A model of cardiac ryanodine receptor gating predicts experimental Ca2+-dynamics and Ca2+-triggered arrhythmia in the long QT syndrome

Abstract

Abnormal Ca²⁺ 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) Ca²⁺ release from Ca²⁺-overloaded sarcoplasmic reticulum (SR) rather than the activation of the L-type Ca²⁺-channel window current. In bradycardia and long QT type 2 (LQT2), a second, non-voltage triggered cytosolic Ca²⁺ 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 Ca²⁺ dynamics in bradycardia and LQT2. Abnormal systolic Ca²⁺-oscillations and EADs caused by SR Ca²⁺-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 Ca²⁺ while a third gate senses luminal junctional SR Ca²⁺. The model predicts EADs in bradycardia and low extracellular [K⁺] and cessation of SR Ca²⁺-release terminate salvos of EADs. Ca²⁺-waves, systolic cell-synchronous Ca²⁺-release, and multifocal diastolic Ca²⁺ release seen in subcellular Ca²⁺-mapping experiments are observed in the 2-dimensional version of the model. These results support the role of SR Ca²⁺-overload, abnormal SR Ca²⁺-release, and the subsequent activation of the electrogenic Na⁺/Ca²⁺-exchanger as the mechanism of TdP. The model offers new insights into the genesis of cardiac arrhythmia and new therapeutic strategies.