This theme covers the two major areas of work outlined below.
Cardiac Energy Metabolism: Oxford has a long tradition in myocardial biology, with particular emphasis on cardiac metabolism. We aim to uncover the true mechanistic role of cardiac metabolic alterations in heart failure, hypertrophy and diabetes, and systematically explore the options for metabolic therapy (substrate utilisation, oxidative phosphorylation, energy transfer and utilisation). Phenotyping of genetically manipulated models with physiological, echocardiographic, MRI and MRS techniques will allow dissection of individual components of the metabolic machinery, and testing the effects of augmentation or suppression of these. Cardiac-derived stem cell therapies and their effects on cardiac function and energetics are also being studied. Hyperpolarised 13C methods will provide novel information on cardiac substrate metabolism. Clinical studies use new MR technologies to assess the myocardial thermodynamic state, intracellular lipids etc., in heart failure, hypertrophy, diabetes and obesity, and will test new therapies targeting cardiac energy metabolism. Approaches are being developed for understanding the role of energy wastage in the sarcomere, and will, for example, test direct myosin activators to improve efficiency of ATP utilisation. The ATP cost of force production, the impact of altered calcium binding, and alterations in downstream kinase cascades are also being studied.
Redox Signalling: The precise pathophysiological role of NO/ROS in atrial fibrillation and heart failure is being investigated and options for therapeutic intervention targeting these mechanisms studied experimentally and clinically. The downstream signalling pathways and target proteins of free radical production are being elucidated in failing myocardium. nNOS expression and activity is manipulated by using viral vectors or transgenic upregulation of the nNOS’ essential co-factor tetrahydrobiopterin. Studies in mutant experimental models form the basis for further comparative and direct intervention, studies in the human myocardium.