Coronary Artery Atherosclerosis

9/4/2014
Coronary Artery Atherosclerosis
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Author: F Brian Boudi, MD, FACP; Chief Editor: Yasmine Subhi Ali, MD, MSCI, FACC, FACP more...
Updated: Mar 24, 2014
Practice Essentials
Coronary artery atherosclerosis is the single largest killer of men and women in the United States. It is the
principal cause of coronary artery disease (CAD), in which atherosclerotic changes are present within the walls of
the coronary arteries.
Essential update: ACC-AHA updates to cholesterol guidelines potentially expands statin

therapy to 12.8M more adults
Pencina et al applied the 2013 cholesterol guidelines of the American College of Cardiology and the American
Heart Association (ACCAHA) to data from the 20052010 National Health and Nutrition Examination Surveys
(NHANES) and estimated that an additional 12.8 million US adults would be eligible for statin therapy as
compared with treatment based on the National Cholesterol Education Program (NCEP) Third Adult Treatment
Panel (ATP III) guidelines.[1, 2]
About 10.4 million of these adults would be eligible to receive statins for primary preventionprimarily older people
(60-75 y) without cardiovascular disease (8.3M), more men (87.4%) than women (53.6%), those with higher blood
pressures, and those with lower LDL-C levels (70 mg/dL).[1, 2] The investigators noted that the potential increase
in numbers of individuals impacted by the new guidelines is based on their 10-year risk of a cardiovascular event
(7.5%).[1, 2]
Signs and symptoms

The signs and symptoms of coronary artery atherosclerosis include the following:
Chest pain
Shortness of breath
Weakness, tiredness, reduced exertional capacity
Dizziness, palpitations
Leg swelling
Weight gain
Diaphoresis
Stable angina pectoris
Intermittent claudication
Mesenteric angina
Tachycardia: Common in persons with acute coronary syndrome (ACS) and acute myocardial infarction
(AMI)
High or low blood pressure
S4 gallop: A common early finding
S3 gallop: An indication of reduced left ventricular function
Heart murmurs
Tachypnea
Xanthelasmas
http://emedicine.medscape.com/article/153647-overview
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Livedo reticularis
Syncope
Leg edema
Rales
See Clinical Presentation for more detail.
Diagnosis
Laboratory tests:
Complete blood count (CBC)
Chemistry panel
Lipid profile
Thyroid function tests: To exclude thyroid disorders
Blood glucose and hemoglobin A1C (HbA1C) measurement: Appropriate in patients with diabetes mellitus
Myocardial fractional flow reserve (FFR)
Coronary flow reserve (CFR)
Lipid studies
C-reactive protein level
Serum markers
Imaging studies:
Echocardiography
Nuclear imaging
Computed tomography
Electron beam CT scanning
Optical coherence tomography imaging
Magnetic resonance imaging
Positron emission tomography
Coronary angiography
Doppler velocity probes
Ultrasonography
See Workup for more detail.
Management
The following are used in the management of angina[3] :
Nitrates
Beta blockers
Statins
Calcium channel blockers
Ranolazine
Other agents used in the treatment of coronary artery stenosis or to aid in the management of stable coronary
artery disease after intervention include the following:
Angiotensin-converting enzyme inhibitors to reduce blood pressure
Antiplatelet agents for acute coronary events
Intravenous glycoprotein IIb/IIIa inhibitors
Aspirin
Clopidogrel
Ticlopidine
HMG-CoA reductase inhibitors, or statins to lower LDL cholesterol levels
Treatment procedures for coronary artery atherosclerosis include the following:
Coronary artery bypass grafting (CABG)
Percutaneous coronary intervention (PCI)
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Partial ileal bypass

