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Effects of gender (men vs. women) on CAC prevalence (CAC 0 vs. CAC 0), adjusted for covariates by logistic regression in patients with type 1 diabetic and nondiabetic control subjects
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The objective of this is study was to examine whether estimated insulin resistance and insulin resistance-related factors are associated with coronary artery calcification (CAC) in 1,420 asymptomatic participants in the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study. A total of 656 patients with type 1 diabetes and 764 control subje...
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Context 1
... the components used to derive the insulin resistance equation, HbA 1c and WHR were associated with CAC in both type 1 diabetic patients and nondiabetic control subjects, as were waist and IAF L23, independent of age, gender, LDL and HDL cholesterol, smoking, and diabetes duration (data not shown). Table 4 shows which covariates explain the effect of gender (male versus female) on CAC prevalence (CAC 0) in type 1 diabetic patients and nondiabetic control sub- jects. In model 1, adjustment for LDL and HDL cholesterol and diabetes duration (in type 1 diabetic patients only) in addition to age, explained some of the male excess in CAC in patients with type 1 diabetes and 40% of the male excess in CAC in control subjects. ...
Context 2
... factors that contribute to the gender differ- ence in calcification in the control population may be different from those in patients with diabetes. However, in CACTI, estimated insulin resistance assessed according to the equation developed by the EDC Study, LDL and HDL cholesterol, as well as body fat distribution, and each substantially explained the gender difference in CAC in control subjects and abolished the already reduced gender difference in calcification in subjects with diabetes (Table 4). In addition, type 1 diabetes had an unfavorable effect on fat distribution in women but not in men, while the beneficial lipid profile with type 1 diabetes was less pronounced in women than in men (Table 1). ...
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Citations
... Measurement of CAC score is an effective marker to refine cardiovascular risk stratification in an asymptomatic population [19,20]. Across age groups, asymptomatic adults with diabetes have higher median CAC scores than individuals without diabetes [21][22][23]. However, a meta-analysis of eight studies (6521 patients) revealed that 28.5% had a CAC score < 10, indicating that nearly 3 in 10 patients had very little or no calcified coronary artery atherosclerosis [24]. ...
Purpose of Review
The study aims to describe methods for detecting subclinical coronary artery disease (CAD) and their potential implications in asymptomatic patients with diabetes.
Recent Findings
Imaging tools can assess non-invasively the presence and severity of CAD, based on myocardial ischemia, coronary artery calcium score, and coronary computed tomography coronary angiography. Subclinical CAD is common in the general population ageing 50 to 64 years with any coronary atherosclerosis present in 42.1% and obstructive CAD in 5.2%. In patients with diabetes, an even higher prevalence has been noted. The presence of myocardial ischemia, obstructive CAD, and the extent of coronary atherosclerosis provide powerful risk stratification regarding the risk of cardiovascular events. However, randomized trials evaluating systematic screening in the general population or patients with diabetes have demonstrated only moderate impact on management and no significant impact on patient outcomes.
Summary
Despite providing improved risk stratification, systematic screening of CAD is not recommended in patients with diabetes.
... 1,2 None the less, people with type 1 diabetes (T1D), who have normal or even elevated levels of HDL cholesterol (HDL-C), 2,3 also have an increased risk of atherosclerotic CVD. [3][4][5] As a continuous variable, low levels of HDL-C associate with increased risk of incident CVD in the general population and in people with T1D. 1,2 Categorical analysis reveals a nonlinear association of HDL-C in T1D, with risk increasing in both the lowest (<50 mg/dL) and highest (>80 mg/dL) HDL-C groups. 2 However, genetic variations that affect HDL-C levels do not associate with CVD in the general population, 6 while randomized clinical trials of pharmacological interventions aimed at raising HDL-C have failed to reduce CVD in statin-treated patients. ...
Background: Cholesterol efflux capacity (CEC) negatively correlates with cardiovascular disease risk. Small HDL particles account almost quantitively for CEC, perhaps mediated through efflux of outer leaflet plasma membrane phospholipids by ABCA1. People with type 1 diabetes (T1D) are at increased risk of coronary artery disease (CAD) despite normal levels of HDL-cholesterol (HDL-C). We therefore tested the hypotheses that small HDL particles (HDL-P)—rather than HDL-C levels—predict incident CAD in T1D.
Methods: Incident CAD (CAD death, myocardial infarction, and/or coronary revascularization) was determined in a cohort of 550 participants with childhood-onset T1D. HDL-P was quantified by calibrated ion mobility analysis. CEC and phospholipid efflux were quantified with validated assays.
