PDF(Pubmed)
Abstract：
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.
摘要：
肥厚型心肌病（HCM）的特征是不对称的左心室肥厚，室性心律失常,和可能导致猝死的心肌细胞功能障碍。HCM与肌节蛋白的突变有关，通常以常染色体显性性状传播。这项计算机模拟研究的目的是评估电生理活动改变的机制，收缩性，调节能量代谢，和单电池水平HCM中的交叉桥循环。为了调查这一点，我们开发了一个包含电生理学的人心室心肌细胞模型，新陈代谢，和力量的产生。该模型通过其再现实验观察到的人类HCM动力学特性的能力得到了验证，该动力学特性是由（a）由改变的Ca2/钙调素激酶II信号传导途径引起的几种离子通道和Ca2处理蛋白的重塑和（b）增加的Ca2敏感性肌丝蛋白。我们的模拟显示磷酸肌酸与ATP的比率降低（-9％），表明能量消耗和供应之间存在负的不匹配。使用空间肌丝半肌节模型，我们还比较了分离的分数，弱束缚，以及在控制和HCM条件下强烈约束的交叉桥。我们的模拟表明，与控制条件相比，HCM在力产生状态下具有更多的跨桥。总之,我们的模型表明，受损的跨桥动力学伴随着ATP供需比之间的负失配。这表明，提高这一比例可能会降低HCM猝死的发生率。
