Pediatric Hypertrophic Cardiomyopathy

The definition and classification of hypertrophic cardiomyopathy (HCM) have varied over the decades, primarily because the phenotypic expression of ventricular hypertrophy can result from a myriad of diseases, especially among children. In the past, this disease entity has been called idiopathic hypertrophic subaortic stenosis (IHSS), asymmetric septal hypertrophy (ASH), dynamic muscular subaortic stenosis, diffuse muscular subaortic stenosis, hypertrophic subaortic stenosis, Teare disease, Brock disease, and hypertrophic obstructive cardiomyopathy (HOCM).

At present, most authorities agree to call this disease entity "hypertrophic cardiomyopathy," which is then subdivided into obstructive and nonobstructive types, depending upon the presence of left ventricular outflow tract obstruction. For the purposes of this article, HCM 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 HCM is myocardial hypertrophy that is inappropriate and often asymmetric and that occurs in the absence of an obvious inciting hypertrophic stimulus. Although any region of the left ventricle can be affected, hypertrophy frequently involves the interventricular septum, which can result in outflow tract obstruction. Patients typically have preserved systolic function with impaired left ventricular compliance that results in diastolic dysfunction, whether or not outflow tract obstruction is present.

HCM has a complex set of symptoms and potentially devastating consequences for patients and their families. The clinical presentation and course vary widely; some children are completely asymptomatic, whereas others experience sudden cardiac death (see Presentation.) In fact, among adolescent children, HCM is the leading cause of sudden cardiac death during exertion.

HCM is a chronic illness that imposes lifestyle restrictions. Management of pediatric HCM 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.[1, 2] (See Treatment.)

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 (HCM). These defects result in myofibril disarray and fibrosis that progress over time and contribute 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 HCM 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; ischemia, cell death, and scar formation result.

Although the ventricle becomes hypertrophic, 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 occur. The impaired ventricular compliance and diastolic dysfunction lead 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 HCM genotype but a negative phenotype suggest that administration of the calcium channel blocker diltiazem before the development of ventricular hypertrophy may prevent disease in this animal model.[3] Studies of calcium channel blocker therapy in presymptomatic humans are currently being conducted.

Since the initial descriptions of HCM, the feature that has attracted greatest attention is the dynamic pressure gradient across the left ventricular 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 decreases obstruction. The degree of obstruction does not correlate with the risk of sudden cardiac death.

In 1989, Jarcho et al reported the genetic basis for hypertrophic cardiomyopathy (HCM) and the existence of a disease gene located on the long arm of chromosome 14, which was subsequently found to encode for the beta cardiac myosin heavy chain.[4] At least 15 different genes on at least 6 chromosomes are associated with HCM, 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 (see the image below). An estimated 60% of HCM cases carry mutations in 1 of 8 sarcomere protein genes, primarily variants of nonsense MYBPC3 and missense MYH7.[5]

Pediatric Hypertrophic Cardiomyopathy. Sarcomeric genes involved in hypertrophic cardiomyopathy (adapted from Priori 1999).

Familial HCM 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 for HCM is commercially available. Among patients who are clinically diagnosed and undergo genetic testing, 50-80% have a positive test result. This suggests that novel HCM 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 HCM. These include inborn errors of metabolism (eg, Pompe disease and Barth syndrome), malformation syndromes (eg, Noonan syndrome), and neuromuscular disorders (eg, Friedrich ataxia, Duchenne muscular dystrophy).[6]

Two specific glycogen-storage disorders can also lead to familial HCM 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 result in Danon disease. Ventricular hypertrophy secondary to athletic conditioning—the so-called athlete’s heart—should also be considered in the differential diagnosis.

United States statistics

Hypertrophic cardiomyopathy (HCM) is relatively common in the United States, with an estimated prevalence of 0.2% (1 case per 500 population[7] ) in adults. 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 on echocardiography in approximately 25% of first-degree relatives of patients with HCM, a finding consistent with variable expressivity.

International statistics

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

Race-, age-, and sex-related demographics

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

This condition 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 HCM, the median age at diagnosis is 7 years; one third are diagnosed before age 1 year.

The genetic inheritance pattern is autosomal dominant, without any sex predilection. Although no sex difference is noted among infants diagnosed with HCM before age 1 year, among children diagnosed after age 1 year, HCM 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 left ventricular outflow obstruction in males, thus resulting in more prominent physical examination findings.

