eMedicine Specialties > Cardiology > Myocardial Disease and Cardiomyopathies

Cardiomyopathy, Hypertrophic

Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice

Updated: Aug 27, 2009

Introduction

Background

Hypertrophic cardiomyopathy (HCM) 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.¹ The disorder has a variable presentation and carries a high incidence of sudden death. In fact, HCM is the leading cause of sudden cardiac death in both preadolescent and adolescent children. The hallmark of the disorder is myocardial hypertrophy that is inappropriate, often asymmetric, 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 interventricular septum, which results in an obstruction of flow through the left ventricular (LV) outflow tract.

Decades ago, HCM was written about and known as idiopathic hypertrophic subaortic stenosis (IHSS) or asymmetric septal hypertrophy (ASH). These terms were replaced by hypertrophic cardiomyopathy because the segmental hypertrophy can occur in any segment of the ventricle, not just the septum. Furthermore, this entity can present without subaortic obstruction to flow, yet still carry the same ominous risk of arrhythmogenic sudden death and many of its clinical symptoms.

HCM can be separated into obstructive and nonobstructive types. Obstructive HCM is due to midsystolic obstruction of flow through the LV outflow tract as a result of a Bernoulli effect–induced systolic anterior mitral valve movement toward the septum. The significance of this obstruction, however, is highly controversial. Some investigators and experts believe the obstruction has less to do with the overall hemodynamic and pathophysiologic manifestations of this entity than the inappropriate segmental hypertrophy, which, with its increased myocardial oxygen consumption and substrate for fatal ventricular arrhythmias, has much more significance in the overall clinical picture of this entity and the treatment and prognosis of HCM.

Pathophysiology

Since the initial descriptions of hypertrophic cardiomyopathy, the feature that has attracted the greatest attention is the dynamic pressure gradient across the LV outflow tract. The pressure gradient appears to be related to further narrowing of an already small outflow tract (by the marked asymmetric septal hypertrophy and possibly an abnormal location of the mitral valve) by the systolic anterior motion of the mitral valve against the hypertrophied septum. The likely cause of this is a Venturi effect resulting from increased ejection velocity produced by the abnormal LV outflow tract orientation and geometry.

In addition, most patients have abnormal diastolic function, whether or not a pressure gradient is present, which impairs ventricular filling and increases filling pressure, despite a normal or small ventricular cavity. These patients have abnormal calcium kinetics and subendocardial ischemia, which are related to the profound hypertrophy and myopathic process.

Hypertrophic cardiomyopathy is a familial disease with an autosomal dominant pattern of inheritance.² There are defects in several of the genes encoding for the sarcomeric proteins, such as myosin heavy chain, actin, tropomyosin, and titin.^3,4 Multiple mutations have been identified, with genotype-specific risks of mortality and degree of hypertrophy. Interestingly, the genetic basis of ventricular hypertrophy does not directly correlate with prognostic risk stratification. Patients with some mutations, such as specific tropomyosin substitutions, have only a mild degree of ventricular hypertrophy, with little or no LV outflow tract obstruction, but they still carry a disproportionately high risk of sudden death.⁵

Frequency

United States

HCM is reported in 0.5% of the outpatient population referred for echocardiography.⁶ The overall prevalence of HCM is low and has been estimated to occur in 0.05-0.2% of the population.⁷ Morphologic evidence of disease is found by echocardiography in approximately 25% of first-degree relatives of patients with HCM. Genetic testing still is in the early stages of research development but can be used to identify asymptomatic family members with the same mutation as the proband (index case).

Mortality/Morbidity

HCM survival rates have improved over the past decades, with a 2006 study reporting that published sudden death rates over the past 10 years being lower than previously published figures (median 1.0% (range 0.1–1.7) v 2.0% (0–3.5)). Nevertheless, HCM still carries a high risk for mortality and morbidity.⁸

• Sudden death: Most patients are asymptomatic. Unfortunately, the first clinical manifestation of the disease in such individuals may be sudden death, likely from ventricular tachycardia or fibrillation. Younger patients, particularly children, have a much higher mortality rate. Children have a much greater degree of ventricular hypertrophy and are much more symptomatic early on in the disease course, most likely because more malignant genotypes are present earlier in life. The more benign mutations do not elicit a clinical or echocardiographic phenotype or symptoms in the pediatric population. Death often is sudden, unexpected, and typically is associated with sports or vigorous exertion. Early diagnosis is of prime importance in order to prescribe an appropriate level of safe activity. Screening of first-degree relatives is useful to identify additional affected family members prior to the onset of significant symptoms or sudden death.^9,10,11
• Arrhythmia: Patients can have a myriad of arrhythmias, including atrial fibrillation, atrial flutter, ventricular ectopy, ventricular tachycardia, and ventricular fibrillation. These patients are among the highest-risk group for ventricular fibrillation and pose difficult therapeutic decisions for risk reduction.
• Heart failure: Patients have a high likelihood of recurrent heart failure resulting from both mitral regurgitation and profound diastolic dysfunction. HCM is a progressive condition that worsens over time, as does the gradient across the LV outflow tract if left untreated. Systolic function usually is well preserved until the late stages of the disease. Angina is rare in children but common in adults. Syncope and presyncope are common and may identify individuals at high risk for sudden death.

Sex

• HCM is slightly more common in males than in females. However, the genetic inheritance pattern is autosomal dominant, without sex predilection. Modifying genetic, hormonal, and environmental factors may lead to a higher likelihood of identification in males, increased symptomatology, or higher degrees of LV outflow obstruction, with more prominent findings upon physical examination.
• HCM usually presents at a younger age in females. Females tend to be more symptomatic and are more likely to be disabled by their symptoms than males.

