Antiarrhythmic and cardiac electrophysiological effects of SZV-270, a novel compound with combined Class I/B and Class III effects, in rabbits and dogs.

Abstract

Cardiovascular diseases are the leading causes of mortality. Sudden cardiac death is most commonly caused by ventricular fibrillation (VF). Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and a major cause of stroke and heart failure. Pharmacological management of VF and AF remains suboptimal due to limited efficacy of antiarrhythmic drugs and their ventricular proarrhythmic adverse effects. In this study, the antiarrhythmic and cardiac cellular electrophysiological effects of SZV-270, a novel compound, were investigated in rabbit and canine models. SZV-270 significantly reduced the incidence of VF in rabbits subjected to coronary artery occlusion/reperfusion and reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged the frequency-corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations, blocked I Kr in isolated cardiomyocytes (Class III effects), and reduced the maximum rate of depolarization (V max) at cycle lengths smaller than 1000ms in ventricular preparations (Class I/B effect). Importantly, SZV-270 did not provoke Torsades de Pointes arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. In conclusion, SZV-270 with its combined Class I/B and III effects can prevent reentry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.