Sarver Heart Center

Dedicated to research and the treatment of heart failure

Heart FailureHeart Failure

Douglas Larson, Ph.D.Douglas Larson, Ph.D.Sarver Heart CenterSarver Heart Center

Heart FailureOutline

1. Overview

2. Historical aspects

3. Pathophysiology

4. Hemodynamic measurements

5. Neurohumoral Mechanisms

6. Therapeutics

Heart Failure• Heart failure is characterized by depressed

ventricular contractility and impaired relaxation

• Heart failure is a clinical syndrome with many causes

• Heart failure is defined as limited cardiac output to accomplish daily activities

• Heart failure leads to the accumulation of blood in the veins and lymphatics – affecting the lungs, liver, and kidneys.

Epidemiology of Heart Failure in the US

•More deaths from heart failure than from all forms of cancer combined

•4.7 million symptomatic patients; estimated 10 million in 2037

• Incidence: About 550,000 new cases/year

•Prevalence is 1% between the ages of 50 and 59, progressively increasing to >10% over age 80

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Heart Failure• Heart failure will affect one in four Americans

and all of these cases involve altered diastolic function (American Heart Assoc).

• Diastolic heart failure has recently been reported to have a mortality rate of 23% during a 3.1 year follow-up with optimized medical therapy (Jones,R.C. J Am Coll.Cardiol.2004).

Survival Curve- Heart Failure

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DigitalisDiureticsACE inhibitorsBeta blockersSpironolactone

Heart Failure• Most striking, the mortality rate of heart

failure is only exceeded by that of pancreatic cancer (personal communication, Dr. Gregg Fonarow, UCLA).

• Today the heart failure DRG accounts for the highest hospital admission classification in the United States.

Heart Failure

Further Definition

Heart Failure

Systolic DiastolicEjection fraction < 30%

Ejection fraction > 30%

Cardiac Index < 2.4 L/m2

Normal ejection fraction is 60-70%

Heart Failure• Current systolic heart failure therapeutics

affect symptoms, appreciably prolong life expectancy, but are not curative.

• Current diastolic heart failure therapeutics affect symptoms however without reducing mortality rate.

• This suggests a failure in treating the underlying mechanisms.

Dev

elo

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ent

of

Hea

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re• Initiators: Hypertension, aging,

myocardial infarction, viral infection, vavlular dysfunction, diabetes

• Compensatory: myocyte and extracellular matrix remodeling

• Decompensation phase: • Remodeled extracellular matrix collagen,

• Altered calcium cycling protein expression and function,

• Disordered cytoskeletal proteins, and

• Dilated cardiomyopathy (DCM)

Stage AHypertension

CADDiabetes mellitus

Cardiotoxins

Stage BPrevious MI

LV systolic dysfunctionAsymptomatic

valvular disease

Stage CKnown structural

diseaseShortness of breathReduced exercise

tolerance

Stage DSymptoms with

maximal medical therapy

ACC /AHA Guidelines for the Management of Chronic Heart FailureJACC 38;2101-2113:2001

Class NYHA Classification

Class I (Mild)

No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, or dyspnea (shortness of breath).

Class II (Mild)

Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results in fatigue, palpitation, or dyspnea.

Class III (Moderate)

Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity causes fatigue, palpitation, or dyspnea.

Class IV (Severe)

Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is increased.

Question

Heart failure will affect:A.1 in 1000 Americans

B.1 in 100 Americans

C.1 in 20 Americans

D.1 in 4 Americans

Answer

Heart failure will affect:A.1 in 1000 Americans

B.1 in 100 Americans

C.1 in 20 Americans

D.1 in 4 Americans

Heart FailureOutline

1. Overview

2. Historical aspects

3. Pathophysiology

4. Hemodynamic measurements

5. Neurohumoral Mechanisms

6. Therapeutics

Heart Failure

History:

Clinical observations. Two thousand years ago, Hippocratic Corpus first described heart failure patients with what may have been rheumatic valvular disease.

Heart FailureHistory:

Anatomic Pathology. Galen understood that heart failure was associated with enlargement of cardiac muscle but did not understand that the heart was for pumping blood.

Galen believed that the heart was to generate the vital spirit (pneuma) and this forestalled any understanding of the pathophysiology of heart failure for centuries.

Heart Failure

History: Circulatory Physiology. In 1628, William Harvey published De Motu Cordis that identified the failing cardiac pump with dyspnea and edema Flint in the middle of the nineteenth century recognized the progressive clinical deterioration and poor prognosis associated with ventricular dilation and was the first to suggest hypertrophy as an adaptive response to wall stress.

Heart Failure

History:

Cardiac Hemodynamics. In the early years of the twentieth century Starling of England and Wiggers of the United States were able to interpret the pressure and flow abnormalities associated with heart failure.

Heart FailureHistory:

Molecular Biology. A major change in the above paradigm is now occurring due to the unexpected and counter-intuitive adverse effects of inotropes such as dobutamine, phosphodiesterase inhibitors (milrinone), vasodilators including diltiazem and digitalis.

