T-Type Ca2+ Channel Blockade Prevents Sudden Death in Mice With Heart Failure
T-Type Ca2+ Channel Blockade Prevents Sudden Death in Mice With Heart Failure
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DOI：
10.1161/circulationaha.109.857011
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发表时间：
2009-09-01
期刊：
影响因子：
37.8
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
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作者：
Kinoshita, Hideyuki;Kuwahara, Koichiro;Nakao, Kazuwa
背景-预防慢性心力衰竭患者猝死的药物干预仍然有限。越来越多的证据表明，心室T型Ca 2+通道表达增加有助于心力衰竭的进展。方法和结果-我们比较了依非地平和米贝拉地尔，双重T和L型钙通道阻滞剂，与尼群地平，一种选择性L型钙通道阻滞剂，在心脏特异性，显性阴性形式的神经元限制性沉默因子转基因小鼠（dnNRSF-Tg），这是一种有用的导致猝死的扩张型心肌病小鼠模型。依福地平，而不是尼群地平，大大提高dnNRSF-Tg小鼠的生存。接受依氟地平或米贝拉地尔治疗的dnNRSF-Tg小鼠的心律失常性显着降低。Efonidipine通过逆转静息膜电位的去极化和纠正心脏自主神经系统的不平衡而起作用，否则在dnNRSF-Tg小鼠的心室肌细胞中观察到。此外，最近鉴定的高度选择性T型Ca 2+通道阻滞剂依福地平的R（-）-异构体类似地改善dnNRSF-Tg小鼠的存活率。Efonidipine也降低了猝死和embrymogenicity在小鼠急性myocardialinfarction. Conclusions T型钙通道阻滞剂通过复极化静息膜电位和改善心脏自主神经系统的失衡，减少了扩张型心肌病小鼠模型的心律失常。T型钙通道阻滞剂也可预防心肌梗死小鼠的猝死。我们的研究结果表明，T型钙通道阻滞剂是一种潜在的有用的方法，以防止心脏衰竭患者猝死。（循环。2009;120：743-752）。
Background-Pharmacological interventions for prevention of sudden arrhythmic death in patients with chronic heart failure remain limited. Accumulating evidence suggests increased ventricular expression of T-type Ca2+ channels contributes to the progression of heart failure. The ability of T-type Ca2+ channel blockade to prevent lethal arrhythmias associated with heart failure has never been tested, however.Methods and Results-We compared the effects of efonidipine and mibefradil, dual T- and L-type Ca2+ channel blockers, with those of nitrendipine, a selective L-type Ca2+ channel blocker, on survival and arrhythmogenicity in a cardiac-specific, dominant-negative form of neuron-restrictive silencer factor transgenic mice (dnNRSF-Tg), which is a useful mouse model of dilated cardiomyopathy leading to sudden death. Efonidipine, but not nitrendipine, substantially improved survival among dnNRSF-Tg mice. Arrhythmogenicity was dramatically reduced in dnNRSF-Tg mice treated with efonidipine or mibefradil. Efonidipine acted by reversing depolarization of the resting membrane potential otherwise seen in ventricular myocytes from dnNRSF-Tg mice and by correcting cardiac autonomic nervous system imbalance. Moreover, the R(-)-isomer of efonidipine, a recently identified, highly selective T- type Ca2+ channel blocker, similarly improved survival among dnNRSF-Tg mice. Efonidipine also reduced the incidence of sudden death and arrhythmogenicity in mice with acute myocardial infarction.Conclusions-T-type Ca2+ channel blockade reduced arrhythmias in a mouse model of dilated cardiomyopathy by repolarizing the resting membrane potential and improving cardiac autonomic nervous system imbalance. T-type Ca2+ channel blockade also prevented sudden death in mice with myocardial infarction. Our findings suggest T-type Ca2+ channel blockade is a potentially useful approach to preventing sudden death in patients with heart failure. (Circulation. 2009;120:743-752.)