Mutation-specific differences in arrhythmias and drug responses in CPVT patients : simultaneous patch clamp and video imaging of iPSC derived cardiomyocytes

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Pölönen , R P , Swan , H & Aalto-Setälä , K 2020 , ' Mutation-specific differences in arrhythmias and drug responses in CPVT patients : simultaneous patch clamp and video imaging of iPSC derived cardiomyocytes ' , Molecular Biology Reports , vol. 47 , no. 2 , pp. 1067-1077 . https://doi.org/10.1007/s11033-019-05201-y

Title: Mutation-specific differences in arrhythmias and drug responses in CPVT patients : simultaneous patch clamp and video imaging of iPSC derived cardiomyocytes
Author: Pölönen, R. P.; Swan, H.; Aalto-Setälä, K.
Contributor organization: HUS Heart and Lung Center
University of Helsinki
Kardiologian yksikkö
Date: 2020-02
Language: eng
Number of pages: 11
Belongs to series: Molecular Biology Reports
ISSN: 0301-4851
DOI: https://doi.org/10.1007/s11033-019-05201-y
URI: http://hdl.handle.net/10138/325283
Abstract: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac disease characterized by arrhythmias under adrenergic stress. Mutations in the cardiac ryanodine receptor (RYR2) are the leading cause for CPVT. We characterized electrophysiological properties of CPVT patient-specific induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) carrying different mutations in RYR2 and evaluated effects of carvedilol and flecainide on action potential (AP) and contractile properties of hiPSC-CMs. iPSC-CMs were generated from skin biopsies of CPVT patients carrying exon 3 deletion (E3D) and L4115F mutation in RYR2. APs and contractile movement were recorded simultaneously from the same hiPSC-CMs. Differences in AP properties of ventricular like CMs were seen in CPVT and control CMs: APD90 of both E3D (n = 20) and L4115F (n = 25) CPVT CMs was shorter than in control CMs (n = 15). E3D-CPVT CMs had shortest AP duration, lowest AP amplitude, upstroke velocity and more depolarized diastolic potential than controls. Adrenaline had positive and carvedilol and flecainide negative chronotropic effect in all hiPSC CMs. CPVT CMs had increased amount of delayed after depolarizations (DADs) and early after depolarizations (EADs) after adrenaline exposure. E3D CPVT CMs had the most DADs, EADs, and tachyarrhythmia. Discordant negatively coupled alternans was seen in L4115F CPVT CMs. Carvedilol cured almost all arrhythmias in L4115F CPVT CMs. Both drugs decreased contraction amplitude in all hiPSC CMs. E3D CPVT CMs have electrophysiological properties, which render them more prone to arrhythmias. iPSC-CMs provide a unique platform for disease modeling and drug screening for CPVT. Combining electrophysiological measurements, we can gain deeper insight into mechanisms of arrhythmias.
Subject: hiPSC
Cardiomyocyte
CPVT
Patch clamp
Contraction
Carvedilol
Flecainide
POLYMORPHIC VENTRICULAR-TACHYCARDIA
CARDIAC RYANODINE RECEPTOR
CALCIUM TRANSIENTS
ACTION-POTENTIALS
COMMON DEFECT
CA2+ RELEASE
MODEL
WAVES
DEPOLARIZATION
REPOLARIZATION
1182 Biochemistry, cell and molecular biology
Peer reviewed: Yes
Rights: unspecified
Usage restriction: openAccess
Self-archived version: publishedVersion


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