Heart Failure

History:Molecular Biology. Equally unexpected has been the long-term benefits of adrenergic receptor blockers.

These pharmacological experiences demonstrated that heart failure is not just an inotropic and lusitropic disorder.

Heart Failure

History:

Molecular Biology. Today, the major problem in heart failure is now recognized as altered gene expression and immunological mediation of disordered cell growth, and deterioration of the cardiac interstitium.

Question

Which of the following increases the life expectancy of heart failure patients?A. Dobutamine

B. Beta-blockers

C. Digitalis

D. Milrinone

Answer

Which of the following increases the life expectancy of heart failure patients?A. Dobutamine

B. Beta-blockers

C. Digitalis

D. Milrinone

Heart FailureOutline

1. Overview

2. Historical aspects

3. Pathophysiology

4. Hemodynamic measurements

5. Neurohumoral Mechanisms

6. Therapeutics

HEART FAILURE

Mismatch: inflow to output.

A

B

C

A

B

C

Arterial Pressure Tracing

Pressure-volume loops

Normal Restrictive Dilated

Volume

Pre

ssur

e

A

B

C

A

B

C

Arterial Pressure Tracing

Pressure-volume loops

Normal Diastolic HF Systolic HF

Volume

Pre

ssur

e

SVSV

Examples of Common Causes of Heart Failure

• Hypertension

• Aortic Valvular Stenosis

• Viral cardiomyopathy

• Infarction

• Senescence

• Thyrotoxicosis

• Idiopathic

Heart Failure

Etiology:

• Gene mutation

• Single:

• Duchenne’s Musclular Dystrophy

• Familial hypercholesterolemia (FH)

• Multiple

• Genotype

• Environmental

Myocardial infarction (MI)

• MI is recognized as a leading cause of systolic heart failure.

Heart FailureOutline

1. Overview

2. Historical aspects

3. Pathophysiology

4. Hemodynamic measurements

5. Neurohumoral Mechanisms

6. Therapeutics

TIME

Acuteevent

CompensatoryRemodeling

HeartFailure

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Time Course of Heart Failure

Decompensated

Heart Failure

PRESSURE OVERLOAD

Heart Failure

VOLUME OVERLOAD

Normal Cardiomyocyte

Intercalated disk folding

Intercalated disk folding

Z-band slippage

Z-band slippage

QuestionDecompensated heart failure is:A. The primary event that occurs

subsequent to myocardial injury

B. Is related to myocyte slippage and cardiac dilation

C. Is reversible with beta-blockers

D. Is related to the remodeling of the ventricular geometry to optimize ventricular function.

AnswerDecompensated heart failure is:A. The primary event that occurs

subsequent to myocardial injury

B. Is related to myocyte slippage and cardiac dilation

C. Is reversible with beta-blockers

D. Is related to the remodeling of the ventricular geometry to optimize ventricular function.

Heart FailureOutline

1. Overview

2. Historical aspects

3. Pathophysiology

4. Hemodynamic measurements

5. Neurohumoral Mechanisms

6. Therapeutics

Sympathetic

Pathogenesis of congestive heart failure

• A number of compensatory mechanisms come into play during the development of chronic heart failure in the body's attempt to maintain perfusion pressure and increase cardiac output: • Augmented sympathetic activity

• Sodium and water retention

• Myocardial hypertrophy

• Ventricular dilatation

Specific Neurohumoral Mechanisms

• In most patients with congestive heart failure, the changes in the peripheral circulation (decreased cardiac output) is accompanied by activation of:

• renin-angiotensin system (RAS)

•sympathetic nervous system

•aldosterone.

RASDecrease blood pressureIncreased sympathetic activityDecreased extracellular volume

Juxtaglomerlular cells release renin

Angiotensinogen Angiotensin I Angiotensin II

ACE

Increases blood pressure - vasoconstrictionActs upon the adrenal cortex to release aldosteroneStimulates the release of vasopressin – fluid retentionFacilitates norepinephrine release from nerve endings

Ang II

• Treating hypertension and heart failure with ACE inhibitors (ACEi) and AII receptor antagonists (ARB) can be used to decrease arterial pressure, ventricular afterload, blood volume and hence ventricular preload, as well as inhibit and perhaps reverse cardiac and vascular hypertrophy and pathologic remodeling.

Angiotensin II (Ang II)

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Sympathetic NS & Heart Failure

• Epinephrine: sympathetic CNS

1, vasoconstriction

2, negative feedback for NE

1, cardiac specific increased function

2, smooth muscle relaxation

• Norepinephrine: powerful stimulator is ATII.

mainly 1,2

*The heart failure state stimulates sympathetic

outflow thus adding to the Ang II effects.

