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Background: The cholesterol efflux capacity of high density lipoprotein (HDL) is negatively associated with cardiovascular risk. Small HDL particles account almost quantitatively for cholesterol efflux capacity, perhaps mediated through efflux of cholesterol and outer leaflet plasma membrane phospholipids by ABCA1 (ATP binding cassette subfamily A member 1). People with type 1 diabetes are at increased coronary artery disease (CAD) risk despite normal HDL-cholesterol concentrations. We therefore tested the hypothesis that small HDL particles (HDL-P)-rather than HDL-cholesterol-predict incident CAD in type 1 diabetes., Methods and Results: Incident CAD (CAD death, myocardial infarction, or coronary revascularization) was determined in 550 individuals with childhood-onset type 1 diabetes. HDL-P was quantified by calibrated ion mobility analysis and cholesterol efflux capacity was quantified with validated assays. During a median follow-up of 26 years, 36.5% of the participants developed incident CAD, for an incidence density of 181.3 per 10 000 person-years. In multivariable Cox models, neither HDL-cholesterol nor apolipoprotein A1 concentration was significantly associated with CAD risk. In contrast, higher extra-small HDL-P concentrations were significantly associated with decreased CAD risk (hazard ratio [HR], 0.26 [95% CI, 0.14-0.50]). Weaker associations were observed for total HDL-P (HR, 0.88 [95% CI, 0.83-0.93]), small HDL (HR, 0.83 [95% CI, 0.68-1.02]), medium HDL (HR, 0.79 [95% CI, 0.71-0.89]), and large HDL (HR, 0.72 [95% CI, 0.59-0.89]). Although cholesterol efflux capacity was negatively associated with incident CAD, this association was no longer significant after adjustment for total HDL-P., Conclusions: Lower concentrations of total HDL-P and HDL subpopulations were positively associated with incident CAD independently of HDL-cholesterol, apolipoprotein A1, and other common CVD risk factors. Extra-small HDL was a much stronger predictor of risk than the other HDLs. Our data are consistent with the proposal that extra-small HDL plays a critical role in cardioprotection in type 1 diabetes, mediated by macrophage cholesterol efflux by the ABCA1 pathway.

Background: In type 1 diabetes, women lose their relative protection (compared to men) against coronary artery disease (CAD), while high-density lipoprotein cholesterol (HDL-C) is less strongly associated with lower CAD risk in women., Objective: We aimed to assess whether sex differences in the HDL particle concentration (HDL-P) and cholesterol efflux capacity (CEC) association with CAD may explain these findings., Methods: HDL-P (calibrated differential ion mobility analysis) and total and ATP binding cassette transporter A1 (ABCA1)-specific CEC were quantified among 279 men and 271 women with type 1 diabetes (baseline mean age 27·8 years; diabetes duration, 19·6 years). Clinical CAD was defined as CAD death, myocardial infarction and/or coronary revascularization., Results: Women had higher large HDL-P levels and marginally lower concentrations of small HDL-P and ABCA1-specific CEC than men. No sex differences were observed in extra-small HDL-P, medium HDL-P and total CEC. During a median follow-up of 26 years, 37·6 % of men and 35·8 % of women developed CAD (p = 0·72). In multivariable Cox models stratified by sex (p Total HDL-P x sex interaction =0·01), HDL-P was negatively associated with CAD incidence in both sexes. However, associations were stronger in men, particularly for extra-small HDL-P (hazard ratio (HR) men =0·11, 95 % confidence interval (CI): 0·04-0·30; HR women =0·68, 95 % CI: 0·28-1·66; p interaction =0·001). CEC did not independently predict CAD in either sex., Conclusion: Despite few absolute differences in HDL-P concentrations by sex, the HDL-P - CAD association was weaker in women, particularly for extra-small HDL-P, suggesting that HDL-P may be less efficient in providing atheroprotection in women and perhaps explaining the lack of a sex difference in CAD in type 1 diabetes., Competing Interests: Declaration of competing interest T.C., R.G.M., J.W.H., T.J.O. and T.V. have no relevant conflicts of interest to disclose. K.E.B. serves on the Scientific Advisory Board of Esperion Therapeutics., (Copyright © 2024. Published by Elsevier Inc.)