Studies among children with hypertrophic cardiomyopathy (HCM) suggest that mortality is lower than previously reported, probably because disease recognition has improved, allowing diagnosis of patients with less severe disease.[8] The overall mortality is approximately 1% per year. Infants diagnosed with HCM before age 1 year appear to have the highest mortality rates; a 5 year survival rate of ~70% was found in the Pediatric Cardiomyopathy Registry.[8] Infants who survive beyond age 1 year or children diagnosed after age 1 year have an overall mortality of 1% per year.[9]

Sudden death is the most common cause of death in children with HCM. A subgroup of children appear to have a higher risk of sudden cardiac death, reportedly as high as 4-6%. Given the overall mortality of 1% per year, it appears that children not in this higher-risk subgroup have very low mortalities, with a possible normal life expectancy. A recent study demonstrated that 25% of HCM patients, detected by school screening, exhibited life-threatening events during 15-year follow-up.[10]

Complications

Complications of HCM may include the following:

• Congestive heart failure

• Arrhythmia

• Infective mitral endocarditis

• Atrial fibrillation with mural thrombosis formation

• Sudden death

Individuals with hypertrophic cardiomyopathy (HCM) should be advised to avoid strenuous activity, anaerobic exercise (eg, weightlifting), and high-level competitive sports. Activity restrictions should be imposed.[7]

Family members of persons with HCM should learn cardiopulmonary resuscitation (CPR). Both the patient and the family members should be referred for psychosocial counseling.

Patients with hypertrophic cardiomyopathy (HCM) may be asymptomatic. When present, symptoms may include dyspnea, syncope, presyncope, angina, palpitations, orthopnea, paroxysmal nocturnal dyspnea, congestive heart failure, and dizziness. Some children may present with sudden cardiac death as their first manifestation.

Sudden cardiac death

Sudden cardiac death is the most devastating presenting manifestation and, unfortunately, may be the first clinical manifestation of the disease, even among asymptomatic patients.[7] It has the highest incidence in preadolescent and adolescent children and is typically associated with sports or vigorous exertion. Indeed, HCM has been identified as the most common cause of sudden death in the athlete following physical activity.[11, 12, 13]

In more than 80% of individuals with HCM, the arrhythmia that causes sudden death is ventricular fibrillation. Many patients with HCM develop ventricular fibrillation after atrial fibrillation, atrial flutter, supraventricular tachycardia associated with Wolff-Parkinson-White syndrome, ventricular tachycardia, 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, or an implantable cardioverter defibrillator.[14] Because this is an autosomal dominantly inherited disease, screening of first-degree relatives with physical examination, electrocardiography (ECG), and echocardiography is useful to identify additional family members with HCM before the onset of significant symptoms or sudden death.

Dyspnea

Dyspnea is the most common presenting symptom, occurring in as many as 90% of symptomatic patients. It is largely a consequence of elevated left ventricular diastolic filling pressures and transmission of those elevated pressures back into the pulmonary circulation. The elevated left ventricular filling pressures principally result from impaired diastolic compliance as a result of marked hypertrophy of the ventricle.

Syncope

Syncope is a common symptom of HCM, 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 left ventricular 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 HCM who are 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 commonly in patients with HCM and identifies a subgroup of patients who may be at increased risk for sudden death. Like syncope, presyncope warrants 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 HCM 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 HCM. They are usually due to arrhythmia, such as premature atrial and ventricular beats, sinus pauses, intermittent atrioventricular (AV) block, atrial fibrillation, atrial flutter, supraventricular tachycardia, or ventricular tachycardia. Nonsustained ventricular tachycardia is another marker for a higher risk of sudden death.

Orthopnea and paroxysmal nocturnal dyspnea

Although orthopnea and paroxysmal nocturnal dyspnea are uncommon in children, these early signs of congestive heart failure are observed in individuals with severe cases of HCM. They occur when impaired diastolic function and elevated left ventricular 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. It is observed in individuals with severe cases of HCM. Congestive heart failure may occur as a result of a combination of impaired diastolic function and subendocardial ischemia. Systolic function in children with HCM 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, as a consequence of both mitral regurgitation and profound diastolic dysfunction.

Dizziness

Dizziness is common in children with HCM who have elevated pressure gradients across the left ventricular outflow tract. Worsened by exertion, dizziness may be exacerbated by hypovolemia after 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 or a Valsalva maneuver during defecation) that decrease preload and afterload and increase the pressure gradient across the left ventricular 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.

Most children with hypertrophic cardiomyopathy (HCM) do not have outflow tract obstruction and, therefore, may have completely normal physical examination findings. Abnormalities related to heart sounds, cardiac impulses, or murmurs may, however, be noted.

Heart sounds

The first heart sound (S1) is normal in patients with HCM. The second heart sound (S2) is usually split; however, in some patients with HCM and extreme outflow gradients, S2 is split paradoxically. A third heart sound (S3) or gallop is common in children with HCM but does not have the same ominous significance as in patients with valvular aortic stenosis or in adults. A fourth heart sound (S4) is frequently heard and is due to the impact of atrial systole against a highly noncompliant left ventricle.