Age

• In general, HCM has a bimodal peak of occurrence. The most common presentation is in the third decade of life, but it may present in persons of any age, from newborns to elderly individuals.
• In children, inherited cases are found in an age range from newborn (ie, stillborn babies) to adult. The peak incidence is in these cases is in the second decade of life.
• In adults, the peak distribution is in the fourth through the sixth decades of life.

Clinical

History

Symptoms can include sudden cardiac death, dyspnea, syncope and presyncope, angina, palpitations, orthopnea, paroxysmal nocturnal dyspnea, congestive heart failure, and dizziness.

• Sudden cardiac death
  • This is the most devastating presenting manifestation of HCM. It has the highest incidence in preadolescent and adolescent children and is particularly related to extreme exertion. The risk of sudden death in children is as high as 6% per year.
  • In more than 80% of cases, the arrhythmia that causes sudden death is ventricular fibrillation. Many of these cases degenerate into ventricular fibrillation from rapid atrial arrhythmias, such as fibrillation, supraventricular tachycardia, or Wolff-Parkinson-White syndrome, while others result from ventricular tachycardia and low cardiac output hemodynamic collapse.
• Dyspnea
  • This is the most common presenting symptom, occurring in as many as 90% of symptomatic patients.
  • Dyspnea largely is a consequence of elevated LV diastolic filling pressures (and transmission of those elevated pressures back into the pulmonary circulation). The elevated LV filling pressures principally are caused by impaired diastolic compliance as a result of marked hypertrophy of the ventricle.
• Syncope
  • Syncope is a very common symptom, resulting from inadequate cardiac output upon exertion or from cardiac arrhythmia. It occurs more commonly in children and young adults with small LV chamber size and evidence of ventricular tachycardia upon ambulatory monitoring.
  • Alternatively, syncope may be caused by arrhythmias, either tachycardias or bradycardias. Some patients with HCM have abnormalities in sinus node function, leading to sick sinus syndrome with alternating tachyarrhythmias and bradyarrhythmias or severe bradyarrhythmias.
  • Syncope and presyncope identify patients at high risk of sudden death and warrant an urgent workup and aggressive treatment.
• Presyncope
  • Presyncope includes "graying-out" spells that occur in the erect posture and can be relieved by immediately lying down.
  • They occur quite commonly and identify patients at high risk for sudden death.
  • These symptoms are exacerbated by vagal stimulation. Presyncope also may occur with nonsustained atrial or ventricular tachyarrhythmias.
• Angina
  • Typical symptoms of angina are quite common in patients with HCM and may occur in the absence of detectable coronary atherosclerosis.
  • Impaired diastolic relaxation and markedly increased myocardial oxygen consumption are caused by ventricular hypertrophy that results in subendocardial ischemia, particularly during exertion.
• Palpitations
  • Palpitations are common.
  • These result from arrhythmias, such as premature atrial and ventricular beats, sinus pauses, atrial fibrillation, atrial flutter, supraventricular tachycardia, and ventricular tachycardia.
• Orthopnea and paroxysmal nocturnal dyspnea
  • These are early signs of congestive heart failure and, while relatively uncommon, are observed in patients with severe HCM and result from impaired diastolic function and elevated LV filling pressure.
  • Orthopnea and paroxysmal nocturnal dyspnea result from pulmonary venous congestion.
• Congestive heart failure
  • This is relatively uncommon but is observed in patients with severe HCM.
  • It may occur as a result of a combination of impaired diastolic function and subendocardial ischemia.
  • Systolic function in these patients almost always is well preserved.
• Dizziness
  • Dizziness is common in patients with HCM with elevated pressure gradients across the LV outflow tract. It is worsened by exertion and may be exacerbated by hypovolemia following high levels of exertion or increased insensible fluid loss (eg, during extreme heat).
  • Dizziness also may occur as a result of maneuvers, such as rapid standing or Valsalva during defecation, or certain medications, such as diuretics, nitroglycerin, and vasodilating antihypertensive agents, that decrease preload and afterload and increase the pressure gradient across the LV outflow tract.
  • Dizziness also may be secondary to arrhythmia-related hypotension and decreased cerebral perfusion. Nonsustained arrhythmias often cause symptoms of dizziness, lightheadedness, and presyncope, whereas sustained arrhythmias are more likely to lead to syncope, collapse, and/or sudden cardiac death.

Physical

• Double apical impulse results from a forceful left atrial contraction against a highly noncompliant left ventricle. This occurs quite commonly in adults.
• Triple apical impulse results from a late systolic bulge that occurs when the heart is almost empty and is performing near-isometric contraction. This is a highly characteristic finding of HCM; however, it occurs less frequently than the double apical impulse.
• First heart sound is normal.
• Second heart sound usually is normally split, but in some patients with severe outflow gradients, it is paradoxically split.
• An S₃ gallop is common in children, but it does not have the same ominous significance as in patients with valvular aortic stenosis. When it occurs in adults, it signifies decompensated congestive heart failure.
• A fourth heart sound, an S₄, frequently is heard and results from atrial systole against a highly noncompliant left ventricle.
• Jugular venous pulse reveals a prominent a wave caused by diminished right ventricular compliance secondary to massive hypertrophy of the ventricular septum.
• Double carotid arterial pulse is common. The carotid pulse rises quickly because of the increased velocity of blood through the LV outflow tract and into the aorta. The carotid pulse then declines in mid systole as the gradient develops. This is followed by a secondary rise in carotid pulsation during late systole.
• Apical precordial impulse frequently is displaced laterally and usually is abnormally forceful and enlarged.
• Systolic ejection murmur typically is a systolic ejection crescendo-decrescendo murmur, which is best heard between the apex and left sternal border and radiates to the suprasternal notch but not to the carotid arteries or neck. The murmur and the gradient across the LV outflow tract diminish with any increase in preload (eg, Mueller maneuver, squatting) or increase in afterload (eg, handgrip). The murmur and the gradient increase with any decrease in preload (eg, Valsalva maneuver, nitrate administration, diuretic administration, standing) or with any decrease in afterload (eg, vasodilator administration).
• 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.

