eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Cardiology

Cardiomyopathy, Hypertrophic

Author: Charles I Berul, MD, Professor of Pediatrics, George Washington University School of Medicine; Chief, Division of Cardiology, Children's National Medical Center
Coauthor(s): Christina Y Miyake, MD, Senior Fellow in Electrophysiology and Pacing, Children's Hospital Boston
Contributor Information and Disclosures

Updated: Aug 25, 2009

Introduction

Background

The definition and classification of hypertrophic cardiomyopathy (HCM) has varied over the decades, primarily because the phenotypic expression of ventricular hypertrophy can result from a myriad of diseases, especially among children. For purposes of this article, hypertrophic cardiomyopathy is a primary cardiac disorder that results from known or suspected genetic defects in sarcomeric proteins of the cardiac myocyte. The disorder is thought to be inherited in an autosomal dominant fashion with variable penetrance and variable expressivity. 

The hallmark of hypertrophic cardiomyopathy is myocardial hypertrophy that is inappropriate and often asymmetric that occurs in the absence of an obvious inciting hypertrophy stimulus. Although any region of the left ventricle (LV) can be affected, hypertrophy frequently involves the interventricular septum which can result in outflow tract obstruction. Patients typically have preserved systolic function with impaired LV compliance that results in diastolic dysfunction whether or not outflow tract obstruction is present. 

Hypertrophic cardiomyopathy has a complex set of symptoms and potentially devastating consequences for patients and their families. The clinical presentation and course widely varies; some children are completely asymptomatic, whereas others experience sudden cardiac death. In fact, among adolescent children, hypertrophic cardiomyopathy is the leading cause of sudden cardiac death during exertion. Management of pediatric hypertrophic cardiomyopathy patients involves long-term care and close observation (especially during puberty), medical or surgical treatment for symptoms, identification and treatment of those at risk for sudden death, and screening of other at-risk family members.

Pathophysiology

Defects in genes that encode for the sarcomeric proteins (eg, myosin heavy chain, actin, tropomyosin, titin) provide the molecular basis for most cases of familial hypertrophic cardiomyopathy. These defects result in myofibril disarray and fibrosis that progresses over time and contributes to ventricular hypertrophy. The chaotic cellular architecture occurs even in areas of the myocardium that are not hypertrophied and may be arrhythmogenic substrates for ventricular tachycardia or ventricular fibrillation. 

Patients with hypertrophic cardiomyopathy also have abnormal intramural coronary arteries, with thickened intima leading to vessel narrowing and possible inability to supply the oxygen demand of the hypertrophied myocardium. This leads to ischemia, cell death, and scar formation. Although the ventricle hypertrophies, the ventricular cavity itself does not dilate, remaining normal or even small in size. The contractile (systolic) function of the ventricle remains intact; however, impaired relaxation and filling often occurs. This impaired ventricular compliance and diastolic dysfunction leads to elevated end diastolic pressures. 

In late stages of the disease, patients may progress to heart failure with ventricular dilatation. Studies in mice with a positive hypertrophic cardiomyopathy genotype but a negative phenotype suggest that administration of the calcium channel blocker diltiazem prior to the development of ventricular hypertrophy may prevent disease in this animal model.¹  Studies of calcium channel blocker therapy in presymptomatic humans are currently being conducted.   

Since the initial descriptions of hypertrophic cardiomyopathy, the feature that has attracted greatest attention is the dynamic pressure gradient across the LV outflow tract. The pressure gradient appears to be related to several factors, including hypertrophy of the interventricular septum into the outflow tract, possible abnormalities in location of the mitral valve apparatus, and systolic anterior motion of the mitral valve against the hypertrophied septum. The degree of obstruction varies among patients. Some patients have no gradient whereas others develop obstruction only with exertion. The obstruction is also dynamic and depends on the patient's volume status; volume depletion increases the outflow gradient whereas volume repletion increases obstruction. The degree of obstruction does not correlate with risk of sudden cardiac death.

