Autoantibodies Against Methylglyoxal-Modified Apolipoprotein B100 and ApoB100 Peptide Are Associated With Less Coronary Artery Atherosclerosis and Retinopathy in Long-Term Type 1 Diabetes.

OBJECTIVE: Methylglyoxal (MGO), a reactive aldehyde forming advanced glycation end products (AGEs), is increased in diabetes and recognized by the immune system, resulting in anti-AGE-specific autoantibodies. The association of these immune responses with macro- and microvascular complications in type 1 diabetes remains unclarified. We investigated associations between MGO-modified apolipoprotein B100 (apoB100) and apoB100 peptide 5 (MGO-p5) autoantibodies and coronary atherosclerosis and retinopathy in type 1 diabetes. RESEARCH DESIGN AND METHODS: IgM and IgG against MGO-apoB100 and MGO-p5 were measured by ELISA in plasma from 103 subjects with type 1 diabetes and 63 control subjects (Dialong study) and in a replication cohort of 27 subjects with type 1 diabetes (Oslo study). Coronary atherosclerosis was assessed by computed tomography coronary angiography or intravascular ultrasound. Retinopathy was classified by retinal photos. RESULTS: MGO-apoB100 IgM and MGO-p5 IgM levels were higher in subjects with diabetes with no coronary artery stenosis compared with subjects with significant stenosis (median [interquartile range]: 96.2 arbitrary units [AU] [71-126.8] vs. 54 AU [36.1-85.4], P = 0.003 for MGO-apoB100; and 77.4 AU [58-106] vs. 36.9 AU [28.9-57.4], P = 0.005 for MGO-p5). MGO-apoB100 IgM and MGO-p5 IgM were associated with less severe coronary stenosis after adjusting for confounders (odds ratio 0.2 [95% CI 0.05-0.6], P = 0.01; and 0.22 [0.06-0.75], P = 0.02). The inverse association of MGO-p5 IgM and coronary stenosis was confirmed in the replication cohort. Subjects with proliferative retinopathy had significantly lower MGO-apoB100 IgM and MGO-p5 IgM than those with background retinopathy. CONCLUSIONS: Autoantibodies against AGE-modified apoB100 are inversely associated with coronary atherosclerosis and proliferative retinopathy, suggesting vascular protective effects of these autoantibodies in type 1 diabetes.

Collagen methionine sulfoxide and glucuronidine/LW-1 are markers of coronary artery disease in long-term survivors with type 1 diabetes. The Dialong study.

OBJECTIVES: Type 1 diabetes is a risk factor for coronary heart disease. The underlying mechanism behind the accelerated atherosclerosis formation is not fully understood but may be related to the formation of oxidation products and advanced glycation end-products (AGEs). We aimed to examine the associations between the collagen oxidation product methionine sulfoxide; the collagen AGEs methylglyoxal hydroimidazolone (MG-H1), glucosepane, pentosidine, glucuronidine/LW-1; and serum receptors for AGE (RAGE) with measures of coronary artery disease in patients with long-term type 1 diabetes. METHODS: In this cross-sectional study, 99 participants with type 1 diabetes of ≥ 45-year duration and 63 controls without diabetes had either established coronary heart disease (CHD) or underwent Computed Tomography Coronary Angiography (CTCA) measuring total, calcified and soft/mixed plaque volume. Skin collagen methionine sulfoxide and AGEs were measured by liquid chromatography-mass spectrometry and serum sRAGE/esRAGE by ELISA. RESULTS: In the diabetes group, low levels of methionine sulfoxide (adjusted for age, sex and mean HbA1c) were associated with normal coronary arteries, OR 0.48 (95% CI 0.27-0.88). Glucuronidine/LW-1 was associated with established CHD, OR 2.0 (1.16-3.49). MG-H1 and glucuronidine/LW-1 correlated with calcified plaque volume (r = 0.23-0.28, p<0.05), while pentosidine correlated with soft/mixed plaque volume (r = 0.29, p = 0.008), also in the adjusted analysis. CONCLUSIONS: Low levels of collagen-bound methionine sulfoxide were associated with normal coronary arteries while glucuronidine/LW-1 was positively associated with established CHD in long-term type 1 diabetes, suggesting a role for metabolic and oxidative stress in the formation of atherosclerosis in diabetes.

