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Abstract Most dyslipidemic conditions have been linked to an increased risk of cardiovascular disease. Over the past few years major advances have been made regarding the genetic and metabolic basis of dyslipidemias. Detailed characterization of the genetic basis of familial lipid disorders and knowledge concerning the effects of environmental factors on the expression of dyslipidemias have increased substantially, contributing to a better diagnosis in individual patients. In addition to these developments, therapeutic options to lower cholesterol levels in clinical practice have expanded even further in patients with familial hypercholesterolemia and in subjects with cardiovascular disease. Finally, promising upcoming therapeutic lipid lowering strategies will be reviewed. All these advances will be discussed in relation to current clinical practice with special focus on common lipid disorders including familial dyslipidemias. Highlights • Advances have been made regarding the genetic and metabolic basis of dyslipidemias. • The expression of dyslipidemias depends on genetic and environmental factors. • The first step in clinical care in dyslipidemias is establishing the diagnosis. • Therapeutic options to lower cholesterol levels have expanded even further. [ABSTRACT FROM AUTHOR]

Diabetes mellitus type 2 (T2DM) has been associated with an increased cardiovascular risk. Improving glycaemia or other traditional cardiovascular risk factors may reduce cardiovascular risk in patients with T2DM. However, single risk intervention in T2DM has not provided convincing evidence in the reduction of cardiovascular risk. The aim of this paper is to provide an overview of clinical trials involving reduction of cardiovascular outcomes in patients with T2DM. Trials with glucose lowering therapies have shown conflicting results. Intensive therapy to reduce glycaemia has shown some benefit on composite cardiovascular endpoints but these benefits take a longer period to emerge. Recent studies with empagliflozin and glucagon-like peptide-1 (GLP-1) agonists show promising results, but the mechanisms are most likely not mediated by improved glycaemia, given the relatively rapid effects. Both LDL-cholesterol and blood pressure reduction have been proven by large meta-analysis to reduce both cardiovascular events and mortality in all patients with T2DM. Treatment of microalbuminuria and anti-platelet therapy have only been proven in diabetic patients with increased cardiovascular risk. Classical lifestyle interventions have been disappointing with respect to cardiovascular outcome, possibly due to limited weight reduction. So far, the strongest evidence lies on bariatric surgery and a multifactorial intervention to reduce mortality and cardiovascular events in the long term. [ABSTRACT FROM AUTHOR]

Background. Obesity and asthma are associated. There is a relationship between lung function impairment and the metabolic syndrome. Whether this relationship also exists in the morbidly obese patients is still unknown. Hypothesis. Low-grade systemic inflammation associated with the metabolic syndrome causes inflammation in the lungs and, hence, lung function impairment. Methods. This is cross-sectional study of morbidly obese patients undergoing preoperative screening for bariatric surgery. Metabolic syndrome was assessed according to the revised NCEP-ATP III criteria. Results. A total of 452 patients were included. Patients with the metabolic syndrome (n = 293) had significantly higher blood monocyte (mean 5.3 versus 4.9, P = 0.044) and eosinophil percentages (median 1.0 versus 0.8, P = 0.002), while the total leukocyte count did not differ between the groups. The FEV1/FVC ratio was significantly lower in patients with the metabolic syndrome (76.7% versus 78.2%, P = 0.032). Blood eosinophils were associated with FEV1/FVC ratio (adj. B .0.113, P = 0.018). Conclusion. Although the difference in FEV1/FVC ratio between the groups is relatively small, in this cross-sectional study, and its clinical relevance may be limited, these data indicate that the presence of the metabolic syndrome may influence lung function impairment, through the induction of relative eosinophilia. [ABSTRACT FROM AUTHOR]

