Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University , Blacksburg, Virginia.
Center for Heart and Reparative Medicine Research, Virginia Tech Carilion Research Institute , Roanoke, Virginia.
Am J Physiol Heart Circ Physiol. 2019 Apr 1;316(4):H849-H861. doi: 10.1152/ajpheart.00083.2018. Epub 2019 Feb 1.
We previously demonstrated that altering extracellular sodium (Na) and calcium (Ca) can modulate a form of electrical communication between cardiomyocytes termed "ephaptic coupling" (EpC), especially during loss of gap junction coupling. We hypothesized that altering Na and Ca modulates conduction velocity (CV) and arrhythmic burden during ischemia. Electrophysiology was quantified by optically mapping Langendorff-perfused guinea pig ventricles with modified Na (147 or 155 mM) and Ca (1.25 or 2.0 mM) during 30 min of simulated metabolic ischemia (pH 6.5, anoxia, aglycemia). Gap junction-adjacent perinexal width ( W), a candidate cardiac ephapse, and connexin (Cx)43 protein expression and Cx43 phosphorylation at S368 were quantified by transmission electron microscopy and Western immunoblot analysis, respectively. Metabolic ischemia slowed CV in hearts perfused with 147 mM Na and 2.0 mM Ca; however, theoretically increasing EpC with 155 mM Na was arrhythmogenic, and CV could not be measured. Reducing Ca to 1.25 mM expanded W, as expected during ischemia, consistent with reduced EpC, but attenuated CV slowing while delaying arrhythmia onset. These results were further supported by osmotically reducing W with albumin, which exacerbated CV slowing and increased early arrhythmias during ischemia, whereas mannitol expanded W, permitted conduction, and delayed the onset of arrhythmias. Cx43 expression patterns during the various interventions insufficiently correlated with observed CV changes and arrhythmic burden. In conclusion, decreasing perfusate calcium during metabolic ischemia enhances perinexal expansion, attenuates conduction slowing, and delays arrhythmias. Thus, perinexal expansion may be cardioprotective during metabolic ischemia. NEW & NOTEWORTHY This study demonstrates, for the first time, that modulating perfusate ion composition can alter cardiac electrophysiology during simulated metabolic ischemia.
我们之前的研究表明，改变细胞外钠（Na）和钙（Ca）可以调节心肌细胞之间的一种电通讯形式，称为“电突触耦合”（EpC），尤其是在缝隙连接偶联丧失时。我们假设改变 Na 和 Ca 可以调节缺血期间的传导速度（CV）和心律失常负担。通过光学映射 Langendorff 灌注豚鼠心室，在模拟代谢性缺血（pH6.5、缺氧、无葡萄糖）期间，用 147 或 155mM 的 Na 和 1.25 或 2.0mM 的 Ca 对电生理学进行了量化。用透射电子显微镜和 Western 免疫印迹分析分别定量了缝隙连接旁周向宽度（W），候选心脏电突触，连接蛋白（Cx）43 蛋白表达和 Cx43 在 S368 处的磷酸化。代谢性缺血使用 147mM Na 和 2.0mM Ca 灌注的心脏的 CV 减慢；然而，理论上增加 155mM Na 以增加 EpC 是致心律失常的，并且无法测量 CV。如预期的那样，将 Ca 降低至 1.25mM 会扩大 W，这与 EpC 减少一致，但减轻了 CV 减慢，同时延迟了心律失常的发作。用白蛋白渗透压降低 W 的结果进一步支持了这一结果，这加剧了缺血期间的 CV 减慢和早期心律失常，而甘露醇扩大了 W，允许传导，并延迟了心律失常的发作。在各种干预措施期间，Cx43 表达模式与观察到的 CV 变化和心律失常负担之间的相关性不足。总之，在代谢性缺血期间降低灌流液中的钙会增强旁周扩张，减轻传导减慢，并延迟心律失常。因此，旁周扩张在代谢性缺血期间可能具有心脏保护作用。
新的和值得注意的是，本研究首次表明，调节灌流液离子组成可以改变模拟代谢性缺血期间的心脏电生理学。