Effects of long-term statin-treatment on coronary atherosclerosis in patients with inflammatory joint diseases.

BACKGROUND: The effect of statins over time on coronary atherosclerosis in patients with inflammatory joint diseases (IJD) is unknown. Our aim was to evaluate the change in coronary plaque morphology and volume in long-term statin-treated patients with IJD. METHODS: Sixty-eight patients with IJD and carotid artery plaque(s) underwent coronary computed tomography angiography before and after a mean of 4.7 (range 4.0-6.0) years of statin treatment. The treatment target for low density lipoprotein cholesterol (LDL-c) was ≤1.8 mmol/L. Changes in plaque volume (calcified, mixed/soft and total) and coronary artery calcification (CAC) from baseline to follow-up were assessed using the 17-segment American Heart Association-model. RESULTS: Median (IQR) increase in CAC after statin treatment was 38 (5-236) Agatston units (p<0.001). Calcified and total plaque volume increased with 5.6 (0.0-49.1) and 2.9 (0.0-23.5) mm3, respectively (p<0.001 for both). The median (IQR) change in soft/mixed plaque volume was -10 (-7.1-0.0), p = <0.001. Patients who had obtained the LDL-c treatment target at follow-up, experienced reduced progression of both CAC and total plaque volume compared to patients with LDL-c >1.8mmol/L (21 [2-143] vs. 69 [16-423], p = 0.006 and 0.65 [-1.0-13.9] vs. 13.0 [0.0-60.8] mm3, p = 0.019, respectively). CONCLUSIONS: A progression of total atherosclerotic plaque volume in statin-treated patients with IJD was observed. However, soft/mixed plaque volume was reduced, suggesting an alteration in plaque composition. Patients with recommended LDL-c levels at follow-up had reduced atherosclerotic progression compared to patients with LDL-c levels above the treatment target, suggesting a beneficial effect of treatment to guideline-recommended lipid targets in IJD patients.

Coronary plaque characteristics and epicardial fat tissue in long term survivors of type 1 diabetes identified by coronary computed tomography angiography.

OBJECTIVES: The aim was to assess coronary atherosclerosis, plaque morphology and associations to cardiovascular risk factors and epicardial adipose tissue (EAT) in patients with long duration of type 1 diabetes mellitus (T1DM). MATERIALS AND METHODS: Eighty-eight patients with ≥ 45 year T1DM duration and 60 controls underwent coronary CT angiography (CCTA) for evaluation of coronary artery plaque volume (total, calcified or mixed/soft), coronary artery calcification score (CAC) and EAT. RESULTS: Plaques were detected in 75 (85%) T1DM patients and 28 (47%) controls, p < 0.01. Median (interquartile range) plaque volume (mm3) in T1DM vs. controls was: 21.0 (1.0-66.0) vs. 0.2 (0.0-7.1), p < 0.01 for calcified, 0.0 (0.0-8.7) vs. 0.0 (0.0-0.0), p < 0.01 for soft/mixed and 29.5 (3.9-95.8) vs. 0.4 (0.0-7.4), p < 0.01 for total plaque volume. Median CAC was 128 (13-671) vs. 1 (0.0-39.0), p < 0.01 in T1DM vs. controls. Median EAT volume did not differ between the groups; 52.3 (36.1-65.5) cm3 vs. 55 (38.3-79.6), p = 0.20. No association between CAC or plaque volumes and EAT were observed. Low time-weighted LDL-cholesterol and HbA1c for 30 years were associated with having plaque volume < 25th percentile, OR (95% CI) 0.18 (0.05-0.70), p = 0.01 and 0.45 (0.20-1.00), p < 0.05, respectively. Time-weighted LDL-c was linearly associated with CAC (beta 0.82 (95% CI 0.03-1.62), p = 0.04) and total plaque volume (beta 0.77 (95% CI 0.19-1.36), p = 0.01). CONCLUSION: Long-term survivors of T1DM have a higher prevalence of coronary atherosclerosis compared to controls. Low LDL-cholesterol and HbA1c over time have a protective effect on coronary atherosclerosis. EAT volume was not associated with coronary atherosclerosis in T1DM patients.

