Recent Updated Pathogenesis and

Management of Heart Failure:

The role of Angiotensin Receptor Blockers?

Dr. dr. ANWAR SANTOSO, SpJP(K), FIHA, FAsCC, FICA.

Dept. of Cardiology Faculty of Medicine ~ University of Indonesia
National Cardiovascular Centre Harapan Kita Hospital - INDONESIA

DiabetesistheNo.1riskfactor
forHFinwomenwithcoronarydisease

VBWG

HERS study
Diabetes

3.1
2.9

Atrial fibrillation
Myocardial infarction >1 event

2.5

Creatinine clearance <40

2.3
2.1

Systolic BP 140
Current smoking

1.9

BMI >35

1.9

Left bundle branch block

1.6
1.5

LV hypertrophy

0.5

1.5

2.5

3.5

Adjusted hazard ratio

Bibbins-Domingo K Jr et al. Circulation.2004;110:1424-30.

The Donkey Analogy

Ventricular dysfunction limits a patient's ability to perform the
routine activities of daily living

Compensatory Mechanisms:
Sympathetic Nervous System
Decreased MAP

Sympathetic Nervous System

Contractility

Tachycardia

Vasoconstriction

MAP = (SV x HR) x TPR

Sympathetic Activation in Heart

Failure
CNS sympathetic outflow
Cardiac sympathetic
activity
1receptors

2receptors

Sympathetic
activity to kidneys
+ peripheral vasculature

1receptors

Myocardial toxicity
Increased arrhythmias

1-

Activation
of RAS

Vasoconstriction
Sodium retention

Disease progression
Packer. Progr Cardiovasc Dis. 1998;39(suppl I):39-52.

1-

Compensatory Mechanisms:
Renin-Angiotensin-Aldosterone
(RAAS)
Angiotensinogen
Renin
Angiotensin I
Angiotensin
Converting
Enzyme

Angiotensin II

AT I receptor
Vasoconstriction
Oxidative Stress
Cell Growth

Vascular remodeling
LV remodeling
Proteinuria

Compensatory Mechanisms:
Renin-Angiotensin-Aldosterone
(RAAS)

Renin-Angiotensin-Aldosterone
( renal perfusion)
Salt-water retention
Thirst

Sympathetic
augmentation

Vasoconstriction

MAP = (SV x HR) x TPR

Compensatory Mechanisms:
Neurohormonal Activation Vasopressin

Decreased systemic blood pressure

Central baroreceptors
-

Increased systemic blood pressure

Vasoconstriction

Stimulation of hypothalamus, which produces

vasopressin for release by pituitary gland

Release of vasopressin by pituitary gland

Compensatory Neurohormonal
Stimulation: Summary
Decreased Cardiac Output
Sympathetic
nervous system
Contractility

Heart
rate

Renin-angiotensin
system
Vasoconstriction

Anteriolar

+
Stroke
volume

Circulating volume

Venous

Maintain
blood
pressure

Cardiac
output

Antidiuretic hormone
(vasopressin)

Venous return
to heart
(preload)

Peripheral edema
and pulmonary
congestion

Proposed Pathogenesis of Heart Failure

Gonzales A, et. al. J Am Coll Cardiol 2011; 58: 1833 - 43

Compensatory Mechanisms
Ventricular Remodeling
Alterations in the hearts size, shape, structure, and function brought about
by the chronic hemodynamic stresses experienced by the failing heart.

Curry CW, et al. Mechanical dyssynchrony in dilated cardiomyopathy with intraventricular conduction
delay as depicted by 3D tagged magnetic resonance imaging. Circulation 2000 Jan 4;101(1):E2.

Classification of Heart
Failure

A
B

ACCF/AHA Stages of HF
At high risk for HF but without structural
heart disease or symptoms of HF.
Structural heart disease but without signs
or symptoms of HF.
Structural heart disease with prior or
current symptoms of HF.

Refractory HF requiring specialized

interventions.

NYHA Functional Classification

None
I

No limitation of physical activity.

Ordinary physical activity does not cause
symptoms of HF.

No limitation of physical activity.

Ordinary physical activity does not cause
symptoms of HF.

II

Slight limitation of physical activity.

Comfortable at rest, but ordinary physical
activity results in symptoms of HF.

III

Marked limitation of physical activity.

Comfortable at rest, but less than ordinary
activity causes symptoms of HF.

IV

Unable to carry on any physical activity

without symptoms of HF, or symptoms of
HF at rest.