Causes

• Abnormal calcium kinetics
  • The actual causes of HCM include defects in the genes encoding for several of the sarcomeric proteins. Additional data link abnormal myocardial calcium kinetics as the cause of the inappropriate myocardial hypertrophy and specific features of HCM, particularly in patients with diastolic functional abnormalities.
  • Abnormal myocardial calcium kinetics and abnormal calcium fluxes from an increase in the number of calcium channels result in an increase in intracellular calcium concentration, which, in turn, may produce hypertrophy and cellular disarray.
• Genetic causes 
  • Familial HCM occurs as an autosomal dominant Mendelian-inherited disease in approximately 50% of cases. Some, if not all, of the sporadic forms of the disease may be caused by spontaneous mutations.
  • At least 6 different genes on at least 4 chromosomes are associated
  • Familial HCM occurs as an autosomal dominant Mendelian-inherited disease in approximately 50% of cases. Some, if not all, of the sporadic forms of the disease may be caused by spontaneous mutations.
  • At least 6 different genes on at least 4 chromosomes are associated with HCM, with more than 50 different mutations discovered thus far. Familial HCM is a genetically heterogenous disease in that it can be caused by genetic defects at more than one locus.
  • In 1989, Seidman and collaborators first reported the genetic basis for HCM. They reported the existence of a disease gene located on the long arm of chromosome 14. Subsequently, they found this to be the gene encoding for beta cardiac myosin heavy chain.
  • Wide variation exists in the phenotypic expression of a given mutation of a given gene, with variability in clinical symptoms and the degree of hypertrophy expressed. Phenotypic variability is related to the differences in genotype, with specific mutations associated with particular symptoms, the degree of hypertrophy, and the prognosis.⁹

• Other suggested causes
  • Abnormal sympathetic stimulation: Heightened responsiveness of the heart to the excessive production of catecholamines or the reduced neuronal uptake of norepinephrine might cause HCM.
  • Abnormally thickened intramural coronary arteries: These do not dilate normally, which leads to myocardial ischemia. This progresses to myocardial fibrosis and abnormal compensatory hypertrophy.
  • Subendocardial ischemia: This is related to abnormalities of the cardiac microcirculation that deplete the energy stores essential for the sequestration of calcium during diastole. Subendocardial ischemia results in persistent interaction of the contractile elements during diastole and increased diastolic stiffness.
  • Cardiac structural abnormalities: These include a catenoid configuration of the septum, which results in myocardial cell hypertrophy and disarray.

Differential Diagnoses

Aortic Stenosis
Cardiomyopathy, Restrictive
Glycogen Storage Disease, Type II

Other Problems to Be Considered

Aortic stenosis, supravalvular

Workup

Laboratory Studies

• No specific laboratory blood tests are required in the workup of HCM.
• Genetic testing is not widely available at this time but is becoming increasingly available in this disease setting. In research situations or in larger pedigrees, genotyping is informative for the identification of additional family members once the proband's genotype has been determined.

