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

Abstract

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stressedprovoked ventricular arrhythmia. CPVT is treated by b-adrenergic receptor blockers, Na + channel inhibitors, sympathetic denervation, or by implanting a defibrillator. We showed recently that blockers of SK4 Ca 2+-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.

Ventricular arrhythmia suppression with ivabradine in a patient with catecholaminergic polymorphic ventricular tachycardia refractory to nadolol, flecainide, and sympathectomy

“…Ivabradine did not prevent the arrhythmic pacing of human‐induced pluripotent stem cell–derived cardiomyocytes, nor preclude the aberrant SA nodal calcium transients in vitro. Moreover, ivabradine was unable to reduce ventricular ectopy and tachyarrhythmias in CASQ2 p.D307H transgenic mice with CPVT 21 . These findings are in contrast to the observed effects in three patients with CPVT due to genetic alterations in RYR2 (two mutations carriers, one exon 3 deletion carrier), who responded to ivabradine with suppression of ventricular ectopy and arrhythmias.…”

Small and Intermediate Calcium Activated Potassium Channels in the Heart: Role and Strategies in the Treatment of Cardiovascular Diseases

“…However, ivabradine, similarly to β-blockers, requires dosing adjustments and has limited benefits mainly due to its specific effect on the PP interval elongation. A recent study based on an animal model of CASQ2 CPVT has shown that the decrease in the sinus rhythm provoked by ivabradine was not sufficient to improve the arrhythmic features observable with telemetric ECG recordings (Bueno-Levy et al, 2020). However, the same publication showed that SK4 blockade attenuates arrhythmic features, probably due to the AVN blockade and subsequent PR segment elongation in addition to the effect on the SAN and the PP interval.…”

Effect of Ivabradine on Cardiac Ventricular Arrhythmias: Friend or Foe?

“…Last but not least, ivabradine was ineffective in a mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT) [ 69 ].…”

“…This in turn reduces O-linked N-acetylglucosamination of Ca 2+ -Calmodulin dependent protein kinase II and consequently reduces RyR sensitivity to Ca 2+ [ 72 ]. However, ivabradine was ineffective in the model of CPVT: it did not prevent abnormal Ca 2+ transients or arrhythmias resulting from abnormally increased RyR sensitivity in a transgenic mouse model of CPVT in vivo or in human induced pluripotent cells, exposed to isoproterenol [ 69 ].…”