Chin Med J (Taipei) 1998;61:S106.

Mechanisms, Pathophysiology, and Management of Hypertrophic Cardiomyopathy

David A. Kass, M.D.

Johns Hopkins Medical Institutions, Baltimore, MD USA

Abstract

Hypertrophic cardiomyopathy (MCH) has two primary forms. One is an inherited disorder that involves mutations localized to one of the contractile proteins in the heart (beta-myosin heavy-chain, myosin essential and regulatory light chains, troponin T, alpha-tropomyosin, and myosin C-protein). The second is an acquired disease occurring with chronic cardiac overload states - most commonly poorly regulated hypertension. Despite major differences in etiology, both forms of HCM display many common pathophysiologic characteristics.

Hyperdynamic ventricular contraction with small volumes and cavity obliteration and/or obstruction (the latter more common in the familial disorder in conjunction with marked asymmetric hypertrophy) is very common. This is also associated with a marked stiffening of the ventricle at end-systole as measured by end-systolic pressure-volume relations (8-10 mm Hg/mL for HCM versus =2 mm, Hg/mL in normal hearts). Increased ventricular systolic stiffening contributes to volume load sensitivity - for example the hypotension that occurs with preload reduction maneuvers such as sudden standing or Valsalva. Cavity obliteration also means that systolic internal loads are considerable increasing metabolic demand within the wall and likely contributing to progressive myocyte damage and fibrosis. Both forms of hypertrophy also result in diastolic chamber abnormalities, with delayed relaxation, a reduced amplitude of early rapid filling, and reduced chamber compliance. Reserve limitations are also present - such as loss of the normal positive force-frequency dependence, and are thought to relate to abnormalities of calcium handling.

Until recently, most experimental data related to HCM involved models of increased afterload. However, there are now novel murine models of familial HCM that replicate single gene mutations in specific contractile proteins. The most extensively studied to date is based on a single amino-acid substitution (R403Q) in the beta-myosin heavy chain. Animals develop muscle fiber disarray, fibrosis, ventricular systolic stiffening, and abnormalities in diastolic pressure decay. Studies with this model are for the first time revealing muscle and chamber abnormalities that can be linked to the mutation itself versus those that develop over time.

Treatment of HCM principally involves depression of systolic function and improvement of diastolic filling. Calcium channel blockers such as verapamil, and other agents such as disopyrimide, have potent negative inotropic effects. The former can also enhance early filling characteristics although the extent to which it improves chamber passive stiffness is unclear. Beta-blockers are useful for chronotropic control, since HCM ventricles are preload-dependent and become easily compromised at faster rates. Surgical myotomy/myectomy is reserved for asymmetric FHC with marked cavity gradients, and has proven to be very useful. This therapy may provide some of its benefit by inducing contractile depression. Recent studies suggest that ventricular pacing with a short PR interval can also benefit HCM patients. Early promising data were uncontrolled, and results of more recent placebo controlled trials shows symptomatic improvement that is somewhat out of proportion to measurable functional improvement. Our laboratory recently completed a randomized clinical trial in 9 patients with secondary HCM (i.e. nonobstructive, with hypertension), and found a substantial rise in exercise duration (6.25 to 9.8 mins) and VO2-max (14.1 to 16.7 mlO2/min/kg) only during the pacingON period. Pacing therapy works primarily by inducing discoordinate wall motion and principally effects systole. These and other ongoing trials are providing new avenues to treat this complex disorder.

[Chin Med J (Taipei) 1998;61:S106.]