Abstract: Background: Plant stanols have been recommended in combination with individualized dietary interventions to reduce plasma cholesterol concentrations. It is unclear whether plant stanols in combination with dietary guidance in patients already using optimal doses of statins will further reduce fasting and postprandial lipids compared with standard care. Study Design: This single-blind, randomized study investigated the effect of plant stanols in margarines, combined with a lipid-lowering dietary intervention, in patients already on lipid-lowering medications at maximal doses not reaching their target lipid levels. Nutrition education was based on the stages of change theory. The control group (which served as the standard care control group) was also taking optimal doses of statins. This group received a margarine without plant stanols and a leaflet with Dutch nutrition guidelines. Fasting lipids were measured once in venous samples and postprandial lipemia was assessed by self-measured triglycerides in an outpatient setting. All subjects were given a capillary triglyceride measuring device (Accutrend GCT, Roche Diagnostics, Mannheim, Germany) and were instructed to measure their capillary triglycerides at six fixed time-points throughout the day on three different days. The mean area under the triglyceride curve represented total daylong triglyceridemia, which has been shown to reflect postprandial triglyceridemia. Twenty patients were included, 11 in the intervention group and 9 in the control group. Results: In the plant stanol group, low-density lipoprotein cholesterol decreased significantly by 15.6% compared with a reduction of only 7.7% in the control group. The daylong triglyceridemia was similar in both groups at the beginning and at the end of the study, and no change was observed by the intervention. Conclusion: Intensive dietary intervention with addition of plant stanols results in clinically relevant reduction of low-density lipoprotein cholesterol in patients optimally treated with statins, compared with similar patients on statins receiving only standard care. The use of a plant stanol-enriched margarine did not decrease postprandial triglyceridemia in these patients. [Copyright &y& Elsevier]

Aims: To assess the relationship between the degree of loss of foot sensation at baseline and incidence of foot ulceration (DFU).Methods: Diabetic patients (n = 416) participating in the observational Rotterdam Diabetic Foot (RDF) Study were followed prospectively (median 955.5 days (IQR, 841.5-1121)). Subjects underwent sensory testing of the feet (39-item RDF Study Test Battery) at baseline and were assessed regarding incident DFU. Seven groups of incremental degree of sensory loss were distinguished, according to the RDF-39 sum score. Kaplan-Meier and regression analyses were used to determine the independent hazard of baseline variables for new DFU.Results: 40 participants developed DFUs. The mean incident rate of new-onset ulceration from study start was 4.5 (95%CI: 3.3 to 6.1) per 100 person-years, which increased significantly from 0 to 67.70 in the seven groups (p < 0.0005). Predictors for DFUs were higher RDF-39 score (aHR: 1.173, p < 0.0005) and kidney function (aHR: 1.022, p = 0.016). Prior DFU suggests increased mortality risk.Conclusions: The degree of sensory loss at baseline was associated with progression to DFU during follow-up. Grading the loss of sensation using the RDF Study Test Battery may result in a more precise risk stratification compared to the use of the 10 g monofilament according to current guidelines. [ABSTRACT FROM AUTHOR]

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]

Summary: The prevalence of nonalcoholic fatty liver disease (NAFLD) and the more severe and inflammatory type, nonalcoholic steatohepatitis (NASH), is increasing rapidly. Especially in high‐risk patients, that is those with obesity, metabolic syndrome, and type 2 diabetes mellitus, the prevalence of NAFLD can be as high as 80% while NASH may be present in 20% of these subjects. With the worldwide increase of obesity, it is most likely that these numbers will rise. Since advanced stages of NAFLD and NASH are strongly associated with morbidity and mortality—in particular, cardiovascular disease, liver cirrhosis, and hepatocellular carcinoma—it is of great importance to identify subjects at risk. A great variety of noninvasive tests has been published to diagnose NAFLD and NASH, especially using blood‐ and imaging‐based tests. Liver biopsy remains the gold standard for NAFLD/NASH. This review aims to summarize the different mechanisms leading to NASH and liver fibrosis, the different noninvasive liver tests to diagnose and evaluate patients with severe obesity. [ABSTRACT FROM AUTHOR]

