Pathophysiology: Heart Failure - Columbia University · 2009-12-10 · 12/9/2009 1 Pathophysiology: Heart Failure Mat Maurer, MD Associate Professor of Clinical Medicine Objectives

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Pathophysiology:Heart Failure

Mat Maurer, MDAssociate Professor of Clinical Medicine

ObjectivesAt the conclusion of this seminar, learners will be able to:1. Define heart failure as a clinical syndrome2 Define and employ the terms preload afterload contractilty remodeling2. 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

failure5. Interpret pressure volume loops / Starling curves and identify contributing

mechanisms for heart failure statemechanisms 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

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Heart Failure

• Not a disease• Not a disease• A syndrome

– From "syn“ meaning "together“ and "dromos" meaning "a running“.

– A group of signs and symptoms that occur together d h t i ti l b litand 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 p y ,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.

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Epidemiology Heart Failure: The Problem

12

US • 3.5 million in 1991, 4.7 million

i 2000 ti t d 10 illi i

4

6

8

10

ure

Patie

nts

in th

e U

(Mill

ions

)

in 2000, estimated 10 million in 2037

• Incidence: 550,000 new cases/year

• Prevalence: 1% ages 50--59, >10% over age 80

0

2

4

1991 2000 2037

Hea

rt F

ailu

• More deaths from HF than from all forms of cancer combined

• Most common cause for hospitalization in age >65

Heart Failure Paradigms

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Heart Failure: Classifications

S t li Di t liRight vs. LeftCardiac vs.Non-cardiac

Heart Failure

Systolic vs. Diastolic gSided

Non cardiac

Dilated vs.Hypertrophic vs.

Restrcitive

Compensated vs.Decompensated

High vs. Low OutputAcute vs. Chronic Forward vs.

Backward

Cardiac Muscle FunctionPreload Afterload Contractility

i i

Tens

ion

(g)

b

a c

d

Tens

ion

(g)

d

ΔLd Tens

ion

(g)

a

g

f

b

e

+norepinephrine

a

b

c ΔLa

•The length of a cardiacmuscle fiber prior to theonset of contraction.

Muscle Length (mm) Muscle Length (mm)

•The force against whicha cardiac muscle fiber must shorten.

Muscle Length (mm)

•The force of contractionindependent of preloadand afterload.

•Frank Starling •Isotonic Contraction •Inotropic State

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From Muscle to Chamber

The Pressure Volume Loop

Syst

ole

asto

leD

ia

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The Pressure Volume Loop

P

Pres

sure

esP

Volume

P

Compliance/Stiffness vs Capacitance

0

5

10

15

20

25

V Pr

essu

re (m

mH

g)

Slope = stiffness= 1/compliance

Capacitance = volume at specified pressure

EDPVR

50 “Diastolic Dysfunciton”

20 40 60 80 100 120 140-5

LV Volume (ml)

LV

0 50 100 150 200 2500

10

20

30

40

50

LV Volume (ml)

LV P

ress

ure

(mm

Hg)

Normal

y

“Remodeling”

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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 FunctionPreload 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

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Frank Starling Curves

PulmonaryCongestion

Hyp

oten

sion

Pathophysiology - PV Loop

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Pathophysiology of Heart Failure

Myocardial Insult/Stimuli/Damagey g

Pump dysfunction

A i i f hActivation of neurohormones•Catecholamines•Angiontensin II

•Cytokines

Remodeling•Hypertrophy

•Fibrosis•Apoptosis

Myocardial injury to the heart (CAD, HTN, CMP, valvular disease)

Neurohormonal Activation in Heart Failure

Initial fall in LV performance, ↑ wall stress

Peripheral vasoconstrictionSodium retention

H d i lt ti

Remodeling and progressiveworsening of LV function

Activation of RAS and SNS

Fibrosis, apoptosis,hypertrophy,

cellular/molecular

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

Heart failure symptomsFatigueActivity altered Chest congestionEdemaShortness of breath

Morbidity and mortalityArrhythmiasPump failure

Hemodynamic alterationscellular/molecular alterations,myotoxicity

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Neurohormonal Activation in Heart Failure

Angiotensin II Norepinephrine

Hypertrophy, apoptosis, ischemia,Hypertrophy, apoptosis, ischemia,arrhythmias, remodeling, fibrosis

Morbidity and Mortality

↑ CNS sympathetic outflow

↑ Vascular sympathetic activity

Adrenergic Pathway in Heart Failure Progression

↑ Cardiac sympathetic activity ↑ Renal sympathetic activity

α1β1β1 β2 α1 α1

Sodium retentionMyocyte hypertrophy

Myocyte injuryIncreased arrhythmias

Disease progression

Vasoconstriction Activationof RAS

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Neurohormonal Balance in Heart Failure

Myocardial Injury Fall in LV Performance

Neurohormones in Heart Failure

ANPBNP

Activation of RAAS and SNS(endothelin, AVP, cytokines)