Imaging Studies

• Two-dimensional echocardiography and Doppler studies
• Two-dimensional echocardiography is diagnostic for HCM. Color Doppler flow studies typically reveal mitral regurgitation.¹²
• Spectral continuous-wave Doppler studies in patients with obstructive HCM reveal an elevated flow velocity across the LV outflow tract. Severe obstructive HCM typically has a flow velocity greater than 4 m/s, and a gradient across the LV outflow tract of greater than 50 mm Hg is considered severe.
• Echocardiography also typically reveals diastolic dysfunction with reduced LV compliance and a mitral valve ratio of E wave to A wave of less than 1 (usually <0.8). Systolic function is good, and, in fact, the LV ejection fraction usually is high to normal at the time of diagnosis. The LV diameter is at the lower limit of normal or smaller than normal.
• The hallmarks of the obstructive type of HCM consist of systolic anterior motion of the anterior mitral valve leaflet and asymmetric septal hypertrophy with a ratio of septal wall thickness to posterior wall thickness of greater than 1.4:1.
• The septum not only is relatively thicker than the posterior wall, it is also typically at least 4-6 mm thicker than normal for each age group. Massive hypertrophy with septal wall thickness of greater than 25 mm has been noted in rare cases, particularly in infants with glycogen storage defects, as are observed in patients with Pompe disease.
• An unusual echocardiographic pattern consisting of a ground-glass appearance has been noted in portions of the hypertrophied myocardium in some patients. This pattern may be related to the abnormal cellular architecture and myocardial fibrosis that have been observed in pathological studies.
• A narrowing of the LV outflow tract occurs in many patients with HCM. This contributes to the creation of a pressure gradient in a small number of patients.
• The hallmark of HCM associated with a pressure gradient is the abnormal systolic motion of the anterior leaflet of the mitral valve (ie, systolic anterior motion) and, in rare cases, the systolic motion of the posterior leaflet. Three explanations for the systolic anterior motion of the mitral valve have been offered, as follows:
• The 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.
• The mitral valve is pushed against the septum because of its abnormal position in the outflow tract.
• 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 (Venturi effect).
• Several other echocardiographic findings may be present, as follows:
• A small LV cavity may be present secondary to marked hypertrophy of the myocardium and encroachment into the LV cavity.
• Reduced septal motion and thickening during systole may occur, particularly of the upper septum, resulting from disarray of the myofibrillar architecture and abnormal contractile function.
• The motion of the posterior wall may be normal or increased.
• The rate of closure of the mitral valve in mid diastole may be reduced secondary to a decrease in LV compliance or abnormal transmitral flow during diastole.
• Mitral valve prolapse, a rare echocardiographic occurrence in HCM, may be present.
• Partial systolic closure or, more commonly, coarse systolic fluttering of the aortic valve related to turbulent blood flow in the outflow tract may occur. Abnormalities in diastolic function may be demonstrated by echocardiography and Doppler recordings in approximately 80% of patients with HCM, independent of the presence or absence of a systolic pressure gradient.
• The presence of mitral regurgitation virtually always is confirmed by Doppler echocardiography in patients with HCM who have a systolic gradient.
• In general, a summary of echocardiography findings includes abnormal systolic anterior leaflet motion of the mitral valve, LV hypertrophy, left atrial enlargement, small ventricular chamber size, septal hypertrophy with septal-to-free wall ratio greater than 1.4:1, mitral valve prolapse and mitral regurgitation, decreased mid aortic flow, and partial systolic closure of the aortic valve in mid systole.
• Chest radiograph
• Chest radiograph (CXR) findings are variable. The cardiac silhouette may range from normal to markedly increased.
• Left atrial enlargement frequently is observed, especially when significant mitral regurgitation is present. This is manifested by a "double-density" appearance on CXR.
• Radionuclide imaging
• Radionuclide imaging with thallium or technetium may show reversible defects, mostly in the absence of coronary artery disease.
• Thallium or technetium scintigraphy may reveal defects in myocardial perfusion, even in the setting of angiographically normal coronary arteries.
• These reversible defects evident on radionuclide scanning are more common in children and adolescents with a history of sudden death or syncope, which suggests that myocardial ischemia is a significant factor in the mechanism of the demise of younger patients with HCM.

Other Tests

• Electrocardiography
  • Common findings include ST-T wave abnormalities and LV hypertrophy. Other findings observed on ECG include axis deviation (right or left), conduction abnormalities (P-R prolongation, bundle-branch block), sinus bradycardia with ectopic atrial rhythm, and atrial enlargement. One mutation has been identified that is associated with both HCM and Wolff-Parkinson-White syndrome.
  • Uncommon findings include an abnormal and prominent Q wave in the anterior precordial and lateral limb leads, short P-R interval with QRS suggestive of preexcitation, atrial fibrillation (poor prognostic sign), and a P-wave abnormality, including left atrial enlargement.
• Holter monitoring and event electrocardiography: Findings commonly include atrial and ventricular ectopy, sinus pauses, wandering atrial pacemaker, atrial tachycardia, atrial fibrillation and/or flutter, and nonsustained ventricular tachycardia.

