People with type 1 diabetes, especially those with poor glycemic control, are at a very increased risk for cardiovascular disease than the general population. Even more confusing, in individuals with type 1 diabetes, many cardiovascular risk factors are not in line with known risk factors associated with type 2 diabetes.
Dr. Myra Lipes, Investigator in the Immunobiology Section at the Joslin Diabetes Center at Harvard Medical School, has worked for more than a decade to understand what causes an increased risk of cardiovascular disease in patients with type 1 diabetes and what can be done about that.
Heart failure in particular has recently been recognized as an important type 1 complication with a national register-based study that shows a tenfold increase in the risk of heart failure in individuals with poor glycemic control. In addition, there is a higher case fatality rate in type 1 diabetes than in type 2 diabetes, which suggests different mechanisms for heart failure might be involved in type 1 diabetes.
Myra Lipes, Investigator in the Immunobiology Section at the Joslin Diabetes Center at Harvard Medical School
Given the burden of heart failure in type 1 diabetes, early identification of patients with certain risks is very important.
New research from Dr.’s lab Lipes in Joslin showed that in people with type 1 diabetes without known cardiovascular disease, the presence of autoantibodies to cardiac muscle protein is associated with evidence of cardiac magnetic resonance imaging (CMR) that shows an increase in left ventricular volume (the main heart pumping chamber), increased muscle mass and reduced pumping function (ejection fraction), a feature associated with a higher risk of failure in the general population. This new study was published in Circulation.
Antibodies are usually produced by the immune system and circulate in the blood, playing an important role in the body’s defense against infection. In people who tend to be autoimmune, the body misidentifies its own protein as a threat and attack. This is what happens with type 1 diabetes – the immune system thinks the pancreatic beta cells are the invaders and destroy them. In this situation, antibodies are called autoantibodies. So, it might not be too surprising that this type 1 diabetes complication also involves an incorrect immune response to heart muscle cells.
Previous studies conducted by Dr. Lipes has shown that a mouse model of type 1 diabetes develops dilated cardiomyopathy (weakened heart muscle) and premature heart failure associated with the presence of autoantibodies directed against cardiac muscle protein. His group also showed that poor glycemic control in patients with type 1 diabetes – but not in those with type 2 diabetes – was associated with cardiac autoimmunity. Unexpected findings are similar rates of cardiac autoantibodies in patients with type 1 diabetes, who are young and without diabetes complications, and a cohort of heart failure with Chagas cardiomyopathy, which is thought to be caused by chronic inflammation of the heart muscle (“myocarditis”), increasing the likelihood of dysfunction myocardial associated subclinical autoimmune in type 1 diabetes “said Dr. Lipes.
In this study, Lipes wanted to determine whether the widening cardiac phenotype seen in mouse models and Chagas patients was also present in people with type 1 diabetes who have this circulating autoantibody. He and his team used data collected from participants involved in the Diabetes Control and Complications (DCCT) study post-Diabetes Epidemiology Intervention and Complications (EDIC) follow-up studies, and consisted of people who had type 1 diabetes for an average of 28 year. As part of this study, participants were imaged with CMR, a gold standard noninvasive imaging technique to assess the structure and function of the heart.
“In this study, we measured autoantibodies against cardiac muscle protein in blood samples taken from CMR imaging in 892 EDIC participants without known cardiovascular disease,” Lipes said. “And then we examined where the presence of heart antibodies was associated with CMR evidence of myocardial dysfunction.”
They found that although recent A1c levels were similar in participants with and without cardiac autoantibodies, the presence of cardiac autoantibodies identified patients with worse glycemic control in the past, indicating that cardiac autoantibodies were a marker of long-term glycemic exposure. In addition, they found that CMR scanning of people with two or more autoantibodies showed an enlarged heart. They sorted patients into categories based on the number of circulating autoantibodies, which indicates that people with more of these specific autoantibodies have clearer changes in the heart. This finding did not weaken after adjusting for traditional cardiovascular risk factors, suggesting this change was mainly due to cardiac autoimmunity.
They know from previous research that the heart can have structural and functional changes related to the metabolic problems of diabetes itself; However, this relationship is relatively simple. For example, higher A1C levels are associated with slightly smaller left ventricular volume that is not clinically significant. But this research shows that higher A1C levels can trigger additional autoimmune responses that damage the heart in different and clearer ways that lead to enlargement and worse function, features that are known to be associated with a higher risk of heart failure.
“This points to a new process that involves the heart and is associated with poor glycemic control in type 1 diabetes,” Lipes said.
Because cardiac autoantibodies can be detected in a simple blood test, this study opens new avenues for detecting potential heart failure in patients with type 1 diabetes.
“Given the high burden of heart failure in type 1 diabetes, heart antibodies can allow early identification of people at higher risk of heart failure,” Lipes said. “And, of course, understanding the main causes of heart failure is important because it can lead to therapeutic approaches that are targeted at improving outcomes in these patients.”
Sousa, G.R., et al. (2020) Cardiac Immunity Associated with Subclinical Myocardial Dysfunction in Type 1 Diabetes Mellitus Patients. Circulation. doi.org/10.1161/CIRCULATIONAHA.119.044539.