Inotropicagents

Vasodilators

Diuretics

ACE inhibitors

Aldosteroneinhibitors

HF RX

Markers for Heart Failure diagnosis and Prognosis

Markers of Heart Failure• Neurohormonal

• Brain Natriuretic Peptide (BNP)

• Plasma Norepinephrine

• Myocyte Injury and Matrix Remodeling• Troponins

• Matrix metalloproteinases (MMP)

• PIIINP = Pro-Col III cleaved propeptide

• Inflammation• C-reactive protein, IL-6, TNF-• Soluble IL-2 receptor, CD40-CD154

Natriuretic Peptides (ANP and BNP)

BNP/

ANP versus BNP• The Atrial Natriuretic Peptide (ANP) is

highly stimulated during heart failure.• Constitutively secreted by the atria

• Brain Natriuretic Peptide (BNP) • Secreted by ventricles only during heart

failure.Therefore BNP serves as an important

marker of CHF

BNP

• Serum concentrations of BNP parallels the ejection fraction of the left ventricle.

• Therefore it has become a highly reliable serum marker of heart failure and therapeutic efficacy.

BNPandSurvival

Control and heart failurepatients

BNP

Clinica Chimca Acta 306;19-26:2001

BNP versus Ejection Fraction

BNP Levels

• <100 pg/mL no heart failure

• 100-500 pg/mL suggestive of heart failure

• >500 pg/mL high likely-hood of heart failure

BNP Levels

• Drug therapy for chronic heart failure has been reported to reduce plasma BNP levels.ACEi reduce 40%ARB reduce 10%-blockers reduce 60%Aldosterone blockers reduce 55%

Question

Which of the following BNP levels indicates decompensated heart failure?

A.78 pg/mL

B.159 pg/mL

C.373 pg/mL

D.885 pg/mL

Answer

Which of the following BNP levels indicates decompensated heart failure?

A.78 pg/mL

B.159 pg/mL

C.373 pg/mL

D.885 pg/mL

Heart FailureOutline

1. Overview

2. Historical aspects

3. Pathophysiology

4. Hemodynamic measurements

5. Neurohumoral Mechanisms

6. Therapeutics

HF Therapeutics

• Digitalis: increase inotropy • Dobutamine: increase inotropy • Milrinone: increase inotropy• Beta- blockers: decrease

sympathetic outflow• Diuretics – Lasix: diuresis, naturesis• Spironolactone: aldosterone blocker• ACEi and ARB: vasodilation • Nesiritide: diuresis, vasodilation

Heart Failure Therapies

Medical:• Carvedilol (Coreg) is an and blocker.

• Carvedilol is one of the most efficacious medical therapies for heart failure.

• With NYHA II and III patients, it does not significantly change the survival slope.

Effect of Carvedilol ( and blockade) on Progression in Mild or Moderate Heart Failure

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0.8

0.6

00 50 100 150 200 250 300 350 400 0 50 100 150 200 400

MILD (NYHA II) MODERATE (NYHA III)

Carvedilol(n=232)

Carvedilol(n=133)

Placebo(n=134)

Placebo(n=145)

P=.008 P=.019Risk reduction48%

Risk reduction39%

Days Days

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Nesiritide - Natrecor® • An i.v. recombinant BNP that induces:

• arterial & venous vasodilation,

• increases water and sodium excretion,

• lowers pulmonary capillary wedge pressure & systemic arterial pressures and

• increases cardiac output.

HF Therapeutics• Digitalis:

• Dobutamine: Increased mortality rate

• Milrinone:

• Beta- blockers: decrease heart rate

• Diuretics – Lasix: K+ depletion

• Spironolactone: Interaction w/ other Rx

• ACEi and ARB: Hypotension

• Nesiritide: Increase mortality rateby 80%

Heart Failure Therapies

Medical: NEW• Cardiac

Resynchronization Therapy (CRT) - resynchronizing the activity of the right and left ventricles in patients with heart failure and ventricular dysynchrony.

Heart Failure Therapies

Medical:• Do medical therapies modulate the

cause or survival?

• In general: ACE inhibitors, & blockers, and CRT help symptoms but only marginally prolong life.

IABP = very temporary

SURGERY

Coronary ArteryBypass Graft (CABG) –

Prolongs life

Heart Failure Therapies

SURGERY

Transplantation-Prolongs life~ 10 years

Heart Failure Therapies

VADS andTotal Artificial Heart –Prolongs life

Heart Failure Therapies

HEART FAILURE

• In general, none of these therapeutic approaches actually addresses the underlying mechanisms of heart failure!

• Thus our research is dedicated to defining pathways and techniques that may provide a therapeutic reversal of the heart failure condition.

Our research goal is to show that the immune status accounts for:

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Survivors

Died

What factors account What factors account for these survivors versusfor these survivors versusthose who do not survive?those who do not survive?

Question

The two leading causes of heart failure are:

A.MI and alcoholic cardiomyopathy

B.Viral and idiopathic

C.Genetic and diabetes

D.Hypertension and aging

Answer

The two leading causes of heart failure are:

A.MI and alcoholic cardiomyopathy

B.Viral and idiopathic

C.Genetic and diabetes

D.Hypertension and aging

Thank You

Questions?Questions?

Adoptive Transfer II

Altered cardiac function can be adoptively transferred through lymphocytes.