The Hyperpolarization-Activated Cyclic-Nucleotide-Gated Channel Blocker Ivabradine Does Not Prevent Arrhythmias in Catecholaminergic Polymorphic Ventricular Tachycardia.

Hanna Bueno-Levy,Michael Arad,Shiraz Haron-Khun,Edith Hochhauser,Asher Peretz,Dor Yadin,Bernard Attali,David Weisbrod

doi:10.3389/fphar.2019.01566

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stressed-provoked ventricular arrhythmia. CPVT is treated by β-adrenergic receptor blockers, Na+ channel inhibitors, sympathetic denervation, or by implanting a defibrillator. We showed recently that blockers of SK4 Ca2+-activated K+ channels depolarize the maximal diastolic potential, reduce the heart rate, and attenuate ventricular arrhythmias in CPVT. The aim of the present study was to examine whether the pacemaker channel inhibitor, ivabradine could demonstrate anti-arrhythmic properties in CPVT like other bradycardic agents used in this disease and to compare them with those of the SK4 channel blocker, TRAM-34. The effects of ivabradine were examined on the arrhythmic beating of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) from CPVT patients, on sinoatrial node (SAN) calcium transients, and on ECG measurements obtained from transgenic mice model of CPVT. Ivabradine did neither prevent the arrhythmic pacing of hiPSC-CMs derived from CPVT patients, nor preclude the aberrant SAN calcium transients. In contrast to TRAM-34, ivabradine was unable to reduce in vivo the ventricular premature complexes and ventricular tachyarrhythmias in transgenic CPVT mice. In conclusion, ivabradine does not exhibit anti-arrhythmic properties in CPVT, which indicates that this blocker cannot be used as a plausible treatment for CPVT ventricular arrhythmias.

Highlights

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, potentially fatal, inherited arrhythmia disease
We showed that SK4 channel blockers decrease the heart rate, depolarize the maximal diastolic potential (MDP), and attenuate ventricular arrhythmias in transgenic CPVT mice
We examined both in vitro and in vivo whether ivabradine could exhibit anti-arrhythmic properties in CPVT as other bradycardic agents such as b-adrenergic receptor blockers or SK4 channel inhibitors

Summary

Introduction

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare, potentially fatal, inherited arrhythmia disease. It is often triggered by stress leading to polymorphic ventricular tachycardia in otherwise structurally normal hearts (Priori and Chen, 2011; Lieve et al, 2016). While CASQ2 mutants are “loss of function” mutations, the RyR2 mutations are “gain of function” mutations, both of which lead to diastolic Ca2+ leakage (Priori et al, 2002; Chopra and Knollmann, 2011; Priori and Chen, 2011; Arad et al, 2012; Lieve et al, 2016; Roston et al, 2017)

Objectives

Methods

Results

Conclusion