Mahajan Aman, Sato Daisuke, Shiferaw Yohannes, Baher Ali, Xie Lai-Hua, Peralta Robert, Olcese Riccardo, Garfinkel Alan, Qu Zhilin, Weiss James N
UCLA Cardiovascular Research Laboratory, Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
Biophys J. 2008 Jan 15;94(2):411-23. doi: 10.1529/biophysj.106.98590.
The L-type Ca current (I(Ca,L)), essential for normal cardiac function, also regulates dynamic action potential (AP) properties that promote ventricular fibrillation. Blocking I(Ca,L) can prevent ventricular fibrillation, but only at levels suppressing contractility. We speculated that, instead of blocking I(Ca,L), modifying its shape by altering kinetic features could produce equivalent anti-fibrillatory effects without depressing contractility. To test this concept experimentally, we overexpressed a mutant Ca-insensitive calmodulin (CaM(1234)) in rabbit ventricular myocytes to inhibit Ca-dependent I(Ca,L) inactivation, combined with the ATP-sensitive K current agonist pinacidil or I(Ca,L) blocker verapamil to maintain AP duration (APD) near control levels. Cell shortening was enhanced in pinacidil-treated myocytes, but depressed in verapamil-treated myocytes. Both combinations flattened APD restitution slope and prevented APD alternans, similar to I(Ca,L) blockade. To predict the arrhythmogenic consequences, we simulated the cellular effects using a new AP model, which reproduced flattening of APD restitution slope and prevention of APD/Ca(i) transient alternans but maintained a normal Ca(i) transient. In simulated two-dimensional cardiac tissue, these changes prevented the arrhythmogenic spatially discordant APD/Ca(i) transient alternans and spiral wave breakup. These findings provide a proof-of-concept test that I(Ca,L) can be targeted to increase dynamic wave stability without depressing contractility, which may have promise as an antifibrillatory strategy.
L型钙电流（I(Ca,L)）对正常心脏功能至关重要，它还调节促进心室颤动的动态动作电位（AP）特性。阻断I(Ca,L)可预防心室颤动，但仅在抑制收缩力的水平上有效。我们推测，与其阻断I(Ca,L)，通过改变动力学特征来改变其形状可能会产生等效的抗纤颤作用而不降低收缩力。为了通过实验验证这一概念，我们在兔心室肌细胞中过表达一种对钙不敏感的突变型钙调蛋白（CaM(1234)）以抑制钙依赖性I(Ca,L)失活，并结合ATP敏感性钾电流激动剂吡那地尔或I(Ca,L)阻滞剂维拉帕米，使动作电位时程（APD）维持在接近对照水平。在吡那地尔处理的肌细胞中细胞缩短增强，但在维拉帕米处理的肌细胞中细胞缩短受到抑制。两种组合均使APD恢复斜率变平并预防了APD交替现象，类似于I(Ca,L)阻断。为了预测致心律失常后果，我们使用一种新的动作电位模型模拟细胞效应，该模型再现了APD恢复斜率变平以及预防APD/Ca(i)瞬变交替现象，但维持了正常的Ca(i)瞬变。在模拟的二维心脏组织中，这些变化预防了致心律失常的空间不协调的APD/Ca(i)瞬变交替现象和螺旋波破裂。这些发现提供了一个概念验证测试，即可以靶向I(Ca,L)来增加动态波稳定性而不降低收缩力，这可能有望成为一种抗纤颤策略。