Frequency

United States

Hypertrophic cardiomyopathy is relatively common, with an estimated prevalence of 0.2% (1 case per 500 population) in adults. Recent studies among children suggest a lower incidence for disease expression beginning in childhood, with a rate of 3-5 cases per 1 million children. Morphologic evidence of disease is found using echocardiography in approximately 25% of first-degree relatives of patients with hypertrophic cardiomyopathy, consistent with variable expressivity.

International

The prevalence of hypertrophic cardiomyopathy is thought to be similar throughout the world; however certain variants, for example apical hypertrophy, may be more predominant among Asians.

Mortality/Morbidity

Studies among children with hypertrophic cardiomyopathy suggest that the mortality rate is lower than previously reported, likely due to the fact that disease recognition has improved, allowing diagnosis of patients with less severe disease.² The overall mortality rate is approximately 1% per year. Infants diagnosed with hypertrophic cardiomyopathy before age 1 year appear to have the highest mortality rates. Infants who survive beyond age 1 year or children diagnosed after age 1 year have an overall mortality rate of 1% per year. Among patients with hypertrophic cardiomyopathy, a subgroup of children appear to have a higher risk of sudden cardiac death, reportedly as high as 4-6%. With an overall mortality rate of 1% per year, this suggests that children not in this subgroup have very low mortality rates, with a possible normal life expectancy.

Race

Hypertrophic cardiomyopathy does not have a racial or ethnic predisposition and has been reported in patients of all races.

Sex

The genetic inheritance pattern is autosomal dominant without gender predilection. Although no sex difference is noted among infants diagnosed with hypertrophic cardiomyopathy before age 1 year, among children diagnosed after age 1 year, hypertrophic cardiomyopathy is more commonly identified in males than in females. Modifying genetic, hormonal, and environmental factors may lead to higher likelihood of identification, more apparent symptoms, or higher degrees of LV outflow obstruction in males, allowing for more prominent physical examination findings.

Age

Hypertrophic cardiomyopathy may occur at any age from the newborn to the elderly. Overall, its most common presentation is in the third decade of life. Among children younger than 18 years diagnosed with hypertrophic cardiomyopathy, the median age at diagnosis is 7 years and one third are diagnosed before age 1 year.

Clinical

History

Patients with hypertrophic cardiomyopathy (HCM) may be asymptomatic. Symptoms can include sudden cardiac death, dyspnea, syncope, presyncope, angina, palpitations, orthopnea, paroxysmal nocturnal dyspnea, congestive heart failure, and dizziness.

