Oates Institute for Experimental Therapeutics, Vanderbilt University School of Medicine, Division of Clinical Pharmacology, Nashville, TN 37232-0575, USA.
Circ Arrhythm Electrophysiol. 2011 Apr;4(2):128-35. doi: 10.1161/CIRCEP.110.959916. Epub 2011 Jan 26.
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT.
We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2(-/-) myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca(2+) waves at clinically relevant concentrations, whereas Na(+) channel inhibitors without RyR2 blocking properties did not. In Casq2(-/-) mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n=5 to 9 mice, P<0.05). QRS duration was not significantly different, indicating a similar degree of Na(+) channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy.
RyR2 cardiac Ca(2+) release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2(-/-) mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on β-blockers.
儿茶酚胺多形性室性心动过速（CPVT）是由心脏兰尼碱受体（RyR2）或肌浆网钙结合蛋白 2（Casq2）突变引起的，治疗较为困难。Ic 类抗心律失常药物氟卡尼可阻断 RyR2 通道，预防小鼠和人类 CPVT。尚不清楚其他 I 类抗心律失常药物是否也能阻断 RyR2 通道，以及 RyR2 通道抑制在 CPVT 的抗心律失常疗效中起到多大作用。
我们首先测量了在美国上市的所有 I 类抗心律失常药物（奎尼丁、普鲁卡因胺、双异丙吡胺、利多卡因、美西律、氟卡尼和普罗帕酮）对整合到脂质双层中的单个 RyR2 通道的影响。只有氟卡尼和普罗帕酮抑制 RyR2 通道，而 S-对映体普罗帕酮的效力明显低于 R-普罗帕酮或氟卡尼。在 Casq2（-/-）心肌细胞中，普罗帕酮对映体和氟卡尼在临床相关浓度下显著减少致心律失常性 Ca2+波，而不具有 RyR2 阻断特性的 Na+通道抑制剂则没有。在 Casq2（-/-）小鼠中，5mg/kg R-普罗帕酮或 20mg/kg S-普罗帕酮可预防运动引起的 CPVT，而普鲁卡因胺（20mg/kg）或利多卡因（20mg/kg）则无效（n=5 至 9 只小鼠，P<0.05）。QRS 持续时间无显著差异，表明 Na+通道抑制程度相似。在临床上，普罗帕酮（900mg/d）预防了一位对最大标准药物治疗和双侧星状神经节切除术均无反应的 22 岁 CPVT 患者的 ICD 电击。
RyR2 心脏 Ca2+释放通道抑制似乎决定了 I 类药物预防 Casq2（-/-）小鼠 CPVT 的疗效。普罗帕酮可能是 CPVT 患者在β受体阻滞剂治疗下的氟卡尼替代药物。