Background: Increased triglycerides (TG) are associated with atherosclerosis. We determined free-living non-fasting TG concentrations in healthy Dutch subjects. Methods: Capillary TG (TGc) was self-measured by 109 males and 104 females during 3 days, on six fixed time-points each day; fasting, before and 3 h after lunch, before and 3 h after dinner and at bedtime. Daylong TGc-profiles were calculated as area under the mean TGc-curve (TGc-AUC). Reference values for “high” and “normal” daylong TGc concentrations were calculated as the 95th and 75th percentiles, respectively. Results: Fasting TGc were higher in males compared with females (1.41±0.75 versus 1.27±0.59 mmol/l), resulting in higher TGc-AUC (25.4±10.4 versus 20.6±9.8 mmol h/l). The highest TGc-concentrations were found in the evening. The majority of subjects (95%) had TGc during the evening below 4.6 mmol/l in males and below 3.7 mmol/l in females. Seventy-five percent of the subjects had TGc during the evening below 2.9 mmol/l in males and below 2.2 mmol/l in females. During the day (with exclusion of post-dinner TGc), 95% of the subjects had TGc below 3.7 mmol/l in males and below 3.6 mmol/l in females. Finally, 75% of the subjects had TGc during the day below 2.5 mmol/l in males and 1.7 mmol/l in females. Conclusions: The present data may help to delineate normal ranges of non-fasting TG and could be used to detect groups at risk for atherosclerosis on the basis of a disturbed TG metabolism. [Copyright &y& Elsevier]

Abstract: Current guidelines for the management of dyslipidaemias recommend measuring lipid profiles in the fasting state. The primary lipid targets are traditionally plasma total cholesterol and low-density lipoprotein-cholesterol (LDL-C) levels. However, triglycerides, apolipoprotein (apo) B and non-high-density lipoprotein-cholesterol (non-HDL-C) are also suitable parameters to assess cardiovascular risk and to guide lipid-lowering therapy. The advantage of the use of these variables is that they can be used in both the fasting and non-fasting state. In most cases, postprandial lipid profiles in combination with apo B are as useful as fasting lipid profiles for the differentiation between familial lipid disorders, such as heterozygous familial hypercholesterolemia, familial combined hyperlipidemia and familial hypertriglyceridemia. This article will address the interpretation, applications and limitations of a non-fasting lipid profile for daily clinical practice. [Copyright &y& Elsevier]

Aims: Sensory loss and impaired balance are considered risk factors of incident falls. The aim of this study was to assess the relationship between degree of foot sensation and balance, risk of falls, incidence of fall-related injuries and costs in a cohort of patients with diabetes.Methods: (Non)-neuropathic subjects participating in the Rotterdam Diabetic Foot Study were followed prospectively. Subjects underwent sensory testing of the feet (39 item Rotterdam Diabetic Foot Study Test Battery (RDF-39)); balance was assessed at the second follow-up (Brief-BESTest) as were data on incident falls. Medical records and financial data were abstracted to estimate fall-related morbidity and in-hospital costs.Results: A higher RDF-39 score, cerebral artery disease, type 2 diabetes, height and age were predictors of the Brief-BESTest total score. 41/296 patients (13.9%) reported two or more falls during follow-up. Predictors for recurrent falls were a higher RDF-39 score (aOR: 1.124, p < 0.0005), male gender (aOR: 0.319, p = 0.016), age (aOR: 0.938, p = 0.003) and type 2 diabetes (aOR: 3.157, p = 0.100). Thirty-one patients used medical resources (median US$ 440.45 (IQR: 179-1162).Conclusions: Degree of sensory loss correlates significantly with an increased imbalance and risk of falls. The RDF-39 may be used as stratification tool in medical decision-making and patient information. [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]

Background Leucocyte activation is an obligatory factor in the development of atherosclerosis. The postprandial situation has been associated to increased leucocyte activation in several disorders, such as type 2 diabetes mellitus and familial combined hyperlipidaemia. Our study aim was to evaluate the effect of post- OGTT hyperglycaemia on leucocyte activation in patients with familial hypercholesterolemia ( FH). Materials and methods Patients who met the diagnostic criteria for heterozygous FH and healthy volunteers were asked to undergo an oral glucose tolerance test. Leucocyte activation markers CD11b and CD66b were determined by flow cytometry. Post- OGTT changes were calculated as area under the curve ( AUC) and the incremental area under the curve corrected for baseline values ( dAUC). The impact of being an FH patient and using statins on the time-dependent profile of the leucocyte activation markers was studied with repeated measurements analysis. Results Thirteen FH patients using statins, nine FH patients without statins and 14 healthy volunteers were included. FH subjects on statins had a slightly higher HbA1c than those not using these drugs or controls. Post- OGTT glucose levels were significantly higher in patients with FH when compared to healthy controls ( P = 0·001). These effects were independent from the use of statins. Conclusions Surprisingly, our study shows impaired post- OGTT glucose excursions in patients with FH compared to healthy volunteers. Post- OGTT hyperglycaemia may be related to persistent post- OGTT activation of monocytes in FH patients compared to healthy controls, and therefore, it may contribute to the development of cardiovascular disease in patients with FH. [ABSTRACT FROM AUTHOR]

