CELLULAR MECHANISMS OF ARRHYTHMIAS IN HYPERTROPHIED AND FAILING MYOCARDIUM

Understanding the electrophysiological basis for arrhythmias associate d with left ventricular hypertrophy and heart failure could lead to im proved therapeutic measures to prevent or treat potentially lethal rhy thm disorders. Cellular mechanisms that could generate abnormal rhythm ic activity in the diseased heart include afterpotentials (early after depolarizations and delayed afterdepolarizations), reentry, and enhanc ed automaticity. The available experimental evidence points to afterpo tentials as the most likely mechanism for generating arrhythmias in th e hypertrophied and failing heart. Afterpotentials occur when the norm al balance between inward and outward currents is altered in such a wa y that an abnormal net inward depolarizing current develops during or after the action potential. An early afterdepolarization occurs when t he depolarizing inward current increases before repolarization, thus i nterrupting the normal course of repolarization. Early afterdepolariza tions could play a central role in generating arrhythmias because they appear to be the electrical abnormality most likely to develop in hyp ertrophied and failing myocardium in which the principal electrical ab normality is a prolonged action potential. The prolonged duration of r epolarization provides an arrhythmogenic substrate in which conditions that augment inward depolarizing currents or reduce outward repolariz ing currents are more likely to evoke triggered activity arising from early or delayed afterdepolarizations. The prolonged duration of the a ction potential and early afterdepolarizations might also contribute t o development of reentry by creating conditions necessary to support r eentrant excitation. Enhanced automaticity has not been demonstrated a s a mechanism for arrhythmias in hypertrophied and failing myocardium. If early afterdepolarizations play a major role in evoking arrhythmia s in the hypertrophied and failing heart, then therapeutic measures de signed to prevent early afterdepolarizations should inhibit the develo pment of arrhythmias. The development of agents that selectively reduc e the prolonged duration of repolarization in hypertrophied myocardium could be useful as antiarrhythmic agents. The development of such age nts requires a more detailed understanding of the ionic mechanisms res ponsible for prolonging repolarization in hypertrophied and failing my ocardium. In the meantime, a prudent approach to minimizing the develo pment of arrhythmias in patients with heart failure is to avoid condit ions and drugs that promote the development of afterpotentials.