The Missing Link for Cardiovascular Disease in Type 1 Diabetes Mellitus? Hyperglycemia-induced Cardiac Autoimmunity
Much of what is known about the pathogenesis of cardiovascular (CV) disease in individuals with diabetes has come from studies of type 2 diabetes. In fact, the American College of Cardiology ASCVD Risk Estimator Plus1 and previous versions of CV risk calculators by the American College of Cardiology and the American Heart Association do not distinguish between the two major types of diabetes, despite important differences in pathophysiology. Cardiovascular disease in type 1 versus type 2 diabetes has the following important distinctions: presentation at a younger age, women and men are affected equally, high LDL-c, low HDL-c and insulin resistance play a less important role, and coronary involvement tends to be more diffuse with a concentric pattern.2 Results from studies in patients with type 2 diabetes point to a greater role for hypertension, dyslipidemia, and insulin resistance than hyperglycemia to CV risk,3 whereas the long-term follow-up of patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT), Epidemiology of Diabetes Interventions and Complications (EDIC) study, demonstrates a key role for hyperglycemia persisting over 30 years of follow-up.4 In fact, there was a 30% CV disease risk reduction in the intensive treatment group even after more than two decades at a mean hemoglobin A1c (HbA1c) similar to that of the conventional treatment group.4 Although HbA1c is associated with many traditional CV disease risk factors in type 1 diabetes, these only account for approximately 50% of the effect of hyperglycemia on risk for CV disease.5 However, this seems to change over time as individuals with type 1 diabetes age, and the predictive association of mean HbA1c on CV events becomes increasingly mediated by traditional CV risk factors.6 All of this begs the question: What is the role of hyperglycemia in mediating CV disease in type 1 diabetes?
Type 1 diabetes, the immune mediated form of diabetes, results from the body's immune system targeting insulin producing β-cells within the pancreatic islets. It is appreciated that people with type 1 diabetes are at an increased risk for developing other autoimmune disorders, such that the lifetime risk for developing autoimmune thyroid disease is ~20% and approaches 10% for celiac disease (gluten sensitivity).8 There is also accumulating evidence that cardiac autoimmunity develops in type 1 diabetes as well. Following an acute myocardial infarction, individuals with type 1 diabetes have immune responses directed against a self-protein within the myocardium, α-cardiac myosin, consisting of inflammatory T-cell responses and antibodies directed against this protein.9 Importantly, individuals without diabetes and persons with type 2 diabetes do not have these immune responses post-myocardial infarction, indicating that type 1 diabetes patients have an 'inflamed heart' following an acute coronary event. Sousa and colleagues build upon these findings in their recent article, "Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus".7 By measuring antibodies directed against α-cardiac myosin and other cardiac muscle proteins in the peripheral blood prior to a CV disease event, they show that these autoantibodies are more prevalent in type 1 diabetes patients who have poor glycemic control as defined by HbA1c ≥9.0%. Interestingly, the presence of autoantibodies was very low to nonexistent in people with type 1 diabetes having a HbA1c ≤7.0% and those with type 2 diabetes. Furthermore, the presence of multiple cardiac autoantibodies (≥2) was associated with higher coronary artery calcium (CAC) scores, a marker of coronary atherosclerosis, and higher levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation.
These studies outlined by Sousa, et al. are provocative and hypothesis-generating, demonstrating a possible association between cardiac autoimmunity and CV disease events using samples and clinical history from a subset of subjects in the DCCT/EDIC as well as a carefully chosen set of controls.7 Subjects with type 1 diabetes and cardiac autoantibodies were found to have a higher risk of a variety of CV disease events including coronary artery bypass graft, CV death, nonfatal myocardial infarction, and heart failure, which developed up to 26 years after the first autoantibody was detected. Surprisingly, hyperglycemia per se was insufficient for development of cardiac autoimmunity, since subjects with type 2 diabetes did not exhibit cardiac autoimmunity. In addition, DCCT/EDIC subjects with hyperglycemia exhibited cardiac autoimmunity similar to that found in the subjects with chronic Chagas disease, who develop a cardiomyopathy mediated by proinflammatory CD4+ T-cells reactive to cardiac myosin, but without hyperglycemia. These lines of evidence point to a central role for hyperglycemia induced cardiac autoimmunity as a potential novel mechanism for increased CV disease risk in type 1 diabetes. A major limitation with these studies was the small number of CV disease events in the cohort of patients studied. However, the findings strongly implicate chronic hyperglycemia in the pathogenesis of accelerated coronary artery disease in type 1 diabetes. Furthermore, the results provide more evidence for achieving optimal glycemic control in type 1 diabetes patients.
