hypertrophic cardiomyopathy. learning objectives understand the prevalence of hypertrophic...

Hypertrophic Hypertrophic CardiomyopathyCardiomyopathy

Learning Objectives Learning Objectives Understand the prevalence of hypertrophic cardiomyopathy and Understand the prevalence of hypertrophic cardiomyopathy and

the genetic basis for the disease the genetic basis for the disease Appreciate the pathophysiology of hypertrophic cardiomyopathy Appreciate the pathophysiology of hypertrophic cardiomyopathy Be able to identify the various clinical presentations of the Be able to identify the various clinical presentations of the

disease disease Learn how to diagnose hypertrophic cardiomyopathy using Learn how to diagnose hypertrophic cardiomyopathy using

different modalities different modalities Understand the typical natural history of the disease Understand the typical natural history of the disease Recognize the importance of implantable cardioverter Recognize the importance of implantable cardioverter

defibrillators in the prevention of sudden cardiac death in this defibrillators in the prevention of sudden cardiac death in this population population

Appreciate emerging therapeutic strategies and current Appreciate emerging therapeutic strategies and current research research

CaseCase17 yo male professional basketball player with no 17 yo male professional basketball player with no known PMH collapses on the playing floor during known PMH collapses on the playing floor during practice and subsequently arrests. He had been practice and subsequently arrests. He had been having some exertional dyspnea for a few months having some exertional dyspnea for a few months prior to this incident but it did not affect his activity prior to this incident but it did not affect his activity level. He was told growing up that he had a “heart level. He was told growing up that he had a “heart murmur” that was never formally investigated. He murmur” that was never formally investigated. He was taking no medications, and there was no family was taking no medications, and there was no family history of cardiac disease in his family. An autopsy history of cardiac disease in his family. An autopsy later revealed that the patient had hypertrophic later revealed that the patient had hypertrophic cardiomyopathy. cardiomyopathy.

Background Background

Prevalence of HCM: 1:500 to 1:1000 Prevalence of HCM: 1:500 to 1:1000 individuals individuals

This occurrence is higher than previously thought, This occurrence is higher than previously thought, suggesting a large number of affected but undiagnosed suggesting a large number of affected but undiagnosed people people

Men and African-Americans affected by almost Men and African-Americans affected by almost 2:1 ratio over women and Caucasians 2:1 ratio over women and Caucasians

Global disease with most cases reported from Global disease with most cases reported from USA, Canada, Western Europe, Israel, & Asia USA, Canada, Western Europe, Israel, & Asia

Historical Perspective Historical Perspective

HCM was initially described by Teare in HCM was initially described by Teare in 1958 1958

Found massive hypertrophy of ventricular septum in Found massive hypertrophy of ventricular septum in small cohort of young patients who died suddenly small cohort of young patients who died suddenly

Braunwald was the first to diagnose HCM Braunwald was the first to diagnose HCM clinically in the 1960s clinically in the 1960s

Many names for the disease Many names for the disease Idiopathic hypertrophic subaortic stenosis (IHSS)Idiopathic hypertrophic subaortic stenosis (IHSS)Muscle subaortic stenosis Muscle subaortic stenosis Hypertrophic obstructive cardiomyopathy (HOCM)Hypertrophic obstructive cardiomyopathy (HOCM)

Genetic Basis of HCM Genetic Basis of HCM

Causes: Inherited, Causes: Inherited, acquired, unknown acquired, unknown

Autosomal dominant Autosomal dominant inheritance pattern inheritance pattern

>450 mutations in 13 >450 mutations in 13 cardiac sarcomere & cardiac sarcomere & myofilament-related myofilament-related genes identified genes identified

?? Role for ?? Role for environmental factors environmental factors

Alcalai et al. J Cardiovasc Electrophysiol. 19(1): Jan 2008.

Genetics of HCMGenetics of HCM

Alcalai et al. J Cardiovasc Electrophysiol 2008;19:105.

