A model of cardiac ryanodine receptor gating predicts experimental Ca-dynamics and Ca-triggered arrhythmia in the long QT syndrome.

Abnormal Ca handling is well-established as the trigger of cardiac arrhythmia in catecholaminergic polymorphic ventricular tachycardia and digoxin toxicity, but its role remains controversial in Torsade de Pointes (TdP), the arrhythmia associated with the long QT syndrome (LQTS). Recent experimental results show that early afterdepolarizations (EADs) that initiate TdP are caused by spontaneous (non-voltage-triggered) Ca release from Ca-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca elevation increases gradually in amplitude, occurs before overt voltage instability, and then precedes the rise of EADs. Here, we used a modified Shannon-Puglisi-Bers model of rabbit ventricular myocytes to reproduce experimental Ca dynamics in bradycardia and LQT2. Abnormal systolic Ca-oscillations and EADs caused by SR Ca-release are reproduced in a modified 0-dimensional model, where 3 gates in series control the ryanodine receptor (RyR2) conductance. Two gates control RyR2 activation and inactivation and sense cytosolic Ca while a third gate senses luminal junctional SR Ca. The model predicts EADs in bradycardia and low extracellular [K] and cessation of SR Ca-release terminate salvos of EADs. Ca-waves, systolic cell-synchronous Ca-release, and multifocal diastolic Ca release seen in subcellular Ca-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca-overload, abnormal SR Ca-release, and the subsequent activation of the electrogenic Na/Ca-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.