Undiagnosed coronary artery disease in long-term type 1 diabetes. The Dialong study.

AIMS: We studied the total prevalence of obstructive coronary artery disease (CAD), undiagnosed CAD and absent CAD in persons with ≥45-year duration of type 1 diabetes (T1D) versus controls, and associations with mean HbA1c, LDL-cholesterol and blood pressure over 2-3 decades. METHODS: We included 76% (n = 103) of all persons with T1D diagnosed ≤1970 attending a diabetes center and 63 controls without diabetes. We collected 20-30 years of HbA1c, LDL-cholesterol and blood pressure measurements. Participants without previously diagnosed coronary heart disease (CHD) underwent Computed Tomography Coronary Angiography (CTCA). Undiagnosed obstructive CAD was defined as any coronary stenosis >50% on CTCA, absent CAD as no detected plaque, and total obstructive CAD as either obstructive CAD on CTCA or previous CHD diagnosis. RESULTS: The prevalence of undiagnosed, absent and obstructive CAD was 24% (21/88), 16% (14/88) and 35% (36/103) in T1D versus 10% (6/60), 50% (30/60) and 14% (9/63) in controls (all p < 0.05). Mean HbA1c was associated with undiagnosed obstructive CAD (OR 2.30 95% C.I. 1.13-4.69), while mean LDL-cholesterol was inversely associated with absent CAD (0.12, 0.04-0.43). CONCLUSIONS: The prevalence of undiagnosed obstructive CAD was high (24%) in this cohort of long-term survivors with T1D. Mean LDL-cholesterol and HbA1c were associated with CAD.

Associations between coronary and carotid artery atherosclerosis in patients with inflammatory joint diseases.

OBJECTIVE: Low association between cardiac symptoms and coronary artery disease (CAD) in patients with inflammatory joint diseases (IJD) demands for objective markers to improve cardiovascular risk stratification. Our main aim was to evaluate the prevalence and characteristics of CAD in patients with IJD with carotid artery plaques. Furthermore, we aimed to assess associations of carotid ultrasonographic findings and coronary plaques. METHODS: Eighty-six patients (61% female) with IJD (55 with rheumatoid arthritis, 21 with ankylosing spondylitis and 10 with psoriatic arthritis) and carotid artery plaque were referred to coronary CT angiography (CCTA). CAD was evaluated using the modified 17-segment American Heart Association model. Calcium score, plaque composition, segment involvement score and segment stenosis score were assessed and correlated to the carotid artery plaques and cardiovascular disease risk factors in logistic and linear regression analyses. Risk prediction models were tested with various cut-off values for associating variables. RESULTS: Fifty-five patients (66%) had CAD assessed by CCTA and 36 (43%) of these had coronary plaques defined as either mixed or soft. Eleven patients (13%) had obstructive CAD. The best risk prediction model (area under the curve: 0.832, 95% CI 0.730 to 0.935) included the combination of variables with cut-off values: age ≥55 years (OR: 12.18, 95% CI 2.80 to 53.05), the carotid-intima media thickness ≥0.7 mm (OR: 4.08, 95% CI 1.20 to 13.89) and carotid plaque height ≥1.5 mm (OR: 8.96, 95% CI 1.68 to 47.91), p<0.05. CONCLUSION: Presence of carotid plaque is alone not sufficient to identify patients at risk for CAD, and a combination of ultrasonographic measurements may be useful in risk stratification of patients with IJD. TRIAL REGISTRATION NUMBER: NCT01389388, Results.