Results: During a median follow-up of 26 years, 36.5% of the participants developed incident CAD. In multivariable Cox models, levels of HDL-C and apolipoprotein A-I (APOA1) did not predict CAD risk. In contrast, extra-small HDL particle levels strongly and negatively predicted risk (hazard ratio [HR]=0.25, 95% confidence interval [CI]=0.13–0.49). An increased concentration of total HDL particles (T-HDL-P) (HR=0.87, CI=0.82–0.92) and three other HDL sizes were weaker predictors of risk: small HDL (HR=0.80, 0.65–0.98), medium HDL (HR=0.78, CI=0.70–0.87) and large HDL (HR=0.72, CI=0.59–0.89). Although CEC negatively associated with incident CAD, that association disappeared after the model was adjusted for T-HDL-P. Isolated small HDLs strongly promoted ABCA1-dependent efflux of membrane outer leaflet phospholipids.
Conclusions: Low concentrations of T-HDL-P and all four sizes of HDL subpopulations predicted incident CAD independently of HDL-C, APOA1, 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 small HDLs play a critical role in cardioprotection in T1D, which might be mediated by macrophage plasma membrane outer leaflet phospholipid export and cholesterol efflux by the ABCA1 pathway.
... The Coronary Artery Calcification in Type 1 Diabetes (CACTI) study is an observational prospective cohort to examine the progression of coronary artery calcification as a predictor of atherosclerosis and cardiovascular events, accounting for traditional cardiovascular risks in adults with and without T1D [24,25]. Cross-sectional data from this cohort have previously reported that the consumption of an atherogenic diet is associated with coronary calcification [26] and low fiber intake is associated with poor glycemic control in adults with and/or without T1D [27]. ...
Dietary fiber, an essential bioactive compound in plant-based diets, is of public health concern based on habitual low intakes in the general population. Not much data are available on how habitual dietary fiber is associated with glycemic control in type 1 diabetes (T1D) as well as in prediabetes and normoglycemic adults. To address this gap, we conducted a six-year longitudinal analysis of an original cohort in adults with and without T1D (n = 1255; T1D: n = 563; non-diabetes mellitus (non-DM): n = 692). Dietary data were collected from a validated food frequency questionnaire, biochemical measures were obtained after an overnight fast, and anthropometric measurements were collected at baseline as well as after three and six years for the follow-up study. Glycated hemoglobin (HbA1c) and estimated insulin sensitivity (eIS) were the main outcomes examined. In adjusted analyses, dietary fiber intake was inversely associated with HbA1c in a minimally adjusted model, but it was positively associated with eIS in a model involving all relevant covariates in non-DM adults. These associations were not significant in the T1D group. Furthermore, when examined by HbA1c cut-offs for glycemic control, an inverse association with dietary fiber was only observed in adults with prediabetes (all p < 0.05). At a six-year mean (±SD) dietary fiber intake of 17.4 ± 8.8 g for non-DM and 17.0 ± 8.2 g for the T1D group, protective associations against poor glycemic control were observed in those without diabetes and in prediabetes.
... T1D was defined as currently on insulin therapy, diagnosed before age 30 years, and immediately on insulin therapy or a clinical course consistent with T1D. (15) Controls were defined as no medical history of diabetes with HbA1c <5.7% as published previously. (16,17) Menopause was defined as no menstrual periods for at least 12 consecutive months, a history of hysterectomy with bilateral oophorectomy, or a history of hysterectomy without oophorectomy and with serum follicle-stimulating hormone (FSH) >40 IU/L. ...
Compromised bone structural and mechanical properties are implicated in the increased fracture risk in type 1 diabetes (T1D). We investigated bone structure and turnover by histomorphometry in postmenopausal women with T1D and controls without diabetes using tetracycline double‐labeled transiliac bone biopsy. After in vivo tetracycline double labeling, postmenopausal women with T1D of at least 10 years and without diabetes underwent transiliac bone biopsy. An expert blinded to the study group performed histomorphometry. Static and dynamic histomorphometry measurements were performed and compared between the two groups. The analysis included 9 postmenopausal women with T1D (mean age 58.4 ± 7.1 years with 37.9 ± 10.9 years of diabetes and HbA1c 7.1% ± 0.4%) and 7 postmenopausal women without diabetes (mean age 60.9 ± 3.3 years and HbA1c 5.4% ± 0.2%). There were no significant differences in serum PTH (38.6 ± 8.1 versus 51.9 ± 23.9 pg/mL), CTX (0.4 ± 0.2 versus 0.51 ± 0.34 ng/mL), or P1NP (64.5 ± 26.2 versus 87.3 ± 45.3 ng/mL). Serum 25‐hydroxyvitamin D levels were higher in T1D than in controls (53.1 ± 20.8 versus 30.9 ± 8.2 ng/mL, p < 0.05). Bone structure metrics (bone volume, trabecular thickness, trabecular number, and cortical thickness) were similar between the groups. Indices of bone formation (osteoid volume, osteoid surface, and bone formation rate) were 40% lower in T1D and associated with lower activation frequency. However, the differences in bone formation were not statistically significant. Long‐standing T1D may affect bone turnover, mainly bone formation, without significantly affecting bone structure. Further research is needed to understand bone turnover and factors affecting bone turnover in people with T1D. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
... 7 Participants extracted from the Human Urinary Proteome Database were part of four prospective studies with diverse clinical settings. 13,[15][16][17][18][19] There were 34 participants (18 progressed to CAD and 16 did not) enroled in the Coronary Artery Calcification in Type I Diabetes (CACTI) study between 2000 and 2002 and followed up for over 2.4 years. 15,16 A total of 64 patients (32 progressed to CAD and 32 did not) with chronic kidney disease were from the outpatient clinic of the Nephrology section of the Ghent University Hospital (Belgium). ...
