Effect of Extended-Release Niacin on High-Density Lipoprotein (HDL) Functionality, Lipoprotein Metabolism, and Mediators of Vascular Inflammation in Statin-Treated Patients.

BACKGROUND: The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment. METHODS AND RESULTS: In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity. CONCLUSIONS: ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL-C-raising effect. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054508.

Effects of bariatric surgery on human small artery function: evidence for reduction in perivascular adipocyte inflammation, and the restoration of normal anticontractile activity despite persistent obesity.

OBJECTIVES: The aim of this study was to investigate the effects of bariatric surgery on small artery function and the mechanisms underlying this. BACKGROUND: In lean healthy humans, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity-associated conditions such as the metabolic syndrome and type II diabetes where there is evidence of adipocyte inflammation and increased oxidative stress. METHODS: Segments of small subcutaneous artery and perivascular fat were harvested from severely obese individuals before (n = 20) and 6 months after bariatric surgery (n = 15). Small artery contractile function was examined in vitro with wire myography, and perivascular adipose tissue (PVAT) morphology was assessed with immunohistochemistry. RESULTS: The anticontractile activity of PVAT was lost in obese patients before surgery when compared with healthy volunteers and was restored 6 months after bariatric surgery. In vitro protocols with superoxide dismutase and catalase rescued PVAT anticontractile function in tissue from obese individuals before surgery. The improvement in anticontractile function after surgery was accompanied by improvements in insulin sensitivity, serum glycemic indexes, inflammatory cytokines, adipokine profile, and systolic blood pressure together with increased PVAT adiponectin and nitric oxide bioavailability and reduced macrophage infiltration and inflammation. These changes were observed despite the patients remaining severely obese. CONCLUSIONS: Bariatric surgery and its attendant improvements in weight, blood pressure, inflammation, and metabolism collectively reverse the obesity-induced alteration to PVAT anticontractile function. This reversal is attributable to reductions in local adipose inflammation and oxidative stress with improved adiponectin and nitric oxide bioavailability.

PCOS and peripheral AMH levels in relation to FSH receptor gene single nucleotide polymorphisms.

OBJECTIVES: To determine if an association exists between the follicle-stimulating hormone receptor (FSHR) gene p.Asn680Ser polymorphism and polycystic ovary syndrome (PCOS) or with high anti-mullerian hormone (AMH) levels without PCOS. PATIENTS: Fifty-eight women with PCOS, 24 women with high AMH (>44.5 pmol/L) without PCOS and 80 healthy ethnically matched female controls. MAIN OUTCOME MEASURES: Prevalence of the FSHR p.Asn680Ser polymorphism, baseline serum AMH levels and response to ovulation induction with clomiphene citrate. RESULTS: The frequency of FSHR p.Asn680Ser genotypes were not significantly different between PCOS patients, patients with high AMH without PCOS and controls (p = 0.88). Of the women with PCOS, 34/58 were on clomiphene citrate treatment and 12/34 were resistant. There was no association between sensitivity or resistance to clomiphene and p.Asn680Ser genotypes (p = 0.38). CONCLUSIONS: There is no evidence that FSHR p.Asn680Ser genotypes are associated with PCOS, high AMH levels or response to clomiphene citrate.

Low soluble P-selectin may facilitate early exclusion of acute myocardial infarction.

BACKGROUND: Suspected cardiac chest pain accounts for over 25% of medical admissions but, as only a minority have acute coronary syndromes, there is a tremendous potential to reduce unnecessary admissions. We evaluated five markers of plaque rupture or instability as indicators that would allow safe early exclusion of acute myocardial infarction (AMI) at the time of presentation. METHODS: Blood was drawn at the time of presentation from patients presenting to the Emergency Department with suspected cardiac chest pain and tested for cTnT and 5 novel biomarkers (pregnancy-associated plasma protein A (PAPP-A), thrombospondin, CD40 ligand, E-selectin and P-selectin). The primary outcome was a diagnosis of AMI. The secondary outcome was the occurrence of death, AMI or urgent revascularization (adverse cardiac events, ACE) within 30 days. RESULTS: 713 patients were included. Median time from symptom onset to venepuncture was 210 min. Only P-selectin and PAPP-A had value for diagnosis of AMI, with C-statistics of 0.68 (95% CI 0.63-0.73) and 0.57 (0.51-0.63) respectively. On multivariate analysis, P-selectin, cTnT and ECG ischemia independently predicted ACE. A model combining all three had 97.6% sensitivity, 52.8% specificity and 99.0% negative predictive value (NPV) for AMI. Use of this model could obviate the need for hospital admission in 44.2% of patients, 2.5% of whom would be expected to develop ACE. CONCLUSIONS: P-selectin has early diagnostic value for AMI and prognostic value independent of cTnT and ECG findings. The combination of P-selectin, cTnT and ECG has high NPV. Further research into this promising biomarker is warranted.

The relationships between AMH, androgens, insulin resistance and basal ovarian follicular status in non-obese subfertile women with and without polycystic ovary syndrome.

