ELECTROPHYSIOLOGICAL, RATE-DEPENDENT, AND AUTONOMIC EFFECTS OF THE CLASS-III ANTIARRHYTHMIC ALMOKALANT AFTER MYOCARDIAL-INFARCTION IN THE PIG

Ventricular arrhythmias remain a major problem, in particular in patie nts with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agen ts should preferably not only have pure antiarrhythmic effects, but sh ould also be free from adverse autonomic properties. In the present st udy, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarctio n. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 mu mol . kg(-1). min(-2), continuous in fusion: 0.0025 mu mol . kg(-1). min(-1)) from 292 +/- 25 to 308 +/- 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES], from 249 +/- 19 to 261 +/- 16 ms (PCL 400 ms +1ES), and from 209 +/- 1 8 to 219 +/- 18 ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 +/- 27 to 186 +/- 29 ms IP < 0.05) and at PCL 300 ms: from 159 +/- 29 to 174 +/- 27 ms (P < 0.05). The ventricular m onophasic action potential durations (MAPD) were similarly prolonged a nd the ratio VERP/MAPD did not change. Prolongation of MAPD after almo kalant remained present at short pacing cycle lengths. Before almokala nt infusion, sustained monomorphic ventricular tachycardia (VT) was in ducible in two pigs, and nonsustained VT in a third animal. After almo kalant, only one pig remained inducible. Two weeks after myocardial in farction, heart rate variability and baroreflex sensitivity were reduc ed. Furthermore, subsequent electrophysiological testing transiently r educed these parameters of autonomic activity. During almokalant howev er, no changes in autonomic functions were observed after programmed s timulation. Heart rate variability decreased after myocardial infarcti on from 6.3 +/- 2.5 ms to 5.4 +/- 4.2 ms (P = NS). After programmed st imulation, it further decreased to 2.8 +/- 2.0 ms (P = 0.028). Almokal ant infusion prevented autonomic deterioration: 3.3 +/- 2.2 ms before stimulation and 3.3 +/- 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengt hs. The results indicate absence of reverse rate dependence and of adv erse autonomic changes.