In high- and intermediate-risk patients with 3-vessel disease, PCI was associated with significantly higher rates of
revascularization and of major adverse cardiac and cerebrovascular events than CABG[4, 5] ; the 2 procedures were
equally effective in the treatment of low-risk patients with 3-vessel disease and in low- and intermediate-risk
patients with left main CAD.
See Treatment and Medication for more detail.
Image library
Cardiac catheterization and coronary angiography in the left panel show s severe left anterior descending coronary artery stenosis. This
lesion w as treated w ith stent placement in the left anterior descending coronary artery, as observed in the right panel.
Background
Coronary artery atherosclerosis is the single largest killer of men and women in the United States. It is the
principal cause of coronary artery disease (CAD), in which atherosclerotic changes are present within the walls of
the coronary arteries. CAD is a progressive disease process that generally begins in childhood and manifests
clinically in middle to late adulthood.
The word atherosclerosis is of Greek origin and literally means focal accumulation of lipid (ie, athere [gruel]) and
thickening of arterial intima (ie, sclerosis [hardening]). Atherosclerosis is a disease of large and medium-sized
muscular arteries and is characterized by the following:
Endothelial dysfunction
Vascular inflammation
Buildup of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall
Atherosclerotic buildup results in the following:
Plaque formation
Vascular remodeling
Acute and chronic luminal obstruction
Abnormalities of blood flow
Diminished oxygen supply to target organs
By impairing or obstructing normal blood flow, atherosclerotic buildup causes myocardial ischemia. (See
Pathophysiology.)
Approximately 14 million Americans have CAD. Each year, 1.5 million individuals develop acute myocardial
infarction (AMI), the most deadly presentation of CAD, and more than 500,000 of these individuals die. (See
Epidemiology.)
Nonetheless, there has been a 30% reduction in mortality from CAD since the late 20th century. Many factors
have contributed to this, including the introduction of coronary care units, coronary artery bypass grafting (CABG),
thrombolytic therapy, percutaneous coronary intervention (PCI), and a renewed emphasis on lifestyle modification.
(See Treatment Strategies and Management.)
A major advance in the treatment of coronary artery atherosclerosis has been the development of a refined
understanding of the nature of atherosclerotic plaque and the phenomenon of plaque rupture, which is the
predominant cause of acute coronary syndrome (ACS) and AMI. Cardiologists now know that in many cases
(perhaps more than half), the plaque that ruptures and results in the clinical syndromes of ACS and AMI is less
than 50% occlusive. These so-called vulnerable plaques, as compared with stable plaques, consist of a large lipid
core, inflammatory cells, and thin, fibrous caps that are subjected to greater biomechanical stress, thus leading to
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rupture that perpetuates thrombosis and ACS. The process of plaque rupture is illustrated in the diagram below.
A vulnerable plaque and the mechanism of plaque rupture.
The treatment of such ruptured plaques has taken a leap forward with the widespread use of newer antiplatelet and
antithrombotic agents. Nonetheless, the greatest impact on the CAD epidemic can only be achieved through
therapies tailored to prevent the rupture of these vulnerable plaques. Such plaques are likely more prevalent than
occlusive plaques are. Currently, it is not possible to clinically identify most vulnerable plaques, and no data
support the local treatment of them. On the other hand, strong evidence from many randomized trials supports the
efficacy of statin-class drugs in lipid lowering and of angiotensin-converting enzyme (ACE) inhibitors in improving
endothelial function, with the use of both types of agents likely leading to plaque stabilization. (See Medication.)
Anatomy
The healthy epicardial coronary artery consists of the following 3 layers:
Intima
Media
Adventitia
The intima is an inner monolayer of endothelial cells lining the lumen; it is bound on the outside by internal elastic
lamina, a fenestrated sheet of elastin fibers. The thin subendothelial space in between contains thin elastin and
collagen fibers along with a few smooth muscle cells (SMCs).
The media are bound on the outside by an external elastic lamina that separates them from the adventitia, which
consists mainly of fibroblasts, SMCs, and a matrix containing collagen and proteoglycans.
The endothelium is the monolayered inner lining of the vascular system. It covers almost 700 m2 and weighs 1.5
kg.
The endothelium has various functions. It provides a nonthrombogenic surface via a surface covering of heparan
sulfate and through the production of prostaglandin derivatives such as prostacyclin, which is a potent vasodilator
and an inhibitor of platelet aggregation.
The endothelium secretes the most potent vasodilator, endothelium-derived relaxing factor (EDRF), a thiolated form
of nitric oxide. EDRF formation by endothelium is critical in maintaining a balance between vasoconstriction and
vasodilation in the process of arterial homeostasis. The endothelium also secretes agents that are effective in
lysing fibrin clots. These agents include plasminogen and procoagulant materials, such as von Willebrand factor
and type 1 plasminogen activator inhibitor. In addition, the endothelium secretes various cytokines and adhesion
molecules, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1, and numerous
vasoactive agents, such as endothelin, A-II, serotonin, and platelet-derived growth factor, which may be important
in vasoconstriction.
Endothelium, through the above mechanisms, regulates the following:
Vascular tone
Platelet activation
Monocyte adhesion and inflammation
Thrombus generation
Lipid metabolism
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Cellular growth and vascular remodeling
Pathophysiology
Initially thought to be a chronic, slowly progressive, degenerative disease, atherosclerosis is a disorder with
periods of activity and quiescence. Although a systemic disease, atherosclerosis manifests in a focal manner and
affects different organ systems in different patients for reasons that remain unclear
Plaque growth and vascular remodeling

