recent updated pathogenesis and management of heart failure:

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

VBWG

Diabetes is the No. 1 risk factor for HF in women with coronary disease

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

Adjusted hazard ratio

Diabetes

Atrial fibrillation

Myocardial infarction >1 event

Creatinine clearance <40

Current smoking

BMI >35

Left bundle branch block

LV hypertrophy

Systolic BP ≥140

3.12.9

2.5

2.3

2.1

1.9

1.9

1.6

1.5

0 0.5 1 1.5 2 2.5 3 3.5

HERS study

The Donkey Analogy The Donkey Analogy The Donkey Analogy The Donkey Analogy

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

↑↑↑↑MAP = (↑↑↑↑SV x ↑↑↑↑HR) x ↑↑↑↑TPR

Sympathetic Nervous System

↑ Contractility Tachycardia Vasoconstriction

Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms:

Sympathetic Nervous SystemSympathetic Nervous SystemSympathetic Nervous SystemSympathetic Nervous System

Decreased MAP

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

↑ CNS sympathetic outflow

Disease progression

↑ Cardiac sympatheticactivity

β1-receptors

β2-receptors

α1-receptors

VasoconstrictionSodium retention

Myocardial toxicityIncreased arrhythmias

↑ Sympatheticactivity to kidneys

+ peripheral vasculature

Activationof RAS

α1- β1-

Sympathetic Activation in Heart FailureSympathetic Activation in Heart FailureSympathetic Activation in Heart FailureSympathetic Activation in Heart Failure

Vasoconstriction

Oxidative Stress

Cell Growth Proteinuria

LV remodeling

Vascular remodeling

Angiotensinogen

Angiotensin I

Angiotensin II

AT I receptor

Renin

AngiotensinConverting

Enzyme

Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms:

ReninReninReninRenin----AngiotensinAngiotensinAngiotensinAngiotensin----Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)

↑↑↑↑MAP = (↑↑↑↑SV x ↑↑↑↑HR) x ↑↑↑↑TPR

Renin-Angiotensin-Aldosterone(↓↓↓↓ renal perfusion)

Salt-water retentionThirst

Sympatheticaugmentation

Vasoconstriction

Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms:

ReninReninReninRenin----AngiotensinAngiotensinAngiotensinAngiotensin----Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)

Decreased systemic blood pressure

Central baroreceptors

Stimulation of hypothalamus, which producesvasopressin for release by pituitary gland

Release of vasopressin by pituitary glandVasoconstriction

Increased systemic blood pressure

-

Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms: Compensatory Mechanisms:

NeurohormonalNeurohormonalNeurohormonalNeurohormonal Activation Activation Activation Activation –––– VasopressinVasopressinVasopressinVasopressin

Compensatory Compensatory Compensatory Compensatory NeurohormonalNeurohormonalNeurohormonalNeurohormonal Stimulation: Stimulation: Stimulation: Stimulation:

Summary Summary Summary Summary

Decreased Cardiac Output

Sympatheticnervous system

Renin-angiotensinsystem

Antidiuretic hormone(vasopressin)

Heartrate

Contractility Vasoconstriction Circulating volume

Anteriolar

Maintainblood

pressure

Cardiacoutput

Strokevolume

+

-+

Venous

Venous return to heart

( preload)

Peripheral edemaand pulmonary

congestion

Proposed Pathogenesis of Heart Failure

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

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.

Compensatory MechanismsCompensatory MechanismsCompensatory MechanismsCompensatory Mechanisms

Ventricular Remodeling

Alterations in the heart’s size, shape, structure, and function brought about by the chronic hemodynamic stresses experienced by the failing heart.

Classification of Heart Failure

ACCF/AHA Stages of HF NYHA Functional ClassificationA At high risk for HF but without structural

heart disease or symptoms of HF.None

B Structural heart disease but without signs or symptoms of HF.

I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.

C Structural heart disease with prior or current symptoms of HF.

I 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.

D Refractory HF requiring specialized interventions.

Diagnosis of Heart Failure

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

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

Diagnosis of Heart Failure

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

Diagnostic flowchart for patients suspected Heart Failure

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

Treatment options for patients with chronic symptomatic systolic Heart Failure

Diuretics, ACE Inhibitors and ARB’sDiuretics, ACE Inhibitors and ARB’sDiuretics, ACE Inhibitors and ARB’sDiuretics, ACE Inhibitors and ARB’s

Reduce the number of sacks on the wagon

Pharmacologic Treatment for Stage C HFrEF

Pharmacological Treatment for

Stage C HFrEF (cont.)

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 inhibitor-intolerant, unless contraindicated, to reduce morbidity and mortality.

I IIa IIb III

I IIa IIb III

I IIa IIb III

Drugs Commonly Used for HFrEF

(Stage C HF)

Drug Initial Daily Dose(s) Maximum Doses(s)Mean Doses Achieved in

Clinical TrialsACE InhibitorsCaptopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d (421)Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/d (412)Fosinopril 5 to 10 mg once 40 mg once ---------Lisinopril 2.5 to 5 mg once 20 to 40 mg once 32.5 to 35.0 mg/d (444)Perindopril 2 mg once 8 to 16 mg once ---------Quinapril 5 mg twice 20 mg twice ---------Ramipril 1.25 to 2.5 mg once 10 mg once ---------Trandolapril 1 mg once 4 mg once ---------ARBsCandesartan 4 to 8 mg once 32 mg once 24 mg/d (419)Losartan 25 to 50 mg once 50 to 150 mg once 129 mg/d (420)Valsartan 20 to 40 mg twice 160 mg twice 254 mg/d (109)Aldosterone AntagonistsSpironolactone 12.5 to 25 mg once 25 mg once or twice 26 mg/d (424)Eplerenone 25 mg once 50 mg once 42.6 mg/d (445)

Pharmacological Treatment for

Stage C HFrEF (cont.)

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.

I IIa IIb III

I IIa IIb III

Pharmacological Treatment for

Stage C HFrEF (cont.)

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.

I IIa IIb III

I IIa IIb III

Harm

ßßßß----BlockersBlockersBlockersBlockers

Limit the donkey’s speed, thus saving energy

Digitalis CompoundsDigitalis CompoundsDigitalis CompoundsDigitalis Compounds

Like the carrot placed in front of the donkey

VBWG

ACC/AHA stages of systolic HF and treatment options

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

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

Pharmacological treatments in (NYHA class II – IV) symptomatic systolic Heart Failure

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

Treatments that may cause harm in symptomatic Heart Failure

• EvidenceEvidenceEvidenceEvidence----based guideline based guideline based guideline 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 reduces mortality, improves QOL and preserves health reduces mortality, improves QOL and preserves health reduces mortality, improves QOL and preserves health

care resourcescare resourcescare resourcescare resources.

• Ongoing research is needed to answer the remaining

questions including: prevention, nonpharmacological therapy

of HF including dietary adjustments, treatment of HFdietary adjustments, treatment of HFdietary adjustments, treatment of HFdietary adjustments, treatment of HFppppEF, EF, EF, EF,

management of hospitalized HF, effective reduction in HF management of hospitalized HF, effective reduction in HF management of hospitalized HF, effective reduction in HF management of hospitalized HF, effective reduction in HF

readmissions, more precise use of devicereadmissions, more precise use of devicereadmissions, more precise use of devicereadmissions, more precise use of device----based therapy, based therapy, based therapy, based therapy,

smaller MCS platforms and cellsmaller MCS platforms and cellsmaller MCS platforms and cellsmaller MCS platforms and cell----based regenerative therapybased regenerative therapybased regenerative therapybased regenerative therapy.

Conclusions