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
Department of Pharmacology, School of Medicine, University of California, Davis, CA, USA.
Division of Cardiology, Department of Medicine, Barnes-Jewish Hospital, Washington University in St Louis, St Louis, MO, USA.
J Physiol. 2016 Feb 1;594(3):567-93. doi: 10.1113/JP271282. Epub 2015 Dec 30.
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.
氟卡尼治疗儿茶酚胺能多形性室性心动过速（CPVT）的疗效机制尚不清楚。模型预测表明，钠通道效应不足以解释氟卡尼在CPVT中的疗效。本研究是朝着预测CPVT情况下药物疗效的治疗机制迈出的第一步，然后利用这些机制指导建模和模拟以预测替代药物疗法。儿茶酚胺能多形性室性心动过速（CPVT）是一种遗传性心律失常综合征，其特征是在β肾上腺素能刺激期间，结构正常的心脏出现致命性室性心律失常。目前的治疗策略包括β受体阻滞剂、氟卡尼和植入式心脏复律除颤器（ICD）——这些方法均未完全有效，且每种方法都有相关风险。最近，氟卡尼在CPVT治疗中引起了广泛关注，但其治疗疗效的作用机制尚不清楚。在本研究中，我们进行了计算机诱变以构建CPVT模型，然后使用计算建模和模拟方法来预测CPVT情况下的药物机制和疗效。进行了实验以验证模型结果。我们的模拟表明，钠通道效应不足以解释氟卡尼在CPVT中的疗效。此外还测试了纯钠通道阻滞剂利多卡因和抗心绞痛药物雷诺嗪，发现它们也无效。当我们测试氟卡尼、β受体阻滞剂和钙调蛋白激酶II（CaMKII）抑制的低剂量联合治疗时，我们的模型预测其治疗效果优于氟卡尼单药治疗。模拟表明，多药联合治疗方法可能会减轻目前困扰CPVT药物治疗的副作用和促心律失常风险。重要的是，我们对CPVT一种新型联合治疗的预测得到了实验证实。我们的模拟表明，氟卡尼在CPVT中的治疗疗效不太可能源于与钠通道的主要相互作用，采用替代的多药治疗方案可能会有好处。
