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Circulation. 2019 Feb 5;139(6):730-743. doi: 10.1161/CIRCULATIONAHA.118.036068.

Glycemic Control, Cardiac Autoimmunity, and Long-Term Risk of Cardiovascular Disease in Type 1 Diabetes Mellitus.

Author information

1
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA (G.R.S., D.P., A.G., H.L., A.D., M.A.L.).
2
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (G.R.S., H.L., A.D., M.A.L.).
3
Department of Pediatrics, Yale University, New Haven, CT (A.G.).
4
Department of Women and Children's Health, University of Padova, Italy (A.G.).
5
Barbara Davis Center for Childhood Diabetes, University of Colorado, Anschutz Medical Campus, Aurora (L.Y.).
6
Laboratory of Genetics and Molecular Cardiology, Heart Institute, University of Sao Paulo, Brazil (A.C.P.).
7
Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City (M.K.).

Abstract

BACKGROUND:

Poor glycemic control is associated with increased risk of cardiovascular disease (CVD) in type 1 diabetes mellitus (T1DM); however, little is known about mechanisms specific to T1DM. In T1DM, myocardial injury can induce persistent cardiac autoimmunity. Chronic hyperglycemia causes myocardial injury, raising the possibility that hyperglycemia-induced cardiac autoimmunity could contribute to long-term CVD complications in T1DM.

METHODS:

We measured the prevalence and profiles of cardiac autoantibodies (AAbs) in longitudinal samples from the DCCT (Diabetes Control and Complications Trial) in participants with mean hemoglobin A1c (HbA1c) ≥9.0% (n=83) and ≤7.0% (n=83) during DCCT. We assessed subsequent coronary artery calcification (measured once during years 7-9 in the post-DCCT EDIC [Epidemiology of Diabetes Interventions and Complications] observational study), high-sensitivity C-reactive protein (measured during EDIC years 4-6), and CVD events (defined as nonfatal myocardial infarction, stroke, death resulting from CVD, heart failure, or coronary artery bypass graft) over a 26-year median follow-up. Cardiac AAbs were also measured in matched patients with type 2 diabetes mellitus with HbA1c ≥9.0% (n=70) and ≤7.0% (n=140) and, as a control for cardiac autoimmunity, patients with Chagas cardiomyopathy (n=51).

RESULTS:

Apart from HbA1c levels, the DCCT groups shared similar CVD risk factors at the beginning and end of DCCT. The DCCT HbA1c ≥9.0% group showed markedly higher cardiac AAb levels than the HbA1c ≤7.0% group during DCCT, with a progressive increase and decrease in AAb levels over time in the 2 groups, respectively ( P<0.001). In the HbA1c ≥9.0% group, 46%, 22%, and 11% tested positive for ≥1, ≥2, and ≥3 different cardiac AAb types, respectively, similar to patients with Chagas cardiomyopathy, compared with 2%, 1%, and 0% in the HbA1c ≤7.0% group. Glycemic control was not associated with AAb prevalence in type 2 diabetes mellitus. Positivity for ≥2 AAbs during DCCT was associated with increased risk of CVD events (4 of 6; hazard ratio, 16.1; 95% CI, 3.0-88.2) and, in multivariable analyses, with detectable coronary artery calcification (13 of 31; odds ratio, 60.1; 95% CI, 8.4-410.0). Patients with ≥2 AAbs subsequently also showed elevated high-sensitivity C-reactive protein levels (6.0 mg/L versus 1.4 mg/L in patients with ≤1 AAbs; P=0.003).

CONCLUSIONS:

Poor glycemic control is associated with cardiac autoimmunity in T1DM. Furthermore, cardiac AAb positivity is associated with an increased risk of CVD decades later, suggesting a role for autoimmune mechanisms in the development of CVD in T1DM, possibly through inflammatory pathways.

KEYWORDS:

autoantibodies; biomarkers; cardiovascular diseases; diabetes mellitus; hyperglycemia

PMID:
30586738
PMCID:
PMC6361693
[Available on 2020-02-05]
DOI:
10.1161/CIRCULATIONAHA.118.036068

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