... 13,[15][16][17][18][19] There were 34 participants (18 progressed to CAD and 16 did not) enroled in the Coronary Artery Calcification in Type I Diabetes (CACTI) study between 2000 and 2002 and followed up for over 2.4 years. 15,16 A total of 64 patients (32 progressed to CAD and 32 did not) with chronic kidney disease were from the outpatient clinic of the Nephrology section of the Ghent University Hospital (Belgium). They were recruited between 2011 and 2014 and followed up until June 2017. ...
... Data sets extracted from the Human Urinary Proteome Database were previously published, and relevant studies were conducted in compliance with the Helsinki declaration for research in humans and received an approval from the responsible review boards. 13,[15][16][17][18][19] Coronary artery disease endpoint was defined as myocardial infarction, acute coronary syndrome, new-onset angina pectoris, ischaemic cardiomyopathy, and coronary revascularization. In the validation, 115 individuals experienced CAD endpoints, including 57 with new myocardial infarctions. ...
Aims:
Coronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD.
Methods:
Urinary proteome was analysed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham and SCORE2 risk score were available in 737 participants. Bioinformatics analysis was performed based on the CAD-associated peptides.
Results:
The novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an AUC of 0.82 (95% CI: 0.78-0.87) for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66-0.77) and ACSP75 (AUC: 0.53, 95% CI: 0.47-0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80-0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with CAD (HR: 1.54, 95% CI: 1.26-1.89, P < 0.0001) higher risk of CAD. The new classifier further improved the risk reclassification of CAD on top of the Framingham or SCORE2 risk score (net reclassification index: 0.61, 95% CI: 0.25-0.95, P = 0.001; 0.64, 95% CI: 0.28-0.98, P = 0.001, correspondingly).
Conclusions:
A novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention.
... Shauer et al., found that high levels of insulin resistance were associated not only with poorer glycemic control, but also with higher calcification scores [48]. Insulin resistance appears to predict the extent of CAC and may be associated with a higher risk of CVD, particularly in patients with diabetes; in contrast, insulin appears to exert a protective effect on CV [49]. In vitro, glucose promotes a phenotypic transition of VSMCs to osteogenic cells; numerous studies have suggested that NO decreases platelet activation and counteracts the proliferation and migration of VSMCs [50][51][52]. ...
The pathogenesis of vascular calcification (VC) in diabetes mellitus (DM) has not been completely elucidated. VC often occur in patients with DM and chronic kidney disease (CKD). The incidence of VC in diabetic patients is more frequent than in nondiabetic patients, which is an important cause of cardiovascular (CV) morbidity and mortality. VC is a progressive transformation of the vascular wall; it results from an active and complex phenomenon affecting particularly the vascular smooth muscle cells (VSMCs). It leads to a change in the phenotype of the VSMCs towards an osteoblastic-like phenotype. DM is associated with specific risk factors in addition to hyperglycemia, such as increased oxidative stress, proinflammatory state, hypertension, and chronic kidney disease (CKD) promoting endothelial dysfunction. This article provides an overview and update of the pathophysiological data on the role of DM in VC progression.
... CAC presence has been associated with a history of MI and the prevalence of angiographic stenosis ≥ 50%, but not with angina pectoris or ischemic ECG changes, in male participants of the EDC study [173]. The Coronary Artery Calcification in T1DM (CACTI) study examined the prevalence of CAC in 652 asymptomatic participants with T1DM and 764 healthy control subjects [174]. The study found a higher prevalence of CAC in people with diabetes across all the age-group comparisons to healthy subjects. ...
Purpose of Review
This narrative review appraises research data on the potentially harmful effect of obesity and insulin resistance (IR) co-existence with type 1 diabetes mellitus (T1DM)-related cardiovascular (CVD) complications and evaluates possible therapeutic options.