Aims: Dietary intake provides a potential intervention target to reduce the high risk for coronary artery disease (CAD) in type 1 diabetes. This effort aimed to identify patterns of nutrient intake in young/middle-aged adults with type 1 diabetes and to examine associations between those patterns and development of CAD., Methods: Principal component analysis was used to derive nutrient intake patterns among 514 individuals with childhood-onset (<17 years old) type 1 diabetes aged 18+ years and free of CAD (defined as CAD death, myocardial infarction, revascularization, ischemia, or study physician diagnosed angina). Cox models were used to assess the association between nutrient patterns and CAD incidence over 30-years of follow-up., Results: Three nutrient principal components (PC) were identified: PC1 (high caffeine and saccharin intake), PC2 (high alcohol and caffeine, lower intake of essential nutrients) and PC3 (higher fiber/micronutrients, low alcohol). In unadjusted Cox models, only PC1 (negatively) and PC2 (positively) were associated with CAD risk. These associations were no longer significant after adjusting for diabetes duration., Conclusions: Important dietary components underlying the three patterns identified may have been influenced by diabetes duration or age. Future research can continue to explore patterns of nutrient intake over time and CAD development in type 1 diabetes., (Copyright © 2021. Published by Elsevier Inc.)

Background: To compare in individuals with type 1 diabetes the prediction of incident coronary artery disease (CAD) by components of resting blood pressure-systolic, diastolic, pulse pressure, and mean arterial pressure., Methods: In 605 participants without known CAD at baseline and followed sequentially for 25 years, we used Cox modeling built for each blood pressure component associated with incident CAD, overall and stratified by age (<35 and ≥35 years) or hemoglobin A1c (HbA1c) (<9% and ≥9%)., Results: Baseline mean age and diabetes duration were 27 and 19 years, respectively. We observed an early asymptote and then fall in diastolic blood pressure in their late 30s and early 40s in this group of type 1 diabetes individuals, followed by an early rise of pulse pressure. Adjusted hazard ratios (HR) (95% con) for CAD associated with 1 SD pressure increase were 1.35 (1.17, 1.56) for systolic pressure; 1.30 (1.12, 1.51) for diastolic pressure; 1.20 (1.03, 1.39) for pulse pressure; and 1.35 (1.17, 1.56) for mean arterial pressure. Pulse pressure emerged as a strong predictor of CAD at age ≥ 35 years (HR: 1.49 [1.15, 1.94]) and for HbA1c ≥ 9% (HR: 1.32 [1.01, 1.72])., Conclusions: Individuals with type 1 diabetes may manifest early vascular aging by an early decline in diastolic blood pressure and rise in pulse pressure, the latter parameter becoming a comparable to systolic blood pressure in predictor incident CAD in those aged over 35 years and those with poor glycemic control., (© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Aim: To assess the role of periodontal disease (PD) as a predictor of coronary artery disease (CAD) and mortality in a prospective type 1 diabetes (T1D) cohort and to evaluate the role of smoking in this relationship., Methods: Data were based on 320 participants of the Pittsburgh Epidemiology of Diabetes Complications study of T1D who, during 1992-94, received a partial mouth periodontal exam, and who were followed for up to 19 years to ascertain complication incidence. PD was defined as clinical attachment loss of ≥4 mm for at least 10% of the examined sites. Predictors of all-cause mortality; Hard CAD (CAD death, myocardial infarction or revascularization), and Total CAD (Hard CAD, angina, ischemic ECG) were assessed using Cox models., Results: During 19 years of follow-up, 33.7% (97/288) developed CAD, 27.3% (83/304) developed Hard CAD, and 16.9% (54/320) died. Among current smokers, 46.4% (26/56) developed CAD, 42.7% (24/56) developed Hard CAD and 29.5% (18/61) died. PD was not associated with all-cause mortality, although it was a significant predictor of both CAD (HR = 1.12, CI = 1.01-1.23) and Hard CAD (HR = 1.30, CI = 1.11-1.51). As smoking modified the PD-CAD and PD-Hard CAD associations, analyses were stratified by smoking status. PD was associated with an increased risk of CAD (HR = 1.25, CI = 1.03-1.50) and Hard CAD (HR = 1.85, CI = 1.17-2.93) only among smokers., Conclusion: PD was a significant predictor of CAD and Hard CAD among current smokers with T1D., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: We aimed to determine optimal blood pressure (BP) thresholds for minimizing coronary artery disease (CAD) risk in people with childhood-onset type 1 diabetes., Research Design and Methods: The Pittsburgh Epidemiology of Diabetes Complications (EDC) Study participants without known CAD at baseline ( n = 605) were included and followed for 25 years. The associations of time-weighted BP measures (systolic BP [SBP], diastolic BP [DBP], and mean arterial pressure) with incident CAD were examined by using Cox models. Areas under the receiver operating characteristic curve (AUC) were summarized by different cut points of time-weighted BPs. Risk stratification analyses were then performed on the basis of BP (<120/80 vs. ≥120/80 mmHg) and HbA 1c (<8% vs. ≥8%)., Results: Baseline mean age was 27 years. Half of the cohort were women and 98% were white. A dose-gradient association was observed for categorized time-weighted BPs and CAD. According to AUC, the optimal cut point for SBP was 120 mmHg and for DBP was 80 mmHg. BP ≥120/80 mmHg was associated with a 1.9 times (95% CI 1.4, 2.6) greater risk of developing CAD than that for BP <120/80 mmHg. Participants with good control of both BP and HbA 1c had BP <120/80 mmHg and HbA 1c <8%. Those with only high BP (hazard ratio [HR] 2.0 [95% CI 1.1, 3.9]) carried a similar risk of developing CAD as those with only high HbA 1c (HR 1.6 [95% CI 0.97, 2.8])., Conclusions: The optimal BP threshold associated with minimal CAD risk is 120/80 mmHg in young adults with childhood-onset type 1 diabetes., (© 2019 by the American Diabetes Association.)

