It is well known that heart failure (HF) typically coexists with atrial fibrillation (AF). However, until now, no clear mechanism has been established that relates HF to AF. In this study, we apply a multiscale computational framework to establish a mechanistic link between atrial myocyte structural remodeling in HF and AF. Using a spatially distributed model of calcium (Ca) signaling, we show that disruption of the spatial relationship between L-type Ca channels (LCCs) and ryanodine receptors results in markedly increased Ca content of the sarcoplasmic reticulum (SR). This increase in SR load is due to changes in the balance between Ca entry via LCCs and Ca extrusion due to the sodium-calcium exchanger after an altered spatial relationship between these signaling proteins. Next, we show that the increased SR load in atrial myocytes predisposes these cells to subcellular Ca waves that occur during the action potential (AP) and are triggered by LCC openings. These waves are common in atrial cells because of the absence of a well-developed t-tubule system in most of these cells. This distinct spatial architecture allows for the presence of a large pool of orphaned ryanodine receptors, which can fire and sustain Ca waves during the AP. Finally, we incorporate our atrial cell model in two-dimensional tissue simulations and demonstrate that triggered wave generation in cells leads to electrical waves in tissue that tend to fractionate to form wavelets of excitation. This fractionation is driven by the underlying stochasticity of subcellular Ca waves, which perturbs AP repolarization and consequently induces localized conduction block in tissue. We outline the mechanism for this effect and argue that it may explain the propensity for atrial arrhythmias in HF.

中文翻译：

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重构促进心房肌细胞中钙稳态的促心律失常破坏

众所周知，心力衰竭 (HF) 通常与心房颤动 (AF) 共存。然而，到目前为止，还没有建立明确的机制将 HF 与 AF 联系起来。在这项研究中，我们应用多尺度计算框架来建立 HF 和 AF 心房肌细胞结构重塑之间的机械联系。我们使用钙 (Ca) 信号的空间分布模型，表明 L 型 Ca 通道 (LCC) 和兰尼碱受体之间空间关系的破坏导致肌浆网 (SR) 的 Ca 含量显着增加。SR 负载的这种增加是由于在这些信号蛋白之间的空间关系发生改变后，由于钠钙交换器导致的通过 LCC 进入的 Ca 和 Ca 挤出之间的平衡发生了变化。下一个，我们表明心房肌细胞中增加的 SR 负荷使这些细胞易于发生在动作电位 (AP) 期间发生并由 LCC 开口触发的亚细胞 Ca 波。这些波在心房细胞中很常见，因为在大多数这些细胞中缺乏发育良好的 t 小管系统。这种独特的空间结构允许存在大量孤立的兰尼碱受体，它们可以在 AP 期间发射和维持 Ca 波。最后，我们将我们的心房细胞模型结合到二维组织模拟中，并证明细胞中的触发波生成导致组织中的电波倾向于分馏以形成激发小波。这种分馏是由亚细胞 Ca 波的潜在随机性驱动的，扰乱 AP 复极，从而在组织中诱导局部传导阻滞。我们概述了这种效应的机制，并认为它可以解释 HF 中房性心律失常的倾向。