Pathophysiology: Heart Failure

Mat Maurer, MD Associate Professor of Clinical Medicine

Objectives
At the conclusion of this seminar, learners will be able to: 1. Define heart failure as a clinical syndrome 2. Define and employ the terms preload, afterload, contractilty, remodeling, diastolic dysfunction, compliance, stiffness and capacitance. 3. Describe the classic pathophysiologic steps in the development of heart failure. 4. Delineate four basic mechanisms underlying the development of heart failure 5. Interpret pressure volume loops / Starling curves and identify contributing mechanisms for heart failure state. 6. Understand the common methods employed for classifying patients with heart failure. 7. Employ the classes and stages of heart failure in describing a clinical scenario

Heart Failure
Not a disease A syndrome From "syn meaning "together and "dromos" meaning "a running. A group of signs and symptoms that occur together and characterize a particular abnormality. Diverse etiologies Several mechanisms

Heart Failure: Definitions

An inability of the heart to pump blood at a sufficient rate to meet the metabolic demands of the body (e.g. oxygen and cell nutrients) at rest and during effort or to do so only if the cardiac filling pressures are abnormally high. A complex clinical syndrome characterized by abnormalities in cardiac function and neurohormonal regulation, which are accompanied by effort intolerance, fluid retention and a reduced longevity A complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.

Epidemiology Heart Failure: The Problem

H ea rt F a ilu re P a tien ts in th e U S (M illio n s )
12 10 8 6 4 2 0 1991 2000 2037

3.5 million in 1991, 4.7 million in 2000, estimated 10 million in 2037 Incidence: 550,000 new cases/year Prevalence: 1% ages 50--59, >10% over age 80 More deaths from HF than from all forms of cancer combined Most common cause for hospitalization in age >65

Heart Failure Paradigms

Heart Failure: Classifications

Right vs. Left Sided Cardiac vs. Non-cardiac Systolic vs. Diastolic

Dilated vs. Hypertrophic vs. Restrcitive

Heart Failure

Compensated vs. Decompensated

Acute vs. Chronic

Forward vs. Backward

High vs. Low Output

Cardiac Muscle Function

Preload
Tension (g) Tension (g)

Afterload
Tension (g)

Contractility
+norepinephrine

d b a c

b La Ld c a d
Muscle Length (mm)

b g e a
Muscle Length (mm)

Muscle Length (mm)

The length of a cardiac muscle fiber prior to the onset of contraction. Frank Starling

The force against which a cardiac muscle fiber must shorten. Isotonic Contraction

The force of contraction independent of preload and afterload. Inotropic State

From Muscle to Chamber

The Pressure Volume Loop

Diastole

Systole

The Pressure Volume Loop

P
es

Pressure

d oa el r P

PV

ES

Volume

Compliance/Stiffness vs Capacitance

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EDPVR

LV Pressure (mmHg)

20 15 10 5 0 -5 20 40 60 80 100 120 140

Capacitance = volume at specified pressure

Slope = stiffness = 1/compliance

ED PV

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Diastolic Dysfunciton

LV Pressure (mmHg)

40 30 20 10 0 0 50 100

Normal
Remodeling

LV Volume (ml)

150

200

250

LV Volume (ml)

Afterload (Arterial Properties)

Ea (Arterial Elastance)
If TPR = [MAP - CVP] / CO, and CO = SV * HR Substituting the second equation into the first we obtain: TPR = [MAP - CVP] / (SV*HR) Making two simplifying assumptions. 1. CVP is negligible compared to MAP. 2. MAP is approximately equal to the end-systolic pressure in the ventricle (Pes). Then, TPR = Pes / (SV*HR) Which can be rearranged to: Pes/SV TPR * HR.

