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

Calcium (Ca) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca levels are regulated by a variety of Ca-handling proteins. In turn, Ca modulates numerous electrophysiological processes. Accordingly, Ca-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 Ca handling under physiological and pathological conditions. However, numerous questions involving the Ca-dependent regulation of different macromolecular complexes, cross-talk between Ca-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 Ca-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.