people each year than all other causes combined. Of the 57 million deaths that
occurred globally in 2008, 36 millionalmost two thirdswere due to NCDs,
comprising mainly cardiovascular diseases (CVDs), cancers, diabetes and chronic
lung diseases. About one fourth of global NCD-related deaths take place before the
age of 60 and the combined burden of these diseases is rising fastest among lowerincome countries, populations and communities, where they impose large, avoidable costs in human, social and economic terms. NCDs are caused, to a large extent,
by four behavioural risk factors that are pervasive aspects of economic transition,
rapid urbanization and 21st-century lifestyles: tobacco use, unhealthy diet, insufficient physical activity and the harmful use of alcohol. Together these behavioural
risk factors are strongly associated to other major cardiovascular (CV) risk factors
including hypertension, diabetes, obesity and metabolic syndrome [1].
Interventions to prevent NCDs on a population-wide basis are not only achievable but also cost effective. The income level of a country or population is not a
barrier to success. Low-cost solutions can work anywhere to reduce the major risk
factors for NCDs.
Currently, the main focus of health care for NCDs in many low- and middleincome countries is hospital-centred acute care. NCD patients present at hospitals
when CVD, cancer, diabetes and chronic respiratory disease have reached the point
of acute events or long-term complications. This is a very expensive approach that
will not contribute to a significant reduction of the NCD burden. It also denies
people the health benefits of taking care of their conditions at an early stage.
P. Giannuzzi, MD (*)
Department of Cardiology, Salvatore Maugeri Foundation IRCCS,
Scientific Institute for Clinical Care and Research of Veruno, Verona, Italy
e-mail: pantaleo.gianuzzi@fsm.it
DOI 10.1007/978-3-319-22357-5_22
237
238
P. Giannuzzi
Evidence from high-income countries shows that a comprehensive focus on

prevention and improved treatment following CV events has led to dramatic declines
in mortality rates. Similarly, progress in cancer treatment combined with early
detection and screening interventions have improved survival rates for many cancers in high-income countries. Survival rates in low and middle-income countries,
however, remain very low. A combination of population-wide and individual interventions can reproduce successes in many more countries through cost-effective
initiatives that strengthen overall health systems [2, 3].
Strategies for Preventive Cardiology: Population-Wide versus

Individual Approach
A strategic objective in the fight against the CVD epidemic must be to ensure early
detection and care using cost-effective and sustainable health-care interventions.
High-risk individuals and those with established CVD can be treated with regimens of low-cost generic medicines that significantly reduce the likelihood of death
or vascular events. A regimen of aspirin, statin and blood pressure-lowering agents
could significantly reduce vascular events in people at high CV risk and is considered a best buy. When coupled with preventive measures such as smoking cessation,
therapeutic benefits can be profound. Another best buy is administration of aspirin
to people who develop a myocardial infarction (MI). In all countries, these best buys
need to be scaled up and delivered through a primary health-care approach [4].
What is needed are high levels of commitment, good planning, community
mobilization and intense focus on a small range of critical actions. With these, quick
gains will be achieved in reducing the major behavioural risk factors: tobacco use,
harmful use of alcohol, unhealthy diet and physical inactivity, together with key risk
factors for cancer, notably some chronic infections.
Notable interventions where impact is evident include tobacco tax increases and
restrictions on smoking in public places and workplaces; alcohol tax increases and
restriction of sales; mandatory and voluntary salt reduction; and improved access to
places for physical activity such as walking.
In addressing CVD, the population-wide approach to prevention has great potential to decrease disease burden, but it does not provide an adequate response to the
need to strengthen health care for people with CVD. The disease burden can be
reduced considerably in the short- to medium-term if the population-wide approach
is complemented by health-care interventions for individuals who either already
have CVD or those who are at high risk. CVDs can best be addressed by a combination of primary prevention interventions targeting whole populations, by measures
that target high-risk individuals and by improved access to essential health-care
interventions for people with CVDs [47].
For primary prevention of coronary heart disease (CHD) and stroke, individual
health-care interventions can be targeted to those at high total CV risk or those with
single risk factor levels above traditional thresholds, such as hypertension and hypercholesterolemia [4]. The former approach is more cost effective than the latter and
Individual Interventions for Prevention and Control of CVDs
239
has the potential to substantially reduce CV events [1, 4, 6]. Furthermore,

application of this approach is also feasible in primary care in low-resource settings,
including by non-physician health workers [8, 9]. It has been estimated that a regimen
of aspirin, statin and blood pressure-lowering agents may significantly reduce the risk
of death from CVD in people at high cardiovascular risk (people with a 10-year cardiovascular risk equal to or above 15 %, and those who have suffered a previous
cardiovascular event). Providing such a regimen to those eligible between 40 and 79
years of age has been estimated to avert about one fifth of cardiovascular deaths in the
next 10 years, with 56 % of deaths averted in people younger than 70 years [4].
For secondary prevention of cardiovascular disease (prevention of recurrences
and complications in those with established disease), aspirin, beta-blockers,
angiotensin-converting enzyme inhibitors and lipid-lowering therapies lower the risk
of recurrent cardiovascular events, including in those with diabetes. The benefits of
these interventions are largely independent, so that when used together with smoking
cessation, about three quarters of recurrent vascular events may be prevented [5].
Currently there are major gaps in the implementation of secondary prevention
interventions that can even be delivered in primary care settings [6, 7]. General
practitioners are critical to the implementation and success of CVD prevention programmes. In most countries, they deliver the majority of consultations and provide
most public health medicine (preventive care, disease screening, chronic disease
monitoring, and follow-up). In the case of CVD prevention they have a unique role
in identifying individuals at risk of but without established CVD and assessing their
eligibility for intervention based on their profile. Thus, the physician in general
practice is the key person to initiate, coordinate, and provide long-term follow-up
for CVD prevention, while the practising cardiologist should be the advisor in cases
where there is uncertainty over the use of preventive medication or when usual preventive options are difficult to apply [6, 7].
Nurse-co-ordinated prevention programmes are also effective across a variety of
practice settings and should be well integrated into healthcare systems. Nurse case
management models tested in several randomized trials of secondary prevention
have shown significant improvements in risk factors, exercise tolerance, glucose
control, and appropriate medication use, along with decreases in cardiac events and
mortality, regression of coronary atherosclerosis, and improved patient perception
of health compared with usual care. Other studies have demonstrated the effectiveness of nurse-led prevention clinics in primary care compared with usual care, with
greater success in secondary as opposed to primary prevention [10, 11].
Hospital-Based Programmes: Specialized Prevention Centres

All patients with CVD should be discharged from hospital with clear guidelineorientated treatment modality recommendations to minimize the risk of further
adverse events. The new ESC Guidelines provide a check list of measures necessary
at discharge from hospital to ensure that intense risk factor modification and lifestyle change are implemented in all patients following the diagnosis of acute
240
P. Giannuzzi
coronary syndromes, including recommendation for enrolment in a cardiovascular

prevention and rehabilitation programme [7].
After a cardiovascular event, secondary preventive efforts within a structured
rehabilitation programme have been shown to be particularly important and costeffective. Intensive research in the field of preventive cardiology has sustained the
evolution of Cardiac Rehabilitation (CR) programs, once limited to exercise training, into comprehensive secondary prevention (SP) centres. CR after cardiac events
or interventions in a specialized centre helps to maintain long-term adherence to the
optimal treatment programme by educating the patient and repeatedly emphasizing
the importance of maintaining the prescribed treatments and recommended lifestyle. Data demonstrate that CR/SP programs reduce cardiovascular risk and event
rates, foster healthy behaviours, and promote active lifestyles [1215].
There is compelling scientific evidence that CR is an effective treatment for
patients with CHD [7, 1215]. The meta-analysis of 8940 patients from 48 trials of
cardiac rehabilitation showed that a structure service, compared to usual care, was
associated with a reduction in all-cause mortality: odds ratio 0.80 (95 % CI 0.68
0.93), and cardiac mortality 0.74 (0.610.96) [16]. Another meta-analysis of the
effectiveness of secondary prevention programmes of 63 randomised controlled trials
including 21,295 patients showed a summary risk ratio for all-cause mortality 0.85
(0.770.94) and for recurrent myocardial infarction 0.83 (0.740.94) [17]. In the
systematic review of trials of secondary prevention, multidisciplinary disease management programmes led to a reduction in hospital admissions and recurrent myocardial infarction [14, 15]. So the distinction between cardiac rehabilitation and
secondary prevention is artificial and these meta-analyses demonstrate the overall
benefits of an integrated multidisciplinary and comprehensive multifactorial approach
to reducing cardiovascular risk, cardiovascular events and all-cause mortality.
However, despite the strength of this evidence, CR in Europe continues to be
considerably underused with poor referral and low participation rate. The results of
the EUROASPIRE III survey showed inadequate lifestyle and risk factor control
and underuse of cardiac rehabilitation in Europe. Less than half of patients with
CHD were advised to follow a CR programme and just over a third actually participated in some form of cardiac rehabilitation. Yet, of those who were advised to
attend a CR/SP programme, four-fifths did so. These results are similar to those of
the EUROASPIRE Il survey, which demonstrated that two in five coronary patients
reported receiving advice to follow a CR programme and only one third actually
attended in some form of CR. The comparison between those 13 countries which
participated in both EUROASPIRE Il and III surveys demonstrated that the proportion of patients advised to follow a CRP increased from 44.5 to 55.7 % (p < 0.0001)
and; the participation rate also increased from 38.0 to 46.1 % (p < 0.0001). In
EUROASPIRE III, there was considerable variations in participation in a CR programme between European countries, with the highest attendance reported in
Lithuania and Ireland, the lowest in Turkey, Cyprus and Russian Federation, and
virtually no attendance in Greece and Spain. These differences are most likely to
reflect the heterogeneity of health care systems and the availability of CR/SP services in some regions of Europe [18, 19].
241
Addressing factors that limit participation is particularly important given recent

data that demonstrate an inverse relationship between CR/SP programme participation and adverse cardiovascular events. The relationship between the number of CR/
SP sessions attended and cardiovascular outcomes was recently evaluated in an
analysis of Medicare claims data including 30,161 patients with CHD (with recent
coronary artery bypass surgery, MI, or acute coronary syndrome) who attended at
least 1 CR/SP session [20]. After 4 years of follow-up, patients who attended 36
sessions had a 14 % lower risk of death and a 12 % lower risk of MI than those who
attended 24 sessions; a 22 % lower risk of death and a 23 % lower risk of MI than
those who attended 12 sessions; and a 47 % lower risk of death and a 31 % lower
risk of MI than those who attended 1 session. However, only 18 % of the patients
completed the maximum 36 sessions. This dose-dependent improvement further
highlights the importance of patient retention in CR/SP programs. Clinical outcomes following percutaneous coronary intervention were recently assessed in a
retrospective analysis of 2395 patients (40 % of whom attended CR) Participation
in CR was associated with decreased all-cause mortality (hazard ratio 0.530.55,
p < 0.001), although no effect on cardiac death or MI was noted [21].
These important and recent findings further support the recommendations provided in clinical guidelines, and reimbursement policy instituted in many countries, as well.
CR/SP programmes are based on long-established models involving hospital,
ambulatory, community or home-based programmes, according to the local and
national traditions. However, most of the CR programmes rely mainly on short-term
interventions and are not adequately implemented in the long-term. Short-term
interventions are unlikely to bring in long-term benefits with regard to lifestyle and
risk factor management, improve quality of life, or decrease morbidity and mortality. Recent studies as EUROACTION and GIObal Secondary Prevention strategiEs
to Limit (GOSPEL) studies provided scientific evidence for the beneficial long-term
effect and improved prognosis in patients with CHD [22, 23]. The EUROACTION
model of a nurse-Ied preventive cardiology programme in patients with CHD is a
contemporary example of what a comprehensive approach to reducing total cardiovascular risk can achieve. This cluster randomised controlled trial demonstrated
improved lifestyle and risk factor outcomes compared to usual care. Over one year
EUROACTION prevented smoking relapse, increased fruit and vegetable consumption and physical activity with a corresponding reduction in weight and waist circumference and improved blood pressure and lipid control and increased prescribing
of ACE inhibitors and statins [22]. The GOSPEL study was multi-centre, randomized, controlled trial comparing a long-term multifactorial educational and behavioural intervention coordinated by a cardiologist versus usual care after a standard
CR programme following MI [23]. At 3 years all the clinical endpoints were reduced
by the intensive intervention: cardiovascular mortality, nonfatal MI and stroke by
33 % and cardiac death plus nonfatal M I by 36 %, total stroke by 32 % and total
mortality by 21 %. So, there is considerable potential to further reduce the risk of
CVD in existing CR/SP programmes.
242
P. Giannuzzi
Different patterns of rehabilitative care are currently delivered by specialized

hospital-based teams: residential CR for more complicated, disabled patients; and
outpatient CR for more independent, low-risk and clinically stable patients requiring less supervision. Whereas the core components and goals of CR/SP are standardized and documented in recent position papers, the structure and type of cardiac
rehabilitation units vary in different countries [14, 15]. While the objectives are
identical to those of the outpatient CR programs, residential rehabilitation programs
are specifically structured to provide more intensive and/or complex interventions,
and have the advantage being able to start early after the acute event, to include
more complicated high-risk or clinically unstable patients, to include more severely
incapacitated and/or elderly patients (especially those with co-morbidity), and thus,
to facilitate the transition from the hospital phase to a more stable clinical condition
which may allow the maintenance of an independent life at home. One major disadvantage of residential programs is the relatively short duration of intervention with
regard to risk factor management and lifestyle changes. Therefore, residential CR
programs should be followed up by a long-term outpatient risk reduction and secondary prevention program, with appropriate clinical and functional monitoring.
Home-based rehabilitation programs directed by physicians and coordinated by
nurses have also been developed as a way of expanding the delivery of secondary
prevention services.
Conclusions
All coronary patients should be advised and have the opportunity to access a comprehensive cardiovascular prevention and rehabilitation programme, addressing all
aspects of lifestylesmoking cessation, healthy eating and being physically
activetogether with more effective management of blood pressure, lipids and glucose. To achieve the clinical benefits of a multidisciplinary and multifactorial prevention programme we need to integrate professional lifestyle interventions with
effective risk factor management, and evidence based drug therapies, appropriately
adapted to the medical, cultural, and economic setting of a country. The challenge
is to engage and motivate cardiologists, physicians and health professionals to routinely practice high quality preventive cardiology and a health care system which
invests in prevention.
References
1. Global status report on noncommunicable disease 2010. Geneva: World Health Organization;
2011.
2. Global strategy for the prevention and control of noncommunicable diseases. Geneva: World
Health Organization; 2000.
243
3. Prevention of cardiovascular disease: guidelines for assessment and management of total

cardiovascular risk. Geneva: World Health Organization; 2007.
4. Lim SS, et al. Prevention of cardiovascular disease in high-risk individuals in low-income and
middleincome countries: health effects and costs. Lancet. 2007;370:205462.
5. Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002;360:23.
6. Graham I, Atar D, Borch-Johnsen K, et al. European Guidelines on Cardiovascular Disease
Prevention in Clinical Practice: Fourth Joint Task Force of the European Society of Cardiology
and Other Societies on Cardiovascular Disease Prevention in Clinical Prevention in Clinical
Practice (Constituted by representatives of nine societies and by invited experts).
Eur J Cardiovasc Prev Rehabil. 2007;14 Suppl 2:S1113.
7. Perk J, De Backer G, Golhke H, et al. European Guidelines on Cardiovascular Disease
Prevention in Clinical Practice: Fifth Joint Task Force of the European Society of Cardiology
and Other Societies on Cardiovascular Disease Prevention in Clinical Prevention in Clinical
Practice (Constituted by representatives of nine societies and by invited experts). Eur Heart
J. 2012;33(13):1635701.
8. Package of essential noncommunicable disease interventions for primary health care in lowresource setting. Geneva: World Health Organization; 2010.
9. Abegunde DO, et al. Can non-physician health-care workers assess and manage cardiovascular
risk in primary care? Bull World Health Organ. 2007;85:43240.
10. Berra K, Fletcher BJ, Hayman LL, Miller NH. Global cardiovascular disease prevention: a call
to action for nursing: the global burden of cardiovascular disease. J Cardiovasc Nurs.
2011;26:S12.
11. Koelewijn-van Loon MS, van der Weijden T, Ronda G, van Steenkiste B, Winkens B, Elwyn
G, Grol R. Improving lifestyle and risk perception through patient involvement in nurse-led
cardiovascular risk management: a cluster-randomized controlled trial in primary care. Prev
Med. 2010;50:3544.
12. Giannuzzi P, Saner H, Bjrnstad H, et al. Secondary prevention through cardiac rehabilitation:
position paper of the working group on cardiac rehabilitation and exercise physiology of the
European Society of Cardiology. Eur Heart J. 2003;24:12738.
13. Piepoli MF, Corr U, Benzer W, et al. Secondary prevention through cardiac rehabilitation:
from knowledge to implementation. A position paper from the Cardiac Rehabilitation Section
of the European Association of Cardiovascular Prevention and Rehabilitation. Eur J Cardiovasc
Prev Rehabil. 2010;17:117.
14. Balady GJ, Ades PA, Bittner VA, Franklin BA, Gordon NF, Thomas RJ, Tomaselli GF, Yancy
CW. Referral, enrolment, and delivery of cardiac rehabilitation/secondary prevention programs at clinical centers and beyond: a presidential advisory from the American Heart
15. Piepoli MF, Corr U, Adamopoulos S, Benzer W, Bjarnason-Wehrens B, Cupples M, Dendale
P, Doherty P, Gaita D, Hfer S, McGee H, Mendes M, Niebauer J, Pogosova N, GarciaPorrerro E, Rauch B, Schmid JP, Giannuzzi P. Secondary prevention in the clinical management of patients with cardiovascular diseases. Core components, standards and outcome
measures for referral and delivery. Eur J Prev Cardiol. 2012 Jun 20.
16. Taylor RS, Brown A, Ebrahim S, et al. Exercise-based rehabilitation for patients with coronary
heart disease: systematic review and meta-analysis of randomized controlled trials. Am J Med.
2004;116:78292.
17. Clark AM, Hartling L, Vandermeer B, et al. Meta-analysis: secondary prevention programs for
patients with coronary artery disease. Ann Intern Med. 2005;143:65972.
18. Kotseva K, Wood D, De Backer G, et al., on behalf of EUROASPIRE Study Group.
Cardiovascular prevention guidelines the clinical reality: a comparison of EUROASPIRE I,
II and III surveys in 8 European countries. Lancet. 2009;372:92940.
19. Kotseva K, Wood D, De Backer G, et al., on behalf of EUROASPIRE Study Group.
EUROASPIRE III: a survey on the lifestyle, risk factors and use of cardioprotective drug thera-
244
20.
21.
22.
23.
P. Giannuzzi
pies in coronary patients from twenty two European countries. Eur J Cardiovasc Prev Rehabil.
2009;16:12137.
Hammill BG, Curtis LH, Schulman KA, Whellan DJ. Relationship between cardiac rehabilitation and long-term risks of death and myocardial infarction among elderly Medicare beneficiaries. Circulation. 2010;121:6370.
Goel K, Lennon RJ, Tilbury RT, Squires RW, Thomas RJ. Impact of cardiac rehabilitation on
mortality and cardiovascular events after percutaneous coronary intervention in the community. Circulation. 2011;123:234452.
Wood DA, Kotseva K, Connolly S, et al., on behalf of the EUROACTION Study Group.
EUROACTION: A European Society of Cardiology demonstration project in preventive
cardiology. A paired cluster randomised controlled trial of a multi-disciplinary family based
preventive cardiology programme for coronary patients and asymptomatic high risk individuals. Lancet. 2008;371:19992012.
Giannuzzi P, Temporelli PL, Marchioli R, et al. Global secondary prevention strategies to limit
event recurrence after myocardial infarction: results of the GOSPEL study, a multicenter, randomized controlled trial from the Italian Cardiac Rehabilitation Network. Arch Intern Med.
2008;168:2194204.
Social Mobilization for Cardiovascular

Disease Prevention and Control
Carlos Alberto Machado
According to the World Health Organization (WHO), 36 million (63 %) of the 57 million deaths that occurred in 2008 resulted from chronic non-communicable diseases
(NCD), with particularly notable contributions from cardiovascular diseases (CVD),
diabetes, cancer and chronic respiratory diseases. Nearly 80 % of these deaths from
chronic diseases (29 million) occurred in middle- and low-income countries (developing countries), and 26 % of these deaths were regarded as premature [1].
NCD are the most common cause of death in most American countries. In 2007,
CVD accounted for 30 % of deaths from all causes in the Americas, including
662,011 deaths from ischemic heart disease (299,415 women and 362,596 men) and
336,809 deaths from cerebrovascular disease (183,689 women and 153,120 men).
The situation is particularly complex in Latin America, where 40 % of deaths
occurred during individuals most productive life stages [2].
In Brazil, similarly to other countries, NCD are the leading health problem,
accounting for 72 % of deaths from all causes, with CVD (31.3 %), cancer (16.3 %),
diabetes (5.2 %) and chronic respiratory disease (5.8 %) as the most notable
NCD. These NCD affect individuals from all socioeconomic strata, with the greatest effects on vulnerable groups, including the elderly and individuals with little
education and low incomes [3]. Approximately 300,000 Brazilians die each year
from CVD, which include heart attack, stroke, cardiac and renal failure and sudden
death; this death total corresponds to 820 deaths per day, 30 deaths per hour or one
death every two minutes [3, 4].
C.A. Machado, M.D. (*)

