Progress in Modeling Cardiac Myocyte Calcium Cycling and Investigating Arrhythmia Mechanisms: A Study Focused on the Ryanodine Receptor

GAO Ying; ZHANG Yucheng; WANG Wenyao; SU Xuanyi; SONG Zhen

doi:10.11999/JEIT250957

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GAO Ying, ZHANG Yucheng, WANG Wenyao, SU Xuanyi, SONG Zhen. Progress in Modeling Cardiac Myocyte Calcium Cycling and Investigating Arrhythmia Mechanisms: A Study Focused on the Ryanodine Receptor[J]. Journal of Electronics & Information Technology. doi: 10.11999/JEIT250957

Citation:

GAO Ying, ZHANG Yucheng, WANG Wenyao, SU Xuanyi, SONG Zhen. Progress in Modeling Cardiac Myocyte Calcium Cycling and Investigating Arrhythmia Mechanisms: A Study Focused on the Ryanodine Receptor[J]. Journal of Electronics & Information Technology. doi: 10.11999/JEIT250957

Citation:

GAO Ying, ZHANG Yucheng, WANG Wenyao, SU Xuanyi, SONG Zhen. Progress in Modeling Cardiac Myocyte Calcium Cycling and Investigating Arrhythmia Mechanisms: A Study Focused on the Ryanodine Receptor[J]. Journal of Electronics & Information Technology. doi: 10.11999/JEIT250957

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Progress in Modeling Cardiac Myocyte Calcium Cycling and Investigating Arrhythmia Mechanisms: A Study Focused on the Ryanodine Receptor

doi: 10.11999/JEIT250957 cstr: 32379.14.JEIT250957

1.
Pengcheng Laboratory, Shenzhen 518000, China
2.
Southern University of Science and Technology, Shenzhen 518055, China
3.
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100096, China

Funds: The National Natural Science Foundation of China(82172067)

Accepted Date: 2025-12-29
Rev Recd Date: 2025-12-29

Available Online: 2026-01-08

Abstract

Abstract

Significance Ryanodine receptor (RyR) is an essential regulator of cardiac intracellular calcium homeostasis by controlling the release of Ca²⁺ from the sarcoplasmic reticulum (SR). Its functional abnormalities, such as overactivation or impaired activity, are critical mechanisms underlying early and delayed afterdepolarizations, significantly increasing the risk of arrhythmias. The dynamic coupling between electrical activity and calcium cycling in cardiomyocytes involves highly dynamic and spatially organized processes that are challenging to fully capture experimentally. Conventional experimental techniques, such as animal models and pharmacological studies, are limited by high costs and difficulties in controlling variables. As a result, developing mathematical models and computer simulations of the RyR has become a crucial approach for investigating RyR function regulation under physiological and pathological conditions, as well as its arrhythmogenic mechanisms. This review provides a systematic overview of RyR biology and modeling. It begins by synthesizing RyR structural features and fundamental functional properties to establish a mechanistic basis for gating and regulation. Next, it evaluates contemporary and emerging modeling techniques, outlining the merits and limitations of various computational approaches. The review then summarizes the integration of RyR models into cardiac Ca²⁺ cycling frameworks and their applications across cardiomyocyte subtypes. Furthermore, the review covers arrhythmogenic mechanisms arising from RyR dysfunction and examines targeted drug therapies designed to normalize channel activity. Finally, it highlights artificial intelligence and cardiac digital twins as emerging paradigms for advancing RyR modeling and therapeutic applications. Progress The accumulation of RyR structural data has driven continuous innovation in modeling strategies. Early models often used phenomenological strategies that were practical but mechanistically limited. Markov models now represent the dominant computational framework for simulating RyR gating behavior, enabling detailed replication of calcium sparks and other key events through discrete state transitions. A key advantage of deterministic integration over other numerical methods for solving Markov models is its superior computational efficiency and remarkable flexibility in adapting to diverse cardiomyocyte types. However, it ignores the stochastic nature of RyR opening and fails to reproduce stochastic fluctuations in intracellular calcium concentration, potentially leading to discrepancies between simulations and physiological reality. In contrast, stochastic Markov models can capture these random behaviors, which are critical for investigating arrhythmogenic phenomena like calcium waves. However, they necessitate substantial experimental data and considerable computational resources, consequently hindering their broader-scale application. The development of artificial intelligence methods, including the use of deep neural networks to compress Markov models into single equations, has substantially improved computational efficiency. Meanwhile, structural biology advances have clarified the conformational dynamics of RyRs and subunit cooperativity in gating, especially in diastolic calcium leak, prompting more detailed models like those incorporating subunit interactions or molecular dynamics. Additionally, various RyR models have been successfully integrated into cardiac action potential frameworks, serving as powerful tools for investigating arrhythmogenic mechanisms like delayed afterdepolarizations (DADs) and early afterdepolarizations (EADs). These models not only enhance the understanding of electrical disturbances caused by RyR dysfunction but also provide a valuable platform for antiarrhythmic drug screening and mechanistic research. Conclusion Several RyR models have been developed that accurately simulate essential physiological processes such as calcium sparks, enabling broad application in cardiomyocyte calcium dynamics studies. However, current modeling efforts face considerable challenges:(1) Lack of a unified modeling framework. There is still no unified RyR model capable of accurately simulating calcium dynamics across the wide spectrum of physiological and pathological conditions. To select appropriate model for intracellular calcium handling, careful evaluation of the specific effects of different models is necessary. (2) Computational burden restricts multiscale integration. While multiscale models are essential to bridge arrhythmic mechanisms from cellular calcium dynamics to tissue-level propagation by incorporating heterogeneity, their high computational cost presents a formidable barrier to scaling for clinically relevant applications. (3) Underdeveloped pacemaker cell models. Existing research focuses largely on ventricular and atrial myocytes, while pacemaker cell models are relatively underdeveloped and often employ “common pool” approximations that fail to capture spatial calcium gradients. Future research should therefore prioritize the development of detailed pacemaker cell models that represent calcium release unit (CRU) networks and incorporate realistic RyR dynamics. While still in early stages of development for RyR modeling, emerging approaches like artificial intelligence and cardiac digital twins thus offer substantial potential to advance both mechanistic understanding and applications in precision medicine. Prospects The future of RyR research will increasingly rely on combining multidisciplinary advances across structural biology, biophysics, and computational science. Integrative efforts are essential to bridge molecular-scale conformational changes of RyR to organ-level cardiac function, which will enable the creation of scalable and clinically actionable models that not only deepen mechanistic insight but also accelerate translational innovation in precision cardiology. Emerging tools like AI and cardiac digital twins offer a pathway toward clinically relevant, multi-scale cardiac models that incorporate patient-specific electrophysiology and calcium handling. Such models could profoundly improve our understanding of arrhythmia mechanisms and heart failure pathophysiology, while also serving as predictive platforms for mechanism-based personalized antiarrhythmic therapy development.
- ryanodine receptor,
- cardiac myocyte,
- calcium cycling,
- arrhythmias

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References(149)

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