Hypertrophic cardiomyopathy (HCM) is defined as left ventricular (LV) hypertrophy in the absence of abnormal loading conditions (valve disease, hypertension, congenital heart defects) sufficient to explain the degree of hypertrophy. Although asymmetrical septal hypertrophy was first described in the late 19th century, it was only after landmark reports by Sir Russell Brock (later Lord Brock) in 1957 and Donald Teare in 1958 that HCM became established as a clinical entity. Subsequent clinical, angiographic, and echocardiographic studies defined the characteristic morphologic and clinical features of the disease. Advances in molecular techniques have resulted in the current view of HCM as a disease primarily of the cardiac sarcomere.
Morphology and Pathophysiology
Macroscopically, myocardial hypertrophy in sarcomeric HCM is most commonly asymmetrical, predominantly affecting the interventricular septum (asymmetrical septal hypertrophy). Other patterns also occur, including concentric, midventricular (sometimes associated with a diverticulum at the LV apex), and apical.
Coexistent right ventricular hypertrophy is common but rarely, if ever, occurs in isolation. There are often associated abnormalities of the mitral valve (MV) and papillary muscles, which are also frequently displaced anteriorly. In addition, there is often an area of endocardial fibrosis on the septum beneath the aortic valve caused by repeated contact with the anterior leaflet during systolic anterior motion (SAM) of the anterior MV leaflet. Myocardial bridging of the left anterior descending coronary artery is also described in individuals with HCM.
Histologically, the hallmark of familial HCM is a triad of myocyte hypertrophy, myocyte disarray (architectural disorganization in the alignment of adjacent myocytes), and interstitial fibrosis. Myocyte disarray occurs in many pathologic processes, but its presence in more than 10% of the ventricular myocardium is considered a highly specific marker for HCM. Myocyte disarray can occur in the presence of only minimal macroscopic LV hypertrophy.
The pathophysiology of HCM is complex and involves a number of different components.
The major pathophysiologic consequence of LV hypertrophy is impairment of LV diastolic properties. Prolonged or incomplete LV relaxation results in a reduced rate and magnitude of rapid filling, leading to reduced LV diastolic volume, reduced stroke volume, and altered diastolic pressure-volume relationships. The net result is elevation of LV end-diastolic pressures and symptoms of reduced exercise tolerance, dyspnea, and pulmonary edema.
Global measures of LV systolic function, such as ejection fraction on echocardiogram, are often normal. However, abnormalities in regional myocardial contractility are described in HCM and progression to LV dilatation and systolic impairment is a recognized complication in a subgroup of patients. Although a number of markers associated with progression to systolic impairment have been identified, predicting which patients are at risk of developing end-stage disease remains a challenge.
Left Ventricular Outflow Tract Obstruction
Left ventricular outflow tract (LVOT) obstruction in HCM is caused by contact between the anterior leaflet of the MV and the interventricular septum during systole (SAM of the MV). This phenomenon is thought to result from drag forces on the leaflet resulting from anterior displacement of the papillary muscles, although the Venturi effect (causing the leaflet to be sucked against the septum) may also play a role. Approximately one-third of patients with HCM have LVOT obstruction at rest. In another one-third of patients, without outflow obstruction at rest, a gradient can be provoked by physiologic and pharmacologic interventions that diminish LV end-diastolic volume or increase LV contractility such as the Valsalva maneuver. This is known as latent LVOT obstruction. LVOT obstruction causes acute reductions in cardiac output, elevated LV filling pressures, and myocardial ischemia, which can result in symptoms of chest pain, exertional dyspnea, presyncope, and syncope.
Atrial fibrillation (AF) is the most common sustained arrhythmia in adults with HCM, with a prevalence and annual incidence of 22.5% and 3.2%, respectively. Patients with HCM and AF are at increased risk of thromboembolic events (stroke and peripheral embolism) with a prevalence and annual incidence of 27% and 4% respectively. Increasing age and left atrial (LA) enlargement (resulting from LVOT obstruction or diastolic dysfunction) are associated with paroxysmal or permanent AF and thromboembolic events. Ventricular extrasystoles are common in 25% of HCM patients having nonsustained ventricular tachycardia (VT) on ambulatory electrocardiographic monitoring. The presence of nonsustained VT is an important risk factor for sudden death.