The lesions of atherosclerosis do not occur in a random fashion. Hemodynamic factors interact with the activated
vascular endothelium. Fluid shear stresses generated by blood flow influence the phenotype of the endothelial
cells by modulation of gene expression and regulation of the activity of flow-sensitive proteins.
Atherosclerotic plaques (or atheromas), which may require 10-15 years for full development, characteristically
occur in regions of branching and marked curvature at areas of geometric irregularity and where blood undergoes
sudden changes in velocity and direction of flow. Decreased shear stress and turbulence may promote
atherogenesis at these important sites within the coronary arteries, the major branches of the thoracic and
abdominal aorta, and the large conduit vessels of the lower extremities.
A study by Samady et al suggests low shear segments in the coronary arteries develop greater plaque and
necrotic core progression and constrictive remodeling, whereas high shear segments develop greater necrotic core
and calcium progression, regression of fibrous and fibrofatty tissue, and excessive expansive remodeling.[6] This
suggests a transformation to a more vulnerable phenotype.
The earliest pathologic lesion of atherosclerosis is the fatty streak, which is observed in the aorta and coronary
arteries of most individuals by age 20 years. The fatty streak is the result of focal accumulation of serum
lipoproteins within the intima of the vessel wall. Microscopy reveals lipid-laden macrophages, T lymphocytes, and
smooth muscle cells in varying proportions. The fatty streak may progress to form a fibrous plaque, the result of
progressive lipid accumulation and the migration and proliferation of SMCs.
Platelet-derived growth factor, insulinlike growth factor, transforming growth factors alpha and beta, thrombin, and
angiotensin II (A-II) are potent mitogens that are produced by activated platelets, macrophages, and dysfunctional
endothelial cells that characterize early atherogenesis, vascular inflammation, and platelet-rich thrombosis at sites
of endothelial disruption. The relative deficiency of endothelium-derived nitric oxide further potentiates this
proliferative stage of plaque maturation.
The SMCs are responsible for the deposition of extracellular connective tissue matrix and form a fibrous cap that
overlies a core of lipid-laden foam cells, extracellular lipid, and necrotic cellular debris. Growth of the fibrous plaque
results in vascular remodeling, progressive luminal narrowing, blood-flow abnormalities, and compromised oxygen
supply to the target organ. Human coronary arteries enlarge in response to plaque formation, and luminal stenosis
may occur only when the plaque occupies more than 40% of the area bounded by the internal elastic lamina.
Developing atherosclerotic plaques acquire their own microvascular network, the vasa vasorum, which are prone to
hemorrhage and contribute to progression of atherosclerosis.[7]
As endothelial injury and inflammation progress, fibroatheromas grow and form the plaque. As the plaque grows, 2
types of remodeling, positive remodeling and negative remodeling, occur, as illustrated in the image below.
Positive and negative arterial remodeling.

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Positive remodeling is an outward compensatory remodeling (the Glagov phenomenon) in which the arterial wall
bulges outward and the lumen remains uncompromised. Such plaques grow further; however, they usually do not
cause angina, because they do not become hemodynamically significant for a long time. In fact, the plaque does
not begin to encroach on the lumen until it occupies 40% of the cross-sectional area. The encroachment must be
at least 50-70% to cause flow limitation. Such positively remodeled lesions thus form the bulk of the vulnerable
plaques, grow for years, and are more prone to result in plaque rupture and ACS than stable angina, as
documented by intravascular ultrasonography (IVUS) studies.
Many fewer lesions exhibit almost no compensatory vascular dilation, and the atheroma steadily grows inward,
causing gradual luminal narrowing. Many of the plaques with initial positive remodeling eventually progress to the
negative remodeling stage, causing narrowing of the vascular lumen. Such plaques usually lead to the
development of stable angina. They are also vulnerable to plaque rupture and thrombosis.
Plaque rupture
Denudation of the overlying endothelium or rupture of the protective fibrous cap may result in exposure of the
thrombogenic contents of the core of the plaque to the circulating blood. This exposure constitutes an advanced or
complicated lesion. The plaque rupture occurs due to weakening of the fibrous cap. Inflammatory cells localize to
the shoulder region of the vulnerable plaque. T lymphocytes elaborate interferon gamma, an important cytokine
that impairs vascular smooth muscle cell proliferation and collagen synthesis. Furthermore, activated
macrophages produce matrix metalloproteinases that degrade collagen.
These mechanisms explain the predisposition to plaque rupture and highlight the role of inflammation in the
genesis of the complications of the fibrous atheromatous plaque. A plaque rupture may result in thrombus
formation, partial or complete occlusion of the blood vessel, and progression of the atherosclerotic lesion due to
organization of the thrombus and incorporation within the plaque.
Plaque rupture is the main event that causes acute presentations. However, severely obstructive coronary
atheromas do not usually cause ACS and MI. In fact, most of the atheromas that cause ACS are less than 50%
occlusive, as demonstrated by coronary arteriography. Atheromas with smaller obstruction experience greater wall
tension, which changes in direct proportion to their radii.
Most plaque ruptures occur because of disruption of the fibrous cap, which allows contact between the highly
thrombogenic lipid core and the blood. These modestly obstructive plaques, which have a greater burden of soft
lipid core and thinner fibrous caps with chemoactive cellular infiltration near the shoulder region, are called
vulnerable plaques. The amount of collagen in the fibrous cap depends on the balance between synthesis and
destruction of intercellular matrix and inflammatory cell activation.
T cells that accumulate at sites of plaque rupture and thrombosis produce the cytokine interferon gamma, which
inhibits collagen synthesis. Already-formed collagen is degraded by macrophages that produce proteolytic
enzymes and by matrix metalloproteinases (MMPs), particularly MMP-1, MMP-13, MMP-3, and MMP-9. The
MMPs are induced by macrophage- and SMC-derived cytokines such as IL-1, tumor necrosis factor (TNF), and
CD154 or TNF-alpha. Authorities postulate that lipid lowering stabilizes the vulnerable plaques by modulating the
activity of the macrophage-derived MMPs.
Histologic composition and structure

