Hypertrophic Cardiomyopathy

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Hypertrophic Cardiomyopathy Josef Stehlik,
MD, MPH University of Utah School of
Medicine December 13, 2005
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• Hypertrophic Cardiomyopathy
• pathogenesis
• pathophysiology
• clinical manifestations
• natural history
• treatment

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• Why a Whole Lecture on This Topic?
• traditional example of a genetic cardiac disease
  with characteristic structural myocardial as well
  as hemodynamic abnormalities, and physical exam
  findings
• may be lethal at young age
• the past decade or two brought revolutionary
  advances in our understanding of the pathogenesis
  of the disease
• favorite topic for all sorts of exams

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• History
• - disease was first described in the 1950s
  in England
• the diagnosis was originally made based on
  physical findings and M-mode echocardiography
• clustering of disease in families, autosomal
  dominant inheritance pattern

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• Pathogenesis
• Macroscopic examination of the myocardium
• - the ventricular wall is thickened,
  preferentially
• affecting the interventricular septum
• even when the hypertrophy is diffuse it is
  usually
• asymmetrical, affecting some parts of the
  myocardium
• more than others
• the ventricular cavity is
• typically small
• the mitral valve often has
• elongated leaflets and is
• misshapen

Shirani J et. al, JACC 2000
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• Pathogenesis
• Microscopic examination of the myocardium
• - myocyte hypertrophy and disarray
• myocardial fibrosis
• the myocardial interstitium has
  increased amount
• of fibroblasts, fibrin and collagen
• - smaller than normal intramural coronary
  arteries

Adapted from Shirani J et. al, JACC 2000
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Pathogenesis
Focal distribution of myocyte disarray (to the
left) adjacent to normal parallel alignment of
myocytes Adapted from Varnavaa AM et al.,
Heart 200084476-482
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• Reasons for ventricular hypertrophy
• Myocardial hypertrophy frequently happens in
  conditions causing increased afterload.
• The ventricle is working against high pressure,
  or pumping higher than normal volume.
• Left ventricular hypertrophy
• systemic hypertension
• aortic valve stenosis

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• Reasons for ventricular hypertrophy
• Myocardial hypertrophy frequently happens in
  conditions causing increased afterload.
• Ventricle working against high pressure, or
  pumping higher than normal volume.
• Right ventricular hypertrophy
• pulmonary hypertension
• asthma, COPD
• pulmonary thromboembolic disease
• primary pulmonary hypertension
• pulmonary valve stenosis
• left-to-right shunts (volume overload)

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• Reasons for ventricular hypertrophy
• Myocardial hypertrophy frequently happens in
  conditions causing increased afterload.
• Ventricle working against high pressure, or
  pumping higher than normal volume.
• In these conditions
• the hypertrophy is symmetric
• the ventricle eventually dilates as it cannot
  cope with
• the pressure and/or volume overload

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• Hypertrophic Cardiomyopathy
• absence of high blood pressure or valvular
  stenosis
• left ventricular cavity usually small
• ventricular hypertrophy is asymmetric
• search for a genetic abnormality that might be
  causing
• this disease
• mutation of b-myosin heavy chain, one of the
  proteins of
• the myocardial sarcomere

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Components of the Sarcomere
Adapted from Spirito, P. et al. N Engl J Med
1997336775-785
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Hypertrophic Cardiomyopathy
Adapted from Spirito, P. et al. N Engl J Med
1997336775-785
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• Hypertrophic Cardiomyopathy
• various degree of hypertrophy
• various degree of obstruction
• various age at presentation
• various mortality risk

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Hypertrophic Cardiomyopathy
Spirito, P. et al. N Engl J Med 1997336775-785
gt 140
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• Pathophysiology
• - dynamic left ventricular outflow tract
  obstruction
• mitral regurgitation
• diastolic dysfunction
• myocardial ischemia
• cardiac arrhythmias

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Adapted from Nishimura, N Engl J Med 2004
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• Dynamic left ventricular outflow tract
• obstruction
• the original classic feature
• we now know that it is absent in about half of
  the patients, and the severity of the obstruction
  varies greatly in those who do have it
• The causes of obstruction
• - narrowed left ventricular outflow tract due
  to hypertrophied interventricular septum
• - anterior displacement of the mitral valve
  leaflets during systole (SAM- systolic anterior
  motion of the mitral valve).

