Zacopride, a Novel IK1 Activator, is a Potential Effective Treatment for Triggered Arrhythmia in Susceptible Human Hearts

Abstract

Ventricular tachycardia (VT) due to irregular ectopic beats is the leading cause of sudden arrhythmic death in the US. Compromised IK1 current has been reported to be involved in VT in heart failure in both animals and humans. Hence, an antiarrhythmic approach should augment the IK1 current. However, the lack of IK1-specific pharmacological tools, in particular a specific agonist, was a major constraint to further investigate IK1 in the past. Recently, a novel discovery of an IK1-specific agonist, zacopride, which suppressed triggered VT in rats, has been published. Yet, humans exhibit lower repolarization reserve contributions from IK1 compared to animals, confirming species-specific determinants of repolarization and the limitations of animal models for human disease. Thus, we sought to study the efficacy of zacopride on triggered arrhythmia in muscles isolated from both end-stage failing and non-failing human hearts ex-vivo. Under near physiologic conditions, our data show that muscles from non-failing hearts were more susceptible to isoproterenol/caffeine-induced arrhythmia compared to those from failing ones. Zacopride dose-dependently suppressed these arrhythmic activities in susceptible muscles. In cardiac muscles not susceptible to the arrhythmogenic effects of isoproterenol/caffeine, zacopride up to 100μM neither shows pro-arrhythmic activities nor affects the force of contraction. To understand the antiarrhythmic mechanism of zacopride next investigations will focus on its effects on both action potential and Ca2+ dynamics via optical mapping. This could represent a critical translational step for this drug towards clinical application in VT.