The relation between body iron stores and adipose tissue function in patients with manifest vascular disease.

BACKGROUND: We investigated whether plasma ferritin levels through the pro-inflammatory effects of free iron are associated with adipose tissue dysfunction in a relevant population of patients with manifest vascular disease who would potentially benefit the most from further aetiological insights. MATERIALS AND METHODS: In a cohort of 355 patients with vascular diseases, the association between plasma ferritin and adiponectin levels was quantified using linear regression analysis. Interleukin-6 and adiponectin levels were measured in medium from pre-adipocytes and adipocytes after incubation with increasing concentrations of Fe(III)-citrate and after co-incubation with iron chelators or radical scavengers. RESULTS: Increasing ferritin plasma concentrations were not related to plasma adiponectin levels in patients without (ß -0·13; 95% CI -0·30 to 0·04) or with the metabolic syndrome (ß -0·04; 95% CI -0·17 to 0·10). Similar results were found in patients who developed a new cardiovascular event in the follow-up period. In vitro, incubation with increasing concentrations of Fe(III)-citrate-induced inflammation in pre-adipocyte cultures as witnessed by increased IL-6 secretion at 30 µm Fe(III)-citrate vs. control (500 ± 98 pg/mL vs. 194 ± 31 pg/mL, P = 0·03). Co-incubation of pre-adipocytes with iron chelators or radical scavengers prevented this inflammatory response. Incubation of adipocytes with 30 µm Fe(III)-citrate did not influence adiponectin secretion compared with control. CONCLUSIONS: In patients with vascular disease, there is no association between plasma ferritin and adiponectin levels. In vitro, free iron induces an inflammatory response in pre-adipocytes, but not in adipocytes. This response was blocked by co-incubation with iron chelators or radical scavengers. Adiponectin secretion by adipocytes was not influenced by free iron.

Endothelial progenitor cell levels in obese men with the metabolic syndrome and the effect of simvastatin monotherapy vs. simvastatin/ezetimibe combination therapy.

AIMS: Endothelial progenitor cells (EPCs) contribute to endothelial regeneration and thereby protect against cardiovascular disease (CVD). Patients with manifest CVD have reduced EPC levels, but it is not clear if this also occurs in subjects at high CVD risk without manifest atherosclerotic disease. Therefore, we aimed to first, measure circulating levels of EPCs in subjects without manifest CVD but at high cardiovascular risk due to obesity and presence of the metabolic syndrome. Second, we evaluated the effect on EPC levels of two lipid-lowering treatments. METHODS AND RESULTS: Circulating CD34+KDR+ EPC levels were reduced by nearly 40% in obese men with the metabolic syndrome compared to non-obese healthy controls (331 +/- 193 vs. 543 +/- 164 EPC/mL, P = 0.006). In a randomized double-blind cross-over study comparing intensive lipid-lowering treatment using 80 mg simvastatin mono-treatment with combination treatment of 10 mg simvastatin and 10 mg ezetimibe, we found a similar treatment effect on EPC levels. Secondary analyses of these data suggested that both treatment regimens had increased circulating EPCs to control levels (626 +/- 428 after combination treatment, P < 0.01; 524 +/- 372 EPC/mL after monotherapy, P < 0.05). Serum levels of EPC-mobilizing factor SCF-sR correlated with reduced EPC levels and normalized concurrently with treatment. CONCLUSION: EPC levels are reduced in apparently healthy men with abdominal obesity and the metabolic syndrome, even in the absence of manifest CVD. This is important as EPCs contribute to endothelial regeneration and thereby protect against CVD. SCF-sR may be a candidate serum marker of circulating EPC levels. Treatment with low-dose statin with ezetimibe combination therapy or high-dose statin monotherapy has similar effects on the reduced EPC levels.

Lipid-lowering therapy does not affect the postprandial drop in high density lipoprotein-cholesterol (HDL-c) plasma levels in obese men with metabolic syndrome: a randomized double blind crossover trial.

