β-Adrenergic modulation of arrhythmogenesis and identification of targeted sites of antiarrhythmic therapy in Timothy (LQT8) syndrome: A theoretical study

Timothy syndrome (TS) is a malignant form of congenital long QT syndrome with a mode of arrhythmia onset often triggered by enhanced sympathetic tone. We sought to explore mechanisms by which β-adrenergic stimulation (BAS) modulates arrhythmogenesis and to identify potential targeted sites of antiarrhythmic therapy in TS. Using a dynamic Luo-Rudy ventricular myocyte model incorporated with detailed intracellular Ca²⁺ cycling, along with its one-dimensional multicellular strand, we simulated various clinical scenarios of TS, with stepwise increase in the percentage of G406R Ca _v1.2 channels from 0 to 11.5 and 23%, and to 38.5 and 77%, respectively, for heterozygous and homozygous states of TS1 and TS2. Progressive prolongation of action potential duration (APD) and QT interval, accompanied by amplification of transmural dispersion of repolarization, steepening of APD restitution, induction of delayed afterdepolariztions (DADs), and both DAD and phase 3 early afterdepolariztion-mediated triggered activities, correlated well with the extent of G406R Ca_v1.2 channel mutation. BAS amplified transmural dispersion of repolarization, steepened APD restitution, and facilitated inducibility of DAD-mediated triggered activity. Systematic analysis of intracellular Ca²⁺ cycling revealed that sarcoplasmic reticulum Ca²⁺ ATPase (uptake current) played an essential role in BAS-induced facilitation of DAD-mediated triggered activity and, in addition to L-type calcium current, it could be an effective site of antiarrhythmic therapy under the influence of BAS. Thus G406R Ca_v1.2 channel mutation confers not only a trigger, but also a substrate for lethal ventricular arrhythmias, which can be exaggerated by BAS. It is suggested that, besides β-adrenergic blockers and L-type calcium current channel blockers, an agent aimed at reduction of sarcoplasmic reticulum Ca²⁺ ATPase uptake current may provide additional antiarrhythmic effect in patients with TS.