Mechanism of ventricular arrhythmias in the Long QT Syndrome

Alexander, Cherry (2020) Mechanism of ventricular arrhythmias in the Long QT Syndrome. PhD thesis, University of Glasgow.

Abstract

The Long QT Syndrome (LQTS) is associated with life-threatening ventricular arrhythmias, as there is a risk of developing a specific form of ventricular tachycardia, called Torsade des points (TdP), which can degenerate into ventricular fibrillation (VF). TdP is typically induced by a premature ventricular complex (PVC) which interacts with a vulnerable substrate to produce re-entry. LQTS can be congenital or acquired and in many cases the first presentation is sudden cardiac death (SCD). Treatment options for congenital LQTS include beta-blockers and the implantable-cardioverter defibrillator (ICD). While an ICD prevents SCD they do not reduce arrhythmia burden.

The cellular basis for QT prolongation is prolongation of the cardiac action potential (AP). Under these conditions isolated cells may develop early afterdepolarisations (EADs), which can induce a triggered AP, a possible mechanism of PVC induction. In intact hearts, where electrotonic coupling exists, synchronisation of cellular EADs would be required to produce a triggered AP. On the basis of this understanding, therapeutic approaches have been targeted at abolition of EADs and shortening the AP, which so far have been ineffective. The aim of this study was to investigate the mechanism of PVC induction in LQTS in an intact rabbit heart. A pharmacological model of LQT was established and characterised using dual optical mapping of voltage (Vm) and calcium (Ca2+). As expected, Ca2+-driven EADs and associated PVCs, bursts and TdP were produced under LQT states. However, our data suggests induction of PVCs was not mediated by synchronisation of cellular EADs but rather through electrotonic triggering as a result of steep voltage gradients found at the border of long AP islands. EADs were seen to occur within the long AP islands and were responsible for causing a dynamic increase in local voltage gradients and so indirectly contributed to PVC initiation. Given the Vm-Ca2+ dynamics and Vm range of the observed PVCs, we hypothesised that the initial upstroke was supported by reactivation of ICaL. In keeping with this, low doses of L-type Ca2+ channel (LTCC) block caused abolition of PVCs, crucially without loss of the LQTS substrate, with EADs and long AP islands still present at the time PVCs were abolished. This suggests a novel therapeutic approach that, instead of targeting EADs, uses low dose LTCC blockade to abolish PVCs and thereby to prevent TdP induction in the presence of QT prolongation. In addition, our data suggest that PVC induction and the pro-arrhythmic potential in LQTS is a tissue-level phenomenon that cannot be elucidated from cellular behaviour alone.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Long QT Syndrome, ventricular arrhythmias, early afterdepolarisations, voltage gradients, L-Type calcium channel blockade.
• Subjects: Q Science > Q Science (General); R Medicine > R Medicine (General); R Medicine > RC Internal medicine
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health > Cardiovascular & Metabolic Health
• Funder's Name: British Heart Foundation (BHF)
• Supervisor's Name: Myles, Dr. Rachel
• Date of Award: 2020
• Depositing User: 20199 C Alexander
• Unique ID: glathesis:2020-81469
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 29 Jan 2025 10:01
• Last Modified: 29 Jan 2025 12:17
• Thesis DOI: 10.5525/gla.thesis.81469
• URI: https://theses.gla.ac.uk/id/eprint/81469