Cardiac impulse

The apical precordial impulse is frequently displaced laterally and is usually abnormally forceful and increased. A double apical impulse, resulting from a forceful left atrial contraction against a highly noncompliant left ventricle, occurs commonly in children with HCM. A triple apical impulse, resulting from a late systolic bulge that occurs when the heart is almost empty and is performing near-isometric contraction, is highly characteristic but is less frequent than a 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 intensity of the murmur directly varies with the subaortic gradient across the left ventricular outflow tract.

Because obstruction is dynamic and directly related to volume status, left ventricular outflow tract obstruction and murmur diminish with any increase in preload (eg, that elicited by a Valsalva maneuver, a Mueller maneuver, or squatting) or increase in afterload (eg, that elicited by a handgrip). The murmur and the gradient increase with any decrease in preload (eg, that elicited by nitrate medications, diuretics, or 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 left ventricular outflow gradients.

A diastolic decrescendo murmur of aortic regurgitation is heard in 10% of children with HCM, although mild aortic regurgitation can be detected by Doppler echocardiography in 33% of patients with the disorder.

Other findings

The jugular venous pulse reveals a prominent ‘a’ wave due to diminished right ventricular compliance secondary to massive hypertrophy of the ventricular septum.

A double carotid arterial pulse may occur. The carotid pulse rises quickly because of increased velocity of blood through the left ventricular 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.

Children with a clinical diagnosis of ventricular hypertrophy should undergo appropriate laboratory evaluation to rule out other etiologies of hypertrophic cardiomyopathy (HCM).

No specific laboratory testing is required in patients diagnosed with HCM; however, genetic testing should be considered and is available for 9 sarcomeric genes, including MYH7, MYBPC3, TNNT2, TNNI3, TNNC1, TPM1, ACTC, MYL2, and MYL3 and one regulator CAV3. Approximately 50-80% of patients have positive results. If the genotype of the proband is determined, mutation testing is available and should be used to identify additional family members with HCM. Genetic testing is also available for the storage disorders with ventricular hypertrophy.[17]

Common electrocardiographic (ECG) findings in individuals with hypertrophic cardiomyopathy (HCM) include ST-T wave abnormalities and left ventricular hypertrophy (see the image below). Other findings include axis deviation (right or left), conduction abnormalities (eg, PR prolongation or bundle branch block), sinus bradycardia with ectopic atrial rhythm, and atrial enlargement.[18] In a genetic syndrome due to mutations in AMP-activated PRKAG2, HCM has been associated with inherited Wolff-Parkinson-White syndrome and conduction defects.

Pediatric Hypertrophic Cardiomyopathy. ECG of a 16-year-old with hypertrophic cardiomyopathy (HCM), demonstrating left ventricular hypertrophy pattern and "pseudo-preexcitation."

Uncommon findings include an abnormal and prominent Q wave in the anterior precordial and lateral limb leads, a short PR interval with QRS suggestive of preexcitation, atrial fibrillation (a poor prognostic sign), and P-wave abnormalities (including left atrial enlargement).

Holter monitoring

Findings on Holter monitoring commonly include atrial and ventricular ectopy, sinus pauses, wandering atrial pacemaker, intermittent or variable atrioventricular (AV) block, and nonsustained atrial or ventricular arrhythmias.

Two-dimensional echocardiography is the main diagnostic tool for evaluating patients with suspected hypertrophic cardiomyopathy (HCM) (see the image below). The septum in individuals with HCM is relatively thicker than the posterior wall. The left ventricular diameter is at the lower limit of normal or smaller than normal. The left atrium may be enlarged as a result of left ventricular noncompliance.

Pediatric Hypertrophic Cardiomyopathy. Hypertrophic cardiomyopathy. Image courtesy of Michael E. Zevitz, MD

Doppler echocardiography can be used to reveal an elevated flow velocity across the left ventricular outflow tract. Systolic anterior motion (SAM) of the anterior mitral valve is one of the hallmarks of obstructive HCM. The following explanations for SAM of the mitral valve have been offered:

• The mitral valve is pushed against the septum because of its abnormal position in the outflow tract (ie, drag effect)

• The 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 (ie, Venturi effect)

Systolic function in individuals with HCM is typically normal or even hyperdynamic. Diastolic dysfunction with decreased left ventricular compliance is common and is independent of the presence or absence of outflow tract obstruction.

Abnormalities in mitral inflow patterns or tissue Doppler tracings may reveal a mitral valve E/A ratio (ratio of early transmitral flow/late flow with atrial contraction) below 1 (usually < 0.8) or an abnormal tissue Doppler E wave lower than 10 cm/sec. Interestingly, patients who have positive genotype findings but negative phenotype findings appear to demonstrate abnormal tissue Doppler patterns, particularly abnormally low E wave velocities.

