Department of Pharmacology, University of California Davis, Davis, CA 95616, USA.
Department of Physiology and Biophysics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Int J Mol Sci. 2021 May 26;22(11):5645. doi: 10.3390/ijms22115645.
: The mechanisms underlying dysfunction in the sinoatrial node (SAN), the heart's primary pacemaker, are incompletely understood. Electrical and Ca-handling remodeling have been implicated in SAN dysfunction associated with heart failure, aging, and diabetes. Cardiomyocyte [Na] is also elevated in these diseases, where it contributes to arrhythmogenesis. Here, we sought to investigate the largely unexplored role of Na homeostasis in SAN pacemaking and test whether [Na] dysregulation may contribute to SAN dysfunction. : We developed a dataset-specific computational model of the murine SAN myocyte and simulated alterations in the major processes of Na entry (Na/Ca exchanger, NCX) and removal (Na/K ATPase, NKA). : We found that changes in intracellular Na homeostatic processes dynamically regulate SAN electrophysiology. Mild reductions in NKA and NCX function increase myocyte firing rate, whereas a stronger reduction causes bursting activity and loss of automaticity. These pathologic phenotypes mimic those observed experimentally in NCX- and ankyrin-B-deficient mice due to altered feedback between the Ca and membrane potential clocks underlying SAN firing. : Our study generates new testable predictions and insight linking Na homeostasis to Ca handling and membrane potential dynamics in SAN myocytes that may advance our understanding of SAN (dys)function.
: 窦房结（SAN）功能障碍的潜在机制尚不完全清楚，SAN 是心脏的主要起搏器。心力衰竭、衰老和糖尿病与 SAN 功能障碍相关，电重构和 Ca 处理重构都与 SAN 功能障碍有关。这些疾病中心肌细胞[Na]也升高，它有助于心律失常的发生。在这里，我们试图研究 Na 动态平衡在 SAN 起搏中的作用，检验[Na]失调是否可能导致 SAN 功能障碍。: 我们开发了一个特定于数据集的小鼠 SAN 心肌细胞计算模型，并模拟了 Na 内流（Na/Ca 交换器，NCX）和去除（Na/K ATP 酶，NKA）的主要过程的变化。: 我们发现，细胞内 Na 稳态过程的变化可以动态调节 SAN 的电生理。轻度降低 NKA 和 NCX 功能会增加心肌细胞的发放率，而较强的降低会导致爆发活动和自动性丧失。这些病理表型模拟了在 NCX 和锚蛋白-B 缺陷小鼠中观察到的实验性改变，因为 SAN 发放所基于的 Ca 和膜电位时钟之间的反馈发生改变。: 我们的研究产生了新的可测试的预测和见解，将 Na 稳态与 SAN 心肌细胞中的 Ca 处理和膜电位动力学联系起来，这可能有助于我们理解 SAN（功能）障碍。