Myocardial ToxicityChange in Gene Expression

Peripheral Vasoconstriction Sodium/Water Retention

HF SymptomsMorbidity and Mortality

Remodeling andProgressive

Worsening ofLV Function

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

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Pathophyisiology of myocardial remodeling:

Insult / Remodeling Stimuli

Myocyte Hypertrophy

Altered interstitial matrix

Ventricular Enlargement

Increased Wall Stress•↑ Wall Stress

•Cytokines•Neurohormones•Oxidative stress

Altered interstitial matrix

Fetal Gene Expression

Altered calcium handling proteins

Myocyte Death

Systolic Dysfunction

DiastolicDysfunction

Response Short-term Effects (mainly adaptive;

h h t h t

Long-term Effects (mainly deleterious; h i h t f il )

Acute and Chronic Responses –Benefits and Harm

hemorrhage, acute heart failure)

chronic heart failure)

Salt and water retention Augments preload Pulmonary congestion, anasarca

Vasoconstriction Maintains pressure for perfusion of vital organs (brain, heart)

Exacerbates pump dysfunction, increases cardiac energy expenditure

Sympathetic stimulation Increases heart rate and ejection Increases energy expenditureSympathetic stimulation Increases heart rate and ejection Increases energy expenditure

Cytokine activation Vasodilatation Skeletal muscle catabolism, deterioration of endothelial function, impaired contraction, LV remodeling.

Hypertrophy Unloads individual muscle fibers Deterioration and death of cardiac cells: cardiomyopathy of overload

Increased collagen May reduce dilatation Impairs relaxation

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Laplace’s Law

h

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

h

Remodeling – Concentric vs. Eccentric

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Ventricular Remodeling

Pathophysiology of Heart Failure

Four Basic MechanismsFour Basic Mechanisms1. Increased Blood Volume (Excessive Preload)2. Increased Resistant to Blood Flow (Excessive

Afterload)3. Decreased contractility4. Decreased Filling

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Increased Blood VolumeAortic

Regurgitation AI + Neurohormones AI + Remodeling

AI +Etiologies AINormalP t AI+N

Na RetentionVasoconstriction

VentricularRemodeling

AI + Remodeling

104/45

63

2.6

20

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

15

3.0

80

128/50

AI

10PCWP (mm Hg)

3.8Cardiac Output (L/min)

64SV (ml)

140/75BP (mm Hg)

NormalParameter

25

4.3

82

130/50

AI+Neuro-Hormones

Increased AfterloadHypertension

↑ Ea

HTN + DD HTN + DD + HF

Etiologies Parameter Normal HTNHTN +

Heart failureHTN + DD

↑ Ea

Diastolic Dysfunction


Remodeling

Etiologies•Aortic Stenosis•Aortic Coarctation•Hypertension

Parameter Normal HTN

BP (mm Hg) 131/76 150/100

SV (ml) 57 52

Cardiac Output (L/min) 4.0 3.6

PCWP (mm Hg) 10 10

Heart failure161/105

57

4.0

23

HTN + DD140/92

49

3.4

13

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Decreased ContractilityMI MI + Heart Failure MI + Remodeling

Etiologies • Ischemic Cardiomyopathy MI + MI +

d li



– Myocardial Infarction– Myocardial Ischemia

• Myocarditis• Toxins

– Anthracycline – Alcohol– Cocaine

Neurohormones90/54

46

3.2

25

Remodeling

87/44

46

3.2

23

Parameter Normal MIBP (mm Hg) 124/81 80/40

SV (ml) 60 42


PCWP (mm Hg) 12 17

Decreased FillingNormal HCM HCM + HF

Etiologies • Mitral Stenosis


P t N l HCM HCM +


• Mitral Stenosis• Constriction• Restrictive Cardiomypoathy• Cardiac Tamponade• Hypertrophic

Cardiomyopathy• Infiltrative Cardiomyopathy

Parameter Normal HCM

BP (mm Hg) 124/81 95/47

SV (ml) 63 50


PCWP (mm Hg) 10 17

HCM +HF

105/53

55

3.8

26

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Part II



Heart Failure


Non cardiac


Restrcitive



Backward

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Types of Heart Failure

SHF Diastolic

P th h i l Impaired Contraction Impaired fillingPathophysiology Impaired Contraction Impaired filling

Demographics All ages > 60 years

1° Cause Coronary Artery Disease Hypertension

Systolic Versus Diastolic Failure

NormalNormalSystolicSystolic

D f tiD f tiDiastolicDiastolic

DysfunctionDysfunction

essu

re

essu

re

essu

re

NormalNormalDysfunctionDysfunction

⇓ Contractility

⇓ Capacitance

DysfunctionDysfunction

Volume

Pr

Volume

Pr

Volume

Pr

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Systolic Versus Diastolic Failure



