Initiation of ventricular arrhythmia in the acquired long QT syndrome

Alexander, C., Bishop, M. J., Gilchrist, R. J., Burton, F. L., Smith, G. L. and Myles, R. C. (2023) Initiation of ventricular arrhythmia in the acquired long QT syndrome. Cardiovascular Research, 119(2), pp. 465-476. (doi: 10.1093/cvr/cvac103) (PMID:35727943) (PMCID:PMC10064840)

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Aims: Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS). Methods and results: Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (P < 0.0001 vs. control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and peak VGs were more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs. 44 ± 27 ms, P < 0.0001) and spatially (1.0 ± 0.7 vs. 3.6 ± 0.9 mm, P < 0.0001). PVCs were initiated at estimated voltages of ∼ −40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with ICaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of ICaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL, respectively) abolished both PVCs and TdP in the continued presence of aLQTS. Conclusion: These data demonstrate that ICaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Burton, Dr Francis and Myles, Dr Rachel and Smith, Professor Godfrey and Alexander, Dr Cherry and Gilchrist, Rebecca
Authors: Alexander, C., Bishop, M. J., Gilchrist, R. J., Burton, F. L., Smith, G. L., and Myles, R. C.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
Journal Name:Cardiovascular Research
Publisher:Oxford University Press
ISSN (Online):1755-3245
Published Online:21 June 2022
Copyright Holders:Copyright © 2022 The Authors
First Published:First published in Cardiovascular Research 119(2): 465-476
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172005The role of sarcoplasmic reticulum calcium in the generation of early after-depolarisations and ventricular arrhythmias in the long QT syndromeRachel MylesBritish Heart Foundation (BHF)FS/15/50/31500Institute of Cardiovascular & Medical Sciences
171105Heterogeneity of sympathetic stimulation as a mechanism of ventricular arrhythmia following myocardial infarctionRachel MylesWellcome Trust (WELLCOTR)105907/Z/14/ZInstitute of Cardiovascular & Medical Sciences