INTRODUCTION: The postprandial lipid metabolism in metabolic syndrome patients is disturbed and may add to the increased cardiovascular risk in these patients. It is not known whether postprandial high density lipoprotein-cholesterol (HDL-c) metabolism is also affected and whether this can be influenced by statin and/or ezetimibe treatment. METHODS: Prospective, randomized, double blind, crossover trial comparing simvastatin 80 mg with simvastatin/ezetimibe 10 mg/10 mg treatment for 6 weeks on postprandial HDL-c metabolism in 15, nonsmoking, male, obese metabolic syndrome patients (Adult Treatment Panel III, ATPIII). Only study medication was allowed. HDL-c concentrations, cholesteryl ester transfer (CET), CET protein (CETP) mass and adiponectin were measured before and after oral fat loading. ClinicalTrials.gov NCT00189085. RESULTS: Plasma HDL-c levels remained stable during continuous fasting following an overnight fast. Pre-fat load HDL-c concentrations without treatment, after simvastatin and simvastatin/ezetimibe treatment were 1.15 +/- 0.04, 1.16 +/- 0.05 and 1.11 +/- 0.04 mmol/l. Fat load induced a 11% drop in HDL-c plasma levels; 1.02 +/- 0.05 mmol/l (P < 0.001) which was not affected by either therapy. Triglyceride levels during fat load were similar after both treatments. Total CET increased from 9.73 +/- 0.70 to 12.20 +/- 0.67 nmol/ml/h (P = 0.004). Four hours after fat loading CETP mass was increased while adiponectin levels were decreased, irrespective of treatment. DISCUSSION: HDL-c levels decrease as CET increases after fat loading in obese metabolic syndrome patients. This is not influenced by either simvastatin or simvastatin/ezetimibe treatment. After fat loading, CETP mass and CET increased, and adiponectin decreased pointing towards a potential role for intra-abdominal fat. Decreased postprandial HDL-c levels may contribute to the increased cardiovascular risk in metabolic syndrome patients on top of already low HDL-c levels.

The effects of low-dose simvastatin and ezetimibe compared to high-dose simvastatin alone on post-fat load endothelial function in patients with metabolic syndrome: a randomized double-blind crossover trial.

BACKGROUND AND AIMS: Insulin resistance is associated with postprandial hyperlipidemia and endothelial dysfunction. Patients with metabolic syndrome, characterized by insulin resistance, are at increased cardiovascular risk. The aim of the present study was to investigate whether a similar low-density lipoprotein cholesterol (LDL-c) reduction with combination therapy of low-dose simvastatin and ezetimibe or with high-dose simvastatin alone has similar effects on (post-fat load) endothelial function. METHODS: Randomized, double blind, crossover trial in 19 male obese patients with metabolic syndrome with high-dose simvastatin 80 mg versus combination therapy of low-dose simvastatin 10 mg with ezetimibe 10 mg. Fasting and post-fat load lipids and endothelial function (brachial artery flow-mediated dilation) were determined. RESULTS: Fasting LDL-c concentrations (2.1 +/- 0.5 mmol/L) and fasting endothelial function (6.9 +/- 0.8 vs. 7.6 +/- 1.2%) were the same after both treatments. Although post-fat load plasma triglycerides concentrations were higher (3.2 +/- 0.4 vs. 2.6 +/- 0.2 mmol x h/L) with combination therapy compared to monotherapy, ApoB particles were comparable (0.9 +/- 3.3 vs. -0.2 +/- 2.3 g x h/L). Combination therapy did not decrease post-fat load endothelial function (7.6 +/- 1.2 vs. 7.7 +/- 1.6%), contrary to high-dose simvastatin monotherapy (6.9 +/- 0.8 vs. 4.3 +/- 0.6%). CONCLUSIONS: Combination therapy with low-dose simvastatin and ezetimibe preserved post-fat load endothelial function, contrary to treatment with high-dose simvastatin monotherapy in male metabolic syndrome patients. There were no differences in fasting lipid profiles and endothelial function.

Low plasma levels of adiponectin are associated with low risk for future cardiovascular events in patients with clinical evident vascular disease.

