Determinants of Accelerated CVD in Type 1 Diabetes

描述(申请人提供)：心血管疾病的预防和治疗仍然是1型糖尿病(T1D)管理中的一个关键问题。自1999年以来，冠状动脉钙化在1型糖尿病(CACTI)研究(R01 HL61753)中研究了654名T1D患者和766名非糖尿病对照组(年龄20-55岁)冠状动脉粥样硬化的发展和进展。在基线(4/00-3/02)和3年随访(1/03-5/04)期间，使用电子束断层扫描(EBT)和一组经典的和新的心血管危险因素对该队列进行了检查。在这里，我们建议使用这项大型队列研究的储存样本来研究心血管并发症的机制，并将具有良好特征的研究参与者纳入两项子研究，利用新技术：理清炎症、免疫反应和糖尿病相关代谢因素在冠状动脉钙化进展中的作用。这些过程将通过CACTI基线和3年随访样本在200名冠状动脉粥样硬化显著进展的受试者和200名对照组受试者中进行表征。前瞻性采集外周血检测炎症因子(CRP、MMP-9、WBC、MPO、纤维蛋白原、PAI-1)和参与动脉粥样硬化的免疫反应因子，如sIL-2R、CD40/CD40L、细胞因子组合和氧化型低密度脂蛋白自身抗体。为了进一步了解胰岛素抵抗在T1D患者动脉粥样硬化加速中的作用，我们使用正常血糖高胰岛素钳夹技术对48名T1 DM患者和48名非糖尿病对照组进行了研究。通过对具有显著斑块负荷的非糖尿病受试者和T1D患者的深入检查，来表征冠状动脉斑块和功能推论的T1D特异性形态。重新分析已经从仙人掌研究糖尿病并发症流行病学研究(T.Orchard，Pi)和EURODIAB研究(J.Fuller，Pi)中联合收集的前瞻性数据，以开发以致命性和非致命性ML、血运重建或心绞痛以及中风、外周动脉疾病和特定原因的死亡率以及以冠状动脉钙化为特征的亚临床冠状动脉粥样硬化的发病率和进展率的T1D患者临床CAD发病率的更普遍的估计。

DESCRIPTION (provided by applicant): Prevention and treatment of cardiovascular disease remains to be a critical problem in the management of type 1 diabetes (T1D). Since 1999, Coronary Artery Calcification in Type 1 Diabetes (CACTI) study (R01 HL61753) has studied development and progression of coronary atherosclerosis in 654 T1D patients and 766 non-diabetic controls (age 20-55). This cohort has been examined using the electron beam tomography (EBT) and a battery of classical and novel cardiovascular risk factors during the baseline (4/00-3/02) and 3-year follow-up examination (1/03-5/04). Here, we are proposing to investigate mechanisms of cardiovascular complications using stored samples from this large cohort study and to include well-characterized study participants in two substudies utilizing novel techniques to: Disentangle the role of inflammation, immune response and diabetes-related metabolic factors in progression of coronary artery calcification. These processes will be characterized, usingCACTI baseline and 3-year follow-up samples, in 200 subject whose coronary atherosclerosis progressed significantly and 200 control subjects. Prospectively collect peripheral blood samples for measurement of inflammatory (CRP, MMP-9, WBC, MPO, fibrinogen, PAI-1) and immune response factors involved in atherosclerosis, such as SIL-2R, CD40/CD40L, cytokine panel as well as autoantibodies to oxidized LDL. To further our understanding of the role of insulin resistance in accelerated atherosclerosis among T1D patients by studying 48 T1 DM patients and 48 non-diabetic controls using euglycemic hyperinsulinemic clamps. To characterize T1D-specific morphology of coronary plaque and functional corollaries through indepth examination of T1D and non-diabetic subjectes identified with significant plaque burden. Re-analyze jointly already collected prospective data from the CACTI Study the Epidemiology of Diabetes Complications Study (T. Orchard, PI) and the EURODIAB study (J. Fuller, PI), to develop more generalizable estimates of the incidence of clinical CAD in T1D patients, defined by fatal and non-fatal Ml, revascularization or angina, as well as stroke, peripheral artery disease and cause-specific mortality and the incidence and progression rate of subclinical coronary atherosclerosis, characterized by coronary artery calcification.