Autoregulation of excitation-Ca2+ signaling-contraction and arrhythmogenesisin cardiomyocyte under mechanical load.

Abstract

The heart pumps blood into circulation against the mechanical load from vascular resistance and actively regulates cardiomyocyte contraction to compensate for load changes. We conducted Cell-in-Gel experiments to decipher the mechano-chemo-electro-transduction (MCET) mechanisms that transduce the mechanical load during cell contraction to regulate the excitation-Ca2+ signaling-contraction (E-C) coupling. Our experimental studies reveal that MCET increases the L-type Ca2+ current and action potential duration, which increases the Ca2+ entry during the cardiac cycle; increases the diastolic SR Ca2+ content, the systolic SR Ca2+ release, and the Ca2+ uptake; and increases the cytosolic Ca2+ transient, resulting in MCET-Ca2+ gain. The MCET-Ca2+ gain enhances contractility in response to increased load. Hence, MCET provides feedback loops in the E-C coupling system, which may enable autoregulation of the dynamic system when mechanical load changes. Based on experimental data, we developed quantitative models to incorporate the MCET feedback loops into the E-C coupling system to study the nonlinear dynamic system's behavior. Model simulations show that autoregulation of E-C coupling contractility naturally arises from the MCET feedback, enabling the cardiomyocyte to autoregulate contractility in compensatory response to load changes. However, excessively high load causes SR Ca2+ overload, spontaneous Ca2+ release, and arrhythmogenic activities. These model predictions are verified by experimental data. In conclusion, our experimental and modeling studies reveal an Autoregulatory E-C coupling dynamic system in the cardiomyocytes contracting under mechanical load. Deciphering the autoregulatory E-C couplingdynamics and MCET mechanisms will be essential for understanding how the heart autoregulates contractility in compensatory response to physiological load changes to maintain cardiac output, and why pathological loading (i.e., hypertension, TAC pressure-overload) leads to arrhythmias and heart failure.