Cardiac Chamber Function

Preload Afterload Contractility

EDV EDP Wall stress at end diastole

Aortic Pressure Total peripheral resistance Arterial impedance Wall stress at end systole

Pressure generated at given volume. Inotropic State

Frank Starling Curves

Hypotension

Pulmonary Congestion

Pathophysiology - PV Loop

Pathophysiology of Heart Failure

Myocardial Insult/Stimuli/Damage Pump dysfunction Activation of neurohormones
Catecholamines Angiontensin II Cytokines

Remodeling
Hypertrophy Fibrosis Apoptosis

Neurohormonal Activation in Heart Failure

Myocardial injury to the heart (CAD, HTN, CMP, valvular disease) Initial fall in LV performance, wall stress
Activation of RAS and SNS

Remodeling and progressive worsening of LV function

Fibrosis, apoptosis, hypertrophy, cellular/molecular alterations, myotoxicity

Peripheral vasoconstriction Sodium retention Hemodynamic alterations

Heart failure symptoms Fatigue Activity altered Chest congestion Edema Shortness of breath

Morbidity and mortality Arrhythmias Pump failure

RAS, renin-angiotensin system; SNS, sympathetic nervous system.

Neurohormonal Activation in Heart Failure

Angiotensin II Norepinephrine

Hypertrophy, apoptosis, ischemia, arrhythmias, remodeling, fibrosis

Morbidity and Mortality

Adrenergic Pathway in Heart Failure Progression

CNS sympathetic outflow Vascular sympathetic activity

Cardiac sympathetic activity

Renal sympathetic activity

Myocyte hypertrophy Myocyte injury Increased arrhythmias

Vasoconstriction

Activation of RAS

Sodium retention

Disease progression

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Neurohormonal Balance in Heart Failure

Neurohormones in Heart Failure

Myocardial Injury Fall in LV Performance Activation of RAAS and SNS (endothelin, AVP, cytokines) Myocardial Toxicity Change in Gene Expression ANP BNP Remodeling and Progressive Worsening of LV Function Peripheral Vasoconstriction Sodium/Water Retention

Morbidity and Mortality

HF Symptoms

Shah M et al. Rev Cardiovasc Med. 2001;2(suppl 2):S2

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Pathophyisiology of myocardial remodeling:

Insult / Remodeling Stimuli
Wall Stress Cytokines Neurohormones Oxidative stress

Increased Wall Stress

Myocyte Hypertrophy Altered interstitial matrix Fetal Gene Expression Altered calcium handling proteins Myocyte Death

Ventricular Enlargement Diastolic Dysfunction Systolic Dysfunction

Acute and Chronic Responses Benefits and Harm

Response Short-term Effects (mainly adaptive; hemorrhage, acute heart failure)
Augments preload Maintains pressure for perfusion of vital organs (brain, heart) Increases heart rate and ejection Vasodilatation

Long-term Effects (mainly deleterious; chronic heart failure)

Pulmonary congestion, anasarca Exacerbates pump dysfunction, increases cardiac energy expenditure Increases energy expenditure Skeletal muscle catabolism, deterioration of endothelial function, impaired contraction, LV remodeling. Deterioration and death of cardiac cells: cardiomyopathy of overload Impairs relaxation

Salt and water retention Vasoconstriction

Sympathetic stimulation Cytokine activation

Hypertrophy Increased collagen

Unloads individual muscle fibers May reduce dilatation

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Laplaces Law

Where P = ventricular pressure, r = ventricular chamber radius and h = ventricular wall thickness

Remodeling Concentric vs. Eccentric

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Ventricular Remodeling

Pathophysiology of Heart Failure

Four Basic Mechanisms
1. Increased Blood Volume (Excessive Preload) 2. Increased Resistant to Blood Flow (Excessive Afterload) 3. Decreased contractility 4. Decreased Filling

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Increased Blood Volume

Aortic Regurgitation AI + Neurohormones AI + Remodeling

Na Retention Vasoconstriction

Ventricular Remodeling

Etiologies Mitral Regurgitation Aortic Regurgitation Volume Overload Left to Right Shunts Chronic Kidney Disease

Parameter
BP (mm Hg) SV (ml) Cardiac Output (L/min) PCWP (mm Hg)

Normal
140/75 64 3.8 10

AI
128/50 80 3.0 15

AI+NeuroHormones
130/50 82 4.3 25

AI + Remodeling
104/45 63 2.6 20

Increased Afterload
Hypertension
Ea

HTN + DD
Na Retention Vasoconstriction Remodeling

HTN + DD + HF

Diastolic Dysfunction

Etiologies Aortic Stenosis Aortic Coarctation Hypertension

Parameter
BP (mm Hg) SV (ml) Cardiac Output (L/min) PCWP (mm Hg)

