人类心房颤动发生机制：复极时程恢复和激活时程离散的临床与计算研究。
Mechanisms of human atrial fibrillation initiation: clinical and computational studies of repolarization restitution and activation latency.
机构信息
University of California San Diego, San Diego, CA, USA.
出版信息
Circ Arrhythm Electrophysiol. 2012 Dec;5(6):1149-59. doi: 10.1161/CIRCEP.111.969022. Epub 2012 Oct 1.
BACKGROUND
Mechanisms of atrial fibrillation (AF) initiation are incompletely understood. We hypothesized that rate-dependent changes (restitution) in action potential duration (APD) and activation latency are central targets for clinical interventions that induce AF. We tested this hypothesis using clinical experiments and computer models.
METHODS AND RESULTS
In 50 patients (20 persistent, 23 paroxysmal AF, 7 controls), we used monophasic action potential catheters to define left atrial APD restitution, activation latency, and AF incidence from premature extrastimuli. Isoproterenol (n=14), adenosine (n=10), or rapid pacing (n=36) was then initiated to determine impact on these parameters. Compared with baseline in AF patients, isoproterenol and rapid pacing decreased activation latency (64±14 versus 31±13 versus 24±14 ms; P<0.05), steepened maximum APD restitution slope (0.8±0.7 versus 1.7±0.5 versus 1.1±0.5; P<0.05), and increased AF incidence (12% versus 64% versus 84%; P<0.05). Conversely, adenosine shortened APD (P<0.05), yet increased activation latency (86±27 ms; P=0.002) so that maximum APD restitution slope did not steepen (1.0±0.5; P=NS), and AF incidence was unchanged (10%; P=NS). In controls, no intervention steepened APD restitution or initiated AF. Computational modeling revealed that isoproterenol steepened APD restitution by increased L-type calcium current and decreased activation latency via enhanced rapid delayed potassium reactifier current inactivation, whereas rapid pacing steepened APD restitution via increased cardiac inward potassium rectifier current.
CONCLUSIONS
Steep APD restitution is a common pathway for AF initiation by isoproterenol and tachycardia via reduced activation latency that enables engagement of steep APD restitution at rapid rates. Modeling suggests that AF initiation from each intervention uses distinct ionic mechanisms. This insight may help design interventions to prevent AF.
背景
心房颤动（AF）的发生机制尚不完全清楚。我们假设动作电位时程（APD）和激活潜伏期的速率依赖性变化（ restitution ）是诱导 AF 的临床干预的核心靶点。我们使用临床实验和计算机模型来检验这一假设。
方法和结果
在 50 例患者（持续性 20 例，阵发性 AF23 例，对照组 7 例）中，我们使用单相动作电位导管定义左心房 APD restitution 、激活潜伏期和从过早的 extras timuli 诱发的 AF 发生率。然后启动异丙肾上腺素（n=14）、腺苷（n=10）或快速起搏（n=36），以确定对这些参数的影响。与 AF 患者的基线相比，异丙肾上腺素和快速起搏降低了激活潜伏期（64±14 比 31±13 比 24±14ms；P<0.05），最大 APD restitution 斜率变陡（0.8±0.7 比 1.7±0.5 比 1.1±0.5；P<0.05），AF 发生率增加（12%比 64%比 84%；P<0.05）。相反，腺苷缩短了 APD（P<0.05），但增加了激活潜伏期（86±27ms；P=0.002），因此最大 APD restitution 斜率没有变陡（1.0±0.5；P=NS），AF 发生率不变（10%；P=NS）。在对照组中，没有干预措施使 APD restitution 变陡或引发 AF。计算模型表明，异丙肾上腺素通过增加 L 型钙电流和通过增强快速延迟钾反应剂电流失活来缩短激活潜伏期，从而使 APD restitution 变陡，而快速起搏则通过增加心脏内向钾整流电流使 APD restitution 变陡。
结论
APD restitution 变陡是异丙肾上腺素和心动过速引发 AF 的共同途径，通过降低激活潜伏期，使快速率下的陡峭 APD restitution 得以实现。模型表明，每种干预措施引发 AF 的离子机制不同。这种洞察力可能有助于设计预防 AF 的干预措施。
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