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Heart failure Overiew

Michael Nassif, MD MScAssistant Professor of Medicine (Cardiology)

Saint Luke’s Mid America Heart InstituteUniversity of Missouri-Kansas City

§ Research grants astra zeneca and boerhinger ingelheim

§ Speaking honoraria Abbott

Relevant Financial Disclosure Statement

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Prevalence of heart failure for adults ≥20 years by sex

and age (NHANES: 2011–2014)

Emelia J. Benjamin et al. Circulation. 2017;135:e146-e603 Copyright © American Heart Association, Inc. All rights reserved.

Projected US prevalence of HF 2012 to 2030

Circ Heart Fail Volume (3):606-619 May 21, 2013

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HFrEF or HFpEF

HFpEF• Preserved systolic LV function• No LV dilation• Concentric LV remodeling• Diastolic LV dysfunction

HFrEF• Systolic LV dysfunction• LV dilation• Eccentric LV remodeling• Diastolic LV dysfunction

HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; LV, left ventricularJessup M, Brozena S. N Engl J Med .2003;348:2007-2018.

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Volume Overload

Pressure Overload

Loss of Myocardium

Impaired Contractility

LV DysfunctionEF < 40%

¯ CardiacOutput

Hypoperfusion

­ End Systolic Volume

­End Diastolic Volume

Pulmonary Congestion

Left Ventricular Dysfunction

Hemodynamic Basis for HF Symptoms

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Initially Adaptive, Deleterious if Sustained

ResponseShort-Term Effects Long-Term Effects

Salt and Water Retention Augments Preload Pulmonary Congestion, Anasarca

Vasoconstriction Maintains BP for perfusion of vital organs

Exacerbates pump dysfunction (excessive afterload), increases cardiac energy expenditure

Sympathetic Stimulation Increases HR and ejection Increases energy expenditure

Neurohormonal Responses to ImpairedCardiac Performance

Jaski, B, MD: Basics of Heart Failure: A Problem Solving Approach

Neurohormonal Model of Heart Failure

N Engl J Med. 1996;334:374-381. Prog Cardiovasc Dis. 1998;41:39-52.

Hypertension MI/CAD Myocarditis

Injury to the Heart

Angiotensin I Norepinephrine

Mortality and disease progression

Angiotensin IIVasoconstriction

Cardiac/vascular hypertrophyAldosterone secretion

Sodium retention

a1-ReceptorsArrhythmia, sudden death,

vascular resistance, adverse lipid effects,

impaired renal blood flow, myocyte cell death,

hypertrophy, Na+ retention

b2-Receptors

Arrhythmia, sudden death,potassium loss

b1-ReceptorsArrhythmia,

myocyte cell death, hypertrophy, LVD

ACEinhibition

Nonselective b-blockade with a1-blockade

Renin-angiotensinsystem (RAS) activation

Selective b-blockade

Sympathetic nervous system(SNS) activation

Nonselective b-blockade

Angiotensic Rec Blocker

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• EF</=35%, NYHA II - IV• Enalapril (n=1285) v placebo (n=1284)

N Engl J Med. 1991 Aug 1;325(5):293-302.

Angiotensin Receptor Blockers (ARBs)

• Block AT1 receptors, which bind circulating angiotensin II

• RAAS Inhibition

• Ex: losartan, valsartan, candesartan, irbesartan

• Rec’d pts w systolic HF, intolerant to ACE-I (cough or angioedema)

• Same risk of renal impairment or hyperkalemia

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• EF ≤ 40%, NYHA II-IV, ACE-I Intolerant• Candesartan (n=1013) v placebo (n=1015) for

CV death or HF admit

Lancet 2003; 362: 772–776

Lancet 2003; 362: 772–776

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Neprilysin Inhibition

PARADIGM-HF

• Sacubitril/valsartan (n=4187) v enalapril (n=4212)

• CV death & HF admit• Mostly NYHA II (70%) & III (24%)• Mean SBP 122 mmHg, mean LVEF ~ 30%• Mean Age ~ 64 years• 93% on BB, 55% on MRAs• Minority (16%) with ICDs

N Engl J Med 2014; 371:993-1004

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Beta-Blockers

• Cardioprotective effects due to blockade of excessive SNS stimulation

• Carvedilol, metoprolol succinate, bisoprolol

• In the short-term, beta blocker decreases myocardial contractility; increase in EF after 1-3 months of use

• Decr mortality (30-35%), hospitaliztions

• Incr LVEF (reverse remodelling), NYHA status

Sympathetic Activation

b1receptors

b2receptors

a1receptors

Cardiotoxicity

Metoprolol, Bisoprolol, Atenolol

Propranolol

Carvedilol, Bucindolol

Selectivity of b-Blocking Agents

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• EF ≤ 35%, death or CV hospitalization• Carvedilol (n=696) v placebo (398)• NYHA II - IV

N Engl J Med 1996;334:1349-55

• EF < 35%, NYHA II-IV• All-cause mortality and admit• Metop TARTRATE (n=1518) v

carvedilol (n=1511)

Lancet. 2003 Jul 5;362(9377):7-13.

