Altered Myocardial Fatty Acid Metabolism in Obesity

描述(由申请人提供)： 肥胖(身体质量指数和30公斤/平方米)影响着4300多万美国人，特别是当涉及腹部或内脏(AO)时，与心脏发病率和死亡率增加有关。根据肥胖实验模型的研究结果和我们对患有AO的人类的初步研究，我们假设在患有AO的人类中，脂肪分解增加导致向血浆中释放的脂肪酸增加，从而导致向心脏的脂肪酸输送增加。特别是当与胰岛素抵抗相结合时，这会导致心肌脂肪酸代谢增加。我们进一步假设，心肌底物代谢的这种变化与心脏收缩和舒张期功能的异常有关。此外，我们认为，在进一步增加脂肪酸输送的情况下，心肌中性脂积累增加，这反过来可能与心脏收缩和舒张期功能的进一步下降相平行。我们将通过在一组经过良好筛选的瘦身和黎鳌类受试者中进行一系列高度复杂的实验来证明或反驳这一假设，这些实验利用正电子发射计算机断层扫描对心肌基质代谢进行量化，超声心动图测量左心室收缩和舒缩功能，以及稳定的同位素测量全身脂肪酸和葡萄糖动力学。这些测量将在各种条件下获得，旨在评估适度体重减轻、胰岛素可获得性和血浆脂肪酸水平对AO患者心肌基质代谢、机械功能和全身基质代谢之间关系的影响。如果成功，拨款申请中描述的研究结果将证实，在肥胖实验模型中观察到的心肌脂肪酸代谢异常在患有AO的人类中也存在。这些信息将形成更有针对性的研究的基础，旨在阐明导致这些异常的机制，并可能为患有AO的人类带来显著的临床益处。

DESCRIPTION (provided by applicant): Obesity (body mass index > 30 kg/m 2) affects more than 43 million Americans, and particularly when involving the abdomen or viscera (AO), is associated with increased cardiac morbidity and mortality. Based on the results of studies in experimental models of obesity and our preliminary studies in humans with AO, we hypothesize that in humans with AO, increased lipolysis leading to increased release of fatty acids into the plasma results in increased fatty acid delivery to the heart. Particularly when combined with insulin resistance this results in an increase in myocardial fatty acid metabolism. We further hypothesize that this shift in myocardial substrate metabolism is associated with abnormalities in ventricular systolic and diastolic function. Moreover, we believe that under conditions that further increase fatty acid delivery, myocardial accumulation of neutral lipids is increased, which in turn may be paralleled by a further decline in ventricular systolic and diastolic function. We will prove or disprove this hypothesis by performing a series of highly-complex experiments that utilize PET quantification of myocardial substrate metabolism, echocardiographic measurements of left ventricular systolic and diastolic function and stable isotopic measurements of whole-body fatty acid and glucose kinetics in a well-screened group of lean and Class-lI AO subjects. The measurements will be obtained under a variety of conditions designed to assess the influence of moderate weight loss, insulin availability, and plasma fatty acid levels on the relationship between myocardial substrate metabolism, mechanical function and whole-body substrate metabolism in AO. If successful, the results of the studies described in the grant application will provide confirmation that the abnormalities in myocardial fatty acid metabolism observed in experimental models of obesity are seen in humans with AO. Such information will form the basis for more targeted studies designed to elucidate the mechanisms responsible for these abnormalities and potentially result in significant clinical benefit for humans with AO.