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Klop B.,Center for Diabetes and Vascular Medicine | Hazes J.M.W.,Erasmus Medical Center | Cabezas M.C.,Center for Diabetes and Vascular Medicine
Atherosclerosis | Year: 2013

Patients with rheumatoid arthritis (RA) carry an excess risk for cardiovascular disease, which is comparable to the risk in patients with type 2 diabetes mellitus. The mechanisms involved are partly related to traditional cardiovascular risk factors, disease-associated inflammation and undertreatment of traditional cardiovascular disease (CVD) risk factors. Since atherosclerosis is an inflammatory disease, the auto-immune mediated inflammation observed in RA patients contributes to increased endothelial dysfunction, oxidative stress and activation and vascular migration of leukocytes. This concept is underscored by the CVD risk reduction that is seen by anti-inflammatory disease modifying anti-rheumatic drugs such as methotrexate and TNFα inhibitors. The evidence for underdiagnosis and undertreatment of traditional CVD risk factors in RA strengthens the potential benefit of structured CVD risk management in these patients. Current cardiovascular guidelines recommend screening and treatment of CVD risk factors in RA patients, without well defined treatment targets. At present, there is a lack of scientific evidence to establish treatment targets for CVD risk factors in RA. Therefore, expanding research regarding screening and treatment of traditional CVD risk factors in RA patients is needed. © 2013 Elsevier Ireland Ltd.


De Vries M.A.,Center for Diabetes and Vascular Medicine | Alipour A.,Center for Diabetes and Vascular Medicine | Klop B.,Center for Diabetes and Vascular Medicine | Van Der Meulen N.,Center for Diabetes and Vascular Medicine | And 3 more authors.
Metabolism: Clinical and Experimental | Year: 2015

Background. Leukocyte activation has been associated with vascular complications in type 2 diabetes mellitus (T2DM). Hyperglycemia may be involved in this leukocyte activation. Our aim was to investigate the role of elevated glucose concentrations on leukocyte activation in patients with a wide range of insulin sensitivity. Methods. Leukocyte activation was determined after ingestion of 75 gram glucose in subjects with T2DM, familial combined hyperlipidemia (FCH) and healthy controls. Leukocyte activation markers were measured by flow cytometry. Postprandial changes were calculated as the area under the curve (AUC), and the incremental area under the curve corrected for baseline values (dAUC). Results. 51 subjects (20 T2DM, 17 FCH and 14 controls) were included. Fasting neutrophil CD66b expression and CD66b-AUC were respectively 36% and 39% higher in T2DM patients than in controls (p = 0.004 and p = 0.003). Fasting neutrophil CD66b expression correlated positively with glucose-AUC (Spearman's rho 0.481, p < 0.001) and HbA1c (rho 0.433, p = 0.002). Although fasting monocyte CD11b expression was not significantly different between subjects, monocyte CD11b-AUC was 26% higher in T2DM than in controls (p = 0.006). Similar trends were observed for FCH patients. Monocyte CD11b-dAUC correlated positively with glucose-AUC (rho 0.322, p = 0.022) and HbA1c (rho 0.319, p = 0.023). Conclusions. These data suggest that both acute and chronic hyperglycemia, associated with insulin resistance as seen in T2DM and FCH, are involved in the increased fasting and postprandial leukocyte activation observed in these conditions. © 2015 Elsevier Inc. All rights reserved.


Van Wijk J.P.H.,University Utrecht | Hoepelman A.I.M.,University Utrecht | De Koning E.J.P.,Leiden University | Rabelink T.J.,Leiden University | Cabezas M.C.,Center for Diabetes and Vascular Medicine
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective- To compare the effects of rosiglitazone (8 mg/d, n=19) and metformin (2 g/d, n=18) on postprandial lipemia in patients with HIV-lipodystrophy. Methods and results- Lipodystrophy in HIV is associated with insulin resistance and disturbed postprandial triglyceride and free fatty acid (FFA) metabolism. We conducted an open randomized 6-month study with standardized 10-h oral fat-loading tests at baseline and after treatment. Rosiglitazone (-34%) and metformin (-37%) reduced homeostasis model assessment similarly (P<0.05). Rosiglitazone did not change the area under the curve for FFA and triglyceride; however, it did reduce the area under the curve for hydroxybutyric acid (a marker of hepatic FFA oxidation) by 25% (P<0.05). Rosiglitazone increased the area under the curve for remnantlike particle cholesterol by 40% (P<0.01) compared with baseline. Metformin did not change any of the postprandial measurements. Conclusion- Rosiglitazone improved insulin sensitivity and decreased postprandial hydroxybutyric acid levels in patients with HIV-lipodystrophy, suggesting improved FFA handling. Despite metabolic improvements, rosiglitazone caused a marked increase in postprandial remnantlike particle cholesterol, which may adversely affect cardiovascular risk. Metformin did not affect postprandial lipemia and could be used to treat insulin resistance in this population. © 2011 American Heart Association. All rights reserved.


