Perturbed calcium handling in an ovine model of cardiac failure following myocardial infarction: role of phosphodiesterases

Abstract

Ventricular arrhythmias and heart failure (HF) are the major complications following myocardial infarction (MI). There is still a lack of knowledge regarding how cellular calcium (Ca2+) handling is altered in the early stages of cardiac failure, an issue emerging primarily from the lack of preclinical models that faithfully present most of the features of HF from ischemic diseases. The L-type Ca2+ channel (LTCC) plays an obscure role in the progression of Ca2+ homeostasis dysregulation. The aim of this thesis is to improve our fundamental understanding of the evolution of Ca2+ handling in ventricular myocytes following a necrosis of the myocardium. For this purpose, two ovine occlusion-reperfusion MI models with mild and moderate declines in cardiac function have been developed. They are models of intermediate ischemic heart disease without decompensated HF. Changes in contractility, electrical properties, and cellular Ca2+ homeostasis are consistent with observations in humans, making them translational models. Details on alterations of the key effectors of the ECC process include alterations in the sarcoplasmic reticulum and sarcolemmal Ca2+ flux. In particular, the LTCC appears to be dysregulated as a result of changes in the beta-3-adrenergic receptor/endothelial nitric oxide synthase (beta-3-AR/eNOS) pathway.

Date of Award	31 Dec 2022
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Andy Trafford (Supervisor), David Eisner (Supervisor) & Katharine Dibb (Supervisor)