Modeling autoregulation of cardiac excitation-Ca-contraction and arrhythmogenic activities in response to mechanical load changes

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.