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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