Heart Failure


Non cardiac


Restrcitive



Backward

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Decompensated Heart Failure



Heart Failure


Non cardiac


Restrictive



Backward

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High vs. Low Output Failure

• Causes:A i– Anemia

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



Heart Failure


Non cardiac


Restrictive



Backward

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Dilated vs. Hypertrophic vs. Restrictive

Type Definition Sample EtiologiesDilated Dilated left/both

ventricle(s) with impaired contraction

Ischemic, idiopathic, familial, viral, alcoholic, toxic, valvular

Hypertrophic Left and/or right ventricular hypertrophy

Familial with autosomal dominant inheritance

Restrictive Restrictive filling and Idiopathic amyloidosisRestrictive Restrictive filling and reduced diastolic filling of one/both ventricles, Normal/near normal systolic function

Idiopathic, amyloidosis, endomyocardial fibrosis

Dilated vs. Hypertrophic vs. Restrictive

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Clinical ManifestationsSymptoms

R d d i l• Reduced exercise tolerance• Shortness of breath• Congestion• Fluid retention• Difficulty in sleeping• Weight loss

Diagnosis of heart failure

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

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II

NYHA ClassificationClass Patient Symptoms

Mild • No limitation of physical activityII

IIII

IIIIII

Mild p y y• No undue fatigue, palpitation or dyspnea

Mild• Slight limitation of physical activity• Comfortable at rest• Less than ordinary activity results in fatigue,

palpitation, or dyspnea

Moderate• Marked limitation of physical activity

C f t bl t tIIIIII

IVIV

Moderate • Comfortable at rest• Less than ordinary activity results in fatigue,

palpitation, or dyspnea

Severe• Unable to carry out any physical activity without

discomfort• Symptoms of cardiac insufficiency at rest• Physical activity causes increased discomfort

ACC/AHA Staging System

STAGE ASTAGE A High risk for developing HFHigh risk for developing HF

STAGE BSTAGE B Asymptomatic LV dysfunctionAsymptomatic LV dysfunction

STAGE CSTAGE C Past or current symptoms of HFPast or current symptoms of HF

STAGE DSTAGE D EndEnd--stage HFstage HF

Hunt, et al. J Am Coll Cardiol. 2001; 38:2101-2113.

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Stage Patient DescriptionHigh risk for developing heart failure

• Hypertension


AA developing heart failure • Coronary artery disease• Diabetes mellitus• Family history of cardiomyopathy

Asymptomatic heart failure

• Previous myocardial infarction• Left ventricular systolic dysfunction• Asymptomatic valvular disease

Symptomatic heart • Known structural heart disease

BB

CC Symptomatic heart failure

Known structural heart disease• Shortness of breath and fatigue• Reduced exercise tolerance

Refractory end-stage heart failure

• Marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

CC

DD

Goals of Treatment

1 Identification and correction of underlying1. Identification and correction of underlying condition causing heart failure.

2. Elimination of acute precipitating cause of symptoms.

3. Modulation of neurohormonal response to pprevent progression of disease.

4. Improve long term survival.

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Etiologies• Ischemic cardiomyopathy • Valvular cardiomyopathyValvular cardiomyopathy • Hypertensive cardiomyopathy.• Inflammatory cardiomyopathy • Metabolic cardiomyopathy • General system disease• Muscular dystrophies• 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

V l O l d• 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

Stage Patient TreatmentHigh risk for developing heart failure

• Hypertension

Treatment

AA • Optimal pharmacologic therapy (OPT)developing heart failure • Coronary artery disease• Diabetes mellitus• Family history of cardiomyopathy

Asymptomatic heart failure

• Previous myocardial infarction• Left ventricular systolic dysfunction• Asymptomatic valvular disease

Symptomatic heart • Known structural heart disease

BB

CC • OPT

Optimal pharmacologic therapy (OPT)• Aspirin, ACE inhibitors, statins, b-blockers,

a-b-blockers (carvedilol) diabetic therapy

• OPT• ICD if left ventricular (LV) dysfunction (systolic)

present

Symptomatic heart failure

Known structural heart disease• Shortness of breath and fatigue• Reduced exercise tolerance

Refractory end-stage heart failure

• Marked symptoms at rest despite maximal medical therapy (e.g., those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

CC

DD

• OPT• ICD if LV dysfunction (systolic) present• CRT (if QRS wide, LVEF≤35%)

• OPT• Intermittent IV inotropes• ICD as a bridge to transplantation• CRT • Other devices (LVAD, pericardial restraint)

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Treatment of Acute Heart Failure


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Summary

• Complex Clinical Syndrome• Complex Clinical Syndrome• Multiple Etiologies and Classification Systems• Physiologic Understanding Essential

htt // l bi d /it /h / di l/h t i /http://www.columbia.edu/itc/hs/medical/heartsim/

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Pathophysiology: Heart Failure - Columbia University · 2009-12-10 · 12/9/2009 1 Pathophysiology: Heart Failure Mat Maurer, MD Associate Professor of Clinical Medicine Objectives