Myocardial bioenergetic abnormalities in experimental uremia

Alistair MS Chesser,1 Steven M Harwood,2 Martin J Raftery,1 Muhammad M Yaqoob1,2 1Department of Nephrology, Barts Health NHS Trust, Royal London Hospital, 2Translational Medicine and Therapeutics, William Harvey Research Institute, John Vane Science Centre, Queen Mary University of London, London, UK Purpose: Cardiac bioenergetics are known to be abnormal in experimental uremia as exemplified by a reduced phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. However, the progression of these bioenergetic changes during the development of uremia still requires further study and was therefore investigated at baseline, 4 weeks and 8 weeks after partial nephrectomy (PNx). Methods: A two-stage PNx uremia model in male Wistar rats was used to explore in vivo cardiac and skeletal muscles' bioenergetic changes over time. High-energy phosphate nucleotides were determined by phosphorus-31 nuclear magnetic resonance (31P-NMR) and capillary zone electrophoresis. Results: 31P-NMR spectroscopy revealed lower PCr/ATP ratios in PNx hearts compared to sham (SH)-operated animals 4 weeks after PNx (median values given ± SD, 0.64±0.16 PNx, 1.13±0.31 SH, P<0.02). However, 8 weeks after PNx, the same ratio was more comparable between the two groups (0.84±0.15 PNx, 1.04±0.44 SH, P= not significant), suggestive of an adaptive mechanism. When 8-week hearts were prestressed with dobutamine, the PCr/ATP ratio was again lower in the PNx group (1.08±0.36 PNx, 1.55±0.38 SH, P<0.02), indicating a reduced energy reserve during the progression of uremic heart disease. 31P-NMR data were confirmed by capillary zone electrophoresis, and the changes in myocardial bioenergetics were replicated in the skeletal muscle. Conclusion: This study provides evidence of the changes that occur in myocardial energetics in experimental uremia and highlights how skeletal muscle bioenergetics mirror those found in the cardiac tissue and so might potentially serve as a practical surrogate tissue during clinical cardiac NMR investigations. Keywords: PCr/ATP ratio, 31P-NMR, uremic cardiomyopath