Influence of RyR2 Inhibition Kinetics on Calcium Sparks and Waves in a 3D Model of a Cardiac Cell

Although excess Ca2+ release through RyR2 in diastole is a key factor in arrhythmia, not all RyR2 antagonists have an antiarrhythmic action. Flecainide, carvedilol and dantrolene are RyR2 inhibitors with an anti-arrhythmic blocking action whereas tetracaine is a RyR2 inhibitor with a pro-arrhythmic action. Block by these agents is known to have different RyR2 blocking kinetics and different effects on Ca2+ sparks and waves. However, it is not clear how the different RyR2 blocking kinetics produce different calcium release properties in intact cells.We have developed a 3D model of Ca2+ dynamics, which is based on realistic morphological parameters and RyR2 kinetics. By including different kinetic models for block of RyR2, we find that open state block of RyR2 stabilises Ca2+ release. In contrast, the closed state block of RyR2 has the effect of increasing the positive feedback of Ca2+ on SR Ca2+ release; the net result is an increase in the amplitude of Ca2+ sparks, destabilization of SR Ca2+ cycling.