Modeling Calcium Cycling in the Heart: Progress, Pitfalls, and Challenges
Zhilin Qu1,2, Dasen Yan3, Zhen Song3
1Department of Medicine, David Geffen School of Medicine, University of California, A2-237 CHS, 650 Charles E. Young Drive South, Los Angeles, CA 90095, USA.
Insights
This review explores cardiac calcium (Ca) cycling models, from single ryanodine receptors (RyRs) to tissue scales. It details current modeling approaches, their limitations, and future challenges in understanding heart function and arrhythmias.
Area of Science:
- Cardiovascular Physiology
- Computational Biology
- Biophysics
Background:
- Intracellular calcium (Ca) cycling is crucial for cardiac excitation-contraction coupling and arrhythmogenesis.
- Cardiac myocytes feature calcium release units (CRUs) composed of ryanodine receptors (RyRs) that generate Ca sparks.
- A complex CRU network exhibits diverse spatiotemporal Ca dynamics, including sparks, waves, and oscillations.
Purpose of the Study:
- To review the progress in modeling cardiac Ca cycling dynamics across different scales.
- To analyze the advantages and disadvantages of various modeling approaches.
- To identify future challenges in modeling cardiac Ca cycling at the tissue level.
Main Methods:
- Review of existing literature on cardiac Ca cycling models.
- Analysis of models ranging from single RyRs to whole-tissue simulations.
- Discussion of computational approaches and their limitations.
Main Results:
- Models of varying temporal and spatial scales have been developed to study cardiac Ca dynamics.
- Significant challenges exist in accurately modeling the CRU network and tissue-scale Ca cycling.
- Current models offer insights but require further development for comprehensive understanding.
Conclusions:
- Modeling cardiac Ca cycling is complex due to intricate CRU networks and spatiotemporal dynamics.
- Further advancements are needed to bridge the gap between single-cell and tissue-level models.
- Improved models are essential for a deeper understanding of cardiac function and disease.
Abstract:
Intracellular calcium (Ca) cycling in the heart plays key roles in excitation-contraction coupling and arrhythmogenesis. In cardiac myocytes, the Ca release channels, i.e., the ryanodine receptors (RyRs), are clustered in the sarcoplasmic reticulum membrane, forming Ca release units (CRUs). The RyRs in a CRU act collectively to give rise to discrete Ca release events, called Ca sparks. A cell contains hundreds to thousands of CRUs, diffusively coupled via Ca to form a CRU network. A rich spectrum of spatiotemporal Ca dynamics is observed in cardiac myocytes, including Ca sparks, spark clusters, mini-waves, persistent whole-cell waves, and oscillations. Models of different temporal and spatial scales have been developed to investigate these dynamics. Due to the complexities of the CRU network and the spatiotemporal Ca dynamics, it is challenging to model the Ca cycling dynamics in the cardiac system, particularly at the tissue sales. In this article, we review the progress of modeling of Ca cycling in cardiac systems from single RyRs to the tissue scale, the pros and cons of the current models and different modeling approaches, and the challenges to be tackled in the future.
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