Hyperglycemia in type 1 diabetes likely results in increased CV risk through multiple diverse mechanisms including cardiovascular autonomic neuropathy10; however, the current study suggests a novel mechanism by which hyperglycemia in type 1 diabetes may lead to increased CV risk through induction of cardiac autoimmunity, and will require further investigations to confirm this observation. If this finding is confirmed in a larger cohort, new biomarkers could be developed to predict CV risk, and innovative therapeutic approaches targeting this mechanism could reduce CV risk in type 1 diabetes mellitus. Where does this leave us for future investigations? Validation of cardiac autoantibodies as biomarkers of CV disease events is needed, and answers to the following questions, among many others: Does improving glycemic control decrease markers of cardiac autoimmunity? Do other therapies such as statins or the newer anti-diabetic agents reduce cardiac autoimmunity? Is this the missing link we have been searching for, and is immunologic intervention required to reduce the burden of CV disease in type 1 diabetes?
- American College of Cardiology. ASCVD Risk Estimator Plus. March 2019. Available at: http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/. Accessed May 24, 2019.
- de Ferranti SD, de Boer IH, Fonseca V, et al. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care 2014;37:2843-63.
- Low Wang CC, Hess CN, Hiatt WR, Goldfine AB. Clinical Update: Cardiovascular Disease in Diabetes Mellitus: Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes Mellitus Mechanisms, Management, and Clinical Considerations. Circulation 2016;133:2459-502.
- Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study Research Group. Intensive Diabetes Treatment and Cardiovascular Outcomes in Type 1 Diabetes: The DCCT/EDIC Study 30- Year Follow-up. Diabetes Care 2016;39:686-93.
- Bebu I, Braffett BH, Orchard TJ, Lorenzi GM, Lachin JM,DCCT/EDIC Research Group. Mediation of the Effect of Glycemia on the Risk of CVD Outcomes in Type 1 Diabetes: The DCCT/EDIC Study. Diabetes Care 2019;42:1284-89 Mar20 Epub
- Bebu I, Braffett BH, Pop-Busui R, et al. The relationship of blood glucose with cardiovascular disease is mediated over time by traditional risk factors in type 1 diabetes: the DCCT/EDIC study. Diabetologia 2017;60:2084-91.
- Sousa GR, Pober D, Galderisi A, et al. Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus. Circulation 2019;139:730-43.
- Hughes JW, Riddlesworth TD, DiMeglio LA, Et al. Autoimmune Diseases in Children and Adults With Type 1 Diabetes From the T1D Exchange Clinic Registry. J Clin Endocrinol Metab 2016 ;101:4931-37.
- Gottumukkala RV, Lv H, Cornivelli L, et al. Myocardial infarction triggers chronic cardiac autoimmunity in type 1 diabetes. Sci Transl Med 2012;4:138ra80.
- Pop-Busui R, Braffett BH, Zinman B, et al. Cardiovascular Autonomic Neuropathy and Cardiovascular Outcomes in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Diabetes Care 2017;40:94- 100.
Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Invasive Cardiovascular Angiography and Intervention, Prevention, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Heart Failure, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Interventions and Coronary Artery Disease, Hypertension
Keywords: Metabolic Syndrome X, Hemoglobin A, Diabetes Mellitus, Type 1, Diabetes Mellitus, Type 2, Coronary Artery Disease, Hydroxymethylglutaryl-CoA Reductase Inhibitors, C-Reactive Protein, Risk Factors, Autoantibodies, Insulin Resistance, American Heart Association, Celiac Disease, Cardiac Myosins, Autoimmunity, CD4-Positive T-Lymphocytes, Hyperglycemia, Blood Glucose, Insulin, Myocardial Infarction, Coronary Artery Bypass, Myocardium, Heart Failure, Dyslipidemias, Cardiomyopathies, Hypertension, Risk Reduction Behavior, Inflammation, Chagas Disease, Thyroid Diseases, Glutens, Cohort Studies, Epidemiologic Studies
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