Aims/hypothesis: We sought to assess the role of coronary artery calcification (CAC) and its progression in predicting incident coronary artery disease (CAD) in individuals with type 1 diabetes using data from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study., Methods: The present study examined 292 participants who had at least one CAC measure and were free from CAD at baseline; 181 (62%) had repeat CAC assessments 4-8 years later and did not develop CAD between the two CAC measures. The HRs of incident CAD events were estimated using Cox models in categorised or in appropriately transformed CAC scores. C statistics and net reclassification improvement (NRI) were used to assess the added predictive value of CAC for incident CAD., Results: At baseline, the mean age of participants was 39.4 years and the mean diabetes duration was 29.5 years. There were 76 participants who experienced a first incident CAD event over an average follow-up of 10.7 years. At baseline, compared with those without CAC (Agatston score = 0), the adjusted HR (95% CI) in groups of 1-99, 100-399 and ≥400 was 3.1 (1.6, 6.1), 4.4 (2.0, 9.5) and 4.8 (1.9, 12.0), respectively. CAC density was inversely associated with incident CAD in those with CAC volume ≥100 (HR 0.3 [95% CI 0.1, 0.9]) after adjusting for volume score. Among participants with repeated CAC measures, annual CAC progression was positively associated with incident CAD after controlling for baseline CAC. The HR (95% CI) for above vs below the median annual CAC volume progression was 3.2 (1.2, 8.5). When compared with a model that only included established risk factors, the addition of CAC improved the predictive ability for incident CAD events in the whole group., Conclusions/interpretation: CAC is strongly associated with incident CAD events in individuals with type 1 diabetes; its inclusion in CAD risk models may lead to improvement in prediction over established risk factors.

Background and Aims: We assessed the predictive role of coronary artery calcification (CAC) in clinically relevant cognitive impairment in 148 middle-aged individuals with childhood-onset type 1 diabetes (T1D) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) Study., Methods: Baseline CAC was measured in 1996-98 and repeated 4-8 years later. Per extensive neuropsychological testing in 2010-15, 28% (41/148) of participants met the study definition of clinically relevant cognitive impairment (two or more of 7 select test scores ≥1.5SD worse than demographically appropriate published norms). Logistic regression models with backward selection were constructed for statistical analysis., Results: Mean age and T1D duration at first CAC measure were 37 and 29 years, respectively. A greater burden of initial CAC was associated with cognitive impairment determined 14 years later. Compared to Agatston score = 0, odds ratio (OR) and 95% confidence intervals (CI) of 0<-100, 100<-300 and >300 were 1.4 (0.6, 3.6), 2.3 (0.6, 9.7), and 7.9 (1.6, 38.5), respectively. With both initial and progression of CAC in the multivariable model, backward selection retained only CAC progression, showing it was significantly associated with cognitive impairment (OR [95% CI]: 1.7 [1.1, 2.9]). In those with an initial CAC>0, CAC density was marginally, inversely, associated with cognitive impairment when controlling for CAC volume (OR [95%CI]: 0.3 (0.1, 1.2), p value = 0.078)., Conclusions: Greater CAC burden was associated with clinically relevant cognitive impairment in middle-aged adults with childhood-onset T1D. CAC progression appears to be a more powerful predictor than initial calcification., (Copyright © 2018. Published by Elsevier B.V.)