Cardiovascular Health Promotion from the Brazilian Society of Cardiology, Rio de Janeiro, USA
e-mail: carlos.a.machado@uol.com.br
DOI 10.1007/978-3-319-22357-5_23
245
246
C.A. Machado
The NCD-related situation involves high socioeconomic costs for countries, particularly low- and middle-income nations. Approximately 80 % of cases of CVD
and type 2 diabetes and approximately one-third of cancer cases could be prevented
if common risk factors, including tobacco smoking, physical inactivity, inadequate
diet and alcohol abuse, could be eliminated [5].
Several determinants hinder the control of CVD, the primary contributor to
NCD. The main determinants are a lack of awareness of the importance of CVD,
which leads to a dearth of funding and resources for the prevention and control of
these diseases; challenges associated with prioritizing government and donor
resources targeting CVD; the impairment of healthcare services in low- and middleincome countries with respect to supporting the prevention, diagnosis and treatment
of CVD; difficulties in relationships between governments and the private sector,
which are complicated by conflicts between share holder interests and public health
goals; uncertainty regarding the applicability and effectiveness of programs and
services in the context of local implementation; and the fragmentation of global
measures for preventing CVD [6].
There is a clear gap between the current knowledge published in the literature
regarding the primary and secondary prevention of NCD and the implementation of
planned actions in clinical practice. It is necessary to understand the complex relationship between healthcare policies and changes in individual behavior, which are
affected by environmental factors and appropriate access to the healthcare system.
Recently, the WHO published a document titled The World Health Report 2013
that drew attention to the need for more creative research to expand the universal
coverage provided by healthcare systems and reduce effectiveness gaps in the practical implementation of proposed measures. This report described a 5 % increase in
investment in health-related research during the 2000s in low- and middle-income
countries. The report also focused on the social mobilization that had occurred in
these countries, emphasizing the fact that many publications were derived from
emerging countries, including China, Brazil and India, and represented the result of
collaborations among universities, governments, international organizations and the
private sector. However, the report also noted the need to establish national and global
networks to coordinate research, collaboration and information exchange among
countries, with a focus on social inclusion as a means of modifying societies [7].
The policies developed for preventing CNCD should be directed toward lifestyle
changes and should particularly target the four common modifiable risk factors of
tobacco smoking, physical inactivity, inadequate diet and alcohol abuse. These factors are affected by economic growth, globalization and unplanned urbanization.
Thus, success in implementing those policies will only be achieved with involvement from multiple public and private sectors that encompasses social mobilization.
Beyond investments in health alone, joint planning of the education, agriculture,
economy, trade, urbanization and transport sectors, among others, is necessary [8].
Conversely, there exists a unique window of opportunity to control the metabolic
factors responsible for CNCD, such as obesity, hypertension and dyslipidemia.
Social mobilization and integrated actions involving various entities in organized
Social Mobilization for Cardiovascular Disease Prevention and Control
247
civil society, including scientific societies, patient associations and the government,
are essential to impacting these indicators.
The Brazilian Society of Cardiology (Sociedade Brasileira de Cardiologia
SBC) has an important tradition of promoting these social mobilization actions
through the National Program for the Prevention of Cardiovascular Diseases
(Programa Nacional de Preveno das Doenas Cardiovasculares). These actions
include national campaigns corresponding to theme days for warning about
traditional risk factors, such as the 12 8 campaign and a campaign to raise awareness of the need to reduce salt in food; comprehensive programs for treating congenital heart diseases and training physicians to focus on CVD; and initiatives to
train the general populace and healthcare professionals in appropriate responses to
cardiovascular emergencies.
Strategic actions to combat CVD are based on an alliance among the SBC, the
government, civil society, schools and the family unit. Several actors have been
enlisted for these actions, including primary education students, who were mobilized through the SBC program SBC Vai a Escola [SBC goes to school]. In addition,
a government decree created a healthy eating program in schools, and teachers and
students received training as health-promoting agents. The Brazilian population was
mobilized through walks and other actions. Moreover, teaching materials and field
work were used to clarify the importance of diagnosing and treating CVD to this
population. Furthermore, a samba school used its samba plot to spread a message
indicating the need to reduce salt intake, and families were mobilized through a
partnership with the Pastoral Healthcare (Pastoral da Sade) religious organization.
Recently, 200 leaders of National Pastoral Healthcare of the National Conference
of Brazilian Bishops (Pastoral Nacional da Sade da Conferncia Nacional dos
Bispos do Brasil -PNS-CNBB) were recently trained. In turn, these leaders will
train 100,000 PNS-CNBB agents operating in the 15,000 parishes of the Brazilian
Catholic Church. This action resulted from the Campaign for Preventing and
Fighting Against Hypertension (Campanha de Preveno e Combate Hipertenso)
initiative titled Treating High Blood Pressure is an act of faith in life (Tratar a
Presso Alta ato de f na vida), which was implemented throughout Brazil in
2008 and 2009.
Actions conducted in partnership with governments must also be emphasized. In
2000, the Brazilian Societies of Cardiology, Nephrology, Hypertension and Diabetes
and the National Associations of Hypertensive and Diabetic Patients proposed the
creation of a National Program for Hypertension and Diabetes Education to the
Brazilian Ministry of Health. This proposal was accepted, leading to the process of
implementing the plan for the reorganization of Arterial Hypertension (AH) and
Diabetes Mellitus (DM) Care, which sought to increase the prevention, diagnosis
and treatment of AH, DM and other risk factors for CVD by reorganizing the approximately 44,000 units of the Primary Healthcare Services Network/Public Healthcare
System (Rede Bsica dos Servios de Sade/Sistema nico de SadeSUS) to provide these units with problem-solving capacities and improve quality of care.
The aforementioned action sought to improve the quality of life of the Brazilian
population by reducing numbers of hospitalizations, emergency room visits and
248
C.A. Machado
spending relating to the treatment of complications; early retirements; and cardiovascular mortality. Several strategies have been implemented, including the training
of multipliers to update primary health services professionals in the SUS and campaigns to detect and treat AH and DM; these campaigns encouraged the promotion
of healthy habits and the registration and linking of patients to Primary Healthcare
Units (Unidades Bsicas de SadeUBS)
Approximately 14,000 healthcare professionals were trained as multipliers, with
two professionals reached per UBS. Approximately 23 million capillary blood glucose tests were performed in 73 % of the target population examined by the SUS;
borderline and definitive cases of DM were detected in 12.8 and 3.6 % of the test
results, respectively. The blood pressures of approximately 12.5 million individuals
were measured, and 36 % of these individuals had blood pressures higher than
140/90 mmHg. A policy and specific budget for AH and DM drugs were created; as
a result, these drugs and necessary supplies to perform capillary blood glucose tests,
including syringes, needles and strips, became available through the UBS system. A
national registry of diabetic and/or hypertensive patients (HiperDia) was created,
allowing federal, state and municipal managers to plan for the resources required to
care for this population.
To monitor and evaluate this project, several entities were created, including the
National Coordination, which is responsible for managing actions associated with
project implementation; the National Committee, which includes representatives
from the Ministry of Health, the Brazilian Societies of Cardiology, Nephrology,
Hypertension and Diabetes, the National Federations of Hypertensive and Diabetic
Patients, the National Council of Health Secretaries (Conselho Nacional de
Secretrios de SadeCONASS) and the National Council of Municipal Health
Secretariats (Conselho Nacional de Secretarias Municipais de SadeCONASEMS);
and state committees. These entities provided advice and monitored the Plan for the
Reorganization of AH and DM Care at the national and state levels.
In Brazil, this plan induced changes in the healthcare provided to hypertensive
and diabetic patients by basic health services in sampled municipalities [9], and
participation in the program therefore became mandatory for all Brazilian municipalities. In 2008, a report from the Ministry of Health indicated that the mortality
rate from CVD had decreased by 20 % during the prior 20 years; this decrease was
attributed to greater control of tobacco smoking, hypertension, diabetes and dyslipidemia, among other factors [10].
Interdisciplinarity, inter-sector involvement and social participation in the formation of work teams are key to the successful achievement of the WHO-proposed
objective of reducing mortality from NCD by 25 % in 2015. The high-level committees formed by professional societies, the public and private sectors, and the populace will contribute to the sustainability of planning actions that pervade local
policies, thereby creating a critical mass that will contribute to short- and long-term
changes and supporting the transition from a biomedical approach to an approach
based on social determinants of health [11].
Social Mobilization for Cardiovascular Disease Prevention and Control
249
References
1. Global status report on noncommunicable diseases 2010. World Health Organization; 2011.
2. Prioridades para la salud cardiovascular en las Amricas. Organizao Panamericana de la
Salud, Washington; 2011.
3. Plano de Aes Estratgicas para o Enfrentamento das Doenas Crnicas No Transmissveis
no Brasil 20112022. Ministrio da Sade Secretaria de Vigilncia Sade.
4. Andrade JP, Arnett DK, Pinto F, Pieiro D, Smith Jr SC, Mattos LAP, et al. Brazilian Society
of cardiology letter from Rio de Janeiro III Brazil prevent/I Latin American prevent.
Arq Bras Cardiol. 2013;100(1):35.
5. World Health Organization. Action plan for the global strategy for the prevention and control
of noncommunicable diseases. The World Health Report from 2008. World Health
Organization; 2008.
6. Fuster V, Kelly BB, Vedanthan R. Promoting global cardiovascular health. Moving forward.
Circulation. 2011;123:16718.
7. Research for Universal Health Coverage. The World Health Report 2013. World Health
Organization; 2011.
8. Mendis S. The policy agenda for prevention and control of non-communicable diseases. Br
Med Bull. 2010;96:2343.
9. Avaliao do Plano de Reorganizao da Ateno Hipertenso Arterial e ao Diabetes Mellitus
no Brasil/Ministrio da Sade, Organizao. Pan-Americana da Sade Braslia: Ministrio
da Sade; 2004.
10. Sade Brasil 2008: 20 anos de Sistema nico de Sade (SUS) no Brasil/Ministrio da Sade,
Secretaria de Vigilncia em Sade, Departamento de Anlise de Situao em Sade. Braslia:
Ministrio da Sade; 2009.
11. Social Determinants of Health Discussion Paper 9. Integration of social determinants of health
and equity into health strategies, programmes and activities: health equity training process in
Spain. World Health Organization; 2013.
Frugal Innovation: Solutions for Sustainable

Global Cardiovascular Health
Donna K. Arnett and Steven A. Claas
In recent decades cardiovascular disease (CVD) rates have dropped in some parts of
the developed world; however, the incidence of CVD has increased in other regions,
especially those characterized by low- and middle-incomes [1, 2]. A cursory summary of global trends for one important CVD risk factor, elevated blood pressure
(BP), is illustrative:
High BP (systolic BP (SBP) 140 or diastolic BP (DBP) 90 mmHg) is currently the leading cause of global disease burden [3].
In 2008, 1 billion individuals worldwide had uncontrolled BP [4].
From 1980 to 2008, mean systolic blood pressure (SBP) declined by 7.3 mmHg in
high-income countries, but increased by 3.3 mmHg in low-income countries [4].
Worldwide, SBP is highest in low-income and middle-income countries [4].
Fewer than half of those who have uncontrolled hypertension are aware of their
BP status. Of those receiving drug treatment, only one-third have BP controlled
to target levels [5].
Given this global picture of BP and its control (and that of other CV risk factors,
such as blood cholesterol levels [6]), trends in CVD event rates are unsurprising.
For example, for adults age 3575 years living in China (classified in 2011 as an
upper-middle income country; however, according to the World Bank as of 2014,
nearly 100 million people in China still lived below the national poverty level [7]),
D.K. Arnett, M.S.P.H., Ph.D. (*)
Department of Epidemiology, School of Public Health, University of Alabama
School of Medicine, Birmingham, AL, USA
American Heart Association, Dallas, TX, USA
e-mail: arnett@uab.edu
S.A. Claas, M.S.
Department of Epidemiology, School of Public Health, University of Alabama
at Birmingham, Birmingham, AL, USA
e-mail: sclass@uab.edu
DOI 10.1007/978-3-319-22357-5_24
251
252
D.K. Arnett and S.A. Claas
the rate of coronary events plus strokes increased from 2.3 to 4.4 % annually in the
period from 1984 to 1999 [8]. In the low-income countries of Africa, projections
suggest that, by 2030, CVD will be the leading cause of deathcontributing 13.4 %
of total mortality (compared to 13.2 % for HIV/AIDS) [9]. Globally, coronary heart
disease is projected to rank as the fifth highest cause of disability-adjusted life-years
lost in low-income countries by 2030 [9]. The 20032009 Prospective Urban Rural
Epidemiological (PURE) study, which recruited 153,996 adults from 628 urban and
rural communities in high-, upper-middle-, lower-middle-, or low-income countries, found that an overwhelming majority of individuals in the upper-middle-,
lower-middle-, or low-income nations suffering from acute coronary syndrome or
stroke receive no treatment [10].
In sum, these CVD risk factor, event, and treatment trends point to a future for
low- and middle-income countries that commentators have described as dismal
and a population emergency that will cost tens of millions of preventable deaths
in the coming decades [11]. Overshadowing these trends are a number systemic and
economic truths: prevention and treatment strategies capable of reducing population
level CVD risk factors and event rates exist; however, existing approaches are economically unviable and unsustainable for those populations and nations most in
need [11]. Upon publication of the findings of the Global Burden of Metabolic Risk
Factors of Chronic Diseases Collaborating Group, which included some of the
trends noted above, editors of The Lancet stated with conviction that Failure to
make population-based cardiovascular health a greater priority, particularly in lowincome and middle-income countries, is unconscionable. This chapter discusses a
possible paradigm with which solutions to this global crisis may be understood and
ultimately addressed.
What Is Frugal Innovation?

The crux of the looming global CVD crisis can be succinctly summarized: CVD
event rates can be successfully reduced by targeting modifiable risk factors such as
hypertension, tobacco use, dyslipidemia, obesity, and diabetes. However, behavioral and pharmacological interventions to improve risk scores and reduce CVD
burden have been developed in high-income countries with established healthcare
systems and reimbursement infrastructures in place to provide and pay for goods
and services. In short, current solutions are built upon a low-volume, high-cost paradigm that is unsustainable in low- and middle-income countries.
The term frugal innovation (sometimes frugal engineering) signifies the
effort to reduce the cost of a product or a service, usually by reducing its complexity, to make that product or service available to moretypically lower-income
people. In many ways, it turns the traditional innovation and development paradigm
on its head: high-tech innovation typically starts with a radical development (e.g.,
an implantable cardiac pacemaker) and innovation is characterized by incremental
improvement, addition of features, increasing complexity, and, very often, increased
Frugal Innovation: Solutions for Sustainable Global Cardiovascular Health
253
cost (e.g., an implantable, microprocessor controlled, rate-responsive, MRI-safe

cardiac pacemaker with data logging, remote diagnostics, drug-eluting leads, etc.).
Frugal innovation is sometimes called disruptive innovation because it shakes up
existing economic constraints and aims to open new, high-volume markets to
affordable solutions. Examples of frugal innovation can be found in many different
domains. For example, the Godrej & Boyce Manufacturing Company based in
Mumbai, India sought a frugal solution to the problem of food storage in that country. Only about 20 % of households in India have access to refrigeration and about
around one-third of all food spoils before it can be consumed. Godrej & Boyce
developed the US $70 Chotukool, a 7.8-kg (17.2-lb), 45-l (2746-in.3), batterypowered plastic refrigerator that can cool down to 810 C (4650 F) [12]. Frugal
innovation is not restricted to physical products but can also include services. For
example, through radical outsourcing and contractual arrangements, the Bharti
Airtel telecommunications company is able to offer cellular phone service for US
$0.01 per minute [13], thereby making telecommunication affordable to millions of
people for whom such services were previously out of reach.
These examples illustrate the high-volume, low-cost business model that frugal
solutions engender, a model that must be adopted by healthcare industries and infrastructures if the looming global CVD crisis is to be averted.
Frugal Innovation in Medicine and Healthcare

Frugal Device Innovations
The need for frugal innovation in healthcare is well illustrated by the medical device
market. In 2010 the device industrywhich is dominated by a small number of
manufacturers headquartered mostly in high-income countriesgenerated about
US $260 billion in sales; notably, just 13 % of the worlds population accounted for
76 % of total medical device use [14]. However, a number of innovative devices that
exemplify the high-volume, low-cost model have been developed and successfully
deployed in low-income regions. Perhaps the most famous of these is the Jaipur
foot. This prosthetic limb (sometimes referred to as the Jaipur leg) was developed
collaboratively by Dr. P. K. Sethi and Pandit Ram Chandra Sharma in 1968 [15].
Although the design of the device was acclaimed upon its invention, it was the business and management skills of Devendra Raj Mehta that transformed the Jaipur foot
from a good idea into a global phenomenon and the darling of the frugal innovation
movement. The ultralight, durable prosthesis costs about US $45 compared to US
$12,000 for a similar US-made device. The light, durable Jaipur prosthesis allows
its wearers not only to stand and walk, but also run, climb trees, and pedal bicycles.
The success of the Jaipur foot derives not only from its innovative design, but also
from the non-profit organization (the Bhagwan Mahaveer Viklang Sahayata Samiti
or BMVSS) established by Mehta to bring the prosthesis to those who need it. Since
254
the founding of the BMVSS in 1975, more than 400,000 individuals in some 26
nations have been fitted with a Jaipur foot [16].
There are other frugal medical device success stories. The General Electric (GE)
corporation markets a US $3000 (cf. the high-income market device at US $12,000)
baby warmer called the Lullaby in 62 countries [14]. A collaboration between
biomedical engineers at Rice University, the University of Malawi, Texas Childrens
Hospital, and the 3rd Stone Design company resulted in the development of a bubble continuous positive airway pressure (bCPAP, a neonatal respiratory-assist
device) machine that costs US $160 to build (cf. the high-income market device sold
at about US $6000) [14]. A device invented by Argentinian car mechanic Jorge
Odn demonstrates that frugal innovations are not merely less expensive versions of
the tools used in high-income nations. The Odn device is a fetal extraction tool that
can, in many cases, replace forceps or vacuum extractors during vaginal delivery.
The Odn device (currently undergoing trials) consists of an insertion tool, a disposable plastic sheath, and a hand air pump. The lubricated plastic sheath is inserted
into the birth canal and is wrapped around the babys head; the air pump is used to
gently inflate an inner compartment of the sheath, which grips the babys head. The
sheath can then be pulled to extract the infant. Although the Odn devices relatively
low cost qualifies it as a frugal innovation, the fact that it can be used safely by nonexperts in a non-clinical setting greatly increases the devices potential impact in
low-income areas where complicated births must be handled without the services of
a trained physician and a modern delivery suite [17].
In general, frugally innovative medical and healthcare devices must have the following characteristics: [14]
Devices must be safe and effective in the hands of the available healthcare workforce (e.g., technicians with minimal training).
Devices must be appropriate for the local infrastructure (e.g., hand- or solarpowered in areas lacking a reliable power supply).
Devices must be appropriate for the local environment (e.g., able to withstand
extremes of heat and cold, exposure to dust and moisture).
Devices must be designed for intensive and prolonged use and have a sustainable
cost-of-ownership over the lifetime of the device (i.e., durability may be as or
more important than initial cost).
Devices must not require constant inputs of high-cost or difficult to procure disposable components (e.g., custom tubes, fittings, batteries, etc.).
Frugal Service Innovations