Recent Findings
Obesity and IR have increasingly been emerging in patients with T1DM. Genetic, epigenetic factors, and subcutaneous insulin administration are implicated in the pathogenesis of this coexistence. Accumulating evidence implies that the concomitant presence of obesity and IR is an independent predictor of worse CVD outcomes.
Summary
The prevalence of obesity and IR has increased in patients with T1DM. This increase can be partly attributed to general population trends but, additionally, to iatrogenic weight gain caused by insulin treatment. This association might be the missing link explaining the excess CVD burden observed in patients with T1DM despite optimal glycemic control. Data on newer agents for type 2 diabetes mellitus (T2DM) treatment are unraveling novel ways to challenge this aggravating coexistence.
... Differences in CVD risk factors by sex appear as early as adolescence in type 1 diabetes [46]. In the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study, women with type 1 diabetes exhibited a more adverse adiposity profile than women without diabetes while there was no difference in men by diabetes status [50]. Furthermore, in the same study, lipids and adiposity measures explained much of the excess coronary artery calcification in women with type 1 diabetes. ...
Purpose of Review
Despite improvements in treatment, people with type 1 diabetes continue to have increased cardiovascular disease (CVD) risk. Glycemic control does not fully explain this excess CVD risk, so a greater understanding of other risk factors is needed.
Recent Findings
The authors review the relationship between glycemia and CVD risk in adults with type 1 diabetes and summarize evidence regarding other factors that may explain risk beyond glycemia. Insulin resistance, weight gain, sex differences, genetics, inflammation, emerging markers of risk, including lipid subclasses and epigenetic modifications, and future directions are discussed.
Summary
As glycemic control improves, an increased focus on other CVD risk factors is warranted in type 1 diabetes. Novel markers and precision medicine approaches may improve CVD prediction, but a lack of type 1 diabetes-specific guidelines for lipids, blood pressure, and physical activity are likely impediments to optimal CVD prevention in this high-risk population.
... Despite significant advances, individuals with T1DM are at risk of comorbidities, particularly vascular complications [3]. Patients with T1DM have a 4-to-10-fold greater risk of cardiovascular disease (CVD) than healthy controls [4][5][6][7]. ...
Objective:
Inflammation is a major factor in endothelial dysfunction (ED) which is the earliest predictor of cardiovascular disease and premature mortality in type 1 diabetes mellitus (T1DM) patients. This study aimed to describe the possible relationship between plasma lipids and inflammatory and ED biomarkers in young Emirati patients with and without T1DM.
Methods:
This case-control study included 158 patients with T1DM and 157 healthy controls from the local population of the United Arab Emirates (UAE). Anthropometric data, clinical variables, lipid profiles, liver enzymes, HbA1c, inflammatory, and ED biomarkers were measured for all participants using sophisticated techniques and assays.
Results:
The mean ages ± SD of patients with T1DM and healthy controls was 19.3 ± 6.4 years (59.5% females) and 9.2 ± 6.8 years (61.5% females), respectively. The mean duration of T1DM was 9.3 ± 5.7 years, with HbA1c of 8.9 ± 2.1%. BMI, WC, SBP, and DBP significantly differed between the two groups. The mean lipid profiles (HDL, TG, TC, ApoA, and ApoB), liver enzymes (GGT, ALT), inflammatory (IL-6, adiponectin, TNF-α, hs-CRP), and ED biomarker levels (ICAM-1, VCAM-1, selectin, and ET-1) were also significantly different between patients and controls. Based on Spearman's rank and logistic regression analysis, there was a significant association between elevated lipid profile, liver enzymes, inflammatory markers, and ED markers in T1DM patients compared to controls. Among the biomarkers studied, ApoA, ApoB, and TC were significantly increased in T1DM patients compared to controls.
Conclusion:
This study revealed a strong association between an elevated lipid profile and inflammatory and ED markers with T1DM, which could lead to cardiovascular events in the UAE population.
... We used 181 serum samples from patients with T1DM in the CACTI study (18) for our analyses. The CACTI study prospectively evaluated 1,416 subjects (652 patients with T1DM and 764 nondiabetic subjects), 19-56 years of age, for a wide range of complications of diabetes (19). At enrollment, subjects were diagnosed with T1DM before the age of 30 years or had autoantibodies and a clinical course consistent with T1DM. ...
Atherosclerotic cardiovascular disease (CVD) is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome have been shown to associate with prevalent CVD in T1DM. We therefore sought to determine which proteins carried by HDL might predict incident CVD in T1DM patients. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study (CACTI). We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). We found that only one HDL protein—SFTPB (pulmonary surfactant protein B)—predicted incident CVD in all of the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P = 0.022). In addition, plasma fractionation demonstrated that plasma SFTPB is nearly entirely bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status and a wide range of confounding factors, including HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost entirely bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker—and perhaps mediator—of CVD risk in patients with T1DM.
