title: In silico prediction of drug therapy in catecholaminergic polymorphic ventricular tachycardia.
abstract: 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.
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Pei-Chi
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Division of Cardiology, Department of Medicine, Barnes-Jewish Hospital, Washington University in St Louis, St Louis, MO, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Moreno
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics, Department of Medicine, Cardiology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Christina Y
authors.initials: CY
authors.lastname: Miyake
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Vaughn-Behrens
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Mao-Tsuen
authors.initials: MT
authors.lastname: Jeng
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Eleonora
authors.initials: E
authors.lastname: Grandi
authors.affiliation: Cardiovascular Research Institute, Department of Molecular Physiology & Biophysics, Department of Medicine, Cardiology, Baylor College of Medicine, Houston, TX, USA.|Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, and the Cardiovascular Research Institute, Houston, TX, USA.
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.affiliation: Centre for Molecular Simulation, Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Sergei Y
authors.initials: SY
authors.lastname: Noskov
authors.affiliation: Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
authors.forename: Colleen E
authors.initials: CE
authors.lastname: Clancy
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004562:Electrocardiography; D005424:Flecainide / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D008955:Models, Cardiovascular; D011817:Rabbits; D019837:Ryanodine Receptor Calcium Release Channel / Q000502:physiology; D015222:Sodium Channels / Q000502:physiology; D017180:Tachycardia, Ventricular / Q000188:drug therapy / Q000503:physiopathology*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D000889:Anti-Arrhythmia Agents; D019837:Ryanodine Receptor Calcium Release Channel; D015222:Sodium Channels; D005424:Flecainide