Background: The diabetic foot imposes significant burden on healthcare systems. Obtaining knowledge on the extent of the costs of diabetic foot ulcers (DFUs) is of value to health care researchers investigating cost-effectiveness of interventions that prevent these costly complications.Objectives: To estimate the in-hospital costs associated with the treatment of DFUs by a multidisciplinary diabetic foot team.Methods: Persons with DFUs presenting to our team in 2013 and 2014 were followed and use of care was estimated. Exclusion criteria were a single visit only and ulcers above the ankle. Demographic data and per-person incremental clinical outcomes (e.g., healing with or without amputation and rehabilitation) were assessed. Resource use was identified, measured and multiplied by unit costs.Results: Eighty-nine persons were identified with 56 persons meeting the inclusion criteria (with 69 DFU episodes). The median in-hospital care was 17weeks (inter quartile range: 7-34). Average in-hospital costs were US$ 10,827 (range: 702-82,880) per DFU episode. Primary healed DFUs costs on average US$ 4830, single minor amputations on average US$ 13,580, multiple minor amputations on average US$ 31,835 and major amputations on average US$ 73,813 per episode. Costs differed significantly between groups (p<0.001).Conclusion: DFUs are associated with substantial immediate and long-term in-hospital costs. Our study provides estimates of these costs, aiding researchers and health policy analysis. [ABSTRACT FROM AUTHOR]

Introduction: No data are available for normative values of cutaneous threshold and spatial discrimination in the feet. We developed clinically applicable reference values in relation to the nerve distributions of the feet.Methods: We determined foot sensation in 196 healthy individuals. Cutaneous threshold (1-point static discrimination, S1PD) was tested with monofilaments (0.008 to 300 gram) and spatial discrimination (2-point static [S2PD] and moving [M2PD] discrimination) on five locations per foot.Results: There was a significant age-dependent increase in S1PD, S2PD, and M2PD values (P < 0.05). No significant differences were found between both feet. S1PD values differed up to 0.8 g between genders. There were no significant differences between genders for S2PD and M2PD measurements. M2PD values were generally lower than S2PD values.Conclusions: This study provides age-related normative values for foot sensation to help clinicians assess sensory deficits in relation to aging and identify patients with underlying nerve problems. Muscle Nerve 56: 399-407, 2017. [ABSTRACT FROM AUTHOR]

Background The binding of apolipoprotein (apo) B-containing lipoproteins to circulating erythrocytes (ery-apoB) is associated with a decreased prevalence of atherosclerosis. In this study, we evaluated ery-apoB as a possible prognostic factor in cardiovascular events and all-cause mortality, in a prospective cohort study. Materials and methods Ery-apoB was measured by flow cytometry in subjects with and without cardiovascular disease ( CVD). The primary endpoint was the cardiovascular event rate. Secondary endpoints were all-cause mortality and the combined endpoint of all-cause mortality and cardiovascular events (any event rate). A Cox regression analysis with univariate and multivariate analyses and Kaplan-Meier survival analysis was performed. Results Follow-up data were available of 384 subjects. Subjects were divided according to high (> 2·0 au, n = 60), intermediate (0·2-2·0 au, n = 274) or low (< 0·2 au, n = 50) ery-apoB. Median follow-up was 1767 days ( IQR 1564-2001). In univariate analysis, low ery-apoB was associated with increased all-cause mortality [ HR 9·9 (1·2-79·0), P = 0·031] and any event rate [ HR 3·4 (95% CI 1·3-8·7), P = 0·012]. In a Cox regression analysis, only a history of CVD was significantly associated with any event rate [ HR 3·6 (1·6-8·0), P = 0·002], while low ery-apoB showed a trend [ HR 2·4 (0·9-6·4), P = 0·07]. In a subgroup analysis, in subjects with a history of CVD, ery-apoB was significantly associated with all-cause mortality (log rank P = 0·021) and any event rate (log rank P = 0·009). Conclusions Low ery-apoB is associated with increased mortality and cardiovascular risk, especially in patients with a prior history of CVD. These subjects may benefit from more aggressive secondary prevention treatment. [ABSTRACT FROM AUTHOR]

