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

这个K-01申请提出了一个为期5年的指导培训和研究计划，以发展专业知识， 心肌基质代谢的测量、分析和解释以及干预措施， 伴有代谢并发症（即血糖受损）的HIV感染者的心室功能异常 耐受性、脂肪再分配）。教学培训将包括心血管疾病、核 医学和心脏超声检查。这项提案的主要目的是测试两种胰岛素的效果- 敏化干预，心肺运动训练（GET）计划和噻唑烷二酮（TZD）， 对HIV感染者外周和心肌基质代谢及左心室功能的影响 糖耐量受损（HIV+IGT）。在HIV-IGT中，假设减少的外周血和 心肌葡萄糖利用率和外周及心肌FFA氧化水平升高与左室肥厚相关。 心室功能障碍此外，GET和TZD治疗都将改善心室功能， 心肌葡萄糖利用率增加。最后，由于心肌血流量增加的叠加效应， GET后的血流，GET将提供比TZD治疗更大的LV功能改善。结果 这一建议预计将证明GET和TZD治疗代谢性疾病的疗效。 在HIV感染者中诱导LVD。该提案的假设将通过随机、密切 在监督下接受为期四个月的GET或TZD治疗心肌基质代谢、血流量和 在术前和术后即刻测量心室功能和外周底物代谢 完成每一次干预。心肌底物代谢和血流量将通过 放射性同位素示踪剂方法和正电子发射断层扫描（PET）成像，心室功能， 标准2-D和多普勒超声心动图，以及稳定同位素示踪的外周底物代谢 方法学和质谱法。候选人将接受具体的培训和指导， 导师和教师咨询委员会，并将得到华盛顿大学的全力支持， 优秀的研究环境。该奖项将有助于完成候选人的长期职业生涯 成为外周和心肌代谢领域的独立研究科学家， 机械功能并发症。

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.