A 17-year-old male basketball player collapsed during practice and suffered cardiac arrest. An autopsy later revealed he had hypertrophic cardiomyopathy (HCM), a genetic heart condition where the heart muscle becomes abnormally thick. HCM is a leading cause of sudden cardiac death in young athletes. The patient had previously noticed some shortness of breath with exertion but it did not limit his activity. He was found to have a heart murmur as a child but it was never investigated. HCM causes the left ventricle to become thickened and stiff, which can obstruct blood flow out of the heart and cause heart failure, chest pain, arrhythmias, and sudden cardiac death.

1. Hypertrophic
Cardiomyopathy
Dr. Fuad Farooq
Resident Cardiology
Aga Khan University Hospital

2. Case
17 years old male professional basketball player with no
known past medical history 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.

3. Background
 Hypertrophic cardiomyopathy is a genetic
disorder that is typically inherited in an
autosomal dominant fashion with variable
penetrance and variable expressivity
 The disease has complex symptomatology and
potentially devastating consequences for patients
and their families
 HCM is the leading cause of sudden cardiac
death in preadolescent and adolescent children

4. Background
 The hallmark of the disorder is myocardial
hypertrophy that is inappropriate, often
asymmetrical and occurs in the absence of an
obvious inciting hypertrophy stimulus
 This hypertrophy can occur in any region of the
left ventricle but frequently involves the IVS,
which results in an obstruction of flow through
the LVOT

5. Background
 Prevalence of HCM: 0.05-0.2% of the population
 This occurrence is higher than previously thought, suggesting a
large number of affected but undiagnosed people
 Morphologic evidence of disease is found by
echocardiography in approximately 25% of first-degree
relatives of patients with HCM
 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
Maron BJ et al. Circulation. Aug 15 1995;92(4):785-9

6. 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)

7. Genetic Basis of HCM
 Autosomal dominant inheritance
pattern
 >450 mutations in 13 cardiac
sarcomere & myofilament
(myosin heavy chain, actin,
tropomyosin, and titin) related
genes identified
 Genotype specific risks for
mortality and degree of
hypertrophy
 Genetic basis of ventricular
hypertrophy does not directly
correlate with prognostic risk
stratification
Alcalai et al. J Cardiovasc Electrophysiol 2008;19:104-110.

8. Genetics of HCM
Alcalai et al. J Cardiovasc Electrophysiol 2008;19:105.

9. Patterns

10. Pathophysiology of HCM
The pathophysiology of HCM involves 4
interrelated processes:
 Left ventricular outflow obstruction
 Diastolic dysfunction
 Myocardial ischemia
 Mitral regurgitation

11. 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

12. LV Outflow Obstruction in HCM
 Explanations for the SAM of the mitral valve
1. Mitral valve is pulled against the septum by contraction
of the papillary muscles, which occurs because of the
valve's abnormal location and septal hypertrophy
altering the orientation of the papillary muscles
2. Mitral valve is pushed against the septum because of its
abnormal position in the outflow tract
3. Mitral valve is drawn toward the septum because of the
lower pressure that occurs as blood is ejected at high
velocity through a narrowed outflow tract (Venturi
effect)

13. 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

14. Freedom from HCM related deaths
Maron MS et al. NEJM. 2003;348:295.

15. Pathophysiology of HCM
The pathophysiology of HCM involves 4
interrelated processes:
 Left ventricular outflow obstruction
 Diastolic dysfunction
 Myocardial ischemia
 Mitral regurgitation

16. 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
 Increased filling pressures  increased pulmonary venous
pressure

17. Pathophysiology of HCM
The pathophysiology of HCM involves 4
interrelated processes:
 Left ventricular outflow obstruction
 Diastolic dysfunction
 Myocardial ischemia
 Mitral regurgitation

18. 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 and increased myocardial oxygen consumption
 Increased filling pressures
 Resulting in subendocardial ischemia

19. Pathophysiology of HCM
The pathophysiology of HCM involves 4
interrelated processes:
 Left ventricular outflow obstruction
 Diastolic dysfunction
 Myocardial ischemia
 Mitral regurgitation

20. Pathophysiology of HCM
 Mitral Regurgitation
 Results from the systolic anterior motion of the
mitral valve
 Variations in leaflet length (posterior/anterior leaflet
length mismatch) – restrict the ability of the
posterior leaflet to follow the anterior leaflet and to
coapt effectively resulting in MR
 Severity of MR directly proportional to LV outflow
obstruction
 Results in symptoms of dyspnea, orthopnea in HCM
patients