BACKGROUND: Adiponectin is considered to have anti-inflammatory, insulin-sensitizing, and antiatherosclerotic properties. In the present prospective study, the relationship between metabolic syndrome (Adult Treatment Panel III) and adiponectin plasma levels and the relationship between plasma adiponectin levels and future cardiovascular events were investigated. METHODS: A case-cohort study of 431 patients with clinical evident vascular disease from the Second Manifestations of ARTerial Disease study. The relationship between adiponectin plasma levels and new vascular events was investigated with Cox regression, adjusted for potential confounders and effect modifiers (age, sex, renal function [modification of diet in renal disease], body mass index, high sensitive C-reactive protein, use of angiotensin converting enzyme-inhibition and/or AII antagonists, and presence of metabolic syndrome or impaired renal function). RESULTS: Plasma adiponectin levels were lower in patients with metabolic syndrome as compared with patients without (7.9 +/- 0.3 vs 5.2 +/- 0.3 microg/mL) and decreased with the number of components. During a mean follow-up of 2.3 years, 216 patients had a new cardiovascular event. Lower adiponectin plasma levels were associated with a lower risk for future cardiovascular events (hazard ratio 0.50, 95% confidence interval 0.25-0.99). This relationship was not influenced by renal function, body mass index, and renin-angiotensin system-blocking agents or modified by metabolic syndrome and impaired renal function. CONCLUSION: In patients with clinical evident vascular disease, lower adiponectin levels were associated with a lower cardiovascular risk. Therefore, it may be hypothesized that the potential antiatherosclerotic properties of adiponectin do not apply for patients with already established vascular disease.

Defining the metabolic syndrome: Resolving unresolved issues?

BACKGROUND: Several definitions exist for the metabolic syndrome. In concert with the blood pressure and glucose criteria of the NCEP definition, it has now been suggested that the use of fibrates and nicotinic acid be incorporated into the dyslipidemia criteria. While statins are the drugs most widely prescribed for lowering LDL-cholesterol, they also affect triglyceride and HDL-cholesterol levels. The aims of the present study were (1) to investigate how adding lipid-lowering therapy to the NCEP definition might influence the prevalence of the metabolic syndrome and (2) to compare the characteristics of patients identified according to the newly proposed IDF definition with those identified according to the NCEP definition. METHODS: We conducted a cross-sectional study on 2373 patients with clinically manifest vascular disease. In order to allow for the influence of lipid-lowering therapy on the identification of patients with the metabolic syndrome, the NCEP definition was modified in two ways. In NCEP-rev1, the use of lipid-lowering agents fulfilled the hypertriglyceridemia criterion; in NCEP-rev2, triglycerides and HDL-cholesterol plasma concentrations were recalculated for lipid-lowering agents. RESULTS: The prevalence of the metabolic syndrome was 41% according to the NCEP definition, 50% according to the NCEP-rev1, 44% according to the NCEP-rev2, and 52% according to the IDF definition. Patients identified only with the NCEP definition had lower HDL-cholesterol, higher triglycerides, and higher fasting glucoses levels than patients only diagnosed with the IDF definition. CONCLUSION: Adding the use of lipid-lowering drugs to the NCEP definition may lead to the identification of an additional group of patients at an elevated risk for cardiovascular diseases and diabetes. The NCEP definition of the metabolic syndrome identifies patients with a worse cardiovascular risk profile than patients qualifying for the metabolic syndrome with the IDF definition in a cohort of patients with clinical manifestations of vascular disease.

Presence of the metabolic syndrome does not impair coronary collateral vessel formation in patients with documented coronary artery disease.

