Role of alterations in refractoriness and conduction in the genesis of reentrant arrhythmias. Implications for antiarrhythmic effects of class III drugs.
Despite the fact that a number of different electrophysiologic mechanisms are capable of causing cardiac arrhythmias, reentrant excitation has emerged as the most important mechanism causing life-threatening arrhythmias that arise in the ventricles. Pharmacologic therapy of arrhythmias caused by reentry is aimed at preventing the conditions that either facilitate the initiation of the circulating reentrant excitation wave or the conditions that permit its persistence. This involves alterations in either refractoriness or conduction by the drugs. Both atrial and ventricular tachyarrhythmias may follow premature depolarizations that occur at a critical coupling interval to a previous excitation. One desirable property of antiarrhythmic drugs might be to prevent the initiation of reentrant excitation by the triggering premature impulse. Mechanisms are described to show how drugs that prolong the action potential duration (class III antiarrhythmic drugs) might have this effect. It is, however, emphasized that drug effects that have been documented in electrophysiologic studies on normal myocardium might not occur in an arrhythmogenic region that has pathologic alterations, because of changes in the properties of ion channels of the diseased myocardial cells. Antiarrhythmic drugs might also terminate ongoing reentrant excitation by causing block of conduction in the reentrant pathway, at least for one beat. Class III drugs are expected to stop the perpetuation of reentry by prolonging the action potential duration and the refractory period of myocardial fibers in the reentrant circuit to such an extent that the propagating reentrant impulse no longer finds excitable myocardium but blocks in refractory tissue. Therefore, the effectiveness of this drug class to terminate reentry should depend on at least 2 factors: the size of the excitable gap as the reentrant impulse moves around the circuit, which may be related to the mechanism that causes reentry, and the degree to which the drugs can prolong the action potential duration and refractory period at the rapid rates of tachycardia. Each of these factors is discussed with relation to the proposed mechanism of action of drugs that prolong repolarization.
Wit
A L
AL
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York.
Coromilas
J
J
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D013611:Tachycardia, Atrioventricular Nodal Reentry / Q000188:drug therapy* / Q000503:physiopathology*; D013615:Tachycardia, Sinoatrial Nodal Reentry / Q000188:drug therapy* / Q000503:physiopathology*
D000889:Anti-Arrhythmia Agents