Ryanodine receptor dysfunction and triggered activity in the heart
Ryanodine receptor dysfunction and triggered activity in the heart
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DOI：
10.1152/ajpheart.00924.2006
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发表时间：
2007-05-01
影响因子：
4.8
通讯作者：
Laurita, Kenneth R.
中科院分区：
文献类型：
--
作者：
Katra, Rodolphe P.;Oya, Toshiyuki;Laurita, Kenneth R.
心律失常的发生越来越多地与心脏ryanodine受体（RyR）功能障碍有关。然而，RyR功能异常和心脏中的血栓形成之间的机制关系尚不清楚。我们假设，在异常RyR条件下，触发活动将由依赖于钙处理的透壁异质性的自发钙释放（SCR）事件引起。我们在犬左心室楔形标本（n = 28）中进行了细胞内钙和跨膜电位的高分辨率光学标测。快速起搏用于在由FKBP 12.6解离和β-肾上腺素能刺激（20-150 μ M雷帕霉素，0.2 μ M异丙肾上腺素）诱导的正常和异常RyR条件下启动触发活性。在异常RyR条件下，几乎所有的制剂都经历了SCR并触发活性，与对照、雷帕霉素或单独的异丙肾上腺素条件相反。此外，在RyR异常条件下，通常观察到复杂心动过速（单形和多形心动过速）。雷帕霉素和异丙肾上腺素洗脱后，未观察到触发活性。触发活动和SCR更易发生在心外膜而不是心内膜（P < 0.01）。有趣的是，触发活动和SCR事件的发生不能解释细胞质钙水平，而是快速钙再摄取动力学。这些数据表明，在异常RyR条件下，触发活动是由多个SCR事件，依赖于更快的钙再摄取动力学附近的心外膜。此外，SCR的多个区域可能是与RyR功能障碍相关的多灶性心律失常的机制。
Arrhythmogenesis has been increasingly linked to cardiac ryanodine receptor (RyR) dysfunction. However, the mechanistic relationship between abnormal RyR function and arrhythmogenesis in the heart is not clear. We hypothesize that, under abnormal RyR conditions, triggered activity will be caused by spontaneous calcium release (SCR) events that depend on transmural heterogeneities of calcium handling. We performed high-resolution optical mapping of intracellular calcium and transmembrane potential in the canine left ventricular wedge preparation (n = 28). Rapid pacing was used to initiate triggered activity under normal and abnormal RyR conditions induced by FKBP12.6 dissociation and P-adrenergic stimulation (20-150 mu M rapamycin, 0.2 mu M isoproterenol). Under abnormal RyR conditions, almost all preparations experienced SCRs and triggered activity, in contrast to control, rapamycin, or isoproterenol conditions alone. Furthermore, under abnormal RyR conditions, complex arrhythimas (monomorphic and polymorphic tachycardia) were commonly observed. After washout of rapamycin and isoproterenol, no triggered activity was observed. Surprisingly, triggered activity and SCRs occurred preferentially near the epicardium but not the endocardium (P < 0.01). Interestingly, the occurrence of triggered activity and SCR events could not be explained by cytoplasmic calcium levels, but rather by fast calcium reuptake kinetics. These data suggest that, under abnormal RyR conditions, triggered activity is caused by multiple SCR events that depend on the faster calcium reuptake kinetics near the epicardium. Furthermore, multiple regions of SCR may be a mechanism for multifocal arrhythmias associated with RyR dysfunction.