Effects of DRP-1 Inhibitors in Healthy and Diseased Myocardium

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Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
Coronary heart disease (CHD) continues to be one of the foremost contributors to morbidity and mortality in developed countries. Leading risk factors that include elevated blood pressure, hypercholesterolaemia, tobacco use, sedentary lifestyles and excess caloric consumption significantly contribute to these alarmingly high mortality rates and prompt the search for targeted interventions that are clinically effective. Myocardial ischaemia, occurring in ischaemic heart disease (IHD) or during cardiac surgery, reduces coronary blood flow to the metabolically active myocardium – the former primarily due to progression of coronary vascular atherosclerosis and associated thromboembolism, the latter due to the need to arrest perfusion of myocardial tissue in different surgical scenarios (e.g. cardiac transplant, by-pass surgery, valve surgery). Insufficient blood flow to the myocardium reduces oxygen and metabolic substrate delivery, and removal of waste products. Since the myocardium is highly oxidative, periods of ischaemia are detrimental, with brief episodes causing cardiac dysfunction and more prolonged insult leading to cell death. Reduced oxygen delivery and subsequent reoxygenation can profoundly impact mitochondrial function, the energy producing ‘powerhouses’ of the cell. Emerging research has confirmed that mitochondria are a network of dynamic organelles undergoing cycles of fragmentation (fission) and elongation (fusion), a quality control process thought to maintain a healthy population of mitochondria matched to prevailing metabolic conditions. Mitochondrially targeted interventions have thus emerged as an exciting therapeutic option across organ systems and diseases, including in the heart and IHD. However, the heart is somewhat unique in its mitochondrial phenotype, with evidence the healthy heart possesses a fragmented mitochondrial population that generates the highest densities and respiratory capacity in mammalian cells. Moreover, these mitochondria d