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Background: Peroxisome proliferator-activated receptor (PPAR) agonists may have favorable outcomes on non-alcoholic fatty liver disease. This study serves as proof of concept to evaluate whether dual PPAR-α/γ agonists improve non-invasive tests of liver steatosis and fibrosis. Methods: This is a post-hoc analysis of a randomized, double-blind, placebo-controlled, multi-center trial comprising 7226 patients with type 2 diabetes mellitus and recent coronary artery disease randomized to receive aleglitazar, a PPAR-α/γ agonists, or placebo for two years. Main outcomes were change in non-invasive tests for liver steatosis and fibrosis: Liver Fat Score (LFS), Liver Accumulation Product (LAP), Fibrosis-4 (FIB-4), and NAFLD Fibrosis Score (NFS). Results: LFS, LAP and FIB-4 decreased upon treatment, whereas scores in the placebo group remained the same or increased (P<0.001). NFS responded differently but remained consistently lower than placebo. In the treatment group more participants shifted to a lower FIB-4 and NFS category, or improved in respect to the LAP cut-off values compared to the placebo group (P<0.001 for FIB-4 and LAP, P<0.004 for NFS). LFS had a low discriminative power in this study. Conclusion: This post-hoc analysis showed improvement of non-invasive tests of liver steatosis and fibrosis after starting dual PPAR-α/γ agonist treatment, adding to the evidence that this pathway has potential in non-alcoholic fatty liver disease treatment. [ABSTRACT FROM AUTHOR]

Background: Obesity is related to increased cardiovascular risk. It is unknown whether increasing levels of obesity also increase levels of cardiovascular risk factors and systemic inflammation. This study describes the relationship between classic cardiovascular risk factors and inflammatory markers with BMI in a group of obese and non-obese subjects.Materials and Methods: Obese subjects (BMI ≥ 30 kg/m2; n = 576; mean ± SD BMI 43.8 ± 7.58 kg/m2) scheduled for bariatric surgery were included. The reference population consisted of non-obese volunteers (BMI < 30 kg/m2; n = 377, BMI 25.0 ± 2.81 kg/m2). The relationship between BMI quintiles and the levels of cardiovascular risk factors was analyzed. Adipose tissue volumetry was performed in 42 obese subjects using abdominal CT scans.Results: The obese group included more women and subjects with type 2 diabetes mellitus, hypertension, and current smoking behavior. In obese subjects, HDL-C and triglycerides decreased with increasing BMI. Systolic and diastolic blood pressure, total cholesterol, LDL-C, and apoB were not related to BMI in the obese group, in contrast to the non-obese group. Inflammatory markers CRP, leukocyte count, and serum complement C3 increased with increasing BMI in the obese group, while these relations were less clear in the non-obese group. The subcutaneous adipose tissue surface was positively correlated to BMI, while no correlation was observed between BMI and visceral adipose tissue.Conclusions: Markers of inflammation are strongest related to BMI in obese subjects, most likely due to increased adipose tissue mass, while cardiovascular risk factors do not seem to deteriorate above a certain BMI level. Limited expansion capacity of visceral adipose tissue may explain these findings. [ABSTRACT FROM AUTHOR]

Introduction: Type 2 diabetes mellitus (T2DM) and obesity are both related to increased risk of cardiovascular disease and mortality. Early atherosclerotic vascular changes can be detected by non-invasive tests like carotid artery intima-media thickness (cIMT) and pulse wave velocity (PWV). Both cIMT and PWV are significantly impaired in T2DM patients and in obese patients, but the additional effect of T2DM on these vascular measurements in obese subjects has not been evaluated.Methods: Two hundred morbidly obese patients with or without T2DM were enrolled in a prospective cohort study and underwent extensive laboratory testing, including cIMT and PWV measurements. The cohort was divided into a group with and a group without T2DM.Results: Within this cohort, 43 patients (21.5%) were diagnosed with T2DM. These patients were older and had more often (a history of) hypertension as compared to patients without T2DM. HbA1c levels were significantly increased, while LDL cholesterol was significantly lower and the use of statins higher than in non-diabetic participants. cIMT and PWV were significantly increased in subjects suffering from T2DM. The variability in cIMT and PWV was related to differences in age and systolic blood pressure, but not to the presence of T2DM.Conclusion: While T2DM negatively affects the vasculature in morbid obesity, hypertension and age seem to be the major risk factors, independent from the presence of T2DM.Clinical Trial Registration: Dutch Trial Register NTR5172. [ABSTRACT FROM AUTHOR]

