IONIC MECHANISMS OF ISCHEMIA-RELATED VENTRICULAR ARRHYTHMIAS

The aim of this review is the utmost simplification of the cellular el ectrophysiologic background of ischemia-related arrhythmias. In the ac ute and subacute phase of myocardial infarction, arrhythmias can be ca used by an abnormal impulse generation, abnormal automaticity or trigg ered activity caused by early or delayed afterdepolarizations (EAD and DAD), or by abnormalities of impulse conduction (i.e., reentry). This paper addresses therapeutic intervention aimed at preventing the depo larization of ''pathologic'' slow fibers, counteracting the inward cal cium (Ca) influx that takes place through the L-type channels (Ca anta gonists), or hyperpolarizing the diastolic membrane action potential, increasing potassium (K) efflux (K-channel openers) in arrhythmias gen erated by an abnormal automaticity (ectopic tachycardias or accelerate d idioventricular rhythms). If the cause of enhanced impulse generatio n is related to triggered activity, and since both EAD and DAD are dep endent on calcium currents that can appear during a delayed repolariza tion, the therapeutic options are to shorten the repolarization phase through K-channel openers or Ca antagonists, or to suppress the inward currents directly responsible for the afterdepolarization with Ca blo ckers. Magnesium seems to represent a reasonable choice, as it is able to shorten the action potential duration and to function as a Ca anta gonist. Abnormalities of impulse conduction (reentry) account for the remainder of arrhythmias that occur in the acute and subacute phase of ischemia and for most dysrhythmias that develop during the chronic ph ase. Reentrant circuits due to ischemia are usually Na channel-depende nt. Drug choice will depend on the length of the excitable gap: in cas e of a short gap (ventricular fibrillation, polymorphic ventricular ta chycardia, etc.), the refractory period has been identified as the mos t vulnerable parameter, and therefore a correct therapeutic approach w ill be based on drugs able to prolong the effective refractory period (K-channel blockers, such as class III antiarrhythmic drugs); on the o ther hand, for those arrhythmias characterized by a long excitable gap (most of the monomorphic ventricular tachycardias), the most appropri ate therapeutic intervention consists of depressing ventricular excit- ability and conduction by use of sodium-channel blockers such as mexil etine and lidocaine. Compared with other class I antiarrhythmic agents , these drugs minimally affect refractoriness and exhibit a use-depend ent effect and a voltage-dependent action (i.e., more pronounced on th e ischemic tissue because of its partial depolarization).