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• Dynamic left ventricular outflow tract
• obstruction
• The severity of obstruction increases with
• - any maneuver that increases the force of
  contraction
• - any maneuver that decreases filling of the
  ventricle

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• Dynamic left ventricular outflow tract
• obstruction
• The severity of obstruction increases with
• - any maneuver that increases the force of
  contraction
• ? exercise
• ? positive inotropic agents
• - any maneuver that decreases filling of the
  ventricle
• ? volume depletion
• ? sudden assumption of upright
  posture
• ? tachycardia
• ? Valsalva maneuver

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Nomenclature Idiopathic Hypertrophic Subaortic
Stenosis (IHSS) Hypertrophic Obstructive
Cardiomyopathy (HOCM) Assymetric Septal
Hypertrophy (ASH) Muscular Subaortic Stenosis
(MSS) Hypertrophic Cardiomyopathy (WHO)
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• 2. Mitral Regurgitation
• non-coaptation of mitral leaflets in systole (at
  the time when the mitral valve should be closed)
  due to systolic anterior motion of the anterior
  mitral leaflet (SAM)
• structural abnormalities
• of the mitral apparatus

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• 3. Diastolic Dysfunction
• the myocardium is stiff, non-compliant
• the left ventricular diastolic pressure is
  elevated
• the filling of the ventricle in diastole is
  impaired
• the early diastolic filling phase (when most of
  the filling occurs under normal conditions) is
  prolonged and diminished and most of the filling
  occurs late in ventricular diastole, during the
  atrial systole
• many symptoms are a result of diastolic
  dysfunction

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PAo systolic
Pressure
LVEDP
SV
Volume
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• 4. Myocardial ischemia
• occurs in the absence significant stenosis of
  epicardial coronary arteries
• (i.e. coronary angiogram would be clean)
• The mechanisms of ischemia include
• -    supply/demand mismatch due to increased
  muscle mass
• - increased wall tension due to impaired
  relaxation during diastole
• -   abnormal intramyocardial arteries

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• 5. Arrhythmias
• Paroxysmal supraventricular arrhythmias
• - occur in 30-50, result in shorter
  diastolic filling
• time patients have palpitations,
  shortness of
• breath, may experience syncope
• Atrial fibrillation
• - 15-20, poorly tolerated not only
  is the time
• for diastolic filling decreased, but
  patients loose
• the atrial kick
• Non-sustained ventricular tachycardia
• - occurs during ambulatory monitoring
  in 25 of
• patients

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• 5. Arrhythmias
• Sustained ventricular tachycardia/ventricular
  fibrillation
• this is the lethal event for many
  patients with
• hypertrophic cardiomyopathy
• it is more likely to happen during
  intense physical
• exertion

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Clinical Manifestations The estimates of
prevalence and mortality have varied based on the
source of data. Originally thought to be rare (1
in 2000) and lethal (3-6/year) vs. Unselected
population 1 in 500 (0.2) Overall yearly
mortality below 1
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• Clinical Manifestations
• dyspnea
• fatigue
• decreased functional capacity
• angina pectoris
• dizziness
• syncope
• sudden cardiac death
• no symptoms
• The severity of symptoms does not necessarily
  correlate with the severity of outflow
  obstruction.
•  

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• Physical Exam
• systolic murmur best heard between the apex and
• left sternal border
• - increases in intensity with maneuvers
  that
• decrease preload (Valsalva, squatting to
  
• standing position).
• - does not radiate to the carotid arteries
• sustained apical impulse
• S4
• bisferiens pulse (carotids, femoral arteries)  

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• Diagnostic Tests
• CXR mostly normal
• routine blood-work unremarkable
• EKG usually shows marked LVH
• Echocardiogram is the diagnostic test of
  choice

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• Echocardiogram
• Typical features
• asymmetric hypertrophy of the myocardium
• (septal)
• LVOT obstruction either resting, or provoked
  
• (Valsalva, exercise, amyl-nitrate)
• systolic anterior motion of the anterior mitral
  valve
• leaflet (SAM)
• mitral regurgitation

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Nishimura, R. A. et al. N Engl J Med
20043501320-1327
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Morgensen et al., J Am Coll Cardiol, 2004
442315-2325
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• Heart Catheterization
• (not required for the diagnosis)
• - systolic pressure gradient within the body of
  the
• left ventricle (again, either resting or
  provoked)
• elevated left ventricular end-diastolic
  pressure
• elevated pulmonary capillary wedge pressure (LA
  
• pressure) with a tall a-wave and v- wave (MR)
• spike and dome arterial tracing (pulsus
  bisferines
• equivalent)
• Brockenbrough-Braunwald phenomenon
• increased gradient and decreased aortic
• pressure in the beat following a ventricular
  
• extrasystole

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Adapted from Nishimura, N Engl J Med 2004
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Adapted from Nishimura, N Engl J Med 2004
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• Natural History
• as viewed in the past
• most patients become symptomatic at an early
  age
• in their teens, twenties and thirties, and
  are at a
• significant risk for sudden cardiac death.
• what are we thinking in the age of wide-spread
  
• echocardiography use
• - the disease may not become apparent till
  late,
• 60 years or older
• - varied influence of the specific genetic
  mutation
• - variable phenotypial penetrance
• - variable mortality - less that 1/year
  in
• unselected population, in excess of
  6/year in
• patients with high risk features

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• Natural History
• Risk factors for cardiac death
• -        marked ventricular wall hypertrophy
  (gt30mm)
• -        young age at presentation (lt14 years)
• -        history of syncope
• - history of aborted cardiac arrest
•        family history of sudden cardiac death
• - certain genetic mutations
• sudden cardiac death
• progressive heart failure
• burnt-out hypertrophic cardiomyopathy