Frugal innovations manifest not only as tangible hardware technologies, but also as
streamlined, well managed organizations that provide a needed service. In the realm
of healthcare, the Aravind Eye Hospitals of India best exemplify innovative services. About 12 million Indians are blind, many as a result of cataracts, a disease
255
with an earlier onset in India than in the West. Founded by Dr. Govindappa
Venkataswamy in 1976 to address this need, the Aravind Eye organization has
grown from a single 11-bed hospital to a network of hospitals and care centers
throughout India with nearly 3000 beds. Avarinds success is due in large part to
Dr. Venkataswamys obsession with efficiency: Venkataswamy even spent time at
McDonalds Hamburger University in Illinois studying the time and motion principles and quality control standards the fast food empire employs in its franchises. In
Aravind Eye Hospital surgical suites, doctors stand between two operating tables.
While one patient is undergoing surgery, the next is being prepared on the adjacent
table. After finishing one procedure, the surgeons need do little more than turn to
begin work on the next patient. In 1992, faced with rising costs from suppliers,
Aravind established Aurolab, an in-network manufacturer of intraocular lenses.
Aurolab can supply the lenses at about US $2 per unit (cf. often more than US
$600 in high-income markets). Since its foundation, Aravind doctors have treated
>32 million patients and performed >4 million surgeries and currently performs
60 % as many eye surgeries annually as the UKs National Health System.
Complication rate after surgery is half that reported in Britain, and the surgeries can
be performed at about one one-thousandth of the cost. Most remarkably, the Aravind
Eye Hospitals are self-sustaining: paying customers who may opt for higher-end
services (such as private, air conditioned rooms) subsidize those who are able to pay
little to nothing [18, 19].
Frugal Innovation in Cardiovascular Disease Prevention

and Treatment
The realm of cardiovascular healthcare is not without its own instances of frugal
innovation in the domains of devices, drugs, and services.1 For example, in the early
2000s, a group of researchers and engineers at GE Healthcare in India noted that the
type of high-end diagnostic equipment they were designing was practically nonexistent in the local clinics and hospitals they visited. They proposed to develop a
prototype electrocardiogram (ECG) device that would serve the needs of lowincome communities and clinics. As GEs traditional business model, even in India,
catered to high-end buyers, managers were reluctant to green-light a high-volume,
low-cost product. However, after demonstrating that they had a functional, low-cost
design and a viable marketing and distribution plan, the project team was allocated
To date, perhaps the clearest articulation of the status of and need for frugal innovation in cardiovascular healthcare was offered by Professor Stephen MacMahon of The George Institute for
Global Health in the Lewis A. Conner Memorial Lecture at the 2012 American Heart Associations
Scientific Sessions. A video of Professor MacMahons lecture and information about The George
Institutes pioneering work can be found at http://www.georgeinstitute.org. The authors of this
chapter are indebted to Professor MacMahons research and advocacy in this area.
256
a modest budget and an even more modest timeline for product development. In less
than two years, the MAC 400 ECG was released. This laptop-sized device made use
of inexpensive off-the-shelf microprocessors; simplified signal-processing algorithms; and a small, durable paper strip printer adapted from those used in ticket
kiosks in dusty bus terminals. The MAC 400 was sold for US $1500 (cf. its semiportable predecessor that cost US $10,000) and was a success for GE Healthcare.
Since the introduction of the MAC 400, GE has continued to develop and market a
line of low-cost ECGs. As processing power has increased and the cost of other
components has decreased, the price tag of the newer devices has dropped to about
one-third of the original MAC 400, allowing clinicians to provide ECG services at
US $0.20 per test [20].
Providing adequate healthcare in low-income nations is sometimes made difficult by a paucity of practicing physicians. In India, for example, most primary
healthcare is delivered by nonphysician health workers (NPHWs). To date, Indian
public health efforts administered by NPHWs have focused primarily on maternal
and child health programs and have had considerable success. Researchers sought
to determine whether the work of NPHWs could successfully be extended to cardiovascular care. The Rural Andhra Pradesh Cardiovascular Prevention Study
(RAPCAPS) was conducted in 44 villages in India from 20062008. In one arm of
the study, the villages were randomized to either a clinical intervention treatment
group or a control group. The primary objective of treatment was to boost the identification of individuals at high risk for CV events (i.e., those with a self-reported
history of stroke, heart attack, or angina) who might be candidates for drug therapy.
Treatment consisted of use of an opportunistic clinical screening tool (a simple,
hard-copy algorithm) by NPHWs. For those individuals assessed to be high-risk, the
algorithm was used to determine appropriate treatment decisions. After assessment
by NPHWs, patients consulted with physicians and the physicians recorded their
treatment decisions. About 18 months after initiation of the opportunistic clinical
screening, every household in every treatment and control village was surveyed to
identify high-risk individuals and question them whether they had been assessed
for risk of heart disease/stroke/angina by a health-care provider in the past 12
months? The percentage of high-risk individuals identified in the household survey
who reported having been screened for CVD was 12 % higher in the treatment villages compared to the control villages (63.4 % vs. 51.4 %, P = 0.026). Additionally,
comparisons of NPHW assessments vs. physician assessments revealed that only
3 % of the individuals classified as high risk by NPHWs would have been classified
as low risk by physicians. Drug treatment decisions made by the NPHWs using the
algorithm were the same as those made by the physicians in 88.5 % of cases of
suspected stroke and 87.2 % of cases of suspected heart attack or angina. These
findings suggest the services of NPHWs could potentially be used to improve CV
care in rural India. The authors acknowledge that NPHWs would doubtless make
more diagnostic and management decision errors than trained doctors, but the
adverse impact of such errors would be minimal: high-risk individuals misclassified
257
as low-risk might not receive appropriate treatment, but it is likely they would have
gone untreated without an NPHW CV program anyway, given current treatment
rates; low-risk individuals misclassified as high-risk would be unlikely to suffer
serious adverse events given the excellent overall safety of the various CV drug
therapies available [21].
Another Indian effort, spearheaded in 2000 by Dr. Devi Shetty, aims to be the
heart surgery equivalent of the Aravind Eye Hospitals. Dr. Shettys initial 1000-bed
hospital, located near the electronics manufacturing district of Bengaluru,
specializes in cardiovascular care and surgery. Adopting a philosophy of high efficiency, high patient throughput, and a tiered fee structure similar to Aravind, by
2010 the Narayana Institute of Cardiac Sciences (as it is now known) was performing about 600 heart surgeries a week. The high number of patients treated in the
hospitals operating rooms allows surgeons to specialize and gain a high level of
efficiency and expertise in a particular procedure. Open heart surgery costs an average of US $2000 (cf. US $20,000100,000 in the US) and success rates match the
best seen in the US. The success of the cardiac hospital has lead to explosive growth:
Narayana Health now operates 23 multispecialty hospitals in 14 cities [22, 23].
Elements of Frugal Innovation

Innovations are always radical, novel, imaginative, unobvious. For this reason we
will not dare to offer a simple recipe for something that is, by definition, not attainable through routine means. There are, however, a number of elements that seem to
characterize frugal innovations. These may serve as guideposts for those seeking
frugal solutions to seemingly intractable problems.
Frugal innovations target the bottom of the pyramid. A term introduced by Prahalad
and Hart, the bottom of the pyramid refers to high-population, low-income markets [24]. In short, frugal innovations adopt a high-volume, low-cost profit model.
Frugal innovations are disruptive. These innovations disrupt current economic
systems, service infrastructures, distribution channels, public-private and other
boundaries, andperhaps most importantlytightly held (and, therefore, often
tacit) paradigms about how things must work.
Frugal innovations are not necessarily scaled-back, cheaper versions of existing
technologies or systems. Frugal innovations achieve more with fewer resources.
Frugal innovations employ appropriate technologiesthat is, appropriate for
the intended goal, the physical environment, and the end user.
Frugal innovations do not allow the perfect to be the enemy of the good. The
standards used to judge an innovation in one country, culture, region, or economic stratum should not be used to judge those deployed elsewhere. Frugal
innovations are best conceived and assessed at the level of populationnot individualbenefit and gain.
258
Conclusion
In his Lewis A. Conner Memorial Lecture at the 2012 American Heart Associations
Scientific Sessions, Stephen MacMahon spoke bluntly to his audience of CV
researchers, clinicians, and public health practitioners: the tremendous advances in
CV science, public health/disease prevention, diagnosis, surgery, and medicine that
higher-income nations have enjoyed for the past decades represent only the opening
maneuvers in a much larger campaign against a looming global CVD epidemic. We
may one day look back and see the development of risk scores, echocardiographic
imaging, and our well furnished pharmacopeia as trivial achievements when compared to the task of spreading these advances to a global population. Frugal innovation provides a conceptual way forward. Recently initiated academic programs,
such as the Frugal Innovation Lab sponsored by the School of Engineering at Santa
Clara University; [25] publications, such as The Journal of Frugal Innovation by
Springer; conferences, such as the International Conference on Frugal Innovation
planned for February, 2015 in Singapore; [26] and research funding opportunities,
such as the Indo-US Collaborative Program on Affordable Medical Devices sponsored by the US National Institutes of Health [27] all attest to a growing recognition
of the unmet needs and untapped potential of those at the bottom of the pyramid.
From the population perspective, the bottom of the pyramid represents not only a
market for procedures and devices to treat existing disease, but also a public health
target for three levels of disease prevention: secondary prevention among those at
highest risk (i.e., those who have suffered an event), primary prevention (i.e., prevention among those with risk factors), and primordial prevention (i.e., the prevention of the development of risk factors). While the systems needed to attack primary
and secondary prevention may progress most expeditiously through frugal and
innovative therapeutic systems (e.g., medications for blood pressure, cholesterol,
and diabetes management), primordial prevention presents a unique challenge: the
need not only to change the beliefs and attitudes within populations about cardiovascular health, but also to devise frugal and innovative disease prevention solutions where healthy options become the default options for entire populations. If
successful, such frugal innovations will disrupt the predicted dismal risk factor,
event, and treatment trends and reverse a population emergency that will cost tens
of millions of preventable deaths [11] in the coming decades.
References
1. Reddy KS. Cardiovascular disease in non-western countries. N Engl J Med.
2004;350:243840.
2. Ford ES, Ajani UA, Croft JB, Critchley JA, Labarthe DR, Kottke TE, Giles WH, Capewell
S. Explaining the decrease in U.S. deaths from coronary disease, 19802000. N Engl J Med.
2007;356:238898.
259
3. Lim SS, Vos T, Flaxman AD, Danaei G, Shibuya K, Adair-Rohani H, Amann M, Anderson
HR, Andrews KG, Aryee M, Atkinson C, Bacchus LJ, Bahalim AN, Balakrishnan K, Balmes
J, Barker-Collo S, Baxter A, Bell ML, Blore JD, Blyth F, Bonner C, Borges G, Bourne R,
Boussinesq M, Brauer M, Brooks P, Bruce NG, Brunekreef B, Bryan-Hancock C, Bucello C,
Buchbinder R, Bull F, Burnett RT, Byers TE, Calabria B, Carapetis J, Carnahan E, Chafe Z,
Charlson F, Chen H, Chen JS, Cheng AT, Child JC, Cohen A, Colson KE, Cowie BC, Darby S,
Darling S, Davis A, Degenhardt L, Dentener F, Des Jarlais DC, Devries K, Dherani M, Ding
EL, Dorsey ER, Driscoll T, Edmond K, Ali SE, Engell RE, Erwin PJ, Fahimi S, Falder G,
Farzadfar F, Ferrari A, Finucane MM, Flaxman S, Fowkes FG, Freedman G, Freeman MK,
Gakidou E, Ghosh S, Giovannucci E, Gmel G, Graham K, Grainger R, Grant B, Gunnell D,
Gutierrez HR, Hall W, Hoek HW, Hogan A, Hosgood HD, 3rd, Hoy D, Hu H, Hubbell BJ,
Hutchings SJ, Ibeanusi SE, Jacklyn GL, Jasrasaria R, Jonas JB, Kan H, Kanis JA, Kassebaum
N, Kawakami N, Khang YH, Khatibzadeh S, Khoo JP, Kok C, Laden F, Lalloo R, Lan Q,
Lathlean T, Leasher JL, Leigh J, Li Y, Lin JK, Lipshultz SE, London S, Lozano R, Lu Y, Mak
J, Malekzadeh R, Mallinger L, Marcenes W, March L, Marks R, Martin R, McGale P, McGrath
J, Mehta S, Mensah GA, Merriman TR, Micha R, Michaud C, Mishra V, Mohd Hanafiah K,
Mokdad AA, Morawska L, Mozaffarian D, Murphy T, Naghavi M, Neal B, Nelson PK, Nolla
JM, Norman R, Olives C, Omer SB, Orchard J, Osborne R, Ostro B, Page A, Pandey KD, Parry
CD, Passmore E, Patra J, Pearce N, Pelizzari PM, Petzold M, Phillips MR, Pope D, Pope CA,
3rd, Powles J, Rao M, Razavi H, Rehfuess EA, Rehm JT, Ritz B, Rivara FP, Roberts T,
Robinson C, Rodriguez-Portales JA, Romieu I, Room R, Rosenfeld LC, Roy A, Rushton L,
Salomon JA, Sampson U, Sanchez-Riera L, Sanman E, Sapkota A, Seedat S, Shi P, Shield K,
Shivakoti R, Singh GM, Sleet DA, Smith E, Smith KR, Stapelberg NJ, Steenland K, Stockl H,
Stovner LJ, Straif K, Straney L, Thurston GD, Tran JH, Van Dingenen R, van Donkelaar A,
Veerman JL, Vijayakumar L, Weintraub R, Weissman MM, White RA, Whiteford H, Wiersma
ST, Wilkinson JD, Williams HC, Williams W, Wilson N, Woolf AD, Yip P, Zielinski JM, Lopez
AD, Murray CJ, Ezzati M, AlMazroa MA, Memish ZA. A comparative risk assessment of
burden of disease and injury attributable to 67 risk factors and risk factor clusters in 21 regions,
19902010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet.
2012;380:222460.
4. Danaei G, Finucane MM, Lin JK, Singh GM, Paciorek CJ, Cowan MJ, Farzadfar F, Stevens
GA, Lim SS, Riley LM, Ezzati M. National, regional, and global trends in systolic blood pressure since 1980: systematic analysis of health examination surveys and epidemiological studies with 786 country-years and 5.4 million participants. Lancet. 2011;377:56877.
5. Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A, Bahonar A, Chifamba J,
Dagenais G, Diaz R, Kazmi K, Lanas F, Wei L, Lopez-Jaramillo P, Fanghong L, Ismail NH,
Puoane T, Rosengren A, Szuba A, Temizhan A, Wielgosz A, Yusuf R, Yusufali A, McKee M,
Liu L, Mony P, Yusuf S. Prevalence, awareness, treatment, and control of hypertension in rural
and urban communities in high-, middle-, and low-income countries. Jama. 2013;310:
95968.
6. Farzadfar F, Finucane MM, Danaei G, Pelizzari PM, Cowan MJ, Paciorek CJ, Singh GM, Lin
JK, Stevens GA, Riley LM, Ezzati M. National, regional, and global trends in serum total
cholesterol since 1980: systematic analysis of health examination surveys and epidemiological
studies with 321 country-years and 3.0 million participants. Lancet. 2011;377:57886.
7. World Bank Group. The World Bank: working for a world free of poverty. 2014. www.
worldbank.org. Accessed 28 May 2014.
8. Zhao D, Wu Z, Wang W, Yue L, Zhou M. The trend of incidence rate of acute coronary events
from 19841997 in Beijing area: Sino-MONICA project. China J Cardiol. 2000;28:147.
9. Mensah GA. Ischaemic heart disease in Africa. Heart. 2008;94:83643.
10. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi R, Iqbal
R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-Jaramillo P, Oguz A,
Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren A, Teo KK. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and
260
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.

low-income countries (the PURE Study): a prospective epidemiological survey. Lancet.
2011;378:123143.
Anand SS, Yusuf S. Stemming the global tsunami of cardiovascular disease. Lancet.
2011;377:52932.
Chotukool: Keeping things cool with frugal innovation. WIPO magazine. 2014. http://www.
wipo.int/wipo_magazine/en/2013/06/article_0003.html. Accessed 28 May 2014.
Airtel. 2014. www.airtel.in. Accessed 28 May 2014.
Emerging economies drive frugal innovation. Bull World Health Organ. 2013;91:67.
Jaipur foot: the real story. GoodNewsIndia, Magazine. 2014. http://www.goodnewsindia.com/
index.php/magazine/story/jaipur-foot/. Accessed 28 May 2014.
Kanani R. Jaipur foot: one of the most technologically-advanced social enterprises in the
world. Forbes. 2014. http://www.forbes.com/sites/rahimkanani/2011/08/08/jaipur-foot-oneof-the-most-technologically-advanced-social-enterprises-in-the-world/. Accessed 28 May
2014.
Kelland K. Analysis: Healthcare sees emerging future in frugal innovation. Reuters. 2014.
http://www.forbes.com/sites/rahimkanani/2011/08/08/jaipur-foot-one-of-the-mosttechnologically-advanced-social-enterprises-in-the-world/. Accessed 28 May 2014.
Rosenberg T. A hospital network with a vision. The New York Times. 2014. http://opinionator.
blogs.nytimes.com/2013/01/16/in-india-leading-a-hospital-franchise-with-vision. Accessed
28 May 2014.
Aravind Eye Care System. 2014. http://www.aravind.org/. Accessed 28 May 2014.
Musselwhite N. How GE healthcare married community needs with corporate imperatives and
birthed a business segment and a movement. Geo Strategy Partners. http://www.slideshare.net/
ajaydiit/iem-assignment. Accessed 28 May 2014.
Joshi R, Chow CK, Raju PK, Raju KR, Gottumukkala AK, Reddy KS, Macmahon S, Heritier
S, Li Q, Dandona R, Neal B. The rural Andhra Pradesh cardiovascular prevention study
(RAPCAPS): a cluster randomized trial. J Am Coll Cardiol. 2012;59:118896.
Narayana Health. 2014. http://www.narayanahealth.org/. Accessed 28 May 2014.
First break all the rules: the charms of frugal innovation. Economist. 2014. http://www.economist.com/node/15879359. Accessed 28 May 2014.
Prahalad CK, Hart SL. The fortune at the bottom of the pyramid. strategy+business. 2002. First
Quarter.
Frugal Innovation Lab. Santa Clara University. 2014 http://www.scu.edu/engineering/frugal/.
Accessed 28 May 2014.
International conference on frugal innovation: 2527 February 2015 Singapore. National
University of Singapore. 2014. https://sites.google.com/site/frugalmeeting/. Accessed 28 May
2014.
Indo-US collaborative program on affordable medical devices (R03). US National Institutes of
Health. 2014. http://grants.nih.gov/grants/guide/pa-files/PAR-13-390.html. Accessed 28 May
2014.
Atrial Fibrillation and Stroke Prevention

Antonio Carlos Camargo de Carvalho, Renato D. Lopes,
and Angelo A.V. de Paola
Introduction
Atrial fibrillation (AF) is a supraventricular arrhythmia, usually tachycardic, where
in irregular atrial activation occurs, almost always leading to the loss of 2025 % of
cardiac output. These values may be higher in cases of hypertrophic myocardium
resulting from hypertension or hypertrophic cardiomyopathy [1].
AF mostly occurs in late-onset cardiomyopathies, pericarditis, mitral valve disease, bradycardiatachycardia syndrome (where it may present with low ventricular
rate) and acute myocardial infarction [2]. AF is almost always concomitant with
severe myocardial damage in patients with the latter condition and causes onset or
worsening of heart failure in all of these conditions. In this chapter we will exclu-
A.C.C. de Carvalho, M.D., Ph.D. (*)

Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil
e-mail: tillacarvalho@gmail.com
R.D. Lopes, M.D., Ph.D.
Paulista School of Medicine, Federal University of Sao Paulo, Sao Paulo, USA
Division of Cardiology, Duke University Medical Center, Durham, NC, USA
Brazilian Institute of Clinical Research, Sao Paulo, Brazil
e-mail: renato.lopes@duke.edu
A.A.V. de Paola, M.D., Ph.D.
Paulista School of Medicine, Federal University of So Paulo, So Paulo, Brazil
Arrhythmia Department of the Paulista School of Medicine, Federal University of So Paulo,
So Paulo, Brazil
e-mail: depaola@uol.com.br
DOI 10.1007/978-3-319-22357-5_25
261
262
A.C.C. de Carvalho et al.
sively focus on its relevance as a primary arrhythmia in the genesis and onset of
thromboembolic events. We will not discuss the advantages and disadvantages of
rhythm control or reversal of AF, paroxysmal or persistent AF, or AF triggered by
extracardiac problems.
Prevalence and Relevance of the Problem

AF is currently a relevant problem, and its importance has been increasing as the
world population ages, which suggests we may have an actual AF epidemic in the
coming decades. Public health programs must be prepared to face that challenge, or
they will risk having expenses much higher than those predicted for the treatment of
stroke sequelae.
Currently, AF is already the most commonly found arrhythmia in clinical
practice and accounts for approximately one-third of hospitalizations for rhythm
disturbances in the US. Its prevalence in the general population is approximately
0.41.0 %, although it reaches approximately 6 % of the population in the sixth
decade of life and 910 % in septuagenarian or octogenarian patients, thus showing
an explosive growth among the elderly population. It is estimated that the US population with AF will increase from the current 2 million people to approximately
12 million by 2050 [35].
The importance of AF is acknowledged in Brazil, where significant changes in
the population distribution have occurred recently, with an increase in the average
life expectancy of the population, although the Brazilian numbers are not yet fully
known. To determine and analyze those numbers with adequate knowledge and to
adequately establish future treatment plans, the Brazilian Society of Cardiology
(Sociedade Brasileira de CardiologiaSBC) established in 2011 a National
Registry on Atrial Fibrillation [6], already underway, coordinated by Renato Lopes,
which plans to catalog 5000 cases of AF in 60 centers distributed across all Brazilian
regions, with completion scheduled for 2016.
Those numbers certainly will provide concrete and regional epidemiological
data on etiology and treatments that will help in outlining public health projects
aimed at minimizing the problems caused by AF.
In 2012, we surveyed data from 2009 to 2011 on AF in a tele-electrocardiogram
(tele-ECG)system, which records electrocardiograms from 60 outpatient healthcare centers and from 120 ambulances of the Emergency Medical Service (Servio
de Atendimento Movl de Urgncia, SAMU) in the city of So Paulo. AF or atrial
flutter was present in 4919 of 209,341 (2.3 %) consecutive electrocardiograms analyzed, evenly distributed over the three years analyzed, and the heart rate was
higher than 100 beats per minute [7] in 1863 cases (Fig. 1). Those numbers confirm
that the AF problem is constant, prevalent and, as we shall see below in the treatment section, very serious.
263
3.00%
2.50%
2.00%
AF
1.50%
AFRVR
1.00%
Atrial flutter
0.50%
0.00%
AF
2009
2010
2011
Mean
2.51%
2.25%
1.89%
2.22%
AFRVR
0.93%
0.79%
0.94%
0.89%
Atrial flutter
0.14%
0.12%
0.12%
0.13%
Total ECGs analyzed: 209,341

