Endothelium-dependent Flow-mediated Vasodilation Research Articles

Lack of association between flow-mediated endothelium-dependent vasodilatation and biomarkers of endothelial dysfunction in patients with severe rheumatoid arthritis

Accelerated atherogenesis is one of the main reasons for the increased mortality observed in patients with rheumatoid arthritis (RA) [1]. Progressive impairment of macrovascular and microvascular endothelium-dependent vasodilatation is associated with increased risk of cardiovascular complications. Endothelial function can be noninvasively assessed by postocclusive reactive hyperemia, either as increase in the brachial artery blood flow, as flowmediated vasodilatation of the afferent artery (macrovascular), or as increase in skin microcirculatory flow detected by laser Doppler. Both macrovascular and microvascular studies have confirmed the presence of endothelial dysfunction in patients with long-standing RA [2, 3]. Elevated circulating levels of soluble adhesion molecules are also associated with cardiovascular risk factors and predict atherosclerosis and CV events [4, 5]. Measurement of these biomarkers of endothelial activation and dysfunction has confirmed the presence of endothelial dysfunction in patients with RA [6]. Since administration of anti-TNF-a resulted in a rapid improvement in endothelial function in patients with this chronic inflammatory disease [7], and reduction in some biomarkers of endothelial dysfunction was also observed in these patients following anti-TNF-a drugs [8], an issue of potential interest may be to establish whether a correlation between the levels of soluble biomarkers of endothelial dysfunction and the presence of impairment of endothelium-dependent vasodilatation exists in patients with RA. In this regard, Meyer et al. [9] assessed whether microvascular changes in capillary blood cell velocity had correlation with levels of soluble adhesion molecules in 30 patients with RA. However, no correlation between capillary blood cell velocity and serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin) was found. To further investigate into this issue, we aimed to determine whether levels of serum biomarkers of endothelial dysfunction might correlate with values of macrovascular flowmediated endothelium-dependent vasodilatation in 14 patients with severe RA refractory to conventional diseasemodifying anti-rheumatic drugs. Ethical approval and informed consent were obtained. All patients had severe disease (DAS28 in all cases greater than 3.2), refractory to conventional disease-modifying anti-rheumatic drugs including methotrexate, and were receiving periodical treatment with infliximab therapy. Evaluation of brachial M. A. Gonzalez-Gay (&) Department of Rheumatology, Hospital Universitario Marques de Valdecilla, IFIMAV, Avenida de Valdecilla s/n, 39008 Santander, Spain e-mail: miguelaggay@hotmail.com

Lack of association of IL6R rs2228145 and IL6ST/gp130 rs2228044 gene polymorphisms with cardiovascular disease in patients with rheumatoid arthritis

Interleukin-6 (IL-6) is a key mediator of inflammation in rheumatoid arthritis (RA) and its actions may be controlled by the IL-6 receptor (IL-6R). IL-6 transducer (IL-6ST/ gp130) is the signal transducing subunit of the IL-6R. We assessed the influence of the IL6R and the IL6ST/gp130 genes in the risk of cardiovascular (CV) disease in RA. For this purpose, 1250 Spanish patients with RA were genotyped for the IL6R rs2228145 and IL6ST/gp130 rs2228044 functional gene polymorphisms. Patients were stratified according to the presence or absence of CV events. Also, a subgroup of patients without CV events was assessed for the presence of subclinical atherosclerosis using two surrogate markers of atherosclerosis (flow-mediated endothelium-dependent vasodilatation and carotid intima-media thickness). No significant differences in the genotype and allele frequencies for both gene polymorphisms between patients with and without CV events were observed. It was also the case when values of surrogate markers of atherosclerosis were compared according to IL6R and IL6ST genotype frequencies. In conclusion, our results do not confirm an association of IL6R rs2228145 and IL6ST/gp130 rs2228044 polymorphisms with CV disease in RA.

