Edwards Andrew G, Mørk Halvor, Stokke Mathis K, Lipsett David B, Sjaastad Ivar, Richard Sylvain, Sejersted Ole M, Louch William E
Institute for Experimental Medical Research, Oslo University Hospital, University of Oslo, Oslo, Norway.
Department of Pharmacology, University of California, Davis, Davis, CA, United States.
Front Physiol. 2021 Oct 12;12:744730. doi: 10.3389/fphys.2021.744730. eCollection 2021.
Dysfunctional sarcoplasmic reticulum Ca handling is commonly observed in heart failure, and thought to contribute to arrhythmogenesis through several mechanisms. Some time ago we developed a cardiomyocyte-specific inducible SERCA2 knockout mouse, which is remarkable in the degree to which major adaptations to sarcolemmal Ca entry and efflux overcome the deficit in SR reuptake to permit relatively normal contractile function. Conventionally, those adaptations would also be expected to dramatically increase arrhythmia susceptibility. However, that susceptibility has never been tested, and it is possible that the very rapid repolarization of the murine action potential (AP) allows for large changes in sarcolemmal Ca transport without substantially disrupting electrophysiologic stability. We investigated this hypothesis through telemetric ECG recording in the SERCA2-KO mouse, and patch-clamp electrophysiology, Ca imaging, and mathematical modeling of isolated SERCA2-KO myocytes. While the SERCA2-KO animals exhibit major (and unique) electrophysiologic adaptations at both the organ and cell levels, they remain resistant to arrhythmia. A marked increase in peak L-type calcium ( ) current and slowed decay elicited pronounced prolongation of initial repolarization, but faster late repolarization normalizes overall AP duration. Early afterdepolarizations were seldom observed in KO animals, and those that were observed exhibited a mechanism intermediate between murine and large mammal dynamical properties. As expected, spontaneous SR Ca sparks and waves were virtually absent. Together these findings suggest that intact SR Ca handling is an absolute requirement for triggered arrhythmia in the mouse, and that in its absence, dramatic changes to the major inward currents can be resisted by the substantial K current reserve, even at end-stage disease.
肌浆网钙处理功能失调在心力衰竭中普遍存在，并被认为通过多种机制导致心律失常的发生。不久前，我们培育了一种心肌细胞特异性可诱导SERCA2基因敲除小鼠，其显著之处在于，对肌膜钙内流和外流的主要适应性改变在很大程度上克服了肌浆网再摄取功能的缺陷，从而使收缩功能相对正常。按照传统观点，这些适应性改变也可能会显著增加心律失常的易感性。然而，从未对这种易感性进行过测试，而且有可能是小鼠动作电位（AP）的极快速复极化使得肌膜钙转运发生巨大变化，却不会实质性地破坏电生理稳定性。我们通过遥测心电图记录在SERCA2基因敲除小鼠中研究了这一假设，并对分离的SERCA2基因敲除心肌细胞进行了膜片钳电生理学、钙成像及数学建模研究。虽然SERCA2基因敲除动物在器官和细胞水平均表现出主要的（且独特的）电生理适应性改变，但它们仍对心律失常具有抗性。L型钙电流峰值显著增加以及衰减减慢导致初始复极化明显延长，但后期复极化加快使动作电位总时程恢复正常。在基因敲除动物中很少观察到早期后去极化，即便观察到，其机制也介于小鼠和大型哺乳动物的动力学特性之间。正如预期的那样，几乎不存在自发的肌浆网钙火花和钙波。这些研究结果共同表明，完整的肌浆网钙处理功能是小鼠触发心律失常的绝对必要条件，并且在其缺失的情况下，即使在疾病终末期，大量的钾电流储备也能抵抗主要内向电流的显著变化。