Procedures

• Cardiac catheterization
• Although not required for the diagnosis of hypertrophic cardiomyopathy, a diagnostic cardiac catheterization is useful to determine the degree of outflow obstruction, cardiac hemodynamics, diastolic characteristics of the left ventricle and LV anatomy, and, of particular importance, the coronary anatomy. Cardiac catheterization is also reserved for situations when invasive modalities of therapy, such as a pacemaker or surgery, are being considered.
• Therapeutic cardiac catheterization interventions, utilized in well selected cases of hypertrophic cardiomyopathy, include transcatheter septal alcohol ablation to relieve the LV outflow obstruction by intentional infarction of a portion of the interventricular septum.
• Cardiac catheterization frequently discloses diminished diastolic left ventricular compliance, and in cases of obstructive hypertrophic cardiomyopathy, a systolic pressure gradient within the body of the left ventricle which is separated from a subaortic chamber by the second septum and anterior leaflet of the mitral valve and abuts the septum. The subaortic pressure gradient may be quite labile and may very between 0 and 175 mm Hg in the same patient under different conditions.
• The arterial pressure tracing found on cardiac catheterization may demonstrate a "spike and dome" configuration similar to the carotid pulse recording. As a consequence of diminished left ventricular compliance, the mean left atrial pressure and, particularly, the a wave, in the left atrial pressure pulse and left ventricular end-diastolic pressures are usually elevated.
• Artifactual outflow gradients may occur if the left ventricular catheter becomes entrapped in the trabeculae of a markedly hypertrophied left ventricle. 
• Cardiac output may be depressed in patients with long-standing severe gradients, but, in the majority of patients, it is normal. Occasionally, cardiac output is elevated in patients with markedly hyperdynamic left ventricular systolic function.
• Hemodynamic abnormality in hypertrophic cardiomyopathy is not limited to the left side of the heart. Approximately one fourth of patients demonstrate pulmonary hypertension. It is usually mild, but, in some cases, it can be moderate to severe, due (at least in part) to elevated mean left atrial pressures as a consequence of diminished left ventricular compliance. A pressure gradient in the right ventricular outflow tract occurs in approximately 15% of patients who have obstruction to left ventricular outflow and appears to result from markedly hypertrophied right ventricular tissue. Right atrial and right ventricular end-diastolic pressures may be slightly elevated.
• A feature characteristic of hypertrophic cardiomyopathy is the variability and lability of the left ventricular outflow gradient.  A patient may demonstrate a large gradient on one occasion and have none at another time. In some patients without a resting gradient, it may be temporarily provoked.
• Three basic mechanisms involved in the production of dynamic gradients include increased contractility, decreased preload, and decreased afterload. In many patients with hypertrophic cardiomyopathy, the gradient is mid-ventricular and may be intensified by increased contractility, which exerts a direct muscular sphincter action. The stimuli that provoke or intensify left ventricular outflow tract gradients in hypertrophic cardiomyopathy generally improve myocardial performance in normal subjects and in patients with most other forms of heart disease. Conversely, reductions in contractility or increases in preload or afterload, which increased left ventricular dimensions, reduce or abolish the left ventricular outflow gradient.
• One of the most potent stimuli for enhancing the left ventricular outflow gradient is postextrasystolic potentiation, which may occur after a spontaneous premature contraction or be induced by mechanical stimulation with a catheter.  The resultant increase in contractility in the beat after the extrasystole is so marked that it produces an increase in the outflow gradient. A characteristic change often occurs in the directly recorded arterial pressure tracing, which, in addition to displacing a more marked spike and dome configuration, exhibits a pulse pressure that fails to increase as expected or actually decreases (the so-called Brockenbrough-Braunwald phenomenon). This is one of the more reliable signs of dynamic obstruction of the left ventricular outflow tract. In some patients, the postextrasystolic murmur is attenuated despite an increase in the outflow gradient, apparently because, in this setting, the murmur mirrors to a greater degree changes in the severity of mitral regurgitation than changes in the outflow tract gradient.
• Left ventriculography typically shows a hypertrophied ventricle and the presence of an outflow gradient. The anterior leaflet of the mitral valve moves anteriorly during systole and encroaches on the outflow tract. Associated with this motion is mitral regurgitation, which is a constant finding in patients with gradients.  The left ventricular 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.
• In patients older than 45 years of age, obstructive coronary artery disease may be present, although the symptoms of ischemic pain are indistinguishable from those of patients with normal coronary angiograms and hypertrophic cardiomyopathy. The left anterior descending and septal perforator coronary arteries may demonstrate phasic narrowing and associated abnormalities of flow during systole
• Electrophysiology studies
• A diagnostic electrophysiology study using programmed electrical stimulation may identify conduction abnormalities, sinus node dysfunction (SND), and the potential for inducible arrhythmias.
• The prognostic correlation of inducible arrhythmias with spontaneous clinical arrhythmias and/or sudden death is not entirely clear. Several studies have shown a relationship between electrophysiology results and risk stratification for sudden cardiac death, but other studies have not been able to demonstrate a direct relationship.

Histologic Findings

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 patients with HCM. Fibrosis is prominent and may be extensive enough to produce grossly visible scars. Abnormal intramural coronary arteries, with a reduction in the size of the lumen and thickening of the vessel wall, are common in patients with HCM and occur in more than 80%. This abnormality most frequently occurs in the ventricular septum and accompanies extensive fibrosis in the affected walls of the heart.

Treatment

Medical Care

• Evaluation usually can be conducted on an outpatient basis. Inpatient studies and surgical treatment also may be necessary.
• Medical and surgical therapy is used to reduce ventricular contractility or increase ventricular volume, increase ventricular compliance and outflow tract dimensions, and, in the case of obstructive HCM, reduce the pressure gradient across the LV outflow tract. Paramount to any therapy is reduction in the risk of sudden death by identification of these patients early on and effective medical and/or surgical implantation of an automatic defibrillator.¹³

Surgical Care

• Left ventricular myomectomy
• LV myomectomy is used for patients with severe symptoms refractory to therapy and an outflow gradient of more than 50 mm Hg, either with provocation or with rest.
• The procedure typically is successful in abolishing the outflow gradient; most patients have symptomatic improvement for at least 5 years.
• The reduction in LV outflow gradient may not correlate with a risk reduction for sudden death or overall mortality. Furthermore, the outflow gradient may increase gradually over time and return to the same level as before, requiring a repeat procedure or additional medical therapy.
• Mitral valve replacement: Mitral valve replacement is reserved for those patients with severe mitral regurgitation due to systolic anterior movement of the mitral valve, particularly when mitral regurgitation (large regurgitant fraction) is associated with the development congestive heart failure, largely due to), or pulmonary hypertension.
• Pacemaker implantation
• The ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities recommend permanent pacing for SND or AV block in patients with HCM and may be considered in medically refractory symptomatic patients with hypertrophic cardiomyopathy and significant resting or provoked LV outflow tract obstruction.¹⁴
• Transvenous dual-chamber pacing has been used for patients with HCM. 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 LV outflow tract obstruction.¹⁵
• Many patients feel an improvement in symptoms and can have a reduction in prescribed medication.
• Note again that a reduction in LV outflow tract gradient does not necessarily mean a reduction in vulnerability to ventricular arrhythmias and sudden death. Therefore, permanent pacing in patients with HCM has been used as adjunctive therapy by some investigators rather than as primary treatment. The reported results are widely variable, with a significant placebo effect and variability in patient outcomes.^16,17  
• Catheter septal ablation 
• Transvenous catheter ablation of the septal region has been performed using selective arterial ethanol infusion to destroy myocardial tissue.¹⁸
• The procedure involves infusing 96% ethanol down the first septal branch of the left anterior descending artery and inducing a therapeutic infarction of the proximal interventricular septal myocardium. This leads to a remodeling of the septum, which decreases the marked septal thickening characteristic of HCM and results in a decrease of the gradient across the LV outflow tract. In this manner, the procedure is analogous to a surgical myomectomy, in attempting to decrease the amount of septal ventricular myocardium and thereby reducing the LV outflow tract gradient.
• The procedure has been used in clinical practice since the early 1990s and the reported results have been excellent, with significant reduction symptoms, particularly in the incidence of heart failure.^19,20
• In many centers, it is the surgical procedure of choice for HCM.
• Implantable cardioverter defibrillator
• The implantable cardioverter defibrillator (ICD) has been used for the prevention of sudden arrhythmic death.
• Transvenous placement is similar in technique to permanent pacemaker implantation and can be performed in either the electrophysiology laboratory or operating room.
• 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 shown to be life saving. In recent, large, well-designed prospective studies in adults with coronary artery disease and low ejection fraction surviving myocardial infarction, the ICD has been demonstrated to be superior to antiarrhythmic drug therapy.²¹
• Ongoing studies are being performed to assess the value of ICD therapy in cardiomyopathy. Smaller studies in children and personal and anecdotal experience appear to strongly favor utilization of the ICD in patients with HCM and arrhythmias, aborted sudden death, malignant genotype or family history, and other factors that may increase mortality and, particularly, sudden arrhythmic death risk.

