TY - JOUR
T1 - The hyperpolarization-activated cyclic-nucleotide-gated channel blocker ivabradine does not prevent arrhythmias in catecholaminergic polymorphic ventricular tachycardia
AU - Bueno-Levy, Hanna
AU - Weisbrod, David
AU - Yadin, Dor
AU - Haron-Khun, Shiraz
AU - Peretz, Asher
AU - Hochhauser, Edith
AU - Arad, Michael
AU - Attali, Bernard
N1 - Publisher Copyright:
Copyright © 2020 Bueno-Levy, Weisbrod, Yadin, Haron-Khun, Peretz, Hochhauser, Arad and Attali.
PY - 2020
Y1 - 2020
N2 - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stressed-provoked 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 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.
AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited, stressed-provoked 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 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.
KW - Cardiac arrhythmia
KW - Catecholaminergic polymorphic ventricular tachycardia
KW - Ivabradine
KW - Pacemaker
KW - Potassium channel
KW - SK4
KW - Ventricular arrhythmias
UR - http://www.scopus.com/inward/record.url?scp=85078984034&partnerID=8YFLogxK
U2 - 10.3389/fphar.2019.01566
DO - 10.3389/fphar.2019.01566
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C2 - 32009964
AN - SCOPUS:85078984034
SN - 1663-9812
VL - 10
JO - Frontiers in Pharmacology
JF - Frontiers in Pharmacology
M1 - 1566
ER -