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

项目摘要/摘要 1型糖尿病(T1D)与心血管疾病的过度发病率和死亡率有关，这会导致8-18岁 预期寿命更短。数据中心/电子数据中心和基于人口的登记册研究表明 高血糖是T1D患者心血管疾病的最大危险因素。患有T1D的患者通常不会分享 与2型糖尿病(T2D)相同的心血管危险因素，以及最近的DCCT/EDIC中介分析 研究表明，传统的危险因素只解释了43%的高血糖对心血管疾病风险的长期影响。一位少校 目前这项提议的目标是检验心脏自身免疫是心脏自身免疫“缺失”的介体这一假设。 高血糖对T1D患者心血管疾病风险的长期影响。 T1D是一种自身免疫性疾病，被认为是由于T细胞对β细胞损伤的反应失调引起的。 虽然这种疾病过程是T细胞介导的，但胰岛自身抗体的存在，特别是对≥2的抗体 胰岛AAB型，强烈预测临床T1D的发生。我们的小组此前曾表示， 心肌梗死(MI)诱导持续前炎症(Th1)CD4+T细胞和AAB对心脏的反应 肌球蛋白在T1D患者中存在，但在T2D患者中不存在。利用DCCT的纵向样本，我们最近 研究表明，在T1D患者中，血糖控制不良会导致心脏自身免疫的发展，AS 由≥-2心脏AAB型定义。出乎意料的是，≥2AABS在深静脉血栓形成期间的阳性与 心血管事件和冠状动脉钙化(CAC)的风险增加，CAC是动脉粥样硬化的标志 几十年后。此外，≥2 AABS确定了随后高敏C反应升高的患者 蛋白(HsCRP)，炎症的标志，增加了心脏自身免疫产生 炎症状态，这可能将AAB与动脉粥样硬化性心血管疾病的结局联系起来。为了支持这一想法，我们的 初步研究表明，具有心脏自身免疫性的T1D患者循环水平升高 提示适应性免疫上调的细胞因子，包括升高的促炎Th1细胞因子 与动脉粥样硬化的形成有关。然而，我们之前的DCCT研究并不是为了研究心血管疾病的结果， 只有12%的队列被研究，以及少量的心血管疾病结果。在这里，我们建议使用 NIDDK存储库中的DCCT/EDIC样本和数据集，以： 目的1：确定：a)心脏自身免疫是否是T1D患者长期心血管疾病预后的决定因素； 不受传统风险因素的影响；加入心脏AAB可提高心血管疾病的预测能力 传统危险因素和B)心脏自身免疫是高血糖对心血管疾病长期影响的中介 风险(即“新陈代谢记忆”)。目的2：确定心脏自身免疫是否与升高有关 HsCRP和上调的获得性免疫标志物。确定潜在的细胞因子和炎症途径 这可能会将AABS与T1D中心血管疾病结局的风险增加联系起来。如果成功，我们的研究可能会改变我们的 了解T1D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.