Systemic Oxidative Stress and Endothelial Dysfunction is Associated With an Attenuated Acute Vascular Response to Inhaled Prostanoid in Pulmonary Artery Hypertension Patients

Background Systemic endothelial dysfunction and increased oxidative stress have been observed in pulmonary arterial hypertension (PAH). We evaluate whether oxidative stress and endothelial dysfunction are associated with acute pulmonary vascular bed response to an inhaled prostanoid in PAH patients. Methods Fourteen idiopathic PAH patients and 14 controls were included. Oxidative stress was assessed through plasma malondialdehyde (MDA) levels and xanthine oxidase (XO) and endothelial-bound superoxide dismutase (eSOD) activity. Brachial artery endothelial-dependent flow-mediated vasodilation (FMD) was used to evaluate endothelial function. Hemodynamic response to inhaled iloprost was assessed with transthoracic echocardiography. Results PAH patients showed impaired FMD (2.8 ± 0.6 vs. 10.7 ± 0.6%, P < .01), increased MDA levels and XO activity (0.6 ± 0.2 vs. 0.3 ± 0.2 μM, P < .01 and 0.04 ± 0.01 vs. 0.03 ± 0.01 U/mL, P = .02, respectively) and decreased eSOD activity (235 ± 23 vs. 461 ± 33 AUC, P < .01). Iloprost improved right cardiac output (3.7 ± 0.6 to 4.1 ± 1.2 L/min, P = .02) and decreased pulmonary vascular resistance (4.1 ± 1.1 to 2.9 ± 0.9 Wood U, P = .01). Changes in right cardiac output after prostanoid inhalation correlated significantly with baseline eSOD activity and FMD (Rho: 0.61, P < .01 and Rho: 0.63, P = .01, respectively). Conclusion PAH patients show increased systemic oxidative stress and endothelial dysfunction markers. Response to inhaled prostanoid is inversely related to both parameters.

Endothelial Function and High-Sensitivity C-reactive Protein Levels in Patients With Chagas Disease Living in a Nonendemic Area

Introduction and objectives The number of patients with Chagas disease in Spain has increased significantly. Chronic inflammation and endothelial dysfunction have been considered among the physiopathological mechanisms of Chagas heart disease. However, there have been conflicting data from clinical studies. Our purpose was to assess endothelial function and systemic levels of nitric oxide and high-sensitivity C-reactive protein in patients with the indeterminate form and with chronic Chagas cardiomyopathy living in a nonendemic area. Methods Flow-mediated endothelium-dependent vasodilatation and nitroglycerin-mediated vasodilatation were assessed with high-resolution ultrasound of the brachial artery in 98 subjects (32 with the indeterminate form, 22 with chronic Chagas cardiomyopathy and 44 controls). Nitric oxide and high-sensitivity C-reactive protein levels were measured in peripheral venous blood. Results Mean age was 37.6 ± 10.2 years and 60% were female. Nitroglycerin-mediated vasodilatation was significantly reduced in chronic Chagas cardiomyopathy compared to controls (median 16.8% vs 22.5%; P = .03). No significant differences were observed in flow-mediated vasodilatation and nitric oxide levels, although a trend towards lower flow-mediated vasodilatation after correction by baseline brachial artery diameter was observed in chronic Chagas cardiomyopathy. Levels of C-reactive protein were significantly higher in patients with the indeterminate form and with Chagas cardiomyopathy compared with controls ( P < .05). Conclusions Reduced nitroglycerin-mediated vasodilatation suggesting dysfunction of vascular smooth muscle cells was found in patients with chronic Chagas cardiomyopathy living in a nonendemic area. Higher C-reactive protein levels were observed in the indeterminate form and early stages of chronic Chagas cardiomyopathy, which could be related to the inflammatory response to the infection or early cardiovascular involvement.

