Cardiovascular disease is the leading cause of death in the U.S. despite improvements in prevention, detection, and treatment. Although the cause of heart failure is multi-factorial, there is increasing evidence that a mismatch in myocardial energy supply and demand contributes to the development of left ventricular dysfunction. Heart uses chemical energy in the form of adenosine triphosphate (ATP) to support systolic and diastolic function. The creatine kinase (CK) system acts as the primary ATP reserve for the heart and instantaneously supplies ATP for its contractile function. Changes in the CK system are seen in heart failure in both the human and animal myocardium indicative of impaired delivery of ATP to energy consuming systems. Therefore it is logical to hypothesize that the development of new noninvasive quantitative methods for serial studies of energy metabolism would be especially valuable for enhancing our understanding of the development and progression of heart failure. Magnetization transfer phosphorous-31 magnetic resonance spectroscopy (MRS) is an ideal tool to measure the kinetics of high energy phosphate metabolism in living tissue, and has been used for such in isolated heart preparations and open chest animal experiments. Methods for in vivo CK flux measurements in hearts have been lagging because of the sensitivity and complexity of the technique. The major problems arise from long examination time and signal contamination from the skeletal muscles in chest wall, which is further exacerbated by respiratory motion. A new approach to measure in vivo CK flux, overcoming the issues of lengthy examination time will be developed. Coupled with novel approach to eliminate signal contamination from the chest muscles using inhomogeneous magnetic field gradient surface spoiling will lead to clinically useful MRS technique to quantify myocardial CK flux in vivo and, thus provide accurate evaluation of energy metabolite turnover in the heart. The initial technique development will focus on small animal experiments and the results will be compared to open chest experiments to evaluate the accuracy of the technique. In vivo sensitivity of the technique will be established using a diabetic rat heart model where CK flux is expected to vary over a large range. Correlations will be obtained with the biochemical measurements of CK isoenzyme. The research project will conclude with the development and feasibility testing of the technique for clinical research.

Public Health Relevance

(provided by applicant): Obesity, diabetes and related complications especially cardiovascular disease are a huge burden on individuals in particular and US economy in general. Development of new and improved techniques to understand in vivo metabolism and generate new knowledge will be of paramount importance to understand, diagnose, treat and manage these complications. The proposed project aims to develop new methodology to measure and understand energy disorders in cardiovascular disease and the techniques developed will be critically useful to advance basic research and medical care.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Research Scientist Development Award - Research & Training (K01)
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Special Emphasis Panel (ZEB1-OSR-B (O2))
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Erim, Zeynep
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Washington University
Schools of Medicine
Saint Louis
United States
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