Investigation of the role of PMCA1 in cardiac electrical function and heart rhythm stability

Abstract

Arrhythmias are a leading cause of death and disability worldwide and currently affect more than 2 million people in the UK alone. The development of abnormal heart rhythms are a major clinical problem, influencing the morbidity and mortality of heart failure with 50% of all heart failure deaths being associated with an arrhythmic event. Genetic determinants are a key factor in arrhythmic development and by identifying new genetic contributions to arrhythmic development we can tackle some of the major issues related to treatment development including identifying at risk individuals and identifying new therapeutic pathways. Plasma membrane calcium ATPase 1 (PMCA1, Atp2b1) is emerging as a key contributor to cardiac physiology, involved in calcium handling and myocardial signalling. In addition, genome wide association studies have associated PMCA1 in several areas of cardiovascular disease including hypertension and myocardial infarction. Therefore, we hypothesise a novel role for PMCA1 in heart rhythm stability, with reduced PMCA1 expression resulting in an increased susceptibility to arrhythmic events. To determine the role of PMCA1 in heart rhythm stability, heart rhythm and arrhythmia susceptibility was assessed in a cardiomyocyte-specific PMCA1 deletion (PMCA1CKO) mouse model. PMCA1CKO mice developed abnormal heart rhythms related to ventricular repolarisation dysfunction and displayed an increased susceptibility to both atrial and ventricular arrhythmias. Furthermore, the changes in heart rhythm occurred in the absence of any structural cardiomyopathy. Preliminary work to identify a potential mechanism by which PMCA1 may influence heart rhythm was performed. PMCA1CKO mice displayed altered expression of key cardiac ion channels. This included the downregulation of Kcnd2 (Kv4.2) which is involved in ventricular repolarisation. Furthermore, large-scale proteomic analysis identified downregulation of several proteins in PMCA1CKO model, notably calsequestrin which has been previously associated with arrhythmic development. Other work involving pro-arrhythmic stress experiments found that while sympathetic stress did not result in further heart rhythm dysfunction in PMCA1CKO mice, ageing and heart failure appeared to influence heart rhythm stability in relation to reduced PMCA1 expression. In conclusion, this study has identified a novel role of PMCA1 in heart rhythm stability, with reduced PMCA1 cardiac expression resulting in an increased risk of arrhythmia development. By identifying PMCA1 as a genetic determinant of arrhythmia vulnerability, we have not only further increased the understanding of heart rhythm control but also identified PMCA1 as a potential therapeutic target in the treatment of arrhythmic disorders.

Date of Award	1 Aug 2018
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Elizabeth Cartwright (Supervisor) & Xin Wang (Supervisor)