Integrated Modeling of Cardiac Metabolism and Transport

University Of Michigan At Ann Arbor, Ann Arbor MI

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): ATP synthesis in the healthy mammalian heart is primarily oxidative, with greater than 95% of ATP synthesized in the mitochondria via oxidative phosphorylation. In the failing heart, ATP synthesis is compromised, with result that that chemical energy, in the form of the ATP hydrolysis potential, available for the heart to do work is diminished. This R01 research program, which was first funded in April 2004 and renewed in September 2008, has made substantial progress in both elucidating the physiological mechanisms underlying control of oxidative phosphorylation and in determining how these mechanisms break down in heart failure. Specifically, we have: (1.) disproved the previous accepted theory that oxidative phosphorylation and energetic state in the heart are maintained in the absence of a feedback mechanism; (2.) demonstrated how inorganic phosphate acts as the key feedback signal controlling the rate of mitochondrial ATP synthesis in the heart in vivo; and (3.) shown how the depletion of cytoplasmic metabolite pools in the myocardium affects energetic state in heart failure. The proposal for renewed funding focuses on more deeply characterizing our understanding of the oxidative metabolism in the heart, and translating our basic findings to human studies. We will expand and develop our computer models of myocardial energy metabolism by utilizing the substantial foundation of software and data resources that we have established. Models will be parameterized and validated based on kinetic time-course experiments using purified mitochondria obtained from male Dahl S and SS.BN13 rats maintained on low- and high-salt diets. (The high-salt Dahl S is an established hypertensive dilated myopathy model, where the SS.BN13 groups serve as controls.) In parallel human studies, we will obtain the first in vivo measurements of phosphate metabolites in human hearts over a range of work rates and the first measurements of energetic state in healthy and diseased subjects during exercise. These studies will determine if, and to what extent, the ability of ATP synthesis to keep up with increasing demand provides additional insight into clinical phenotypes. Finally, based on the findings from the rat models and human studies, we will use computer simulation to determine if and how changes in energy state can explain cardiac pumping failure in vivo.