Differential effects of β1- and β2-adrenergic receptor block in long QT syndrome type 3: an in silico population study

Purpose Long QT syndrome type 3 (LQT3) is caused by a gain-of-function mutation in the voltage-gated sodium channel Nav1.5, resulting in an increased late sodium current (INaL) that prolongs action potential duration (APD) and promotes the development of early afterdepolarizations (EAD). LQT3 is commonly treated with therapies involving β-adrenergic receptor blockers. However, recent studies suggest that β-blockers may not provide a beneficial clinical effect in LQT3 patients, potentially explaining the increased risk of mortality during cardiac events compared to other long QT subtypes. This study investigates the underlying mechanisms of selective β-receptor block using a population-based computational approach. Methods A population of 983 virtual human ventricular myocytes with enhanced INaL (representing LQT3) simulated, enabling electrophysiological and β-adrenergic analysis under conditions of varying degrees of β1- and β2-block. Susceptibility to arrhythmic events was quantified via APD prolongation or occurrence of EADs, and differences in susceptibility pathways, phosphorylation states, and ion current conductances were analyzed between susceptible and non-susceptible subpopulations. Results Our results demonstrate that β1-block increases susceptibility, primarily via reduced IKs phosphorylation. In contrast, full β2-block reduces susceptibility, primarily via reduced ICaL phosphorylation, while partial β2-block does not. Differences in ionic current conductances in the susceptible and non-susceptible sub-populations are consistent with β-block driving imbalances in depolarizing and repolarizing currents. Conclusions Our findings motivate the development and preclinical testing of more selective β2-blocking agents, which could improve therapeutic outcomes in LQT3 patients.