Ischemia-Induced Action Potential Shortening is Blunted by d-Sotalol in a Pig Model of Reversible Myocardial Ischemia

Abstract

The purpose of this study was to investigate, in an anesthetized pig model of low-flow myocardial ischemia, the electrophysiologic effects of the class III drug d-sotalol during myocardial ischemia. Serial monophasic action potential (MAPD90) recordings and refractory period determinations from the anterior and posterior left ventricular wall were taken in 25 pigs during baseline, after low-flow posterior wall ischemia, after d-sotalol infusion under nonischemic conditions, and after repeated posterior wall ischemia while continuing the drug. Measurements were done at 60 and 150 beats/min after radiofrequency ablation of atrioventricular conduction. At baseline, MAPD90 and refractory periods were comparable in the anterior and posterior wall (323 +/- 15 vs. 318 +/- 10 ms, and 267 +/- 10 vs. 262 +/- 11 ms at 60 beats/min, respectively). In the absence of d-sotalol, low-flow regional ischemia was associated with a significant shortening of MAPD90 in the posterior versus the anterior wall (267 +/- 20 vs. 317 +/- 20 ms at 60 beats/min; p = 0.006). Similarly, ischemia-induced shortening of the refractory periods in the posterior wall was apparent (230 +/- 16 ms in the posterior wall vs. 274 +/- 14 ms in the anterior wall at 60 beats/min). In contrast, ischemia was no longer associated with shortening of MAPD90 (360 +/- 17 ms posterior wall and 360 +/- 20 ms anterior wall at 60 beats/min) and refractory periods (304 +/- 19 ms posterior wall vs. 316 +/- 15 ms anterior wall at 60 beats/min) during combined posterior wall ischemia and d-sotalol infusion. Similar findings were obtained during pacing at 150 beats/min. d-Sotalol attenuates ischemia-induced action potential shortening. This property should decrease dispersion of cardiac repolarization and be antiarrhythmic. On the other hand, longer APD under ischemic conditions may favor calcium overload, which may trigger new arrhythmias.

Thiazolidinedione drugs block cardiac KATP channels and may increase propensity for ischaemic ventricular fibrillation in pigs

“…Shortening of MAP duration is the expected response to ischaemia, due primarily to opening of K ATP channels [1]. The magnitude of observed changes was similar to those demonstrated by other investigators in dogs and pigs [4,34].…”

The autonomic nervous system and ventricular arrhythmias in myocardial infarction and heart failure

“…Studies in cats and canine models of ischemia revealed that sympathetic stimulation creates both the electrophysiological substrate and the trigger for VT/VF by reducing action potential duration, increasing dispersion of repolarization, and causing early after depolarizations (EADs) and delayed after depolarizations (DADs), Table . Action potential shortening and increased dispersion of repolarization (as also evidenced by increased T‐peak to T‐end interval) have been demonstrated in chronic porcine infarct models, in response to sympathetic nerve stimulation …”

“…[36][37][38] Action potential shortening and increased dispersion of repolarization (as also evidenced by increased T-peak to T-end interval) have been demonstrated in chronic porcine infarct models, in response to sympathetic nerve stimulation. 39,40 Inflammation and ischemia also injure axons of the autonomic nerves, resulting in denervation. Studies in canine models of MI and humans undergoing catheter ablation for recurrent VA demonstrate that denervation is observed within the infarcted myocardium as well as nearby viable myocardium.…”