Exercise and TZD Effects on Myocardial Substrate Metabolism and Function in HIV

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This K-01.application proposes a 5-year mentored training and research plan to develop expertise in measurement, analysis and interpretation of, and interventions for, myocardial substrate metabolism and ventricular function abnormalities in HIV-infected people with metabolic complications (i.e. impaired glucose tolerance, fat redistribution). Didactic training will include coursework in cardiovascular diseases, nuclear medicine, and cardiac sonography. The primary aim of this proposal is to test the effects of two insulin- sensitizing interventions, a cardiorespiratory exercise training (GET) program and a thiazolidinedione (TZD), on peripheral and myocardial substrate metabolism and left ventricular function in HIV-infected individuals with impaired glucose tolerance (HIV+IGT). In HIV-IGT, it is hypothesized that reduced peripheral and myocardial glucose utilization and elevated peripheral and myocardial FFA oxidation is associated with left ventricular dysfunction. Furthermore, both GET and TZD treatment will improve ventricular function through an increase of myocardial glucose utilization. Lastly, due to an additive effect of increased myocardial blood flow following GET, GETwill provide a greater improvement in LV function than TZD treatment. Results from this proposal are projected to demonstrate the efficacy of GETand TZD for the treatment of metabolically induced LVD in HIV-infected people. Hypotheses for this proposal will be tested through randomized, closely supervised, four-month treatments of either GET or TZD. Myocardial substrate metabolism, blood flow and ventricular function and peripheral substrate metabolism will be measured before and immediately following completion of each intervention. Myocardial substrate metabolism and blood flow will be measured by radioisotope tracer methodology and Positron Emission Tomography (PET) imaging, ventricular function by standard 2-D and Doppler echocardiography, and peripheral substrate metabolism by stable-isotope tracer methodology and mass spectrometry. The candidate will receive specific training and guidance by exemplary mentors and a faculty advisory committee and will receive the full support of Washington University's outstanding research environment. This award will assist in accomplishing the candidate's long-term career goal of becoming an independent research scientist in the field of peripheral and myocardial metabolic and mechanical function complications in HIV.