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The association between endothelial dysfunction and cardiovascular outcomes in a population-based multi-ethnic cohort.

BACKGROUND: Brachial artery flow-mediated dilation (FMD) may predict cardiovascular events in selected high-risk patients. Whether FMD testing predicts cardiovascular events in asymptomatic, lower risk individuals from the general population is unknown. METHODS AND RESULTS: As a part of a multi-ethnic, prospective cohort study, the Northern Manhattan Study, we examined FMD by high-resolution ultrasonography in 842 community participants who were free of stroke or myocardial infarction. Lower FMD levels predicted cardiovascular events (myocardial infarction, stroke and vascular death) at 36 months of follow-up (hazard ratio (HR)=1.12 for every 1% decrease in FMD, 95% CI 1.01-1.25, p=0.03). The risk of events in patients with FMD in the lower two tertiles (FMD<7.5%) was significantly higher than those in the highest tertile (HR=3.28, 95% CI 1.07-10.06, p=0.04 for lowest versus highest tertile, and HR=3.05, 95% CI 1.03-9.66, p=0.04 for middle versus highest tertile). In a multivariate analysis including cardiovascular risk factors, the increase in risk associated with FMD was no longer statistically significant. CONCLUSIONS: Non-invasive FMD testing predicts incident cardiovascular events in this multi-ethnic, population-based sample, but its predictive value is not independent of cardiovascular risk factors.

Aged↗

Markers of endothelial dysfunction in the prediction of coronary artery disease in type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study.

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.

Adult↗

Endothelial dysfunction and hypertension in diabetes mellitus.

Although the net balance between vasoconstriction and vasodilation determines the tone of the blood vessel, the vasodilatory-vasoconstrictive response following a challenge may also be determined by the intrinsic mechanical and biological properties of the vascular smooth muscle. This article reviews the action of nitric oxide, acetylcholine,and insulin; the effects of hyperglycemia, increase in free fatty acids, diabetes, and obesity on the vasculature; treatment of hypertension in diabetes; the benefits of lowering blood pressure and intensity of blood pressure control; and compares specific antihypertensive therapies on cardiovascular outcomes. The effects of antihypertensive therapy on microvascular complications, choice of antihypertensive regimen, antioxidant and anti-inflammatory effects of antihypertensive drugs, and the potential role of antidiabetic drugs in the treatment of hypertension are also presented.

Acetylcholine↗

The RAGE axis and endothelial dysfunction: maladaptive roles in the diabetic vasculature and beyond.

Receptor for advanced glycation end product (RAGE) is a member of the immunoglobulin superfamily of cell surface molecules. The ligand-RAGE axis is emerging as a central mechanism linked to vascular injury and atherosclerosis in diabetes and in euglycemia. The repertoire of RAGE ligands, including advanced glycation end products, S100/calgranulins, high-mobility group box 1, amyloid-beta peptide, and Mac-1, transcends RAGE biology from specifically the science of diabetic complications to central aspects of the inflammatory response and oxidative stress. Experiments in cell culture and in vivo support the notion that interaction of RAGE ligands with RAGE activates key signal transduction pathways that modulate fundamental cellular properties, thereby leading to vascular and inflammatory cell perturbation. These considerations support the premise that the ligand-RAGE axis may be an important target for therapeutic intervention in cardiovascular disease and, fundamentally, in initiation and amplification of inflammatory responses.

Animals↗