Jæger Karoline Horgmo, Louch William E, Tveito Aslak
Simula Research Laboratory, Oslo, Norway.
Institute for Experimental Medical Research, Oslo University Hospital and University of Oslo, Oslo, Norway.
Physiol Rep. 2025 Jul;13(13):e70461. doi: 10.14814/phy2.70461.
Cardiomyocytes exhibit significant cell-to-cell variability due to differences in protein expression and post-translational modifications in the cell membrane and the intracellular machinery. Resulting variability in action potential propagation and configuration is proposed to promote arrhythmia. However, such effects may be suppressed by tight electrical coupling of cells in the healthy heart, but not during pathological conditions where gap junction function is impaired. To investigate this, we employed a cell-based mathematical model of cardiac electrophysiology, in which we systematically modified properties of individual cells and intercellular electrical connectivity (gap junctions). Despite the inclusion of marked variation in properties between cells, we observed electrical homogeneity when cells were well coupled. In contrast, lower and/or more variable gap junction connectivity resulted in nonhomogeneous action potential configuration and irregular timing of the depolarizing and repolarizing electrical wavefronts. Pro-arrhythmic early after depolarizations also occurred under these conditions. These effects were effectively dampened in highly coupled cells. Nevertheless, differences in calcium homeostasis were not negated by gap junction coupling, indicating a limit to which electrical connections can homogenize mechanical function. Our findings underscore the critical role of intercellular coupling in maintaining cardiac stability and highlight the importance of studying cardiomyocytes within a syncytium rather than in isolation.
由于细胞膜和细胞内机制中蛋白质表达及翻译后修饰的差异，心肌细胞表现出显著的细胞间变异性。动作电位传播和形态的这种变异性被认为会促进心律失常。然而，在健康心脏中，细胞间紧密的电耦合可能会抑制这种影响，但在缝隙连接功能受损的病理状态下则不然。为了对此进行研究，我们采用了一种基于细胞的心脏电生理数学模型，在该模型中我们系统地改变了单个细胞的特性以及细胞间电连接性（缝隙连接）。尽管细胞之间的特性存在显著差异，但当细胞耦合良好时，我们观察到了电均匀性。相反，较低和/或更具变异性的缝隙连接连通性导致动作电位形态不均匀以及去极化和复极化电前沿的时间不规则。在这些条件下也会出现促心律失常的早期后除极。在高度耦合的细胞中，这些影响得到了有效抑制。然而，缝隙连接耦合并未消除钙稳态的差异，这表明电连接使机械功能均匀化存在一定限度。我们的研究结果强调了细胞间耦合在维持心脏稳定性中的关键作用，并突出了在合胞体中而非孤立地研究心肌细胞的重要性。