Total ECGs with AF and flutter: 4,919
Fig. 1 Atrial fibrillation and atrial flutter data from the tele-ECG system. AFRVR atrial fibrillation
with rapid ventricular response (DeMoraes et al. [7])
Stroke and Other Complications in AF

The occurrence of AF is associated with important comorbidities that worsen quality of life and decrease survival rate. The need to take more medications, with higher
costs to patients, more frequent blood sampling for laboratory tests, more frequent
visits to the doctors office or hospitalizations, complications from the use of anticoagulants, increased fatigue with more frequent development of heart failure and
functional limitations resulting from limb paralysis are factors that significantly
worsen quality of life, not to mention in crease risk of death [8, 9].
However, the most worrisome AF data are on stroke. People with AF have a
stroke rate approximately fivefold that of the general population, 15 % of all strokes
occur in people with AF (25 % among elderly), and the risk of stroke in AF increases
from 1.5 per year in the age group from 50 to 59 years to 23.5 % per year in the age
group of 8089 years [10, 11].The average risk of stroke in AF in the studies Atrial
Fibrillation Investigators, Stroke Prevention and Atrial Fibrillation-SPAF and in the
Framingham cohorts [1214] ranged from 3.0 to 4.2 % per year, being higher in
many elderly people. The risk factors identified for stroke in patients with AF are
outlined in Table 1.
We should also keep in mind that AF is the main cause of embolic events of
cardiac origin, occurring in nearly half those events, followed distantly by acute
myocardial infarction (AMI) and left ventricular aneurysm [15].Furthermore,
AF-related stroke is a more severe stroke, with a higher likelihood of causing significant motor sequelae and twice as likely to leave the patient permanently bedridden; therefore, it has a higher likelihood of death [10, 11].
However, we must remember that thromboembolic events occur in other
areas in patients with FA, although stroke is frequently the most severe outcome.
264
Table 1 Risk of stroke in atrial fibrillation
Study
Atrial fibrillation
investigators
Patient population
Five randomized studies
N = 1593, 106 strokes in an average
follow-up period of 1.4 years
Risk factors identified

Age
Hypertension
Prior cerebral ischemia
Diabetes
106/1.593 = 6 %/1.4 = 4.2 % per year

Stroke prevention and atrial Two randomized studies
FibrillationSPAF
N = 854, 68 strokes in an average
follow-up period of 2.3 years
Blood pressure> 160 mmHg

Prior cerebral ischemia
Recent heart failure
Combination of age 75
years and female gender
68/854 = 7 %/2.3 = 3.0 % year

Framingham heart study
Newly identified AF
N = 705
Age
Female
Diabetes
1.26.6 % per year according to the risk score

Source: Atrial Fibrillation Investigators; [12] SPAF; [13] risk score from Framingham heart
study [14]
The incidence of stroke ranged from 48 to 82 %, the incidence of limb embolism

ranged from 13 to 38 %, and visceral embolism occurred in 442 % of patients
in several case series that analyzed arterial embolism in AF [1620]
Risk Scores for Stroke and Bleeding

The attempt to characterize risk factors for stroke and systemic embolism in nonvalvular AF in several studies [1214] led to the identification of the following elements that comprise the CHADS2 (congestive heart failure, hypertension, advanced
age, diabetes, stroke) score in 2001: Prior stroke or transient ischemic attack (TIA),
2 points, and 1 point each for diabetes mellitus, heart failure, hypertension and
advanced age (>75 years). Thus, the score ranges from 0 to 6 and is easy to use: 0
means low risk, 1 means intermediate risk, and 2 or higher means high risk for
events. CHADS2 [21] provides an adjusted risk of stroke ranging from 1.9 % in
patients with risk 018.2 % for patients with score 6 and is recommended in several
guidelines as a good indicator of risk of stroke and embolic events [22].
In 2010, Lip et al., based on data from the EuroSurvey, proposed a refinement of
CHADS2, the CHA2DS2-VASc [23], which ranges from 0 to 9 points. In that new
score system, hypertension, diabetes and heart failure (or ejection fraction <40 %)
continue to score 1 point, as in CHADS2; stroke or TIA (or any other thromboembolic event) continues to score 2 points; age older than 75 years scores 2 points; age
between 65 and 74 years of age 1 point; and the presence of vasculopathy in another
265
area and female gender also score 1 point. That new score is more sensitive in the
low-risk range and apparently enables us to better separate who effectively lacks
risk factors and is not required to use anticoagulants from who has low risk but
requires medications.
It is extremely important to accurately assess the risk of bleeding when intending
to indicate the use of oral anticoagulants. That condition is particularly difficult in
AF because many known risk factors for the occurrence of thromboembolic events
are also risk factors for bleeding, including heart failure, advanced age, hypertension, prior stroke and concomitant use of antiplatelet drugs. The HAS-BLED [24]
risk score was developed using scores from 0 to 9, and a score >3 indicates a high
risk of bleeding (Table 2). That score serves as a counterpoint to the clinical decision of whether to use anticoagulants in a patient with AF and reminds us of the
limitations we face in decision-making processes because a patient at high risk for
stroke most likely will also be a patient at high-risk for bleeding. In those cases, the
careful use of drugs at lower doses, or a slightly lower international normalized ratio
(INR) in the case of warfarin, is most likely the most indicated.
Warfarin: Advantages, Complications and Limitations

Warfarin has been used for over 50 years and is undoubtedly a highly effective drug.
It was initially used in humans only after thoroughly proving it caused severe bleeding and death in rats because of its anticoagulant effect. Due to the prothrombotic
effect that occurs in some conditions and in AF with consequent severe systemic
thromboembolic events, there was a demand for an effective anticoagulant, and
hence, the opportunity to use warfarin emerged.
Table 2 Breakdown of the CHA2DS2-VASc score and annual rate of stroke according to the
number of points scored in that scale
Abbreviation
C
H
A2
D
S2
V
A
Sc
Parameter
CHF -congestive heart
failure
Hypertension
Age> 75 years
Diabetes
Prior stroke or TIA
Vascular disease
Age between 65 and 74
years
Female gender
Modified based on references [23, 24, 41]
Value
1
Points in CHA2DS2
VASc score
0
Annual rate of
stroke* (%)
0
1
2
1
2
1
1
1
2
3
4
5
6
1.3
2.2
3.2
4.0
6.7
9.8
7
8
9
9.6
6.7
15.2
266
Several studies have shown a significant reduction of events in patients treated

with warfarin versus placebo or antiplatelet drugs, and the meta-analysis by Hart
et al. [25] showed a 61 % decrease in the risk of stroke, 31 % decrease in death rates,
and 44 % decrease in stroke or acute myocardial infarction (AMI).
Warfarin exercises its anticoagulant effect by inhibiting the -carboxylation of
vitamin K-dependent coagulation factors (factors II, VII, IX and X), and its effect
may be measured by analyzing the result of the INR. Normal INR has an approximate
value of 1, and we usually try to keep the INR between 2 and 3 because values higher
than 3 significantly increase the risk of bleeding; conversely, INR values lower than 2
do not provide adequate protection against thromboembolic events. Thus, patients
using warfarin must remain in a narrow INR range to prevent the risk of ischemic
stroke (low INR, inadequate anticoagulation) or hemorrhagic stroke or other severe
bleeding events (high INR, excessive anticoagulation). Thus, the individual use of
warfarin has a severe risk of bleeding, and there is also the risk of its being ineffective
if not within an optimal therapeutic range. Warfarin may also be used in patients with
chronic renal failure or undergoing dialysis.
The narrow therapeutic range is one of the main limitations to the use of warfarin.
We could further note that warfarin, combined with insulin, is one of the most commonly cited drugs that cause complications in emergency room visits in the US [26].
Other important limitations include interactions with food and drugs, the need to
collect blood periodically for INR tests and important laboratorial variations in the
INR analysis, which may cause serious problems of under or overdosing. There is
some resistance from physicians in using the drug in very elderly individuals or
those with increased risk of bleeding, which contributes to a high number of patients
needing to take the medication who are ultimately excluded from the treatment.
Some studies estimate that the number of high-risk patients who are not treated with
warfarin may reach 50 %, regardless of whether it is a university or general hospital
[27]. Furthermore, there is evidence that warfarin use does not increase with higher
CHADS2 scores, remaining at approximately 60 % of the optimal use, which is
highly undesirable because it prevents many patients in extreme need from receiving
this medication [28]. Data have been published confirming the care required when
using warfarin in very elderly patients: Hylek et al. [29] reported 13 % severe hemorrhagic complications in people older than 80 years, with 26 % of patients discontinuing the treatment after using warfarin for one year. Those data emphasize the need to
use warfarin with discretion and common sense, ensuring that patients are able to
understand the caution required when using that type of drug and that patients will
not stop taking the drug, use other drugs concomitantly or miss the collection of INR
In So Paulo, returning to the tele-ECG experiment mentioned above [7], we
found that 70 % of AF cases diagnosed were classified as high-risk, although only
24 % of those cases were anticoagulated with warfarin and made no use of new
drugs. All of the difficulties in using warfarin combined with the difficulty to
schedule appointments in the Brazilian public health system, the consultations
with different physicians each time, the fear that cardiologists have in prescribing
a high-risk drug, especially to elderly patients, and comorbidities that may lead
patients to take other medications, including anti-inflammatory drugs, make it
extremely difficult to succeed in reaching a suitable level of regular warfarin use.
267
Therefore, many strokes that could be prevented are not, even though the drug has
an extremely low cost. Thus, similar to other undeveloped countries, Brazil has a
lower rate of permanently adequate INR (meaning improper medication, nonstandardized laboratories or external interference with the drug), which, added to
the logistical difficulties of the Brazilian healthcare system, hinders even more the
proper maintenance of the treatment. The information to be collected from the AF
Registry of the Brazilian Society of Cardiology will be extremely important to
better assess that scenario and confirm or refute the results found in So Paulo in
the AF sample analyzed through tele-ECG.
Antiplatelet Drugs and New Therapeutic Options

Aspirin
Aspirin is always less effective than warfarin. Aspirin compared to placebo reduced
stroke by 19 %, being more effective in secondary than primary prevention (40 and
125 NNT, respectively) and reduced by 13 % stroke with sequelae [25]. Most studies,
except SPAF 1, showed no expressive and significant results with the use of aspirin.
Clopidogrel
The ACTIVE-W [30] study compared warfar into aspirin and clopidogrel in 6706
patients with AF and at least one additional risk for vascular events. The study was
discontinued early by the Data and Safety Monitoring Board (DSMB) due to warfarins superiority (primary objective consisting of stroke, non-Central Nervous
System (CNS) systemic embolism, AMI or vascular deathannual risk of 3.90 %
in the warfarin group and 5.60 % in the aspirin + clopidogrel group). In turn, the
ACTIVE-A [31] study tested aspirin + clopidogrel compared to aspirin alone in
patients deemed unsuited to receive warfarin, with AF and another risk factor for
vascular events. The combination resulted in an 11 % decrease in the primary objective when compared to aspirin alone, although bleeding increased from above 1.3 %
per year to 2.0 % per year. Briefly, three years of treatment with aspirin + clopidogrel would prevent 28 strokes compared to the use of aspirin alone, although they
would cause 20 severe bleeding events, including three fatal. The indication of the
combined use of aspirin + clopidogrel instead of aspirin alone in patients who cannot take warfarin is still questionable, was not approved by the Federal Drug
Administration (FDA) and became much farther from approval upon the release of
new anti-Xa agents and direct thrombin inhibitors.
The development of new antithrombotic agents that would provide new therapeutic options involves a number of prerequisites to achieve an optimal drug: as or
more effective than warfarin, with a larger therapeutic window, with a low number
of adverse effects; lack of need for routine monitoring of anticoagulation, absence
268
or low level of food or drug interactions, oral fixed dose, rapid onset and termination
of drug action, and, finally, low cost.
Although not all of those prerequisites may be achieved, some new drugs meet
several of them, and with those qualifications, they are already or will soon be available in the international and Brazilian market. We will briefly describe below the
main new products currently used for the prevention of stroke in AF.
Dabigatran
Dabigatran is a direct thrombin inhibitor, which proved effective in the RELY study
[32] when compared to warfarin. The study evaluated 18,113 patients with nonvalvular AF and tested two doses of dabigatran: 110 mg twice daily did not perform
worse than warfarin regarding stroke and systemic embolism prevention (0.91 relative risk, RR [95 % confidence interval, CI 0.531.11]; p < 0.001 for non-inferiority),
albeit showing a lower number of major bleeding events (dabigatran, 2.71 % per
year; and warfarin, 3.36 % per yearp = 0.003). The results with a dose of 150 mg
twice daily were superior compared to warfarin regarding stroke and systemic
embolism (0.66 RR [95 % CI 0.530.82]; p < 0.001 for dabigatran superiority),
albeit with results similar to warfarin regarding major bleeding events. Due to concerns about bleeding, the FDA approved a dose of 75 mg twice daily for patients
with creatinine clearance ranging from 15 to 30 ml/min, and the drug should not be
used in patients with clearance <15 ml/min or patients undergoing dialysis [33].
Thus, the lower dose could be more indicated in cases of increased risk of bleeding,
and the higher dose could be chosen in cases of reduced risk of bleeding, considering that the higher dose was superior to warfarin in decreasing thromboembolic
events while it performed similarly regarding the risk of severe bleeding. The realworld clinical practice will reveal whether those parameters of the RELY study are
maintained and whether the drugs effect in the elderly is well tolerated.
Rivaroxaban
Rivaroxaban is an oral inhibitor of factor Xa that ultimately inhibits thrombin formation through tissue factor pathways and the intrinsic pathway. Rivaroxaban was
evaluated in the ROCKET-AF study (focused on cases with the highest-risk
CHADS2) and was compared to warfarin in 14,264 patients with non-valvular AF at
a dose of 20 mg once daily (15 mg/day in chronic renal patients with clearance from
30 to 49 ml/min, excluding from the study patients with clearance <30) for noninferiority assessment, and the number of strokes or systemic embolism was the
primary objective [34]. In the intention-to-treat (ITT) analysis, 2.1 % events per
year occurred with rivaroxaban and 2.4 % per year with warfarin (hazard ratio, HR
0.88 [95 % CI 0.741.03]; p < 0.001 for non-inferiority),and the total rates of major
269
or minor bleeding events were 14.9 % for rivaroxaban and 14.5 % for warfarin (HR
1.03; p = 0.44). However, a relative reduction of 33 % in intracranial bleeding and of
50 % in fatal bleeding occurred when compared to warfarin. Rivaroxaban is a valid
alternative to treat AF, especially in high-risk cases for bleeding and, like the other
new agents, requires no treatment monitoring through blood testing.
Apixaban
Apixaban is another oral inhibitor of factor Xa used twice daily, excreted biliarily
(two-thirds) and renally (one-third), similarly to rivaroxaban. Apixaban was evaluated in the ARISTOTLE study [35] in 18,201 patients and compared to warfarin.
The study showed a rate of stroke and systemic embolism of 1.27 % per year in the
apixaban group and of 1.60 % in the warfarin group (HR 0.79 [95 % CI 0.660.95];
p < 0.0001 for non-inferiority and 0.011 for superiority). A relative decrease of 49 %
in hemorrhagic stroke (0.51 HR [95 % CI 0.350.75]), 31 % in severe bleeding
(0.69 HR [95 % CI 0.600.80]) and 11 % in overall mortality rate (0.89 HR [IC
95 % 0.800.99]) were observed. This drug will likely have a very successful release
into the market thanks to its excellent results in the ARISTOTLE study. It needs to
be used twice daily and may apparently be used safely inpatients with renal dysfunction, although the data supporting that hypothesis were derived from a substudy
of the main study with a small number of patients. There is no antidote for apixaban,
and it is unclear whether an antidote will be necessary because of the short half-life
of this drug. Preliminary studies are ongoing to assess the effect of a universal antidote against any factor Xa inhibitor.
Edoxaban
Edoxaban is an oral anti-Xa agent with renal and gastrointestinal excretion evaluated
in comparison to warfarin in the ENGA-GE-AF TIMI 48 study [36], which randomized 21,105 patients with non-valvular AF for less than one year and with a CHADS2
score higher than 2. The study had an average follow-up of 2.8 years. Dose correction
was performed for chronic renal failure patients (from 60 to 30 mg), and the primary
objective was the number of strokes and systemic embolism events. The drug at doses
of 30 and 60 mg were not inferior to warfarin regarding the primary objective or
regarding safety, leading to a 46 and 53 % reduction in hemorrhagic stroke at doses
of 60 and 30 mg, respectively, and reducing severe bleeding by 20 % at the highest
dose and by 53 % at the lowest dose. A slight increase in ischemic stroke occurred
with the lowest dose, although the mortality rate from cardiovascular causes decreased
with the dose of 60 mg (4.43 % 3.85 %, 0.87 HR and 95 % CI 0.780.96).
The RELY, ROCKET AF, ARISTOTLE and ENGAGE AF studies overall showed
similar non-inferiority and safety results. Although the positive points have been
270
emphasized above, some important aspects may be limiting for new agents: medications
that need to be used twice daily, which decreases compliance with treatment; use in
patients with severe kidney disease; lack of specific antidotes in the event of severe
bleeding; and, although it may be minimized with a shorter half-life, how those agents
behave pre- and post-electrical cardioversion or post-ablation in electrophysiological
studies. The use of prothrombin complex may be useful to reverse the anticoagulation of
Xa inhibitors in emergency situations. The main characteristics of warfarin, the main
three new anticoagulant drugs approved for use in Brazil, and the comparisons of specific effects of those agents with warfarin are shown in Table 3.
These differences and contrasts occur in Brazil regarding not only drug use but
also interventions: [37] in FA, only 1000 ablations per year are being performed in
50 centers in the country, with a 70 % success rate; these are good results but affect
only a few patients.
Recent Guidelines
Recent guidelines from the American College of Cardiology/American Heart
Association (ACC/AHA)-2011, European Society of Cardiology (ESC) and
American College of Clinical Pharmacology (ACCP), the latter from 2012 [3840],
generally reinforce the notion that thrombin inhibitors and anti-Xa agents should be
used as an alternative to warfarin and as a class I indication when there is a risk
score above 1, without specific indication of which score. Risk factors, cost, tolerability, patient preference and drug and food interactions should be considered in
the choice of drug. The Guideline from the Brazilian Society of Cardiology on
Antiplatelet and Anticoagulant drugs in Cardiology from 2013, currently available
online [41],recommends CHA2DS2-VASc as the risk score.
The above guidelines generally agree that AF without risk factors for stroke
should be treated with aspirin (81325 mg/day) as class I, with a strong tendency for
questioning the use of aspirin alone. Patients with moderate-risk factors (age older
than 75 years or hypertension or heart failure or ejection fractionEF <35 % or
diabetes) should be treated with aspirin or warfarin (2.03.0 INR), with the ACCP
Guideline expressing a preference for warfarin rather than aspirin. Cases of AF and
high-risk factors for stroke (stroke or prior TIA, non-SNC embolism, mitral stenosis, valve prosthesis) should be anticoagulated with warfarin (2.03.0 INR).
The indication of dabigatranin the Brazilian Guideline for Anticoagulant Drugs
(Diretriz Brasileira de Anticoagulantes) [41] is classified as IA, and rivaroxaban is
classified as IB. We transcribe below the considerations made for both drugs using
the original tables (Tables 4 and 5) included in that guideline; Apixaban is now
available in Brazil but it was not at the time the last Guidelines was written and
therefore does not have a Brazilian guidelines indication. Its indication by Brazilian
doctors has followed the American and European guidelines as by Table 4 .
There is no indication of anticoagulation in AF alone in patients younger than 60
years who lack risk factors.
271
Table 3 Main characteristics of warfarin, dabigatran, rivaroxaban and apixaban and changes
found in the number of ischemic and bleeding events of the new agents compared to warfarin
Year of FDA
approval
Mechanism of
action
Oral
bioavailability of
drugs
Main excretion
pathway of drugs
Need to control
anticoagulation
Time until peak
effect
Half-life
Dose usually
recommended
Use in patients
with severe
chronic renal
failure or
undergoing
dialysis
Interactions with
other drugs
Warfarin
1954
Dabigatran
2010
Rivaroxaban
2011
Apixaban
2012
Inhibition of
factors II, VII,
IX, X
100 %
Selective
inhibition
factor IIa
37 %
Selective
inhibition factor
Xa
80 %
Selective
inhibition factor
Xa
66 %
100 % biliary
20 % biliary
80 % renal
No
65 % biliary
35 % renal
No
56 % fecal
25 % renal
No
1h
2.54 h
13 h
1217 h
713 h
815 h
110150 mg
2/day
> Risk of
bleeding
with
1530 ml/
min creat cl,
use then
75 mg 2/
day with no
info on
patients
undergoing
dialysis
Rifampicin,
quinidine,
amiodarone
20 mg 1/day
5 mg 2/day
With 3049 ml/

