HYPERTROPHIC

CARDIOMYOPATHY
 BACKGROUND

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

 This occurrence is higher than previously thought, suggesting a large
number of affected but undiagnosed people
 Men and African- Americans af fected by almost 2:1 ratio over
women and Caucasians
 Global disease with most cases reported from USA , Canada,
Western Europe, Israel, & Asia
 HISTORICAL PERSPECTIVE

 HCM was initially described by Teare in 1958

 Found massive hypertrophy of ventricular septum in small cohort of
young patients who died suddenly
 Braunwald was the first to diagnose HCM clinically in the
1960s
 Many names for the disease
 Idiopathic hypertrophic subaortic stenosis (IHSS)
 Muscle subaortic stenosis
 Hypertrophic obstructive cardiomyopathy (HOCM)
 GENETIC BASIS OF HCM

 Causes: Inherited,
acquired, unknown
 Autosomal dominant
inheritance pattern
 >450 mutations in
13 cardiac
sarcomere &
myofilament-related
genes identified
 ?? Role for
environmental
factors
Alcalai et al. J Cardiovasc Electrophysiol. 19(1): Jan 2008.
 GENETICS OF HCM

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

 PATHOPHYSIOLOGY OF HCM

The pathophysiology of HCM involves 4 interrelated processes:

Left ventricular outflow obstruction

Diastolic dysfunction
Myocardial ischemia
Mitral regurgitation
 LV OUTFLOW OBSTRUCTION IN HCM

 Long-standing LV outflow obstruction is a major determinant

for heart failure symptoms and death in HCM patients
 Subaortic outflow obstruction is caused by systolic anterior
motion (SAM) of the mitral valve – leaflets move toward the
septum
 LV OUTFLOW OBSTRUCTION IN HCM

 Physiological Consequences of Obstruction

 Elevated intraventricular pressures
 Prolongation of ventricular relaxation
 Increased myocardial wall stress
 Increased oxygen demand
 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.
 PATHOPHYSIOLOGY OF HCM

 Diastolic Dysfunction
 Contributing factor in 80% of patients
 Impaired relaxation
 High systolic contraction load
 Ventricular contraction/relaxation not uniform
 Accounts for symptoms of exertional dyspnea
 Abnormal diastolic filling  increased pulmonary venous pressure
 PATHOPHYSIOLOGY OF HCM

 Myocardial Ischemia
 Often occurs without atherosclerotic coronary artery disease
 Postulated mechanisms
 Abnormally small and partially obliterated intramural coronary arteries as
a result of hypertrophy
 Inadequate number of capillaries for the degree of LV mass
 PATHOPHYSIOLOGY OF HCM

 Mitral Regurgitation
 Results from the systolic anterior motion of the mitral valve
 Severity of MR directly proportional to LV outflow obstruction
 Results in symptoms of dyspnea, orthopnea in HCM patients
 INTEGRATED PATHOPHYSIOLOGY

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

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

 Angina (70-80%)
 Syncope (20%), Presyncope (50%)
 outflow obstruction worsens with increased contractility during
exertional activities
 Sudden cardiac death
 HCM is most common cause of SCD in young people, including
athletes
 PHYSICAL EXAMINATION

 Carotid Pulse
 Bifid – short upstroke & prolonged systolic ejection
 Jugular Venous Pulse
 Prominent a wave – decreased ventricular compliance
 Apical Impulse
 Double or triple
 Heart Sounds
 S4 usually present due to hypertrophy
 PHYSICAL EXAMINATION

 Murmur
 Medium-pitch crescendo-decrescendo systolic murmur along LLSB
without radiation
 Dynamic maneuvers
 Murmur intensity increases with decreased preload
(i.e. Valsalva)
 Murmur intensity decreases with increased preload
(i.e. squatting, hand grip)
 PHYSICAL EXAMINATION IN HCM

Braunwald E. Atlas of Internal Medicine. 2007.

