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

Calcium (Ca2þ) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca2þ levels are regulated by a variety of Ca2þ-handling proteins. In turn, Ca2þ modulates numerous electrophysiological processes. Accordingly, Ca2þ-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of after depolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca2þ-handling under physiological and pathological conditions. However, numerous questions involving the Ca2þ-dependent regulation of different macromolecular complexes, cross-talk between Ca2þ-dependentregulatory pathways operating over a wide range of time scales, and bidirectional interactions between electro physiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca2þ-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca2þ-handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca2þ-handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca2þhandling and highlight how synergy between in vitro and
in silico studies may help to answer several of these issues.