Consultations

• Cardiologist
• Cardiothoracic surgeon
• Cardiac electrophysiologist
• Geneticist

Diet

• No special diet is required.
• The patient should avoid excessive weight gain.

Activity

• Avoid strenuous exercise.
• Competitive level sports should not be permitted if any of the following is present:
• Significant outflow gradient
• Significant ventricular or supraventricular arrhythmia
• Marked LV hypertrophy
• History of sudden death in relatives with HCM
• Identified malignant genotype
• Young Age (<30 years)
• Abnormal blood pressure response to exercise
• History of syncope, particularly in children
• Although avoidance of intense physical exertion is probably appropriate, participation in noncompetitive level recreational sports activities is not believed to be contraindicated.
• Cardiovascular screening before participation in competitive sports appears to reduce the frequency of unexpected sudden death from hypertrophic cardiomyopathy, although whether large scale screening of athletes is administratively feasible or cost-effective remains to be determined.^22,23
• Sudden death often occurs during exercise, but also demonstrates a circadian distribution, with clustering of deaths in the morning and early evening.

Medication

The purpose of pharmacologic therapy is to reduce the pressure gradient across the LV outflow tract by reducing the inotropic state of the left ventricle, improving compliance of the left ventricle, and reducing diastolic dysfunction. To date, only one pharmacologic agent, amiodarone (Cordarone), has been shown to reduce the incidence of arrhythmogenic sudden cardiac death.^24,25

Beta-adrenergic blocking agents

Reduce inotropic state of left ventricle. Decrease diastolic dysfunction and increase LV compliance, thereby reducing pressure gradient across LV outflow tract. Decrease myocardial oxygen consumption, thereby reducing myocardial ischemia potential. Decrease heart rate, thus reducing myocardial oxygen consumption and reducing myocardial ischemia potential.

Metoprolol (Lopressor)

First-line therapy in treatment of both obstructive and nonobstructive HCM. Rarely, patients may require up to 200 mg PO bid to achieve desired effect. Dose titrated to heart rate between 50 and 60 bpm.

Dosing

Adult

25-100 mg PO bid

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effects; toxicity may increase with coadministration of sparfloxacin, phenothiazines, astemizole (recalled from US market), calcium channel blockers, quinidine, flecainide, and contraceptives; may increase toxicity of digoxin, flecainide, clonidine, epinephrine, nifedipine, prazosin, verapamil, and lidocaine

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure, bradycardia, asthma, cardiogenic shock, AV conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce signs and symptoms of acute hypoglycemia and may decrease clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; monitor patient closely and withdraw drug slowly; during IV administration, carefully monitor BP, heart rate, and ECG

Atenolol (Tenormin)

Selectively blocks beta1 receptors with little or no effect on beta2 types.

Dosing

Adult

25-100 mg/d PO in AM or divided bid

Pediatric

Not established

Interactions

Coadministration with aluminum salts, barbiturates, calcium salts, cholestyramine, NSAIDs, penicillins, and rifampin may decrease effects; haloperidol, hydralazine, loop diuretics, and MAOIs may increase toxicity

Contraindications

Documented hypersensitivity; congestive heart failure, pulmonary edema, cardiogenic shock, AV conduction abnormalities, heart block (without a pacemaker)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may reduce symptoms of acute hypoglycemia and mask signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism and cause thyroid storm; monitor patients closely, and withdraw drug slowly; during IV administration, carefully monitor BP, heart rate, and ECG

Sotalol (Betapace)

Class III antiarrhythmic agent that blocks K+ channels, prolongs action potential duration, and lengthens QT interval. Noncardiac selective beta-adrenergic blocker that may be helpful in the use of conversion from and suppression of atrial fibrillation and flutter.

Dosing

Adult

80-320 mg PO bid

Pediatric

Not established

Interactions

Aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease bioavailability and plasma levels, possibly resulting in decreased pharmacologic effect; cardiotoxicity may increase when administered concurrently with sparfloxacin, astemizole (recalled from US market), calcium channel blockers, quinidine, flecainide, and contraceptives; toxicity increases when administered concurrently with digoxin, flecainide, acetaminophen, clonidine, epinephrine, nifedipine, prazosin, haloperidol, phenothiazines, and catecholamine-depleting agents

Contraindications

Documented hypersensitivity; sinus bradycardia, second-degree and third-degree AV block

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Beta-adrenergic blockade may decrease signs and symptoms of acute hypoglycemia and clinical signs of hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly, and monitor patient closely; caution in hypokalemia, peripheral vascular disease, hypomagnesemia, congestive heart failure, and congestive heart failure

Propranolol (Inderal)

Class II antiarrhythmic nonselective beta-adrenergic receptor blocker with membrane-stabilizing activity that decreases automaticity of contractions.
Dose titrated to heart rate between 50-60 bpm.

