Hypertrophic Cardiomyopathy

DEFINITION AND ETIOLOGY

Hypertrophic cardiomyopathy (HCM) is defined as hypertrophy of the myocardium more than 1.5 cm, without an identifiable cause (Fig. 1). Other causes of left ventricular (LV) hypertrophy, such as long-standing hypertension and aortic stenosis, must be excluded before HCM can be diagnosed. As our understanding of the genetics of HCM progresses, HCM will likely be diagnosed based on genetic testing, with transthoracic echocardiography (TTE) used to assess the phenotypic manifestations and clinical severity of the disease.

Figure 1 Gross pathology specimen of hypertrophic cardiomyopathy (HCM).

Marked septal hypertrophy of the left ventricle (LV) can be seen.

PREVALENCE AND RISK FACTORS

HCM is the most common genetic cardiovascular disease. Genetic mutations resulting in HCM primarily involve the cardiac sarcomere but may also involve the connective tissue matrix. The prevalence in the general adult population for people with phenotypic evidence of HCM is 1 per 500. Men are more often affected than women and blacks more often than whites. In young adults, HCM is the most common cause of sudden cardiac death.

Strenuous exercise by increasing afterload, such as heavy weight lifting, could theoretically increase the magnitude of LV hypertrophy and worsen obstruction in subjects with preexisting HCM. Risk factors for the development of end-stage HCM (manifesting as LV systolic dysfunction and LV dilatation) include younger age at onset of HCM, a family history of HCM, greater ventricular wall thickness, and certain genetic mutations.

PATHOPHYSIOLOGY AND NATURAL HISTORY

More than 150 mutations in 10 genes, primarily involving the myosin, actin, or troponin components of the cardiac sarcomere, have been identified as causes of HCM. Five of these mutations are considered especially malignant in light of their propensity for sudden cardiac death. However, a recent study of 293 HCM patients at the Mayo Clinic has assessed the prevalence of these malignant mutations and found that only three patients, or approximately 1%, had one of the malignant mutations for HCM. There are varying expressions of mutations for HCM.

HCM can be considered obstructive or nonobstructive, depending on the presence of a left ventricular outflow tract (LVOT) gradient, either at rest or with provocative maneuvers. Alternatively, HCM can be classified based on location of the hypertrophy, such as the proximal septum or the apex. Finally, there appear to be distinct forms of HCM at different ages. Younger patients often have more diffuse hypertrophy and reversal of septal curvature (Fig. 2), whereas older patients tend to have focal proximal septal hypertrophy, with a sigmoid septal morphology (Fig. 3). These may be two different disease processes, because subjects with reversal of septal curvature were found to have an almost 80% yield for screening for HCM-associated mutations but those with a sigmoid septum had less than a 10% yield. Hypertrophy often develops or worsens during the adolescent growth spurt. An apical variant of HCM also exists (Fig. 4).

Figure 2 Diffuse hypertrophy variant of hypertrophic cardiomyopathy (HCM).

This pattern of hypertrophy is classically seen in younger patients. Ao, aorta; IVS, interventricular septum; LA, left atrium; LV, left ventricle.

Figure 3 Proximal septal hypertrophy variant of hypertrophic cardiomyopathy (HCM).

This pattern of hypertrophy is classically seen in older patients. Ao, aorta; LA, left atrium; LV, left ventricle.

Figure 4 Apical hypertrophy variant of hypertrophic cardiomyopathy (HCM).

In this type of HCM the hypertrophy involves mainly the apex.

LV hypertrophy usually involves thickening of the proximal portion of the interventricular septum, resulting in narrowing of the LVOT. Systolic anterior motion (SAM) of the mitral valve can occur if the mitral valve leaflets are pulled or dragged anteriorly toward the ventricular septum. SAM results in LVOT obstruction and mitral regurgitation. Consequently, the left ventricle has to generate higher pressures to overcome the LVOT obstruction. Premature closure of the aortic valve can occur and is caused by the decline in pressure distal to the LVOT obstruction.

The obstruction that occurs with HCM is dynamic, unlike the fixed obstructions of aortic stenosis and subvalvular aortic membranes. In dynamic obstruction, the degree of obstruction depends more on cardiac contractility and loading conditions than on fixed obstructions. An underfilled left ventricle results in greater obstruction, because there is less separation between the interventricular septum and mitral valve. Augmenting cardiac contractility also increases LVOT obstruction, because a more vigorous contraction is more likely to cause the obstructing components to come together. Most patients with HCM have a favorable prognosis. Complications of HCM include atrial fibrillation, ventricular arrhythmias, congestive heart failure, and sudden cardiac death.

End-stage HCM, which occurs in 5% of those with HCM, manifests as systolic LV dysfunction, thinning of the LV wall, and dilation of the ventricular cavity. Sudden cardiac death tends to occur in younger patients and can occur during heavy exertion, light exertion, or even at rest. In an unselected community-based population with HCM, the estimated incidence of sudden cardiac death is approximately 0.1% to 0.7% per year. HCM can also result in restrictive cardiomyopathy.

SIGNS AND SYMPTOMS

The clinical course of HCM is variable. Most patients with HCM are asymptomatic. For symptomatic patients, the occurrence and severity of symptoms do not necessarily correlate with the magnitude of the LVOT gradient. Symptoms appear to be associated more with the severity of mitral regurgitation and diastolic dysfunction.