OBJECTIVE: The metabolic syndrome confers an increased risk for cardiovascular morbidity and mortality. The presence of coronary collaterals may have beneficial effects during myocardial ischemia and may improve cardiovascular outcome in patients with coronary artery disease. Impaired collateral formation could be one of the reasons for the increased cardiovascular risk in patients with the metabolic syndrome. The aim of the present study was to determine the influence of the metabolic syndrome and insulin resistance on the presence of coronary collaterals. RESEARCH DESIGNS AND METHODS: We conducted a cross-sectional study in 227 patients referred for elective percutaneous transluminal coronary angioplasty to the University Medical Centre Utrecht. The metabolic syndrome was diagnosed according to Adult Treatment Panel III, and homeostasis model assessment of insulin resistance (HOMA-IR) and quantitative insulin sensitivity check index (QUICKI) were used to quantify insulin resistance. Coronary collaterals were graded with Rentrop's classification. Rentrop grade >/=1 indicated the presence of collaterals. Results were adjusted for age, sex, and severity of coronary artery disease. RESULTS: A total of 103 patients (45%) were diagnosed with the metabolic syndrome. There was no association between the metabolic syndrome and the presence of coronary collateral formation (odds ratio [OR] 1.2 [95% CI 0.7-2.0]). Also, the degree of insulin resistance was not related to the presence of coronary collaterals. The OR for HOMA-IR (highest versus lowest tertile) was 0.7 (0.3-1.5) and for QUICKI (lowest versus highest tertile) 0.8 (0.4-1.6). CONCLUSIONS: The metabolic syndrome and insulin resistance are not related to the presence of coronary collaterals in patients with documented coronary artery disease.

Prevalence of the metabolic syndrome in patients with coronary heart disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm.

Metabolic syndrome patients are at increased risk for developing cardiovascular morbidity and mortality. The increasing prevalence of the metabolic syndrome in various asymptomatic populations has been well documented, however, limited information is available about the prevalence in manifest atherosclerotic vascular disease patients. The aim of this study is to determine the overall and gender-specific prevalence of the metabolic syndrome and its components in these patients. This cross-sectional survey of 1117 patients, aged 18-80 years, mean age 60+/-10 years, comprised patients with coronary heart disease (n=527), cerebrovascular disease (n=258), peripheral arterial disease (n=232) or abdominal aortic aneurysm (n=100). Metabolic syndrome was defined by Adult Treatment Panel III. The prevalence of the metabolic syndrome in the study population was 46%: 58% in PAD patients, 41% in CHD patients, 43% in CVD patients and 47% in AAA patients. Overall, women had a higher prevalence than men (56% versus 43%). Age did not influence the metabolic syndrome prevalence; crude odds ratios (crude OR) 1.00 (95% CI: 0.99-1.02). Our results demonstrate a high prevalence of the metabolic syndrome in patients with manifest atherosclerotic vascular disease. Screening for metabolic syndrome in patients with high risk for new vascular incidents may identify patients with even higher vascular risk and may direct anti-atherosclerotic treatment in order to prevent new vascular incidents in the same or another vascular bed.

Metabolic syndrome and the risk of new vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral arterial disease or abdominal aortic aneurysm.

AIMS: To investigate the vascular risk associated with Metabolic Syndrome (MetS) according to different clinical criteria with subsequent vascular events and all-cause mortality in patients with coronary artery disease, cerebrovascular disease, peripheral artery disease or abdominal aortic aneurysm and to examine whether patients with MetS at treatment goals for systolic blood pressure (SBP) or low density lipoprotein-cholesterol (LDL-c) level are still at elevated risk. METHODS AND RESULTS: Prospective study of 3196 patients with a history or recent diagnosis of clinically manifest vascular disease. During a median follow-up of 3.2 years (interquartile range 1.4-5.4 years), 331 patients died and 373 patients experienced a first vascular event. National Cholesterol Education Program (NCEP) and revised NCEP (NCEP-R)-defined MetS were related to increased risk of vascular events [HR - hazard ratio 1.50 (95% CI - confidence interval 1.22-1.84) and 1.50 (1.22-1.87)] and all-cause mortality [HR 1.49(1.20-1.84) and 1.43 (1.14-1.78)]. Results were similar in the 2472 patients without type 2 diabetes (DM2) and localization of vascular disease; SBP-category (<140 or > or =140 mmHg) or LDL-category (<2.5 or > or =2.5 mmol/L) did not affect this relation. CONCLUSION: In patients with various manifestations of atherosclerosis, presence of NCEP and NCEP-R-defined MetS is associated with increased risk of cardiovascular events and all-cause mortality, independently of the presence of DM2. This risk is significantly higher than the risk associated with International Diabetes Federation-defined MetS. Also in patients at treatment goals for SBP (<140 mmHg) or LDL-c (<2.5 mmol/L) according to current guidelines, presence of NCEP-R-defined MetS points to a higher vascular risk.

