Cardiomyocyte calcium handling in health and disease: Insights from in vitro and in silico studies

Abstract

Calcium (Ca²⁺) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca²⁺ levels are regulated by a variety of Ca²⁺-handling proteins. In turn, Ca²⁺ modulates numerous electrophysiological processes. Accordingly, Ca²⁺-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca²⁺ handling under physiological and pathological conditions. However, numerous questions involving the Ca²⁺-dependent regulation of different macromolecular complexes, cross-talk between Ca²⁺-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca²⁺-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca²⁺ handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca²⁺ handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca²⁺ handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.

Keywords: Arrhythmia; Calcium handling; Cardiomyocyte; Computational modeling; Electrophysiology.