Pathophysiology of HCMPathophysiology of HCM

The pathophysiology of HCM involves 4 The pathophysiology of HCM involves 4 interrelated processes:interrelated processes:

Left ventricular outflow obstruction Left ventricular outflow obstruction Diastolic dysfunction Diastolic dysfunction Myocardial ischemia Myocardial ischemia Mitral regurgitation Mitral regurgitation

LV Outflow Obstruction in HCMLV Outflow Obstruction in HCM

Long-standing LV outflow obstruction is a Long-standing LV outflow obstruction is a major determinant for heart failure major determinant for heart failure symptoms and death in HCM patients symptoms and death in HCM patients

Subaortic outflow obstruction is caused by Subaortic outflow obstruction is caused by systolic anterior motion (SAM) of the mitral systolic anterior motion (SAM) of the mitral valve – leaflets move toward the septumvalve – leaflets move toward the septum

LV Outflow Obstruction in HCMLV Outflow Obstruction in HCM

Physiological Consequences of Physiological Consequences of Obstruction Obstruction Elevated intraventricular pressures Elevated intraventricular pressures Prolongation of ventricular relaxation Prolongation of ventricular relaxation Increased myocardial wall stress Increased myocardial wall stress Increased oxygen demand Increased oxygen demand Decrease in forward cardiac output Decrease in forward cardiac output

Massive left ventricular hypertrophy, mainly confined to the septum

Histopathology showing significant myofiber disarray and interstitial fibrosis

Cell Research. 2003;13(1):10.

Maron MS et al. NEJM. 2003;348:295.


Diastolic Dysfunction Diastolic Dysfunction Contributing factor in 80% of patients Contributing factor in 80% of patients Impaired relaxation Impaired relaxation

High systolic contraction load High systolic contraction load Ventricular contraction/relaxation not uniform Ventricular contraction/relaxation not uniform

Accounts for symptoms of exertional dyspneaAccounts for symptoms of exertional dyspneaAbnormal diastolic filling à increased pulmonary Abnormal diastolic filling à increased pulmonary

venous pressure venous pressure


Myocardial Ischemia Myocardial Ischemia Often occurs without atherosclerotic coronary Often occurs without atherosclerotic coronary

artery disease artery disease Postulated mechanismsPostulated mechanisms

Abnormally small and partially obliterated intramural Abnormally small and partially obliterated intramural coronary arteries as a result of hypertrophy coronary arteries as a result of hypertrophy

Inadequate number of capillaries for the degree of Inadequate number of capillaries for the degree of LV mass LV mass


Mitral Regurgitation Mitral Regurgitation Results from the systolic anterior motion of the Results from the systolic anterior motion of the

mitral valve mitral valve Severity of MR directly proportional to LV Severity of MR directly proportional to LV

outflow obstruction outflow obstruction Results in symptoms of dyspnea, orthopnea in Results in symptoms of dyspnea, orthopnea in

HCM patients HCM patients

Integrated PathophysiologyIntegrated Pathophysiology

Braunwald. Atlas of Heart Diseases: Cardiomyopathies, Myocarditis, and Pericardial Disease. 1998.

Clinical Presentation Clinical Presentation

Dyspnea on exertion (90%), orthopnea, Dyspnea on exertion (90%), orthopnea, PND PND

Angina (70-80%) Angina (70-80%) Syncope (20%), Presyncope (50%) Syncope (20%), Presyncope (50%)

outflow obstruction worsens with increased outflow obstruction worsens with increased contractility during exertional activities contractility during exertional activities

Sudden cardiac deathSudden cardiac deathHCM is most common cause of SCD in young HCM is most common cause of SCD in young

people, including athletes people, including athletes

Physical Examination Physical Examination

Carotid PulseCarotid PulseBifid – short upstroke & prolonged systolic ejection Bifid – short upstroke & prolonged systolic ejection

Jugular Venous Pulse Jugular Venous Pulse Prominent Prominent a wavea wave – decreased ventricular – decreased ventricular

compliance compliance

Apical Impulse Apical Impulse Double or triple Double or triple

Heart SoundsHeart SoundsS4 usually present due to hypertrophy S4 usually present due to hypertrophy

Physical Examination Physical Examination

MurmurMurmurMedium-pitch crescendo-decrescendo systolic Medium-pitch crescendo-decrescendo systolic

murmur along LLSB without radiation murmur along LLSB without radiation Dynamic maneuvers Dynamic maneuvers

Murmur intensity increases with decreased Murmur intensity increases with decreased preload (i.e. Valsalva)preload (i.e. Valsalva)

Murmur intensity decreases with increased Murmur intensity decreases with increased preload (i.e. squatting, hand grip) preload (i.e. squatting, hand grip)

Physical Examination in HCMPhysical Examination in HCM

Braunwald E. Atlas of Internal Medicine. 2007.