Exercise stress echocardiography

Exercise stress echocardiography has been found to be a good prognostic tool in adults with HCM. Children with left ventricular outflow tract gradients higher than 30 mmHg at rest and with exercise were found to have a 5 times higher risk for development of symptoms or adverse clinical outcomes during follow-up.[19] Consequently, exercise stress echocardiography may be useful for prognostication.

Chest radiography

Chest radiography findings vary in patients with hypertrophic cardiomyopathy (HCM). The cardiac silhouette may range from normal to being markedly increased. Left atrial enlargement may be observed, especially if significant mitral regurgitation is present.

Cardiac magnetic resonance imaging (CMRI)

CMRI is helpful in identifying patients with fibrosis and serves as an adjunct evaluation of anatomy and outflow tract obstruction in patients with poor echocardiographic windows.

CMRI can be particularly useful in evaluating left ventricular thickening to identify the cause, diagnosis, and/or prognostic factors; determine the left ventricular geometry; and decision making regarding serial follow-up and therapeutic options.[20]

Areas of delayed enhancement on MRI correlate with areas of fibrosis and can be found in a subset of patients with HCM. These patients may be at increased risk for arrhythmias, including nonsustained ventricular tachycardia. Findings of fibrosis may have implications for risk stratification for sudden cardiac death in this group of patients.

In patients with hypertrophic cardiomyopathy (HCM), a diagnostic hemodynamic catheterization may be useful to determine the degree of outflow obstruction, assess the diastolic characteristics of the left ventricle, and define ventricular as well as coronary arterial anatomy.

Transcatheter septal alcohol ablation to relieve the left ventricular outflow obstruction has been performed as an alternative to surgical myectomy in adults, but it is not commonly performed in children (see Treatment).

A diagnostic electrophysiologic study may reveal conduction abnormalities, sinus node dysfunction, and the potential for inducible arrhythmias using programmed electrical stimulation. However, the prognostic correlation of inducible arrhythmias with spontaneous clinical arrhythmias or sudden death is not entirely clear.

Several studies have demonstrated a relationship between electrophysiologic study results and risk stratification, although others have not been able to demonstrate a direct relationship. Electrophysiologic studies may also be used to identify a substrate that is amenable to catheter ablation, such as atrial flutter or ventricular tachycardia.

Myocardial hypertrophy and gross disorganization of the muscle bundles result in a characteristic whorled pattern; cell-to-cell disarray and disorganization of the myofibrillar architecture within a given cell occur in almost all individuals with hypertrophic cardiomyopathy (HCM). Fibrosis is prominent and may be extensive enough to produce grossly visible scars.

Abnormal intramural coronary arteries, with reduced lumen sizes and thickening of the vessel wall, are common, occurring in more than 80% of patients. This abnormality occurs most frequently in the ventricular septum and accompanies extensive fibrosis in the affected walls of the heart.

Medical management of hypertrophic cardiomyopathy (HCM) in children should focus on the following:

• Ruling out secondary causes

• Following for progression of disease and identifying those with obstruction

• Controlling symptoms and restricting activity (with avoidance of volume depletion)

• Identifying those at risk for sudden cardiac death

• Screening family members

Evaluation of the patient with HCM can usually be conducted on an outpatient basis. Inpatient studies and treatment may be necessary as well. Admit patients with HCM for testing, electrophysiology procedures, and/or surgical intervention. 

Consultations may be indicated with the following specialists:

• Cardiologist

• Cardiothoracic surgeon

• Cardiac electrophysiologist

• Geneticist

Ruling out secondary causes

Evaluation, especially in children, should be performed to rule out the following secondary causes of cardiac hypertrophy:

• Athlete’s heart: Long-term athletic conditioning can result in ventricular hypertrophy but typically causes a concentric hypertrophy with an associated increase in left ventricular diastolic dimension, unlike primary HCM. When this differentiation is difficult, the following criteria favor HCM: unusual patterns of left ventricular hypertrophy, left ventricular cavity size smaller than 45 mm (in adults and older adolescents), left atrial enlargement, bizarre electrocardiographic (ECG) patterns, abnormal left ventricular filling, family history of HCM, and decreased left ventricular wall thickness after deconditioning.

• Inborn errors of metabolism

• Mitochondrial disorders

• Neuromuscular disorders

Following for disease progression

Children with HCM are at particular risk for development or progression of outflow tract obstruction and should be followed yearly with serial echocardiography during puberty.