Función endotelial y concentración de proteína C reactiva de alta sensibilidad en pacientes con enfermedad de Chagas que viven en áreas no endémicas

Introduction and objectives The number of patients with Chagas disease in Spain has increased significantly. Chronic inflammation and endothelial dysfunction have been considered among the physiopathological mechanisms of Chagas heart disease. However, there have been conflicting data from clinical studies. Our purpose was to assess endothelial function and systemic levels of nitric oxide and high-sensitivity C-reactive protein in patients with the indeterminate form and with chronic Chagas cardiomyopathy living in a nonendemic area. Methods Flow-mediated endothelium-dependent vasodilatation and nitroglycerin-mediated vasodilatation were assessed with high-resolution ultrasound of the brachial artery in 98 subjects (32 with the indeterminate form, 22 with chronic Chagas cardiomyopathy and 44 controls). Nitric oxide and high-sensitivity C-reactive protein levels were measured in peripheral venous blood. Results Mean age was 37.6 ± 10.2 years and 60% were female. Nitroglycerin-mediated vasodilatation was significantly reduced in chronic Chagas cardiomyopathy compared to controls (median 16.8% vs 22.5%; P = .03). No significant differences were observed in flow-mediated vasodilatation and nitric oxide levels, although a trend towards lower flow-mediated vasodilatation after correction by baseline brachial artery diameter was observed in chronic Chagas cardiomyopathy. Levels of C-reactive protein were significantly higher in patients with the indeterminate form and with Chagas cardiomyopathy compared with controls ( P < .05). Conclusions Reduced nitroglycerin-mediated vasodilatation suggesting dysfunction of vascular smooth muscle cells was found in patients with chronic Chagas cardiomyopathy living in a nonendemic area. Higher C-reactive protein levels were observed in the indeterminate form and early stages of chronic Chagas cardiomyopathy, which could be related to the inflammatory response to the infection or early cardiovascular involvement. Full English text available from: www.revespcardiol.org

Phosphodiesterase-5A (PDE5A) is localized to the endothelial caveolae and modulates NOS3 activity

It has been well demonstrated that phosphodiesterase-5A (PDE5A) is expressed in smooth muscle cells and plays an important role in regulation of vascular tone. The role of endothelial PDE5A, however, has not been yet characterized. The present study was undertaken to determine the presence, localization, and potential physiologic significance of PDE5A within vascular endothelial cells. We demonstrate primary location of human, mouse, and bovine endothelial PDE5A at or near caveolae. We found that the spatial localization of PDE5A at the level of caveolin-rich lipid rafts allows for a feedback loop between endothelial PDE5A and nitric oxide synthase (NOS3). Treatment of human endothelium with PDE5A inhibitors resulted in a significant increase in NOS3 activity, whereas overexpression of PDE5A using an adenoviral vector, both in vivo and in cell culture, resulted in decreased NOS3 activity and endothelium-dependent vasodilation. The molecular mechanism responsible for these interactions is primarily regulated by cGMP-dependent second messenger. PDE5A overexpression also resulted in a significant decrease in protein kinase 1 (PKG1) activity. Overexpression of PKG1 rapidly activated NOS3, whereas silencing of the PKG1 gene with siRNA inhibited both NOS3 phosphorylation (S1179) and activity, indicating a novel role for PKG1 in direct regulation of NOS3. Our data collectively suggest another target for PDE5A inhibition in endothelial dysfunction and provide another physiologic significance for PDE5A in the modulation of endothelial-dependent flow-mediated vasodilation. Using both in vitro and in vivo models, as well as human data, we show that inhibition of endothelial PDE5A improves endothelial function.

