Etiology
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the cardiac sarcomere, caused by mutations in genes that encode different components of the contractile apparatus.[15] The disease is genetically heterogeneous, with over 270 identified mutations in 13 causative genes.[16][17] Mutations in the beta-cardiac myosin heavy chain are the most common (44% of mutations), with mutations in the myosin binding protein C gene second in frequency (35% of mutations).[17] Mutations in the troponin I, troponin T, and alpha-tropomyosin genes account for 10% to 15% of mutations.[17] Up to 5% of patients may have more than one mutation.[18] Phenotypic expression of disease is heterogeneous even within families with the same genetic defect.[4] The overall yield of genetic testing is low in HCM, with no causative gene identified in approximately 50% of patients.[19]
Pathophysiology
Presence of one of the responsible genetic mutations leads to septal thickening from myocyte hypertrophy as well as abnormal, thickened, disorganized collagen matrix. Septal hypertrophy may be diffuse or localized to one particular location of the septum. In the most classic form, hypertrophy is most marked in the septum immediately below the aortic valve.[4] The hypertrophied septum may lead to left ventricular (LV) outflow tract obstruction, either in isolation or in association with systolic anterior motion of the mitral valve.[4] Systolic anterior motion of the mitral valve occurs in response to turbulent flow in the subaortic region wherein the anterior leaflet of the mitral valve is pulled into the subaortic region, thereby leading to further obstruction.
Obstruction may alternatively be confined to the midcavity of the left ventricle. This occurs as a result of midseptal hypertrophy and hypertrophy of the LV papillary muscles. Patients develop intracavitary systolic obstruction secondary to apposition of the septum and the papillary muscles. These patients typically do not have systolic anterior motion of the mitral valve as the obstruction is lower in the ventricular cavity. Isolated hypertrophy of the apex may also occur (apical HCM).[4] Increased obstruction will occur in response to an increase in heart rate, myocardial contractility, reduced ventricular volume, and peripheral vasodilation. Most patients demonstrate impaired diastolic relaxation irrespective of the presence of hypertrophy.[4] Diastolic dysfunction leads to increased filling pressures and is argued to be the primary source of symptoms in many patients, particularly young people.[4][20]
Myocardial ischemia is common and likely multifactorial in origin. It may be due to increased myocardial oxygen demand and reduced myocardial capillary density relative to the LV hypertrophy, small vessel disease, compression of septal perforating arteries, myocardial bridging (characterized by a segment of a major epicardial coronary artery tunneling through the myocardium), obstruction to LV outflow, and increased coronary vascular resistance due to abnormal LV relaxation and impaired filling.[4] The presence of symptoms may be due to the degree of subaortic stenosis at rest and with exercise, impaired diastolic relaxation, arrhythmias, impaired systolic contraction in the absence of obstruction, and ischemia.[4]
Classification
Obstructive versus nonobstructive
Disease is classified as obstructive or nonobstructive based on the presence or absence of left ventricular outflow tract obstruction on echocardiography at rest.[1][2] A resting pressure gradient between the left ventricle and the aorta is present in 37% of patients. An additional 33% will have provocable obstruction (e.g., obstruction with exercise), such that the majority of patients have some degree of obstruction.[3] There is not a strong correlation between symptoms and the degree of obstruction and, in fact, patients with severe obstruction may be asymptomatic.[4]
Site of obstruction
Patients may be classified based on the site of maximal left ventricular obstruction:[4]
Subaortic obstruction (classic)
Midventricular obstructive HCM
Apical HCM
Complex obstructive HCM
Some patients may also have coexisting right ventricular (RV) obstruction. The incidence of RV systolic obstruction in HCM has been reported as 15% to 92% by catheterization studies.[5]
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