Numerous epidemiologic studies from North America, Europe, Japan, and China have consistently reported a prevalence of unexplained LV hypertrophy of approximately 1 in 500 adults. The prevalence of HCM in childhood is unknown, however, retrospective population-based studies from the United States and Australia have reported an annual incidence of between 0.24 and 0.47 per 100,000 children.
HCM is usually inherited as an autosomal dominant trait; however, de novo mutations and incomplete penetrance can result in new familial cases.
Sixty percent of adults with HCM have mutations in genes that encode the proteins of the cardiac sarcomere. The majority of mutations are found in the β-myosin heavy chain (MYH7) and myosin-binding protein C (MYBPC3). Other genes that are less commonly affected include cardiac troponin T (TNNT2), cardiac troponin I (TNNI3), alpha-tropomyosin (TPM1), α-cardiac actin (ACTC), essential myosin light chain (MYL3), regulatory myosin light chain (MYL2), cardiac troponin C (TNNC1), α-myosin heavy chain (MYH6), and titin (TTN). The mechanisms by which sarcomeric gene mutations cause HCM are incompletely understood but may relate to abnormal myocardial bioenergetic pathways. Patients with sarcomeric mutations in general present at a younger age and have a stronger family history of sudden cardiac death (SCD).
Pathogenic mutations have also been identified in nonsarcomeric genes such as myozenin (MYOZ2) and telethonin (TCAP) genes that encode z-disc proteins in a small number of adult patients. In 5% to 10% of patients, HCM is associated with inborn errors of metabolism (eg, Anderson-Fabry disease), neuromuscular disorders (eg, Friedreich ataxia), malformation syndromes (eg, Noonan syndrome), or mitochondrial disorders ( Table 61.1 ).
|Sarcomeric protein disease||Obesity|
|Glycogen storage disease||Infants of diabetic mothers|
|Adenosine monophosphate (AMP) kinase||Athletic training|
|(Wolff-Parkinson-White, HCM, conduction disease)|
|Danon disease||Amyloid (AL/prealbumin)|
|Lysosomal storage diseases|
|Disorders of fatty acid metabolism|
|Syndromic HCM: Noonan syndrome, LEOPARD syndrome, Friedreich ataxia|
The underlying cause of pediatric HCM is thought to be more heterogeneous than that seen in the adult population. It was previously thought that mutations in sarcomeric protein genes were rare in the pediatric population; however, recent studies have shown their presence in over 50% of idiopathic childhood HCM.
Presentation and Outpatient Assessment
Most individuals with HCM have few, if any, symptoms. Frequently, the diagnosis is made during family screening or incidentally on detection of a murmur. When symptoms are present, they are most commonly dyspnea, chest pain, palpitations, or syncope. Echocardiographic findings of LVOT obstruction do not correlate well with symptom severity.
Patients may complain of typical anginal-type chest pain on exertion or atypical chest pains. The cause of chest pain in these patients is often multifactorial and includes myocardial ischemia due to increased LV wall mass, LV outflow obstruction, increased wall stress due to elevated diastolic pressures, and microvascular abnormalities. Systolic compression of epicardial and intramural vessels (myocardial bridging) is very common but is not usually of clinical importance.
Symptoms of heart failure (dyspnea and fatigue) are common. In some patients this is associated with well-maintained systolic function and evidence of diastolic dysfunction with impaired filling, while in others, symptoms are likely attributable to poor systolic function and LVOT obstruction.
Syncope is also relatively common and may result from LVOT obstruction, abnormal vascular responses, and atrial and ventricular arrhythmias. Syncope is a well-recognized risk factor for SCD.