Dyspnea on exertion is the most common symptom. Other complaints include chest pain with exertion, syncope or near syncope, or palpitations. Eating can exacerbate symptoms caused by splanchnic vasodilation and the resulting decrease in cardiac preload. Symptoms are often progressive. If patients develop some of the complications of HCM, such as atrial fibrillation or congestive heart failure, symptoms accompanying those particular conditions can occur, such as palpitations and orthopnea, paroxysmal nocturnal dyspnea, or leg edema, respectively.

Physical examination provides several clues suggestive of HCM. Palpation of the carotid pulse aids in distinguishing HCM from aortic stenosis or the presence of a subvalvular aortic membrane. With HCM, the carotid upstroke is brisk, because there is little resistance during early systole in ejecting the blood through the LVOT into the aorta. As systole progresses, LVOT obstruction occurs in HCM, resulting in a collapse in the pulse and then a secondary increase, a finding termed a bisferiens pulse. In contrast, because the fixed obstruction of aortic stenosis or subvalvular aortic membranes is present during the entire cardiac cycle, the carotid upstroke in these entities is the classic parvus et tardus pulse (small amplitude and delayed upstroke), a carotid pulse with delayed upstroke and amplitude. Thus, if any patient with a diagnosis of HCM has decreased carotid pulses, one should suspect misdiagnosis and carry out further investigation into fixed obstruction of the LVOT.

The lungs are usually clear and the jugular venous pressure normal. The point of maximal impulse will be forceful and sustained, and a palpable S₄ gallop may be present. The classic auscultatory finding for HCM is a crescendo–decrescendo systolic murmur along the left sternal border that increases with the Valsalva maneuver. Almost all cardiac murmurs decrease in intensity during Valsalva, with the exception of HCM, so this maneuver is a crucial part of the cardiac examination if HCM is suspected (Table 1). The Valsalva maneuver decreases preload, which results in decreased filling of the left ventricle. An underfilled left ventricle results in an increase in LVOT obstruction. Similarly, rising from squatting to standing decreases left ventricle preload and increases the intensity of the murmur. Finally, amyl nitrite, a profound vasodilator, decreases preload and causes a reflex tachycardia. This results in a louder murmur because of an increased degree of obstruction. In addition, it is imperative to auscultate carefully for a mitral regurgitation murmur; such a finding can indicate systolic anterior motion of the mitral valve, with accompanying mitral regurgitation. The remainder of the examination is generally unremarkable.

Table 1 Effects of Physiologic and Pharmacologic Maneuvers on Hypertrophic Cardiomyopathy

DIAGNOSIS

Laboratory Tests

Blood work generally is unremarkable. A chest radiograph may suggest LV hypertrophy but often is normal because the hypertrophy in HCM involves the ventricular septum. The electrocardiogram should show LV hypertrophy and occasionally may also have a pseudoinfarct pattern, in which Q waves are present despite the absence of coronary artery disease. Left atrial abnormality may be present if the patient has had long-standing mitral regurgitation from SAM of the mitral valve. Atrial fibrillation also may be present.

Imaging

Echocardiography is the gold standard for diagnosing HCM (see Figs. 2 to 4). With transthoracic echocardiogram (TTE), the septum can be well visualized and measured in the parasternal long, apical long, apical four-chamber, and parasternal short axis views. On TTE, one should note the septal thickness, location and pattern of hypertrophy, site and degree of left LVOT obstruction, presence of SAM of the mitral valve, presence of premature closure of the aortic valve, and any change in severity of obstruction with provocation. If no LVOT gradient is present in patients with HCM or suspected HCM, patients should undergo provocative testing with squatting, the Valsalva maneuver, or amyl nitrite to determine whether there is latent obstruction. To assess the functional significance of LVOT obstruction further, we often perform stress echocardiography studies in patients with HCM. Some patients have minimal resting gradients but develop large gradients with exercise. In our experience, supervised stress tests in patients with HCM are safe.

Transesophageal echocardiography and magnetic resonance imaging are other potential modalities for diagnosing HCM, particularly in subjects with technically difficult echocardiographic studies. Both modalities have superior resolution to transthoracic echocardiography but are more costly and, in the case of transesophageal echocardiography, more invasive.

Diagnostic Procedures and Differential Diagnosis

HCM should be differentiated from valvular aortic stenosis and a subvalvular aortic membrane. In aortic stenosis, the aortic valve is calcified and has restricted mobility. In HCM, the obstruction occurs below the aortic valve, and the valve structure and function are preserved. However, with aging, degenerative calcific disease of the aortic valve can make it difficult to distinguish between the two entities. A subvalvular aortic membrane is sometimes difficult to visualize on transthoracic echocardiography.

Continuous-wave Doppler imaging is useful in differentiating HCM from fixed obstructions, such as valvular aortic stenosis and a subvalvular membrane. Doppler imaging measures the velocity of blood over time. Fig. 5 illustrates the differences between Doppler signals from HCM and from fixed obstructions. With HCM, the continuous Doppler signal has a late systolic dagger shape; the obstruction is late peaking because of its dynamic nature. During early systole, blood still flows through the LVOT; however, with continued contraction of the left ventricle, exacerbated by systolic anterior motion of the mitral valve, the outflow tract area diminishes and an outflow tract gradient then develops. In contrast, a fixed obstruction is present during all of systole. Thus, the continuous-wave Doppler signal for fixed obstructions is a smoother contour that peaks earlier.