Objective
Although our recent findings provide strong evidence that cardiac autoantibodies (AAbs) strongly predict cardiovascular risk in type 1 diabetes (T1D) in the very well-established DCCT/EDIC cohort, the adoption of any new biomarker into risk stratification for clinical trials or into clinical care requires external validation in independent populations. Here, we propose to validate the predictive value of cardiac AAbs for cardiovascular disease (CVD) events in two complementary prospective T1D complications cohorts: 1) The Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO), a large (n=5,777 total) contemporary population-representative cohort with a substantial number of participants having pre-existing or first CVD events (n=644 total); and 2) CACTI, a longstanding, deeply phenotyped U.S.-based T1D cohort with numerous measures of subclinical atherosclerosis, in which we already have obtained promising preliminary results. We will then determine whether the effect of cardiac AAbs on increased risk of CVD in these cohorts is primarily mediated by HLA genetics and particular inflammatory cytokines, instead of traditional risk factors, as was shown in our previous studies.
Background Rationale
Cardiovascular disease (CVD) is the leading cause of premature death in people with T1D, particularly individuals with a history of poor glucose control who can experience a >10-fold increased risk of cardiovascular death compared to the general population. Although it has long been postulated that T1D may carry a unique and specific risk for CVD, relatively little has been known about the risk factors specific to T1D.
T1D is an autoimmune disease that is postulated to arise from an over-zealous immune response to injured islet β-cells. Although the disease is mediated by immune cells (T lymphocytes) the presence of multiple (i.e., ≥2) islet AAbs are strong predictors of the development of T1D. Our group previously showed that injury from a heart attack is associated with aberrant autoimmune responses against the heart in people with T1D, but not those with type 2 diabetes (T2D), suggesting a T1D-specific process. Using stored blood samples from the landmark NIH Diabetes Control and Complications Trial (DCCT), we then showed that poor glucose control, which also causes heart injury, induces the production of cardiac autoantibodies in people with T1D. Very interestingly, the presence of ≥2 cardiac AAbs was associated with a higher risk of serious cardiovascular problems, including heart attacks, decades later. We further found that ≥2 cardiac autoantibodies was associated with increased levels of C-reactive protein, a marker of systemic inflammation, suggesting that inflammation might be the mechanism by which cardiac autoimmunity leads to increased risk for CVD in T1D.
These provocative findings prompted us to identify the nature of the underlying inflammatory process. In more recent studies on ~900 people with T1D followed in the same DCCT/EDIC study, we found that the presence of ≥2 cardiac AAbs was associated with >5-fold increased risk of having a CVD event over the subsequent 7 years. Furthermore, we discovered that individuals with ≥2 cardiac AAbs had extremely elevated levels of a broad range of cytokines – proteins that regulate inflammation and promote the development of CVD. We further found that the increased risk for CVD was mainly due to a particular cytokine that is already known to drive inflammation and cause CVD, and for which inhibitors are available and proven therapeutics in other disease settings. These findings point to the potential role of cardiac autoantibody screening to identify individuals at highest risk for CVD who could benefit from new therapeutic approaches.
Description of Project
Cardiovascular disease (CVD) is the leading cause of premature death in people with type 1 diabetes (T1D), particularly individuals with a history of poor glucose control who can experience a >10-fold increased risk of cardiovascular death compared to the general population. Although it has long been postulated that T1D may carry a unique and specific risk for CVD, little has been known about the risk factors specific to T1D.
Type 1 diabetes is an autoimmune disease that is thought to arise from an over-zealous immune response to injured islet β-cells. Although the disease is mediated by immune cells (T lymphocytes) the presence of multiple (i.e., ≥2) islet autoantibodies are strong predictors of the development of T1D. Our group previously showed that injury from a heart attack is associated with aberrant autoimmune responses against the heart in people with T1D, but not those with type 2 diabetes (T2D), suggesting a T1D-specific process. Using stored blood samples from the landmark NIH Diabetes Control and Complications Trial (DCCT), we then showed that poor glucose control, which also causes heart injury, induces the production of cardiac autoantibodies in people with T1D. Very interestingly, the presence of ≥2 cardiac autoantibodies was associated with a higher risk of serious cardiovascular problems, including heart attacks, decades later. We further found that ≥2 cardiac autoantibodies was associated with increased levels of C-reactive protein, a marker of systemic inflammation, suggesting that inflammation might be the mechanism by which cardiac autoimmunity leads to increased risk for CVD in T1D.
These provocative findings stimulated us to identify the nature of the underlying inflammatory process. In more recent studies on ~900 people with T1D followed in the same DCCT/EDIC study, we found that the presence of ≥2 cardiac autoantibodies was associated with >5-fold increased risk of having a CVD event over the subsequent 7 years. Furthermore, we discovered that individuals with ≥2 cardiac autoantibodies had extremely elevated levels of a broad range of cytokines – proteins that regulate inflammation and promote the development of CVD. We further found that the increased risk for CVD was mainly due to a particular cytokine that is known to drive inflammation and cause CVD, and for which inhibitors are available and proven therapeutics in other disease settings. These findings point to the potential role of cardiac autoantibody screening to identify individuals at highest risk for CVD who could benefit from cytokine inhibitors.
As with the discovery of any new biomarker, we now need to validate our findings in other T1D populations. To this end, we propose to study two well-established complementary T1D complications cohorts: the large (n=4,923), Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO; Dr. Helen Colhoun, PI), that captures 644 individuals with a previous or subsequent first CVD event; and Coronary Artery Calcification in Type 1 Diabetes (CACTI; Dr. Janet Snell-Bergeon, PI), a cohort of adults with T1D (n-638) in the U.S., that has numerous surrogate markers of CVD that could potentially serve as endpoints in future therapeutic trials in T1D.
If this research is successful, these findings could represent a paradigm shift in our understanding of CVD in T1D. Currently, CVD is considered the “same disease” in T1D and T2D, with the approaches to CVD in T1D extrapolated from T2D. Validation of cardiac autoantibodies as robust predictors of CVD in T1D could set the stage for implementing new screening programs to identify individuals at highest risk for CVD outcomes. Confirmation of a linked cytokine-mediated pathway in other well-established T1D cohorts, as is proposed here, could open up the possibility of performing the first-ever immune-targeted (‘precision medicine’) clinical trial to prevent CVD in T1D.
Anticipated Outcome
If this research is successful, these findings could represent a paradigm shift in our understanding of cardiovascular disease (CVD) in type 1 diabetes (T1D). Validation of cardiac autoantibodies as robust predictors of CVD events in other T1D populations could open up the opportunity to implement new screening programs to identify individuals at highest risk for poor CVD outcomes. These highest-risk individuals could then be targeted for more intensive glucose lowering therapies, earlier and more aggressive statin therapy, and other cardioprotective adjunctive therapies. The stage would then also be set for performing cardiovascular intervention trials to investigate new cytokine inhibitors or other new therapies to prevent CVD in T1D.
Relevance to T1D
Currently, CVD is considered the “same disease” in T1D and T2D, with the approaches to CVD in T1D extrapolated from T2D. In contrast to previously studied biomarkers of CVD risk in T1D that have been derived from studies of T2D or the general population and segregate with known risk factors, cardiac autoantibodies are unique in being biomarkers of a pathogenic CVD process specific to T1D. Furthermore, we have shown that the presence of cardiac AAbs is linked to a potentially "druggable pathway" that has been successfully targeted in people with other types of autoimmune diseases. Validation of this pathway in other well-established prospective T1D complications cohorts, as is proposed here, could open up the possibility of performing the first targeted (‘precision medicine’) immune intervention trials to prevent CVD in T1D.