Cardiovascular examination may be normal in HCM. Patients with LVOT obstruction, however, may exhibit a number of typical features. The arterial pulse has a rapid upstroke and downstroke, caused by rapid initial ventricular ejection followed by a sudden decrease in cardiac output. This may be followed by a palpable reflected wave resulting in a bisferiens pulse. The jugular venous pulsation may have a prominent “a” wave, caused by reduced right ventricular compliance. The apical impulse may be sustained or bifid, reflecting an atrial impulse followed by LV contraction; rarely, an additional late systolic impulse, resulting in a triple apical impulse, may be felt. On auscultation, patients with obstructive HCM have an ejection systolic murmur at the left sternal edge radiating to the right upper sternal edge and apex but usually not to the carotid arteries. Given the dynamic nature of LVOT obstruction in HCM, the intensity of the murmur is increased by maneuvers that reduce the preload or afterload, such as standing from a squatting position and the Valsalva maneuver. A concomitant pansystolic, high-frequency murmur of mitral regurgitation at the apex radiating to the axilla may also be heard. Often, a fourth heart sound is also present. In patients with syndromic or metabolic HCM, general examination may provide important diagnostic clues.
Abnormalities in the resting 12-lead electrocardiogram occur in more than 90% of individuals with HCM. These commonly include repolarization abnormalities, pathologic Q waves (most frequently in the inferolateral leads), left-axis deviation, and LA enlargement ( Fig. 61.1 ). Voltage criteria for LV hypertrophy alone are not specific for HCM, because they are often seen in normal teenagers and young adults. Giant negative T waves in the midprecordial leads are characteristically found in patients with apical HCM. Atrioventricular (AV) conduction delay is rare except in certain HCM subtypes (eg, in association with PRKAG2 mutations and mitochondrial disease). A short PR interval (and in some cases, “pseudo-preexcitation” not associated with accessory pathways) is seen in some patients.
All patients should undergo ambulatory monitoring at diagnosis as part of risk stratification for SCD. Ambulatory electrocardiographic monitoring reveals supraventricular arrhythmias in up to 38% of patients and nonsustained VT in 25% of individuals. Sustained VT is uncommon, except in patients with apical aneurysms.
Echocardiography is the gold standard for the diagnosis of HCM ( Box 61.1 ); the presence of LV wall thickness greater than two standard deviations above the body surface area–corrected mean in any myocardial segment (or ≥15 mm in adults) is sufficient for the diagnosis. Although most patients have asymmetrical septal hypertrophy ( Fig. 61.2 ), any pattern of LV hypertrophy is consistent with the diagnosis of HCM, including concentric, eccentric, distal, and apical patterns. It is therefore essential to visualize and accurately measure all LV segments.
Hypertrophy can affect any myocardial segment but most commonly involves the basal ventricular septum.
LVOT obstruction, caused by SAM of the MV, is present in 25% of individuals at rest, but can be provoked by exercise in up to 70% of patients.
SAM is typically associated with posteriorly directed mitral regurgitation.
LV diastolic function is often impaired.
LVOT obstruction is present at rest in approximately 33% of patients, with another 33% of patients having latent or provokable outflow tract obstruction that is caused by SAM of the MV ( Fig. 61.3 ). Echocardiographically, dynamic obstruction in the LVOT is associated with midsystolic closure of the aortic valve, which is often associated with coarse fluttering of the aortic valve on M-mode echocardiography. Continuous wave Doppler assessment is used to quantify the severity of LVOT obstruction, with a characteristic high-velocity, late-systolic peak seen ( Fig. 61.4 ). LVOT obstruction is defined as a peak instantaneous gradient greater than or equal to 30 mm Hg. A gradient greater than or equal to 50 mm Hg is generally recognized as the threshold at which LVOT obstruction becomes hemodynamically significant. In symptomatic patients, if bedside provocation tests do not elicit a gradient of 50 mm Hg or greater, an exercise stress echocardiography is recommended due the significance of LVOT obstruction as a risk factor for SCD.