Giovane R Sousa1,2, David Pober1, Alfonso Galderisi1,3,4, HuiJuan Lv1,2, Liping Yu5, Alexandre C Pereira6, Alessandro Doria1,2, Mikhail Kosiborod7, Myra A Lipes1,2. 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.
RCT Entities:
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.
Authors: Sarah D de Ferranti; Ian H de Boer; Vivian Fonseca; Caroline S Fox; Sherita Hill Golden; Carl J Lavie; Sheela N Magge; Nikolaus Marx; Darren K McGuire; Trevor J Orchard; Bernard Zinman; Robert H Eckel Journal: Circulation Date: 2014-08-11 Impact factor: 29.690
Authors: MyLinh Dang; Jennifer Rockell; Rebecca Wagner; Janet M Wenzlau; Liping Yu; John C Hutton; Peter A Gottlieb; Howard W Davidson Journal: J Immunol Date: 2011-04-06 Impact factor: 5.422
Authors: Giovane R Sousa; David Pober; Alfonso Galderisi; HuiJuan Lv; Liping Yu; Alexandre C Pereira; Alessandro Doria; Mikhail Kosiborod; Myra A Lipes Journal: Circulation Date: 2019-02-05 Impact factor: 29.690
Authors: Matthew DeBerge; Shuangjin Yu; Shirley Dehn; Igal Ifergan; Xin Yi Yeap; Mallory Filipp; Amanda Becker; Xunrong Luo; Stephen Miller; Edward B Thorp Journal: Am J Physiol Heart Circ Physiol Date: 2019-12-06 Impact factor: 4.733
Authors: Teresa Salvatore; Pia Clara Pafundi; Raffaele Galiero; Gaetana Albanese; Anna Di Martino; Alfredo Caturano; Erica Vetrano; Luca Rinaldi; Ferdinando Carlo Sasso Journal: Front Med (Lausanne) Date: 2021-06-30
Authors: Kari Anne Sveen; Kristine Bech Holte; Mona Svanteson; Kristian F Hanssen; Jan Nilsson; Eva Bengtsson; Tore Julsrud Berg Journal: Diabetes Care Date: 2021-04-15 Impact factor: 19.112