Normal
131/76 57 4.0 10

HTN
150/100 52 3.6 10

HTN + DD
140/92 49 3.4 13

HTN + Heart failure

161/105 57 4.0 23

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Decreased Contractility
MI MI + Heart Failure MI + Remodeling
Na Retention Vasoconstriction

Ventricular Remodeling

Etiologies Ischemic Cardiomyopathy

Myocardial Infarction Myocardial Ischemia Parameter
BP (mm Hg) SV (ml) Cardiac Output (L/min) PCWP (mm Hg)

Normal
124/81 60 4.2 12

MI
80/40 42 3.0 17

MI + MI + Remodeling Neurohormones
90/54 46 3.2 25 87/44 46 3.2 23

Myocarditis Toxins
Anthracycline Alcohol Cocaine

Decreased Filling
Normal HCM HCM + HF
Ventricular Remodeling

Na Retention Vasoconstriction

Etiologies Mitral Stenosis Constriction Restrictive Cardiomypoathy Cardiac Tamponade Hypertrophic Cardiomyopathy Infiltrative Cardiomyopathy

Parameter
BP (mm Hg) SV (ml) Cardiac Output (L/min) PCWP (mm Hg)

Normal
124/81 63 4.4 10

HCM
95/47 50 3.5 17

HCM + HF
105/53 55 3.8 26

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Part II

Heart Failure: Classifications

Right vs. Left Sided Cardiac vs. Non-cardiac Systolic vs. Diastolic

Dilated vs. Hypertrophic vs. Restrcitive

Heart Failure

Compensated vs. Decompensated

Acute vs. Chronic

Forward vs. Backward

High vs. Low Output

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Types of Heart Failure

SHF Diastolic

Pathophysiology Demographics 1 Cause

Impaired Contraction All ages Coronary Artery Disease

Impaired filling > 60 years Hypertension

Systolic Versus Diastolic Failure

Systolic Dysfunction
Contractility

Normal

Diastolic Dysfunction

Pressure

Pressure

Pressure

Capacitance

Volume

Volume

Volume

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Systolic Versus Diastolic Failure

Heart Failure: Classifications

Right vs. Left Sided Cardiac vs. Non-cardiac Systolic vs. Diastolic

Dilated vs. Hypertrophic vs. Restrcitive

Heart Failure

Compensated vs. Decompensated

Acute vs. Chronic

Forward vs. Backward

High vs. Low Output

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Decompensated Heart Failure

Heart Failure: Classifications

Right vs. Left Sided Cardiac vs. Non-cardiac Systolic vs. Diastolic

Dilated vs. Hypertrophic vs. Restrictive

Heart Failure

Compensated vs. Decompensated

Acute vs. Chronic

Forward vs. Backward

High vs. Low Output

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High vs. Low Output Failure

Causes:
Anemia Systemic arteriovenous fistulas Hyperthyroidism Beriberi heart disease Paget disease of bone Glomerulonephritis Polycythemia vera Carcinoid syndrome Obesity Anemia Multiple myeloma Pregnancy Cor pulmonale Polycythemia vera

Heart Failure: Classifications

Right vs. Left Sided Cardiac vs. Non-cardiac Systolic vs. Diastolic

Dilated vs. Hypertrophic vs. Restrictive

Heart Failure

Compensated vs. Decompensated

Acute vs. Chronic

Forward vs. Backward

High vs. Low Output

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Dilated vs. Hypertrophic vs. Restrictive

Type Dilated Definition Dilated left/both ventricle(s) with impaired contraction Left and/or right ventricular hypertrophy Restrictive filling and reduced diastolic filling of one/both ventricles, Normal/near normal systolic function Sample Etiologies Ischemic, idiopathic, familial, viral, alcoholic, toxic, valvular Familial with autosomal dominant inheritance Idiopathic, amyloidosis, endomyocardial fibrosis

