Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts.
Increased expression of HCN channels in the ventricular myocardium contributes to enhanced arrhythmicity in mouse failing hearts.
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DOI：
10.1161/jaha.113.000150
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发表时间：
2013-05-24
影响因子：
5.4
通讯作者：
Nakao K
中科院分区：
文献类型：
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作者：
Kuwabara Y;Kuwahara K;Takano M;Kinoshita H;Arai Y;Yasuno S;Nakagawa Y;Igata S;Usami S;Minami T;Yamada Y;Nakao K;Yamada C;Shibata J;Nishikimi T;Ueshima K;Nakao K
药物干预预防慢性心力衰竭患者猝死的疗效仍然有限。现在有证据表明，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有助于其心律失常。尽管如此，诱导HCN通道表达在与心力衰竭相关的增强的心律失常性中的作用以及HCN通道阻断预防致命性心律失常的能力仍然不确定。我们检查了伊伐布雷定（一种特异性HCN通道阻滞剂）对表达心脏特异性显性阴性形式神经元限制性沉默因子的转基因小鼠（dnNRSF‐Tg）存活率和存活率的影响，这是一种有用的导致猝死的扩张型心肌病小鼠模型。伊伐布雷定（7 mg/kg/天，经口）显著降低了dnNRSF‐Tg小鼠的室性快速性心律失常并改善了存活率，但对心率或心脏结构或功能无显著影响。伊伐布雷定最有可能阻止自律性增加，否则在dnNRSF-Tg心室肌细胞中观察到。此外，HCN 2在小鼠中的心脏特异性过表达（HCN 2-Tg）使心脏对慢性β-肾上腺素能刺激诱导的心律失常高度敏感。事实上，从HCN 2-Tg小鼠中分离的心室肌细胞对β-肾上腺素能刺激诱导的异常自律性高度敏感，伊伐布雷定可抑制该异常自律性。伊伐布雷定阻断HCN通道可降低小鼠扩张型心肌病相关致死性心律失常。相反，HCN 2通道的心脏特异性过表达增加β肾上腺素能刺激的促肾上腺素原性。我们的研究结果表明，HCN通道的贡献，在失败的心脏中看到的增加的心律失常，并建议HCN通道阻断是一个潜在的有用的方法，以防止心脏衰竭患者猝死。
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.