Antiarrhythmic Effects of Carvedilol and Flecainide in Cardiomyocytes Derived from Catecholaminergic Polymorphic Ventricular Tachycardia Patients

Stem Cells International
R P PölönenKatriina Aalto-Setälä

Abstract

Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for catecholaminergic polymorphic ventricular tachycardia (CPVT). In this study, we evaluated antiarrhythmic efficacy of carvedilol and flecainide in CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) carrying different mutations in RYR2. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion and L4115 or V4653F mutation in RYR2 and of a healthy individual. Ca2+ kinetics and drug effects were studied with Fluo-4 AM indicator. Carvedilol abolished Ca2+ abnormalities in 31% of L4115F, 36% of V4653F, and 46% of exon 3 deletion carrying CPVT cardiomyocytes and flecainide 33%, 30%, and 52%, respectively. Both drugs lowered the intracellular Ca2+ level and beating rate of the cardiomyocytes significantly. Moreover, flecainide caused abnormal Ca2+ transients in 61% of controls compared to 26% of those with carvedilol. Carvedilol and flecainide were equally effective in CPVT iPSC-CMs. However, flecainide induced arrhythmias in 61% of control cells. CPVT cardiomyocytes carrying the exon 3 deletion had the most severe Ca2+ abnormalities, but they had the best response to drug therapies. According to th...Continue Reading

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Citations

Oct 5, 2019·Nature Reviews. Cardiology·Joost A OfferhausArthur A M Wilde
Sep 10, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Vladena Bauerová-HlinkováJacob A Bauer
Dec 17, 2020·Journal of Cardiovascular Pharmacology·Michelangelo PaciJussi T Koivumäki

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Methods Mentioned

BETA
biopsies
transfection

Software Mentioned

Clampfit
Live Acquisition
SPSS

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