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

Prog Biophys Mol Biol. 2020 Nov;157:54-75. doi: 10.1016/j.pbiomolbio.2020.02.008. Epub 2020 Mar 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrhythmias, Cardiac / metabolism
  • Calcineurin / metabolism
  • Calcium / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Calpain / metabolism
  • Computer Simulation
  • Electrophysiological Phenomena
  • Electrophysiology / methods
  • Excitation Contraction Coupling
  • Humans
  • In Vitro Techniques
  • Membrane Proteins / metabolism
  • Mice
  • Myocardial Contraction
  • Myocytes, Cardiac / metabolism*
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase C / metabolism
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases / genetics
  • Signal Transduction


  • Membrane Proteins
  • Phosphoproteins
  • phospholemman
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Calcineurin
  • Calpain
  • Sarcoplasmic Reticulum Calcium-Transporting ATPases
  • Atp2a2 protein, mouse
  • Calcium