Diagnosis of Heart Failure

Mc Murray JJV, et. al. Eur Heart J 2012; doi: 10. 1093/eurhj/ehs.104

Diagnosis of Heart Failure

Mc Murray JJV, et. al. Eur Heart J 2012; doi: 10. 1093/eurhj/ehs.104

Diagnostic flowchart for patients suspected Heart

Failure

Mc Murray JJV, et. al. Eur Heart J 2012; doi: 10. 1093/eurhj/ehs.104

Treatment options for patients with chronic symptomatic

systolic Heart Failure

Mc Murray JJV, et. al. Eur Heart J 2012; doi: 10. 1093/eurhj/ehs.104

Diuretics, ACE Inhibitors and

ARBs
Reduce the number of sacks on the wagon

Pharmacologic Treatment for Stage

C HFrEF

Pharmacological Treatment
for
Stage C HFrEF (cont.)
I IIa IIb III

I IIa IIb III

A
I IIa IIb III

Diuretics are recommended in patients with HFrEF who

have evidence of fluid retention, unless contraindicated, to
improve symptoms.
ACE inhibitors are recommended in patients with HFrEF
and current or prior symptoms, unless contraindicated, to
reduce morbidity and mortality.
ARBs are recommended in patients with HFrEF with
current or prior symptoms who are ACE inhibitorintolerant, unless contraindicated, to reduce morbidity
and mortality.

Drugs Commonly Used for HFrEF

(Stage C HF)
Drug

Initial Daily Dose(s)

ACE Inhibitors
Captopril
6.25 mg 3 times
Enalapril
2.5 mg twice
Fosinopril
5 to 10 mg once
Lisinopril
2.5 to 5 mg once
Perindopril
2 mg once
Quinapril
5 mg twice
Ramipril
1.25 to 2.5 mg once
Trandolapril
1 mg once
ARBs
Candesartan
4 to 8 mg once
Losartan
25 to 50 mg once
Valsartan
20 to 40 mg twice
Aldosterone Antagonists
Spironolactone
12.5 to 25 mg once
Eplerenone
25 mg once

Maximum Doses(s)

Mean Doses Achieved in

Clinical Trials

50 mg 3 times
10 to 20 mg twice
40 mg once
20 to 40 mg once
8 to 16 mg once
20 mg twice
10 mg once
4 mg once

122.7 mg/d (421)

16.6 mg/d (412)
--------32.5 to 35.0 mg/d (444)
---------------------------------

32 mg once
50 to 150 mg once
160 mg twice

24 mg/d (419)
129 mg/d (420)
254 mg/d (109)

25 mg once or twice
50 mg once

26 mg/d (424)
42.6 mg/d (445)

Pharmacological Treatment
for
Stage C HFrEF (cont.)
I IIa IIb III
A
I IIa IIb III

ARBs are reasonable to reduce morbidity and mortality as

alternatives to ACE inhibitors as first-line therapy for
patients with HFrEF, especially for patients already taking
ARBs for other indications, unless contraindicated.
Addition of an ARB may be considered in persistently
symptomatic patients with HFrEF who are already being
treated with an ACE inhibitor and a beta blocker in
whom an aldosterone antagonist is not indicated or
tolerated.

Pharmacological Treatment
for
Stage C HFrEF (cont.)

I IIa IIb III

Harm
I IIa IIb III

Routine combined use of an ACE inhibitor, ARB, and

aldosterone antagonist is potentially harmful for
patients with HFrEF.

Use of 1 of the 3 beta blockers proven to reduce mortality

(i.e., bisoprolol, carvedilol, and sustained-release
metoprolol succinate) is recommended for all patients with
current or prior symptoms of HFrEF, unless
contraindicated, to reduce morbidity and mortality.

-Blockers
Limit the donkeys speed, thus saving energy

Digitalis Compounds
Like the carrot placed in front of the donkey

ACC/AHAstagesofsystolicHF
andtreatmentoptions

*In appropriate patients

Jessup M, Brozena S. N Engl J Med. 2003;348:2007-18.

VBWG

Pharmacological treatments in (NYHA class II IV)

symptomatic systolic Heart Failure

Mc Murray JJV, et. al. Eur Heart J 2012; doi: 10. 1093/eurhj/ehs.104

Treatments that may cause harm in

symptomatic Heart Failure

Mc Murray JJV, et. al. Eur Heart J 2012; doi: 10. 1093/eurhj/ehs.104

Conclusions
Evidence-based guideline directed diagnosis,
evaluation and therapy should be the mainstay
for all patients with HF.
Effective implementation of guideline-directed
best quality care reduces mortality, improves
QOL and preserves health care resources.
Ongoing research is needed to answer the
remaining questions including: prevention,
nonpharmacological therapy of HF including
dietary adjustments, treatment of HFpEF,
management of hospitalized HF, effective
reduction in HF readmissions, more precise
use of device-based therapy, smaller MCS
platforms and cell-based regenerative