Hypertrophic Restrictive

Dilated vs. Hypertrophic vs. Restrictive

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Clinical Manifestations
Symptoms Reduced exercise tolerance Shortness of breath Congestion Fluid retention Difficulty in sleeping Weight loss

Diagnosis of heart failure

Physical examination Chest X ray EKG Echocardiogram Blood tests: Na, BUN, Creatinine, BNP Exercise test MRI Cardiac catheterization

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NYHA Classification
Class Patient Symptoms
No limitation of physical activity No undue fatigue, palpitation or dyspnea Slight limitation of physical activity Comfortable at rest Less than ordinary activity results in fatigue, palpitation, or dyspnea

I II III IV

Mild Mild

Moderate

Marked limitation of physical activity Comfortable at rest Less than ordinary activity results in fatigue, palpitation, or dyspnea Unable to carry out any physical activity without discomfort Symptoms of cardiac insufficiency at rest Physical activity causes increased discomfort

Severe

ACC/AHA Staging System

STAGE A High risk for developing HF STAGE B Asymptomatic LV dysfunction STAGE C Past or current symptoms of HF STAGE D End-stage HF
Hunt, et al. J Am Coll Cardiol. 2001; 38:2101-2113.

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ACC/AHA Staging System

Stage Patient Description

A B C D

High risk for Hypertension developing heart failure Coronary artery disease Diabetes mellitus Family history of cardiomyopathy Previous myocardial infarction Asymptomatic heart Left ventricular systolic dysfunction failure Asymptomatic valvular disease Known structural heart disease Symptomatic heart Shortness of breath and fatigue failure Reduced exercise tolerance Marked symptoms at rest despite maximal Refractory medical therapy (e.g., those who are recurrently end-stage heart failure hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Goals of Treatment
1. Identification and correction of underlying condition causing heart failure. 2. Elimination of acute precipitating cause of symptoms. 3. Modulation of neurohormonal response to prevent progression of disease. 4. Improve long term survival.

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Etiologies
Ischemic cardiomyopathy Valvular cardiomyopathy Hypertensive cardiomyopathy. Inflammatory cardiomyopathy Metabolic cardiomyopathy General system disease Muscular dystrophies. Neuromuscular disorders. Sensitivity and toxic reactions. Peripartal cardiomyopathy

Percipients /Associated Factors

Inappropriate reduction in the intensity of treatment, including Dietary sodium restriction, Physical activity reduction, Drug regimen reduction, or, most commonly, a combination of these measures. Ischemia Hypertension Anemia Volume Overload Increased Metabolic Demand Infection Thyroid Disease Arrhythmia Asthma/COPD

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Targets of Treatment

Standard Pharmacological Therapy

ACE inhibitors Angiotensin Receptor Blockers Beta Blcokers Diuretics Aldosterone Antagonists Statins Vasodilators Inotropes

Treatment
Stage Patient Treatment

A B C D

High risk for Hypertension Optimal pharmacologic therapy (OPT) developing heart failure Coronary artery disease Aspirin, ACE inhibitors, statins, b-blockers, a-b-blockers Diabetes mellitus (carvedilol) diabetic therapy Family history of cardiomyopathy Previous myocardial infarction Asymptomatic heart OPT ICD if ventricular left ventricular (LV) dysfunction Left systolic dysfunction(systolic) failure present Asymptomatic valvular disease Known structural heart disease Symptomatic heart OPT ICD if LV dysfunction (systolic) present Shortness of breath and fatigue failure CRT (if QRS wide, LVEF35%) Reduced exercise tolerance OPT Marked symptoms at rest despite maximal Refractory IV inotropes medical therapy (e.g., those who are recurrently end-stage heart failure Intermittent ICD as a bridge transplantation hospitalized orto cannot be safely discharged from CRT the hospital without specialized interventions)
Other devices (LVAD, pericardial restraint)

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Treatment of Acute Heart Failure

ACC/AHA Staging System

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Summary
Complex Clinical Syndrome Multiple Etiologies and Classification Systems Physiologic Understanding Essential http://www.columbia.edu/itc/hs/medical/heartsim/

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