CARDIAC METABOLISM, FUNCTION AND VASCULAR DISEASE IN DIABETES MELLITUS

糖尿病患者的心脏代谢、功能和血管疾病

• 批准号: 5214500
• 负责人: Sandor J. Kovacs
• 金额: --
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/5214500
• 关键词: blood glucose; cardiovascular imaging /visualization; clinical research; coronary disorder; diabetes mellitus; digital imaging; enzyme activity; heart catheterization; heart function; heart metabolism; heart ventricle; hemodynamics; human subject; hyperglycemia; insulin; magnetic resonance imaging; noninvasive diagnosis; pathologic process; phospholipase A2; second messengers

The clinical sequelae of hyperglycemia-induced alterations in the generation of lipid second messengers will be examined utilizing a multidisciplinary approach incorporating biochemistry, biophysics, clinical cardiology and diabetology. Subjects with an antecedent diagnosis of diabetes, scheduled for cardiac catheterization at the request of their referring physician and meeting inclusionary criteria will be recruited during the first three years of the project and followed at regular intervals for the duration of the 5 year project. In Specific Aim 1 attention will be focused on glycolytically coupled alterations of lipid second messenger generation and ventricular hemodynamic function in the diabetic state. With each subject serving as their own internal control, alterations in phospholipase activity (assessed through quantification of coronary venous arachidonic acid and lysophospholipid content) will be examined after glucose and insulin administration in the catheterization laboratory. Concomitant alterations in global ventricular function will be assessed during altered glycolytic flux through digitally acquired high-fidelity hemodynamic data and novel model-based image processing methods. In Specific Aims 2 and 3, the rates of progression of macrovascular proximal coronary artery disease, relative to catheterization determined baseline, as a function of time averaged serum glucose levels (HbA1c) and serum lipid and insulin levels sampled at regular intervals will be examined with high performance magnetic field gradient coil MRI using a prototype quadrature 6-element phased array radiofrequency coil. Through noninvasive assessment of the rate of proximal coronary average-lumen narrowing by MRI and the level of metabolic control in two groups, the relationship between hyperglycemia, insulin levels and progression of coronary macrovascular disease will be determined. Based upon a minimum sample size of 250 subjects, a 5% - 7% projected average progression rate of annual macrovascular luminal diameter narrowing, the power to detect a difference in progression rates (average 3.5 year follow-up) in the two groups (HbA1c < 7.8 or greater than or equal to 7.8) at the .05 level of significance is .87. Collectively, this project provides a basis for the clinical interpretation of the basic science observations in Projects 1-3 and examines the feasibility for characterization of the rate of global ventricular dysfunction and macrovascular (proximal coronary artery disease progression in diabetics through noninvasive means.

高血糖症引起的糖尿病性视网膜病变的临床后遗症 脂质第二信使的产生将利用 结合生物化学，生物物理学， 临床心脏病学和糖尿病学。 有先行词的主题 糖尿病的诊断，安排在心脏导管插入术 他们的转诊医生的要求，并符合入选标准 将在项目的前三年招募， 在5年的项目期间定期进行。 在具体目标1中，将关注糖酵解偶联 脂质第二信使产生和心室肌细胞的改变 糖尿病状态下的血液动力学功能。 每一个实验对象 作为其自身的内部对照，磷脂酶活性的改变 （通过定量冠状静脉花生四烯酸和 溶血磷脂含量）将在葡萄糖和胰岛素 在导管插入实验室进行给药。 伴随 期间将评估整体心室功能的变化 通过数字化获取的高保真度改变糖酵解通量 血液动力学数据和新的基于模型的图像处理方法。 在 具体目标2和3，大血管近端的进展率 冠状动脉疾病，相对于导管插入术确定的基线， 作为时间平均血清葡萄糖水平（HbA 1c）和血清 将定期检查血脂和胰岛素水平 使用原型的高性能磁场梯度线圈MRI 正交6元件相控阵射频线圈。 通过 近端冠状动脉平均管腔率的无创评估 两组的MRI狭窄程度和代谢控制水平， 高血糖、胰岛素水平和糖尿病进展之间的关系 将确定冠状动脉大血管疾病。 基于最小 样本量为250例受试者，预计平均进展率为5% - 7% 年大血管管腔直径变窄，检测能力 两组的进展率差异（平均3.5年随访） 0.05水平下的HbA 1c < 7.8或大于或等于7.8组 重要性是0.87。 总的来说，该项目为 项目1-3中基础科学观察结果的临床解释 并审查了全球人口增长率特征化的可行性， 心室功能障碍和大血管（近端冠状动脉 通过非侵入性手段治疗糖尿病患者的疾病进展。