Dosing

Adult

20-80 mg PO qid

Pediatric

0.01-0.1 mg/kg/dose IV over 10 min; 1-2 mg/kg bid

Interactions

Coadministration with aluminum salts, barbiturates, NSAIDs, penicillins, calcium salts, cholestyramine, and rifampin may decrease effects; calcium channel blockers, cimetidine, loop diuretics, and MAOIs may increase toxicity; toxicity of hydralazine, haloperidol, benzodiazepines, and phenothiazines may increase

Contraindications

Documented hypersensitivity; uncompensated congestive heart failure; bradycardia, cardiogenic shock; AV conduction abnormalities

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Beta-adrenergic blockade may decrease signs of acute hypoglycemia and hyperthyroidism; abrupt withdrawal may exacerbate symptoms of hyperthyroidism, including thyroid storm; withdraw drug slowly and monitor closely

Antiarrhythmics

These agents alter the electrophysiologic mechanisms responsible for arrhythmia.

Disopyramide (Norpace)

Decreases inotropic state of left ventricle. Decreases ventricular and supraventricular arrhythmias. Decreases diastolic dysfunction and increases LV compliance, thereby reducing the pressure gradient across the LV outflow tract. Raises threshold for both atrial and ventricular ectopy.

Dosing

Adult

150-300 mg PO q12h

Pediatric

Not established

Interactions

Cardiotoxicity may increase when administered concurrently with sparfloxacin, beta-blockers, cimetidine, macrolides, and quinidine; phenytoin and rifampin may decrease levels

Contraindications

Documented hypersensitivity; second-degree or third-degree AV block; acute MI; severe mitral or aortic regurgitation

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution with concomitant use of beta-blockers or verapamil, may precipitate acute congestive heart failure; caution in angle-closure glaucoma, urinary retention, and myasthenia gravis; adjust dose in renal and hepatic impairment

Amiodarone (Cordarone)

Only agent proven to reduce the incidence and risk of cardiac sudden death, with or without obstruction to LV outflow. Very efficacious in converting atrial fibrillation and flutter to sinus rhythm and in suppressing the recurrence of these arrhythmias.

Dosing

Adult

800-1600 mg PO qd or divided bid/tid for 2 wk, then 200-400 mg qd

Pediatric

Not established

Interactions

Increases effect and blood levels of theophylline, quinidine, procainamide, phenytoin, methotrexate, flecainide, digoxin, cyclosporine, beta-blockers, and anticoagulants; toxicity of the cardiotoxicity of amiodarone is increased by ritonavir, sparfloxacin, and disopyramide; coadministration with calcium channel blockers may cause an additive effect and further decrease myocardial contractility; cimetidine may increase levels

Contraindications

Documented hypersensitivity; complete AV block, intraventricular conduction defects; patients taking ritonavir or sparfloxacin; pulmonary fibrosis

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in thyroid or liver disease

Calcium channel blockers

Alternative to beta-blockers, they decrease inotropic state of the left ventricle, decrease gradient across the LV outflow tract, decrease diastolic dysfunction, and increase diastolic filling of the left ventricle by improving LV diastolic relaxation. May have a better effect on exercise performance.

Verapamil (Calan, Isoptin)

During depolarization, inhibits calcium ion from entering slow channels or voltage-sensitive areas of the vascular smooth muscle and myocardium. Alternative to beta-blocker therapy. Useful in patients with moderate-to-severe COPD.
Use of short-acting calcium channel blockers is being discouraged because of numerous reports of adverse cardiac and hemodynamic events associated with their use, particularly in patients with known coronary artery disease.

Dosing

Adult

SR dosage form: 120-720 mg PO qd
IR dosage form: 80-240 mg PO tid

Pediatric

0.1-0.2 mg/kg/dose IV over 2 min; repeat in 10-30 min prn

Interactions

May increase carbamazepine, digoxin, and cyclosporine levels; coadministration with amiodarone can cause bradycardia and a decrease in cardiac output; when administered concurrently with beta-blockers, may increase cardiac depression; cimetidine may increase levels; may increase theophylline levels

Contraindications

Documented hypersensitivity; severe CHF, sick sinus syndrome, second-degree or third-degree AV block, hypotension (<90 mm Hg systolic)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatocellular injury may occur; transient elevations of transaminases with or without concomitant elevations in alkaline phosphatase and bilirubin have occurred (elevations have been transient and may disappear with continued verapamil treatment); monitor liver function periodically

Natriuretic Peptides

Dilate veins and arteries.

Nesiritide (Natrecor)

Recombinant DNA form of human B-type natriuretic peptides (hBNP), which dilate veins and arteries.
Human BNP binds to particulate guanylate cyclase receptor of vascular smooth muscle and endothelial cells.
Binding to receptor causes increase in cyclic GMP, which serves as second messenger to dilate veins and arteries. Reduces pulmonary capillary wedge pressure and improves dyspnea in patients with acutely decompensated congestive heart failure.

