Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan.
J Am Heart Assoc. 2013 May 24;2(3):e000150. doi: 10.1161/JAHA.113.000150.
The efficacy of pharmacological interventions to prevent sudden arrhythmic death in patients with chronic heart failure remains limited. Evidence now suggests increased ventricular expression of hyperpolarization-activated cation (HCN) channels in hypertrophied and failing hearts contributes to their arrythmicity. Still, the role of induced HCN channel expression in the enhanced arrhythmicity associated with heart failure and the capacity of HCN channel blockade to prevent lethal arrhythmias remains undetermined.
We examined the effects of ivabradine, a specific HCN channel blocker, on survival and arrhythmicity in transgenic mice (dnNRSF-Tg) expressing a cardiac-specific dominant-negative form of neuron-restrictive silencer factor, a useful mouse model of dilated cardiomyopathy leading to sudden death. Ivabradine (7 mg/kg per day orally) significantly reduced ventricular tachyarrhythmias and improved survival among dnNRSF-Tg mice while having no significant effect on heart rate or cardiac structure or function. Ivabradine most likely prevented the increase in automaticity otherwise seen in dnNRSF-Tg ventricular myocytes. Moreover, cardiac-specific overexpression of HCN2 in mice (HCN2-Tg) made hearts highly susceptible to arrhythmias induced by chronic β-adrenergic stimulation. Indeed, ventricular myocytes isolated from HCN2-Tg mice were highly susceptible to β-adrenergic stimulation-induced abnormal automaticity, which was inhibited by ivabradine.
HCN channel blockade by ivabradine reduces lethal arrhythmias associated with dilated cardiomyopathy in mice. Conversely, cardiac-specific overexpression of HCN2 channels increases arrhythmogenicity of β-adrenergic stimulation. Our findings demonstrate the contribution of HCN channels to the increased arrhythmicity seen in failing hearts and suggest HCN channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure.
药物干预预防慢性心力衰竭患者心源性猝死的疗效仍然有限。目前有证据表明，肥厚和衰竭心脏中超极化激活阳离子（HCN）通道的心室表达增加导致其心律失常。然而，HCN 通道表达的诱导在与心力衰竭相关的增强的心律失常以及 HCN 通道阻断预防致命性心律失常中的作用仍未确定。
我们研究了特异性 HCN 通道阻断剂伊伐布雷定对表达心脏特异性显性负性神经元抑制因子（一种导致扩张型心肌病和猝死的有用的小鼠模型）的转基因小鼠（dnNRSF-Tg）的生存和心律失常的影响。伊伐布雷定（每天 7mg/kg 口服）显著降低了 dnNRSF-Tg 小鼠的室性心动过速和心律失常，并改善了其生存率，而对心率或心脏结构或功能没有显著影响。伊伐布雷定很可能防止了 dnNRSF-Tg 心室肌细胞中观察到的自律性增加。此外，心脏特异性过表达 HCN2 （HCN2-Tg）的小鼠心脏对慢性β-肾上腺素能刺激诱导的心律失常非常敏感。事实上，HCN2-Tg 小鼠的心室肌细胞对β-肾上腺素能刺激诱导的异常自律性非常敏感，伊伐布雷定抑制了这种自律性。
伊伐布雷定的 HCN 通道阻断可减少小鼠扩张型心肌病相关的致死性心律失常。相反，心脏特异性过表达 HCN2 通道增加了β-肾上腺素能刺激诱导的心律失常。我们的研究结果表明 HCN 通道对衰竭心脏中增加的心律失常的贡献，并表明 HCN 通道阻断可能是预防心力衰竭患者猝死的一种有用方法。