min creat cl;
15 mg 1/
day without info
on severe renal
failure/dialysis
2.5 mg 2/day
under moderate
dysfunction and
with < bleeding
than warfarin.
Without info on
severe renal
failure/dialysis
CYP3 A 4/5,
ketoconazole,
Macrolide
antibiotics,
clarithromycin
CYP3 A 4/5
ketoconazole,
Macrolide
antibiotics,
clarithromycin
Yes, by INR
Full
anticoagulant
effect within
7296 h
2060 h, mean
40 h
25 mg 1/day,
INR-adjusted
Yes, in both
conditions;
without dose
correction,
although those
patients have >
risk for stroke,
regardless of
drug
Increase the
effect: CYP
450, antiinflammatory
drugs, serotonin
reuptake.
Decrease the
effect:
rifampicin,
ritonavir,
bosentan,
barbiturates
(continued)
272
Table 3 (continued)
Non-inferiority
for stroke and
systemic
embolism
Reduction of
ischemic stroke
Warfarin
Warfarin as
reference
Dabigatran
Yes for 110
and 150 mg
2/day
Rivaroxaban
Yes for 20 mg 1/
day
Apixaban
Yes for 5 mg 2/
day
Warfarin as
reference
Yes, dose
150 mg VO
2.
Yes for both
doses
No
No
Yes
Yes
No
Yes
Yes
No
No
Yes
Reduction of
hemorrhagic
stroke
Reduction of
major bleeding
Warfarin as
reference
Increase of
bleeding/GI
Warfarin as
reference
Reduction of
mortality rate
Warfarin as
reference
Warfarin as
reference
Yes, dose
110 mg VO
2.
Yes, dose
150 mg VO
2.
No
Prospects and Future Planning: How to Diversify Effectively

to Achieve Better Results
After more than 50 years depending almost exclusively on a single drug for the
prevention of stroke in non-valvular AF, we are currently shifting the paradigm and
moving to a new prevention phase. Although warfarin is a powerful drug (and,
therefore, has remained in use for many decades), its rate of complications and especially its limitations have maintained the number of people with adequate treatment
at much lower rates than desired. It is also still unclear whether we should switch
from warfarin to a new agent in stable patients, with permanently adequate INR and
without complications. It is easier to make the decision of changing to new agents
in patients who fail to maintain adequate INR or even present with bleeding.
Thus, the addition of new drugs provided the opportunity to improve the results,
as occurred in the acute coronary syndrome, albeit requiring more refined drug use
criteria to prevent bleeding events from canceling out the gains from the decreases
in ischemia and necrosis. Something similar should occur in the prevention of stroke
with three or, most likely, four new drugs becoming available in the market. In the
absence of direct comparisons between those new agents, specific indications
should emerge and be properly validated for disseminating its use.
None of that will bring benefits if the cost does not allow the dissemination of
these drugs that are at least as effective as warfarin but that, overall, lead to a significant decrease in the hemorrhagic stroke rates, which is already an immeasurable
gain. Furthermore, new ways to educate patients and assess their compliance with
drug treatment and ease of return, and new formats of medical consultation, will
273

Table 4 Recommendations for treatment of atrial fibrillation with dabigatran
Recommendation
class
I
IIa
III
Indications
Dabigatranis recommended as an alternative to warfarin for
patients with non-valvular AF for whom oral
anticoagulation is indicated.
The preferential dose of dabigatran should be 150 mg 2/
day, especially for patients at higher risk for stroke and/
orthromboembolic events, provided they have low risk of
bleeding.
That drug may be indicated as an alternative to the vitamin
K antagonist anticoagulant drug inpatients with difficulty in
maintaining an adequate INR, difficulty of blood collection
for routine laboratorial tests, or by patient choice.
Dabigatranis indicated for patients with non-valvular AF
and CHA2DS2-VASc risk score = 1, under the same
conditions as above.
The preferential dose of dabigatran should be 110 mg 2/day
for patients at higher risk of bleeding (older than or 75
years, creatinine clearance ranging from 30 to 50 ml/min,
history of gastrointestinal or intracranial bleeding,
concomitant use of ASA, clopidogrel, amiodarone, chronic
or abusive use of NSAI, BMI < 18 kg/m2).
At least three weeks of uninterrupted use of dabigatran
(preferentially 150 mg 2/day) is recommended for stable
patients with persistent AF who will be subjected to
electrical or chemical cardioversion, without requiring
monitoring tests. TEE is optional. During four weeks of
cardioversion, the use of dabigatran should be maintained,
and its continuity should be decided based on the
CHA2DS2-VASc risk score.
Dabigatran was not adequately tested and should not be
used inpatients with valve prostheses, hemodynamically
severe valve disease or during pregnancy.
Dabigatranis not indicated for prevention of stroke or
systemic thromboembolism in patients with AF and
CHA2DS2-VASc risk score = 0.
Evidence
level
A
AF Atrial fibrillation, ASA acetylsalicylic acid (aspirin), NSAI nonsteroidal anti-inflammatory, TEE
transesophageal echocardiogram, BMI body mass index, INR international normalized ratio
Reproduced from reference [41] (originally Table 4 of the chapter on Anticoagulation in AF of the
Brazilian Guidelines on Platelet aggregation inhibitors and anticoagulant drugs in Cardiology
(Diretrizes Brasileiras de Antiagregantes Plaquetrios e Anticoagulantes em Cardiologia, 2013)
need to be implemented in developing countries to ensure the potential benefits of

those new therapeutic options reach their full potential. Further measures will be
required, particularly in Brazil, ideally using the partnership between the Brazilian
Society of Cardiology, the Department of Health and the respective State and
Regional Departments to ensure that effective measures of qualification and
expansion of the network are established to rapidly decrease the significant regional
disparities that currently exist.
274
Table 5 Recommendations for treatment of atrial fibrillation with rivaroxaban

Recommendation
class
I
IIa
III
Indications
Rivaroxabanis recommended as an alternative to warfarin
for patients with non-valvular AF for whom oral
anticoagulation is indicated.
The preferential dose of rivaroxaban should be 20 mg 1/
day, provided patients have low risk of bleeding.
That drug may be indicated as an alternative to the vitamin
Kantagonist anticoagulant inpatients with difficulty in
maintaining an adequate INR, difficulty in blood collection
for routine laboratorial tests, or by patient choice.
Rivaroxaban is indicated for patients with non-valvular AF
and CHA2DS2-VASc risk score = 1, under the same
conditions as above.
The preferential dose of rivaroxaban for patients with
creatinine clearance ranging from 3049 ml/min should be
15 mg 1/day.
Rivaroxaban was not adequately tested and should not be
used in patients with valve prostheses, hemodynamically
severe valve disease or during pregnancy.
Rivaroxaban is not indicated for prevention of stroke or
systemic thromboembolism in patients with AF and
CHA2DS2-VASc risk score = 0
Evidence
level
B
B
C
AF Atrial fibrillation, INR international normalized ratio

Reproduced from reference [41] (originally Table 5 of the chapter on Anticoagulation in AF of the
Brazilian Guidelines on Platelet aggregation inhibitors and anticoagulant drugs in Cardiology
(Diretrizes Brasileiras de Antiagregantes Plaquetrios e Anticoagulantes em Cardiologia, 2013)
References
1. De Paola AAV, Barbosa MM, Guimares JI. Livro-tex-to de Cardiologia da Sociedade
Brasileira de Cardiologia. So Paulo: Manole. Seo 27 Arritmias. Captulo 7: Fibrilao e
Flutter Atrial: Diagnstico e Tratamento; 2012.
2. Morady F, Zipes DP. Atrial fibrillation: clinical features, mechanisms, management. In: Bonow
R, Mann DL, Zipes DP, Libby P, editors. Braunwalds textbook of cardiology. 9th ed. Saunders;
2011. Part V Arrhythmias, sudden death and syncope.
3. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults:
national implications for rhythm management and stroke prevention: the anticoagulation and
risk factors in atrial fibrillation (ATRIA) study. JAMA. 2001;285:23705.
4. Furberg CD, Psaty BM, Manolio TA, et al. Prevalence of atrial fibrillation in elderly subjects
(the Cardiovascular Health Study). Am J Cardiol. 1994;74:23641.
5. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, et al. Heart disease
and stroke statistics 2012 update: a report from the AHA. American Heart Association
Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2012 3;125(1):e2
e220. doi:10.1161/CIR.0b013e-31823ac046. (Epub 2011 Dec 15. No abstract available.
Erratum in: Circulation 2012 Jun 5;125(22):e1002).
275
6. Sociedade Brasileira de Cardiologia. Disponvel em: http://cientifico.cardiol.br/http://socios.

cardiol.br/iep-hcor/oque.recall.asp. Acessado em 8 de novem-bro de 2013.
7. De Moraes ERFL, Cirenza C, Rodrigues AAE, Amaral AZ, Reis LPB, Barros Jr EM et al. Alta
prevalncia de fibrilao atrial e baixa taxa de anticoagulao oral: implicaes para o
SUS. Congresso SOCESP; 2012.
8. Thrall G, Lane D, Carroll D, Lip GYH. Quality of life in patients with atrial fibrillation:
a systematic review. Am J Med. 2006;119:448.e1e19.
9. Stewart S, Hart CL, Hole DJ, McMurray JJ. A population-based study of the long-term risks
associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am J Med.
2002;113:35964.
10. Dulli DA, Stanko H, Levine RL. Atrial fibrillation is associated with severe acute ischemic
stroke. Neuroepidemiology. 2003;22:11823.
11. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham
Study. Stroke. 1996;27:17604.
12. Atrial fibrillation investigators. Arch Intern Med 1994;154:144957.
13. SPAF III Writing Committee for the Stroke Prevention in Atrial Fibrillation Investigators.
Patients with nonvalvular atrial fibrillation at low risk of stroke during treatment with aspirin:
Stroke Prevention in Atrial Fibrillation III Study. JAMA 1998;279:12737.
14. Wang TJ, et al. A risk score for predicting stroke or death in individuals with new-onset atrial
fibrillation in the community: the Framingham Heart Study. JAMA. 2003;290:104956.
15. Cerebral embolism task force cardiogenic brain embolism. Arch Neurol. 1986;43:7184.
16. Szekeley P. Systemic embolism and anticoagulant prophylaxis in rheumatic heart disease. Br
Med J. 1964;1(5392):120912.
17. Wood KA, Eisenberg SJ, Kalman JM, Drew BJ, Saxon LA, Lee RJ, et al. Risk of thromboembolism in chronic atrial flutter. Am J Cardiol. 1997;79(8):10437.
18. Casella L, Abelmann WH, Ellis LB. Patients with mitral stenosis and systemic emboli; hemodynamic and clinical observations. Arch Intern Med. 1964;114:77381.
19. Hinton RC, Kistler JP, Fallon JT, Friedlich AL, Fisher CM. Influence of etiology of atrial fibrillation on incidence of systemic embolism. Am J Cardiol. 1977;40:50913.
20. Aberg H. Atrial fibrillation I A study of atrial thrombosis and systemic embolism in a necropsy
material. Akta Med Scand. 1969;185:3739.
21. Gage BF, Waterman AD, Shannon W, et al. Validation of clinical classification schemes for
predicting stroke: results from the National Registry of Atrial Fibrillation. JAMA.
2001;285:286470.
22. Wasmer K, Eckardt L. Management of atrial fibrillation around the world: a comparison of
current ACCF/AHA/HRS, CCS, and ESC guidelines. Europace. 2011;13:136874.
23. Lip GY, Nieuwlaat R, Pisters R, Lane DA, Crijns HJ. Refining clinical risk stratification for
predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based
approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):26372.
24. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score
(HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the
Euro Heart Survey. Chest. 2010;138(5):1093100.
25. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: anti-thrombotic therapy to prevent stroke in
patients who have nonvalvular atrial fibrillation. Ann Intern Med. 2007;146(12):85767.
26. Budinitz BS, et al. National surveillance of emergency department visits for outpatient adverse
drug events. JAMA. 2006;296:185866.
27. Waldo AL, Becker RC, et al. Hospitalized patients with atrial fibrillation and a high risk of
stroke are not being provided with adequate anticoagulation. JACC. 2005;46(9):172936.
28. Piccini JP, Hernandez AF, et al. Quality of care for atrial fibrillation among patients hospitalized for heart failure. JACC. 2009;54:12809.
29. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability
of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation.
2007;115:268996.
276
30. The ACTIVE Writing Group on behalf of the ACTIVE Investigators. Clopidogrel plus aspirin
versus oral anticoagulation for atrial fibrillation in the atrial fibrillation clopidogrel trial with
Irbesartan for prevention of vascular events (ACTIVE W): a randomized controlled trial.
Lancet. 2006;367:190312.
31. ACTIVE Investigators, Connolly SJ, Pogue J, Hart RG, Hohnloser SH, Pfeffer M, Chrolavicius
S, Yusuf S. Effect of clopidogrel added to aspirin in patients with atrial fibrillation. N Engl J
Med. 2009;360(20):206678.
32. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldren J, Parekh A, et al. Dabigatran
versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):113951.
33. Ganetsky M, Babu KM, Salhanick SD, Brown RS, Boyer EW. Dabigatran: review of pharmacology and management of bleeding complications of this novel oral anticoagulant. J Med
Toxicol. 2011;7(4):2817.
34. Patel MR, Mahaffey K, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):88391.
35. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with
atrial fibrillation. N Engl J Med. 2011;365(11):98192.
36. Giuliano RP, Ruff CT, Braunwald E et al. Edoxaban versus warfarin in patients with atrial
fibrillation. N Engl J Med. 2013;369(22):2093104. doi:10.1056/NEJMoa1310907.
37. Fenelon G, Scanavacca M, Ati J, Zimerman L, Magalhes LP, Lorga Filho A, et al. Atrial
fibrillation ablation in Brazil: results of the Registry of the Brazilian Society of Cardiac
Arrhythmias. Arq Bras Cardiol. 2007;89(5):25862;2859.
38. Wann LS, Curtis AB, Ellenbogen KA, Estes 3rd NA, Ezekowitz MD, Jackman WM, et al.
American College of Cardiology Foundation/American Heart Association Task Force. 2011
ACCF/AHA/HRS focused update on the management of patients with atrial fibrillation
(update on dabigatran): a report of the American College of Cardiology Foundation/American
Heart Association Task Force on practice guidelines. Circulation. 2011;123(10):114450.
39. De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, et al. New oral
anticoagulants in atrial fibrillation and acute coronary syndromes: ESC Working Group on
Thrombosis-Task Force on anticoagulants in heart disease position paper. J Am Coll Cardiol.
2012;59(16):141325.
40. You JJ, Singer DE, Howard PA, Lane DA, Eckman MH, Fang MC, et al. American College of
Chest Physicians. Antithrombotic therapy for atrial fibrillation: antithrombotic therapy and
prevention of thrombosis. 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e531S75.
41. Diretrizes Brasileiras de Antiagregantes Plaquetrios e Anticoagulantes em Cardiologia. Arq
Bras Cardiol 2013;101(3 Suppl):193.
A Global Alliance for Cardiovascular Disease

Prevention in Clinical Practice
David A. Wood
Cardiovascular diseases are the leading cause of death worldwide and atherosclerotic disease is the largest contributor to all non-communicable diseases (NCDs)
which include all cancers, diabetes mellitus and chronic lung diseases. In 2008 of
the 57 million deaths globally, 36 millionalmost two thirdswere due to NCDs
and the mortality burden of these diseases is growing rapidly in middle and low
income countries [1]. Many of these deaths are premature and about one quarter of
these NCD deaths worldwide occur in those below the age of 60 years.
Cardiovascular diseases and other NCDs can be prevented. A modern lifestyle
characterized by tobacco use, unhealthy diets and sedentary behaviour, together
with harmful use of alcohol, is the primary determinant of all these diseases which
have aetiologies in common. The combination of unhealthy eating and physical
inactivity lead to overweight and obesity, together with central obesity, elevated
blood pressure, dyslipidaemia and diabetes mellitus. Therefore the potential to prevent CVDs and other NCDs is massive through (1) primordial prevention in whole
populations; (2) identification through screening of the adult population for those at
high multifactorial risk of developing CVD and related diseases followed by primary preventive care; and (3) secondary prevention and rehabilitation for those who
survive their initial presentation with symptomatic atherosclerotic CVD. Feasible
and cost-effective interventions to reduce the burden and impact of NCDs exist, and
sustained action to prevent risk factors and improve health care could avert millions
of preventable premature deaths [25].
At a United Nations High-level meeting of the General Assembly in New York
on 19th and 20th September 2011 the prevention and control of non-communicable diseases worldwide was addressed for the first time. Heads of State and
Government addressed non-communicable diseases with a particular focus on
D.A. Wood (*)
Garfield Weston Professor of Cardiovascular Medicine, International Centre for Circulatory
Health, National Heart and Lung Institute, Imperial College London, London, UK
e-mail: d.wood2@ic.ac.uk
DOI 10.1007/978-3-319-22357-5_26
277
278
D.A. Wood
developmental and other challenges and social and economic impacts, particularly
for developing countries [6].
The General Assembly:
1. Acknowledged that the global burden and threat of non-communicable diseases
constitutes one of the major challenges for development in the twenty-first century, which undermines social and economic development throughout the world
and threatens the achievement of internationally agreed development goals;
2. Recognized that non-communicable diseases are a threat to the economies of
many Member States and may lead to increasing inequalities between countries
and populations;
3. Recognized the primary role and responsibility of Governments in responding to
the challenge of non-communicable diseases and the essential need for the
efforts and engagement of all sectors of society to generate effective responses
for the [?] prevention and control of non-communicable diseases; Recognize
also the important role of the international community and;
4. International cooperation in assisting Member States, particularly developing
countries, in complementing national efforts to generate an effective response to
non-communicable diseases;
5. Reaffirmed the right of everyone to the enjoyment of the highest attainable standard of physical and mental health;
6. Recognized the urgent need for greater measures at the global, regional and
national levels to prevent and control non-communicable diseases in order to
contribute to the full realization of the right of everyone to the highest attainable
standard of physical and mental health.
This High-level meeting called upon the World Health Organisation (WHO)
before the end of 2012, to:
(1) develop a comprehensive global monitoring framework, including a set of indicators, capable of application across regional and country settings, including
through multi-sectoral process, to monitor trends and to assess progress made
in the implementation of national strategies and plans on NCDs;
(2) prepare recommendations for a set of voluntary global targets for the prevention
and control of NCDs.
The UN meeting also urged Member States to consider the development of
national targets and indicators, based on national situations, building on guidance
provided by WHO.
In May 2012 the Ministers of Health at the World Health Assembly proposed a
global target to reduce premature mortality from non-communicable diseases. The
target was a 25 % relative reduction in overall mortality from cardiovascular
diseases, cancer, diabetes, or chronic respiratory diseases by 2025now widely
quoted as the 25 by 25 agenda (Table 1). This was the first of nine voluntary
targets embracing mortality and morbidity, risk factors and national systems
response, all of which were subsequently adopted by 119 member states at a meeting on 5th to 7th November 2012 [7].
A Global Alliance for Cardiovascular Disease Prevention in Clinical Practice
279
Table 1 WHO targets for prevention of noncommunicable diseases