• Sudden cardiac death
  • This is the most devastating presenting manifestation and, unfortunately, may be the first clinical manifestation of the disease, even among asymptomatic patients.
  • Sudden cardiac death has the highest incidence in preadolescent and adolescent children and is typically associated with sports or vigorous exertion.
  • The arrhythmia that causes sudden death is ventricular fibrillation in more than 80% of individuals with hypertrophic cardiomyopathy. For more information, see Ventricular Fibrillation.
  • Many patients with hypertrophic cardiomyopathy develop ventricular fibrillation following atrial fibrillation, atrial flutter, supraventricular tachycardia associated with Wolff-Parkinson-White syndrome, ventricular tachycardia, and/or low–cardiac-output hemodynamic collapse.
  • Early diagnosis is of prime importance if death is to be prevented by prescription of an appropriate level of safe activity, medications, surgery, and/or an implantable cardioverter defibrillator. Because this is an autosomal dominantly inherited disease, screening of first-degree relatives with physical examination, ECG, and echocardiography is useful to identify additional family members with hypertrophic cardiomyopathy before onset of significant symptoms or sudden death.
• Dyspnea
  • Dyspnea is the most common presenting symptom and occurs in as many as 90% of symptomatic patients.
  • Dyspnea is largely a consequence of elevated left ventricular (LV) diastolic filling pressures and transmission of those elevated pressures back into the pulmonary circulation. The elevated LV filling pressures principally result from impaired diastolic compliance as a result of marked hypertrophy of the ventricle.
• Syncope
  • Syncope is a common symptom of hypertrophic cardiomyopathy, resulting from inadequate cardiac output on exertion or from cardiac arrhythmia, either tachycardia or bradycardia. Syncope is more common in children and young adults with small LV chamber size and evidence of ventricular tachycardia on ambulatory monitoring. Some patients have abnormalities in sinus node function, leading to sick sinus syndrome.
  • Syncope identifies children with hypertrophic cardiomyopathy at significantly increased risk of sudden death and warrants an urgent evaluation and aggressive treatment.
• Presyncope
  • Presyncope refers to "graying out" spells that occur in the erect posture and can be relieved by the individual immediately lying down. These symptoms are exacerbated by vagal stimulation.
  • Presyncope may also occur with nonsustained atrial or ventricular tachyarrhythmias.
  • Presyncope occurs quite commonly in patients with hypertrophic cardiomyopathy and identifies a subgroup of patients who may be at increased risk for sudden death. Like syncope, presyncopal episodes warrant a directed evaluation to rule-out malignant arrhythmias. However, dizziness and presyncope are common symptoms in teenagers and may simply represent vasodepressor reaction or a common faint. A thorough investigation is warranted to rule out potential malignant etiology of presyncopal symptoms.
• Angina
  • Typical symptoms of angina are seen in children with hypertrophic cardiomyopathy and occur in the absence of detectable coronary atherosclerosis.
  • Impaired diastolic relaxation and markedly increased myocardial oxygen consumption due to ventricular hypertrophy result in subendocardial ischemia, particularly during exertion.
• Palpitations
  • Palpitations are common in hypertrophic cardiomyopathy.
  • Palpitations are usually due to arrhythmia, such as premature atrial and ventricular beats, sinus pauses, intermittent atrioventricular block, atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia. Nonsustained ventricular tachycardia is another marker for higher risk of sudden death.
• Orthopnea and paroxysmal nocturnal dyspnea
  • Although uncommon in children, these early signs of congestive heart failure are observed in individuals with severe cases of hypertrophic cardiomyopathy.
  • These symptoms occur when impaired diastolic function and elevated LV filling pressure result in pulmonary venous congestion.
• Congestive heart failure
  • Although relatively uncommon in children, congestive heart failure is present in 10% of children at initial presentation, most commonly in infants younger than 1 year. Congestive heart failure is observed in individuals with severe cases of hypertrophic cardiomyopathy.
  • Congestive heart failure may occur as a result of a combination of impaired diastolic function and subendocardial ischemia.
  • Systolic function in children with hypertrophic cardiomyopathy is almost always well preserved, at least until the late stages of the disease.
  • Patients with congestive heart failure have a high likelihood of recurrent heart failure due to both mitral regurgitation and profound diastolic dysfunction.
• Dizziness
  • Dizziness is common in children with hypertrophic cardiomyopathy who have elevated pressure gradients across the LV outflow tract. Worsened by exertion, dizziness may be exacerbated by hypovolemia following high levels of exertion or increased insensible fluid loss (eg, during or after exposure to extreme heat).
  • Dizziness may be caused by medications or maneuvers (eg, rapid standing, Valsalva during defecation) that decrease preload and afterload and increase the pressure gradient across the LV outflow tract.
  • Dizziness also may be caused by arrhythmia-related hypotension and decreased cerebral perfusion. Nonsustained arrhythmias often cause symptoms of dizziness and presyncope, whereas sustained arrhythmias more likely lead to syncope, collapse, and sudden cardiac death.

Physical

Most children with hypertrophic cardiomyopathy do not have outflow tract obstruction and, therefore, may have completely normal physical examination findings.