Aims/hypothesis: Haptoglobin(Hp) 2-2 genotype has been shown to increase coronary artery disease (CAD) risk in numerous type 2 diabetes studies but in only one type 1 diabetes cohort. We assessed the association of Hp2-2 with incident CAD over 26years of follow-up in 1303 Caucasian participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study., Methods: DCCT randomized volunteers with type 1 diabetes to intensive versus conventional therapy within two cohorts: 'primary prevention' with 1-5years diabetes duration and 'secondary intervention' with 1-15years diabetes duration and early retinopathy, with or without albuminuria, but no advanced complications. CAD was defined as myocardial infarction (MI) or death judged to be from CAD, silent MI, angina, coronary revascularization, or congestive heart failure due to CAD., Results: In the entire DCCTcohort, Hp2-2 was not significantly associated with incident CAD or MI. However, in pre-specified exploratory subgroup analyses, an increased MI risk was suggested in the secondary cohort for those with Hp2-2., Conclusions/interpretation: The analysis does not statistically confirm an overall association between Hp 2-2 and incident CAD, however, some suggestions of associations were observed in secondary analyses., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Although oxidative stress (OxS) is thought to contribute to atherosclerosis and coronary artery disease (CAD), little is known about the variability in an individual's ability to respond to OxS. Therefore, we assessed potential indices of response to OxS and evaluated whether they modify the association between OxS and CAD., Research Design and Methods: We evaluated plasma α- and γ-tocopherol per unit cholesterol (potential response markers); urinary 15-isoprostane F2t per milligram creatinine (isoprostane [IsoP], a potential stress marker); and the α-tocopherol-to-IsoP ratio (as a measure of response to stress), measured three times during 20 years of follow-up, in relation to CAD incidence in a cohort with childhood-onset type 1 diabetes (n = 658; mean age at baseline, 28 years; duration of diabetes, 19 years). Participants with three samples (blood and either 24-h or overnight urine) available before the onset of CAD or the end of follow-up (n = 356) were selected for study., Results: In multivariable mixed models, α-tocopherol over time was inversely associated with CAD (β = -0.27; P = 0.02), whereas a direct association was observed for IsoP (β = 0.0008; P = 0.06). Moreover, the α-tocopherol-to-IsoP ratio was strongly and inversely related to CAD incidence (β = -0.72; P = 0.003), whereas in a separate model including α-tocopherol and IsoP, both biomarkers maintained statistical significance. No association was observed for γ-tocopherol (β = -0.22; P = 0.54)., Conclusions: These data suggest that a greater potential capability (α-tocopherol) to respond to OxS (urinary IsoP) relates to CAD incidence.

Objective: To determine whether type A behavior predicts all-cause mortality and incident coronary artery disease (CAD) in a type 1 diabetic population., Research Design and Methods: Follow-up data (22 years) from the Pittsburgh Epidemiology of Diabetes Complications (EDC) study of childhood-onset type 1 diabetes were analyzed for the 506 participants who completed the Bortner Rating Scale (measuring type A behavior) and Beck Depression Inventory (BDI) at baseline (1986-1988). CAD comprised myocardial infarction as determined by hospital records/Q waves on electrocardiogram (ECG), CAD death (determined by a mortality classification committee), angiographic stenosis, ischemic ECG, and angina., Results: There were 128 deaths (25.3%) during follow-up. Univariate analysis showed an inverse relationship between Bortner scores and all-cause mortality (P=0.01), which remained significant after allowing for age, sex, duration, HbA1c, education, smoking, BMI, and physical activity (P=0.03). However, the addition of BDI scores attenuated the relationship (P=0.11) with a significant interaction (P=0.03) such that any protective effect against mortality was limited among individuals with lower BDI scores (bottom three quintiles) (P=0.07), whereas no effect was seen in those with higher BDI scores (P=0.97). Bortner scores showed only a borderline association with incident CAD (P=0.09)., Conclusions: Those with higher type A behavior have lower all-cause mortality in our type 1 diabetic population, an effect that interacts with depressive symptomatology such that it is only operative in those with low BDI scores. Further research should focus on understanding this interaction.

