Role of Abnormal Intracellular Calcium Dynamics in the genesis of electrical alternans in the heart

本研究旨在阐明细胞内钙动力学在电交替中的作用;电交替是致命性室性快速性心律失常发生的临床有用指标。通过应用双视图，快速扫描共聚焦显微镜同时检测细胞内钙动力学和相应的膜电位Langendorff灌注大鼠心脏，我们进行了共聚焦成像的fluo 4-和RH 237-信号在细胞水平。通过这种新的方法，得到了以下结果.我们成功地同时检测了灌流大鼠心脏细胞内钙动力学和膜电位.房室传导阻滞时，个别心肌细胞偶见钙波，无明显的膜去极化.在低钾异丙肾上腺素灌注下，心脏短阵起搏引起触发活动的发生，随后由伴有膜振荡的钙波介导钙振荡.这种钙波介导的振荡膜电位可被ryanodine和钠钙交换阻断剂SEA 0400减弱. Ryanodine减少肌浆网钙释放，不能引起钙交替。然而，在4-5 Hz的心脏高频起搏导致钙交替的发展，而个别心肌细胞表现出没有节拍到节拍交替的动作电位waveforms.In总结目前的结果表明钙波触发活动的发生中的重要作用。另一方面，钙交替可能引起的抑制钙释放功能并不伴随着电交替，这表明电交替是不负责的钙handings的细胞异质性，但在心脏的区域异质性。

This study was designed to clarify the role of intracellular calcium dynamics in the electrical alternans; a clinically useful indicator for the development of fatal ventricular tachyarrhythmias. By applying a dual-view, rapid scanning confocal microscopy for simultaneous detection of both the intracellular calcium dynamics and the corresponding membrane potentials to Langendorff-perfused rat hearts, we conducted confocal imaging of the fluo4- and RH237-signals at cellular levels. With this novel approach, following results were obtained.1. We succeeded in detecting both the intracellular calcium dynamics and membrane potentials simultaneously in the perfused rat heart.2. Under atrio-ventricular conduction block, individual myocytes exhibited calcium waves sporadically with no discernible membrane depolarization.3. Under low K perfusion with isoproterenol, burst pacing of the heart resulted in genesis of triggered activity and subsequent calcium oscillation mediated by calcium waves that were accompanied by membrane oscillation.4. Such calcium wave-mediated oscillatory membrane potentials were attenuated by ryanodine and SEA0400, a blocker for Na-Ca exchange.5. Reduced calcium release from the sarcoplasmic reticulum, by ryanodine failed to evoke calcium alternans. However, high-frequency pacing of the heart at 4-5 Hz resulted in development of calcium alternans, whereas the individual myocytes showed no beat-to-beat alternans of action potential waveforms.In summary the present results indicate an essential role of calcium waves in the genesis of triggered activity. On the other hands, calcium alternans evoked presumably by depressed calcium release function were not accompanied by electrical alternans, suggesting that electrical alternans is not responsible for the cellular heterogeneity of calcium handings, but regional heterogeneity in the heart.