A system devised by Stary et al classifies atherosclerotic lesions according to their histologic composition and
structure.[8]
In a type I lesion, the endothelium expresses surface adhesion molecules E selectin and P selectin, attracting
more polymorphonuclear cells and monocytes in the subendothelial space.
In a type II lesion, macrophages begin to take up large amounts of LDL (fatty streak).
In a type III lesion, as the process continues, macrophages become foam cells.
In a type IV lesion, lipid exudes into the extracellular space and begins to coalesce to form the lipid core.
In a type V lesion, SMCs and fibroblasts move in, forming fibroatheromas with soft inner lipid cores and outer
fibrous caps.
In a type VI lesion, rupture of the fibrous cap with resultant thrombosis causes ACS.
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As lesions stabilize, they become fibrocalcific (type VII lesion) and, ultimately, fibrotic with extensive collagen
content (type VIII lesion).
Etiology
A complex and incompletely understood interaction is observed between the critical cellular elements of the
atherosclerotic lesion. These cellular elements include endothelial cells, smooth muscle cells, platelets, and
leukocytes. Interrelated biologic processes that contribute to atherogenesis and the clinical manifestations of
atherosclerosis are as follows:
Vasomotor function
Thrombogenicity of the blood vessel wall
State of activation of the coagulation cascade
The fibrinolytic system
SMC migration and proliferation
Cellular inflammation
The encrustation theory, proposed by Rokitansky in 1851, suggested that atherosclerosis begins in the intima with
deposition of thrombus and its subsequent organization by the infiltration of fibroblasts and secondary lipid
deposition.
In 1856, Virchow proposed that atherosclerosis starts with lipid transudation into the arterial wall and its interaction
with cellular and extracellular elements, causing "intimal proliferation."
Endothelial injury as the mechanism of atherosclerosis

In his response-to-injury hypothesis, Ross postulated that atherosclerosis begins with endothelial injury, making
the endothelium susceptible to the accumulation of lipids and the deposition of thrombus. The mechanisms of
atherogenesis remain uncertain, but the response-to-injury hypothesis is the most widely accepted proposal.
In the 1990s, Ross and Fuster proposed that vascular injury starts the atherosclerotic process.[9] Such injuries
can be classified as follows:
Type I - Vascular injury involving functional changes in the endothelium, with minimal structural changes,
(ie, increased lipoprotein permeability and white blood cell adhesion)
Type II - Vascular injury involving endothelial disruption, with minimal thrombosis
Type III - Vascular injury involving damage to media, which may stimulate severe thrombosis, resulting in
unstable coronary syndromes
According to the response-tovascular injury theory, injury to the endothelium by local disturbances of blood flow
at angulated or branch points, along with systemic risk factors, perpetuates a series of events that culminate in
the development of atherosclerotic plaque.
As discussed in greater detail below, endothelial damage occurs in many clinical settings and can be
demonstrated in individuals with dyslipidemia, hypertension, diabetes, advanced age, nicotine exposure, and
products of infective organisms (ie, Chlamydia pneumoniae). Damage to the endothelium may cause changes that
are localized or generalized and that are transient or persistent, as follows:
Increased permeability to lipoproteins
Decreased nitric oxide production
Increased leukocyte migration and adhesion
Prothrombotic dominance
Vascular growth stimulation
Vasoactive substance release
Endothelial dysfunction is the initial step that allows diffusion of lipids and inflammatory cells (ie, monocytes, T
lymphocytes) into the endothelial and subendothelial spaces. Secretion of cytokines and growth factors promotes
intimal migration, SMC proliferation, and accumulation of collagen matrix and of monocytes and other white blood
cells, forming an atheroma. More advanced atheromas, even though nonocclusive, may rupture, thus leading to
thrombosis and the development of ACS and MI.
Role of low-density lipoprotein-oxidative stress

