Hypertrophic cardiomyopathy (HCM) is characterised by asymmetric left ventricular hypertrophy, ventricular arrhythmias, and cardiomyocyte dysfunction that may cause sudden death. HCM is associated with mutations in sarcomeric proteins and is usually transmitted as an autosomal-dominant trait. The aim of this in silico study was to assess the mechanisms that underlie the altered electrophysiological activity, contractility, regulation of energy metabolism, and crossbridge cycling in HCM at the single-cell level. To investigate this, we developed a human ventricular cardiomyocyte model that incorporates electrophysiology, metabolism, and force generation. The model was validated by its ability to reproduce the experimentally observed kinetic properties of human HCM induced by (a) remodelling of several ion channels and Ca²⁺-handling proteins arising from altered Ca²⁺/calmodulin kinase II signalling pathways and (b) increased Ca²⁺ sensitivity of the myofilament proteins. Our simulation showed a decreased phosphocreatine-to-ATP ratio (-9%) suggesting a negative mismatch between energy expenditure and supply. Using a spatial myofilament half-sarcomere model, we also compared the fraction of detached, weakly bound, and strongly bound crossbridges in the control and HCM conditions. Our simulations showed that HCM has more crossbridges in force-producing states than in the control condition. In conclusion, our model reveals that impaired crossbridge kinetics is accompanied by a negative mismatch between the ATP supply and demand ratio. This suggests that improving this ratio may reduce the incidence of sudden death in HCM.

中文翻译：

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计算机模拟心肌细胞揭示了 CaMKII 信号传导变化对肥厚型心肌病心肌细胞收缩动力学的影响

肥厚型心肌病（HCM）的特点是不对称的左心室肥厚、室性心律失常和心肌细胞功能障碍，可能导致猝死。 HCM 与肌节蛋白突变有关，通常作为常染色体显性遗传特征传播。这项计算机模拟研究的目的是评估单细胞水平上 HCM 电生理活动、收缩性、能量代谢调节和跨桥循环改变的机制。为了研究这一点，我们开发了一种人类心室心肌细胞模型，该模型结合了电生理学、新陈代谢和力的产生。该模型通过其重现实验观察到的人类 HCM 动力学特性的能力进行了验证，该动力学特性是通过以下方式诱导的：(a) 由 Ca ²⁺ /钙调蛋白激酶 II 信号通路改变引起的多个离子通道和 Ca ²⁺处理蛋白的重塑，以及 (b)肌丝蛋白的Ca ²⁺敏感性增加。我们的模拟显示磷酸肌酸与 ATP 的比率下降 (-9%)，表明能量消耗和供应之间存在负不匹配。使用空间肌丝半肌节模型，我们还比较了对照和 HCM 条件下分离、弱结合和强结合跨桥的比例。我们的模拟表明，HCM 在力产生状态下比在控制状态下具有更多的横桥。总之，我们的模型表明，受损的桥动力学伴随着 ATP 供需比率之间的负不匹配。这表明提高这一比率可能会降低 HCM 猝死的发生率。