Background and aims Inflammation plays a key role in atherosclerosis. The complement system is involved in atherogenesis, and the complement receptor 1 (CR1) plays a role facilitating the clearance of immune complexes from the circulation. Limited evidence suggests that CR1 may be involved in cardiovascular disease. We investigated the relationship between CR1 gene polymorphisms and cardiovascular risk. Methods Single nucleotide polymorphisms (SNPs) within the CR1 region (n = 73) on chromosome 1 were assessed in 5244 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and followed for a mean of 3.2 years. Logistic regression, adjusted for gender, age, country and use of pravastatin, was used to assess the association between the SNPs and cardiovascular disease. Results All 73 SNPs within the genomic region of the CR1 gene on chromosome 1 were extracted. In this region, strong LD was present leading to the occurrence of two haploblocks. Twelve of the 73 investigated CR1 SNPs were significantly associated with the risk of fatal or nonfatal myocardial infarction (all p < 0.05). Moreover, most of the associated SNPs were also associated with levels of serum C-reactive protein (CRP). The global p -value for the tail strength method to control for multiple testing was 0.0489, implying that the null hypothesis of no associated SNPs can be rejected. Conclusions These data indicate that genetic variation within the CR1 gene is associated with inflammation and the risk of incident coronary artery disease. [ABSTRACT FROM AUTHOR]

Background Atherosclerosis is a pro-inflammatory condition, in which leucocyte activation plays an important role. The interaction between circulating leucocytes and apolipoprotein (apo) B-containing lipoproteins results in pro-inflammatory changes of these cells. We aimed to evaluate the relationship between apo B bound to circulating leucocytes and atherosclerosis. Methods Apo B on circulating leucocytes was measured by flow cytometry in subjects with and without cardiovascular disease ( CVD), expressed as mean fluorescent intensity in arbitrary units (au). Carotid intima-media thickness ( cIMT) was measured using B-mode ultrasound. Data are given as median (interquartile range). Results A total of 396 subjects were included, of whom 183 had a history of CVD. Compared to subjects without CVD, patients with CVD had lower apo B bound to neutrophils (12·7 au (9·8-16·2) and 14·2 au (10·1-17·5), respectively, P = 0·038) and to monocytes (2·5 au (1·7-3·1) and 2·7 (1·9-3·6) au, respectively, P = 0·025). No differences were found for lymphocyte-bound apo B. Neutrophil- and monocyte-bound apo B were inversely correlated with cIMT (Spearman's rho: −0·123, P = 0·017 and −0·108, P = 0·035, respectively). Both monocyte- and neutrophil-bound apo B were inversely associated with different factors related to the metabolic syndrome, such as body mass index, triglycerides and complement C3. There was a positive association between erythrocyte-bound apo B and apo B bound to each of the leucocyte classes, possibly reflecting a similar mechanism. Discontinuation of statins in 54 subjects did not influence leucocyte-bound apo B. Conclusion Unexpectedly, the presence of noninternalized apo B-containing lipoproteins on circulating neutrophil and monocyte membranes may represent a protective mechanism against atherosclerosis. [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]

Background and aims The postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers. Methods Leukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h). Results Fasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 ± 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 ± 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression. Conclusion This study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia. [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]

Lipoproteins can induce complement activation resulting in opsonization and binding of these complexes to complement receptors. We investigated the binding of opsonized native LDL and acetylated LDL (acLDL) to the complement receptor 1 (CR1). Binding of complement factors C3b, IgM, C1q, mannose-binding lectin (MBL), and properdin to LDL and acLDL were investigated by ELISA. Subsequent binding of opsonized LDL and acLDL to CR1 on CR1-transfected Chinese Hamster Ovarian cells (CHO-CR1) was tested by flow cytometry. Both native LDL and acLDL induced complement activation with subsequent C3b opsonization upon incubation with normal human serum. Opsonized LDL and acLDL bound to CR1. Binding to CHO-CR1 was reduced by EDTA, whereas MgEGTA only reduced the binding of opsonized LDL, but not of acLDL suggesting involvement of the alternative pathway in the binding of acLDL to CR1. In vitro incubations showed that LDL bound C1q, whereas acLDL bound to C1q, IgM, and properdin. MBL did neither bind to LDL nor to acLDL. The relevance of these findings was demonstrated by the fact that ex vivo up-regulation of CR1 on leukocytes was accompanied by a concomitant increased binding of apolipoprotein B-containing lipoproteins to leukocytes without changes in LDL-receptor expression. In conclusion, CR1 is able to bind opsonized native LDL and acLDL. Binding of LDL to CR1 is mediated via the classical pathway, whereas binding of acLDL is mediated via both the classical and alternative pathways. Binding of lipoproteins to CR1 may be of clinical relevance due to the ubiquitous cellular distribution of CR1. [ABSTRACT FROM AUTHOR]

