Elsevier

Heart Rhythm

Volume 17, Issue 10, October 2020, Pages 1768-1776
Heart Rhythm

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

https://doi.org/10.1016/j.hrthm.2020.05.019Get rights and content

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.

Introduction

Congenital long QT syndrome (LQTS) is the most common inherited cardiac channelopathy affecting ∼1 in 2500 individuals.1 Clinically, LQTS presents with prolongation of the heart rate–corrected QT interval (QTc) on the 12-lead electrocardiogram (ECG) and an increased risk of syncope, seizures, and sudden cardiac death (SCD) secondary to torsades de pointes, the characteristic form of polymorphic ventricular tachycardia (VT) observed in LQTS.2,3 Type 3 long QT syndrome (LQT3), stemming from pathogenic variants in the SCN5A-encoded α subunit of the Nav1.5 voltage-gated sodium channel, accounts for ∼5%–10% of LQTS.3,4

In addition to LQT3, SCN5A gain-of-function variants cause multifocal ectopic Purkinje-related premature contractions (MEPPC), a rare disorder characterized by frequent premature ventricular contractions (PVCs) originating throughout the fascicular-Purkinje system, associated ventricular arrhythmias (VAs), and, in rare circumstances, SCD.5 Interestingly, in a mouse model of LQT3 (ΔKPQ+/−), the action potential–prolonging effects of SCN5A gain of function were accentuated in Purkinje cells, suggesting that the fascicular-Purkinje system plays a critical role in the pathogenesis of LQT3.6

On the basis of these observations, we postulated that a subset of patients with LQT3 might also have a concomitant distinct Purkinje phenotype characterized by abnormal hyperexcitability of the fascicular-Purkinje system. As such, we sought to determine the prevalence and clinical implications of Purkinje-related/fascicular PVCs and short-coupled VAs, suggestive of concomitant Purkinje system hyperexcitability (PSH), in a single-center cohort of patients with LQT3.

Section snippets

Patient population

In this institutional review board–approved study, a retrospective review of the medical records, including commercial- or laboratory-based genetic testing results, was used to identify all patients evaluated in the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic between 2000 and 2018 with ultrarare SCN5A likely pathogenic/pathogenic variants. After the exclusion of patients without a LQT3 phenotype (ie, Brugada syndrome, progressive cardiac conduction disease, idiopathic

Results

Overall, 177 patients with ultrarare SCN5A variants were evaluated at Mayo Clinic between 2000 and 2018. After exclusion of patients without a diagnosis of LQT3, 91 patients (mean age at LQTS diagnosis 25 ± 18 years; mean QTc interval 473 ± 37 ms; 71 of 91 lifelong asymptomatic [78%] and 87 of 91 with an ACMG pathogenic/likely pathogenic SCN5A variant [96%]) were included in the final analyses (Table 1).

In an effort to determine (1) whether a distinct Purkinje-related phenotype was discernible

Discussion

In the present study, we demonstrate that a discernible presumed Purkinje phenotype, termed PSH, characterized primarily by the presence of frequent fascicular PVCs as illustrated in Figure 1 is present in a substantial number of patients with LQT3. Unexpectedly, the alleged PSH was present in one-third of LQT3 cases. Furthermore, short-coupled/PVC-triggered VAs were observed in over half (17 of 30 [57%]) of patients with LQTS and presumed PSH. These short-coupled/PVC-triggered VAs were similar

Conclusion

This study demonstrates, for the first time, that a distinct Purkinje phenotype, characterized primarily by the presence of Purkinje PVCs, is present in one-third of LQT3 cases and increases the risk of potentially lethal VF events. Further study is needed to validate this finding in a larger multicenter cohort of patients with LQT3 and determine whether a discernible, and potentially targetable, cellular electrophysiology phenotype consistently underlies this phenomenon.

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    This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

    Dr Ackerman is a consultant for Abbott, Audentes Therapeutics, Biotronik, Boston Scientific, Daiichi Sankyo, Gilead Sciences, Invitae, LQT Therapeutics, Medtronic, MyoKardia, and UpToDate. Dr Ackerman and Mayo Clinic are involved in an equity/royalty relationship with AliveCor, Blue Ox Health Corporation, and StemoniX. However, none of these entities were involved in this study in any manner. The rest of the authors report no conflicts of interest.

    1

    Drs Barake and Giudicessi contributed equally to this work.

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