• Heart sounds
  • The first heart sound is normal in patients with hypertrophic cardiomyopathy.
  • The second heart sound is usually split; however, in some patients with hypertrophic cardiomyopathy and extreme outflow gradients, the second heart sound is split paradoxically.
  • A third heart sound or gallop is common in children with hypertrophic cardiomyopathy but does not have the same ominous significance as in patients with valvular aortic stenosis or in adults.
  • A fourth heart sound is frequently heard and is due to atrial systole against a highly noncompliant LV.
• Cardiac impulse
  • Apical precordial impulse is frequently laterally displaced and is usually abnormally forceful and enlarged.
  • Double apical impulse, resulting from a forceful left atrial contraction against a highly noncompliant LV, occurs quite commonly in children with hypertrophic cardiomyopathy.
  • Triple apical impulse, resulting from a late systolic bulge that occurs when the heart is almost empty and is performing near-isometric contraction, is a highly characteristic finding; however, triple apical impulse is less frequent than double apical impulse.
• Murmur
  • The outflow murmur typically heard is a systolic ejection, crescendo-decrescendo murmur that is heard best between the apex and left sternal border; it radiates to the suprasternal notch but not to the carotid arteries or neck. The murmur directly varies with the subaortic gradient across the LV outflow tract.
  • Because obstruction is dynamic and directly related to volume status, LV outflow tract obstruction and murmur diminishes with any increase in preload (eg, Valsalva maneuver, Mueller maneuver, squatting) or increase in afterload (eg, handgrip). The murmur and the gradient increase with any decrease in preload (eg, that elicited by nitrate medications, diuretics, standing) or with any decrease in afterload (eg, that elicited by vasodilators).
  • A holosystolic murmur of mitral regurgitation is heard at the apex and left axilla in patients with systolic anterior motion of the mitral valve and significant LV outflow gradients.
  • A diastolic decrescendo murmur of aortic regurgitation is heard in 10% of children with hypertrophic cardiomyopathy, although mild aortic regurgitation can be detected by Doppler echocardiography in 33% of patients with the disorder.
• Other findings
  • Jugular venous pulse reveals a prominent a wave due to diminished right ventricular compliance secondary to massive hypertrophy of the ventricular septum.
  • Double carotid arterial pulse may occur. The carotid pulse rises quickly because of increased velocity of blood through the LV outflow tract into the aorta. The carotid pulse then declines in mid systole as the gradient develops, followed by a secondary rise in carotid pulsation during systole.

Causes

• In 1989, Jarcho et al reported the genetic basis for hypertrophic cardiomyopathy and the existence of a disease gene located on the long arm of chromosome 14, subsequently found to encode for the beta cardiac myosin heavy chain.³  At least 15 different genes on at least 6 chromosomes are associated with hypertrophic cardiomyopathy, and more than 400 different, predominantly missense, mutations have been discovered. These genes encode for sarcomeric proteins such as myosin heavy chain, actin, titin, myosin-binding protein, tropomyosin, and others. 
• Familial hypertrophic cardiomyopathy occurs as an autosomal dominant inherited disease in approximately 50% of individuals with the disorder. The variable penetrance and expression of disease among family members carrying the same genetic defect is explained by certain individual modifier genes that affect presentation. Some, if not all, of the sporadic forms of the disease may be due to spontaneous mutations. Genetic testing is now commercially available. Among patients who are clinically diagnosed and undergo genetic testing, 50-80% have a positive test result. This suggests that novel hypertrophic cardiomyopathy mutations are yet to be discovered.
• In children, the phenotypic expression of ventricular hypertrophy can occur secondary to other pediatric diseases that should be differentiated from hypertrophic cardiomyopathy. These include inborn errors of metabolism (ie, Pompe disease, Barth syndrome), malformation syndromes (ie, Noonan syndrome), and neuromuscular disorders (ie, Friedrich ataxia, Duchenne muscular dystrophy).
• Two specific glycogen-storage disorders can also lead to familial hypertrophic cardiomyopathy and involve defects in protein kinase gamma-2 (PRKAG2), which result in a familial glycogen-accumulation cardiomyopathy associated with Wolff-Parkinson-White syndrome, and defects in lysosomal-associated membrane protein 2 (LAMP2), which results in Danon disease. Ventricular hypertrophy secondary to athletic conditioning, the so-called "Athlete's heart," should also be on the differential diagnosis.

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