Sudden cardiac death (SCD) due to ventricular arrhythmias is a leading cause of premature death and occurs across a broad spectrum of cardiac conditions. Implantable cardioverter-defibrillators (ICDs) are effective in treating ventricular arrhythmias (ventricular tachycardia fibrillation [VF]), but are limited by cost, complications and challenges in risk stratification. Alternative therapeutic approaches targeted at prevention of ventricular arrhythmias are urgently needed.
Decades of research in cardiac electrophysiology have furnished us with a detailed understanding of how remodelling at the cellular level may predispose to arrhythmia in a range of pathologies which cause SCD, from “simple” ion channelopathies to complex structural and electrical phenotypes such as heart failure. However, this knowledge has not yet led to therapeutic advances. Key studies have identified events called afterdepolarisations which are thought to produce the ectopic beats which trigger VT/VF. However, in the intact heart each cardiomyocyte is electrically coupled to neighbouring cells, meaning that cellular afterdepolarisations will be suppressed. Therefore, the mechanism by which afterdepolarisations may be expressed in the whole heart, and so drive arrhythmia, is unknown. This mechanistic understanding of arrhythmias beyond the cardiomyocyte is crucial if we are to develop effective therapies.
My work examines this issue using optical techniques to examine electrophysiology and calcium handling across a variety of spatial scales in the whole heart. We study animal models of disease relevant to patients at risk of arrhythmic SCD, including post-MI left ventricular dysfunction and the long QT syndrome (LQTS). The risk of VT/VF in LQTS is related to the degree of QT prolongation, and pharmacological treatments have been targeted at shortening QT, and/or preventing afterdepolarisations. However, these have been limited by (i) modest effectiveness and (ii) pro-arrhythmic side-effects. Our recent work provides evidence for a new approach to preventing VT/VF in LQTS, based on demonstration of precisely how afterdepolarisations are linked to initiation of arrhythmia in the whole heart. We propose to translate these mechanistic findings to develop a novel therapeutic approach to reduce life-threatening ventricular arrhythmia in patients with LQTS.