Cardiovasc Res. 2017 Mar 1;113(3):354-366. doi: 10.1093/cvr/cvx003.
Anatomical re-entry is an important mechanism of ventricular tachycardia, characterized by circular electrical propagation in a fixed pathway. It's current investigative and therapeutic approaches are non-biological, rather unspecific (drugs), traumatizing (electrical shocks), or irreversible (ablation). Optogenetics is a new biological technique that allows reversible modulation of electrical function with unmatched spatiotemporal precision using light-gated ion channels. We therefore investigated optogenetic manipulation of anatomical re-entry in ventricular cardiac tissue.
Transverse, 150-μm-thick ventricular slices, obtained from neonatal rat hearts, were genetically modified with lentiviral vectors encoding Ca2+-translocating channelrhodopsin (CatCh), a light-gated depolarizing ion channel, or enhanced yellow fluorescent protein (eYFP) as control. Stable anatomical re-entry was induced in both experimental groups. Activation of CatCh was precisely controlled by 470-nm patterned illumination, while the effects on anatomical re-entry were studied by optical voltage mapping. Regional illumination in the pathway of anatomical re-entry resulted in termination of arrhythmic activity only in CatCh-expressing slices by establishing a local and reversible, depolarization-induced conduction block in the illuminated area. Systematic adjustment of the size of the light-exposed area in the re-entrant pathway revealed that re-entry could be terminated by either wave collision or extinction, depending on the depth (transmurality) of illumination. In silico studies implicated source-sink mismatches at the site of subtransmural conduction block as an important factor in re-entry termination.
Anatomical re-entry in ventricular tissue can be manipulated by optogenetic induction of a local and reversible conduction block in the re-entrant pathway, allowing effective re-entry termination. These results provide distinctively new mechanistic insight into re-entry termination and a novel perspective for cardiac arrhythmia management.
解剖性折返是室性心动过速的一个重要机制，其特征为在固定径路中呈环形电传播。目前对其的研究和治疗方法是非生理性的、非特异性的（药物）、具创伤性的（电击）或不可逆转的（消融）。光遗传学是一种新的生物学技术，它利用光门控离子通道，以无与伦比的时空精度实现电功能的可逆调节。因此，我们研究了光遗传学对心室心肌组织中解剖性折返的调控。
我们从新生大鼠心脏获得横向、150μm 厚的心室切片，用慢病毒载体对其进行基因修饰，表达钙转运通道型色氨酸敏化通道（CatCh），即光门控去极化离子通道，或增强型黄色荧光蛋白（eYFP）作为对照。在两个实验组中均能稳定诱发解剖性折返。CatCh 的激活可通过 470nm 图案化照明精确控制，而光学电压映射则可用于研究对解剖性折返的影响。在解剖性折返径路中对局部区域进行照明，仅在 CatCh 表达的切片中终止心律失常活动，方法是在受光区域建立局部和可逆的、去极化诱导的传导阻滞。系统地调整折返径路中受光区域的大小表明，折返可以通过波碰撞或消失而终止，具体取决于照明的深度（透壁性）。计算机模拟研究提示，在亚透壁性传导阻滞部位的源-汇失配是折返终止的一个重要因素。
光遗传学可诱导折返径路中的局部和可逆性传导阻滞，从而调控心室组织中的解剖性折返，有效终止折返。这些结果为折返终止提供了独特的新的机制见解，并为心律失常管理提供了新的视角。
