Ionic bases for electrical remodeling of the canine cardiac ventricle
Ionic bases for electrical remodeling of the canine cardiac ventricle
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DOI：
10.1152/ajpheart.00213.2013
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发表时间：
2013-08-01
影响因子：
4.8
通讯作者：
Rosenbaum, David S.
中科院分区：
文献类型：
--
作者：
Jeyaraj, Darwin;Wan, Xiaoping;Rosenbaum, David S.
新的证据表明，局部心肌应变通过机械电反馈机制触发了心室电重构，然而，应变诱导的心肌电重构的离子机制尚不清楚。为确定其离子基础，对6只接受左心室起搏的犬(n=6)和4只未起搏的对照组(n=4)进行了电刺激改变诱发的VER的比较。从早期激活(低应变)和晚期激活(高应变)左室区分离的犬心外膜肌细胞，测量动作电位(AP)时程(APDS)、离子电流和钙瞬变。早期激活区的VER以最小的时程延长为特征，但AP相1切迹的显著衰减归因于瞬时外向K+电流的减少。相反，晚激活区的VER以明显的时程延长为特征。尽管动作电位时程显著延长，但令人惊讶的是，离子通道密度变化很小，但舒张期钙离子增加了两倍。计算机模拟表明，肌膜离子通道密度的变化只能解释在早期激活区观察到的AP缺口的衰减，而不能解释晚期激活区的动作电位重塑。此外，这些模拟还证实，胞内钙离子通过增强正向模式Na+/Ca~(2+)交换器的活性而导致晚期激活区的时程延长，这一点得到了Na~+/Ca~(2+)交换器蛋白表达增加的证实。最后，对VER后皮肤纤维的评估发现，晚期激活区肌丝钙敏感性的改变与舒张期钙水平的增加有关。总之，我们确定了VER背后的两种不同的离子机制：1)由于肌膜离子通道的重塑而导致的早期激活区域的非应变依赖性变化，而不是钙离子处理的改变；以及2)在犬的晚期激活区域中应变诱导的VER的新的和意想不到的机制，该机制源于肌节钙离子处理的重塑而不是肌膜离子通道的重塑。
Emerging evidence suggests that ventricular electrical remodeling (VER) is triggered by regional myocardial strain via mechanoelectrical feedback mechanisms; however, the ionic mechanisms underlying strain-induced VER are poorly understood. To determine its ionic basis, VER induced by altered electrical activation in dogs undergoing left ventricular pacing (n = 6) were compared with unpaced controls (n = 4). Action potential (AP) durations (APDs), ionic currents, and Ca2+ transients were measured from canine epicardial myocytes isolated from early-activated (low strain) and late-activated (high strain) left ventricular regions. VER in the early-activated region was characterized by minimal APD prolongation, but marked attenuation of the AP phase 1 notch attributed to reduced transient outward K+ current. In contrast, VER in the late-activated region was characterized by significant APD prolongation. Despite marked APD prolongation, there was surprisingly minimal change in ion channel densities but a twofold increase in diastolic Ca2+. Computer simulations demonstrated that changes in sarcolemmal ion channel density could only account for attenuation of the AP notch observed in the early-activated region but failed to account for APD remodeling in the late-activated region. Furthermore, these simulations identified that cytosolic Ca2+ accounted for APD prolongation in the late-activated region by enhancing forward-mode Na+/Ca2+ exchanger activity, corroborated by increased Na+/Ca2+ exchanger protein expression. Finally, assessment of skinned fibers after VER identified altered myofilament Ca2+ sensitivity in late-activated regions to be associated with increased diastolic levels of Ca2+. In conclusion, we identified two distinct ionic mechanisms that underlie VER: 1) strain-independent changes in early-activated regions due to remodeling of sarcolemmal ion channels with no changes in Ca2+ handling and 2) a novel and unexpected mechanism for strain-induced VER in late-activated regions in the canine arising from remodeling of sarcomeric Ca2+ handling rather than sarcolemmal ion channels.