Hermans M.P.,Catholic University of Leuven | Castro Cabezas M.,Center for Diabetes and Vascular Medicine | Strandberg T.,University of Oulu | Ferrires J.,Toulouse University Hospital Center | And 4 more authors.
Current Medical Research and Opinion | Year: 2010

Background: Surveys evaluating plasma lipid goal attainment in patients with coronary heart disease have shown that hypercholesterolaemia is inadequately treated. Limited data account for the reasons behind this. The aim of the CEntralized Pan-European survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS) survey was to evaluate the current use and efficacy of lipid-lowering drugs (LLD), and to identify possible patient/physician characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets recommended by the 2003 European guidelines (Third Joint Task Force). Methods: CEPHEUS was a European, multi-centre, cross-sectional survey conducted in eight countries and involved patients on LLD for >3 months (stable medication >6 weeks). One visit was scheduled for data collection, including fasting lipids. In all but one country, physicians and patients filled in a questionnaire about aspects of hypercholesterolaemia and treatment. Clinical trial registration: NCT00542867 (ClinicalTrials.gov). Results: Of the 15199 patients recruited, 14478 were included in the final analyses. The mean age was 63.2 years, and 45 of patients were female. Overall, 55.3 of the patients achieved their LDL-C target. In multivariate analyses, the factors identified as positive predictors for achieving LDL-C goals included normal body mass index, not smoking, not having metabolic syndrome, being on statin therapy and good treatment adherence. Limitations: The population was a selected group of subjects treated with LLD, and the results cannot be extrapolated to the general population. Patient consent was obtained, which may have selected more motivated patients and induced a positive bias. The physician and patient questionnaires were not validated, but were only used for exploratory purposes. Conclusion: Only 55.3 of patients using LLD achieved the LDL-C target recommended in the 2003 European guidelines. © 2010 Informa UK Ltd All rights reserved.


Klop B.,Center for Diabetes and Vascular Medicine | Rego A.T.D.,Institute for Health Research | Cabezas M.C.,Center for Diabetes and Vascular Medicine
Current Opinion in Lipidology | Year: 2013

Purpose of review: This study reviews recent developments concerning the effects of alcohol on plasma triglycerides. The focus will be on population, intervention and metabolic studies with respect to alcohol and plasma triglycerides. Recent findings: Alcohol consumption and fat ingestion are closely associated and stimulated by each other via hypothalamic signals and by an elevated cephalic response. A J-shaped relationship between alcohol intake and plasma triglycerides has been described. A normal body weight, polyphenols in red wine and specific polymorphisms of the apolipoprotein A-V and apolipoprotein C-III genes may protect against alcohol-associated hypertriglyceridemia. In contrast, obesity exaggerates alcohol-associated hypertriglyceridemia and therefore the risk of pancreatitis. Summary: High alcohol intake remains harmful since it is associated with elevated plasma triglycerides, but also with cardiovascular disease, alcoholic fatty liver disease and the development of pancreatitis. Alcohol-induced hypertriglyceridemia is due to increased very-low-density lipoprotein secretion, impaired lipolysis and increased free fatty acid fluxes from adipose tissue to the liver. However, light to moderate alcohol consumption may be associated with decreased plasma triglycerides, probably determined by the type of alcoholic beverage consumed, genetic polymorphisms and lifestyle factors. Nevertheless, patients should be advised to reduce or stop alcohol consumption in case of hypertriglyceridemia. © 2013 Wolters Kluwer Health.


PubMed | Center for Diabetes and Vascular Medicine and Sint Franciscus Gasthuis
Type: Journal Article | Journal: Frontiers of medicine | Year: 2016

Leukocyte activation has been linked to atherogenesis, but there is little in vivo evidence for its role in the progression of atherosclerosis. We evaluated the predictive value for progression of coronary artery disease (CAD) of leukocyte activation markers in the coronary circulation. Monocyte and neutrophil CD11b, neutrophil CD66b expression and intracellular neutrophil myeloperoxidase (MPO) in the coronary arteries were determined by flow cytometry in patients undergoing coronary angiography. The primary outcome included fatal and nonfatal myocardial infarction or arterial vascular intervention due to unstable angina pectoris. In total 99 subjects who were included, 70 had CAD at inclusion (26 patients had single-vessel disease, 18 patients had twovessel disease and 26 patients had three-vessel disease). The median follow-up duration was 2242 days (interquartile range: 2142-2358). During follow-up, 13 patients (13%) developed progression of CAD. Monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO measured in blood obtained from the coronary arteries were not associated with the progression of CAD. These data indicate that coronary monocyte CD11b, neutrophil CD11b and CD66b expression and intracellular MPO do not predict the risk of progression of CAD.


