MYOCARDIAL FUNCTION AND FFA METABOLISM IN HIV-METABOLIC SYNDROME

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 HIV感染者发生心血管疾病（CVD）和左心室功能障碍（LVD）的风险高于普通人群，但发病机制尚不清楚。 许多HIV感染者发展出代谢综合征（HIV+MS），包括传统的CVD和LVD危险因素（血脂异常、胰岛素抵抗、内脏肥胖），这些因素通常在HIV血清阴性人群中观察到，并被称为“代谢综合征”。“我们已经报道了HIV+MS的特征是循环中游离脂肪酸出现率（FFA Ra）升高（即，增加全身脂肪分解率），以及骨骼肌和肝脏中的脂质积累。 在HIV+MS中，我们假设升高的FFA Ra增加了心肌的FFA输送、摄取和氧化，但心肌FFA摄取最终超过了心脏氧化FFA的能力：可能导致心肌内脂质蓄积。 我们假设，增加心肌FFA摄取和氧化与左心室的结构变化，以及HIV+ MS的心室舒张和收缩功能障碍有关。（使用13 C-棕榈酸盐和质谱法），心肌FFA递送、摄取和氧化（使用放射性标记的棕榈酸盐和心脏正电子发射断层扫描（PET）成像），和左心室（LV）结构，舒张和收缩功能使用2-D和组织多普勒超声心动图）在30个HIV+MS和30个HIV感染的人没有MS。 我们将比较这两组之间的这些参数，并与我们机构目前正在研究该提案的共同研究者在患有和不患有“代谢综合征”的HIV血清阴性人群中量化的完全相同的参数进行比较。 在该项目中，HIV+MS被定义为接受稳定的抗逆转录病毒治疗并经历高脂血症、低HDL胆固醇水平、胰岛素抵抗和内脏肥胖的HIV感染的女性和男性。 研究结果将确定HIV+MS和代谢综合征之间心肌代谢和LV收缩功能的相似性/差异。“这些发现可能提供了全身和心肌FFA代谢失调之间的机制联系，导致LV结构，收缩功能和CVD的改变。 如果是这样，旨在降低HIV+MS患者循环FFA水平的治疗可能会有效降低HIV感染者的CVD和LVD。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The risk for cardiovascular disease (CVD) and left ventricular dysfunction (LVD) is greater in HIV-infected people than in the general population, but the pathogenesis is unclear. Many HIV-infected people develop metabolic syndromes (HIV+MS) that include traditional CVD and LVD risk factors (dyslipidemia, insulin resistance, visceral adiposity) that are commonly observed in HIV-seronegative people and referred to as "The Metabolic Syndrome." We have reported that HIV+MS is characterized by an elevated free fatty acid rate of appearance (FFA Ra) in the circulation (i.e., increased whole-body lipolytic rate), and lipid accumulation in skeletal muscle and liver. In HIV+MS, we hypothesize that the elevated FFA Ra increases FFA delivery, uptake and oxidation by the myocardium, but that myocardial FFA uptake eventually exceeds the ability of the heart to oxidize FFAs: intramyocardial lipid accumulation may result. We hypothesize that increased myocardial FFA uptake and oxidation are associated with structural changes in the left ventricle, and ventricular diastolic and systolic contractile dysfunction in HIV+MS. We propose to quantify whole-body FFA Ra (using 13C-palmitate and mass spectrometry), myocardial FFA delivery, uptake and oxidation (using radio-labeled palmitate and cardiac positron emission tomography (PET) imaging), and left ventricular (LV) structure, diastolic and systolic contractile function using 2-D and tissue Doppler echocardiography) in 30 HIV+MS and 30 HIV-infected people without MS. We will compare these parameters between these 2 groups, and to exactly the same parameters quantified in HIV-seronegative people with and without "The Metabolic Syndrome" who are currently being studied by co-investigators on this proposal at our Institution. For this project, HIV+MS is defined as HIV-infected women and men receiving stable anti-retroviral therapy and experiencing hypertriglyceridemia, low HDL-cholesterol levels, insulin resistance and visceral adiposity. The findings will identify similarities/differences in myocardial metabolism and LV contractile function between HIV+MS and "The Metabolic Syndrome." The findings may provide a mechanistic link between dysregulated whole-body and myocardial FFA metabolism that contributes to alterations in LV structure, contractile function and CVD. If so, treatments designed to reduce circulating FFA levels in HIV+MS, might effectively reduce CVD and LVD in HIV-infected people.