Theoretical investigation of action potential duration dependence on extracellular Ca2+ in human cardiomyocytes

Abstract Reduction in [Ca 2+ ] o prolongs the AP in ventricular cardiomyocytes and the QT c interval in patients. Although this phenomenon is relevant to arrhythmogenesis in the clinical setting, its mechanisms are counterintuitive and incompletely understood. To evaluate in silico the mechanisms of APD modulation by [Ca 2+ ] o in human cardiomyocytes. We implemented the Ten Tusscher-Noble-Noble-Panfilov model of the human ventricular myocyte and modified the formulations of the rapidly and slowly activating delayed rectifier K + currents ( I Kr and I Ks ) and L-type Ca 2+ current ( I CaL ) to incorporate their known sensitivity to intra- or extracellular Ca 2+ . Simulations were run with the original and modified models at variable [Ca 2+ ] o in the clinically relevant 1 to 3 mM range. The original model responds with APD shortening to decrease in [Ca 2+ ] o , i.e. opposite to the experimental observations. Incorporation of Ca 2+ dependency of K + currents cannot reproduce the inverse relation between APD and [Ca 2+ ] o . Only when I CaL inactivation process was modified, by enhancing its dependency on Ca 2+ , simulations predict APD prolongation at lower [Ca 2+ ] o . Although Ca 2+ -dependent I CaL inactivation is the primary mechanism, secondary changes in electrogenic Ca 2+ transport (by Na + /Ca 2+ exchanger and plasmalemmal Ca 2+ -ATPase) contribute to the reversal of APD dependency on [Ca 2+ ] o . This theoretical investigation points to Ca 2+ -dependent inactivation of I CaL as a mechanism primarily responsible for the dependency of APD on [Ca 2+ ] o . The modifications implemented here make the model more suitable to analyze repolarization mechanisms when Ca 2+ levels are altered.