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

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.

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

“…Changes in these three variables are predictive of changes to mechanical function. In particular, increasing levels of Pi, predicted by Tewari et al 30 and Gao et al 23 to impair normal mechanical function in both the failing and the aging heart, are tightly correlated with reduced EF. Thus, these model-derived results, like relationships observed in Figures 3 and 4 , are consistent with the hypotheses that change in the metabolic state of heart during disease causes an impairment mechanical function of the heart.…”

“… Multiscale Myocardial Mechanoenergetic Function. The model integrates previously developed and validated models of cardiomyocyte dynamics, 29 , 30 myocardial energetics, 23 , 35 whole-organ cardiac mechanics, 36 and a simple lumped parameter closed-loop circulatory system representing the systemic and pulmonary circuits. Data from multiple experimental modalities are used to identify model components for each individual animal in this study.…”

“… 22 Computer simulations predict that depletion of cytoplasmic metabolic pool, namely the adenine nucleotide and total creatine pool, plays an under-recognized aspect of energetic dysfunction in aging and hypertrophic decompensation—plays an important role in driving the energetic phenotype. 7 , 23 Analysis of a canine model of pressure overload-induced hypertrophy and failure reveals that this phenomenon explains observations on diminished ATP and CrP/ATP, even without needing to invoke mitochondrial dysfunction. 7 …”

Reduced cardiac muscle power with low ATP simulating heart failure

“…In heart failure, the intracellular ATP level may be reduced by z50% (1-3) relative to the non-failing heart where the intracellular ATP level is z8 mM (4)(5)(6). Similar reductions in myocardial ATP are observed commensurate with reductions in maximal cardiac power output in aging (7). The reduced level of ATP in heart failure has led to the intuitive suggestion that the failing heart is an ''engine out of fuel'' and that the decreased intracellular ATP level directly contributes to impaired cardiac contraction and heart failure (reviewed in (8)).…”