 DIAGNOSTIC EVALUATION

 Electrocardiogram
 Echocardiogram
 Catheterization
ELECTROCARDIOGRAM IN HCM
ECHOCARDIOGRAPHY IN HCM
TRANSESOPHAGEAL ECHO
CARDIAC CATHETERIZATION

Coronary angiography is not

typically necessary in HCM

Hyperdynamic systole function

results in almost complete
obliteration of the LV cavity
 NATURAL HISTORY OF HCM

Cumulative 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 HCM

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

 SUDDEN CARDIAC DEATH IN HCM

 Most frequent in
young adults <30-35
years old
 Primary VF/VT
 Tend to die during or
just following vigorous
physical activity
 Often is 1 st clinical
manifestation of
disease
 HCM is most common
cause of SCD among
young competitive
J Am Coll Cardiol. 2003;42(9):1693.
athletes
 SCD IN COMPETITIVE ATHLETES

Maron B. Atlas of Heart Diseases. 1996

 NATURAL HISTORY OF HCM

Heart Failure Atrial Fibrillation

 Only 10-15% progress  Prevalent in up to 30%
to NYHA III-IV of older patients
 Only 3% will become  Dependent on atrial kick
truly end-stage with – CO decreases by 40%
systolic dysfunction if AF present
Endocarditis Autonomic
 4-5% of HCM patients Dysfunction
 Usually mitral valve  25% of HCM patients
affected  Associated with poor
prognosis
 INFLUENCE OF GENDER & RACE

 Women often remain underdiagnosed and are clinical

recognized after they develop more pronounced symptoms 1
 HCM clinically underrecognized in African- Americans
 Most athletes with SCD due to HCM are undiagnosed African -
Americans 2

1 Olivotto I et al. J Am Coll Cardiol 2005;46:480.

2 Maron BJ et al. J Am Coll Cardiol 2003;41:974.
 TREATMENT OF HCM

 Medical therapy
 Device therapy
 Surgical septal myectomy
 Alcohol septal ablation
ACC Consensus Document. J Am Coll Cardiol. 2003;42(9):1693.
 MEDICAL THERAPY

 Beta-blockers
 Increase ventricular diastolic filling/relaxation
 Decrease myocardial oxygen consumption
 Have not been shown to reduce the incidence of SCD
 Verapamil
 Augments ventricular diastolic filling/relaxation
 Disopyramide
 Used in combination with beta-blocker
 Negative inotrope
 Diuretics
 DUAL-CHAMBER PACING

Proposed benefit: pacing the RV apex will

decrease the outflow tract gradient
Several RCTs have found that the
improvement in subjective measures
provided by dual-chamber pacing is likely a
placebo effect
Objective measures such as exercise capacity
and oxygen consumption are not improved
No correlation has been found between
pacing and reduction of LVOT gradient
 SURGICAL SEPTAL MYECTOMY

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

 ALCOHOL SEPTAL ABLATION

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

Before After
 ALCOHOL SEPTAL ABLATION

Successful short-term outcomes

 LVOT gradient reduced from a mean of 60-70 mmHg
to <20 mmHg
 Symptomatic improvements, increased exercise
tolerance
Long-term data not available yet
Complications
 Complete heart block
 Large myocardial infarctions
No randomized efficacy trials yet for alcohol
septal ablation vs. surgical myectomy
Circulation. 2008; 18(2): 131-9.
 EFFICACY OF THERAPEUTIC STRATEGIES

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

 COIL EMBOLIZATION

 Case report of 20 patients w/ drug -

refractory HCM
 Occlude septal perforator branches
 NYHA functional class and peak
oxygen consumption improved at 6
months
 Significant reduction in septum
thickness by echo

European Heart Journal 2008;29:350.

 IMPLANTABLE Primary &
CARDIOVERTER Secondary
Prevention
DEFIBRILLATORS IN HCM
 Maron BJ et al.
NEJM 2000;342:
365-73.

 Appropriate discharges in
23% of patients
 Rate of appropriate
discharges of 7% per year
 Of 21 patients for which
intracardiac electrograms
were available, 10 shocks
for V T, 9 shocks for VF
 Suggested role for ICDs in
primary & secondary
prevention of SCD
 RISK STRATIFICATION – ICDS

 Primary Prevention Risk Factors for SCD

 Premature HCM-related sudden death in more than 1 relative
 History of unexplained syncope
 Multiple or prolonged NSVT on Holter
 Hypotensive blood pressure response to exercise
 Massive LVH
 How many risk factors warrant ICD placement?
 JAMA. 2007;298(4):
405-12.

