Optogenetic termination of ventricular arrhythmias in the whole heart: towards biological cardiac rhythm management.
Optogenetic termination of ventricular arrhythmias in the whole heart: towards biological cardiac rhythm management.
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DOI：
10.1093/eurheartj/ehw574
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发表时间：
2017-07-14
影响因子：
39.3
通讯作者：
Pijnappels DA
中科院分区：
文献类型：
--
作者：
Nyns ECA;Kip A;Bart CI;Plomp JJ;Zeppenfeld K;Schalij MJ;de Vries AAF;Pijnappels DA
目前对室性心律失常的治疗依赖于通过药物、消融或电击来调节心脏电功能，这些都是非生物的且相当不特异的、不可逆的或创伤性的干预。然而，光遗传学是一种新颖的生物技术，允许使用光门控离子通道以特定的、可逆的和无创伤的方式进行电调制。本研究的目的是探讨光遗传学终止整个心脏的室性心律失常。编码光门控去极化离子通道红激活通道视紫红质（ReaChR）的向心腺相关病毒载体的全身递送导致成年Wistar大鼠心脏中允许ReaChR介导的去极化和起搏的全局心肌细胞限制性转基因表达。接下来，在Langendorff设置中通过短阵起搏在光遗传学修饰的心脏中诱导室性快速性心律失常（VT），然后进行编程的局部心外膜照明。通过心电图记录评估，单次470 nm光脉冲（1000 ms，2.97 mW/mm 2）终止了97%的单形性VT和57%的多形性VT，而无照明时为0%。光学标测显示心律失常终止前电压信号显著延长。药理学动作电位时程（APD）缩短几乎完全抑制光诱导的心律失常终止，表明APD在此过程中的重要作用。光遗传修饰的成年大鼠心脏的短暂局部心外膜照射允许在光遗传修饰后以有效和重复的方式无接触和无电击终止室性心律失常。这些发现可以为心律失常管理的全新生物选择的开发奠定基础。
Current treatments of ventricular arrhythmias rely on modulation of cardiac electrical function through drugs, ablation or electroshocks, which are all non-biological and rather unspecific, irreversible or traumatizing interventions. Optogenetics, however, is a novel, biological technique allowing electrical modulation in a specific, reversible and trauma-free manner using light-gated ion channels. The aim of our study was to investigate optogenetic termination of ventricular arrhythmias in the whole heart. Systemic delivery of cardiotropic adeno-associated virus vectors, encoding the light-gated depolarizing ion channel red-activatable channelrhodopsin (ReaChR), resulted in global cardiomyocyte-restricted transgene expression in adult Wistar rat hearts allowing ReaChR-mediated depolarization and pacing. Next, ventricular tachyarrhythmias (VTs) were induced in the optogenetically modified hearts by burst pacing in a Langendorff setup, followed by programmed, local epicardial illumination. A single 470-nm light pulse (1000 ms, 2.97 mW/mm2) terminated 97% of monomorphic and 57% of polymorphic VTs vs. 0% without illumination, as assessed by electrocardiogram recordings. Optical mapping showed significant prolongation of voltage signals just before arrhythmia termination. Pharmacological action potential duration (APD) shortening almost fully inhibited light-induced arrhythmia termination indicating an important role for APD in this process. Brief local epicardial illumination of the optogenetically modified adult rat heart allows contact- and shock-free termination of ventricular arrhythmias in an effective and repetitive manner after optogenetic modification. These findings could lay the basis for the development of fundamentally new and biological options for cardiac arrhythmia management.
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影响因子：
25
作者：
Lin, John Y.;Knutsen, Per Magne;Muller, Arnaud;Kleinfeld, David;Tsien, Roger Y.
通讯作者：
Tsien, Roger Y.
影响因子：
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作者：
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作者：
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通讯作者：
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影响因子：
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作者：
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通讯作者：
Deisseroth, Karl