Mortality and morbidity
Indicator
Premature mortality from noncommunicable disease
Target: A 25 % relative reduction in
Unconditional probability of dying between
overall mortality from cardiovascular
ages 30 and 70 from cardiovascular diseases,
diseases, cancer, diabetes, or chronic
cancer, diabetes, or chronic respiratory
respiratory diseases.
diseases.
Risk factors
Indicators
Behavioural risk factors
Harmful use of alcohola
Target: At least a 10 % relative reduction
Total (recorded and unrecorded) alcohol per
in the harmful use of alcohol,b as
capita (15+ years old) consumption within a
appropriate, within the national context.
calendar year in litres of pure alcohol, as
Age-standardized prevalence of heavy episodic
drinking among adolescents and adults, as
Alcohol-related morbidity and mortality
among adolescents and adults, as appropriate,
within the national context.
Physical inactivity
Prevalence of insufficiently physically active
prevalence of insufficient physical
adolescents defined as less than 60 min of
activity.
moderate to vigorous intensity activity daily.
Age-standardized prevalence of insufficiently
physically active persons aged 18+ years
(defined as less than 150 min of moderateintensity activity per week, or equivalent).
Salt/sodium intake
Age-standardized mean population intake of salt
(sodium chloride) per day in grams in persons
mean population intake of salt/sodium.a
aged 18+ years.
Tobacco use
Prevalence of current tobacco use among
prevalence of current tobacco use in
adolescents.
persons aged 15+ years.
Age-standardized prevalence of current
tobacco use among persons aged 18+ years.
Biological risk factors
Raised blood pressure
Target: A 25 % relative reduction in the
Age-standardized prevalence of raised blood
prevalence of raised blood pressure or
pressure among persons aged 18+ years (defined
contain the prevalence of raised blood
as systolic blood pressure 140 mmHg and/or
pressure according to national
diastolic blood pressure 90 mmHg).
circumstances.
(continuted)
280
D.A. Wood
Table 1 (continued)
Risk factors
Diabetes and obesityb
Target: Halt the rise in diabetes and
obesity.
Indicators
Age-standardized prevalence of raised blood

glucose/diabetes among persons aged 18+
years (defined as fasting plasma glucose value
7.0 mmol/L (126 mg/dl) or on medication for
raised blood glucose.
Prevalence of overweight and obesity in
adolescents (defined according to the WHO
growth reference for school-aged children and
adolescents, overweightone standard
deviation body mass index for age and sex and
obesetwo standard deviations body mass
index for age and sex).
Age-standardized prevalence of overweight
and obesity in persons aged 18+ years (defined
as body mass index 25 kg/m2 for overweight
and body mass index 30 kg/m2 for obesity).
National systems response
Indicator
Drug therapy to prevent heart attacks and strokes
Target: At least 50 % of eligible people
Proportion of eligible persons (defined as aged 40
receive drug therapy and counselling
years and over with a 10-year cardiovascular risk
(including glycaemic control) to
30 %, including those with existing
prevent heart attacks and strokes.
cardiovascular disease) receiving drug therapy and
counselling (including glycaemic control) to
prevent heart attacks and strokes.
Essential noncommunicable disease medicines and basic technologies to treat major
noncommunicable diseases
Target: An 80 % availability of the
Availability and affordability of quality, safe and
affordable basic technologies and essential efficacious essential noncommunicable disease
medicines, including generics, required
medicines, including generics, and basic
to treat major noncommunicable diseases
technologies in both public and private facilities.
in both public and private facilities.
The targets have a political dimension to all of them and there were important
omissions. Diet is a major determinant of cardiovascular disease and fatty acid compositionsaturated, monounsaturated and polyunsaturatedwas not addressed.
Nor were trans fatty acids which are widely used by the food industry in processed
foods such as margarines. A substantial reduction in saturated fat consumption, and
the elimination of trans fatty acids in all food production, could have a major impact
on reducing the incidence of cardiovascular disease. Substitution of saturated fats in
part with polyunsaturated fatty acids, both n-6 fatty acids which mainly come from
plant foods and n-3 fatty acids coming mainly from fish oils, will further reduce
cardiovascular disease. The current recommendations of professional bodies are to
reduce saturated fat to <10 % of total energy intake and to substitute polyunsaturated fatty acids. Trans fatty acids should be eliminated from the human diet.
281
The omission of fats from the lifestyle targets was political because it will impact
directly on the business of major food manufacturers but this does not preclude
national action. Several countries have already banned the use of trans fatty acids in
all manufactured foods although this product continues to be widely used around
the world. Other important aspects of the diet were also omitted from the targets.
Sugars in the form of simple carbohydrates, widely used in sweetened soft drinks
and other foods are a major source of calories in the diet and regular consumption is
associated with the development of obesity and type 2 diabetes. Sweetened soft
drinks have no nutritional value and therefore have no part in a healthy diet which
should encompass a wide variety of wholegrain products, fresh fruit and vegetables.
The combination of unhealthy eating and physical inactivity is driving the epidemic
of obesity and, as a consequence, type 2 diabetes. To halt the rise in obesity and
diabetes is not sufficient as a target because in some western populations a majority
of the adult population are already overweight. To halt a further rise is important but
this adverse trend needs to be reversed. This requires action at a population level on
adopting healthy eating and becoming more physically active at the same time. To
achieve the recommendation that all adults should spend 2.55.0 h a week on physical activity, or aerobic exercise training of at least moderate intensity, or 12.5 h per
week on vigorous intense exercise, requires radical changes in the built environment
in order to facilitate such activity in everyday life. Lifestyle also impacts directly on
blood pressure, lipids and glucose and although there is a target for blood pressure,
and one for diabetes, there is no target for cholesterol. Low density lipoprotein cholesterol (LDL-C) is a major risk factor for CVD, just like blood pressure and glucose, and high density lipoprotein cholesterol (HDL-C) is protective. The
concentrations of both LDL-C and HDL-C are influenced by lifestyle, both diet and
physical activity, and a target for LDL-C would also have been appropriate.
At the 66th World Health Assembly in May 2013 the WHO Global Action Plan
for the Prevention and Control of Non-communicable Diseases 20132020 was
endorsed [7] (Table 2). The vision is a world free of the avoidable burden of noncommunicable diseases.
The goal is To reduce the preventable and avoidable burden of morbidity,
mortality and disability due to noncommunicable diseases by means of multisectoral collaboration and cooperation at national, regional and global
levels, so that populations reach the highest attainable standards of health
and productivity at every age and those diseases are no longer a barrier to
well-being or socioeconomic development.
The plan contains the following overarching principles and approaches:
Human rights approach recognizes that enjoyment of the highest attainable
standard of health is one of the fundamental rights of every human being as enshrined
in the Universal Declaration of Human Rights.
Equity based approach recognizes the unequal burden of noncommunicable
diseases is influenced by the social determinants of health and that action on these
determinants is essential to reduce the overall burden of noncommunicable diseases
and create inclusive, equitable, economically productive and healthy societies.
282
D.A. Wood
Table 2 WHO global action plan for prevention and control of noncommunicable diseases
Global action plan for the prevention and control of noncommunicable diseases 20132020
Overview
Vision: A world free of the avoidable burden of noncommunicable diseases.
Goal: To reduce the preventable and avoidable burden of morbidity, mortality and disability due
to noncommunicable diseases by means of multisectoral collaboration and cooperation at
national, regional and global levels, so that populations reach the highest attainable standards of
health and productivity at every age and those diseases are no longer a barrier to well-being or
socioeconomic development.
Overarching
Life-course approach
Human rights approach
principles:
Empowerment of people and
Equity-based approach
communities
National action and
Evidence-based strategies
international cooperation and
Universal health coverage
solidarity
Management of real, perceived
Multisectoral action
or potential conflicts of interest
Objectives
1. To raise the priority accorded to the prevention and control of noncommunicable diseases
in global, regional and national agendas and internationally agreed development goals,
through strengthened international cooperation and advocacy.
2. To strengthen national capacity, leadership, governance, multisectoral action and
partnerships to accelerate country response for the prevention and control of
noncommunicable diseases.
3. To reduce modifiable risk factors for noncommunicable diseases and underlying social
determinants through creation of health-promoting environments.
4. To strengthen and orient health systems to address the prevention and control of
noncommunicable diseases and the underlying social determinants through people-centred
primary health care and universal health coverage.
5. To promote and support national capacity for high-quality research and development for
the prevention and control of noncommunicable diseases.
6. To monitor the trends and determinants of noncommunicable diseases and evaluate
progress in their prevention and control.
National action and international cooperation and solidarity recognizes the

primary role and responsibility of governments in responding to the challenge of
noncommunicable diseases and the important role of international cooperation to
assist Member States.
Multisectoral action recognizes the need for multistakeholder engagement and
multisectoral action for health both at government level and elsewhere including
health-in-all-policies and whole-of-government approaches across all sectors (e.g.
health, agriculture, transport, urban planning, etc.) and partnership with civil society
and the private sector.
Life-course approach recognizes that interventions in early life offer the best
chance for primary prevention starting with maternal health and nutrition, reducing
environmental exposures to risk factors, promotion of breast feeding, health promotion for children, adolescents and youth followed by promotion of a healthy working life, healthy ageing and care.
283
Empowerment of people and communities recognizes the need for people and
communities to be empowered in activities for prevention and control of noncommunicable diseases including advocacy, policy, planning, legislation, service provision, education and training, monitoring, research and evaluation.
Evidence-based strategies recognizes that all strategies and practices for prevention and control of noncommunicable diseases should be based on scientific
evidence and/or best practice, cost effectiveness, affordability and public health
principles taking cultural considerations into account.
Universal health coverage recognizes that all people should have access to
nationally determined sets of the needed promotive, preventive, curative and rehabilitative and palliative basic health services and essential, safe, affordable, effective
and quality medicines and diagnostics.
Management of real, perceived or potential conflicts of interest recognizes
that public health policies for the prevention and control of noncommunicable diseases must be protected from undue influence by any form of vested interest.
There are six objectives (Table 2):
Objective 1. To raise the priority accorded to the prevention and control of noncommunicable diseases in global, regional and national agendas and internationally agreed development goals, through strengthened international cooperation and
advocacy.
Advocacy and international cooperation are vital for resource mobilization,
capacity strengthening and advancing the political commitment to reducing premature mortality from noncommunicable diseases. The desired outcomes of this objective are strengthened international cooperation, stronger advocacy, enhanced
resources, improved capacity and creation of enabling environments to attain the
nine voluntary targets.
Objective 2. To strengthen national capacity, leadership, governance, multisectoral action and partnerships to accelerate country response for the prevention and
control of noncommunicable diseases.
As the ultimate guardians of a populations health, governments have the lead
responsibility for ensuring that appropriate institutional, legal, financial and service
arrangements are provided for the prevention and control of noncommunicable diseases. The desired outcomes of this objective are strengthened leadership, increased
resources, improved capacity and creation of enabling environments for forging a
collaborative multisectoral response at a national level in order to attain the nine
voluntary global targets.
Objective 3. To reduce modifiable risk factors for noncommunicable diseases
and underlying social determinants through creation of health promoting
environments.
Governments are the key stakeholders in the development of a national policy
framework for promoting health and reducing risk factors through multisectoral
action using incentives and disincentives, regulatory and fiscal measures, laws and
other policy options, and health education with a special focus on maternal health,
children, adolescents and youth, including prevention of childhood obesity. Although
deaths from noncommunicable diseases mainly occur in adulthood, exposure to risk
284
D.A. Wood
factors begins in childhood and builds up throughout life which underlines the
importance of legislative and regulatory measures to prevent tobacco use, physical
inactivity, unhealthy diet, obesity and harmful use of alcohol.
Objective 4. To strengthen and orient health systems to address the prevention
and control of noncommunicable diseases and the underlying social determinants
through people-centred primary health care and universal health coverage.
For comprehensive care of noncommunicable diseases all people require access
to a nationally determined set of promotive, preventive, curative, rehabilitative and
palliative basic health services. A strengthened health system addressing noncommunicable diseases should aim to improve health promotion, prevention, early
detection, treatment and sustained management of people with or at risk of noncommunicable diseases in order to prevent complications, reduce the need for hospitalizations and costly high-technology interventions and premature deaths.
Objective 5. To promote and support national capacity for high-quality research
and development for the prevention and control of noncommunicable diseases.
Although effective interventions exist for the prevention and control of noncommunicable diseases their implementation is inadequate and comparative, applied and
operational research is required to scale up and maximize the impact of existing interventions. WHOs prioritized research agenda for the prevention and control of noncommunicable diseases provides guidance on future investment in noncommunicable
disease research. The agenda prioritizes (1) research for placing noncommunicable
diseases in the global development agenda and for monitoring; (2) research to understand and influence the multisectoral, macroeconomic and social determinants of
noncommunicable diseases and risk factors; (3) translation and health systems
research for global application of proven cost effective strategies; (4) research to
enable expensive but effective interventions to become accessible and be appropriately used in resource-constrained settings.
Objective 6. To monitor the trends and determinants of noncommunicable
diseases and evaluate progress in their prevention and control.
Monitoring will provide internationally comparable assessments of the trends in
noncommunicable diseases over time, help to benchmark the situation in individual
countries against others in the same region or development category, provide the foundation for advocacy, policy development and coordinated action and help to reinforce
political commitment. Strengthening the capacity of countries to collect, analyse and
communicate data for surveillance and global and national monitoring will require
financial and technical support taking account of innovations and new technologies to
increase effectiveness in data collection and improve data quality and coverage.
The political imprimatur of Heads of State for prevention of NCDs has given the
cardiovascular disease prevention agenda a colossal boost around the world because
atherosclerotic diseases dominates causes of death. To achieve the 25 by 25 ambition prevention of premature heart attacks and strokes will be essential starting with
secondary prevention, because they have already declared themselves to be at high
risk, having survived an acute cardiovascular event, and there is strong scientific evidence that risk can be substantially reduced through the combination of lifestyle, risk
factor and therapeutic management. The next priority is all those at high risk of developing cardiovascular disease, identified by screening the adult population without a
285
history of vascular disease and estimating their total cardiovascular risk, and then
targeting those at highest multifactorial risk. All patients diagnosed with diabetes
mellitus are also included in this high risk group because they are usually at high
multifactorial risk as well [8]. And finally those whose lifestyles through exposure to
tobacco, unhealthy food habits and sedentary behavior puts them on a lifetime trajectory towards obesity, central obesity and ultimately diabetes and cardiovascular disease are the ultimate challenge requiring fiscal and legal instruments to modify the
behaviour of whole populations towards healthier living, productivity and longevity.
In response to this political call for action the European Association for
Cardiovascular Prevention and Rehabilitation (EACPR), formed a Reach Out Task
Force to bring together all those like minded organisations around the world focused
on prevention and rehabilitation in clinical practice. www.escardio.org/communities/eacpr/congresses/pages/global-forum-on-cvd-prevention.aspx.
The mission is to work together as an alliance towards the 25 by 25 agenda by
addressing secondary prevention and rehabilitation and then primary prevention.
The first meeting was convened on the occasion of EuroPRevent in Rome in April
2013 and a list of professional organisations represented at this and subsequent
meetings is given in Table 3.
Coming together in Rome for this first Global Forum had a special historical meaning: it was here where the Forum Romanum was the central public meeting place for
all Romans to exchange ideas and debate their future. In the tradition of this Forum
the elected representatives of societies and organisations with a professional role in
cardiovascular prevention and rehabilitation, were invited from all around the world
for this first Global Forum on Cardiovascular Disease Prevention in Clinical Practice.
The global goal to reduce premature mortality from non-communicable diseasesmost notably cardiovascular diseasesby 25 % by the year 2025 calls for
global cooperation. We need to learn from each other on how best to help our
patientsthose with established cardiovascular disease and those at high risk of
developing cardiovascular diseaseto achieve longer and healthier lives. We need
to create guidelines and standards, drawn from best scientific evidence, for cardiovascular prevention and rehabilitation which are appropriate to the needs of each
country. We need to promote education and training in cardiovascular prevention
and rehabilitation among physicians, nurses and allied professions in order to translate the clinical guidelines into clinical reality. We need to strengthen health services
provision for cardiovascular prevention and rehabilitation, and promote effective
and cost effective service delivery tailored to the needs of each population. We need
to research the burden of lifestyle and related risk factors in our populations, and
how these are changing over time, and what outcomes our patients are achieving in
relation to the standards set in our guidelines. We need to build leadership in cardiovascular prevention and rehabilitation, and promote the organisation of professional
societies in those countries where there are none, to deliver our common agenda to
reduce the burden of cardiovascular disease.
We believe that a Global Alliance on Cardiovascular Prevention in Clinical
Practice could achieve all of this by working together towards the ambitious target
of 25 by 25. Our European Association for Cardiovascular Prevention and
Rehabilitation is reaching out to you as equal partners to build together this global
286
D.A. Wood
Table 3 Professional organisations represented at the global forums for prevention of

cardiovascular disease in clinical practice
American Association of Cardiovascular and Pulmonary Rehabilitation
American Heart Association
American Society for Preventive Cardiology
Australian Cardiovascular Health and Rehabilitation Association
Brazilian Society of Cardiology
British Association for Cardiovascular Prevention and Rehabilitation
Canadian Association of Cardiac Rehabilitation
Chinese Society of Cardiology
Dutch Heart Foundation
Emirates Cardiac Society
European Society of Cardiology
European Association for Cardiovascular Prevention and Rehabilitation
European Society of Cardiology Council on Cardiovascular Nursing and Allied Professions
European Heart Network
Inter-American Society of Cardiology
International Council of Cardiovascular Prevention and Rehabilitation
Iranian Heart Foundation
Irish Heart Foundation
Italian Association against Thrombosis and cardiovascular diseases
Japanese Association of Cardiac Rehabilitation
Prevention Council, Cardiological Society of India
Preventive Cardiovascular Nurses Association
Russian National Society for Cardiovascular Prevention and Rehabilitation
Saudi Heart AssociationSaudi Group for Cardiovascular Prevention and Rehabilitation
World Health Organization
World Heart Federation
alliance for the benefit of all our patients. The principle of a Global Alliance for
CVD Prevention in Clinical Practice was unanimously agreed and a list of potential
roles discussed is given below:
Providing an international forum to share the wealth of experiences of regional
and national organisations in advocating for, delivering and evaluating cardiovascular prevention and rehabilitation programmes for secondary and primary
prevention in different health care settings and economies around the world.
Creating an inventory of all regional and national organisations focussed on prevention and rehabilitation in clinical practice, and a library of professional and
patient resources, to be shared on a common electronic platform and freely
accessible to all health professionals.
Leading the development of international guidelines on CVD prevention for
clinical practice tailored to the needs and resources of high, middle and low
income countries.
287
Creating advocacy tools for health professionals to influence politicians and policy makers to invest in preventive care services in hospital, primary care and the
community.
Sharing, developing and adapting clinical protocols for secondary and primary
prevention services.
Developing regional and national CVD risk estimation models for primary prevention of cardiovascular disease.
Certification of programmes of excellence in preventive and rehabilitative care.
Focus on children, young people and families as incubators of the epidemic of
cardiovascular and other non-communicable diseases.
Promoting the availability and use of essential medicines and technologies in all
countries to reduce the risk of cardiovascular disease.
Engaging the wider professional communitydoctors, nurses, dieticians, physiotherapists, physical activity specialists, occupational therapists, psychologists,
pharmacists and othersin the prevention and rehabilitation agenda.
Building partnerships with international and national sports and leisure service
industries to engage in preventive and rehabilitative care.
Setting up education and training programmes in cardiovascular prevention and
rehabilitation for physicians, nurses and allied professionals in both secondary
and primary care.
Influencing the curricular content for postgraduate and undergraduate medical
education, and the education of other health professionals, to include CVD prevention at a population and individual level.
Engaging patients as ambassadors for prevention and rehabilitation services.
Undertaking international surveys of the delivery of preventive and rehabilitative
care, in both secondary and primary prevention, using standardised methodology
in different health care settings to provide comparisons between countries.
Develop professional leadership in prevention and rehabilitation through the creation of specialist societies, or sub-speciality sections of national societies, in
cardiovascular prevention and rehabilitation.
Bring forward new leadership in CVD prevention among young physicians,
nurses and allied health professionals.
Collaborate with pharmaceutical, device and imaging companies as responsible
partners in research and development in cardiovascular medicine and in delivering evidence based care to all patients.
Utilise health economic modelling in different health economies around the
world to make the case for investing in CVD prevention.
Create a media forum and media training of health professionals for dissemination of key messages on CVD prevention to politicians, policy makers and other
key stakeholders responsible for the CVD prevention agenda at a regional and
national level.
A follow-up Global Forum was convened on August 31st 2013 on the occasion
of the ESC Congress in Amsterdam and the World Heart Federation proposed that
the Global Alliance be formally incorporated into the structures of WHF in order to
align the efforts of all actors engaged in this global agenda to maximize our impact.
288
D.A. Wood
The WHF brings together the continental and national leadership of cardiac societies and heart foundations to urge greater action from policy makers, healthcare
professionals, patient organisations and individuals to work together to reduce the
burden of heart disease and stroke and ensure people all over the world can have
better and longer lives.
References
1. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, Abraham J, Adair T,
Aggarwal R, Ahn SY, Almazroa MA, Alvarado M, Anderson HR, Anderson LM, Andrews KG,
Atkinson C, Baddour LM, Barker-Collo S, Bartels DH, Bell ML, Benjamin EJ, Bennett D,
Bhalla K, Bikbov B, Abdulhak AB, Birbeck G, Blyth F, Bolliger I, Boufous S, Bucello C,
Burch M, Burney P, Carapetis J, Chen H, Chou D, Chugh SS, Coffeng LE, Colan SD,
Colquhoun S, Colson KE, Condon J, Connor MD, Cooper LT, Corriere M, Cortinovis M, De
Vaccaro KC, Couser W, Cowie BC, Criqui MH, Cross M, Dabhadkar KC, Dahodwala N, De
Leo D, Degenhardt L, Delossantos A, Denenberg J, Des Jarlais DC, Dharmaratne SD, Dorsey
ER, Driscoll T, Duber H, Ebel B, Erwin PJ, Espindola P, Ezzati M, Feigin V, Flaxman AD,
Forouzanfar MH, Fowkes FGR, Franklin R, Fransen M, Freeman MK, Gabriel SE, Gakidou E,
Gaspari F, Gillum RF, Gonzalez-Medina D, Halasa YA, Haring D, Harrison JE, Havmoeller R,
Hay RJ, Hoen B, Hotez PJ, Hoy D, Jacobsen KH, James SL, Jasrasaria R, Jayaraman S, Johns
N, Karthikeyan G, Kassebaum N, Keren A, Khoo J-P, Knowlton LM, Kobusingye O, Koranteng
A, Krishnamurthi R, Lipnick M, Lipshultz SE, et al. Global and regional mortality from 235
causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global
Burden of Disease Study 2010. Lancet. 2012;380:2095128.
2. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P,
Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A,
Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvanne M, Scholte Op Reimer WJ,
Vrints C, Wood D, Zamorano JL, Zannad F. European Guidelines on cardiovascular disease
prevention in clinical practice (version 2012). The Fifth Joint Task Force of the European
Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical
Practice (constituted by representatives of nine societies and by invited experts). Developed
with the special contribution of the European Association for Cardiovascular Prevention &
Rehabilitation (EACPR). Eur Heart J. 2012;33:1635701.
3. WHO. WHO report on the global tobacco epidemic 2013. Enforcing bans on tobacco advertising, promotion and sponsorship. ISBN 978 92 4 150587 1 (NLM classification: WM 290)
ISBN 978 92 4 069160 5 (PDF) ISBN 978 92 4 069161 2 (ePub), Luxembourg. 2013. http://
apps.who.int/iris/bitstream/10665/85380/1/9789241505871_eng.pdf?ua=1.
4. WHO/FAO. Diet, nutrition and the prevention of chronic diseases. Geneva; 2003.
5. WHO. Global Recommendations on Physical Activity and Health. ISBN 978 92 4 159 997 9
(NLM classification: QT 255), Switzerland. 2010. http://whqlibdoc.who.int/publications/
2010/9789241599979_eng.pdf?ua=1.
6. UN. Political Declaration of the High-level Meeting of the General Assembly on the Prevention
and Control of Non-communicable Diseases (19 September 2011). Resolution 66/2 66th
Session, Geneva. 2011. http://ish-world.com/downloads/activities/PocketGL_ENGLISH_
AFR-D-E_rev1.pdf.
7. WHO. 66th World Health Assembly. Follow-up to the Political Declaration of the High Level
Meeting of the General Assembly on the Prevention and Control of Non Communicable
Diseases. WHA 66.10. 27th May 2013. 2013.
8. WHO. Prevention of Cardiovascular Disease. Pocket Guidelines for Assessment and Management
of Cardiovascular Risk. ISBN 978 92 4 154726 0 (NLM classification: WG 120), Geneva. 2007.
http://ish-world.com/downloads/activities/PocketGL_ENGLISH_AFR-D-E_rev1.pdf.
Priority Areas for CVD Research