Multicenter registry
study w/ 506 pts
from 1986-2003
Mean follow-up 3.7
yrs
Average age 41
years old
Primary Outcome:
appropriate ICD
interventions
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 athletes (75%
male), mean age 20.5
+/- 5.8 years, no family
hx of HCM
 12-lead ECG, 2D-Echo
 53 athletes (1.5%) had
LVH
 3 athletes (0.08%) had
ECG and echo features
of HCM
HCM VS. ATHLETE’S HEART

Circulation 1995;91.
 CASE

17 yo male professional basketball player with no known

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

 Identification of additional causative mutations

 Risk stratification tools
 Determining more precise indications for ICDs
 Defining most appropriate role for alcohol septal ablation
 ?Gene therapy
 REFERENCES
ACC/ESC Clinical Expert Consensus Document on Hypertrophic Cardiomyopathy. J Am Coll
Cardiol 2003;42(9):1687-1713.

Alcalai et al. Genetic Basis of Hypertrophic Cardiomyopathy. J Cardiovasc Electrophysiol

2008;19:104-110.

Begley, DA et al. Efficacy of implantable cardioverter defibrillator therapy for primary and
secondary prevention of sudden cardiac death in hypertrophic cardiomyopathy. Pacing Clin
Electrophysiol 2003;26(9):1887-96.

Braunwald. Atlas of Internal Medicine. 2007.

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

1998.

Chung MW et al. Hypertrophic Cardiomyopathy: From Gene Defect to Clinical Disease. Cell
Res 2003;13(1):9-20.

Durand, E et al. Non-Surgical Septal Myocardial Reduction By Coil Embolization for

Hypertrophic Obstructive Cardiomyopathy: Early and 6 Months Follow-Up. European Heart
Journal 2008;29:348-55.

Fifer, MA et al. Management of Symptoms in Hypertrophic Cardiomyopathy. Circulation

2008;117:429-39.
 REFERENCES
Fuster et al. Hurst’s The Heart, 12th ed. 2008.

Libby: Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine, 8th ed. 2007.

Maron, BJ et al. Implantable Defibrillators and Prevention of Sudden Death in Hypertrophic

Cardiomyopathy. J Cardiovasc Electrophysiol. 2008;19:1118-1126.

Maron, BJ et al. Implantable Cardioverter-Defibrillators and Prevention of Sudden Cardiac Death

in Hypertrophic Cardiomyopathy. JAMA. 2007;298(4):405-412.

Maron MS et al. Effect of Left Ventricular Outflow Tract Obstruction on Clinical Outcome in
Hypertrophic Cardiomyopathy. NEJM 2003;348(4):295-303.

Maron, BJ et al. Relationship of Race to Sudden Cardiac Death in Competitive Athletes with
Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2003;41(6):974-80.

Maron BJ et al. Efficacy of Implantable Cardioverter Defibrillators for the Prevention of Sudden
Death in Patients with Hypertrophic Cardiomyopathy. NEJM 2000;342(6):365-73.

Maron BJ et al. Efficacy of Implantable Cardioverter Defibrillators For the Prevention of Sudden
Death in Patients with Hypertrophic Cardiomyopathy. NEJM 2000;342:365-73.

Maron BJ et al. Clinical Course of Hypertrophic Cardiomyopathy in a Regional United States

Cohort. JAMA 1999;281(7):650-55.
 REFERENCES
Maron BJ. Atlas of Heart Diseases: Heart Disease in the Presence of Disorders of Other Organ
Systems. 1996.

Miller, MA et al. Risk Stratification of Sudden Cardiac Death in Hypertrophic Cardiomyopathy. Nat
Clin Pract Cardiovasc Med 2007;4(12):667-76.

Nagueh, SF et al. Noninvasive Cardiac Imaging in Patients With Hypertrophic Cardiomyopathy. J

Am Coll Cardiol 2006;48:2410-22.

Nishimura RA et al. Clinical Practice: Hypertrophic Obstructive Cardiomyopathy. NEJM

2004;350(13):1320-7.

Olivotto I et al. Gender-related Differences in the Clinical Presentation and Outcome of

Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2005;46(3):480-7.

Ommen SR et al. Long-Term Effects of Surgical Septal Myectomy on Survival in Patients with
Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol 2005;46(3):470-76.

Ommen SR et al. Comparison of Dual-Chamber Pacing Versus Septal Myectomy For The Treatment
of Patients with Hypertrophic Obstructive Cardiomyopathy: A Comparison of Objective
Homodynamic and Exercise End Points. J Am Coll Cardiol 1999;34(1):191-6.

Sorajja P et al. Outcome of Alcohol Septal Ablation For Obstructive Hypertrophic Cardiomyopathy.
Circulation 2008;118(2):131-9.
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