Variability of the Hypertrophic Response to Overload

1 December, 2011 (21:16) | Heart Diseases | By: Health news

Clinical experience tells us that there is a wide spectrum in the individual hypertrophic response to overload. Most striking are the adolescents in whom massive ventricular hypertrophy develops in the absence of apparent hemodynamic overload; this is, of course, the condition recognized as hypertrophic cardiomyopathy. At the other end of the spectrum are the elderly patients with substantial overloading caused by severe and long-standing systemic hypertension who have relatively less severe left ventricular hypertrophy. In the middle of the spectrum are the hypertensive patients in whom there is no clear relation between the hypertrophic response of the ventricle and the severity and duration of overloading; however, there are reports that the prevalence of hypertensive heart disease for any given level of blood pressure is higher in men than women and in blacks than whites. A suggestion that the attenuation of the hypertrophic response to overload with advancing age may contribute to the high incidence of heart failure in the elderly has recently found support in studies showing a diminished capacity for left ventricular hypertrophy after experimentally induced aortic stenosis94 and insufficiency in aged rats.
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Functional Abnormalities in the Hypertrophied and Failing Heart

The protein-isoform changes that have been described thus far probably represent but a small fraction of the molecular abnormalities that develop in chronically overloaded myocardial cells. Additional but as yet incompletely characterized changes in composition are suggested by important functional abnormalities in the hypertrophied and failing heart that may contribute to the arrhythmias and progressive pump dysfunction that lead to death in patients with congestive heart failure.

Electrophysiologic Abnormalities

Arrhythmias are among the most important determinants of prognosis in patients with congestive heart failure. Although these disorders arise in part from conduction inhomogeneities caused by the enlargement and fibrosis of the hypertrophied heart, there is growing evidence that abnormal isoforms of the ion channels responsible for the heart’s electrical activity may also be synthesized in the failing heart.

Prolongation of the action potential, among the most prominent electrophysiologic abnormalities in hypertrophied myocardial cells, may be due in part to an increase in the slow inward calcium current that maintains depolarization during the plateau of the cardiac action potential. Recent evidence suggests that such prolongation may be due in part to the delayed inactivation of L-type calcium channels. This abnormality may also be due to the attenuation of one or more of the outward potassium currents that cause repolarization, including the transient outward potassium current, the ATP-sensitive potassium current, and both inward and delayed rectifier currents.

A role for these molecular abnormalities in the pathogenesis of arrhythmias in patients with heart failure remains unproved; however, this is a rapidly developing field, and specific peptide regions in the large ion-channel proteins that regulate the opening, closing, and inactivation of the channel have recently been identified. The molecular mechanisms responsible for some of the electrophysiologic abnormalities in the failing heart may be elucidated by studies of single ion-channel molecules, which may uncover a molecular basis for some of the arrhythmias commonly seen in congestive heart failure.