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The most atherogenic type of lipid is the low-density lipoprotein (LDL) component of total serum cholesterol. The
endothelium's ability to modify lipoproteins may be particularly important in atherogenesis. LDLs appear to be
modified by a process of low-level oxidation when bound to the LDL receptor, internalized, and transported through
the endothelium. LDLs initially accrue in the subendothelial space and stimulate vascular cells to produce
cytokines for recruiting monocytes, which causes further LDL oxidation. Extensively oxidized LDL (oxLDL), which
is exceedingly atherogenic, is picked up by the scavenger receptors on macrophages, which absorb the LDL.
Cholesterol accumulation in macrophages is promoted by oxLDL; the macrophages then become foam cells. In
addition, oxLDL enhances endothelial production of leukocyte adhesion molecules (ie, cytokines and growth
factors that regulate SMC proliferation, collagen degradation, and thrombosis [eg, vascular cell adhesion molecule1, intercellular cell adhesion molecule-1]).
Oxidized LDL inhibits nitric oxide synthase activity and increasing reactive oxygen species generation (eg,
superoxide, hydrogen peroxide), thus reducing endothelium-dependent vasodilation. Moreover, oxLDL alters the
SMC response to A-II stimulation and increasing vascular A-II concentrations. The SMCs that proliferate in the
intima to form advanced atheromas are originally derived from the media. The theory that accumulation of SMCs in
the intima represents the sine qua non of the lesions of advanced atherosclerosis is now widely accepted.
Substantial evidence suggests that oxLDL is the prominent component of atheromas. Antibodies against oxLDL
react with atherosclerotic plaques, and plasma levels of immunoreactive altered LDL are greater in persons with
AMI than in controls. Oxidative stress has therefore been recognized as the most significant contributor to
atherosclerosis by causing LDL oxidation and increasing nitric oxide breakdown.
Risk factors for coronary artery atherosclerosis

A number of large epidemiologic studies in North America and Europe have identified numerous risk factors for the
development and progression of atherosclerosis. These factors, which can be classified as either modifiable or
nonmodifiable, include the following:
Hyperlipidemia and dyslipidemia
Hypertension
Cigarette habituation
Air pollution
Diabetes mellitus
Age
Sex
The American College of Cardiology Foundation/American Heart Association 2010 report on cardiovascular risk
assessment in asymptomatic adults recommends global risk scoring (eg, Framingham Risk Score[10] ) and a
family history of cardiovascular disease be obtained in all adult women and men.[11]
Numerous novel risk factors have been identified that add to the predictive value of the established risk factors and
may prove to be a target for future medical interventions.
Risk factors specific to women include pregnancy and complications of pregnancy such as gestational diabetes,
preeclampsia, third trimester bleeding, preterm birth, and birth of an infant small for gestational age. The 2011
update to the American Heart Association guideline for the prevention of cardiovascular disease (CVD) in women
recommends that risk assessment at any stage of life include a detailed history of pregnancy complications. It
also states that postpartum, obstetricians should refer women who experience these complications to a primary
care physician or cardiologist.[12]
The presence of risk factors accelerates the rate of development of atherosclerosis. Diabetes causes endothelial
dysfunction, decreases endothelial thromboresistance, and increases platelet activity, thus accelerating
atherosclerosis.
Established risk factors successfully predict future cardiac events in about 50-60% of patients. A concerted effort
to identify is also being made to validate new markers of future risk of the clinical consequences of atherosclerosis
has been made.
Other risk factors for coronary artery atherosclerosis include the following:
Family history of premature CAD
Hypoalphalipoproteinemia
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Obesity
Physical inactivity
Syndromes of accelerated atherosclerosis - Graft atherosclerosis, CAD after cardiac transplantation
Chronic kidney disease[13]
Systemic lupus erythematosus [14]
Rheumatoid arthritis [15]
Metabolic syndrome[16]
Chronic inflammation
Infectious agents
Increased fibrinogen levels
Increased lipoprotein(a) levels
Familial hypercholesterolemia
Depression
According to the 2011 update to the American Heart Association guideline for CVD prevention in women, risk
factors that are more common or may be more significant in women include psychosocial factors such as
depression and autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The Heart
and Estrogen/progestin Replacement Study evaluated the effects of hormone replacement therapy on
cardiovascular events among postmenopausal women with CAD and found that sudden cardiac death comprised
most cardiac deaths among this group of women.[17] Women with these conditions should be evaluated for CVD
and for other risk factors. Women with clinically evident CVD should also be screened for these conditions, which
can affect adherence or otherwise complicate secondary CVD prevention efforts.[12]
A study by Semba et al, however, suggests that high concentrations of plasma klotho, a recently discovered
hormone that has been implicated in atherosclerosis, are independently associated with a lower likelihood of
having CVD.[18]
For more information, see Risk Factors for Coronary Artery Disease.
Epidemiology
The true frequency of atherosclerosis is difficult, if not impossible, to accurately determine because it is a
predominantly asymptomatic condition. The process of atherosclerosis begins in childhood with the development
of fatty streaks. These lesions can be found in the aorta shortly after birth and appear in increasing numbers in
those aged 8-18 years. More advanced lesions begin to develop when individuals are aged approximately 25 years.
Subsequently, an increasing prevalence of the advanced complicated lesions of atherosclerosis is noted, and the
organ-specific clinical manifestations of the disease increase with age through the fifth and sixth decades of life.
United States statistics