Given the paucity of data in type 1 diabetes concerning lipoprotein-associated phospholipase A( 2) (Lp-PLA(2)), we examined its prospective relationship with coronary artery disease (CAD), as well as the effect of modification by C-reactive protein (CRP) and haptoglobin genotype, in individuals with type 1 diabetes who are at an increased risk for CAD due to also having macroalbuminuria (n=96). Although Lp-PLA(2) activity was univariately predictive of CAD (HR=1.54 per SD, p=0.009), this relationship was not significant after covariate adjustment (p=0.59). There was a significant interaction between Lp-PLA(2) and CRP (p=0.02), i.e. those with both markers greater than the median level were more likely to have a CAD event than those persons with low levels of both (HR=2.89, p=0.06). When stratified by haptoglobin genotype, Lp-PLA(2) was predictive of CAD in persons with the 2/1 (HR=2.40, p=0.05), but not 2/2 (HR=0.66, p=0.27), genotype. The association between Lp-PLA(2) activity and CAD differs by CRP and haptoglobin genotype in this group of persons with type 1 diabetes and macroalbuminuria.

Although coronary artery disease (CAD) is the leading cause of death in type 1 diabetes (T1D), the mechanisms responsible for the greatly increased risk are poorly understood. In particular, the role of glycaemic control is controversial with one study suggesting it predicts CAD mortality but not incidence. In this analysis, of the Pittsburgh Epidemiology of Diabetes Complications study cohort of T1D, we examine whether risk factors differ for CAD morbidity and mortality, with a specific focus on HbA1c and insulin dose. Participants (n=592) were followed for 18 years for incident non-fatal and fatal CAD. Cox stepwise regression was used to determine the independent risk factors for non-fatal and fatal CAD. Mean age and diabetes duration at study baseline were 29 and 20 years, respectively. There were 109 incident non-fatal and 48 fatal CAD events. Baseline HbA(1C) was an independent risk factor for fatal CAD, along with duration of diabetes and albuminuria. In contrast, baseline lower insulin dose was strongly predictive of non-fatal CAD, as was lower renal function, higher diastolic blood pressure, and lipids. HbA(1C) predicts CAD mortality while lower insulin dose and standard CAD risk factors predict CAD morbidity.

Coronary artery disease (CAD), a leading cause of death in type 1 diabetes (T1D), often occurs two or more decades earlier in this population compared to the population without diabetes. Although CAD generally increases with adiposity, this association is unclear in T1D. In this study, we examined associations of adiposity with coronary artery calcium (CAC) in 315 individuals with T1D. Mean age and diabetes duration were 42 and 34 years, respectively, at study entry. CAC, visceral adiposity (VAT) and subcutaneous adiposity (SAT) were determined by electron beam tomography; and BMI and waist circumference (WC) were determined. The presence of CAC was positively associated with VAT, SAT and BMI in men (p<0.05) and with all four adiposity measures in women (p<0.05) after adjustment for age and other traditional cardiovascular risk factors. However, after adjustment, the degree of CAC was not associated with any of the four adiposity measures, with the exception of SAT in women. Women in the lowest tertile of SAT had more CAC than those in the second tertile (p<0.016). Adiposity was positively associated with the presence of CAC, but the relationship with its severity was either inverse or non-existent. This double-edged association emphasises the complex relationship between adiposity and cardiovascular risk in diabetes.

