Cardiac Autoantibodies as Biomarkers for Heart Disease in Type 1 Diabetes

心脏自身抗体作为 1 型糖尿病心脏病的生物标志物

• 批准号: 9186538
• 负责人: MYRA A LIPES
• 金额: $ 37.77万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9186538
• 关键词: Acute Myocarditis; Affect; Antigens; Appearance; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biochemical; Biological Assay; Biological Markers; Biometry; Cardiac; Cardiac Myocytes; Cardiac Myosins; Cardiac development; Cardiovascular Diseases; Cessation of life; Chronic; Cicatrix; Clinical; Clinical Data; Cohort Studies; Complications of Diabetes Mellitus; Data; Data Set; Detection; Development; Diabetes Mellitus; Diagnostic; Disease; Disease Outcome; Etiology; Excess Mortality; Frequencies; Gene Expression Profile; Glycosylated hemoglobin A; Health; Heart; Heart Diseases; Heart Injuries; Heart failure; Human; Hyperglycemia; Immune Targeting; Immunologics; Inbred NOD Mice; Individual; Infarction; Infiltration; Inflammation; Injury; Insulin-Dependent Diabetes Mellitus; Liquid substance; Lymphocyte; Lymphocytic Infiltrate; Magnetic Resonance; Magnetic Resonance Imaging; Measures; Mediator of activation protein; Metabolic; Modeling; Morbidity - disease rate; Myocardial; Myocardial Infarction; Myocardial dysfunction; Myocarditis; Myocardium; Myosin Heavy Chains; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Participant; Pathogenesis; Pathogenicity; Patients; Phase; Phenotype; Predictive Value; Prevalence; Primary Prevention; Process; Registries; Risk; Risk Factors; Role; Sampling; Serum; Specificity; Structure; Structure of beta Cell of islet; Suggestion; Syndrome; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Troponin I; Ventricular Cardiac alpha-Myosin; alpha Actinin; base; cardiovascular disorder risk; cell injury; cohort; diabetic; glycemic control; immune function; islet; mortality; novel; phenotypic data; prevent; prospective; public health relevance; repository; young adult

 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.

 描述(申请人提供)：1型糖尿病(T1D)患者心血管疾病(CVD)的死亡率和发病率过高，但其潜在机制尚不能用已知的心血管疾病危险因素完全解释。我们最近发现，作为T1D的模型，NOD小鼠的实验性心肌梗死(MI)会触发一种慢性心肌梗死后自身免疫综合征(PIA)，其特征是心肌淋巴细胞浸润、梗塞扩大、高滴度心脏自身抗体(AAB)和抗心肌肌球蛋白的T细胞反应。我们进一步证明，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T1D患者，并以广泛用于胰岛AAB检测的“生化”分析为模型，我们开发了一组用于心脏AAB检测的液相分析方法，并在83%的MI后T1D患者中显示阳性。我们进一步鉴定了心肌梗死后T1D患者和非T1D心肌炎患者之间共享的AAB信号，并通过心脏MRI证实了T1D患者心肌炎的存在。我们最近发现，这些AAB信号阳性与T1D患者明显较高的心肌梗死后死亡率相关。我们假设PIA代表一种“缺失”的致病过程，导致T1D患者更糟糕的CVD结局。然而，尽管这些发现强烈暗示了T1D的PIA综合征，但这些研究是横断面的，不能确定MI和心脏自身免疫之间的因果关系。此外，我们最近在一组没有临床心脏病的年轻人队列中观察到高HbA1C水平与心脏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.通过测量纵向收集的DCCT/EDIC心肌梗死前和心肌梗死后标本中AAB出现的时间进程和特异性，确定MI与T1D心脏自身免疫之间的关系。2.通过比较DCCT一级预防常规队列中平均糖化血红蛋白≥为9.0%的受试者和平均糖化血红蛋白≤为7.0%的强化队列受试者的心脏AAB频率，来检查血糖控制和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的存在是否与心脏功能障碍的CMRI证据相关。这些研究将首次对DCCT/EDIC队列的免疫学特征进行表征，这些队列已经在糖尿病并发症方面进行了深入的表型鉴定。为此，我组建了一支出色的团队，拥有糖尿病心脏病(Beckman)、DCCT/EDIC队列的CMRI(Bluemke)和生物统计学(Keenan)方面的专业知识。NIDDK资料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，即心脏自身免疫导致T1D的CVD负担。这些结果可能为T1D的心血管疾病的病因学打开新的窗口，并对这一导致T1D死亡的主要原因具有重要的诊断和治疗意义。