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. There are defects in several of the genes encoding for the sarcomeric proteins, such as myosin heavy chain, actin, tropomyosin, and titin. 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.

Frequency

United States

HCM is reported in 0.5% of the outpatient population referred for echocardiography. The overall prevalence of HCM is low and has been estimated to occur in 0.05-0.2% of the population. 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.

• 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.
• 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.

• 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.

http://emedicine.medscape.com/article/152913-overview