We present the first-ever, fully discrete, stochastic model of triggered cardiac Ca2+ dynamics. Using anatomically accurate subcellular cardiac myocyte geometries, we simulate the molecular players involved in Ca2+ handling using high-resolution stochastic and explicit-particle methods at the level of an individual cardiac dyadic junction. Integrating data from multiple experimental sources, the model not only replicates the findings of traditional in silico studies and complements in vitro experimental data but also reveals new insights into the molecular mechanisms driving cardiac dysfunction under stress and disease conditions. We improve upon older, nondiscrete models using the same realistic geometry by incorporating molecular mechanisms for spontaneous, as well as triggered calcium-induced calcium release (CICR). Action potentials are used to activate L-type calcium channels (LTCC), triggering CICR through ryanodine receptors (RyRs) on the surface of the sarcoplasmic reticulum. These improvements allow for the specific focus on the couplon: the structure-function relationship between LTCC and RyR. We investigate the electrophysical effects of normal and diseased action potentials on CICR and interrogate the effects of dyadic junction deformation through detubulation and orphaning of RyR. Our work demonstrates the importance of the electrophysical integrity of the calcium release unit on CICR fidelity, giving insights into the molecular basis of heart disease. Finally, we provide a unique, detailed, molecular view of the CICR process using advanced rendering techniques. This easy-to-use model comes complete with tutorials and the necessary software for use and analysis to maximize usability and reproducibility. Our work focuses on quantifying, qualifying, and visualizing the behavior of the molecular species that underlie the function and dysfunction of subcellular cardiomyocyte systems.

中文翻译：

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分子水平的电物理心脏重塑：从随机显式粒子模型深入了解兰尼碱受体激活和钙诱导的钙释放


我们提出了有史以来第一个完全离散的随机触发心脏 Ca2+ 动力学模型。使用解剖学上准确的亚细胞心肌细胞几何形状，我们在单个心脏二元连接水平上使用高分辨率随机和显式粒子方法模拟参与 Ca2+ 处理的分子参与者。该模型整合了来自多个实验来源的数据，不仅复制了传统的计算机研究结果并补充了体外实验数据，还揭示了在压力和疾病条件下驱动心功能障碍的分子机制的新见解。我们通过结合自发和触发钙诱导钙释放 （CICR） 的分子机制，使用相同的真实几何结构改进了旧的非离散模型。动作电位用于激活 L 型钙通道 （LTCC），通过肌浆网表面的兰尼碱受体 （RyR） 触发 CICR。这些改进允许特别关注 couplon：LTCC 和 RyR 之间的结构-功能关系。我们研究了正常和患病动作电位对 CICR 的电物理影响，并通过 RyR 的去管和孤立来询问二元连接变形的影响。我们的工作证明了钙释放单位的电物理完整性对 CICR 保真度的重要性，从而深入了解心脏病的分子基础。最后，我们使用先进的渲染技术提供了 CICR 过程的独特、详细的分子视图。这个易于使用的模型配有教程和必要的软件，以便使用和分析，以最大限度地提高可用性和可重复性。 我们的工作重点是量化、限定和可视化构成亚细胞心肌细胞系统功能和功能障碍基础的分子种类的行为。