Coronary artery calcium (CAC) has been previously associated with atherosclerotic plaque disease and coronary events. Thus, identifying predictors of CAC progression may provide new insights for early risk-factor intervention and subsequent reduction of the rates of more severe atherosclerotic disease. The aim of this study was to identify risk factors for CAC progression and evaluate whether risk-factor change was related to CAC progression in a cohort of patients with type 1 diabetes mellitus (DM). Participants in the Pittsburgh EDC Study, a prospective investigation of childhood-onset type 1 DM, who underwent 2 electron beam tomographic screenings 4 years apart were selected for study (n = 222). CAC was calculated using the Agatston method of scoring, and progression was defined as an increase >2.5 in the square root-transformed CAC score. Adjusting for DM duration and initial CAC score, body mass index (BMI; odds ratio [OR] 1.13, 95% confidence interval [CI] 1.01 to 1.26), non-high-density lipoprotein cholesterol (OR 1.01, 95% CI 1.003 to 1.03), and albumin excretion rate (OR 1.30, 95% CI 1.03 to 1.63) were associated with CAC progression. When considering change in risk factors, an increase in BMI (OR 1.38, 95% CI 1.10 to 1.72) was also associated with CAC progression after adjustment. In conclusion, in this cohort with type 1 DM, in addition to baseline BMI, non-high-density lipoprotein cholesterol, albumin excretion rate, and all known coronary artery disease risk factors, weight gain further added to the prediction of CAC progression. Thus, weight control, in addition to lipid and renal management, may help retard atherosclerosis progression in persons with type 1 DM.

Objective: Oxidative stress has been implicated in the development of diabetes and cardiovascular disease. We evaluated the effect of serum antioxidants and total antioxidant reserve (TAR) on coronary artery disease (CAD) incidence in type 1 diabetes., Methods: Subjects were identified from the Pittsburgh Epidemiology of Diabetes Complications Study (EDC) cohort, a 10-year prospective study of childhood-onset type 1 diabetes. Mean age at baseline was 28 and diabetes duration 19 years. Coronary artery disease was defined as physician-diagnosed angina, confirmed MI, stenosis >or=50%, ischemic electrocardiogram (ECG), or revascularization. Controls were gender, age, and diabetes duration (+/-3 years) matched with cases. Samples and risk factors used in analyses were identified from the earliest exam prior to incidence in cases (54 cases, 67 controls)., Results: None of the antioxidant measures (alpha-tocopherol, gamma-tocopherol, retinol, TAR) showed protection against incident CAD overall. However, a protective effect of alpha-tocopherol against CAD was observed among antioxidant supplement users (HR=0.22, 95% CI=0.10-0.49) and in renal disease (HR=0.46, 95% CI=0.23-0.91). Despite similar alpha-tocopherol concentration, there was no protective effect among nonusers of antioxidant supplements., Conclusions: High alpha-tocopherol levels among patients with renal disease and in those using vitamin supplements were associated with lower CAD risk in type 1 diabetes. The specificity of these effects merits further investigation.

Low-density lipoprotein (LDL) oxidation, the immune response it provokes, and lipoprotein subclasses measured by nuclear magnetic resonance (NMR) spectroscopy have explained some of the enhanced coronary artery disease (CAD) risks in Type 1 diabetes. We examined whether cellular adhesion molecules further improve CAD prediction. Participants were identified from the Epidemiology of Diabetes Complications (EDC) cohort, a 10-year prospective study of childhood-onset Type 1 diabetes. Mean age at baseline was 28 years, and diabetes duration was 19 years. CAD incidence was determined by EDC physician-diagnosed angina, confirmed myocardial infarction (MI), stenosis > or =50%, ischemic ECG, or revascularization. Cases were gender, age, and diabetes duration (+/-3 years) matched with the controls. The samples and risk factors used in the analyses were identified from the earliest exam prior to incidence in the cases. Sixty cases and 72 controls (including 43 pairs) had complete information on all covariates. Cox proportional hazard models with backward elimination and conditional logistic regression (for paired analyses) were conducted. Separate analyses were conducted to examine whether E-selectin related differently to soft (ischemic ECG and angina; n=68) or hard (revascularization, MI, and fatal events; n=37) CAD endpoints. Mean E-selectin concentration was elevated among cases (P=.0009) compared to controls. Adjusting for previously established CAD risk factors, E-selectin remained an independent predictor of CAD (HR=1.07, 95% Cl=1.01-1.15). Multivariable models confirmed the importance of E-selectin as a risk factor of soft (HR=1.13, 95% Cl=1.03-1.24; HRs are per standard deviation increase) but not hard CAD. Study results suggest that E-selectin may enhance CAD prediction beyond traditional risk factors or markers of oxidative stress in Type 1 diabetes.