21. Clinical Presentation
 Dyspnea on exertion (90%), orthopnea, PND
 Palpitations (PAC, PVC, sinus pauses, AF, A flutter,
SVT and VT)
 Congestive heart failure (2o to increased filling pressures
and myocardial ischemia)
 Angina (70-80%)
 Syncope (20%), Presyncope (50%)
 Outflow obstruction worsens with increased contractility
during exertional activities resulting in decrease in cardiac
output
 Secondary to arrhythmias

22. Clinical Presentation
 Sudden cardiac death
 HCM is most common cause of SCD in young
people, including athletes
 Can be the first manifestation
 Most common cause is arrhythmias esp. VF either
denovo or AF degenerated into VF 2o accessory
pathway

23. Physical Examination
 Carotid Pulse
 Bifid – rises quickly, then declines in midsystole followed
by a secondary rise in carotid pulsation during late systole
short upstroke & prolonged systolic ejection
 Jugular Venous Pulse
 Prominent a wave – decreased RV compliance
 Apical Impulse
 Double apical impulse - forceful left atrial contraction
against a highly noncompliant left ventricle
 Triple apical impulse results from a late systolic bulge that
occurs when the heart is almost empty and is performing
near-isometric contraction

24. Physical Examination
 Heart Sounds
 S1 usually normal
 S2 usually split but in severe stenosis – paradoxically split
 S3 indicate heart failure
 S4 usually present due to hypertrophy
 Murmur
 Medium-pitch crescendo-decrescendo systolic murmur
along LLSB and apex and radiates to suprasternal notch
 Dynamic maneuvers
 Murmur intensity increases with decreased preload
(i.e. Valsalva, standing, nitrates, diuretics)
 Murmur intensity decreases with increased preload
(i.e. squatting, hand grip)

26. Physical Examination
 Holosystolic murmur at the apex and axilla of
mitral regurgitation is heard in patients with
systolic anterior motion of the mitral valve and
significant LV outflow gradients
 Diastolic decrescendo murmur of aortic
regurgitation is heard in 10% of patients,
although mild aortic regurgitation can be
detected by Doppler echocardiography in 33%
of patients

27. Diagnostic Evaluation
 Electrocardiogram
 Echocardiogram
 Catheterization
 Cardiac MR

28. Electrocardiogram in HCM
LVH with nonspecific ST/T wave abnormalities
Left or right axis deviation, LAE, Conduction abnormalities
Abnormal and prominent Q wave in the anterior precordial and lateral limb leads
A fib with preexitation implies poor prognosis
Findings on Holter monitoring include APC’s VPC’s, sinus pauses, wandering atrial pacemaker,
atrial tachycardia, AF/flutter and nonsustained ventricular tachycardia.

29. Echocardiography in HCM
 2-D echocardiography is diagnostic for HCM
 Abnormal systolic anterior leaflet motion of the mitral valve
 LV hypertrophy
 Left atrial enlargement
 Diastolic dysfunction
 Small ventricular chamber size
 Septal hypertrophy with septal to free wall ratio greater than
1.4:1 (absolute septal wall thickness >15mm)
 SAM of anterior and rarely posterior mitral valve leaflet and
mitral regurgitation
 Decreased mid aortic flow
 Partial systolic closure of the aortic valve in mid systole

35. Cardiac MRI in HCM
 Useful when echocardiography is questionable, particularly with
apical hypertrophy
 Cines loops typically show obstruction and velocity mapping is
useful in the assessment of peak velocities
 SAM of the mitral valve is clearly seen on cardiac MRI
 Improvement in obstruction after septal ablation or
myomectomy can be demonstrated, as can the location and size
of the associated infarction, which are useful for planning repeat
procedures
 Cardiac MRI tagging identifies abnormal patterns of strain, shear,
and torsion in cases of HCM, demonstrating significant
dysfunction in hypertrophic areas of the ventricle

36. Cardiac MRI in HCM
 Gadolinium contrast cardiac MRI - differentiating HCM from
other causes of cardiac hypertrophy and other types of
cardiomyopathy such as, amyloidosis, athletic heart, and Fabry’s
disease
 Late gadolinium enhancement occurring in HCM represents
myocardial fibrosis
 The greater the degree of late gadolinium enhancement, the more likely
that the particular HCM patient has 2 or more risk factors for sudden
death
 More likely the patient has or will develop progression of ventricular
dilation toward heart failure, thereby indicating a poorer prognosis
 Most patients with HCM have no gadolinium enhancement
 Common benign pattern is 2 stripes running along the junction of the
right ventricle insertion into the left ventricle