Diagnostic Evaluation Diagnostic Evaluation

ElectrocardiogramElectrocardiogramEchocardiogram Echocardiogram Catheterization Catheterization

Electrocardiogram in HCMElectrocardiogram in HCM

Echocardiography in HCMEchocardiography in HCM

Transesophageal EchoTransesophageal Echo

Cardiac Catheterization Cardiac Catheterization

Hyperdynamic systole function results in almost complete obliteration of the LV cavity

Coronary angiography is not typically necessary in HCM

Natural History of HCMNatural History of HCMCumulative Survival After Initial Diagnostic Evaluation Among Patients Diagnosed

as Having HCM at 20 Years or Older

Maron, BJ et al. JAMA 1999;281:650-655

Disease Progression in HCMDisease Progression in HCM

ACC Consensus Document. J Am Coll Cardiol. 2003;42(9):1693.

Sudden Cardiac Death in HCM Sudden Cardiac Death in HCM Most frequent in young Most frequent in young

adults <30-35 years oldadults <30-35 years oldPrimary VF/VT Primary VF/VT Tend to die during or Tend to die during or

just following vigorous just following vigorous physical activity physical activity

Often is 1Often is 1stst clinical clinical manifestation of manifestation of disease disease

HCM is most common HCM is most common cause of SCD among cause of SCD among young competitive young competitive athletes athletes

J Am Coll Cardiol. 2003;42(9):1693.

SCD in Competitive Athletes SCD in Competitive Athletes

Maron B. Atlas of Heart Diseases. 1996

Natural History of HCM Natural History of HCM

Heart Failure Heart Failure Only 10-15% progress Only 10-15% progress

to NYHA III-IV to NYHA III-IV Only 3% will become Only 3% will become

truly end-stage with truly end-stage with systolic dysfunction systolic dysfunction

Endocarditis Endocarditis 4-5% of HCM patients 4-5% of HCM patients Usually mitral valve Usually mitral valve

affected affected

Atrial Fibrillation Atrial Fibrillation Prevalent in up to 30% of Prevalent in up to 30% of

older patientsolder patients Dependent on atrial kick Dependent on atrial kick

– CO decreases by 40% – CO decreases by 40% if AF present if AF present

Autonomic Dysfunction Autonomic Dysfunction 25% of HCM patients 25% of HCM patients Associated with poor Associated with poor

prognosis prognosis

Influence of Gender & Race Influence of Gender & Race

Women often remain underdiagnosed and Women often remain underdiagnosed and are clinical recognized after they develop are clinical recognized after they develop more pronounced symptomsmore pronounced symptoms11

HCM clinically underrecognized in African-HCM clinically underrecognized in African-Americans Americans Most athletes with SCD due to HCM are Most athletes with SCD due to HCM are undiagnosed African-Americansundiagnosed African-Americans22

11 Olivotto I et al. Olivotto I et al. J Am Coll CardiolJ Am Coll Cardiol 2005;46:480. 2005;46:480. 2 2 Maron BJ et al. Maron BJ et al. J Am Coll CardiolJ Am Coll Cardiol 2003;41:974. 2003;41:974.

Treatment of HCM Treatment of HCM

Medical therapy Medical therapy Device therapy Device therapy Surgical septal myectomy Surgical septal myectomy Alcohol septal ablationAlcohol septal ablation

ACC Consensus Document. J Am Coll Cardiol. 2003;42(9):1693.

Medical Therapy Medical Therapy

Beta-blockersBeta-blockersIncrease ventricular diastolic filling/relaxation Increase ventricular diastolic filling/relaxation Decrease myocardial oxygen consumption Decrease myocardial oxygen consumption Have not been shown to reduce the incidence of Have not been shown to reduce the incidence of

SCD SCD Verapamil Verapamil

Augments ventricular diastolic filling/relaxation Augments ventricular diastolic filling/relaxation Disopyramide Disopyramide

Used in combination with beta-blocker Used in combination with beta-blocker Negative inotrope Negative inotrope

Diuretics Diuretics

Dual-Chamber Pacing Dual-Chamber Pacing

Proposed benefit: pacing the RV apex will Proposed benefit: pacing the RV apex will decrease the outflow tract gradient decrease the outflow tract gradient

Several RCTs have found that the improvement Several RCTs have found that the improvement in subjective measures provided by dual-chamber in subjective measures provided by dual-chamber pacing is likely a placebo effect pacing is likely a placebo effect

Objective measures such as exercise capacity Objective measures such as exercise capacity and oxygen consumption are not improved and oxygen consumption are not improved

No correlation has been found between pacing No correlation has been found between pacing and reduction of LVOT gradient and reduction of LVOT gradient

Surgical Septal MyectomySurgical Septal Myectomy

Nishimura RA et al. NEJM. 2004. 350(13):1320.