Dosing

Adult

2 mcg/kg IV bolus over 60 s; follow by 0.01 mcg/kg/min continuous infusion; bolus volume (mL) = 0.33 x patient weight (kg); infusion flow rate of bolus (mL/h) = 0.1 x patient wt (kg)

Pediatric

Not established

Interactions

Concurrent administration with ACE inhibitors and other vasodilators may cause hypotension

Contraindications

Documented hypersensitivity; systolic blood pressure <90 mm Hg; patients suspected of having or known to have low cardiac filling pressures, significant valvular stenosis, restrictive or obstructive cardiomyopathy, constrictive pericarditis, pericardial tamponade, or conditions in which cardiac output is dependent upon venous return

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Do not initiate at dose higher than recommended; may affect renal function in patients whose renal function may depend on activity of renin-angiotensin-aldosterone system; may cause hypotension (administer in settings where blood pressure can be monitored closely); discontinue drug if hypotension develops; ventricular tachycardia, nonsustained VT, headache, abdominal pain, back pain, insomnia, anxiety, angina pectoris, nausea, and vomiting may occur

Follow-up

Further Inpatient Care

• Admit for testing and surgical intervention.

Further Outpatient Care

• Carefully monitor medication dose and adverse effects.

Inpatient & Outpatient Medications

• Medications include beta-blockers, calcium channel blockers, and, rarely, diltiazem, amiodarone, and disopyramide.
• Use antitussives may be administered as needed to avoid coughing.
• Avoid inotropic drugs if possible.
• Avoid nitrates and sympathomimetic amines, except in those patients with concomitant coronary artery disease.
• Avoid digitalis because glycosides are contraindicated except in patients with uncontrolled atrial fibrillation.
• Avoid diuretics because of their effect on the LV outflow gradient and ventricular volume.

Transfer

• Transfer may be required for further diagnostic evaluation and electrophysiologic device or surgical intervention.

Deterrence/Prevention

• Patients must abstain from highly strenuous competitive athletic activity and highly strenuous physical exertion, such as shoveling snow or lifting very heavy objects, due to the high risk of arrhythmogenic sudden cardiac death. No acceptable medical recommendation deviates from a total abstinence of these activities.

Complications

• Congestive heart failure
• Ventricular and supraventricular arrhythmias
• Infective mitral endocarditis
• Atrial fibrillation with mural thrombosis formation
• Sudden death

Prognosis

• Reported annual mortality rates in patients with HCM have ranged from less than 1% to 3-6%, and studies suggest that they have significantly improved over the past 40 years.^26,27
• This is a chronic illness with lifestyle restrictions.

Patient Education

• Family members should learn cardiopulmonary resuscitation.
• Refer the patient and family for psychosocial counseling.
• Impose activity restrictions that include total abstinence from highly competitive athletic activities and very strenuous physical exertion, such as lifting heavy objects, lifting weights, and shoveling snow.
• Refer children of patients with HCM, especially those in the pediatric age range, for urgent echocardiography and genetic testing if echocardiogram does not yet reveal overt disease.
• For excellent patient education resources, visit eMedicine's Heart Center. Also, see eMedicine's patient education article Palpitations.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize associated conditions, such as essential hypertension, mitral regurgitation, mitral valve prolapse, and angina pectoris, is a potential pitfall.
• Failure to inform patient and family of exercise restrictions may lead to litigation. Deviation from the strongest of recommendations that the patient refrain from all high-intensity competitive sports is not acceptable due to the high risk of arrhythmogenic sudden cardiac death.
• Failure to recognize signs and symptoms of HCM may lead to legal problems.
• Failure to screen (or recommend screening) first-degree relatives once an index case is identified can be a medicolegal pitfall.

Special Concerns

• Many patients, particularly children, may not be symptomatic. Careful evaluation of a heart murmur may reveal HCM.

Multimedia

Media file 1: Hypertrophic cardiomyopathy.

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Keywords

hypertrophic cardiomyopathy, HCM, hypertrophic obstructive cardiomyopathy, idiopathic hypertrophic subaortic stenosis, IHSS, muscular subaortic stenosis, asymmetric septal hypertrophy, ASH, sudden death, sudden cardiac death, SCD, arrhythmogenic sudden death, myocardial hypertrophy, cardiomyopathy

Contributor Information and Disclosures

Author

Michael E Zevitz, MD, Assistant Professor of Medicine, Finch University of the Health Sciences, The Chicago Medical School; Consulting Staff, Private Practice
Michael E Zevitz, MD is a member of the following medical societies: American College of Cardiology, American College of Physicians, American Medical Association, and Michigan State Medical Society
Disclosure: Nothing to disclose.

Medical Editor

Gary E Sander, MD, PhD, Professor, Department of Internal Medicine, Division of Cardiology, Tulane University Health Sciences Center
Gary E Sander, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American College of Cardiology, American College of Chest Physicians, American College of Physicians, American Federation for Medical Research, American Heart Association, American Society of Hypertension, Heart Failure Society of America, Louisiana State Medical Society, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Frank M Sheridan, MD, Cardiology, Providence Everett Medical Center
Frank M Sheridan, MD is a member of the following medical societies: American College of Cardiology, American Heart Association, and Society for Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

CME Editor

Amer Suleman, MD, Consultant in Electrophysiology and Cardiovascular Medicine, Department of Internal Medicine, Division of Cardiology, Medical City Dallas Hospital
Amer Suleman, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Institute of Stress, American Society of Hypertension, Federation of American Societies for Experimental Biology, Royal Society of Medicine, and Society of Cardiac Angiography and Interventions
Disclosure: Nothing to disclose.

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