Controlling symptoms and restricting activity

Medical and surgical therapy are used to reduce ventricular contractility or increase ventricular volume, to increase ventricular compliance and outflow tract dimensions, and, in obstructive HCM, to reduce the pressure gradient across the left ventricular outflow tract.

Patients with symptoms or evidence of outflow tract obstruction are generally started on calcium channel blocker or beta-blocker therapy. Disopyramide has been used in adults, but has potential proarrhythmic effects and is not typically used in children. Carefully monitor medication dose and adverse effects.

Patients with severe outflow tract obstruction may be candidates for surgical myectomy. Alternative therapies, such as alcohol septal ablation, coil occlusion of septal perforators supplying the hypertrophied ventricular septum,[21] or pacemaker insertion, are less commonly performed in children.

Patients should be advised not to participate in competitive sports or strenuous activity.

Asymptomatic patients

The 2011 joint American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) recommendations for asymptomatic patients with HCM include the following[16] :

• Treat any comorbid conditions that may contribute to cardiovascular disease (eg, hypertension, hyperlipidemia, obesity, diabetes) (class I; level of evidence [LOE]: C)
• Low-intensity aerobic exercise is reasonable as part of a healthy lifestyle (class IIa; LOE: C)
• No well-established evidence exists for the use of beta blockade and calcium channel blockers in effectively affecting clinical outcomes in this population (class IIb; LOE: C)
• Avoid performing septal reduction therapy for asymptomatic children and adults in the presence of normal effort tolerance regardless of the obstruction severity (class III; LOE: C)
• Avoid pure vasodilators and high-dose diuretics, regardless of symptom status, in patients with resting or provocable outflow tract obstruction (class III; LOE: C)

Identifying risk factors for sudden death

Reduction of the risk of sudden death is paramount to any therapy for HCM. Although no strict guidelines are available, suggested risk factors for sudden cardiac death include a history of previous arrest, unexplained syncope, ventricular arrhythmias, a family history of sudden cardiac death, abnormal blood pressure response during exercise stress testing, and a markedly enlarged septum (>3 cm in adult studies). The degree of left ventricular outflow obstruction has not been shown to be a risk factor for sudden death.

Screening family members

All first-degree family members of the patient must be informed and screened for HCM. This entails a detailed history, physical examination, electrocardiography (ECG), and echocardiography. If a genetic defect is known, asymptomatic family members should be gene tested.

Subacute bacterial endocarditis prophylaxis is not required. Beta-blockers and calcium channel blockers (eg, verapamil or diltiazem) are used to treat children with hypertrophic cardiomyopathy (HCM). In individuals with significant tachyarrhythmias, amiodarone and other class III-type antiarrhythmic agents have also been used.

Avoid administration of the following agents:

• Inotropic drugs
• Nitrates and sympathomimetic amines, except in patients with HCM and concomitant coronary artery disease
• Digitalis, because glycosides are contraindicated, except in patients with uncontrolled atrial fibrillation
• Diuretics, because of their effect on left ventricular volume

2011 ACCF/AHA guidelines

The 2011 joint American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) recommendations for symptomatic patients with HCM are outlined below.[16]

Class I recommendations (all level of evidence [LOE]: B)[16]

Use beta-blockers to manage angina or dyspnea in adults with HCM (obstructive or nonobstructive). Take extra care when using these agents in the presence of sinus bradycardia or severe conduction disease.

For symptomatic HCM (angina or dyspnea) refractory to low doses of beta-blockers: Titrate the dose to a resting heart rate below 60-65 bpm (up to a maximum dose based on the recommended dosing of these agents).

For symptomatic (angina or dyspnea) HCM (obstructive or nonobstructive) refractory to beta-blockers or in patients intolerant of, or with contraindications to, beta-blockers: Initiate low-verapamil therapy and titrate up to 480 mg/day. Closely monitor patients with high gradients, advanced heart failure, or sinus bradycardia who are taking verapamil.

For acute hypotension in obstructive HCM that is refractory to fluid administration: Intravenous (IV) phenylephrine or another pure vasoconstrictor is recommended.

Class IIa recommendations[16]

For symptomatic, obstructive HCM (angina or dyspnea) refractory to beta-blockers or verapamil alone: Disopyramide in combination with a beta-blocker or verapamil is reasonable (LOE: B).

For persistent dyspnea in nonobstructive HCM refractory to beta-blockers, verapamil, or the two combined: The addition of oral diuretics is reasonable (LOE: C).

Class IIb recommendations (all LOE: C)[16]

For symptomatic (angina or dyspnea) pediatric HCM patients on beta-blockers: Monitor for adverse effects (eg, depression, fatigue, impaired academic performance).

For persistent congestive symptoms in obstructive HCM refractory to beta-blockers, verapamil, or the two combined: The addition of oral diuretics is reasonable.

