Aims Ventricular tachyarrhythmias (VTs) are common in the pathologically remodelled heart. These arrhythmias can be lethal, necessitating acute treatment like electrical cardioversion to restore normal rhythm. Recently, it has been proposed that cardioversion may also be realized via optically controlled generation of bioelectricity by the arrhythmic heart itself through optogenetics and therefore without the need of traumatizing high-voltage shocks. However, crucial mechanistic and translational aspects of this strategy have remained largely unaddressed. Therefore, we investigated optogenetic termination of VTs (i) in the pathologically remodelled heart using an (ii) implantable multi-LED device for (iii) in vivo closed-chest, local illumination. Methods and results In order to mimic a clinically relevant sequence of events, transverse aortic constriction (TAC) was applied to adult male Wistar rats before optogenetic modification. This modification took place 3 weeks later by intravenous delivery of adeno-associated virus vectors encoding red-activatable channelrhodopsin or Citrine for control experiments. At 8–10 weeks after TAC, VTs were induced ex vivo and in vivo, followed by programmed local illumination of the ventricular apex by a custom-made implanted multi-LED device. This resulted in effective and repetitive VT termination in the remodelled adult rat heart after optogenetic modification, leading to sustained restoration of sinus rhythm in the intact animal. Mechanistically, studies on the single cell and tissue level revealed collectively that, despite the cardiac remodelling, there were no significant differences in bioelectricity generation and subsequent transmembrane voltage responses between diseased and control animals, thereby providing insight into the observed robustness of optogenetic VT termination. Conclusion Our results show that implant-based optical cardioversion of VTs is feasible in the pathologically remodelled heart in vivo after local optogenetic targeting because of preserved optical control over bioelectricity generation. These findings add novel mechanistic and translational insight into optical ventricular cardioversion.

中文翻译：

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在心肌病大鼠模型中通过局部光遗传学靶向和 LED 植入进行光学心室复律

目的 室性快速性心律失常 (VTs) 在病理性重塑的心脏中很常见。这些心律失常可能是致命的，需要进行紧急治疗，如电复律以恢复正常心律。最近，有人提出，心脏复律也可以通过光遗传学由心律失常的心脏本身通过光学控制产生生物电来实现，因此不需要创伤性的高压电击。然而，这一战略的关键机制和转化方面在很大程度上仍未得到解决。因此，我们使用 (ii) 用于 (iii) 体内闭胸局部照明的可植入多 LED 装置研究了病理性重塑心脏中 VT (i) 的光遗传学终止。方法和结果 为了模拟临床相关的事件序列，在光遗传学修饰之前，将横向主动脉缩窄（TAC）应用于成年雄性 Wistar 大鼠。这种修改发生在 3 周后，通过静脉内递送编码红色可激活通道视紫红质或黄水晶的腺相关病毒载体进行对照实验。在 TAC 后 8-10 周，体外和体内诱导 VT，然后通过定制的植入式多 LED 装置对心室尖进行程序化局部照明。这导致在光遗传学修饰后重塑的成年大鼠心脏中有效且重复的 VT 终止，从而导致完整动物中窦性节律的持续恢复。从机制上讲，对单细胞和组织水平的研究共同表明，尽管心脏重塑，患病动物和对照动物之间的生物电产生和随后的跨膜电压反应没有显着差异，从而提供了对观察到的光遗传学 VT 终止鲁棒性的深入了解。结论我们的研究结果表明，由于保留了对生物发电的光学控制，因此在局部光遗传学靶向后，基于植入物的 VT 光学复律在体内病理重塑的心脏中是可行的。这些发现为光学心室复律增加了新的机制和转化洞察力。结论我们的研究结果表明，由于保留了对生物发电的光学控制，因此在局部光遗传学靶向后，基于植入物的 VT 光学复律在体内病理重塑的心脏中是可行的。这些发现为光学心室复律增加了新的机制和转化洞察力。结论我们的研究结果表明，由于保留了对生物发电的光学控制，因此在局部光遗传学靶向后，基于植入物的 VT 光学复律在体内病理重塑的心脏中是可行的。这些发现为光学心室复律增加了新的机制和转化洞察力。