Salam Hama

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.

High-density lipoprotein impedes glycation of low-density lipoprotein

Glycation of low-density lipoprotein (LDL) increases its atherogenicity, but whether high-density lipoprotein (HDL) can protect LDL against glycation is not known. LDL and HDL were isolated from 32 volunteers with serum HDL cholesterol concentrations ranging from 0.76 to 2.01 (mean = 1.36) mmol/L. Glycation of LDL was induced by incubation with 0–80 mmol/L glucose for 7 days at 37°C under nitrogen in the presence of and absence of human HDL. Glycation of LDL apolipoprotein B (apoB) doubled at glucose 50 and 80 mmol/L (both p < 0.001), and this increase was ameliorated by HDL. In the absence of glucose, 0.11 (0.01) [mean (standard error, SE)] mg apoB/mg LDL protein was glycated increasing to 0.22 (0.02) mg/mg at glucose 80 mmol/L in the absence of HDL, but remaining at 0.13 (0.01) mg/mg when autologous HDL was present. Heterologous HDL from a further study of 12 healthy participants was similarly effective in impeding LDL apoB glycation. HDL impeded not only glycation but also the lipid peroxidation, free amino group consumption and increased electrophoretic mobility of LDL which accompanied glycation. HDL from participants with higher serum paraoxonase1 (PON1) was more effective in impeding glycation and the related processes. In conclusion, HDL can impede the glucose-induced glycoxidation of LDL. PON1 may be important for this function of HDL.

Extended-release niacin with laropiprant : a review on efficacy, clinical effectiveness and safety.

Introduction: Although treatment with statins reduces cardiovascular (CV) events in patients with dyslipidemia, a residual 60 – 70% CV risk remains. This CV risk may be inversely related to high-density lipoprotein-cholesterol (HDL-C). Interest in niacin has re-emerged because of its HDL-C raising effects. The flushing associated with niacin which has previously affected patient compliance can now be significantly blocked with laropiprant (LRPT). Areas covered: This review aims to assess the efficacy, clinical effectiveness and safety of extended-release niacin (ERN) with LRPT. The authors searched PubMed and MEDLINE for literature published between January 2006 and November 2011, for efficacy, clinical effectiveness and safety reports of ERN with LRPT. Expert opinion: Niacin has been shown to prevent CV events, reduce mortality and has beneficial effects on vascular endothelial function. Evidence suggests that this is due to its broad-spectrum lipid altering properties, including lowering lipoprotein (a) (Lp(a)), and its pleiotropic actions. While side effects associated with niacin have limited its use in the past, the extended-release formulations and co-administration of LRPT have increased its tolerability, particularly by reducing flushing. The authors advise that ERN should be used in patients with a high risk of cardiovascular disease, who have failed to reach conventional targets.

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.

Impairment of high-density lipoprotein resistance to lipid peroxidation and adipose tissue inflammation in obesity complicated by obstructive sleep apnea.

CONTEXT Obstructive sleep apnea (OSA) complicates morbid obesity and is associated with increased cardiovascular disease incidence. An increase in the circulating markers of chronic inflammation and dysfunctional high-density lipoprotein (HDL) occur in severe obesity. OBJECTIVE The objective of the study was to establish whether the effects of obesity on inflammation and HDL dysfunction are more marked when complicated by OSA. DESIGN AND PATIENTS Morbidly obese patients (n = 41) were divided into those whose apnea-hypoapnea index (AHI) was more or less than the median value and on the presence of OSA [OSA and no OSA (nOSA) groups]. We studied the antioxidant function of HDL and measured serum paraoxonase 1 (PON1) activity, TNFα, and intercellular adhesion molecule 1 (ICAM-1) levels in these patients. In a subset of 19 patients, we immunostained gluteal sc adipose tissue (SAT) for TNFα, macrophages, and measured adipocyte size. RESULTS HDL lipid peroxide levels were higher and serum PON1 activity was lower in the high AHI group vs the low AHI group (P < .05 and P < .0001, respectively) and in the OSA group vs the nOSA group (P = .005 and P < .05, respectively). Serum TNFα and ICAM-1 levels and TNFα immunostaining in SAT increased with the severity of OSA. Serum PON1 activity was inversely correlated with AHI (r = -0.41, P < .03) in the OSA group. TNFα expression in SAT directly correlated with AHI (r = 0.53, P < .03) in the subset of 19 patients from whom a biopsy was obtained. CONCLUSION Increased serum TNFα, ICAM-1, and TNFα expression in SAT provide a mechanistic basis for enhanced inflammation in patients with OSA. Decreased serum PON1 activity, impaired HDL antioxidant function, and increased adipose tissue inflammation in these patients could be a mechanism for HDL and endothelial dysfunction.

