Jobien K. Olijhoek

Sympathetic Activation Markedly Reduces Endothelium-Dependent, Flow-Mediated Vasodilation

OBJECTIVES We sought to evaluate whether increased sympathetic outflow may interfere with flow-mediated dilation (FMD). BACKGROUND Endothelial function, assessed as FMD, is frequently used as an intermediate end point in intervention studies. Many disease states with increased sympathetic tone are also characterized by endothelial dysfunction. METHODS Sixteen healthy volunteers underwent FMD studies with and without concomitant sympathetic stimulation. Intra-arterial nitroglycerin (NTG) infusion was used to assess endothelium-independent vasodilation. Pathophysiologically relevant sympathetic stimulation was achieved by baroreceptor unloading, using a lower body negative pressure box. In a subset of eight volunteers, this protocol was repeated during loco-regional alpha-adrenergic blockade by intra-arterial infusion of phentolamine (PE). Reactive hyperemic flow was assessed with strain-gauge phlethysmography. RESULTS Overall, FMD responses (8.3 +/- 3.4%) were significantly attenuated by concomitant sympathetic stimulation (3.6 +/- 3.4%, p < 0.01). Loco-regional alpha-adrenergic blockade had no effect on baseline FMD responses (10.7 +/- 4.7%), whereas the attenuation by sympathetic stimulation was abolished completely during PE co-infusion (11.5 +/- 3.3%). During intra-arterial NTG infusions, arterial diameters relative to baseline were not significantly different between the four possible stages. CONCLUSIONS Sympathetic stimulation, at a clinically relevant range, significantly impairs the FMD response by an alpha-adrenergic mechanism.

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.

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.

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 μmol/l; p = 0.002) and increased with the presence of its components (from 0 to 5) (12.7 to 15.9 μmol/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 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·h/L) with combination therapy compared to monotherapy, ApoB particles were comparable (0.9 ± 3.3 vs. −0.2 ± 2.3 g·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.

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.