What question did this study set out to answer?

To determine whether flecainide efficacy in catecholaminergic polymorphic ventricular tachycardia depends on specific underlying genetic mutations or is modulated by cellular calcium overload.

August 13, 2019Frontiers in PhysiologyOpen Access

Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload

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Why the study?

Conflicting reports on whether flecainide suppresses spontaneous Ca2+ waves in different CPVT mouse models raised the possibility that its efficacy is mutation-dependent.

Does flecainide reduce spontaneous Ca2+ waves and arrhythmias in Casq2-KO and RyR2-R4496C CPVT models?

Key Points

To determine whether flecainide efficacy in catecholaminergic polymorphic ventricular tachycardia depends on specific underlying genetic mutations or is modulated by cellular calcium overload.
Quantified spontaneous calcium waves in isolated Casq2-knockout and RyR2-R4496C myocytes following 30 minutes of exposure to 6 μM flecainide or vehicle during isoproterenol stimulation across 2 mM and 3 mM extracellular calcium concentrations.
Assessed in vivo ventricular arrhythmia scores in RyR2-R4496C mice (n=12) and Casq2-knockout mice (n=9) challenged with low-dose or high-dose isoproterenol and caffeine.
Flecainide suppressed spontaneous calcium waves in Casq2-knockout myocytes at 2 mM extracellular calcium, but elevated calcium (3 mM) reduced efficacy in Casq2-knockout cells and eliminated efficacy in RyR2-R4496C myocytes.
RyR2-R4496C mice exhibited lower overall arrhythmia scores than Casq2-knockout mice, with high-dose catecholamine and caffeine challenge diminishing flecainide efficacy in both genetic models.

Structured PICO

Does flecainide reduce spontaneous Ca2+ waves and arrhythmias in Casq2-KO and RyR2-R4496C CPVT models?

Population

Casq2-KO and RyR2-R4496C myocytes and mice (n=12 RyR2-R4496C mice, n=9 Casq2 KO mice)

Intervention

Flecainide (6μM for 30 min in vitro; in vivo testing with low or high dose catecholamine challenge)

Comparator

Vehicle

Outcome

Spontaneous Ca2+ waves during a 40s pause after 1Hz pacing train in the presence of isoproterenol (in vitro) and arrhythmia scores (in vivo)surrogate

Flecainide efficacy in CPVT is not mutation-specific but is reduced by calcium overload, which may explain conflicting literature reports.

Discussion

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Implication

Flecainide response in CPVT may differ by mutation; leaves open genotype-specific efficacy questions for clinical translation.

Cite This Study

Hwang et al. (2019) studied this question.

synapsesocial.com/papers/6a7aae25756812e39589b76a https://doi.org/10.3389/fphys.2019.00992

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Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload

Key Points

Structured PICO

Discussion

Implication

Cite This Study

Efficacy of Flecainide in Catecholaminergic Polymorphic Ventricular Tachycardia Is Mutation-Independent but Reduced by Calcium Overload

Key Points

Structured PICO

Discussion

Implication

Cite This Study

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