Walid Barake1, John R Giudicessi2, Samuel J Asirvatham3, Michael J Ackerman4. 1. Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota. 2. Clinician Investigator Training Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota. 3. Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota. 4. Division of Heart Rhythm Services, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; Windland Smith Rice Sudden Death Genomics Laboratory, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota; Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota. Electronic address: ackerman.michael@mayo.edu.
Abstract
BACKGROUND: Gain-of-function variants in the SCN5A-encoded Nav1.5 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 Nav1.5 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.
BACKGROUND: Gain-of-function variants in the SCN5A-encoded Nav1.5sodium 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 Nav1.5 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.
Authors: Balázs Horváth; Norbert Szentandrássy; János Almássy; Csaba Dienes; Zsigmond Máté Kovács; Péter P Nánási; Tamas Banyasz Journal: Pharmaceuticals (Basel) Date: 2022-02-15