Regulation of Ca2+ and electrical alternans in cardiac myocytes:: role of CAMKII and repolarizing currents
Regulation of Ca2+ and electrical alternans in cardiac myocytes:: role of CAMKII and repolarizing currents
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DOI：
10.1152/ajpheart.01347.2006
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发表时间：
2007-06-01
影响因子：
4.8
通讯作者：
Rudy, Yoram
中科院分区：
文献类型：
--
作者：
Livshitz, Leonid M.;Rudy, Yoram
心脏复极交替与心律失常和猝死有关。在细胞水平上，交替涉及动作电位（AP）的逐拍振荡和可能的Ca 2+瞬变（CaT）。由于独立控制Ca 2+和电子系统的实验困难，数学建模提供了额外的见解机制和因果关系。在犬心室肌细胞模型上进行起搏实验，结果表明：（1）CaT交替是肌浆网Ca ~（2+）释放系统不应性的结果，L-型钙电流的改变对CaT交替的影响可忽略不计;（2）晚期AP时CaT-AP偶联通过钠-钙交换体发生，是AP时程（APD）交替的基础; 3）Ca 2 +/钙调素依赖性蛋白激酶11（CaMKII）活性升高，使CaT和APD交替的范围向慢频率扩展，并增加afternans幅度，CaMKII活性降低，抑制CaT和APD交替，发挥抗心律失常作用;快速延迟整流电流（I-Kr）的增加也抑制APD交替，但不抑制CaT交替。因此，CaMKII抑制消除APD afternans消除其原因（CaT交替），而I-Kr。增强通过减弱CaT-APD耦合来实现。模拟鉴定组合的CaMKII抑制和1（Kr）增强作为可能的抗肿瘤干预。
Alternans of cardiac repolarization is associated with arrhythmias and sudden death. At the cellular level, alternans involves beat-to-beat oscillation of the action potential (AP) and possibly Ca2+ transient (CaT). Because of experimental difficulty in independently controlling the Ca2+ and electrical subsystems, mathematical modeling provides additional insights into mechanisms and causality. Pacing protocols were conducted in a canine ventricular myocyte model with the following results: 1) CaT alternans results from refractoriness of the sarcoplasmic reticulum Ca2+ release system; alternation of the L-type calcium current has a negligible effect; 2) CaT-AP coupling during late AP occurs through the sodium-calcium exchanger and underlies AP duration (APD) alternans; 3) increased Ca2+/calmodulin-dependent protein kinase 11 (CaMKII) activity extends the range of CaT and APD altemans to slower frequencies and increases afternans magnitude; its decrease suppresses CaT and APD alternans, exerting an antiarrhythmic effect; and 4) increase of the rapid delayed rectifier current (I-Kr) also suppresses APD alternans but without suppressing CaT alternans. Thus CaMKII inhibition eliminates APD afternans by eliminating its cause (CaT alternans) while I-Kr. enhancement does so by weakening CaT-APD coupling. The simulations identify combined CaMKII inhibition and 1(Kr) enhancement as a possible antiarrhythmic intervention.