Abstract: Background: Levels of apolipoprotein (apo) B48 may be increased in conditions associated with systemic inflammation and increased cardiovascular disease (CVD) risk such as rheumatoid arthritis (RA). We aimed to evaluate apo B48 levels in patients with RA in relation to subclinical atherosclerosis. Methods: Patients with RA (without CVD) and controls without RA but with high CVD risk (based on the presence of diabetes mellitus or a history of CVD) and healthy controls were included in this cross‐sectional study. Carotid intima‐media thickness (cIMT) was measured as a surrogate for vascular damage. Results: In total, 312 patients with RA, 65 controls with high CVD risk and 36 healthy controls were included. Patients with RA had the highest mean apo B48 (10.00 ± 6.65 mg/L) compared to controls with high CVD risk and healthy controls (8.37 ± 5.16 and 5.22 ± 2.46, P < .001). Triglycerides levels were comparable with controls. In RA, apo B48 correlated positively with triglycerides (r = .645; P < .001) but not with cIMT. However, in RA subjects not using lipid or blood pressure lowering medication, a weak correlation was found with cIMT (r = .157; P = .014). RA patients in the highest apo B48 tertile were more often rheumatoid factor positive and anti‐CCP positive compared to the lowest tertile. Conclusion: Rheumatoid arthritis patients have higher levels of apo B48 compared to controls with high CVD risk and healthy controls, with normal levels of triglycerides. This accumulation of atherogenic chylomicron remnants may contribute to the elevated CVD risk in RA patients. [ABSTRACT FROM AUTHOR]

Objective. To investigate the prevalence of underdiagnosis and undertreatment of traditional cardiovascular risk factors in RA patients. Methods. RA patients ≤70 years of age without cardiovascular disease (CVD) or diabetes mellitus were included. Systolic blood pressure and a fasting lipid profile were measured. The 10-year CVD risk was estimated using the Dutch Cardiovascular Risk Management (CVRM) guideline and EULAR modifications of the Systemic Coronary Risk Evaluation tables. Results. A total of 327 patients were included (female gender: 68%). The mean age was 53(11) years [mean (S.D.)]. The median disease duration was 7 years (inter quartile range: 2-14 years). According to the CVRM guideline, 52% of the patients had a CVD risk ≥20% and according to the EULAR guidelines, 18% of the patients had a CVD risk ≥20%. Low-density lipoprotein cholesterol (LDL-C) >2.5 mmol/l was found in >80% of the patients with a CVD risk ≥10% as estimated by both the CVRM and EULAR guidelines, and 32-42% of the patients with a CVD risk ≥10% had a systolic blood pressure >140mmHg, depending on the risk model used. Statins were used in 6% and antihypertensives in 23-25%, and 50-86% of these patients did not reach the recommended treatment targets. Conclusion. Regardless of the adapted risk assessment model used, untreated hypertension and hypercholesterolaemia were frequently found in RA patients with increased CVD risk. Treatment of these cardiovascular risk factors deserves more attention in RA. [ABSTRACT FROM AUTHOR]

Objectives: Rheumatoid arthritis (RA) has been identified as an independent cardiovascular risk factor. The importance of risk factors such as hypertension and hyperlipidemia in the generation of atherosclerosis in RA patients is unclear. This study analyzed clinical parameters associated with carotid intima media thickness (cIMT) in patients with RA. Methods: Subjects with RA and healthy controls without RA, both without known cardiovascular disease, were included. Participants underwent a standard physical examination and laboratory measurements including a lipid profile. cIMT was measured semi-automatically by ultrasound. Results: In total 243 RA patients and 117 controls were included. The median RA disease duration was 7 years (IQR 2–14 years). The median DAS28 was 2.4 (IQR 1.6–3.2) and 114 (50.4%) of the RA patients were in remission. The presence of RA and cIMT were not associated (univariate analysis). Multivariable regression analysis showed that cIMT in RA patients was associated with age (B = 0.006, P<0.001) and systolic blood pressure (B = 0.003, P = 0.003). In controls, cIMT was associated with age (B = 0.006, P<0.001) and smoking (B = 0.097, P = 0.001). Conclusion: cIMT values were similar between RA patients and controls. Hypertension was strongly associated with cIMT in RA patients. After adjustment, no association between cIMT and specific RA disease characteristics was found in this well treated RA cohort. [ABSTRACT FROM AUTHOR]

