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

R P Pölönen1, K Penttinen1, H Swan2

  • 1Faculty of Medicine and Life Sciences and BioMediTech Institute, University of Tampere, Tampere, Finland.

Stem Cells International
|May 16, 2018
PubMed

Insights

Carvedilol and flecainide showed similar effectiveness in treating catecholaminergic polymorphic ventricular tachycardia (CPVT) patient cells. However, flecainide induced arrhythmias in healthy cells, making carvedilol a potentially safer option for CPVT treatment.

Area of Science:

  • Cardiology
  • Genetics
  • Pharmacology

Background:

  • Catecholaminergic polymorphic ventricular tachycardia (CPVT) is primarily caused by mutations in the cardiac ryanodine receptor (RYR2).
  • Patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) offer a valuable model for studying genetic heart conditions and testing drug efficacy.

Purpose of the Study:

  • To evaluate the antiarrhythmic efficacy of carvedilol and flecainide in iPSC-CMs derived from CPVT patients with distinct RYR2 mutations.
  • To compare the safety profiles of carvedilol and flecainide in both CPVT and control iPSC-CMs.

Main Methods:

  • Generation of iPSC-CMs from CPVT patients (carrying RYR2 exon 3 deletion, L4115F, or V4653F mutations) and healthy individuals.
  • Assessment of intracellular calcium (Ca2+) kinetics and drug effects using Fluo-4 AM indicator.
  • Quantification of drug-induced Ca2+ abnormalities and effects on beating rate.

Main Results:

  • Both carvedilol and flecainide demonstrated efficacy in ameliorating Ca2+ abnormalities in CPVT iPSC-CMs, with varying percentages of response across different mutations.
  • Flecainide induced abnormal Ca2+ transients in a significantly higher proportion of control cells (61%) compared to carvedilol (26%).
  • CPVT cells with exon 3 deletion showed the most severe Ca2+ abnormalities but responded best to both drugs, though optimal arrhythmia abolition was not achieved.

Conclusions:

  • Carvedilol and flecainide exhibit comparable effectiveness in CPVT iPSC-CMs, but carvedilol presents a better safety profile due to lower incidence of induced arrhythmias in control cells.
  • iPSC-CMs serve as a robust platform for personalized drug screening and evaluation in CPVT.
  • Neither drug provided complete arrhythmia suppression, indicating a need for further therapeutic strategies for CPVT.

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