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, reduced the incidence of burst-induced AF in a tachypaced conscious canine model of AF. SZV-270 prolonged frequency corrected QT interval, lengthened action potential duration and effective refractory period in ventricular and atrial preparations and blocked IKr in isolated cardiomyocytes (Class III effects), reduced maximum rate of depolarization (Vmax) at cycle lengths smaller than 1000 ms 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 re-entry arrhythmias with reduced risk of provoking drug-induced Torsades de Pointes.

Multichannel modulation of depolarizing and repolarizing ion currents increases the positive rate‐dependent action potential prolongation

“…There is also abundant clinical and experimental evidence suggesting that the combined modulation of several ion currents may result in neutral (neither positive nor reverse) rate‐dependent APD prolongation (Bril et al, 1995, 1998; Dorian & Newman, 2000; Faivre et al, 1999; Hondeghem & Snyders, 1990; Kassotis et al, 2003; Lathrop & Varró, 1989, 1990; Mátyus et al, 2004; Nadler et al, 1998; Qi et al, 1999; Shibata et al, 2012; Varga et al, 2021; VerNooy & Mangrum, 2005). The exact mechanism underlying the attenuation of reverse rate dependence by the combined modulation of several ion currents is unknown.…”

“…For example, verapamil derivatives like BRL‐32872, which block I CaL (L‐type calcium current) and I Kr , show a neutral (i.e., neither positive nor reverse) rate‐dependent APD prolongation (Bril et al, 1995, 1998; Faivre et al, 1999; Nadler et al, 1998). The combination of class I/B (lidocaine, mexiletine) and class III (d‐sotalol) agents also has a favorable rate‐dependent response with antiarrhythmic effects (Lathrop & Varró, 1989, 1990; Mátyus et al, 2004; Varga et al, 2021). Inhibition of I Ks and I Kr , both class III agents, also shows a neutral rate‐dependent APD prolongation (Qi et al, 1999; VerNooy & Mangrum, 2005).…”

Linked biaromatic compounds as cardioprotective agents

“…Importantly, SZV‐270 did not provoke TdP arrhythmia in an anesthetized rabbit proarrhythmia model characterized by impaired repolarization reserve. [ 286 ]…”