Klop B.,Center for Diabetes and Vascular Medicine | Proctor S.D.,University of Alberta | Mamo J.C.,Curtin University Australia | Botham K.M.,Royal Veterinary College | Castro Cabezas M.,Center for Diabetes and Vascular Medicine
International Journal of Vascular Medicine | Year: 2012

Postprandial hyperlipidemia with accumulation of remnant lipoproteins is a common metabolic disturbance associated with atherosclerosis and vascular dysfunction, particularly during chronic disease states such as obesity, the metabolic syndrome and, diabetes. Remnant lipoproteins become attached to the vascular wall, where they can penetrate intact endothelium causing foam cell formation. Postprandial remnant lipoproteins can activate circulating leukocytes, upregulate the expression of endothelial adhesion molecules, facilitate adhesion and migration of inflammatory cells into the subendothelial space, and activate the complement system. Since humans are postprandial most of the day, the continuous generation of remnants after each meal may be one of the triggers for the development of atherosclerosis. Modulation of postprandial lipemia by lifestyle changes and pharmacological interventions could result in a further decrease of cardiovascular mortality and morbidity. This paper will provide an update on current concepts concerning the relationship between postprandial lipemia, inflammation, vascular function, and therapeutic options. © 2012 Boudewijn Klop et al.


Van Wijk J.P.H.,University Utrecht | Cabezas M.C.,Center for Diabetes and Vascular Medicine
International Journal of Vascular Medicine | Year: 2012

The use of combination antiretroviral therapy (CART) in HIV-infected patients has resulted in a dramatic decline in AIDS-related mortality. However, mortality due to non-AIDS conditions, particularly cardiovascular disease (CVD) seems to increase in this population. CART has been associated with several metabolic risk factors, including insulin resistance, low HDL-cholesterol, hypertriglyceridemia and postprandial hyperlipidemia. In addition, HIV itself, as well as specific antiretroviral agents, may further increase cardiovascular risk by interfering with endothelial function. As the HIV population is aging, CVD may become an increasingly growing health problem in the future. Therefore, early diagnosis and treatment of cardiovascular risk factors is warranted in this population. This paper reviews the contribution of both, HIV infection and CART, to insulin resistance, postprandial hyperlipidemia and cardiovascular risk in HIV-infected patients. Strategies to reduce cardiovascular risk are also discussed. © 2012 Jeroen P. H. van Wijk and Manuel Castro Cabezas.


Klop B.,Center for Diabetes and Vascular Medicine | Castro Cabezas M.,Center for Diabetes and Vascular Medicine
Current Cardiovascular Risk Reports | Year: 2012

Cardiovascular disease can be considered a condition of chronic low-grade inflammation. Postprandial hyperlipidemia and obesity can both exacerbate inflammatory processes. Postprandial lipemia stimulates the activation of leukocytes, the production of chemokines, and activation of the complement system. Obesity is also associated with postprandial hyperlipidemia by hepatic overproduction of very low-density lipoprotein (VLDL) and consequently delayed clearance of intestinally derived chylomicrons due to competition for the same metabolic pathways. Insulin resistance is one of the key elements leading to hepatic VLDL overproduction and is also a key factor in the generation of inflammation. These metabolic derangements cause accumulation of atherogenic remnant lipoproteins, which is also a proatherogenic mechanism. Change in lifestyle is the most important therapeutic strategy to stop this vicious circle of postprandial hyperlipidemia, obesity, inflammation, insulin resistance, and cardiovascular disease. © 2011 Springer Science+Business Media, LLC.


Klop B.,Center for Diabetes and Vascular Medicine | Wouter Jukema J.,Leiden University | Rabelink T.J.,Leiden University | Castro Cabezas M.,Center for Diabetes and Vascular Medicine
Panminerva Medica | Year: 2012

Hypertriglyceridemia is a common lipid disorder associated to different, highly prevalent metabolic derangements like diabetes mellitus, the metabolic syndrome and obesity. The choice of treatment depends on the underlying pathogenesis and the consequences for atherosclerosis or pancreatitis. A family history, physical examination and analysis of the lipid profile including measurement of apolipoprotein B or non-HDL-C are necessary to establish the underlying primary or secondary cause. Due to physiological diurnal variations of triglycerides (TG), the time of measurement (fasting or postprandial) should be taken into account when evaluating TG values. Increased awareness arises concerning the impact of postprandial hypertriglyceridemia on the development of atherosclerosis. Hypertriglyceridemia is strongly associated to postprandial hyperlipidemia, remnant accumulation, increased small dense LDL concentrations, low HDL-C, increased oxidative stress, endothelial dysfunction, leukocyte activation and insulin resistance. All these factors are strongly linked to the development of atherosclerosis. Treatment should be aimed at reducing the secretion of triglyceride-rich lipoproteins, increasing intravascular lipolysis and reducing the number of circulating remnants. The main intervention is a change of lifestyle with decreased alcohol consumption, increased physical activity, dietary changes and, if applicable, adaptation of used medication. Fibrates, fish oil and nicotinic acid are the first choice of treatment in sporadic and familial hypertriglyceridemia to reduce the risk of pancreatitis, whereas high dose statins, sometimes in combination with fibrates, nicotinic acid, or fish oil capsules, are indicated for familial combined hyperlipidemia. Statins are necessary to reach low LDL-C concentrations in patients with type 2 diabetes mellitus and statin dosage should be increased when hypertriglyceridemia is present to reach secondary treatment targets for apolipoprotein B or non-HDL-C. Finally, family screening is mandatory to detect familial lipid disorders for early intervention in other family members.

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