Purkinje system hyperexcitability and ventricular arrhythmia risk in type 3 long QT syndrome

Background: Gain-of-function variants in the SCN5A-encoded Na_v1.5 sodium channel cause type 3 long QT syndrome (LQT3) and multifocal ectopic Purkinje-related premature contractions. Although the Purkinje system is uniquely sensitive to the action potential–prolonging effects of LQT3-causative variants, the existence of additional Purkinje phenotype(s) in LQT3 is unknown. Objective: The purpose of this study was to determine the prevalence and clinical implications of frequent fascicular/Purkinje-related premature ventricular contractions (PVCs) and short-coupled ventricular arrhythmias (VAs), suggestive of Purkinje system hyperexcitability (PSH), in a single-center LQT3 cohort. Methods: A retrospective analysis of 177 SCN5A-positive patients was performed to identify individuals with a LQT3 phenotype. Available electrocardiographic, electrophysiology study, device, and genetic data from 91 individuals with LQT3 were reviewed for evidence of presumed fascicular PVCs and short-coupled VAs. The relationship between PSH and ventricular fibrillation events was assessed by Kaplan-Meier and Cox regression analyses. Results: Overall, 30 of 91 patients with LQT3 (33%) exhibited evidence of presumed PSH (fascicular PVCs 30 of 30 [100%]; short-coupled VAs 17 of 30 [56%]). Kaplan-Meier and Cox regression analyses demonstrated an increased risk of ventricular fibrillation events in individuals with LQT3 and PSH (log-rank, P < .03; hazard ratio 3.95; 95% confidence interval 1.15–15.7; P = .03). Interestingly, variants in the voltage-sensing domain regions of Na_v1.5 were more frequently observed in patients with LQT3 and PSH than those without (19 of 30 [63%] vs 9 of 61 [15%]; P < .0001). Conclusion: This study demonstrates that a discernible Purkinje phenotype is present in one-third of LQT3 cases and increases the risk of potentially lethal VAs. Further study is needed to determine whether a distinct cellular electrophysiology phenotype underlies this phenomenon.