Alcohol Septal Ablation Alcohol Septal Ablation

Braunwald. Atlas of Heart Diseases: Cardiomyopathies, Myocarditis, and Pericardial Disease. 1998.


Before After


Successful short-term outcomesSuccessful short-term outcomesLVOT gradient reduced from a mean of 60-70 mmHg LVOT gradient reduced from a mean of 60-70 mmHg

to <20 mmHg to <20 mmHg Symptomatic improvements, increased exercise Symptomatic improvements, increased exercise

tolerance tolerance Long-term data not available yet Long-term data not available yet Complications Complications

Complete heart blockComplete heart blockLarge myocardial infarctionsLarge myocardial infarctions

No randomized efficacy trials yet for alcohol No randomized efficacy trials yet for alcohol septal ablation vs. surgical myectomy septal ablation vs. surgical myectomy

Circulation. 2008; 18(2): 131-9.

Efficacy of Therapeutic StrategiesEfficacy of Therapeutic Strategies

Nishimura et al. NEJM. 2004. 350(13):1323.

Coil Embolization Coil Embolization

Case report of 20 patients Case report of 20 patients w/ drug-refractory HCM w/ drug-refractory HCM

Occlude septal perforator Occlude septal perforator branches branches

NYHA functional class NYHA functional class and peak oxygen and peak oxygen consumption improved at consumption improved at 6 months 6 months

Significant reduction in Significant reduction in septum thickness by echo septum thickness by echo

European Heart Journal 2008;29:350.

Implantable Cardioverter Implantable Cardioverter

Defibrillators in HCMDefibrillators in HCM Primary & Secondary Prevention Primary & Secondary Prevention

Maron BJ et al. NEJM 2000;342:365-73.

Appropriate discharges in Appropriate discharges in 23% of patients 23% of patients

Rate of appropriate Rate of appropriate discharges of 7% per year discharges of 7% per year

Of 21 patients for which Of 21 patients for which intracardiac electrograms intracardiac electrograms were available, 10 shocks were available, 10 shocks for VT, 9 shocks for VFfor VT, 9 shocks for VF

Suggested role for ICDs in Suggested role for ICDs in primary & secondary primary & secondary prevention of SCDprevention of SCD

Risk Stratification – ICDs Risk Stratification – ICDs

Primary Prevention Risk Factors for SCD Primary Prevention Risk Factors for SCD Premature HCM-related sudden death in more Premature HCM-related sudden death in more

than 1 relative than 1 relative History of unexplained syncope History of unexplained syncope Multiple or prolonged NSVT on Holter Multiple or prolonged NSVT on Holter Hypotensive blood pressure response to exercise Hypotensive blood pressure response to exercise Massive LVH Massive LVH

How many risk factors warrant ICD How many risk factors warrant ICD placement?placement?

JAMA. 2007;298(4): 405-12.

Multicenter registry Multicenter registry study w/ 506 pts from study w/ 506 pts from 1986-2003 1986-2003

Mean follow-up 3.7 yrsMean follow-up 3.7 yrsAverage age 41 years Average age 41 years

old old Primary Outcome: Primary Outcome:

appropriate ICD appropriate ICD interventions interventions terminating VF/VT terminating VF/VT

JAMA. 2007;298(4): 405-12.

J Cardiovasc Electrophysiol 2008;19(10).

J Am Coll Cardiol 2008;51(10):1033-9.

3500 asymptomatic elite 3500 asymptomatic elite athletes (75% male), mean athletes (75% male), mean age 20.5 +/- 5.8 years, no age 20.5 +/- 5.8 years, no family hx of HCM family hx of HCM

12-lead ECG, 2D-Echo 12-lead ECG, 2D-Echo 53 athletes (1.5%) had LVH 53 athletes (1.5%) had LVH 3 athletes (0.08%) had ECG 3 athletes (0.08%) had ECG

and echo features of HCMand echo features of HCM

HCM vs. Athlete’s Heart HCM vs. Athlete’s Heart

Circulation 1995;91.

http://circ.ahajournals.org.ezp-prod1.hul.harvard.edu/content/vol91/issue5/images/large/hc0551443002.jpeg

Future Directions Future Directions

Identification of additional causative mutations Identification of additional causative mutations Risk stratification tools Risk stratification tools Determining more precise indications for ICDs Determining more precise indications for ICDs

Defining most appropriate role for alcohol Defining most appropriate role for alcohol

septal ablation septal ablation ?Gene therapy ?Gene therapy

hypertrophic cardiomyopathy. learning objectives understand the prevalence of hypertrophic...

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