Aims: We aimed to gain insight into the underlying pathophysiology of cardiac dysfunction in obesity patients and the improvement of cardiac function after weight loss. Methods: This is a longitudinal study in which 92 cardiovascular biomarkers were measured by multiplex immunoassays in obesity patients without known cardiovascular disease, before and one year after bariatric surgery. Results: Out of 100 eligible patients, 72 patients completed the follow-up. A total of 72 (78%) biomarkers changed significantly. The biomarkers with the highest relative changes represented processes linked mainly to insulin resistance and inflammation. In the patients with persistent subclinical cardiac dysfunction, the baseline values of 10 biomarkers were different from values in patients with normalization of cardiac function. Most of these biomarkers were linked to inflammation or atherosclerosis. Finally, a model was developed to investigate the relationship between changes in the biomarkers and persistent subclinical cardiac dysfunction. Seven biomarkers were retained in this model, mainly linked to inflammation, atherosclerosis, and hypercoagulability. Conclusion: The majority (78%) of cardiovascular biomarkers changed, pointing mainly to modulation of insulin resistance and inflammation. The baseline levels of 10 biomarkers, as well as pre- to post-bariatric surgery changes in seven biomarkers, were related to persistent subclinical cardiac dysfunction after bariatric surgery. [ABSTRACT FROM AUTHOR]

Background Coronary artery disease ( CAD) may reflect generalized inflammation. We evaluated leucocyte activation in subjects with and without CAD in different vascular compartments. Materials and Methods Patients were divided in two groups; subjects without CAD (controls; n = 25) and with stable CAD ( n = 52) based on coronary angiography. After blood sampling from vessels, cardiovascular risk factors and leucocyte activation markers CD11b, CD66b and cytoplasmatic myeloperoxidase ( MPO) were determined by flow cytometry. Results Myeloperoxidase ( MPO) was higher in patients with CAD at all sites compared with controls (188 ± 7 vs. 210 ± 12 au for venous ( P < 0·05), 178 ± 7 vs. 212 ± 12 au for femoral artery ( P = 0·08), 166 ± 7 vs. 195 ± 12 au for abdominal artery ( P < 0·05), 166 ± 6 vs. 189 ± 14 au for left coronary ( P = 0·08) and 163 ± 6 vs. 193 ± 12 au for the right coronary artery ( P < 0·05)). Other markers did not differ between the groups. A gradient of inflammation from peripheral vessels to the coronaries was found by differences in MPO in both groups; from 210 ± 12 au in the venous compartments towards 189 ± 14 and 193 ± 12 au, in the left and right coronaries, respectively, for the controls ( P = 0·001), and from 188 ± 7 au in the venous compartment towards 166 ± 6 and 163 ± 6 au in the left and right coronaries, respectively, for the patients ( P = 0·007). Other leucocyte activation markers did not show such a gradient. Conclusions There is a generalized inflammatory neutrophil gradient for MPO from peripheral vessels towards the coronaries in both patients with CAD and controls. However, patients with CAD show a higher degree of inflammation, mostly in the coronaries. These data strengthen the role of activated neutrophils in CAD. [ABSTRACT FROM AUTHOR]

