Metabolic Control of Cardiac Energetics and Efficiency
Our clinical and animal projects are closely interrelated in that we attempt to understand our findings in the human by studying cellular mechanisms in animal models of common cardiac diseases, including diabetes and heart failure. We use magnetic resonance (MR) techniques with biochemical, physiological and molecular techniques to detect energetic and functional changes in heart and skeletal muscle and determine whether interventions, such as exercise, reverse the abnormalities.
Because we study both animal models and patients, we work on two Oxford sites; basic studies are carried out in the Department of Physiology, Anatomy and Genetics and clinical studies at the Oxford Centre for Clinical Magnetic Resonance Research (OCMR) at the John Radcliffe Hospital.
Current Research Programmes
Metabolic control of gene expression
Insulin resistance and abnormal cardiac and skeletal muscle energetics are found in heart failure patients and, we propose, reflect the same underlying pathogenic mechanism: energy substrate depletion. Our patient studies define the links between insulin resistance, abnormal muscle function and energetics. We use methods that are known to decrease insulin resistance, such as exercise, to determine whether heart and/or skeletal muscle function or energetics improve. In our animal studies we study the chronically failing rat heart, and mice with defined mutations, to determine the impact of each mutation on cardiac energetics, contractile function and efficiency. We believe that the transition to failure involves changes in fatty acid oxidation, nuclear transcription factors, mitochondrial uncoupling, ATP synthesis and glycolysis, with energy substrate depletion the outcome.
Recently, our studies of the diabetic heart in animal models suggested that patients with obesity or type 2 diabetes would have cardiac high energy phosphate metabolism (PCr/ATP ratio) abnormalities. In those patients, we found that the cardiac PCr/ATP ratio was decreased and correlated with the circulating free fatty acid (FFA) concentrations. This correlation suggested an increase in cardiac mitochondrial uncoupling protein (UCP) levels, a conclusion based on previous work on the hyperthyroid heart, in which we showed that increased cardiac UCPs were related to decreased PCr/ATP and lower cardiac efficiency. We went on to find that mitochondrial UCP levels in human heart were related to plasma FFA levels and that other patient groups or healthy controls with raised plasma FFA concentrations also have low cardiac PCr/ATP ratios.
Similarly, we found that the decreased cardiac PCr/ATP in heart failure patients may be related to their whole body insulin resistance, again based on our findings of cardiac insulin resistance and increased mitochondrial UCP levels in the chronic infarction rat model of heart failure. Using normal and genetically modified mice, we have gone on to study the mechanisms whereby circulating FFAs alter the levels of cardiac glucose transporters and mitochondrial UCPs via activation of the peroxisome proliferator activated receptor α (PPARa) nuclear receptors.
These studies will demonstrate whether strategies that improve insulin resistance also improve metabolism and function in heart and skeletal muscle and will increase our knowledge of the biochemical changes associated with heart failure. A better understanding of the primary mechanisms that underlie the energetic and contractile abnormalities in the failing heart will allow the development of new therapeutic strategies for the treatment of existing heart failure and more effective guidelines for its prevention.
Cardiomyogenesis from adult stem cells
A promising, novel approach to the treatment of myocardial infarction and the prevention of heart failure is cell grafting in the damaged myocardium. One of our projects is to determine whether cardiac muscle and vasculature can be derived from adult human stem cells to restore cardiac function and metabolism after coronary occlusion. The preparation and characterization of stem and differentiated progenitor cells is performed by collaborators at the National Blood Service at the John Radcliffe Hospital and we perform the in vivo testing of the stem cells. We deliver stem cells to the damaged tissue after infarction and monitor cell engraftment and the effects on cardiac function non-invasively, using magnetic resonance (MR) imaging. We are determining the optimal donor cell type, method of cell delivery, and timing of cell implantation post infarction.
Current scientific data support the concept that adult stem cells have considerable potential in animals, and even humans. The concept of stem cell plasticity remains to be confirmed and more work must be done in preclinical models if these initial concepts are to be translated into an effective and safe cell therapy for patients. Once we maximise the potential for therapeutic benefit and minimise the possible complications, cellular therapy for myocardial infarction and/or heart failure may even replace the need for long term medical treatment or heart transplantation.
Superior physiological performance through mild ketosis
During periods of stress, elevated catecholamines, steroids and cytokines increase the metabolism of stored fat in the body. The increase in circulating free fatty acids causes insulin resistance, decreases skeletal and cardiac muscular efficiency and may decrease metabolic fuel for the brain, which cannot metabolize fat, but can metabolize ketones. Ketone bodies contain more recoverable metabolic energy than fatty acids and yield 28% more energy on combustion than glucose. We are testing whether the negative effects of elevated free fatty acids can be overcome by mild ketosis.
In collaboration with the National Institutes of Health in the US, we created a diet containing ketone bodies, which caused mild ketosis. We tested the metabolic mechanism underlying the effects of the ketone body diet during extreme exercise, with and without ketosis. Endurance and cognitive function, tested using treadmill exercise and a maze test, respectively, were found to be increased by the ketosis. We propose to further test the ketone diet before during and after 5 days of intense training, in a double-blind placebo-controlled cross-over trial. Exercise testing, cognitive function and skeletal and cardiac muscle energetics will be followed using psychological testing and non-invasive MRI of brain and muscle during exercise.
Should subjects on the ketone body diet have greater metabolic efficiency, and therefore greater endurance and cognitive function, during extreme exercise and psychological stress than those on a normal diet, the diet could be used by athletes and to treat metabolic diseases, such as obesity, Alzheimer’s and Parkinson’s diseases.
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Kieran Clarke is Professor of Physiological Biochemistry and British Heart Foundation Principal Scientist in the Department of Physiology, Anatomy and Genetics at the University of Oxford. She has been in Oxford since 1991 and has over 20 years experience in cardiovascular magnetic resonance (MR) imaging and spectroscopy. She has a PhD in Biochemistry from the University of Queensland in Australia and worked at Harvard University Medical School NMR Laboratory in Massachusetts from 1985 to 1989. Before her current appointment, she was a Group Leader in Biomedical NMR at the National Research Council and Adjunct Professor in the Department of Physiology at Ottawa University in Canada. Professor Clarke currently heads the Cardiac Metabolism Research Group, whose research is directed towards understanding the metabolic control of gene expression in heart failure and in the diabetic heart, and includes the use of stem cells to treat the infarcted heart. She also works on the effects of diet on energy metabolism in heart, brain and skeletal muscle, and thereby on physical and cognitive function.