40. Apical HCM by Echo & CMR
•64 female with CP &
palpitation
•ECG – extensive T wave
inversion
•Echo – akinetic apex &
diastolic dysfunction
•Cine CMR – confirmed
clinical suspicion of apical
HCM

41. High risk HCM
•33 male with HCM and
family history of
sudden death
•Cine CMR shows
HCM with ASH
•After gadolinium
extensive late
enhancement
•Patient was offered an
ICD

42. Cardiac Catheterization
 Diagnostic cardiac catheterization is useful to determine the
degree of LVOT obstruction, cardiac hemodynamics, the
diastolic characteristics of the left ventricle, LV anatomy and
coronary anatomy
 Reserved for situations when invasive modalities of therapy, such
as a pacemaker or surgery, are being considered
 Therapeutic cardiac catheterization interventions, include
transcatheter septal alcohol ablation
 The arterial pressure tracing found on cardiac catheterization
may demonstrate a "spike and dome" configuration

43. Cardiac Catheterization
 Approximately one fourth of patients demonstrate
pulmonary hypertension - usually mild
 Enhancing of LVOT gradient in post PVC
 Results in characteristic change recorded on arterial pressure
tracing - exhibits a pulse pressure that fails to increase as
expected or actually decreases (the so-called Brockenbrough-
Braunwald phenomenon)
 One of the more reliable signs of dynamic obstruction of the
LVOT, intensity of murmur also increased

44. Cardiac Catheterization
• LV gram shows hypertrophied LV
• MR secondary to SAM of mitral
valve
• The LV cavity is often small and
systolic ejection is typically vigorous,
resulting in virtual obliteration of the
ventricular cavity at end systole
• In patients with apical involvement,
the extensive hypertrophy may convey a
spade-like configuration to the left
ventricular angiogram

45. Disease Progression in HCM
ACC Consensus Document. J Am Coll Cardiol. 2003;42(9):1693.

46. 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 J Am Coll Cardiol. 2003;42(9):1693.
young competitive
athletes

47. SCD in Competitive Athletes
Maron B. Atlas of Heart Diseases. 1996

48. Natural History of HCM
 Heart Failure  Atrial Fibrillation
 Only 10-15% progress to  Prevalent in up to 30% of
NYHA III-IV older patients
 Only 3% will become  Dependent on atrial kick –
truly end-stage with CO decreases by 40% if AF
systolic dysfunction present
 Endocarditis  Autonomic Dysfunction
 4-5% of HCM patients  25% of HCM patients
 Usually mitral valve  Associated with poor
affected prognosis

49. Influence of Gender & Race
 Women often remain under diagnosed and are
clinical recognized after they develop more
pronounced symptoms1
 HCM clinically under recognized in African-
Americans
 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.

50. Treatment of HCM
 Medical therapy
 Device therapy
 Surgical septal myomectomy
 Alcohol septal ablation

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

52. 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

53. Dual-Chamber Pacing
 Proposed benefit:
 Pacing the RV apex will decrease the outflow tract gradient
by decreasing projection of basal septum into LVOT
 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

54. Surgical Septal Myectomy
Nishimura RA et al. NEJM. 2004. 350(13):1320.

57. J Am Coll Cardiol 1999;34(1):191-6.

58. Alcohol Septal Ablation

59. Alcohol Septal Ablation
Before After

60. Pre Alcohol Septal Ablation

61. Post Alcohol Septal Ablation

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

63. Overall survival:
93.5% at 2 yrs, 88%
at 4 yrs
Circulation. 2008; 18(2): 131-9.

64. Efficacy of Therapeutic Strategies
Nishimura et al. NEJM. 2004. 350(13):1323.

65. Coil Embolization
 Case report of 20 patients
with 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.

66. Implantable Cardioverter
Defibrillators in HCM
Primary & Secondary Prevention

67.  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
Maron BJ et al. NEJM 2000;342:365-73.

68. 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?

69.  Multicenter registry study
with 506 pts from 1986-2003
 Average age 41 years old
 35% pts - primary
prevention received ICDs
had 1 risk factor
 Primary Outcome:
appropriate ICD
interventions terminating
VF/VT
J Cardiovasc Electrophysiol 2008;19(10).

70.  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
J Am Coll Cardiol. 2008;51(10):1033-9.

71. HCM vs. Athlete’s Heart
Circulation 1995;91.

72. 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

73. Thank You!