BACKGROUND: Hyperandrogenaemia and insulin resistance are prominent features of polycystic ovary syndrome (PCOS) and influence the process of folliculogenesis in women with the endocrinopathy. Anti-Müllerian hormone (AMH) levels are elevated in women with PCOS and studies including IVF subjects have shown that this is a reliable marker of ovarian performance. The aims of this prospective study were to assess the relationship between insulin resistance, androgens and AMH, and whether AMH contributes to altered folliculogenesis in non-obese women with PCOS. METHODS: A total of 232 IVF candidates, 49 of whom had PCOS according to the Rotterdam 2003 consensus criteria, were recruited. AMH levels and ovarian morphology were assessed. The relationships between AMH and insulin resistance and androgenaemia in patients with and without PCOS were studied. RESULTS: PCOS patients were slightly older than controls (median ages 34 and 30 years, respectively). AMH generally increased with antral follicle count (AFC), insulin, homeostatic model assessment of tissue insulin sensitivity (HOMA-IR), testosterone, free androgen index and luteinising hormone, and decreased with chronological age, homeostatic model assessment of steady state beta cell function (HOMA-B) and serum sex hormone binding globulin (SHBG). For these relationships there were no significant differences in the slopes between PCOS and non-PCOS patients. The ratio of AMH per antral follicle (AMH/AF) was higher in PCOS patients. Both PCOS and non-PCOS groups showed a very similar increase in AMH with increases in AFC, but the PCOS patients had consistently higher AMH across all AFC levels. CONCLUSIONS: These observations indicate that AMH is similarly related to insulin resistance and androgens in women with and without PCOS. This effect appears to be independent of age although an indirect causal effect due to ageing or some other mechanism cannot be ruled out. Excessive granulosa cell activity may be implicated in the abnormal follicular dynamic of the syndrome.

Circulating basal anti-Müllerian hormone levels as predictor of ovarian response in women undergoing ovarian stimulation for in vitro fertilization.

OBJECTIVE: To evaluate the clinical value of basal anti-Müllerian hormone (AMH) measurements compared with other available determinants, apart from chronologic age, in the prediction of ovarian response to gonadotrophin stimulation. DESIGN: Prospective cohort study. SETTING: Tertiary referral center for reproductive medicine and an IVF unit. PATIENT(S): Women undergoing their first cycle of controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). MATERIALS AND METHODS: Basal levels of FSH and AMH as well as antral follicle count (AFC) were measured in 165 subjects. All patients were followed prospectively and their cycle outcomes recorded. MAIN OUTCOME MEASURE(S): Predictive value of FSH, AMH, and AFC for extremes of ovarian response to stimulation. RESULT(S): Out of the 165 women, 134 were defined as normal responders, 15 as poor responders, and 16 as high responders. Subjects in the poor response group were significantly older then those in the other two groups. Anti-Müllerian hormone levels and AFC were markedly raised in the high responders and decreased in the poor responders. Compared with FSH and AFC, AMH performed better in the prediction of excessive response to ovarian stimulation-AMH area under receiver operating characteristic curve (ROC(AUC)) 0.81, FSH ROC(AUC) 0.66, AFC ROC(AUC) 0.69. For poor response, AMH (ROC(AUC) 0.88) was a significantly better predictor than FSH (ROC(AUC) 0.63) but not AFC (ROC(AUC) 0.81). AMH prediction of ovarian response was independent of age and PCOS. Anti-Müllerian hormone cutoffs of >3.75 ng/mL and <1.0 ng/mL would have modest sensitivity and specificity in predicting the extremes of response. CONCLUSION(S): Circulating AMH has the ability to predict excessive and poor response to stimulation with exogenous gonadotrophins. Overall, this biomarker is superior to basal FSH and AFC, and has the potential to be incorporated in to work-up protocols to predict patient's ovarian response to treatment and to individualize strategies aiming at reducing the cancellation rate and the iatrogenic complications of COH.

Low grade inflammation, as evidenced by basal high sensitivity CRP, is not correlated to outcome measures in IVF.

PURPOSE: To assess the relationship between low-grade inflammation, measured as basal high sensitivity (hs)-CRP, and IVF outcome. METHODS: We recruited a total of 220 women undergoing infertility work up prior to IVF. Patients were selected for a BMI < 30 kg/m(2) with an upper age limit of 40 years. Serum hs-CRP levels were measured on day 3 of a spontaneous menstrual cycle preceding ovarian stimulation. A sensitive two-site ELISA was used for analysis. Dose of gonadotrophins required, follicles days 8 and 10, number of oocytes collected, number of oocytes fertilised and pregnancy outcome were recorded. RESULTS: Median hs-CRP was 1.08 mg/L (0.43-3.00 mg/L). The hs-CRP was significantly related to BMI (r = 0.386, P < .001) but not to age and smoking habit. There were no significant relationships between basal hs-CRP and any of the measured IVF outcomes. CONCLUSIONS: These findings demonstrate that serum hs-CRP concentration is not a predictive marker of cycle or pregnancy outcome in women undergoing IVF treatment.