Stephan Gielen
Introduction
Advances in science and research rarely happen in big leaps, but rather as continuous developments of long-term trends. In order to predict the future of research in
cardiovascular disease prevention and to identify the priority areas for research that
really need to be addressed in the years to come we therefore have to take a step
back and look at the major trajectories that have ruled epidemiological and clinical
research in prevention in the last decades.
Several specific peculiarities of cardiovascular disease prevention, however,
make this area very difficult and complex to predict and its future development:
From the methodological point of view research in cardiovascular disease prevention ranges from epidemiological observational studies to clinical intervention studies, animal experiments on pathophysiological mechanisms, and studies
on prevention strategies at population level.
With regard to the content of prevention interventions preventive cardiology covers a wide array of risk factors from hypertension to smoking, from hyperlipidaemia to diabetes. These areas are so big that researchers e.g. in hypertension and
diabetes have their own professional societies to coordinate their scientific
efforts. Prevention societies are not in a position to claim ownership to these
areas.
Finally, it is not easy to define cardiovascular disease prevention. Its advantage
(an interdisciplinary approach to preventing the development and the consequences of cardiovascular diseases) is also its disadvantage, because it lacks the
organocentric intuitive approach of traditional medical disciplines such as
S. Gielen, MD (*)
University Hospital, Martin-Luther-University of Halle/Wittenberg,
Ernst-Grube-Str. 40, 06120 Halle, Germany
e-mail: stephan.gielen@uk-halle.de
DOI 10.1007/978-3-319-22357-5_27
289
290
S. Gielen
nephrology, pneumology, and cardiology. In consequence, the boundaries of

what is to be included under the headline cardiovascular prevention are not as
clear as they should.
So how to identify priority areas for research in cardiovascular prevention if even
the definition of the area is not undisputed? (Fig. 1).
I believe that we need to take a stepwise approach. The first priority is to find a
consensus definition of what is and what is not cardiovascular disease prevention (at
least in the context of this textbook). The second priority is to look back into the
history of research and signs in cardiovascular disease prevention and to try to
delineate trajectories of development, which give a direction for the future. The
third priority is to integrate scientific perspectives and demographic developments
into the picture of what the key research areas in cardiovascular disease prevention
will be in the next two decades.
Finding a Consensus Definition of Cardiovascular Disease

Prevention
CVD prevention () is defined as a co-ordinated set of actions, at public and individual level, aimed at eradicating, eliminating, or minimizing the impact of CVDs
and their related disability. The bases of prevention are rooted in cardiovascular
epidemiology and evidence-based medicine. [1]
In this definition proposed by the Fifth Joint Task Force of the European Society
of Cardiology and other societies of cardiovascular disease prevention in clinical
practice some key features of a consensus definition of CVD prevention can be
identified:
It is defined by its aim of reducing CVD and CVD-related events, not by its
means (i.e. hypertension treatment, LDL lowering).
It is not defined by its method of implementation (i.e. at public level to reduce
risk factor prevalence, at individual patient level as secondary prevention of
recurrent events).
While it is rooted in cardiovascular epidemiology and evidence-based medicine
(i.e. the lipidology, hypertensiology, diabetology, etc.) these areas are not part of
the field of CVD prevention. Rather they provide the evidence to identify and to
treat specific risk factors. The key characteristics of CVD prevention, however, is
the integrative approach to all risk factors.
In this sense when speaking of research in CVD prevention we are not speaking
about comparing one antihypertensive medication to another but we are speaking of
medical research or epidemiological studies that identify or quantify the relation of
risk factors and their treatments to cardiovascular outcomes, and examine the pathophysiology of how risk factors translate into cardiovascular disease (Fig. 1).
291
1,000
Deaths in Thousands
Genetic Studies
800
Studies on Implementation
600
Studies on Mechanisms
Studies on Risk Factor Interventions
400
Studies on Risk Factor Epidemiology
200
Observational Clinical Case Studies on Risk Factors

0
1900
1925
1950
1975
2000
2025
2050
Fig. 1 Time-course of cardiovascular mortality in the United States [2] with an overlay of important prevention research phases from the 1940s until today
Major Historic Trajectories of Research in Cardiovascular

Disease Prevention
Phase 1: The Risk Factor Studies
When the death toll from atherosclerotic disease was significantly rising in the first
half of the twentieth century [2] the first big research question was: why? The beginning of research in prevention was therefore defined by the risk factor hypothesis. In
essence the concept of risk factors for diseases implies that any disease is associated
with the presence of non-modifiable (e.g. gender, age, ethnicity) and modifiable risk
factors (e.g. eating habits, exposure to certain environmental conditions, exercise
frequency). The advantage of risk factor research is that it may identify potential
areas for preventive intervention without the need to fully understand the pathophysiology of the disease itself. Risk factor studies are typically carried out in a
large representative population sample of clinically healthy individuals who are
characterized at baseline by a standardized interview and clinical examination and
measurement of physiologic baseline values (i.e. blood pressure, heart rate, exercise
capacity). This large cohort is then longitudinally followed and reexamined e.g. on
an annual basis to confirm the vital status and the presence/absence of the disease
under investigation. Typical clinical end-points in the first cardiovascular risk factor
studies were death from any cause, cardiac death (as confirmed by autopsy or clinical assessment), myocardial infarction (as suspected by typical ECG changes like
Q-waves).
The classical example of a prospective risk factor study that laid the foundation
for future preventive strategies is the Framingham study [3]. In this study smoking,
hypertension, and elevated cholesterol were identified as principal risk factors for
292
S. Gielen
cardiovascular disease [4]. Due to the difficult post-war situation in Europe the first
prevalence studies in Europe did not appear before the 1960s [5]. The era of the
large-scale risk factor studies saw a further landmark publication in 2004, when the
results of the global INTERHEART study were published [6]. Risk factor studies
evolved into two different directions during the last two decades: On the one hand,
risk factor prevalence studies were pooled across Europe to develop a simple and
valid risk prediction model (the SCORE model) [7]. On the other hand, researchers
moved away from traditional environmental risk factors and used high-throughput
genetic testing to identify genes variants such as 9p21 associated with increased
cardiovascular risk [8].
Phase 2: Studies on Risk Factor Interventions

Genetic studies have already lead to new therapeutic approaches in CVD prevention: In the 1970s cardiologists observed that members of a family with hypercholesterolaemia due to a mutation in the LDL-receptor had premature heart attacks in
the second and third decades of life [9]. More recently, it was shown that AfricanAmericans with a loss-of-function mutation of the PCSK9 gene had a 28 % reduction of class LDL-C levels and a reduction of 88 % in the risk of coronary artery
disease [10].
Both observations stimulated the development and clinical prospective testing of
statins and PCSK9 inhibitors, which lower LDL-C independent of statins. Landmark
studies in this area were the 4S study (Scandinavian Simvastatin Survival Study
[11] and many other statin studies. The first outcome studies of the new highly
potent PCSK9 inhibitors have just begun (e.g. ODYSSEY Outcomes) but the large
reductions by two thirds seen in statin-pretreated patients suggest major advances
further reducing cholesterol-related CVD mortality [12].
Prospective randomised risk factor intervention studies are pivotal for proving
that reversal of a risk factor actually results in reduced CVD mortality. They continue to play a significant role in determining target levels for optimal blood pressure, cholesterol levels, glucose levels and other parameters, which can be influenced
by medications (Fig. 2).
Phase 3: Studies on the Molecular Mechanisms Behind the Risk

Factors and Risk Factor Modifications
During the last three decades regular physical exercise has received increased attention to its potent effects on reducing cardiovascular morbidity and mortality.
However, physiological studies were needed to better understand the cardio- and
vasculoprotective effects of the intervention. During the 1990s both animal and
293
Fig. 2 Projections for cardiovascular disease prevalence in high, middle, and low income countries from 2004 to 2030. Please note this significant increase projected for low and medium income
countries. Disease prevalence is likely to decrease in the developed world. Cited after Beaglehole
and Bonita [19]
clinical studies showed that exercise led to improved endothelial function through
repetitive increases in laminar are shear stress at the vascular vessel wall [13, 14].
Studies like these are important in two regards: (1) They replace a statistical
association between increased exercise activity and reduce cardiovascular mortality
by a causal mechanism. Better understanding of this mechanism, in turn, helps to
optimise the treatment intervention in order to achieve greater gains in cardiovascular health. (2) Identifying specific mechanisms related to reduce cardiovascular
events can ideally lead to targets for future pharmaceutical interventions.
294
S. Gielen
Phase 4: Research in CVD Prevention Implementation

Today, we have a well-established concept of non-modifiable and modifiable risk
factors which are potential targets for interventions to prevent the development
and progression of cardiovascular diseases. In PubMed we will find 5266 publications on clinical trials in statin therapy. However, no more than 144 articles have
been published worldwide on clinical trials in cardiovascular prevention
implementation.
Research in this area is fundamentally different from the traditional concept of
full-spectrum multicentre randomised clinical studies. It focuses on testing an
implementation strategy (i.e. a strategy to identify and treat risk factors in certain in
hospital or outpatient environment) versus usual care in its effects on cardiovascular
risk factors or outcomes. A recent example of such a study is a recent publication on
The impact of a bodyweight and physical activity intervention (BeWEL) initiated
through a national colorectal cancer screening programme: randomised controlled
trial. [15] Studies like these are not just scarce but also quite recent: the first ones
were not published before 1989 (Fig. 1).
Future Research Priorities in Cardiovascular Disease

Prevention (Fig. 2)
Priorities always dependent on perspectives. In consequence, we need to speak
about our perspective before we speak about our priorities. The perspective we
should take is based on the principles and goals put forward during the 2011 United
Nations High-Level Meeting on non-communicable diseases. To achieve the goal to
reduce the burden of non-communicable diseases by 25 % until the year 2025 and
even greater reduction in cardiovascular mortality needs to be attained. Since the
increase of cardiovascular morbidity and mortality occurs primarily in evolving
economies and developing countries improving basic preventive interventions in
these countries needs to be a priority. Hence, effective prevention implementation is
key to the success of the WHO 25 25 agenda.
Research in Prevention Implementation

What are the reasons for the current lack of effective prevention implementation?
1. Motivation:
Until now, in the way cardiovascular prevention is presented to the population
and to patients is mostly based on very fact-oriented information how certain types
of life stay behaviour changed the individual risk of developing atherosclerosis
295
or dying from a heart attack. However, relative risk and odds ratio are no terms
that patients understand in relation to their individual life. Additionally, the reiteration of long lists of dos and donts can lead to frustration on the side of the
patient. While we do have plenty of data which information to give to the patient
we clearly lack good clinical research in how to best motivate patients to implement lifestyle changes in their daily life and to continue long beyond the rehabilitation intervention. Motivational research is a key area to reformulate the
prevention message in a way that reaches its target audience and sends a positive
sign of support to the patient, who may be in a vulnerable psychological situation
after a first cardiovascular event.
2. Cost-effectiveness:
Expenses in health care are limited. Although generally prevention interventions
are more cost-effective then sophisticated tertiary care in the setting of acute
events not all prevention interventions are equally cost-effective. Health economy research is needed to determine which treatment thresholds provide the best
costs-effectiveness ratio e.g. for pharmaceutical treatment of hyperlipidaemia or
hypertension.
3. Infrastructure:
At the moment there are wide variations regarding the infrastructure for prevention interventions both at population level end at patient level for high risk individuals. In some countries, for example, patients after an acute myocardial
infarction are hospitalised for up to 3 weeks for postacute in-hospital rehabilitation programs. In other countries, the same patients are discharged from acute
care only 3 or 4 days after the event and I then followed through outpatient secondary prevention programs. We lack well-designed prospective randomised
studies comparing different infrastructures for prevention administration in
regard to their clinical effectiveness and their ability to reduce recurrent events.
The same extends to the question which experts and team members are required
to establish effective prevention programs. Do we always need academic physicians or it can well-educated nurses be equally effective?
Even greater are at the differences in the administration of primary prevention: Some countries establish nurse-led prevention programs in central
offices while others send out teams of preventionists into the homes of the
people.
4. Quality Control:
Prevention programs are only successful if followed long-term. However, only a
very small minority of programs actually performs this type of long-term monitoring of programme compliance. Telemonitoring today provides new means of
following patients over long time in reminding them to continue their efforts in
living a healthy lifestyle. Research is needed to establish effectiveness of
telenursing and telemedicine to improve prevention programme adherence in
both primary and secondary prevention.
296
S. Gielen
Epidemiological Research
Today, we have a very comprehensive knowledge about the risk factors and their
relation to the prevalence of cardiovascular disease. In most Western countries risk
factor prevalence is monitored through multinational cohort studies such as
MONICA or it the Score Project of the European Society of Cardiology. Nonetheless,
in underdeveloped areas of the world epidemiological data on risk factor prevalence
and its change over time is not available. This makes it very difficult to assess longterm changes in risk factor behaviour and to verify if primordial or primary prevention programs actually have an effect on population risk factor prevalence. To
develop a true global picture of risk factor prevalence huge efforts are needed to
coordinate and standardise epidemiological monitoring of changes in risk factor
prevalence and cardiovascular morbidity and mortality in many countries of the
evolving economies and the developing world.
Research in Global Demographic, Social and Nutritional Trends

Risk factor behaviour is closely related to educational level, social demographic
background, and to the social environment (rural versus urban). Especially in evolving economies and developing countries urbanisation and migration from agricultural backgrounds to industrialised cities pose major challenges to cardiovascular
disease prevention. One of the first landmark studies to actually investigate the
effects of urban versus rural living conditions on risk factor prevalence was the
Prospective Urban Rural Epidemiological (PURE) study. A total of 153,996 adults
from 628 urban and rural communities in countries with incomes classified as high
(three countries), upper-middle (seven), lower-middle (three), or low (four) between
January, 2003, and December, 2009 were enrolled. As expected, important quality
indicators of secondary preventive care were lowest in rural areas of low and middle
income countries [16]. Despite its significance, the study was observational and
aimed at quantifying differences in the quality of preventive care, risk factor prevalence, and cardiovascular morbidity and mortality. The next step will be to design
intervention studies aimed at improving basic preventive care and those environments in which we find the largest deficits.
Hand-in-hand with urbanisation comes the change from traditional vegetablebased dietary habits to the urban Western-style diet with its unhealthy consequences
on cardiovascular risk. In the Impact model developed to identify the contribution
of different risk factor changes on the overall change in cardiovascular mortality
obesity and diabetes are the only risk factors that continue to grow despite all prevention efforts. In primordial and primary prevention nutrition is therefore key to
reducing atherosclerotic cardiovascular disease.
297
Apart from urbanisation the demographic change with increasing longevity is

another major challenge in cardiovascular disease prevention. Until recently, age
was always regarded as a non-modifiable risk factor. This view, however, was
recently challenged by Najjar and colleagues who argue that ageing can be indeed
influenced as a potentially modifiable risk factor [17]. Lifelong healthy lifestyles
with regular aerobic exercise can prevent or at least retard the development of endothelial dysfunction and arterial stiffening as early stages of atherosclerosis.
Research in Health Care Structures and Healthcare Legislation

