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首页> 外文期刊>Journal of Molecular and Cellular Cardiology >Molecular correlates of repolarization alternans in cardiac myocytes.
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Molecular correlates of repolarization alternans in cardiac myocytes.

机译：心肌细胞中复极化交替蛋白的分子相关性。

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Arrhythmogenic action potential alternans (APD-ALT) is thought to arise from beat to beat alteration in cellular Ca(2+) cycling. Previously, we found that spatial heterogeneity in APD-ALT between ventricular myocytes is key to the mechanism linking APD-ALT to cardiac arrhythmogenesis. However, the cellular and molecular basis for APD-ALT is poorly understood. To test the hypothesis that spatial heterogeneities in expression and function of calcium cycling proteins underlies heterogeneities in APD-ALT, endocardial and epicardial myocytes were isolated from left ventricular free wall of 20 guinea pig hearts. APD-ALT and Ca(2+) transient alternans (Ca-ALT) were measured simultaneously as stimulus rate was increased progressively. Endocardial myocytes exhibited greater susceptibility to cellular alternans than epicardial myocytes as evidenced by a significantly lower pacing rate threshold for APD-ALT (113 +/ -9 bpm vs. 151 +/- 8 bpm, respectively, P < 0.05) and for Ca-ALT (110 +/- 8 bpm vs. 149 +/- 8 bpm, respectively, P < 0.05). APD-ALT never occurred without Ca-ALT, whereas Ca-ALT was readily induced in the absence of APD-ALT by repetitive constant action potential waveform, suggesting that Ca-ALT was not secondary to APD-ALT. Importantly, there were significant voltage-independent differences in Ca(2+) cycling between endocardial and epicardial myocytes as evidenced by weaker Ca(2+) release (32% lower Ca(2+) amplitude, and 16% longer rise time), and slower Ca(2+) reuptake (24% larger Ca(2+) decay time constant, and 9% longer Ca(2+) transient duration) in endocardial compared to epicardial myocytes. Taken together these data indicate that myocytes that are most susceptible to APD-ALT exhibit impaired Ca(2+) release and reuptake. Moreover, transmural differences in Ca(2+) cycling function was associated with significantly reduced endocardial expression of ryanodine release channel (by 22%) and SERCA2 (by 40%), suggesting a potential molecular basis for spatially heterogeneous APD-ALT. Moreover, transmural differences in expression and function of key SR Ca(2+) cycling proteins may underlie spatial heterogeneity of APD-ALT that has been closely linked to cardiac arrhythmogenesis.
机译：心律失常作用电位交替蛋白（APD-ALT）被认为是由细胞Ca（2+）循环中的搏动变化引起的。以前，我们发现心室肌细胞之间APD-ALT的空间异质性是将APD-ALT与心律失常联系起来的机制的关键。但是，APD-ALT的细胞和分子基础知之甚少。为了验证这一假设，即钙循环蛋白表达和功能的空间异质性是APD-ALT异质性的基础，从20头豚鼠心脏的左心室游离壁中分离出心内膜和心外膜心肌细胞。随着刺激率逐渐增加，同时测量APD-ALT和Ca（2+）瞬时交替蛋白（Ca-ALT）。心内膜心肌细胞对细胞交替蛋白的敏感性高于心外膜心肌细胞，APD-ALT的起搏速率阈值明显降低（分别为113 + / -9 bpm与151 +/- 8 bpm，P <0.05）和Ca- ALT（分别为110 +/- 8 bpm和149 +/- 8 bpm，P <0.05）。没有Ca-ALT的情况下APD-ALT从未发生过，而在不存在APD-ALT的情况下，通过重复的恒定动作电位波形很容易诱导Ca-ALT，这表明Ca-ALT并非继APD-ALT之后。重要的是，心内膜和心外膜心肌细胞之间的Ca（2+）循环存在显着的电压独立差异，这是由较弱的Ca（2+）释放所证实的（Ca（2+）振幅降低32％，上升时间延长16％），和心外膜心肌细胞相比，心内膜的Ca（2+）再摄取较慢（Ca（2+）衰减时间常数大24％，Ca（2+）瞬时持续时间长9％）。综合这些数据，表明对APD-ALT最敏感的心肌细胞显示出受损的Ca（2+）释放和再摄取。此外，Ca（2+）循环功能中的透壁差异与心律失常的ryanodine释放通道（减少22％）和SERCA2（减少40％）的心内膜表达有关，提示空间异质APD-ALT的潜在分子基础。此外，关键SR Ca（2+）循环蛋白的表达和功能的跨壁差异可能是APD-ALT的空间异质性的基础，APD-ALT的空间异质性与心律失常密切相关。

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