In the United States, approximately 14 million persons experience CAD and its various complications. Congestive
heart failure (CHF) that develops because of ischemic cardiomyopathy in hypertensive MI survivors has become
the most common discharge diagnosis for patients in American hospitals. Approximately 80 million people, or
36.3% of the population, have cardiovascular disease.
Annually, approximately 1.5 million Americans have an AMI, a third of whom die. In 2009, 785,000 Americans
were estimated to have suffered a first MI, and about 470,000 Americans were estimated to have had a recurrent
event. An additional 195,000 "silent" heart attacks are estimated to occur each year. About every 34 seconds, an
American will have an MI. CAD remains the number 1 cause of death for men and women in the United States and
is responsible for approximately 20% of all US deaths. From 19952005, the death rate from CAD declined 34.3%,
but the actual number of deaths declined only 19.4%.
International statistics
The international incidence of ACS and AMI, especially in developed countries, is similar to that observed in the
United States. Despite consumption of rich foods, inhabitants of France and the Mediterranean region appear to
have a lower incidence of CAD. This phenomenon (sometimes called the French paradox) is partly explained by
greater use of alcohol, with its possible HDL-raising benefit, and by consumption of the Mediterranean diet, which
includes predominant use of monounsaturated fatty acids, such as olive oil or canola oil, as well as omega-3 fatty
acids, which are less atherogenic. Eskimos have been found to have a lower prevalence of CAD as a result of
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consuming fish oils containing omega-3 fatty acids.

The Spanish cohort of the European Prospective Investigation into Cancer and Nutrition assessed the association
between consumption of fried foods and risk of coronary heart disease. They found that among people living in
Spain, where olive or sunflower oil is commonly used for frying, the consumption of fried foods was not associated
with coronary heart disease or with all-cause mortality. This further suggests that the Mediterranean diet may help
lower the risk of CAD.[19]
Findings from the World Health Organization's Monitor Trends in Cardiovascular Diseases (MONICA) project
involving 21 countries showed a 4% fall in CAD death rates. Improvement in the case fatality rate accounted for
only one third of the decline. However, two thirds of the decline resulted from a reduction in the number of events.
These findings strongly suggest that the largest impact on decreasing the global burden of atherosclerosis will
come from prevention of events.
The frequency of clinical manifestations of atherosclerosis in Great Britain, west of Scotland in particular, is
especially high. The same is true of Scandinavia in general and of Finland in particular. Russia and many of the
former states of the Soviet Union have recently experienced an exponential increase in the frequency of coronary
heart disease that likely is the result of widespread economic hardship and social upheaval, a high prevalence of
cigarette habituation, and a diet high in saturated fats.
Westernization and the rise of coronary heart disease

The frequency of coronary heart disease in the Far East is significantly lower than that documented in the West.
Ill-defined genetic reasons for this phenomenon may exist, but significant interest surrounds the role of diet and
other environmental factors in the absence of clinical atherosclerotic vascular disease in these populations.
Atherosclerotic cardiovascular disease is also rare on the African continent, although growing evidence indicates
that this too is changing, as a result of rapid westernization and urbanization of the traditionally rural and agrarian
African populations. The prevalence of coronary heart disease is also increasing in the Middle East, India, and
Central and South America.[7] The rate of CAD in ethnic immigrant populations in the United States approaches
that of the disease in whites, supporting the role of these putative environmental factors.
Race-associated prevalences of coronary artery disease

The incidence, prevalence, and manifestations of CAD vary significantly with race, as does the response to
therapy.
Blacks appear to have higher morbidity and mortality rates of CAD, even when the statistics are corrected for
educational and socioeconomic status. The risk-factor burden experienced by blacks differs from that of whites.
The prevalence of hypertension, obesity, dysmetabolic syndrome, and lack of physical activity are much higher in
blacks, whereas the prevalence of hypercholesterolemia is lower. Blacks with AMI present for treatment later than
patients do on average, are less often subjected to invasive strategies, and experience greater overall mortality.
(Similar statistics can also be cited for presentation and treatment of patients with stable CAD.)
Asian Indians exhibit a 2- to 3-fold higher prevalence of CAD than do whites in the United States. They also have
greater prevalences of hypoalphalipoproteinemia, high lipoprotein(a) levels, and diabetes.
Sex-associated prevalences of coronary artery disease