In the presence of resting or provocable left ventricular outflow tract obstruction but preserved systolic function, proceed with caution if considering the use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). The efficacy of these agents is not well established for symptomatic (angina or dyspnea) HCM in this setting.

For HCM patients intolerant of, or with contraindications to, verapamil, consider diltiazem.

Class III recommendations: Harm

For symptomatic (angina or dyspnea) HCM in the setting of resting or provocable left ventricular outflow tract obstruction: Potentially harmful medications include nifedipine or other dihydropyridine calcium channel blockers (LOE: C).

For obstructive HCM in the setting of systemic hypotension or severe dyspnea at rest: Verapamil is potentially harmful (LOE: C).

For dyspnea in HCM the absence of atrial fibrillation: Digitalis is potentially harmful (LOE: B).

For symptomatic (angina or dyspnea) HCM in the setting of atrial fibrillation: Monotherapy with disopyramide without beta-blockers or verapamil is potentially harmful (potential enhancement of AV conduction and increased ventricular rate during episodes of atrial fibrillation) (LOE: B).

In the setting of obstructive HCM and acute hypotension: Potentially harmful medications include dopamine, dobutamine, norepinephrine, and other IV inotropic agents (LOE: B).

The 2014 European Society of Cardiology (ESC) recommendations are similar to those of the 2011 ACCF/AHA guidelines.[22]

Left ventricular myectomy is sometimes performed in patients with hypertrophic cardiomyopathy (HCM) who have severe symptoms refractory to therapy and an outflow gradient above 50 mm Hg either with provocation or at rest.

The procedure is typically successful in abolishing the outflow gradient; most patients have symptomatic improvement for at least 5 years. However, the reduction in left ventricular outflow gradient may not correlate with a reduction in the risk of sudden death or overall mortality. Furthermore, the outflow gradient may gradually increase over time and return to the same level as before, necessitating a repeat myectomy or additional medical therapy.

2011 ACCF/AHA guidelines recommendations

Class I recommendations (level of evidence [LOE]: C)[16]

Only experienced operators in the setting of a comprehensive HCM program should perform septal reduction therapy, and only in eligible patients with severe drug-refractory symptoms and left ventricular outflow tract obstruction.

Class IIa recommendations[16]

When considering management options for eligible patients with severe drug-refractory symptoms and left ventricular outflow tract obstruction, it is reasonable to consult with institutions experienced in surgical septal myectomy and alcohol septal ablation (LOE: C).

For most eligible patients with severe drug-refractory symptoms and left ventricular outflow tract obstruction, surgical septal myectomy can be beneficial and is first-line therapy when performed in experienced centers (LOE: B).

For symptomatic children with HCM in the setting of severe resting obstruction (>50 mm Hg) whose condition is refractory to standard medical therapy, surgical septal myectomy can be beneficial when performed in experienced centers (LOE: C).

For eligible adult patients with HCM with left ventricular outflow tract obstruction and severe drug-refractory symptoms (eg, New York Heart Association [NYHA] class III/IV) but who are not surgical candidates, alcohol septal ablation in experienced centers can be beneficial (LOE: B). (See Catheter Septal Ablation.)

Class III recommendations: Harm (all LOE: C)

Septal reduction therapy is not recommended in patients with HCM and the following[16] :

• No symptoms with normal exercise tolerance or symptoms controlled/minimized with optimal medical therapy
• Unless performed as part of a program dedicated to the longitudinal and multidisciplinary care of HCM patients

In addition, for HCM in the setting of left ventricular outflow tract obstruction for which septal reduction therapy is feasible for relief, mitral valve replacement is not recommended.[16]

2014 ESC guidelines recommendations

The 2014 European Society of Cardiology (ESC) recommendations are similar to those of the 2011 ACCF/AHA guidelines.[22] However, the ESC guidelines indicate mitral valve repair should or may be considered, respectively, in the following settings[22] :

• Symptomatic HCM with a resting or provocable left ventricular outflow tract obstruction (≥50 mm Hg) and moderate-to-severe mitral regurgitation not solely caused by systolic anterior motion of the mitral valve (class IIa; LOE: C)
• Resting or provocable left ventricular outflow tract obstruction (≥50 mm Hg) and a maximum septal hypertrophy up to 16 mm at the point of the mitral leaflet–septal contact or in the presence of moderate-to-severe mitral regurgitation following isolated myectomy (class IIb; LOE: C)

Transvenous dual-chamber pacing has been used for patients with hypertrophic cardiomyopathy (HCM), although this is not current clinical practice. The right ventricular septal preexcitation induced by right ventricular apical pacing leads to a “pulling away” of the septum from the outflow region, allowing for an increase in flow with a decrease in left ventricular outflow tract obstruction.

