salicylates and Overweight

Inflammation may contribute to pathological associations among obesity, diabetes mellitus, and cardiovascular disease.. To determine whether targeting inflammation using salsalate compared with placebo reduces progression of noncalcified coronary artery plaque.. In the Targeting Inflammation Using Salsalate in Cardiovascular Disease (TINSAL-CVD) trial participants were randomly assigned between September 23, 2008, and July 5, 2012, to 30 months of salsalate or placebo in addition to standard, guideline-based therapies. Randomization was computerized and centrally allocated, with patients, health care professionals, and researchers masked to treatment assignment. Participants were overweight and obese statin-using patients with established, stable coronary heart disease.. Salsalate (3.5 g/d) or placebo orally over 30 months.. The primary outcome was progression of noncalcified coronary artery plaque assessed by multidetector computed tomographic angiography. Secondary outcomes were other measures of safety and efficacy.. Two hundred fifty-seven participants were randomized to salsalate (n = 129) or placebo (n = 128). Their mean (SD) age was 60.8 (7.0) years, and 94.0% (236 of 251) were male. One hundred ninety participants (89 in the salsalate group and 101 in the placebo group) completed the study. Compared with baseline, there was no increase in noncalcified plaque volume in the placebo-treated patients and no difference in change between the salsalate and placebo groups (mean difference, -1 mm3; 95% CI, -11 to 9 mm3; P = .87). Salsalate treatment decreased total white blood cell, lymphocyte, monocyte, and neutrophil counts and increased adiponectin levels without change in C-reactive protein levels. Fasting glucose, triglycerides, uric acid, and bilirubin levels were decreased in the salsalate group compared with the placebo group, while hemoglobin levels were increased. Urinary albumin levels increased, with tinnitus and atrial arrhythmias more common, in the salsalate group compared with the placebo group.. Salsalate when added to current therapies that include a statin does not reduce progression of noncalcified coronary plaque volume assessed by multidetector computed tomographic angiography in statin-using patients with established, stable coronary heart disease. The absence of progression of noncalcified plaque volume in the placebo group may limit interpretation of the trial results.. clinicaltrials.gov Identifier: NCT00624923.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Double-Blind Method; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Male; Middle Aged; Obesity; Overweight; Plaque, Atherosclerotic; Salicylates

We tested the hypothesis that nuclear factor-kappaB (NF-kappaB) activity contributes to vascular endothelial dysfunction with aging and obesity in humans.. We conducted a randomized, double-blind, placebo-controlled crossover study in 14 nondiabetic overweight or obese (body mass index > or =25 kg/m(2)) middle-aged and older (age 52 to 68 years) adults. Salsalate (nonacetylated salicylate, 4500 mg/d), a compound that inhibits NF-kappaB activity, or placebo was administered for 4-day periods. Plasma salicylate concentrations reached the midtherapeutic range (21.8+/-1.1 mg/100 mL, P< or =0.0001 versus placebo) by day 4 of salsalate treatment. Salsalate increased expression of the inhibitor of NF-kappaB and reduced total and nuclear expression of NF-kappaB in endothelial cells obtained from the subjects (all P<0.05). Salsalate increased brachial artery flow-mediated dilation by 74% (from 4.0+/-0.4% to 6.6+/-0.5%, P<0.001) but did not affect endothelium-independent dilation (P=0.83). The change in brachial artery flow-mediated dilation with salsalate was inversely related to baseline flow-mediated dilation (r=-0.77, P<0.01). Infusion of vitamin C increased brachial artery flow-mediated dilation during placebo (P<0.001) but not after salsalate (P=0.23). Salsalate reduced nitrotyrosine (P=0.06) and expression of NADPH oxidase p47(phox) (P<0.05) in endothelial cells obtained from the subjects but did not influence circulating or endothelial cell inflammatory proteins.. Our findings provide the first direct evidence that NF-kappaB, in part via stimulation of oxidative stress, plays an important role in mediating vascular endothelial dysfunction in overweight and obese middle-aged and older humans.

Topics: Administration, Oral; Aged; Aging; Anti-Inflammatory Agents, Non-Steroidal; Body Mass Index; Cross-Over Studies; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Endothelium, Vascular; Female; Humans; I-kappa B Proteins; Male; Middle Aged; NADPH Oxidases; NF-kappa B; NF-KappaB Inhibitor alpha; Obesity; Overweight; Oxidative Stress; Salicylates; Tyrosine; Vasodilation

Topics: Humans; Insulin Resistance; Lipids; Obesity; Overweight; Prediabetic State; Salicylates

Although there often is a clinical co-incidence of increased adiposity and obstructive sleep apnea, each factor is independently associated with elevated oxidative stress.. We hypothesized that overweight rats exposed to simulated sleep apnea would develop exacerbated oxidative stress leading to impaired endothelium-dependent vasodilation.. Rats were fed either a chow or high-fat diet (HFD; 60% kcal from fat) for 6 weeks. During the final 14 days of each diet, animals were exposed to either air or eucapnic intermittent hypoxia (E-IH) to simulate sleep apnea.. Rats exposed to either E-IH or HFD alone showed increases of 161 and 176%, respectively, in oxidative stress (measured as thiobarbituric acid-reactive substances) compared to chow + air controls. However, oxidative stress was lower following combined HFD + E-IH treatment (132% of chow + air controls) compared to each individual treatment. All three treatment groups, chow + E-IH, HFD + air and HFD + E-IH, had increased blood pressure (144.5 ± 4.4, 148.2 ± 5.6, and 136.2 ± 2.0 mm Hg, respectively, vs. chow + air: 123 ± 2.0 mm Hg) and attenuated acetylcholine (ACh)-mediated vasodilation (78.3, 72.7, and 78.2% of the chow + air response at the highest dose of ACh) compared to chow + air controls. Combined HFD and E-IH treatment did not further impair vasodilation compared to chow + E-IH alone. Vasodilatory responses were normalized by the antioxidant EUK-134 in each treatment group.. Increased adiposity and simulated sleep apnea impair endothelium- dependent vasodilation through enhanced generation of reactive oxygen species (ROS). However, the combined treatment does not exacerbate either ROS generation or vascular dysfunction observed with HFD or E-IH alone.

Topics: Acetylcholine; Adipose Tissue; Animals; Blood Pressure; Dietary Fats; Disease Models, Animal; Humans; Male; Organometallic Compounds; Overweight; Oxidative Stress; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Salicylates; Sleep Apnea, Obstructive; Vasodilation