Cardiac Autoantibodies as Biomarkers for Heart Disease in Type 1 Diabetes

 描述（由申请人提供）：1型糖尿病（T1 D）患者的心血管疾病（CVD）死亡率和发病率过高，但已知的CVD风险因素无法完全解释其潜在机制。我们最近发现NOD小鼠的实验性心肌梗死（MI）（T1 D的模型）触发慢性MI后自身免疫综合征（PIA），其特征在于心肌淋巴细胞浸润、梗死扩大、高滴度心脏自身抗体（AAb）和针对心肌肌球蛋白的T细胞应答。我们进一步表明，PIA可以通过诱导T细胞对心肌肌球蛋白的耐受来预防。将这些发现扩展到T1 D患者，并在广泛用于胰岛AAb检测的“生化”测定法上建模，我们开发了一组用于心脏AAb检测的液相测定法，并在83%的MI后T1 D患者中证明了阳性。我们进一步确定了MI后T1 D患者和无T1 D的心肌炎患者之间共有的AAb特征，并通过心脏MRI证实了T1 D患者中心肌炎的存在。我们最近发现，这些AAb特征的阳性与T1 D患者MI后死亡率显著升高相关。我们假设PIA代表了一种“缺失”的致病过程，导致T1 D患者的CVD结局更差。然而，虽然这些结果强烈提示T1 D患者存在PIA综合征，但这些研究是横断面研究，无法确定MI和心脏自身免疫之间的因果关系。此外，我们最近在一个没有临床心脏病的年轻成人队列中观察到高HbA 1C水平和心脏AAb表达之间的关系。在这里，我们建议使用DCCT/EDIC生物样本和临床数据：1。通过测量从DCCT/EDIC纵向收集的MI前和MI后样本中心脏AAb的出现时间和特异性，确定T1 D中MI与心脏自身免疫之间的关系。确定心脏AAb的表达与MI后不良CVD结局之间是否存在关联; 2.通过比较DCCT一级预防常规队列中平均HbA 1c ≥ 9.0%的受试者与强化队列中平均HbA 1c ≤7.0%的受试者的心脏AAb频率，检查血糖控制与心脏自身免疫之间的关联; 3.确定CMRI定义的心肌瘢痕是否与心脏AAb阳性相关，以及心脏AAb的存在是否与CMRI心功能不全证据相关。这些研究将是第一个对DCCT/EDIC队列进行免疫学特征分析的研究，该队列已经对糖尿病并发症进行了深入的表型分析。为此，我组建了一个优秀的团队，他们在糖尿病心脏病（Beckman）、DCCT/EDIC队列的CMRI（Bluemke）和生物统计学（Keenan）方面具有专业知识。NIDDK存储库中丰富的样本和临床数据提供了一个独特的机会来检验我们的假设，即心脏自身免疫性有助于T1 D中的CVD负担。这些结果可能为T1 D CVD的病因学打开一个新的窗口，并对T1 D死亡的主要原因具有重要的诊断和治疗意义。

 DESCRIPTION (provided by applicant): Patients with type 1 diabetes (T1D) suffer excess mortality and morbidity from cardiovascular disease (CVD), but the underlying mechanisms are not fully explained by known CVD risk factors. We have recently discovered that experimental myocardial infarction (MI) in NOD mice, a model for T1D, triggers a chronic post- MI autoimmune syndrome (PIA) characterized by myocardial lymphocytic infiltration, infarct expansion, high- titer cardiac autoantibodies (AAb) and T cell responses against cardiac myosin. We further showed that PIA could be prevented by inducing T-cell tolerance to cardiac myosin. Extending these findings to T1D patients and modeling on the "biochemical" assays that are widely used for islet AAb detection, we developed a panel of fluid-phase assays for cardiac AAb detection and demonstrated positivity in 83% of post-MI T1D patients. We further identified shared AAb signatures between post-MI T1D patients and myocarditis patients without T1D, and confirmed the presence of myocarditis by cardiac MRI in T1D patients. We have recently found that positivity for these AAb signatures is associated with markedly higher post-MI mortality in T1D patients. We hypothesize that PIA represents a 'missing' pathogenic process that contributes to worse CVD outcomes in patients with T1D. However, while these findings are strongly suggestive of a PIA syndrome in T1D, these studies were cross-sectional and could not establish causality between MI and cardiac autoimmunity. In addition, we have recently observed a relationship between high HbA1C levels and expression of cardiac AAb in a young adult cohort without clinical heart disease. Here, we propose to use the DCCT/EDIC biosamples and clinical data to: 1. Define the relationship between MI and cardiac autoimmunity in T1D by measuring the time course of appearance and specificities of cardiac AAb in longitudinally collected pre- and post- MI samples from DCCT/EDIC. Determine whether there is an association between expression of cardiac AAb and poor post-MI CVD outcomes; 2. Examine the association between glycemic control and cardiac autoimmunity by comparing the frequencies of cardiac AAb in subjects from the DCCT Primary Prevention conventional cohort with mean HbA1c ≥9.0%, to subjects in the intensive cohort with mean HbA1c ≤7.0% and; 3. Determine whether CMRI-defined myocardial scar correlates with positivity for cardiac AAb and whether the presence of cardiac AAb is associated with CMRI evidence of cardiac dysfunction. These studies will be the first to immunologically characterize the DCCT/EDIC cohort that has been deeply phenotyped with respect to diabetic complications. To this end, I have assembled an outstanding team with expertise in diabetic heart disease (Beckman), CMRI of the DCCT/EDIC cohort (Bluemke) and biostatistics (Keenan). The wealth of samples and clinical data in the NIDDK Repository provides a unique opportunity to test our hypothesis that cardiac autoimmunity contributes to the burden CVD in T1D. These results could open a new window on the etiology of CVD in T1D, and have important diagnostic and therapeutic implications for this major cause of T1D mortality.