Many patients with HCM and pacemaker implantation feel that their symptoms improve, allowing a reduction in prescribed medication. However, a reduction in left ventricular outflow tract gradient does not necessarily mean a reduction in vulnerability to ventricular arrhythmias and sudden death.

Some investigators have used permanent pacing in selected HCM patients as adjunctive rather than primary treatment. The reported results vary considerably, with a significant placebo effect and a wide range of patient outcomes. ICDs have essentially replaced pacemakers as cardiac rhythm management devices for HCM (see Implantable Cardioverter Defibrillator).[23, 24, 25, 26]

2008 ACC/AHA/HRS and 2011 ACCF/AHA guidelines recommendations

The 2008 American College of Cardiology (ACC), American Heart Association (AHA), and Hearth Rhythm Society (HRS) recommendations for permanent pacing in patients with HCM include the following indications[27] :

• Sinus node dysfunction or atrioventricular block (class I; level of evidence [LOE]: C)
• Medically refractory symptomatic HCM with significant resting or provoked left ventricular outflow tract obstruction (class IIb; LOE: A); consider implantation with a DDD implantable cardioverter defibrillator (ICD) for patients with class I indications in the presence of sudden cardiac death risk factors

The 2011 joint ACC Foundation (ACCF)/AHA recommendations for pacing in patients with HCM include the following[16] :

• For individuals with a dual-chamber device that was implanted for non-HCM indications, a trial of dual-chamber atrial ventricular pacing from the right ventricular apex is a reasonable consideration for symptomatic relief from left ventricular outflow obstruction (class IIa; LOE: B)
• For medically refractory symptomatic patients with obstructive HCM who are suboptimal surgical candidates for septal reduction, consider permanent pacing (class IIb; LOE: B)

Both the 2008 ACC/AHA/HRS and the 2011 ACCF/AHA guidelines state that permanent pacemaker implantation is not indicated for patients who are asymptomatic or whose symptoms are medically controlled, nor is it indicated for symptomatic patients in the absence of evidence of left ventricular tract outflow obstruction (both class III: harm; LOE: C [2008 guidelines], and LOE: C and B, respectively [2011 guidelines]).[27, 16]

2014 ESC guidelines recommendations

The 2014 European Society of Cardiology (ESC) guidelines recommendations on indications for cardiac pacing in HCM patients with resting or provocable left ventricular outflow tract obstruction (≥50 mm Hg), sinus rhythm, and drug-refractory symptoms include the following to reduce the left ventricular outflow tract gradient or to facilitate beta-blocker and/or verapamil therapy (all class IIb; LOE: C)[22] :

• Sequential atrioventricular pacing, with optimal AV interval, in those who are not candidates for septal myectomy or septal alcohol ablation, or who are at high risk of developing heart block following these procedures
• Consideration of implanting a dual-chamber ICD in individuals with an indication for an ICD

Transvenous catheter ablation of the septal region has been performed by using selective arterial ethanol infusion to destroy myocardial tissue in patients with hypertrophic cardiomyopathy (HCM). The procedure is analogous to a surgical myectomy, in that it attempts to decrease the amount of septal ventricular myocardium, thereby reducing the left ventricular outflow tract gradient.

The main drawbacks include the risk of inadvertent atrioventricular (AV) block and extension of the alcohol-induced infarct, leading to myocardial dysfunction or iatrogenic ventricular septal defects. Studies have demonstrated a higher rate of complications for alcohol septal ablation than for surgical myectomy.[28] Coil occlusion of septal perforators supplying the hypertrophied ventricular septum has similar limitations.[21]

2011 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guidelines

Class IIa recommendations (level of evidence [LOE]: B)[16]

Alcohol septal ablation in experienced centers can be beneficial in eligible adults with HCM with left ventricular outflow tract obstruction and severe drug-refractory symptoms (eg, New York Heart Association [NYHA] class III/IV) who are not surgical candidates.;

Class IIb recommendations[16]

For eligible adults with HCM with left ventricular outflow tract obstruction and severe drug-refractory symptoms who prefer septal ablation following a detailed discussion, alcohol septal ablation in experienced centers may be considered an alternative to surgical myectomy (LOE: B).

However, alcohol septal ablation is not recommended in the setting of HCM with marked (ie, >30 mm) septal hypertrophy as its efficacy is unclear in this scenario (LOE: C).

