Determinants of endothelial function in asymptomatic subjects with and without the metabolic syndrome.

We investigated the determinants of endothelial function in 100 asymptomatic, non-diabetic, non-smokers with and without the metabolic syndrome ((MS)--defined by ATP-III criteria). Subjects with MS (n=24) had greater endothelial dysfunction (ED, P<0.001) than subjects without MS. One-way analysis of variance demonstrated a significant negative linear trend between level of ED (F=21.89; P<0.001) and number of ATP-III metabolic diagnostic criteria present in each subject. In a stepwise multivariate logistic regression model presence/absence of MS was the only independent determinant of ED (P=0.01). Age, gender, LDL cholesterol, C-reactive protein, interleukin-6 and tumour necrosis factor-alpha receptor 2 had no independent influence on endothelial function. In the absence of MS as variable there was no independent association between the remaining variables and endothelial function. Receiver operating characteristic (ROC) curves demonstrated that a combination of age, LDL cholesterol and CRP levels and presence/absence of MS can be used to predict ED (area under curve 0.81+/-0.06) and thus potentially may be used as a simple screening test to identify subjects with the greatest level of ED (sensitivity=0.82, specificity=0.72). Our study demonstrated that subjects with MS had greater ED. The extent of ED increased with presence of each additional ATP-III diagnostic criteria. Presence/absence of MS was the only independent predictor of ED and in conjunction with age, LDL cholesterol and CRP levels could be used as a potential simple clinical screening test for ED.

Divergent effects of angiotensin-converting enzyme inhibition on blood pressure and endothelial function in obese humans.

Endothelial dysfunction is a pivotal early event in the development of atherosclerosis and a characteristic feature of obesity. This study was designed to investigate the effect of angiotensin-converting enzyme (ACE) inhibition on endothelial function in people who were obese but otherwise healthy. We performed a double-blind, randomised, placebo-controlled study examining the effect of the ACE inhibitor perindopril (4 mg per day) on flow-mediated vasodilatation (FMD) of the brachial artery, arterial blood pressure, glucose homeostasis and inflammatory cytokines. Eighteen obese subjects (all body mass index > 30 kg/m2) were randomised to receive perindopril or placebo for four weeks. Perindopril led to a fall in systolic blood pressure from 131 (standard error of mean [SEM] 3) to 117(5) mmHg and diastolic blood pressure from 74(4) mmHg to 68(4) mmHg, both p<0.001. Despite this fall in blood pressure, ACE inhibition had no effect on FMD, 8.2 (1.2)% versus 8.3 (1.5)%, p=0.9. ACE inhibition had no effect on insulin, lipids or circulating cytokines. In healthy obese humans, despite a significant reduction in blood pressure, ACE inhibition had no effect on FMD.

Endothelial function and weight loss in obese humans.

BACKGROUND: Obesity is a major risk factor for the development of endothelial dysfunction. We explored the effect of different degrees of body mass on endothelial function, lipids, systemic inflammation and glucose homeostasis and the effect of surgically-induced weight loss on endothelial function in severely obese humans. METHODS: A cross-sectional study of healthy subjects across a wide range of body fatness was performed to characterize the effect of obesity on flow-mediated dilatation (FMD), systemic inflammation, blood pressure and insulin sensitivity. A longitudinal study was performed to assess the effect of bariatric surgery induced weight loss on these parameters. 73 healthy subjects across a wide range of body mass were recruited; of these, 8 underwent bariatric surgery (median BMI 52.2 kg/m2, interquartile range 50.355.9). Endothelial dependent vasodilatation was measured using the brachial artery vasodilatory response to forearm hyperemia assessed using highresolution ultrasonography. RESULTS: Obese subjects were characterised by a complex collection of abnormalities, with hypertension, impaired glucose homeostasis, systemic inflammation and reduced FMD. BMI < or =25 kg/m2 (median FMD 9.7%, interquartile range 6.8-12.2), BMI >30 kg/m2 (median FMD 6.7% 4.8-7.5), P=0.01 comparing FMD in lean and obese subjects. A mean reduction in weight of 23.4 (4.6) kg produced an improvement in FMD from 5.3% (3.87.0) to 10.2% (7.6-13.3), P=0.01. CONCLUSIONS: Even moderate obesity leads to endothelial dysfunction. In severely obese subjects, FMD is normalized by weight loss. This improvement in FMD is associated with a decline in inflammatory markers, blood pressure and insulin. The improvement in FMD occurred despite patients remaining significantly obese. These results suggest that an integrated approach to improving endothelial function in obese humans may be necessary.

Vascular endothelial function and blood pressure homeostasis in mice overexpressing IGF binding protein-1.

IGFs and their binding proteins (IGFBPs) play a significant role in metabolic regulation, and there is growing evidence that they also exert important vascular effects. IGFBP-1 contributes to glucose counterregulation, and observational studies demonstrate an inverse association between circulating IGFBP-1 levels and cardiovascular risk factors. Furthermore, IGFBP-1 levels are lower in subjects with overt macrovascular disease. We therefore hypothesized that IGFBP-1 exerts potentially beneficial effects, either directly or indirectly, on blood pressure regulation and vascular function. We tested this hypothesis using a unique transgenic mouse, which overexpresses human IGFBP-1, and explored the effect of this protein on metabolic, blood pressure, and vascular homeostasis. IGFBP-1-overexpressing mice exhibited postprandial hyperinsulinemia with preservation of glucocompetence and insulin sensitivity. Blood pressure was unchanged in the fasting state but was significantly lower in transgenic mice after a carbohydrate load. Aortic rings from IGFBP-1-overexpressing mice were hypocontractile in response to vasoconstrictors, and relaxation responses were unimpaired. Basal nitric oxide production was increased and endothelial nitric oxide synthase mRNA expression upregulated in aortae of these mice. Our data suggest that IGFBP-1 plays an important and potentially beneficial role in regulating metabolic and vascular homeostasis.