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Management -  careful family history focused
on sudden cardiac death -  exercise
testing to determine the presence of
exercise-induced LVOT gradient -
counseling regarding avoidance of strenuous
exercise, avoidance of dehydration -
instructions for prophylaxis against infective
endocarditis - all first-degree
family members should be periodically
screened with an echocardiogram
yearly between ages 12-18, every 5 years
thereafter - consider genetic
testing       
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Treatment No randomized clinical trials of
medical therapy. Three classes of
negative-inotropic agents used, often in
combination.
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• Treatment
• Beta-blockers
• - first-line therapy, clinical improvement gt50
  
• - negative inotropic effect decreases outflow
  gradient
• decreased myocardial demand results in reduced
  
• ischemia
• prolonged diastolic filling time results in
  improved LV
• filling as well as improved coronary perfusion
• - may have an antiarrhythmic effect
• please NOTE that in hypertrophic
  cardiomyopathy, as
• opposed to dilated cardiomyopathy, we are
  using beta-
• blockers for their negative inotropic effect

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• Treatment
• Calcium-channel blockers
• useful in patients who do not tolerate
  beta-blockers,
• or in combination with beta-blockers
• Disopyramide
• may be useful in some patients with a resting
  gradient
• due to its strong negative inotropic effects

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• Non-Pharmacological Therapy
• Surgical septal myectomy
• in patients that remain symptomatic (dyspnea or
  angina
• limiting daily activities) despite maximal
  medical
• therapy and have significant resting or
  provoked
• outflow gradient
• the basal interventricular septum is excised
  which
• opens-up the left ventricular outflow

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Surgical Septal Myectomy
Nishimura, R. A. et al. N Engl J Med
20043501320-1327
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• Non-Pharmacological Therapy
• Surgical septal myectomy
• this procedure has been done since the 1960s
• operative mortality is lt1-2
• most patients will have dramatic improvement in
  their
• gradient as well as symptoms
• complications complete heart block (3), VSD
  (lt1),
• AR (lt1)

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• Non-Pharmacological Therapy
• Alcohol-induced septal ablation
• performed percutaneously in cardiac
  catheterization
• laboratory
• 100 alcohol is injected into a septal
  perforator
• - this results in infarction of the injected
  area

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Alcohol-Induced Septal Ablation
Braunwald, E. N Engl J Med 20023471306-1307
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Alcohol-Induced Septal Ablation
Adapted from Hypertrophic Cardiomyopathy,
Cleveland Clinic Heart Center, clevelandclinic.org
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• Non-Pharmacological Therapy
• Alcohol-induced septal ablation
• the gradient is reduced to lt20mm Hg in 70-80
• symptom relief is somewhat lower than with
  surgical
• myectomy
• complications mortality lt1-2, complete heart
  block
• (10-30), VSD, AR, ventricular fibrillation,
  myocardial
• infarction of a larger territory

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• Non-Pharmacological Therapy
• Dual-chamber pacemaker
• ventricular depolarization and contraction
  starting in the
• RV apex may alter the outflow gradient and
  reduce
• symptoms
• results of randomized trials have been neutral
• used in patients with significant symptoms who
  would
• not tolerate surgical therapy

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• Non-Pharmacological Therapy
• Cardiac transplantation
• reserved for patients who are severely
  symptomatic
• despite maximal pharmacological as well as non-
  
• pharmacological therapy
• no significant residual gradient but severe
  disabling
• diastolic dysfunction
• burnt-out hypertrophic cardiomyopathy now with
  
• systolic dysfunction

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• Prevention of Sudden Cardiac Death
• Implantable cardioverter-defibrillators
• indications are evolving
• considered in patients perceived to be at higher
  risk
• for sudden cardiac death
• additional value of identifying the specific
  genetic
• mutation for risk-stratification is being
  studied and
• is likely to be used clinically in the near
  future

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• CAVEATS
• strenuous exercise, especially isometric,
  increases
• the gradient and the probability of hemodynamic
  
• collaps/ventricular arrhythmias/sudden cardiac
  
• death
• dehydration, as well as marked peripheral
• vasodilation can be life-threatening

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• CAVEATS
• atrial fibrillation is poorly tolerated and
  should be
• addressed promptly in the setting of increased
• symptoms and hypotension. The threshold to
• perform electrical cardioversion should be low
• inotropes (dopamine, dobutamine, milrinone)
• should be avoided in patients with hypertrophic
  
• cardiomyopathy. In a hypotensive patient,
  fluids and
• pure vasoconstrictors (phenylephrine) are to be
  
• used

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Self- assessment What is the most frequent
mutation that causes hypertrophic
cardiomyopathy?
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Self- assessment What are the high-risk
features of hypertrophic cardiomyopathy that
predispose to sudden cardiac death?
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Self- assessment What is the most appropriate
treatment for a 19-year-old patient with
hypertrophic cardiomyopathy diagnosed 2 years ago
who just went through an aborted cardiac arrest?
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Apical Hypertrophic Cardiomyopathy
Adapted from Obeid A et al., Circulation. 2001