Class III recommendations: Harm (all LOE: C)

Alcohol septal ablation is not recommended in patients with HCM and the following[16] :

• Concomitant disease that independently warrants surgical correction (eg, coronary artery bypass grafting for coronary artery disease, mitral valve repair for ruptured chordae) when surgical myectomy can be performed as part of the procedure
• Children younger than 21 years or adults younger than 40 years if myectomy is a viable option

The implantable cardioverter defibrillator (ICD) has been used for prevention of sudden arrhythmic death. Transvenous placement is similar in technique to permanent pacemaker implantation. An ICD automatically detects, recognizes, and treats tachyarrhythmias and bradyarrhythmias using tiered therapy (ie, bradycardia pacing, overdrive tachycardia pacing, low-energy cardioversion, and high-energy shock defibrillation).

ICD therapy has been demonstrated to be lifesaving in children with hypertrophic cardiomyopathy (HCM) who receive appropriate shocks for ventricular tachycardia and ventricular fibrillation, even among those on appropriate antiarrhythmic drug therapy.

Smaller studies in children, as well as personal and anecdotal experience, appear to strongly favor using the ICD in HCM patients who have arrhythmias, aborted sudden death, malignant genotype or family history, and other factors that may increase mortality, particularly sudden arrhythmic death risk.[23, 24, 25, 26]

Clearly, in patients who have had an aborted sudden death event or documented sustained ventricular tachyarrhythmias, the ICD is indicated as secondary prevention.

In adults, teenagers, and children, primary prevention is also employed for patients with HCM but without a documented ventricular tachyarrhythmia or aborted sudden death event. Although this is a reasonable indication, the appropriate shock rate is significantly lower in these primary prevention patients.

Additional markers of higher risk (eg, left ventricular wall thickness, nonsustained ventricular tachycardia, abnormal exercise blood pressure response, malignant family history, and other stratifying tests) are useful in identifying patients who have greater ventricular arrhythmia vulnerability.

The main drawbacks to implanting an ICD include the relatively high rate of inappropriate shocks (for sinus tachycardia, supraventricular tachycardia, or lead problems) and a high lead fracture rate, particularly in younger patients.

ICDs last approximately 4-5 years; device failure is usually the result of either battery depletion or lead failure. Young patients require multiple ICD device replacements and lead extraction procedures, which carry additional surgical risks.

No special diet is required in individuals with hypertrophic cardiomyopathy (HCM); however, patients should be instructed to avoid volume depletion, as this can increase pressure gradients across the left ventricular outflow tract. They should also be advised to avoid excessive weight gain.

Strenuous and anaerobic exercise should be avoided.[7] Competitive-level sports are not advised if any of the following are present:

• Significant outflow gradient

• Significant ventricular or supraventricular arrhythmia

• Marked left ventricular hypertrophy

• History of sudden death in relatives with HCM

Beta-blockers and calcium channel blockers are used to treat children with hypertrophic cardiomyopathy (HCM). In individuals with significant tachyarrhythmias, amiodarone and other class III-type antiarrhythmic agents have also been used.

Class Summary

Beta-blockers may decrease outflow obstruction and increase ventricular compliance. No clear evidence indicates that they decrease sudden death. Approximately one half of patients who use beta-blockers feel improvement in symptoms.

Propranolol (Inderal LA)

Propranolol is a nonselective beta-blocker with a long record of use and relative safety. The treatment dose is titrated to produce clinical effect (ie, a reduction in perceived symptoms). Blunting of the maximal heart rate during exercise testing is a good marker for beta-blocker effect. Although propranolol is generally a short-acting agent, long-acting preparations are available. A stable liquid preparation is available and can be used to treat infants.

Atenolol (Tenormin)

Atenolol selectively blocks beta1 receptors, with little or no effect on beta2 types. It may be better tolerated than propranolol (it has more favorable pharmacokinetics and frequently has equivalent efficacy).

Class Summary

Calcium channel blockers are an alternative to beta-blockers. They improve diastolic filling by improving diastolic relaxation and decreasing outflow gradient due to depression of cardiac contractility.

Verapamil (Calan, Isoptin, Verelan)

During depolarization, verapamil inhibits calcium ion from entering slow channels or voltage-sensitive areas of the vascular smooth muscle and myocardium. It may have a better effect on exercise performance. Sustained release formulations with daily dosing are available.

Class Summary

Amiodarone is categorized as a class III antiarrhythmic agent but has antiarrhythmic effects that overlap all 4 Vaughn-Williams antiarrhythmic classes. Its use is generally reserved for potentially life-threatening ventricular arrhythmias.

Amiodarone (Cordarone, Pacerone)

Amiodarone is a complex and potent antiarrhythmic agent with multiple effects on cardiac action potential, exceedingly complex pharmacokinetics, and extracardiac pharmacodynamics. Oral efficacy may take weeks. With the exception of disorders of prolonged repolarization (eg, long QT syndrome), amiodarone may be the drug of choice for life-threatening ventricular arrhythmias refractory to beta-blockade and initial therapy with other agents.