Ventricular arrhythmias: Biomarkers, mechanisms and therapeutic implications

Abstract

Ventricular arrhythmias (VA) are a major contributor to sudden cardiac death (SCD), cardiovascular morbidity and healthcare utilisation. The vast majority of VA are due to structural heart disease (SHD) including ischaemic and non-ischaemic cardiomyopathy (NICM). The past 50 years have seen advances in the treatment of SHD, including revascularisation for ischaemia and medical therapies for heart failure. These have reduced the global burden of SCD; however, this decline has plateaued in recent years, leaving an unresolved population that still experiences VA.

Attempts to identify patients with SHD at highest risk for VA have been based on mechanical markers of left ventricular function which neglect the subtleties of arrhythmogenesis. In SHD, the complex interplay of scar and viable myocardium results in slow conduction and creates a substrate that is vulnerable to re-entry and VA. VA and SCD can occur with only mild systolic impairment and conversely may never occur even in advanced heart failure. Thus, to better identify patients at high risk for VA, it is imperative to better understand the substrate, its architecture and underlying causes.

In this thesis, we aim to advance our understanding of the substrate for VA in ischaemic and non-ischaemic disease processes using multiple modalities. We begin by exploring the yield of coronary assessment in patients presenting with sustained monomorphic ventricular tachycardia (VT), driven by the dogma that acute ischaemia is a trigger for VA. We then develop a large animal ischaemia-reperfusion injury model to better understand the contemporary post-infarct scar architecture using a combination of cardiac imaging and electroanatomic mapping (EAM). Using this model, we also aimed to determine an optimal pacing strategy for uncovering substrate that is vulnerable to re-entry. Finally, we explore the genetic underpinnings of VA and heart failure outcomes in LMNA cardiomyopathy, one of the most malignant phenotypes of NICM.