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.
The proposed studies will be the first to examine the role of autoimmunity in the pathogenesis of CVD in the DCCT/EDIC study cohort. To this end, we will determine whether markers of cardiac autoimmunity are associated with poor CVD outcomes using samples and clinical datasets from the NIDDK Central Repository.
| Sousa, Giovane R; Pober, David; Galderisi, Alfonso et al. (2018) Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus: A DCCT/EDIC Cohort-Based Study. Circulation : |