Carotid arterial stiffness is marginally higher in the metabolic syndrome and markedly higher in type 2 diabetes mellitus in patients with manifestations of arterial disease.

INTRODUCTION: Insulin resistance is generally considered to be of major importance in the pathophysiology of the metabolic syndrome and type 2 diabetes mellitus, both high-risk conditions for cardiovascular complications. Carotid artery stiffness is increasingly recognized as an important predictor of cardiovascular morbidity and mortality. Therefore, in the present study we determined whether the metabolic syndrome (MetSyn) and type 2 diabetes mellitus (DM2) are associated with carotid artery stiffness in patients with already clinical manifestations of arterial disease. METHODS AND RESULTS: A cross-sectional study in 2105 patients with manifest arterial disease (cerebral, coronary or peripheral artery disease, renal artery stenosis or an aneurysm of the abdominal aorta) was performed. The difference in carotid stiffness between patients with and without MetSyn and with and without DM2 was studied with linear regression analysis. Compared to patients without DM2 (N=1112), patients with DM2 (N=301) had significantly higher arterial stiffness (distension -18.5 (-35.1;-1.9) 95% CI/distensibility -1.8 (-2.2;-1.4) 95% CI). Generally, there was a trend of higher carotid stiffness in patients with MetSyn (N=922) compared to patients without (N=1112) MetSyn (distension -9.6 (-21.5;2.3) 95% CI/distensibility -2.0 (-2.6;-1.4) 95% CI). Excluding the patients with also DM2 (N=230) from the MetSyn-group diminished this relation (distension -5.7 (-18.8;7.4) 95% CI/distensibility -1.1 (-1.6;-0.6) 95% CI). Furthermore, in the population as a whole, carotid artery stiffness increased with increasing number of components of the metabolic syndrome (p=0.08 for distension/p< or =0.001 for distensibility). In addition, this association was not as clear after exclusion of the patients with DM2 from the MetSyn-group (p=0.24 for distension/p<0.001 for distensibility). From all the components of the MetSyn only high blood pressure and high fasting glucose influenced the carotid artery stiffness. CONCLUSIONS: We concluded that (increasing number of components of) the metabolic syndrome were associated with marginally higher carotid artery stiffness, while type 2 diabetes was associated with a marked increase in carotid artery stiffness, in patients with already clinical manifestations of arterial disease.

Levels of homocysteine are increased in metabolic syndrome patients but are not associated with an increased cardiovascular risk, in contrast to patients without the metabolic syndrome.

AIM: The metabolic syndrome is associated with increased cardiovascular risk. Elevated plasma homocysteine may cause or result from insulin resistance, and may indicate vascular risk or be actively involved in atherogenesis. The aim of the study was to investigate the relationship between homocysteine, the metabolic syndrome and the incidence of cardiovascular events in patients with manifest vascular disease. METHODS: A cohort of 2169 patients with manifest vascular disease was followed for a mean period of 2.8 years. Plasma homocysteine was measured at baseline. Metabolic syndrome was defined by NCEP criteria. RESULTS: Homocysteine levels were higher in metabolic syndrome patients compared to patients without the metabolic syndrome (14.9+/-0.2 v 14.1+/-0.2 micromol/l; p = 0.002) and increased with the presence of its components (from 0 to 5) (12.7 to 15.9 micromol/l; p<0.001). During follow-up, 52 strokes, 67 myocardial infarctions, 5 fatal ruptures of aortic aneurysms and 53 vascular deaths occurred. Patients without the metabolic syndrome and homocysteine levels in the highest tertile had increased risk for events (HR 1.9; 95% CI 1.0 to 3.5) compared to patients without the metabolic syndrome and homocysteine levels in the lowest tertile. The presence of the metabolic syndrome increased the risk (HR 2.2; 95% CI 1.2 to 4.2), but elevated homocysteine levels further increased the risk only marginally (2.5; 95% CI 1.4 to 4.6). CONCLUSIONS: Metabolic syndrome patients have elevated homocysteine levels, but these higher levels are not associated with an increased risk for new cardiovascular events. In contrast, elevated homocysteine levels confer increased risk in patients without the metabolic syndrome.

