Modeling autoregulation of cardiac excitation-Ca-contraction and arrhythmogenic activities in response to mechanical load changes
Summary: The heart has intrinsic abilities to autoregulate contractile force in response to mechanical load. Recent experimental studies show that cardiomyocytes have mechano-chemo-transduction (MCT) mechanisms that form a closed feedback loop in the excitation-Ca2+ signaling-contraction (E-C) coupl...
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| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-02-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004225000471 |
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| Summary: | Summary: The heart has intrinsic abilities to autoregulate contractile force in response to mechanical load. Recent experimental studies show that cardiomyocytes have mechano-chemo-transduction (MCT) mechanisms that form a closed feedback loop in the excitation-Ca2+ signaling-contraction (E-C) coupling. This closed feedback loop enables autoregulation of contraction in response to mechanical load changes. Here, we develop the first autoregulatory E-C coupling model that couples electrophysiology, Ca2+ signaling, force development and contraction, and MCT feedback. The model recapitulates the experimental data showing that the mechanical load on cardiomyocytes during contraction increases the L-type Ca2+ current, action potential duration, sarcoplasmic reticulum (SR) Ca2+ content, and SR Ca2+ release, giving rise to increased cytosolic Ca2+ transient (MCT-Ca2+ gain) and enhanced contraction. The model also makes non-trivial predictions on the autoregulation of contraction with moderate MCT-Ca2+ gain under a range of physiological load changes, but arrhythmogenic discordant alternans with excessive MCT-Ca2+ gain under pathological overload. |
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| ISSN: | 2589-0042 |