Men traditionally have a higher prevalence of CAD. Women, however, follow men by 10 years, especially after
menopause. (The value of estrogen supplementation for prevention of CAD has been discredited by the Heart and
Estrogen/Progestin Replacement Study [HERS]).[20, 21]
The presence of diabetes, as well as tobacco use, eliminates the protection from heart disease associated with
female sex. In women, as in men, the most common cause of death is CAD, which accounts for more deaths in
women than those related to breast and uterine diseases combined. Women with AMI present later than average,
are less often subjected to invasive strategies, and experience greater overall mortality. (Similar statistics can also
be cited for the presentation and treatment of patients with stable CAD.)
The 2011 update to the American Heart Association guideline for the prevention of cardiovascular disease in
women recommends changes in prevention and treatment practices:[12]
Women should be considered as high risk, and as candidates for aggressive treatment, if their risk of dying
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from any cardiovascular event in the next 10 years is 10% or greater.

Research studies should publish efficacy and adverse drug reactions (ADRs) by gender, as both can differ
in women.
Evidence from clinical trials tends to overestimate the real-world efficacy of therapies in female patients,
who are generally older and have more comorbidities than test subjects. The guideline is now
effectiveness-based rather than evidence-based.
Effectiveness-based considerations have reduced the strength of previous recommendations for use of
aspirin, statins (in women with elevated C-reactive protein but normal cholesterol), and aggressive glycemic
control in diabetes.
The elderly and coronary artery disease

Age is the strongest risk factor for the development of CAD. Most cases of CAD become clinically apparent in
patients aged 40 years or older, but elderly persons experience higher mortality and morbidity rates from it.
Approximately 82% of people who die of CAD are 65 years or older. Complication rates of multiple therapeutic
interventions tend to be higher in the elderly; however, the magnitude of benefit from the same interventions is
greater in this population, because these patients form a high-risk subgroup.
Calculating risk of coronary artery atherosclerosis

Of note, algorithms for predicting the risk of cardiovascular disease have generally been developed for a follow-up
period of no more than 10 years. However, clustering of risk factors at younger ages and increasing life
expectancy suggest the need for longer-term risk prediction.
In a prospective, 30-year follow-up study, standard risk factors (male sex, systolic blood pressure,
antihypertensive treatment, total and high-density lipoprotein cholesterol, smoking, diabetes mellitus), measured
at baseline, were significantly related to the incidence of coronary death, myocardial infarction, and stroke and
remained significant when updated regularly. This 2009 study by Pencina and colleagues, which utilized 4506
participants of the Framingham Offspring cohort, employed an algorithm for predicting 30-year risk for the above
events. The investigators also found that body mass index was associated positively with 30-year risk of such
events, but only in models that did not update risk factors.[10]
Prognosis
As previously mentioned, approximately 1.5 million Americans per year have an AMI, with a third of these events
proving fatal. The survivors of MI have a poor prognosis, carrying a 1.5- to 15-fold higher risk of mortality and
morbidity than the rest of the population.
Historically, for example, 25% of men and 38% of women die within 1 year after having an MI, although these rates
may overstate the 1-year mortality today, given advances in the treatment of CHF and sudden cardiac death.
Among survivors, 18% of men and 34% of women have a second MI within 6 years, 7% of men and 6% of women
die suddenly, 22% of men and 46% of women are disabled with CHF, and 8% of men and 11% of women have a
stroke.
According to a prospective study using data from the Coronary CT Angiography Evaluation for Clinical Outcomes:
An International Multicenter (CONFIRM) Registry, incident mortality and MI rates do not differ significantly between
men and women among patients matched for age, risk factors, symptoms, and extent of CAD.[22] These findings
conflict with those from the Womens Health Initiative, which found that in women with nonspecific or atypical
chest pain, the risk of nonfatal MI is twice as great as that in men.
The prognosis in patients with atherosclerosis depends on the following factors:
Presence of inducible ischemia
Left ventricular function
Presence of arrhythmias
Revascularization potential (complete vs incomplete)
Aggressiveness of risk alteration
Compliance with medical therapy
The prognosis of atherosclerosis also depends on systemic burden of disease, the vascular bed(s) involved, and
the degree of flow limitation. Wide variability is noted, and clinicians appreciate that many patients with critical
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limitation of flow to vital organs may survive many years, despite a heavy burden of disease. Conversely, MI or
sudden cardiac death may be the first clinical manifestation of atherosclerotic cardiovascular disease in a patient
who is otherwise asymptomatic with minimal luminal stenosis and a light burden of disease.
Much of this phenotypic variability is likely to be determined by the relative stability of the vascular plaque burden.
Plaque rupture and exposure of the thrombogenic lipid core are critical events in the expression of this disease
process and determine the prognosis. The ability to determine and quantify risk and prognosis in patients with
atherosclerosis is limited by the inability to objectively measure plaque stability and other predictors of clinical
events.
Patient Education
Education regarding CAD is extremely important. Publications and articles available from the American Heart
Association provide a wealth of information.
The most effective and probably the most cost-efficient means of reducing the burden of disease secondary to
atherosclerosis in the general population is primary prevention. The role of diet and exercise in the prevention of
atherosclerotic cardiovascular disease has been well established. Education of the general population regarding
healthy dietary habits and regular exercise will reduce the prevalence of multiple coronary heart disease risk
factors. (See Treatment Strategies and Management) For patients with risk factors refractory to lifestyle
interventions, education can enhance compliance with prescribed therapy.
For patient education resources, see the Cholesterol Center, as well as High Cholesterol, Lifestyle Cholesterol
Management, Chest Pain, Coronary Heart Disease, Heart Attack, Angina Pectoris, and Statins for Cholesterol.
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Contributor Information and Disclosures

