Download Hypertrophic Cardiomyopathy

Hypertrophic
Cardiomyopathy
Learning Objectives
Understand the prevalence of hypertrophic cardiomyopathy and
the genetic basis for the disease
 Appreciate the pathophysiology of hypertrophic cardiomyopathy
 Be able to identify the various clinical presentations of the
disease
 Learn how to diagnose hypertrophic cardiomyopathy using
different modalities
 Understand the typical natural history of the disease
 Recognize the importance of implantable cardioverter
defibrillators in the prevention of sudden cardiac death in this
population
 Appreciate emerging therapeutic strategies and current
research

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.
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 affected 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 à 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
a wave – decreased ventricular
compliance
 Prominent

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 1st clinical
manifestation of
disease
HCM is most common
cause of SCD among
young competitive
athletes
J Am Coll Cardiol. 2003;42(9):1693.
SCD in Competitive Athletes
Maron B. Atlas of Heart Diseases. 1996
Natural History of HCM

Heart Failure



Only 10-15% progress
to NYHA III-IV
Only 3% will become
truly end-stage with
systolic dysfunction
Endocarditis



4-5% of HCM patients
Usually mitral valve
affected
Atrial Fibrillation



Prevalent in up to 30% of
older patients
Dependent on atrial kick
– CO decreases by 40%
if AF present
Autonomic Dysfunction


25% of HCM patients
Associated with poor
prognosis
Influence of Gender & Race
Women
often remain underdiagnosed and
are clinical recognized after they develop
1
more pronounced symptoms
HCM clinically underrecognized in AfricanAmericans
Most
athletes with SCD due to HCM are
undiagnosed African-Americans2
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 Cardioverter
Defibrillators in HCM
Primary & Secondary Prevention
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 VT, 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):103
3-9.




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.
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
