Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations
Optogenetic defibrillation terminates ventricular arrhythmia in mouse hearts and human simulations
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DOI：
10.1172/jci88950
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发表时间：
2016-10-01
影响因子：
15.9
通讯作者：
Sasse, Philipp
中科院分区：
文献类型：
--
作者：
Bruegmann, Tobias;Boyle, Patrick M.;Sasse, Philipp
室性心律失常是心脏病最严重的并发症之一，可导致心脏性猝死。有风险的患者目前接受植入式除颤器，根据需要提供电击以终止心律失常。然而，强烈的电击会损害心脏并引起剧烈疼痛。因此，我们已经使用心脏组织中光敏通道channelrhodopsin-2（ChR 2）的表达测试了光遗传学除颤。心外膜照射有效地终止了转基因小鼠和野生型小鼠的心脏室性心律失常后，腺相关病毒为基础的基因转移ChR 2。我们还探索了人类心脏的光遗传学除颤，利用最近开发的，临床验证的模拟梗死相关性室性心动过速（VT）的方法。我们的分析表明，红光照射有效地终止VT在患病，ChR 2表达的人类心脏。从机制上讲，我们确定观察到的VT终止是由于ChR 2介导的心肌跨壁去极化，这导致整个心肌壁的电压依赖性Na+通道阻滞，并中断波前传播到照明组织。因此，我们的研究结果表明，光遗传学除颤在小鼠心脏中非常有效，并且有可能转化为人类，以实现无损伤和无痛终止室性心律失常。
Ventricular arrhythmias are among the most severe complications of heart disease and can result in sudden cardiac death. Patients at risk currently receive implantable defibrillators that deliver electrical shocks to terminate arrhythmias on demand. However, strong electrical shocks can damage the heart and cause severe pain. Therefore, we have tested optogenetic defibrillation using expression of the light-sensitive channel channelrhodopsin-2 (ChR2) in cardiac tissue. Epicardial illumination effectively terminated ventricular arrhythmias in hearts from transgenic mice and from WT mice after adeno-associated virus-based gene transfer of ChR2. We also explored optogenetic defibrillation for human hearts, taking advantage of a recently developed, clinically validated in silico approach for simulating infarct-related ventricular tachycardia (VT). Our analysis revealed that illumination with red light effectively terminates VT in diseased, ChR2-expressing human hearts. Mechanistically, we determined that the observed VT termination is due to ChR2-mediated transmural depolarization of the myocardium, which causes a block of voltage-dependent Na+ channels throughout the myocardial wall and interrupts wavefront propagation into illuminated tissue. Thus, our results demonstrate that optogenetic defibrillation is highly effective in the mouse heart and could potentially be translated into humans to achieve nondamaging and pain-free termination of ventricular arrhythmia.