Author
F Brian Boudi, MD, FACP Clinical Associate Professor, University of Arizona College of Medicine (Phoenix
Campus); Fellow, Sarver Heart Center, University of Arizona College of Medicine; Regional Faculty, American
Heart Association; Adjunct Assistant Professor of Medicine, Mid-Western University; Staff Physician, Site
Director for Clinical Rotations Emergency Medicine, Phoenix Veterans Administration Health Care System
F Brian Boudi, MD, FACP is a member of the following medical societies: American Association for the
Advancement of Science, American College of Cardiology, American College of Healthcare Executives,
American College of Physicians, American Society of Echocardiography, American Society of Nuclear
Cardiology, Arizona Medical Association, and Association of Program Directors in Internal Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI Clinical Professor of Medicine, Director of Cardiac
Catheterization and Intervention, Marlon Cardiac Catheterization Laboratory, Director of Cardiovascular
Research, University Medical Center, University of Nevada School of Medicine
Chowdhury H Ahsan, MD, PhD, MRCP, FSCAI is a member of the following medical societies: American
College of Cardiology, American College of Physicians, American Heart Association, American Stroke
Association, and Society for Cardiac Angiography and Interventions
Chief Editor
Yasmine Subhi Ali, MD, MSCI, FACC, FACP President, Nashville Preventive Cardiology, PLLC; Assistant
12/21
9/4/2014
Clinical Professor of Medicine, Vanderbilt University School of Medicine

Yasmine Subhi Ali, MD, MSCI, FACC, FACP is a member of the following medical societies: American College
of Cardiology, American College of Physicians, American Heart Association, American Medical Association,
National Lipid Association, and Tennessee Medical Association
Disclosure: MedStudy Honoraria Independent contractor; MCG--formerly known as Milliman Care Guidelines
Consulting fee Independent contractor
Additional Contributors
Steven J Compton, MD, FACC, FACP Director of Cardiac Electrophysiology, Alaska Heart Institute,
Providence and Alaska Regional Hospitals
Steven J Compton, MD, FACC, FACP is a member of the following medical societies: Alaska State Medical
Association, American College of Cardiology, American College of Physicians, American Heart Association,
American Medical Association, and Heart Rhythm Society
John A McPherson, MD, FACC, FAHA, FSCAI Associate Professor of Medicine, Division of Cardiovascular
Medicine, Director of Cardiovascular Intensive Care Unit, Vanderbilt Heart and Vascular Institute
John A McPherson, MD, FACC, FAHA, FSCAI is a member of the following medical societies: Alpha Omega
Alpha, American College of Cardiology, American Heart Association, Society for Cardiac Angiography and
Interventions, Society of Critical Care Medicine, and Tennessee Medical Association
Disclosure: CardioDx Consulting fee Consulting; Gilead Consulting fee Consulting; Abbott Vascular Corp.
Consulting fee Consulting
James L Orford, MBChB
Andrew P Selwyn, MD, MA, FACC, FRCP
George A Stouffer III, MD Henry A Foscue Distinguished Professor of Medicine and Cardiology, Director of
Interventional Cardiology, Cardiac Catheterization Laboratory, Chief of Clinical Cardiology, Division of
Cardiology, University of North Carolina Medical Center
George A Stouffer III, MD is a member of the following medical societies: Alpha Omega Alpha, American
College of Cardiology, American College of Physicians, American Heart Association, Phi Beta Kappa, and
Society for Cardiac Angiography and Interventions
Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center
College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Medscape Salary Employment
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