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
3.1
2.9
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 AnalogyThe Donkey AnalogyThe Donkey AnalogyThe 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 sympathetic
activity
β1-
receptors
β2-
receptors
α1-
receptors
Vasoconstriction
Sodium retention
Myocardial toxicity
Increased arrhythmias
↑ Sympathetic
activity to kidneys
+ peripheral vasculature
Activation
of 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
Angiotensin
Converting
Enzyme
ReninReninReninRenin----AngiotensinAngiotensinAngiotensinAngiotensin----Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)

↑↑↑↑MAP = (↑↑↑↑SV x ↑↑↑↑HR) x ↑↑↑↑TPR
Renin-Angiotensin-Aldosterone
(↓↓↓↓ renal perfusion)
Salt-water retention
Thirst
Sympathetic
augmentation
Vasoconstriction
ReninReninReninRenin----AngiotensinAngiotensinAngiotensinAngiotensin----Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)Aldosterone (RAAS)

Decreased systemic blood pressure
Central baroreceptors
Stimulation of hypothalamus, which produces
vasopressin for release by pituitary gland
Release of vasopressin by pituitary glandVasoconstriction
Increased systemic blood pressure
-
NeurohormonalNeurohormonalNeurohormonalNeurohormonal ActivationActivationActivationActivation –––– VasopressinVasopressinVasopressinVasopressin

CompensatoryCompensatoryCompensatoryCompensatory NeurohormonalNeurohormonalNeurohormonalNeurohormonal Stimulation:Stimulation:Stimulation:Stimulation:
SummarySummarySummarySummary
Decreased Cardiac Output
Sympathetic
nervous system
Renin-angiotensin
system
Antidiuretic hormone
(vasopressin)
Heart
rate
Contractility Vasoconstriction Circulating volume
Anteriolar
Maintain
blood
pressure
Cardiac
output
Stroke
volume
+
-+
Venous
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

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 Classification
A 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

Diagnosis of Heart Failure

Diagnostic flowchart for patients suspected Heart
Failure

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 Trials
ACE Inhibitors
Captopril 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 ---------
ARBs
Candesartan 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 Antagonists
Spironolactone 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)

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

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

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

Treatments that may cause harm in
symptomatic Heart Failure

• EvidenceEvidenceEvidenceEvidence----based guidelinebased guidelinebased guidelinebased 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 healthreduces mortality, improves QOL and preserves healthreduces mortality, improves QOL and preserves healthreduces 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 HFmanagement of hospitalized HF, effective reduction in HFmanagement of hospitalized HF, effective reduction in HFmanagement 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

Recent Updated Pathogenesis and Management of Heart Failure:

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