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

心脏自身免疫作为 1 型糖尿病心血管结局的调节因素

• 批准号: 10427400
• 负责人: MYRA A LIPES
• 金额: $ 37.02万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10427400
• 关键词: Adult; Atherosclerosis; Autoantibodies; Autoimmune Diseases; Autoimmunity; Beta Cell; C-reactive protein; CD4 Positive T Lymphocytes; Cardiac; Cardiac Myosins; Cardiac development; Cardiovascular Diseases; Cardiovascular system; Clinical; Cohort Studies; Complication; Complications of Diabetes Mellitus; Data Set; Diabetes Mellitus; Diagnostic; Dilatation - action; Disease; Disease Outcome; EFRAC; Early identification; Epidemiology; Event; Excess Mortality; Future; Goals; Hyperglycemia; Immune; Immunologic Factors; Inbred NOD Mice; Individual; Inflammatory; Insulin-Dependent Diabetes Mellitus; Intervention; Lead; Level of Evidence; Life Expectancy; Link; Long-Term Effects; Magnetic Resonance; Measurement; Measures; Mediating; Mediation; Mediator of activation protein; Memory; Metabolic; Modeling; Morbidity - disease rate; Mus; Myocardial Infarction; Myocardial dysfunction; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Participant; Pathway interactions; Patients; Pattern; Phenotype; Plasma; Population-Based Registry; Prevention strategy; Primary Prevention; Process; Risk; Risk Factors; Role; Sampling; Serum; Standardization; Suggestion; T cell response; T-Lymphocyte; Testing; Therapeutic; Time; Up-Regulation; Ventricular; adaptive immunity; atherogenesis; cardiovascular disorder risk; cardiovascular risk factor; cell injury; chemokine; clinical development; cohort; coronary artery calcification; cytokine; diabetes control; follow-up; glycemic control; high risk; immune activation; improved; inflammatory marker; islet; islet cell antibody; mortality; myocardial injury; novel strategies; protein biomarkers; repository; response

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.

项目总结/文摘