Background: Recent data suggest that highly elevated high-density lipoprotein cholesterol (HDL-C) may not always protect against cardiovascular disease. To what degree this is true in type 1 diabetes is unknown, although cardiovascular risk is increased despite elevated mean HDL-C. Objective: To reassess the association between HDL-C and its subfractions with coronary artery disease (CAD) in childhood-onset type 1 diabetes. Methods: Epidemiology of Diabetes Complications study participants free of CAD at baseline (301 men, 298 women; mean age, 27.1 and diabetes duration, 18.9 years) were studied. CAD was defined as angina, ischemic electrocardiogram changes, confirmed myocardial infarction, angiographic stenosis ≥50%, revascularization, or CAD death. Cholesterol in the HDL fraction and HDL3 cholesterol subfraction was measured enzymatically after precipitation with heparin/manganese and dextran sulfate, respectively. Results: During 18 years of follow-up, 29.5% of men and 25.5% of women developed CAD. Although a linear decrease in incidence was observed with increasing HDL-C concentration in men, incidence increased in women at less than 47 mg/dL and greater than 80 mg/dL. These patterns largely reflected the HDL3 cholesterol-CAD association. After multivariable adjustment, the linear, inverse, HDL-C/CAD association persisted in men (hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.94–0.99); in women, the U-shaped relationship lost significance. HDL3 cholesterol remained multivariably associated with CAD in both men (linear association, P = .03) and women (HR 2.31 (95% CI 1.31–4.08) and HR 1.80 (95% CI 1.01–3.23) for the lowest and highest versus the middle quintiles, respectively). Conclusion: The increased CAD risk in women for an HDL-C >80 mg/dL in type 1 diabetes merits further study. Gender specificity could not be determined as only two men had HDL-C >80 mg/dL. [ABSTRACT FROM AUTHOR]

Purpose: To understand the effect of socioeconomic status (SES) on the risk of complications in type 1 diabetes (T1D), we explored the relationship between SES and major diabetes complications in a prospective, observational T1D cohort study. Methods: Complete data were available for 317 T1D persons within 4 years of age 28 (ages 24−32) in the Pittsburgh Epidemiology of Diabetes Complications Study. Age 28 was selected to maximize income, education, and occupation potential and to minimize the effect of advanced diabetes complications on SES. Results: The incidences over 1 to 20 years’ follow-up of end-stage renal disease and coronary artery disease were two to three times greater for T1D individuals without, compared with those with a college degree (p < .05 for both), whereas the incidence of autonomic neuropathy was significantly greater for low-income and/or nonprofessional participants (p < .05 for both). HbA1c was inversely associated only with income level. In sex- and diabetes duration-adjusted Cox models, lower education predicted end-stage renal disease (hazard ratio [HR], 2.9; 95% confidence interval [95% CI], 1.1−7.7) and coronary artery disease (HR, 2.5, 95% CI, 1.3−4.9), whereas lower income predicted autonomic neuropathy (HR, 1.7; 95% CI, 1.0−2.9) and lower-extremity arterial disease (HR, 3.7; 95% CI, 1.1−11.9). Conclusions: These associations, partially mediated by clinical risk factors, suggest that lower SES T1D individuals may have poorer self-management and, thus, greater complications from diabetes. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the extent of cardiovascular benefit of renin-angiotensin system (RAS) inhibition beyond lowering blood pressure (BP) and albuminuria in type 1 diabetes (T1D).Methods: This cohort study included 605 T1D participants from the Pittsburgh Epidemiology of Diabetes Complications study without baseline coronary artery disease (CAD). Participant follow-up extended through 25 years. We implemented marginal structural models to estimate total effect of and controlled direct effect by isolating the role of BP or albuminuria in mediating the relation between RAS inhibitors and CAD.Results: Total effect of longitudinal RAS inhibition treatment was associated with 38% decreased CAD risk (HR [95% CI]: 0.62 [0.23, 1.77]). The controlled direct effect of RAS inhibition was a 27% risk reduction (HR: 0.73 [0.20, 2.59]) when isolating the role of BP and 26% risk reduction (HR: 0.74 [0.16, 3.35]) when isolating the role of albuminuria. The mediation proportion for each 10 mm Hg systolic BP and each 1 log unit of albumin excretion rate were 34% and 37%, respectively.Conclusion: Our findings suggest that BP regulation and albuminuria reduction can only partially explain cardiovascular benefit of RAS inhibition on CAD in T1D, supporting the assertion that RAS inhibitors provide additional cardioprotection beyond lowering BP and albuminuria. [ABSTRACT FROM AUTHOR]