In a recent overview of prevention studies in Europe I concluded by underlining the
importance of the healthcare infrastructure and healthcare legislation for effective
cardiovascular prevention:
Efforts in individual prevention education will be futile if not backed up by
coherent legislative frameworks which reward healthy lifestyles and make risky
lifestyle behaviours unattractive. There is clear evidence from epidemiological studies which laws and taxation mechanisms work [18] the challenge is to implement
them.
Physicians follow the priorities of their healthcare systems. If reimbursement is
best for interventions there is little motivation to invest time and effort in prevention.
Pilot studies are needed which reimbursement mechanisms or other incentives work
best in motivating physicians to focus on prevention and to shift from a procedurecentered to an outcome-focused performance.[19]
Conclusion
To achieve our common goal of reducing global mortality from non-communicable
diseases (especially cardiovascular diseases) by 25 % until 2025 research CVD prevention needs to shift significantly towards implementation-oriented research that
aims at finding practical, cost-effective, sustainable ways to optimise primary and
secondary prevention especially in countries with increasing CVD prevalence. In
the past research was focused on improving individual patient outcomes. Evidence
is accumulating, however, that we need to have the same level of evidence for
population-based interventions through restructuring of healthcare infrastructure
and health care-related legislation.
These priority areas, however, are most likely not the priorities of research communities in the developed countries. Co-ordinated political action is therefore
needed to develop a framework of research support programs that foster the type of
research that is needed to tackle the global epidemic of cardiovascular disease.
298
S. Gielen
References
1. Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus C, Benlian P,
Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M, Germano G, Hobbs R, Hoes A,
Karadeniz S, Mezzani A, Prescott E, Ryden L, Scherer M, Syvnne M, Scholte op Reimer
WJM, Vrints C, Wood D, Zamorano JL, Zannad F, European Association for Cardiovascular
Prevention & Rehabilitation (EACPR), ESC Committee for Practice Guidelines (CPG).
European Guidelines on cardiovascular disease prevention in clinical practice (version 2012).
The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on
Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine
societies and by invited experts). Eur Heart J. 2012;33:1635701.
2. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, Blaha MJ, Dai S, Ford ES, Fox CS,
Franco S, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Huffman MD, Judd
SE, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Mackey RH, Magid DJ,
Marcus GM, Marelli A, Matchar DB, McGuire DK, Mohler ER, Moy CS, et al. Heart disease
and stroke statistics2014 update: a report from the American Heart Association. Circulation.
2014;129:e28292.
3. Dawber TR, Meadors GF, Moore FE. Epidemiological approaches to heart disease: the
Framingham Study. Am J Public Health Nations Health. 1951;41:27981.
4. Kannel WB, Dawber TR, Kagan A, Revotskie N, Stokes J. Factors of risk in the development
of coronary heart diseasesix year follow-up experience. The Framingham Study. Ann Intern
Med. 1961;55:3350.
5. Reid DD, Holland WW, Humerfelt S, Rose G. A cardiovascular survey of British postal workers. Lancet. 1966;1:6148.
6. Yusuf S, Hawken S, Ounpuu S, Dans T, Avezum A, Lanas F, McQueen M, Budaj A, Pais P,
Varigos J, Lisheng L, INTERHEART Study Investigators. Effect of potentially modifiable risk
factors associated with myocardial infarction in 52 countries (the INTERHEART study): case
control study. Lancet. 2004;364:93752.
7. Conroy RM, Pyrl K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D,
Ducimetire P, Jousilahti P, Keil U, Njlstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H,
Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM, SCORE project group. Estimation
of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart
J. 2003;24:9871003.
8. McPherson R, Pertsemlidis A, Kavaslar N, Stewart A, Roberts R, Cox DR, Hinds DA,
Pennacchio LA, Tybjaerg-Hansen A, Folsom AR, Boerwinkle E, Hobbs HH, Cohen JC. A
common allele on chromosome 9 associated with coronary heart disease. Science.
2007;316:148891.
9. Brown MS, Goldstein JL. Familial hypercholesterolemia: a genetic defect in the low-density
lipoprotein receptor. N Engl J Med. 1976;294:138690.
10. Cohen JC, Boerwinkle E, Mosley TH, Hobbs HH. Sequence variations in PCSK9, low LDL,
and protection against coronary heart disease. N Engl J Med. 2006;354:126472.
11. 4S-Study-Group. Randomised trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian simvastatin survival study. Lancet. 1994;344:13839.
12. Robinson JG, Nedergaard BS, Rogers WJ, Fialkow J, Neutel JM, Ramstad D, Somaratne R,
Legg JC, Nelson P, Scott R, Wasserman SM, Weiss R, LAPLACE-2 Investigators. Effect of
evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA.
2014;311:187082.
13. Laughlin MH. Endothelium-mediated control of coronary vascular tone after chronic exercise
training. Med Sci Sports Exerc. 1995;27:113544.
14. Hambrecht R, Wolff A, Gielen S, Linke A, Hofer J, Erbs S, Schoene N, Schuler G. Effect of
exercise on coronary endothelial function in patients with coronary artery disease. N Engl J
Med. 2000;342(7):45460.
299
15. Anderson AS, Craigie AM, Caswell S, Treweek S, Stead M, Macleod M, Daly F, Belch J,
Rodger J, Kirk A, Ludbrook A, Rauchhaus P, Norwood P, Thompson J, Wardle J, Steele
RJC. The impact of a bodyweight and physical activity intervention (BeWEL) initiated through
a national colorectal cancer screening programme: randomised controlled trial. BMJ.
2014;348:g1823.
16. Yusuf S, Islam S, Chow CK, Rangarajan S, Dagenais G, Diaz R, Gupta R, Kelishadi R, Iqbal
R, Avezum A, Kruger A, Kutty R, Lanas F, Lisheng L, Wei L, Lopez-Jaramillo P, Oguz A,
Rahman O, Swidan H, Yusoff K, Zatonski W, Rosengren A, Teo KK, Prospective Urban Rural
Epidemiology (PURE) Study Investigators. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries
(the PURE Study): a prospective epidemiological survey. Lancet. 2011;378:123143.
17. Najjar SS, Scuteri A, Lakatta EG. Arterial aging: is it an immutable cardiovascular risk factor?
Hypertension. 2005;46:45462.
18. Jrgensen T, Capewell S, Prescott E, Allender S, Sans S, Zdrojewski T, De Bacquer D, de
Sutter J, Franco OH, Lgstrup S, Volpe M, Malyutina S, Marques-Vidal P, Reiner Z, Tell GS,
Verschuren WMM, Vanuzzo D, PEP section of EACPR. Population-level changes to promote
cardiovascular health. Eur J Prev Cardiol. 2013;20:40921.
19. Beaglehole R, Bonita R. Global public health: a scorecard. Lancet. 2008;372:198896.
Evidence for Preventing Cardiovascular

Disease
Ian M. Graham and Marie-Therese Cooney
Superior doctors prevent the disease; mediocre doctors treat the disease before evident;
inferior doctors treat the full blown diseaseHuang Dee: Nai Ching 2,600 BC
It is better to healthy than ill or dead. That is the beginning and the end of the only real
argument for preventive medicine. It is sufficient.Geoffrey Rose: The Strategy of
Preventive Medicine, Oxford University Press 1992
Introduction
Suppose that, starting next week, you are Minister for Health. And suppose that, for
the sake of argument, you are not bound by too many political constraints, and that
you have adequate access to data and advice from your medical advisors. You might
consider the following:
1. Population demographicsthe size of population, age and gender distributions,
education, social deprivation and so forth.
2. The major causes of death and disability.
3. Are effective treatments available?
4. Are the causes known? If so, is prevention possible?
5. Resources available and how to allocate themhow to balance need with political and media demands.
I.M. Graham, M.D. (*)

Cardiovascular Medicine, Trinity College Dublin, Dublin, Ireland
Cardiology Emeritus, Royal College of Surgeons in Ireland, Dublin, Ireland
e-mail: ian@grahams.net
M.-T. Cooney, MB, BCH, NUI, MRCPI, PhD.
Department of Age-Related Health Care, St Vincents Hospital, Dublin, Ireland
e-mail: therese.cooney@yahoo.com
DOI 10.1007/978-3-319-22357-5_28
301
302
I.M. Graham and M.-T. Cooney
The Size of the Problem

CVD is the biggest cause of deaths worldwide [1, 2]. More than 17 million people
died from CVDs in 2008, representing 30 % of global deaths. More than 3 million of
these deaths occurred before the age of 60 and could have potentially have been prevented. The percentage of premature deaths from CVDs ranges from 4 % in highincome countries to 42 % in low-income countries, leading to growing inequalities in
the occurrence and outcome of CVDs between countries and populations [1]. CVD
is also a major cause of disability and consumer of resources. While CVD mortality
is dropping in developed countries, it is rising in the developing world and is predicted to cause 23.3 million deaths by 2030 [2]. This is illustrated in Fig. 1, which
shows how the gradient in CVD mortality has shifted from West to East. In contrast,
expenditure on healthcare is broadly inversely proportional to CVD mortality (Fig. 2)
Within Europe, CVD mortality has in general declined in the West and increased
in the East, although it is starting to decline in some Eastern European countries [3].
Brazil has seen a steady reduction in total CVD standardized mortality rates of from
287 to 162/100,000 over the 24-year period from 1980 to 2003 [4].
Atherosclerosis: Slow Development, Fast Death

Atherosclerosis has its antecedents in utero, and may be evident as fatty streaks in
childhood (Fig. 3). It generally develops insidiously over many years before becoming
clinically manifest in middle age or later. Obstructive disease may present as angina,
whereas a potentially fatal acute coronary syndrome represents plaque rupture.
Fig. 1 Westeast gradient in CVD mortality
Evidence for Preventing Cardiovascular Disease
303
Fig. 2 Expenditure on health care
Within about two hours of a coronary artery occlusion due to plaque rupture, one
half of deaths will have occurred and survivors, if not in time for percutaneous intervention (PCI) or thrombolysis, are likely to have sustained irreversible myocardial
damage [5]. The implications of these observations are that treatments such as PCI,
while impressive for those fortunate enough to be in time to benefit from them, will
of course be inapplicable for those who suffer sudden or early death, and palliative
for many others due to the advanced nature of the underlying disease and the likelihood of irreversible myocardial damage.
Risk and Causation

A risk factor may be defined as a characteristic that is associated with the subsequent development of a disease. Establishing a causal relationship between a factor
associated with a disease is generally straightforward if there is a single cause, for
example hypothyroidism. It is more complex if there is a single cause but other factors determine if it becomes manifest, such as tuberculosis. It is more complex again
if there are multiple factors, which could be causal, many of which are co-incidental
characteristics of a rising standard of living.
304
NOMANCLATURE AND
MAIN HISTOLOGY
SEQUENCES IN PROGRESSION
OF ATHEROSCLEROSIS
EARLIEST
ONSET
MAIN GROWTH
CLINICAL
MECHANISM COLLERLATION
Initial lesion
histologically normal
macrophage Infiltration
Isolated foam cells
Fatty streak
from
first
decade
clinically
silent
ENDOTHEHELIAL DYSFUNCTION
mainly intracelluar lipid

accumulation
growth
mainly by
lipid
addition
Intermediate lesion
Intracelluar lipid accumulation

small extracellular lipid pools
Atheroma
from
third
decade
Intracelluar lipid accumulation

core of extracellular lipid
Fibroatheroma
single or multiple lipid cores

fibrotic/calcific layers
Complicated lesion
surface defect
hermatoma-hemorrhage
thrombosis
from
fourth
decade
increased
smooth
muscle
and
collagen
increase
clinically
silent
or overt
thrombosis
and/or
hematoma
Fig. 3 The development of atherosclerosis
Originating in the work of Doll and Hill [6] relating to smoking and lung cancer,
a list of criteria has been developed to allow a judgment as to whether an association
between a putative factor and CVD is sufficiently likely to be one of cause and
effect to justify public health action:
1.
2.
3.
4.
5.
6.
7.
8.
Is causality biologically plausible?

Is the relationship strong?
Is it graded (the stronger the exposure, the greater the likelihood of disease)?
Temporalityis it clear that the presence of the factor preceded the development
of the disease?
Is it independent in that its effect is still evident after adjusting for the effects of
other factor?
Is the association consistent in repeated studies?
Is there agreement between different scientific disciplines (basic science, pathology, epidemiology et cetera)?
Does reducing or removing the factor reduce the risk?
Based on a century of grinding research, the following conclusions may be reasonable with regards to risk factors and CVD:
Clearly causal: High saturated fat die, blood cholesterol level, tobacco smoking,
hypertension.
305

Table 1 Lifestyles and characteristics associated with increased risk of future CVD
Lifestyles
Diet high in
saturated fat,
cholesterol and
calories
Tobacco smoking
Excess alcohol
consumption
Physical inactivity
Biochemical or physiological
characteristics (modifiable)
Elevated plasma cholesterol (LDL
cholesterol)
Low plasma HDL cholesterol
Personal characteristics
(non-modifiable)
Age
Sex
Elevated plasma triglycerides
Family history of CHD or other

atherosclerotic vascular disease
at early age (<55 years in men;
<65 years in woman)
Elevated blood pressure

Hyperglycaemia/diabetes
Obesity
Thrombogenic
Personal history of CHD or other

atherosclerotic vascular disease
Probably or indirectly causal: Overweight, physical inactivity, Lp(a), diabetes,

renal failure, triglycerides, social deprivation.
Uncertain: HDL cholesterol, fibrinogen, high sensitivity CRP, homocysteine.
In the search for direct causes of CVD, the critical importance of the causes of
the causes should not be underestimated, in particular social deprivation, which
drives many of the direct causes of CVD and other causes of premature death; the
poor really do die young [7].
Arising, Table 1 is a conventional classification of risk factors.
It should be noted that age reflects exposure time rather than being a risk factor
as suchthe older one is, the more years one has had to be exposed to nutritional
factors or smoking, for example. Further, the apparent protection afforded to women
is misleadingthey enjoy a deferral of CVD but ultimately as many or more women
die of CVD as men. Inspection of the SCORE risk charts [8] would suggest that
women reach any given level of risk about 10 years later than men.
A Comprehensive Approach to Risk

It was not uncommon in the past for clinicians to state that many patients with CVD
had no risk factors. This arose out of two misconceptions. The first is that an average level of a risk factor my not be the same as a healthy levelin many developed
societies, the average level of cholesterol, for example, is considerably higher than
the optimal level. Secondly, CVD generally arises from the combined effects of
several risk factors, which maybe only modestly increased, as opposed to a more
dramatic risk factor such as familial hyerlipidaemia. This is illustrated in Table 2,
derived from the current Joint European Guidelines on the prevention of CVD in
clinical practice [9]a 60 year old lady with a cholesterol of 8 mmol/l can have a
risk that is 10 times less than that of a 60 year old man with a cholesterol of 5 mmol/l,
306
Table 2 Combined effects of risk factors

Impact of combinations of risk factors on 10 year risk of CVD death
Sex
Age
Chol
BP
Smok
F
60
8
120
No
F
60
7
140
Yes
M
60
6
160
No
M
60
5
180
Yes
Risk %
2
5
8
21
if the lady as no other risk factors and the man has untreated hypertension and is a
smoker. It follows a single factor approach to risk may lead to under- or overtreatment. It is a problem that most trials of risk factor treatment look only at single
factors and not at combined effectsindeed current trials do not tell which person
or persons in Table 2 should receive a statin.
Risk Factor Control and Reduced CVD Mortality

and Morbidity
Multiple meta-analyses have indicated that effective treatment of raised blood cholesterol or raised blood pressure reduces CVD mortality and morbidityfor example those of the Cholesterol Treatment Trialists Collaboration [10] and the
Prospective Studies Collaboration [11]. Impressive though these studies are, often
demonstrating large reductions in relative risk of CVD, the absolute reductions are
much less impressiveeven in the landmark 4S study, conducted in high risk subjects, the 30 % relative reduction in risk of death translates into a less than 4 %
absolute reduction in risk. Subsequent trials in lower risk subjects often show a
reduction in absolute risk of one percent or less. But the rationale for prevention
involves much more than drugs.
Time Trends in CVD Mortality

CVD mortality rates over the past 50 years have risen sharply as countries undergo
the epidemiological transition from pestilence and famine through receding pandemics to degenerative and man-made diseases [13, 14], and then have declined
equally rapidly. Indeed, declines in countries such as Finland [15] preceded the use
of drugs such as statins and did not visibly accelerate after their introduction. In large
part this may be because explained by Geoffrey Roses critical observations [16]:
A large number of people exposed to a small risk may generate many more cases than a
small number exposed to a large risk (p. 24) and
307
A preventive measure that brings large benefits to the community offers little to each participating individual (The prevention paradox, p. 12).
These critical observations underline point 9 in the Abstract of this chapter:

Population and high-risk strategies are complementarybut a high risk strategy in
isolation will be ineffective.
The reasons for secular changes in CVD mortality have been systematically
explored by Simon Capewell using IMPACT modelling [17]. In general, over half
of the reduction on CVD mortality relates to changes in risk factors, especially in
smoking, blood pressure and blood cholesterol. These tend to be partially offset by
adverse changes in physical activity, obesity and diabetes. Observational data on
smoking cessation suggest that it is more effective in reducing risk than any known
drug.
Conclusions
The case for the prevention of CVD has a cohesive logic and evidence base that has
been built up over many decades. It is sufficient to justify intensive public health
action. But a logical evidence base may not be sufficient because prevention requires
long-term planning that is not always politically attractive.
The primary determinants of disease are mainly economic and social, and therefore its
remedies must also be economic and social. Medicine and politics cannot and should not be
kept apart. [16]
References
1. Global Atlas on Cardiovascular Disease Prevention and Control. In: Mendis S, Puska P,
Norrving B editors. Geneva: World Health Organization; 2011.
2. World health Organization Media Centre. Fact Sheet No 317, updated March 2013.
3. Nichols M, Townsend N, Luengo-Fernandez R, Leal J, Gray A, Scarborough P, Rayner
M. European Cardiovascular Disease Statistics 2012. European Heart Network, Brussels,
European Society of Cardiology, Sophia Antipolis; 2012.
4. Curioni C, Cunha CB, Veras RP, Andr C. The decline in mortality from circulatory diseases
in Brazil. Rev Panam Salud Publica. 2009;25(1):915.
5. Steg PG, James SK (Chairpersons). ESC Guidelines for the management of acute myocardial
infarction in patients presenting with ST-segment elevation. Eur Heart J. 2012;33:2569619.
6. Hill AB. The environment and disease: association or causation? Proc R Soc Med.
1965;58:295300.
7. Social determinants of health, Second Edition. The solid facts. In: Wilkinson R, Marmot MR,
editors. WHO 2013: ISBN 92 890 1371 0.
8. Conroy RM, Pyrl K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D,
Ducimetire P, Jousilahti P, Keil U, Njlstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H,
Tverdal A, Wedel H, Whincup P, Wilhelmsen L, Graham IM; SCORE project group. Conroy
RM, Pyrl K, Fitzgerald AP, Sans S, Menotti A, De Backer G, De Bacquer D, Ducimetire
308
9.
10.
11.
12.
13.
14.
15.
16.
17.

P, Jousilahti P, Keil U, Njlstad I, Oganov RG, Thomsen T, Tunstall-Pedoe H, Tverdal A,
Wedel H, Whincup P, Wilhelmsen L, Graham IM; SCORE project group. Eur Heart
J. 2003;24(11):9871003.
Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren WMM, et al. European
Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur J Prev
Cardiol. 2012;19(4):586667.
Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, Peto R, Barnes EH,
Keech A, Simes J, Collins R. Cholesterol Treatment Trialists (CTT) Collaboration Efficacy
and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from
170,000 participants in 26 randomised trials. Lancet. 2010;376:167081.
Prospective Studies Collaboration. Age specific relevance of usual blood pressure to vascular
mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.
The Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study
(4S). Lancet. 1994;344:13839.
Omran AR. The epidemiologic transition. A theory of the epidemiology of population change.
Millbank Mem Fund Q. 1971;49(4):50938.
Olshansky SJ, Ault AB. The fourth stage of the epidemiologic transition; the age of delayed
degenerative diseases. Millbank Q. 1986;64(3):33591.
Puska P. Successful prevention of non-communicable diseases: 25 years experiences with the
North Karelia Project in Finland. Public Health Med. 2002;4(1):57.
Rose G. The strategy of preventive medicine. Oxford University Press; 1992. p. 24 and 12.
Unal B, Critchley JA, Capewell S. Explaining the decline in coronary heart disease mortality
in England and Wales between 1981 and 2000. Circulation. 2004;109:11017.

Jadelson Andrade - Fausto Pinto - Donna Arnett (Eds.) - Prevention of Cardiovascular Diseases - From Current Evidence To Clinical Practice-Springer International Publishing (2015)

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

Jadelson Andrade - Fausto Pinto - Donna Arnett (Eds.) - Prevention of Cardiovascular Diseases - From Current Evidence To Clinical Practice-Springer International Publishing (2015)

Enviado por

Direitos autorais:

Formatos disponíveis

Prevention of

Prevention of Cardiovascular Diseases

Jadelson P. Andrade Fausto J. Pinto

Fausto J. Pinto, M.D., Ph.D.

Originally published in Portuguese

Library of Congress Control Number: 2015945957

Preface by Jadelson P. Andrade

Jadelson P. Andrade, MD, FACC, FESC

Preface by Fausto J. Pinto

Cardiovascular diseases represent the main cause of mortality worldwide, accounting

Preface by Fausto J. Pinto

Fausto J. Pinto, MD, PhD, FESCC, FACC

Preface by Donna K. Arnett

Donna K. Arnett, MSPH, PhD

Global Burden of Non-Communicable, Chronic Diseases ..........................

Cardiovascular Disease Worldwide: A Global Challenge ...........................

Value of Primordial and Primary Prevention for Cardiovascular

How to Estimate Cardiovascular Risk ..........................................................

Tobacco and Alcohol Control: Preventable Risk Factors ...........................

Physical Inactivity: Preventable Risk Factor

Diet and Cardiovascular Health: Global Challenges

Raised Blood Cholesterol: Preventable Risk Factor

Hypertension: Primary Health Care Approach ...........................................

Diabetes: A Primary Health Care Approach ...............................................

Risk Factors in Childhood and Youth ........................................................... 101

Other Determinants of Cardiovascular Diseases:

A Global Alliance for Cardiovascular Disease Prevention

Aloyzio Chechella Achutti, M.D., Ph.D. School of Medicine, Federal University

Ian M. Graham, M.D. Cardiovascular Medicine, Trinity College Dublin, Dublin,

William S. Weintraub, M.D. Center for Outcomes Research, One of Four

Global Burden of Non-Communicable,

Measuring Burden of Disease

M.D. Huffman, MD, MPH (*)

M.D. Huffman and S.C. Smith Jr.

Global Burden of Non-Communicable, Chronic Diseases

Global Burden of Non-Communicable, Chronic Diseases

M.D. Huffman and S.C. Smith Jr.

Age-standardized death rates

Data abstracted from Lozano et al. [3]

Global Burden of Non-Communicable, Chronic Diseases

All disability adjusted life years

Disability adjusted life years per

Data abstracted from Murray et al. [2]

M.D. Huffman and S.C. Smith Jr.

Chronic Lung Diseases

Global Burden of Non-Communicable, Chronic Diseases

Mental and Behavioral Disorders

Shared Risk Factors for Non-Communicable,

M.D. Huffman and S.C. Smith Jr.

Global Burden of Non-Communicable, Chronic Diseases

Box: Nine Voluntary Targets Adopted by Member States of the World

M.D. Huffman and S.C. Smith Jr.

Global Burden of Non-Communicable, Chronic Diseases

Cardiovascular Disease Worldwide: A Global

At the beginning of this century, cardiovascular diseases (CVD) showed an

J.P. Andrade, M.D. (*)

J.P. Andrade et al.

Risk Factors for CVD

Cardiovascular Disease Worldwide: A Global Challenge

Prevention of Risk Factors, Early Diagnosis

J.P. Andrade et al.

United States 68-76

New Zealand 74-81