In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia

Pei Chi Yang, Jonathan D. Moreno, Christina Y. Miyake, Steven B. Vaughn-Behrens, Mao Tsuen Jeng, Eleonora Grandi, Xander H T Wehrens, Sergei Y. Noskov, Colleen E Clancy

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Key points: The mechanism of therapeutic efficacy of flecainide for catecholaminergic polymorphic ventricular tachycardia (CPVT) is unclear. Model predictions suggest that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT. This study represents a first step toward predicting therapeutic mechanisms of drug efficacy in the setting of CPVT and then using these mechanisms to guide modelling and simulation to predict alternative drug therapies. Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by fatal ventricular arrhythmias in structurally normal hearts during β-adrenergic stimulation. Current treatment strategies include β-blockade, flecainide and ICD implementation - none of which is fully effective and each comes with associated risk. Recently, flecainide has gained considerable interest in CPVT treatment, but its mechanism of action for therapeutic efficacy is unclear. In this study, we performed in silico mutagenesis to construct a CPVT model and then used a computational modelling and simulation approach to make predictions of drug mechanisms and efficacy in the setting of CPVT. Experiments were carried out to validate model results. Our simulations revealed that Na+ channel effects are insufficient to explain flecainide efficacy in CPVT. The pure Na+ channel blocker lidocaine and the antianginal ranolazine were additionally tested and also found to be ineffective. When we tested lower dose combination therapy with flecainide, β-blockade and CaMKII inhibition, our model predicted superior therapeutic efficacy than with flecainide monotherapy. Simulations indicate a polytherapeutic approach may mitigate side-effects and proarrhythmic potential plaguing CPVT pharmacological management today. Importantly, our prediction of a novel polytherapy for CPVT was confirmed experimentally. Our simulations suggest that flecainide therapeutic efficacy in CPVT is unlikely to derive from primary interactions with the Na+ channel, and benefit may be gained from an alternative multi-drug regimen.

Original languageEnglish (US)
Pages (from-to)567-593
Number of pages27
JournalJournal of Physiology
Volume594
Issue number3
DOIs
StatePublished - Feb 1 2016

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Flecainide
Computer Simulation
Drug Therapy
Therapeutics
Cardiac Arrhythmias
Polymorphic catecholergic ventricular tachycardia
Pharmaceutical Preparations
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Complementary Therapies
Lidocaine
Mutagenesis
Adrenergic Agents
Pharmacology

ASJC Scopus subject areas

  • Physiology

Cite this

In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia. / Yang, Pei Chi; Moreno, Jonathan D.; Miyake, Christina Y.; Vaughn-Behrens, Steven B.; Jeng, Mao Tsuen; Grandi, Eleonora; Wehrens, Xander H T; Noskov, Sergei Y.; Clancy, Colleen E.

In: Journal of Physiology, Vol. 594, No. 3, 01.02.2016, p. 567-593.

Research output: Contribution to journalArticle

Yang, PC, Moreno, JD, Miyake, CY, Vaughn-Behrens, SB, Jeng, MT, Grandi, E, Wehrens, XHT, Noskov, SY & Clancy, CE 2016, 'In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia', Journal of Physiology, vol. 594, no. 3, pp. 567-593. https://doi.org/10.1113/JP271282
Yang, Pei Chi ; Moreno, Jonathan D. ; Miyake, Christina Y. ; Vaughn-Behrens, Steven B. ; Jeng, Mao Tsuen ; Grandi, Eleonora ; Wehrens, Xander H T ; Noskov, Sergei Y. ; Clancy, Colleen E. / In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia. In: Journal of Physiology. 2016 ; Vol. 594, No. 3. pp. 567-593.
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