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Aldosterone

Cardiac MyocyteHypertrophyNorepinephrine release

FibroblastHyperplasiaCollagen SynthesisFibrosis

Peripheral ArteryVasoconstriction

Endothelial DysfunctionHypertrophy

Decreased Compliance

KidneyPotassium Loss

Sodium Retention

Aldosterone Antagonists• Competitive inhib aldo rec Na-K exchange in distal

convuluted tubule• Spironolactone/Eplerenone

• Reduce heart failure-related morbidity and mortality

• NYHA Class II-IV HF

• Side effects include hyperkalemia and gynecomastia, K+/Cr levels should be closely monitored

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• Spironolactone (n=822) v placebo (n=841)• 1 EP – all-cause death

N Engl J Med 1999:341:709-17.

Days Since Baseline Visit Date0 100 200 300 400 500 600

85

90

95

100

Surv

ival

(%)

P=.01

Fixed-dose HYD/ISDN

Placebo

Hazard ratio=0.57

N Engl J Med. 2004;351:2052.

43% Decrease in Mortality

86% on ACE/ARB74% on B-blocker

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• 1 EP – composite score• Isordil/hydral (n=518) v • placebo (n=532)• African-American patients, NYHA III, IV

N Engl J Med. 2004;351:2052.

SHIFT - Ivabridine

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HFpEF: Prevalence Is IncreasingGWTG-HF: N=110,621 patients hospitalized with HFP<0.0001 for trend of increased HFpEF prevalence

EF, ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fractionOktay AA et al. Curr Heart Fail Rep. 2013;10:401-410/

Metabolic Traits Must Stronger Predicting HFpEF vs HFrEF

Savji N et al, JACC Heart Fail. 2018;6:701-709.

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Lung Chest wall restriction, reduced vital capacity, impaired ventilation and diffusion Obstructive sleep apnea Pulmonary hypertension

Liver Non-alcoholic fatty liver disease Promotes generalized inflammatory state

Visceral adiposity Inflammatory cytokines Adverse neurohormones Increased BNP clearance

Kidney Direct toxic effects of perinephric fat Glomerulomegaly with glomerular dysfunction

Skeletal muscle Increased adipose infiltration Impaired perfusion Decreased diffusive O2 transport Mitochondrial dysfunction

Heart Direct and indirect myocardial lipotoxicity Worsened cardiac mechanics Diastolic dysfunction; increased filling pressures/ volume overload, increased afterload

HFpEF in 2018

HFpEF, heart failure with preserved ejection fractionKitzman D, Shah SJ. JACC. 2016;68:200–203; Borlaug B. Nat Rev Cardiol. 2014;11:507-515.

HFpEF

Obesity, insulin resistance

Pathogenesis of HFpEF

HFpEF, heart failure with preserved ejection fraction

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HFpEF

Abnormal cardiac mechanics

Obesity, insulin resistance

HFpEF, heart failure with preserved ejection fraction

Pathogenesis of HFpEF

Obesity, Insulin Resistance, and Cardiac Mechanics in HyperGEN

P<0.0001 P<0.0001 P<0.0001

Abso

lute

glob

al lo

ngitu

dina

l stra

in (%

)

Body-massindex

Fasting glucose

HOMA-IR

N=2,150

HOMA-IR, homeostatic model assessment of insulin resistanceShah SJ, et al. AHA 2012 [abstract]

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HFpEF: No Treatments?

HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fractionBorlaug BA, Redfield MM. Circulation 2011;123:2006-2013

Caloric Restriction and 7-kg Weight Loss Improve HFpEF

AT, aerobic exercise training; CR, caloric restrictionKitzman D, et al. JAMA. 2016;315:36-46.

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Take home points

• Myocardial injury is only the first step in development LV dilitation and HF

• HFpEF appears to have a very different etiology than HFrEF

• Lots of evidence for HFpEF as a metabolic disease (many ongoing trials