Mechanisms and Clinical Utility of Sustained Ligand-Activated Preconditioning

Abstract

Ischaemic heart disease (IHD) remains a leading cause of global morbidity and mortality, with persistent prevalence in Western populations, and a growing incidence in the developing world. Myocardial ischaemic injury is alleviated through surgical intervention, detrimentally exposing the heart to reperfusion injury. This inevitable and paradoxical injury has driven a field of cardioprotective research aimed at limiting cell death, enhancing standard reperfusion protocols and improving long-term patient outcomes from ischaemia/reperfusion (I/R) injury. Despite promising laboratory results, clinical translation of cardioprotective interventions remains an unrealised goal. Notably, age, co-morbidities and chronic pharmacotherapy negatively influence the efficacy of cardioprotective interventions aimed at limiting I/R injury. Thus, effective interventions that reduce myocardial I/R injury in the settings of ageing and disease are fundamental. Based upon this fundamental premise, this doctoral project investigates a novel opioid therapy termed sustained ligand-activated preconditioning (SLP). Previous work demonstrated that SLP is superior to conventional cardioprotection through engagement of alternative signalling pathways, and exhibits potent and prolonged efficacy in young to aged hearts. Studies executed in this doctorate aimed to further delineate the specific mechanisms involved in generation of the protected SLP phenotype, and determine the clinical utility of SLP using other relevant models of disease and chronic pharmacotherapy.