Hyperglycemia in type 1 diabetes may drive cardiac autoimmunity
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Hyperglycemia is associated with the presence of multiple cardiac antibody types among people with type 1 diabetes, suggesting a novel mechanism for increased cardiovascular risk specific to the disease, according to a speaker.
Adults with type 1 diabetes have a five- to tenfold increased risk for CV events compared with the general population, particularly those with type 1 diabetes and high glucose levels, Myra A. Lipes, MD, an investigator in the section on immunobiology at Joslin Diabetes Center and an assistant professor of medicine at Harvard Medical School, said during an online presentation at the virtual Heart in Diabetes conference. In contrast with type 2 diabetes, hyperglycemia is the strongest modifiable risk factor for CVD in type 1 diabetes; traditional risk factors explain less than half of the excess CV risk.
“It has long been postulated that type 1 diabetes may carry a unique and specific risk for CVD,” Lipes said.
After models demonstrated myocardial infarction induced the production of cardiac antibodies in mice with type 1 diabetes, Lipes and colleagues developed assays for a panel of cardiac autoantibodies and found evidence of cardiac autoimmunity among people with type 1 diabetes after MI.
“We then discovered alpha-myosin is really the main cardiac target of anti-cardiac immune response,” Lipes said. “Furthermore, there was positivity for more than one antibody in 83% of patients with type 1 diabetes post-MI ... vs. 15% for those with type 2 [diabetes] post-MI.”
From such studies, Lipes said researchers generated a hypothesis: Hyperglycemia may represent a separate form of injury that can induce autoimmunity in type 1 diabetes.
“The hypothesis was that subclinical myocardial injury from chronic hyperglycemia would lead to leakage and exposure of heart muscle proteins, and patients with type 1 diabetes would then develop a dysfunctional T-cell response to alpha-myosin,” Lipes said. “This would drive the production of cardiac autoantibodies and subclinical myocardial inflammation and further heart damage, in a vicious cycle.”
Testing the hypothesis
The landmark Diabetes Control and Complications Trial (DCCT) — which tested whether an intensive treatment regimen designed to maintain blood glucose concentrations as close to normal as possible would affect appearance or progression of early vascular complications in type 1 diabetes — provided an ideal opportunity to test this hypothesis, Lipes said. Long-term data on these participants, who were young and free of CVD at baseline, were available from the follow-up Epidemiology of Diabetes Interventions and Complications (EDIC) study (mean diabetes duration, 28 years; mean age, 49 years).
Lipes and colleagues measured autoantibodies to five myocardial antigens at the time of
cardiac magnetic resonance imaging (CMR) among 892 EDIC participants without any known CV events. Within the cohort, 146 participants had cardiac autoantibodies, with 102 (11%) positive for one autoantibody and 44 (5%) positive for at least two autoantibodies.
The researchers found that although the recent HbA1c levels were similar among participants with and without cardiac autoantibodies, the presence of cardiac autoantibodies identified those with worse glycemic control in the past, suggesting that cardiac autoantibodies are markers of long-term glycemic exposure.
In analyses stratified by numbers of circulating autoantibodies, researchers found that participants with more autoantibody types had more pronounced changes to the heart. The findings were published in the March issue of Circulation.
“The impact of hyperglycemia on cardiac autoimmunity was shown by several striking findings,” Lipes said. “First, we found markedly greater numbers of autoantibodies in the HbA1c greater than 9% group compared with the less than 7% group ... 46% of subjects had more than one antibody, 22% had greater than two antibodies, vs. only 2% and 1%, respectively, in the HbA1c less than 7% group. No subject in the HbA1c less than 7% group had three or more antibodies.”
Secondly, and unexpectedly, researchers observed similar profiles when comparing the DCCT participants with an HbA1c of at least 9% with a separate cohort with heart failure from Chagas cardiomyopathy that is believed to be driven by a form of chronic myocarditis with autoimmunity against alpha-myosin, Lipes said.
“In contrast, the DDCT low HbA1c group resembled control subjects,” Lipes said. “Importantly, there was no relationship between glycemic control and cardiac antibodies in a cohort of people with type 2 diabetes and comparable glycemic control.”
Lipes said perhaps the most striking finding was that DCCT participants with the highest titers and numbers of cardiac autoantibodies developed CVD events up to 26 years later. A single, fatal CV event occurred in the only DCCT participant to test positive for all five antibodies, she said.
Inflammation clues
Analyses stratified by number of cardiac autoantibodies also showed that the presence of two autoantibodies was also associated with a threefold increased high sensitivity C-reactive protein (CRP) level, with a median level of 6 mg/L among those with two or more autoantibodies vs. a median high sensitivity CRP of 1.4 mg/L among participants with one or fewer antibodies.
“This suggested that subclinical inflammation may link cardiac autoantibodies to CVD outcomes,” Lipes said.
Lipes noted that primary CV outcomes were a composite of atherosclerotic CV events, not cardiomyopathy or HF. Larger-scale studies involving the entire DCCT and EDIC cohorts with more CV events are pending, she said.
Reference:
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Lipes MA. Glycemic control, cardiac autoimmunity and long-term risk of CVD in T1DM. Presented at: Heart in Diabetes CME Conference; Aug. 21- 24, 2020, 2019; (virtual meeting).
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