The course of vascular risk factors and the occurrence of vascular events in patients with symptomatic peripheral arterial disease.

BACKGROUND: Previous studies have documented an undertreatment of vascular risk factors, and patients with symptomatic peripheral arterial disease (PAD) are at increased risk of recurrent vascular events. We examined which baseline variables are related to future vascular events, investigated the course of vascular risk factors, and compared the number of vascular risk factors at baseline and at follow-up to determine whether risk factor management could be further improved. METHODS: This study involved 461 patients with Fontaine classification II to IV who were enrolled in the SMART study (Second Manifestations of ARTerial disease) from September 1996 to December 2000. Patients underwent a standardized screening program for risk factors and were invited for a follow-up measurement during September 2003 to March 2005, after a mean follow-up of 5.5 years (SD, 1.3 years). In the interim period between baseline and follow-up measurement, patients received usual care. During follow-up, vascular events (mortality, ischemic stroke, and myocardial infarction) and PAD-related events (vascular surgery, interventions, and amputations) were documented in detail. RESULTS: In 2739 person-years of follow-up, 91 vascular events occurred, resulting in a 29.1% (95% confidence interval [CI], 22.8%-35.4%) cumulative incidence proportion of recurrent vascular events. Older age, increased homocysteine levels, impaired renal function, and a history of coronary heart disease at baseline were related to an increased risk of new vascular events. Of the 461 patients, 108 patients died, 20 patients were lost to follow-up, and 333 patients were eligible for follow-up measurement, in which 221 (66%) patients wished to participate. In 8 of the 221 patients, a nonfatal vascular event occurred during follow-up. The prevalence of hypertension increased from 51% to 70% (95% CI, 10%-28%), the prevalence of obesity increased from 54% to 67% (95% CI, 3%-21%), and the prevalence of diabetes mellitus increased from 8% to 16% (95% CI, 2%-14%). At follow-up, fewer patients were current smokers (59% to 37%; 95% CI, -13% to -31%), and fewer patients had increased lipid levels (96% to 73%; 95% CI, -29% to -16%). Medication use increased in all drug categories during follow-up. CONCLUSIONS: Age, increased homocysteine levels, impaired renal function, and a history of coronary heart disease were independent risk factors for vascular events in patients with symptomatic PAD. The prevalence of most risk factors, except for smoking and hyperlipidemia, increased over a 5.5-year period even though medication use increased over the same period.

The metabolic syndrome is associated with advanced vascular damage in patients with coronary heart disease, stroke, peripheral arterial disease or abdominal aortic aneurysm.

AIMS: The metabolic syndrome is associated with an increased risk of cardiovascular disease in patients without a cardiovascular history. We investigated whether the metabolic syndrome is related to the extent of vascular damage in patients with various manifestations of vascular disease. METHODS AND RESULTS: The study population of this cross-sectional survey consisted of 502 patients recently diagnosed with coronary heart disease (CHD), 236 with stroke, 218 with peripheral arterial disease (PAD) and 89 with abdominal aortic aneurysm (AAA). Metabolic syndrome was diagnosed according to Adult Treatment Panel III criteria. Carotid Intima Media Thickness (IMT), Ankle Brachial Pressure Index (ABPI) and albuminuria were used as non-invasive markers of vascular damage and adjusted for age and sex if appropriate. The prevalence of the metabolic syndrome in the study population was 45%. In PAD patients this was 57%; in CHD patients 40%, in stroke patients 43% and in AAA patients 45%. Patients with the metabolic syndrome had an increased mean IMT (0.98 vs 0.92mm, P-value <0.01), more often a decreased ABPI (14% vs 10%, P-value 0.06) and increased prevalence of albuminuria (20% vs 15%, P-value 0.03) compared to patients without this syndrome. An increase in the number of components of the metabolic syndrome was associated with an increase in mean IMT (P-value for trend <0.001), lower ABPI (P-value for trend <0.01) and higher prevalence albuminuria (P-value for trend <0.01). CONCLUSION: In patients with manifest vascular disease the presence of the metabolic syndrome is associated with advanced vascular damage.