Eur J Clin Invest 2012; 42 (4): 365-370 Abstract Background Apolipoprotein (apo) B-containing lipoproteins are closely linked to atherogenesis. These lipoproteins are transported in plasma and are also associated with blood leucocytes. Our aim was to investigate whether apoB-containing lipoproteins are also present on the surface of erythrocytes and investigate the relationship with the presence of atherosclerosis in a cross-sectional study. Materials and methods Erythrocyte-bound apoB (ery-apoB) was measured by flowcytometry in subjects with (CAD+) and without coronary artery disease (CAD−), based on coronary angiography or on a history of cardiovascular disease. Intima media thickness (IMT) measurements were carried out using B-mode ultrasound. The relationship between ery-apoB and clinical and subclinical atherosclerosis was evaluated with binary logistic regression. Results A total of 166 subjects were included (40 CAD+ and 126 CAD−). ApoB was detected on freshly isolated erythrocytes (range: 0·1-5·5 au; mean ± SEM 0·86 ± 0·09 au) in all but nine subjects (four CAD+ and five CAD−). Ery-apoB was lower in CAD+ (0·62 ± 0·09 au) compared to CAD− (1·18 ± 0·10 au; P < 0·001). Higher ery-apoB was associated with a lower risk of CAD (adjusted OR: 0·003 (95% CI: 0·001-0·08; P < 0·001), but the protective effect was diminished with increasing age (adjusted OR: 1·10 (95% CI: 1·04-1·16; P < 0·001). IMT was increased in CAD+ subjects (0·77 ± 0·13 mm) compared to CAD− (0·57 ± 0·14 mm; P < 0·001). A significant negative association was found between ery-apoB and IMT (β = −0·214: 95% CI −0·284 to −0·145; P < 0·001). There was no association between ery-apoB and plasma apoB (Pearson's r = −0·45; P = 0·57). Conclusions Human erythrocytes carry apoB-containing lipoproteins. Subjects with atherosclerosis have lower ery-apoB. High ery-apoB may be protective against atherosclerosis and may reflect an alternative blood cell-mediated lipoprotein transport system in the circulation, in which these lipoproteins less likely interact with the endothelium. [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]

Abstract: Highly active antiretroviral therapy in Human Immunodeficiency Virus (HIV) has been associated with lipodystrophy, insulin resistance and atherosclerosis. We investigated the effects of rosiglitazone or metformin on fasting and postprandial inflammatory and antioxidant variables in HIV-infected males with lipodystrophy. Thirty-one patients were randomly assigned to receive either rosiglitazone (4 mg twice daily) or metformin (1 g twice daily) for 26 weeks. At baseline and after treatment, standardized 10-h oral fat loading tests were performed. Before treatment, inflammatory variables remained unchanged but there was a postprandial decrease in high density lipoprotein (HDL)-cholesterol and paraoxonase (PON1) activity. Rosiglitazone and metformin reduced homeostasis model assessment index (HOMA) similarly (−34% and −37%, respectively, P <0.05 for each). Both treatments increased fasting and postprandial PON1 activity and decreased postprandial monocyte chemoattractant protein 1 (MCP-1) concentrations. However, plasma C-reactive protein (CRP) and Interleukin-6 (IL-6) concentration did not change throughout the study. To decrease insulin resistance results in a higher anti-oxidant and consequent lower pro-inflammatory action of HDL. This may confer protection against accelerated atherosclerosis in these patients. [Copyright &y& Elsevier]

Objective: To describe postprandial lipemia in patients with rheumatoid arthritis (RA) and to analyze its association with subclinical atherosclerosis measured as carotid intima-media thickness (cIMT). Methods: We performed an observational study of 40 patients with RA and 40 sex and age-matched controls. Patients with dyslipidemia were excluded. Pathologically increased cIMT was defined as a carotid thickness greater than the 90th percentile (>p90) for age and sex. Fasting and postprandial plasma lipids, cholesterol, triglycerides, apolipoprotein B48 (ApoB48), and total ApoB were evaluated. The other variables included were clinical and laboratory values, Framingham score, and the 28-joint Disease Activity Score (DAS28). Two multivariate models were constructed to identify factors associated with pathologic cIMT in patients with RA. Results: Fasting lipid values were similar in patients with RA and controls, although those of postprandial ApoB48 were higher (median (IQR), 14.4 (10.8–12.1) vs. 12.1 (2.3–9,8); p = 0.042). Pathologic cIMT was recorded in 10 patients with RA (25%) and nine controls (22.5%). In patients with RA, pathologic cIMT was associated with postprandial ApoB48 (OR (95% CI), 1.15 (1.0–1.3)) and total ApoB (OR [95% CI], 1.12 [1.1–1.2]). The second model revealed a mean increase of 0.256 mm for cIMT in patients with elevated anticitrullinated protein antibodies (ACPAs). Conclusion: Postprandial ApoB48 levels in patients with RA are higher than in controls. Postprandial ApoB48 and total ApoB levels and markers of severity, such as ACPAs, are associated with pathologic cIMT in patients with RA. Our findings could indicate that these atherogenic particles have a negative effect on the endothelium. [ABSTRACT FROM AUTHOR]

