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bioRxiv · 10.1101/560649

Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging

Gao, X.·Jakovljevic, D. G.·Beard, D. A.
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Abstract

Changes in the myocardial energetics associated with aging--reductions in creatine phosphate (CrP)/ATP ratio, total creatine, and ATP--mirror changes observed in failing hearts compared to healthy controls. Similarly, both aging and heart failure are associated with significant reductions in cardiac performance and maximal left ventricular cardiac power output (CPO) compared to young healthy individuals. Based on these observations, we hypothesize that reductions in the concentrations cytoplasmic adenine nucleotide, creatine, and phosphate pools that occur with aging impair the myocardial capacity to synthesize ATP at physiological free energy levels, and that the resulting changes to myocardial energetic status impair the mechanical pumping ability of the heart. The purpose of this study is to test theses hypotheses using an age-structured population model for myocardial metabolism in the adult female population and to determine the potential impact of reductions in key myocardial metabolite pools in causing metabolic/energetic and cardiac mechanical dysfunction associated with aging. To test these hypotheses, we developed a population model for myocardial energetics to predict myocardial ATP, ADP, CrP, creatine, and inorganic phosphate concentrations as functions of cardiac work and age in the adult female population. Model predictions support our hypotheses and are consistent with previous experimental observations. The major findings provide a novel theoretical and computational framework for further probing complex relationships between the energetics and performance of the heart with aging. SignificanceNormal mechanical function of the heart requires that ATP be continuously synthesized at a hydrolysis potential of roughly -60 kJ mol-1. Yet in both the aging and diseased heart the relationships between cardiac work rate and concentrations of ATP, ADP, and inorganic phosphate are altered. Important outstanding questions are: To what extent do changes in metabolite concentrations that occur in aging and heart disease affect metabolic/molecular processes in the myocardium? How are systolic and diastolic functions affected by changes in metabolite concentrations? This study addresses these questions by analyzing relationships between cardiac energy demand and supply using an age-structured population model for human myocardial energetics in women.

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Gao, X., Jakovljevic, D. G., Beard, D. A.. 2019-02-25. Cardiac Metabolic Limitations Contribute to Diminished Performance of the Heart in Aging. https://doi.org/10.1101/560649

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