Effect of Roux-en-Y Bariatric Surgery on Lipoproteins, Insulin Resistance, and Systemic and Vascular Inflammation in Obesity and Diabetes

Purpose Obesity is a major modifiable risk factor for cardiovascular disease. Bariatric surgery is considered to be the most effective treatment option for weight reduction in obese patients with and without type 2 diabetes (T2DM). Objective To evaluate changes in lipoproteins, insulin resistance, mediators of systemic and vascular inflammation, and endothelial dysfunction following Roux-en-Y bariatric surgery in obese patients with and without diabetes. Materials and methods Lipoproteins, insulin resistance, mediators of systemic and vascular inflammation, and endothelial dysfunction were measured in 37 obese patients with (n = 17) and without (n = 20) T2DM, before and 6 and 12 months after Roux-en-Y bariatric surgery. Two way between subject ANOVA was carried out to study the interaction between independent variables (time since surgery and presence of diabetes) and all dependent variables. Results There was a significant effect of time since surgery on (large effect size) weight, body mass index (BMI), waist circumference, triglycerides (TG), small-dense LDL apolipoprotein B (sdLDL ApoB), HOMA-IR, CRP, MCP-1, ICAM-1, E-selectin, P-selectin, leptin, and adiponectin. BMI and waist circumference had the largest impact of time since surgery. The effect of time since surgery was noticed mostly in the first 6 months. Absence of diabetes led to a significantly greater reduction in total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol although the effect size was small to medium. There was a greater reduction in TG and HOMA-IR in patients with diabetes with a small effect size. No patients were lost to follow up. Conclusion Lipoproteins, insulin resistance, mediators of systemic and vascular inflammation, and endothelial dysfunction improve mostly 6 months after bariatric surgery in obese patients with and without diabetes. Clinical Trial Registration www.ClinicalTrials.gov, identifier: NCT02169518. https://clinicaltrials.gov/ct2/show/NCT02169518?term=paraoxonase&cntry1=EU%3AGB&rank=1.

Screening for cardiovascular risk factors in patients admitted for acute coronary syndrome

To the Editor: Diabetes mellitus (DM) is associated with cardiovascular disease and patients with diabetes have worse outcomes after myocardial infarction (MI) compared with those without (1). The prevalence of undiagnosed type 2 diabetes (T2DM) and glucose intolerance is high in patients admitted with acute coronary syndromes. (2). Furthermore, patients with CVD, irrespective of their age, have a prognosis which worsens with increasing glycaemia (3). The current prevalence of diabetes among inpatients in UK hospitals is 5.5–31% (4), rising to 20–25% in high risk patient groups (5). This retrospective audit was undertaken to examine the assessment of glycaemia, lipids and blood pressure management of patients admitted to the Medical Admissions Unit (MAU) of Central Manchester University Hospitals NHS Foundation Trust with a provisional diagnosis of Acute Coronary Syndrome (ACS) between 01 May 2007 and 31 August 2007. We used the Joint British Societies Guideline-2 (JBS2) guidelines (6) as standards for this audit. Data were collected from the medical notes after discharge. All data here are expressed as Mean, 95% CI unless stated otherwise. Significance of the differences was tested by Student’s t-test.

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

Abstract Background In lean healthy human beings, perivascular adipose tissue (PVAT) exerts an anticontractile effect on adjacent small arteries, but this is lost in obesity where there is evidence of adipocyte inflammation and increased oxidative stress. The aim of this study was to investigate the effects of bariatric surgery on small artery function and the underlying mechanisms. Methods Small arteries were isolated from subcutaneous adipose tissue samples obtained by gluteal biopsies from morbidly obese patients (n=15). Vessels were prepared as segments with and without intact PVAT. Response of vessel segments to cumulative doses of norepinephrine was recorded with wire myography. Biopsy samples were re-taken 6 months after bariatric surgery and effect of PVAT on vessel contractility was re-assessed. Vessel segments with intact PVAT were also incubated with blocking peptide for adiponectin receptor 1 (1·6 × 10 −4 mol/L, n=5). PVAT adiponectin levels were assessed by proteomic analysis of samples from obese (n=13) and control (n=10) individuals. Inflammatory profile of PVAT was assessed by staining for macrophages and tumour necrosis factor α. Findings Obese patients had a mean body-mass index of 52 kg/m 2 ; 6 months following surgery and significant weight loss (p Interpretation Damage to the anticontractile property of PVAT in obesity is in part due to a reduction in adiponectin levels within the PVAT and is rescued by weight loss following bariatric surgery. Funding British Heart Foundation.

The role of the renin–angiotensin system blocking in the management of atrial fibrillation

Abstract Objective: To review current available evidence for the role of renin–angiotensin system blockade in the management of atrial fibrillation. Method: We conducted a PubMed and Medline literature search (January 1980 through July 2011) to identify all clinical trials published in English concerning the use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers for primary and secondary prevention of atrial fibrillation. We also discussed renin–angiotensin system and its effects on cellular electrophysiology. Conclusion: The evidence from the current studies discussed does not provide a firm definitive indication for the use of angiotensin converting enzyme inhibitors or angiotensin II receptor blockers in the primary or secondary prevention of atrial fibrillation. Nevertheless, modest benefits were observed in patients with left ventricular dysfunction. In view of the possible benefits and the low incidence of side-effects with angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, they can be given to patients with recurrent AF, specifically those with hypertension, heart failure and diabetes mellitus.