Cardiac Autoimmunity as a Mediator of Cardiovascular Outcomes in Type 1 Diabetes

项目总结/摘要 1型糖尿病（T1 D）与CVD的过度发病率和死亡率相关，其引起8-18年的病程。 预期寿命更短。DCCT/EDIC和基于人群的登记研究表明， 高血糖症是T1 D中CVD的最强有力的危险因素。T1 D患者通常不共享 与2型糖尿病（T2 D）患者相同的CVD风险因素，以及最近的DCCT/EDIC介导分析， 传统危险因素仅能解释高血糖对CVD风险长期影响的43%。一个主要 当前提案的目标是检验心脏自身免疫是心脏免疫系统的“缺失”介质的假设。 高血糖对T1 D患者CVD风险的长期影响。 T1 D是一种自身免疫性疾病，推测是由对β细胞损伤的失调的T细胞应答引起的。 虽然这种疾病的过程是T细胞介导的，胰岛自身抗体（AAb）的存在，特别是≥2 胰岛AAb类型，强烈预测临床T1 D的发展。我们的研究小组先前表明， 心肌梗塞（MI）诱导持续的促炎性（“Th 1”）CD 4 +T细胞和AAb对心脏炎症的应答。 肌球蛋白在T1 D患者中，而不是在T2 D患者中。使用DCCT的纵向样本，我们最近 表明，在T1 D患者中，血糖控制不良诱导心脏自身免疫的发展， 定义为≥ 2种心脏AAb类型。出乎意料的是，DCCT期间≥2个AAb的阳性与 心血管事件和冠状动脉钙化（CAC）（动脉粥样硬化的标志物）的风险增加， 几十年后。此外，≥2个AAb确定了随后高敏C反应性升高的患者 炎症标志物高敏C反应蛋白（hsCRP），增加了心脏自身免疫产生 炎症状态，这可能将AAb与动脉粥样硬化CVD结果联系起来。为了支持这一想法，我们的 初步研究表明，患有心脏自身免疫的T1 D患者的循环水平增加， 提示适应性免疫上调的细胞因子，包括升高的促炎性Th 1细胞因子 与动脉粥样硬化有关然而，我们以前的DCCT研究并不是为了研究CVD的结果， 只有12%的队列研究和少数心血管疾病的结果。在这里，我们建议使用 DCCT/EDIC样本和数据集从NIDDK存储库到： 目的1：确定是否：A）心脏自身免疫是T1 D长期CVD结局的决定因素， 独立于传统的风险因素;增加心脏AAb可改善CVD预测， 传统危险因素和B）心脏自身免疫是高血糖对CVD长期影响的介导因素 风险（即，“代谢记忆”）。目的2：确定心脏自身免疫性是否与升高的 hsCRP和上调的适应性免疫标志物。识别潜在的细胞因子和炎症通路 这可能将AAb与T1 D患者CVD结局风险增加联系起来。如果成功，我们的研究可以改变我们的 了解T1 D中的CVD，并具有重要的诊断和治疗意义。

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is associated with excess morbidity and mortality from CVD, which incurs an 8-18 year shorter life expectancy. The DCCT/EDIC and population-based registry studies have demonstrated that hyperglycemia is the most powerful risk factor for CVD in T1D. Patients with T1D do not generally share the same CVD risk factors as those with type 2 diabetes (T2D), and recent DCCT/EDIC mediation analyses have shown that traditional risk factors explain only 43% of long-term effect of hyperglycemia on CVD risk. A major goal of the current proposal is to test the hypothesis that cardiac autoimmunity is a “missing” mediator of the long-term effects of hyperglycemia on CVD risk in T1D. T1D is an autoimmune disease that is postulated to arise from dysregulated T cell responses to β-cell injury. Although this disease process is T-cell mediated, the presence of islet autoantibodies (AAb), particularly for ≥2 islet AAb types, strongly predicts the development of clinical T1D. Our group previously showed that myocardial infarction (MI) induces sustained proinflammatory (“Th1”) CD4+T cell and AAb responses to cardiac myosin in T1D patients, but not in T2D patients. Using longitudinal samples from the DCCT, we recently showed that in patients with T1D poor glycemic control induces the development of cardiac autoimmunity, as defined by ≥ 2 cardiac AAb types. Unexpectedly, positivity for ≥2 AAbs during DCCT was associated with increased risk of both CVD events and coronary artery calcification (CAC), a marker of atherosclerosis, decades later. In addition, ≥2 AAbs identified patients with subsequently elevated high-sensitivity C-reactive protein (hsCRP), a marker of inflammation, raising the possibility that cardiac autoimmunity produces an inflammatory state, which could link AAb to atherosclerotic CVD outcomes. In support of this idea, our preliminary studies show that T1D patients with cardiac autoimmunity have increased levels of circulating cytokines suggesting adaptive immune upregulation, including elevated proinflammatory Th1 cytokines implicated in atherogenesis. However, our previous DCCT studies were not designed to study CVD outcomes, with only 12% of the cohort studied and a small number of CVD outcomes. Here, we propose to use the DCCT/EDIC samples and datasets from the NIDDK Repository to: Aim 1: Determine whether: A) Cardiac autoimmunity is a determinant of long-term CVD outcomes in T1D, independent of traditional risk factors; adding cardiac AAb improves CVD prediction beyond that provided by traditional risk factors and B) Cardiac autoimmunity is a mediator of long-term effects of hyperglycemia on CVD risk (i.e., “metabolic memory”). Aim 2: Determine whether cardiac autoimmunity is associated with elevated hsCRP and markers of upregulated adaptive immunity. Identify potential cytokines and inflammatory pathways that could link AAbs to increased risk for CVD outcomes in T1D. If successful, our studies could transform our understanding of CVD in T1D, and have major diagnostic and therapeutic implications.