Nallur Shivu, Ganesh (2012)
Ph.D. thesis, University of Birmingham.
The human myocardium is a metabolic omnivore and utilises fatty acids, glucose, ketones, amino acids and lactate to produce energy. Altered metabolism results in cardiac muscle dysfunction and can play a potentially significant role in development of heart failure. Metabolic modulators like Perhexiline are potentially significant new treatments in the management of heart failure and coronary artery disease.
Diabetes is a metabolic disorder that results in altered high energy phosphate kinetics in the myocardium. We demonstrate that microvascular disease plays little role in the development of impaired cardiac energetics in young patients with uncomplicated type 1 diabetes. We have shown an increase in left ventricular torsion in these patients with normal ejection fraction. Coronary microvascular disease and rotational deformation delay play a significant role in the development of increased torsion in these individuals which counteracts the early diastolic dysfunction. Furthermore the left atrial contribution to left ventricular filling is increased in these individuals.
We demonstrate that Perhexiline has a differential action on insulin sensitivity in subjects with and without diabetes. It also increased plasma ketones and triglycerides in these patients. Finally we demonstrate that Perhexiline can be safely used and provides good relief of symptoms when used clinically in subjects with refractory angina and heart failure.
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