Epigenetic marks, and especially DNA methylation, are becoming an important factor in obesity, which could help to explain its etiology and associated comorbidities. Adipose tissue, now considered as an important endocrine organ, produces complement system factors. Complement component 3 (C3) turns out to be an important protein in metabolic disorders, via either inflammation or the C3 subproduct acylation stimulating protein (ASP) which directly stimulates lipid storage. In this study, we analyze C3 DNA methylation in adipose tissue from subjects with a different grade of obesity. Adipose tissue samples were collected from subjects with a different degree of obesity determined by their body mass index (BMI) as: Overweight subjects (BMI ≥ 25 and <30), obese class 1/2 subjects (BMI ≥ 30 and <40) and obese class 3 subjects (BMI ≥ 40). C3 DNA methylation was measured for 7 CpGs by pyrosequencition using the Pyromark technology (Qiagen, Madrid Spain). C3 messenger RNA (mRNA) levels were analyzed by pre-designed Taqman assays (Applied biosystems, Foster City, CA, USA) and ASP/C3a was measured using a ELISA kit. The data were analyzed using the statistic package SPSS. C3 DNA methylation levels were lower in the morbid obese group. Accordingly, C3 methylation correlated negatively with BMI and leptin. However, C3 mRNA levels were more associated with insulin resistance, and positive correlations with insulin, glucose and homeostasis model assessment-estimated insulin resistance (HOMA-IR) existed. ASP correlated negatively with high density lipoprotein (HDL) cholesterol. C3 methylation levels were associated to adiposity variables, such as BMI and leptin, while the C3 mRNA levels were associated to glucose metabolism. [ABSTRACT FROM AUTHOR]

Abstract: The objective was to evaluate whether the soluble fibre Plantago ovata (Po)-husk improves cardiovascular disease (CVD) risk biomarkers including low-density lipoprotein cholesterol (LDL-C). Methods: In a multi-centred, double-blind, placebo-controlled, parallel, randomised trial conducted in primary care-clinics in Spain, France and Holland, mild-moderate hypercholesterolaemic patients (age range: 43–67 years) received 14g/d of Po-husk (n =126) or placebo (microcrystalline-cellulose 14g/d; n =128) in a low saturated fat diet for 8 weeks. Subsequently, if LDL-C remained ≥3.35mmol/L [130mg/dL], participants proceeded with the fibre plus simvastatin (20mg/d) for further 8 weeks. Lipid profile, blood pressure (BP), insulin, oxidised LDL and some gene polymorphisms involved in CVD risk were measured. Results: Relative to placebo, Po-husk reduced plasma LDL-C by −6% (P <0.0002), total cholesterol (TC) by −6%, triglycerides (TG) by −21.6%, apolipoprotein (Apo) B-100 by −6.7%, oxidised LDL by a mean of −6.82U/L (95%CI: 3.15–10.48), insulin by −4.68pmol/L (95%CI: 0.68–8.67) and systolic BP by −4.0mm Hg (95%CI; 1.2–6.7) (P <0.05). The TG-lowering effect in the Po-husk group was magnified by variants in plasminogen-activator-inhibitor (PAI-1; rs1799768) and fatty acid-binding protein (FABP-2; rs1799883) genes. At 16 weeks, the intra-group action of simvastatin (20mg/d) added to Po-husk or placebo was a similar LDL-C reduction. Conclusions: Po-husk, apart from lowering LDL-C, also reduced TG, TG related to certain gene variants, TC, Apo B-100, oxLDL, insulin-resistance and systolic BP in mild-moderate hypercholesterolaemic individuals. Thus, the target patients to receive Po-husk would be those who present a cluster of various CVD risk factors, such as metabolic syndrome. [ABSTRACT FROM AUTHOR]