In Vivo Evaluation of Myocardial Lipids

描述(由申请人提供)： 随着我们成为世界上最胖的国家，肥胖是美国心肌发病率和死亡率的一个日益重要的原因。肥胖通过增加血脂和易患糖尿病和高血压(即传统的心血管危险因素)间接导致心脏病。此外，罗杰·昂格尔最近的工作提出了一个新的假设，即肥胖本身通过促进心脏脂肪变性而构成左收缩功能障碍和肥厚的直接原因。 主要假设：心脏脂肪变性是人类肥胖的一个重要特征，是导致左心室收缩功能下降的原因之一。我进一步假设，人类心脏的这些功能异常是由非胰岛素依赖型糖尿病(2型糖尿病)的发展引起的，并可以通过使用噻唑烷二酮类药物来逆转。 具体目的：在没有心脏病的受试者中，我将使用双门定域质子核磁共振(1H核磁共振)测量室间隔的脂质沉积，并使用磁共振成像(MRI)测量左心室收缩功能，以实现以下特定目的： 目的1：证明1H核磁共振心肌内脂肪含量测量的受试者内的重复性。 目的2：建立肥胖与大范围BMI的心肌脂肪沉积之间的关系，并确定性别和种族对这些关系的影响。 目的3：确定与BMI、年龄、性别和种族相匹配的糖耐量正常者相比，IGT和胰岛素抵抗患者的心肌内脂质沉积是否更多。我假设糖尿病患者和糖尿病前期患者的心肌脂质增加会伴随着左心室收缩功能的降低。 目的：进行随机前瞻性研究，以验证噻唑烷二酮类药物治疗可逆转或减轻心肌脂质含量升高和收缩功能降低的假说。相反，我预测，当糖尿病患者接受对PPAR-γ没有影响的磺脲类尿素酶治疗时，心脏功能异常不会受到影响。

DESCRIPTION (provided by applicant): As we have became the fattest nation in the world, obesity is an increasingly important cause of myocardial morbidity and mortality in the United States. Obesity indirectly contributes to heart disease by increasing plasma lipids and predisposing to diabetes and hypertension (i.e. traditional cardiovascular risk factors). In addition, recent work from Roger Unger advances the novel hypothesis that obesity per se constitutes a direct cause of left systolic ventricular dysfunction and hypertrophy by promoting cardiac steatosis. Major Hypothesis: Cardiac steatosis is an integral feature of human obesity, contributing to decrease of LV systolic function. I further hypothesize that these functional abnormalities of the human heart are provoked by the development of non-insulin dependent diabetes mellitus (type 2 diabetes) and can be reversed by treatment with Thiazolidinediones. Specific Aims: In human subjects without heart disease, I will measure lipid deposition in the ventricular septum using double gated localized proton nuclear magnetic resonance (1H NMR) as well as LV systolic function with magnetic resonance imaging (MRI) to accomplish the following specific aims: Aim 1: To document the intra-subject reproducibility of the 1H NMR measurement of intra-myocardial lipid content. Aim 2: To establish the relation between adiposity and myocardial lipid deposition over a wide range of BMI and determine the impact of gender, and ethnicity on these relations. Aim 3: To determine if intra-myocardial lipid deposition is greater in individuals with IGT and insulin resistance than in these with normal glucose tolerance matched for BMI, age, gender and ethnicity. I hypothesize that the greater myocardial lipid in diabetic and prediabetic individuals will be accompanied by decreased LV systolic function. Aim 4: To perform randomized prospective study to test the hypothesis that the elevated myocardial lipid content and decreased systolic LV function can be reversed or minimized by the treatment with Thiazolidinediones. In contrast, I predict that functional cardiac abnormalities will be unaffected when diabetic subjects are treated with sulfonylureases that have no effect on PPAR-gamma.