Background: Women are relatively protected from cardiovascular disease compared with men. Since morbid obesity is an independent risk factor for cardiovascular disease, the current study investigated whether the association between sex and cardiovascular risk factors and outcomes can be demonstrated in subjects suffering from morbid obesity. Materials and methods: Two hundred subjects enrolled in a study on cardiovascular risk factors in morbid obesity underwent extensive laboratory screening, carotid intima‐media thickness (cIMT) and pulse wave velocity (PWV) measurements. Gender differences were analysed using univariate and multivariable linear regression models. In addition, the effect of menopause on cIMT and PWV was analysed. Results of these models were reported as B coefficients with 95% confidence intervals. Results: The group consisted of 52 men and 148 women, with a mean age of 41 (±11.8) years and a mean body mass index (BMI) of 42.7 (±5.2) kg/m2. Both, cIMT and PWV were significantly higher in men than in women, although the difference in cIMT disappeared after adjustment for covariables such as waist circumference, age, high‐density lipoprotein cholesterol and mean arterial pressure. PWV was associated with sex after adjustments for covariables in morbidly obese patients. Postmenopausal women had significantly increased cIMT and PWV when compared with premenopausal women. Conclusion: Sex differences in PWV persist in subjects suffering from morbid obesity. However, no difference was found in cIMT between morbidly obese men and women after adjustment for classic cardiovascular risk factors. Premenopausal morbidly obese women are protected for cardiovascular disease when compared with postmenopausal morbidly obese women. [ABSTRACT FROM AUTHOR]

Introduction: Patients with Rheumatoid Arthritis (RA) have an increased risk for cardiovascular disease (CVD) compared to the general population. No long term intervention trials on CVD risk factors in RA have been published so far, and a debate on the efficacy of controlling traditional risk factors in RA is ongoing. Methods: In this open-label randomised controlled trial, RA patients <70 years without prior CVD or diabetes mellitus were randomized to either a treat-to-target approach (according to pre-specified treatment targets) or usual care regarding traditional CVD risk factors. The primary outcome was defined as change in carotid intima media thickness (cIMT) as a marker for subclinical atherosclerosis and the secondary outcome was a composite of cardiovascular events. Results: A total of 320 patients underwent randomization and 218 completed 5 years follow-up (115 for treat-to-target group and 103 for usual care). Mean (± SD) baseline cIMT in the treat-to-target group was 0.570 ± 0.108 vs. 0.569 ± 0.113 mm (p=0.91) for usual care. The primary outcome reached statistical significance showing decreased progression of cIMT in those allocated to the treat-to-target intervention compared to usual care (0.029 ± 0.081 vs. 0.056 ± 0.103 mm; p=0.034). There was no difference in antihypertensive treatment between groups, however more patients in the treat-to-target group received statin treatment compared to usual care (48.3% vs. 21.4%; p<0.001), resulting lower LDL-C level (2.5 ± 0.8 vs. 3.1 ± 0.6 mmol/L; p<0.001). Cardiovascular events occurred in 1.3% of the patients in the treat-to-target group vs. 4.7% in those receiving usual care (p=0.048), leading to an absolute risk reduction of 3.4%. The numbers needed to treat to prevent one single cardiovascular event over 5 years was 30, which is much lower than in most secondary prevention CVD intervention trials using anti-hypertensives or lipid lowering therapy in non-RA populations. Conclusions: Intensive treat-to-target intervention of traditional CVD risk factors for primary prevention in RA is efficient. These data underscore the urgency for cardiovascular risk management programs in RA and provide for the first time support for implementation of current guidelines targeting traditional risk factors. [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]