TNFA −308 (rs1800629) polymorphism is associated with a higher risk of cardiovascular disease in patients with rheumatoid arthritis

ObjectiveTo assess the influence of the TNFA rs1800629 (G>A) polymorphism in the risk of cardiovascular (CV) disease and subclinical atherosclerosis in patients with rheumatoid arthritis (RA). Methods587 patients fulfilling the 1987 American College of Rheumatology classification criteria for RA were studied. Patients were genotyped for the TNFA rs1800629 polymorphism using predesigned TaqMan single nucleotide polymorphism genotyping assay. Also, HLA-DRB1 genotyping was performed using molecular based methods. Carotid artery intima-media thickness, flow-mediated endothelium-dependent and endothelium independent vasodilatation, used as surrogate markers of subclinical atherosclerosis, were measured in a subgroup of patients. ResultsWe observed a higher frequency of carriers of the minor allele A among the patients with CV disease (with 37.6% vs. without 27.9%, p=0.06, OR 1.56 [95% confidence interval-CI 0.95–2.54]). Carriers of the minor allele A exhibited a higher risk of CV events after adjustment for demographic and traditional CV risk factors (p=0.023, HR 1.72 [95% CI 1.076–2.74]). Also, a significant interaction between this polymorphism and the presence of the rheumatoid shared epitope (SE) was observed (p=0.024). Due to this, the association between carriers of the minor allele A and CV disease was only present in carriers of the SE, even after adjustment (p=0.001, HR 2.43 [95% CI 1.41–4.19]). No significant association between the TNFA variant and the surrogate markers of subclinical atherosclerosis was observed. ConclusionOur results show that TNFA rs1800629 gene polymorphism is associated with predisposition to CV complications in patients with RA. This predisposition is restricted to individuals carrying the rheumatoid SE.

Correlation between endothelial function and carotid atherosclerosis in rheumatoid arthritis patients with long-standing disease

IntroductionIn this study, we aimed to determine the relationship between flow-mediated endothelium-dependent vasodilatation (FMD) and carotid artery intima-media wall thickness (IMT), two surrogate markers of atherosclerosis, in a series of Spanish patients with rheumatoid arthritis (RA) without clinically evident cardiovascular (CV) disease.MethodsOne hundred eighteen patients who fulfilled the 1987 American College of Rheumatology classification criteria for RA, had no history of CV disease and had at least one year of follow-up after disease diagnosis were randomly selected. Brachial and carotid ultrasonography were performed to determine FMD and carotid IMT, respectively.ResultsCarotid IMT values were higher and FMD percentages derived by performing ultrasonography were lower in individuals with a long duration from the time of disease diagnosis. Patients with a disease duration ≤ 7 years had significantly lower carotid IMT (mean ± SD) 0.69 ± 0.17 mm than those with long disease duration (0.81 ± 0.12 mm in patients with ≥ 20 years of follow-up). Also, patients with a long disease duration had severe endothelial dysfunction (FMD 4.0 ± 4.0% in patients with disease duration from 14.5 to 19.7 years) compared with those with shorter disease duration (FMD 7.4 ± 3.8% in patients with disease duration ≤ 7 years). Linear regression analysis revealed that carotid IMT was unrelated to FMD in the whole sample of 118 patients. However, carotid IMT was negatively associated with FMD when the time from disease diagnosis ranged from 7.5 to 19.7 years (P = 0.02).ConclusionsIn patients with RA without CV disease, endothelial dysfunction and carotid IMT increased with the duration of RA. The association between FMD and carotid IMT values was observed only in patients with long disease duration.

Lack of association between ADIPOQ rs266729 and ADIPOQ rs1501299 polymorphisms and cardiovascular disease in rheumatoid arthritis patients

To assess the potential association between ADIPOQ rs266729 and rs1501299 gene polymorphisms, either isolated or in combination, and cardiovascular disease in patients with rheumatoid arthritis (RA), 674 patients seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo, and Hospital San Carlos, Madrid, Spain, were analyzed. Genotyping was performed using predesigned TaqMan assays (Applied Biosystems, Foster City, CA). Carotid intima-media thickness, flow-mediated endothelium-dependent and endothelium-independent post-nitroglycerin vasodilatation, which are used as surrogate markers of subclinical atherosclerosis, were measured in a subsample. No significant differences in the genotype, allele or allele combination frequencies of both polymorphisms were found between RA patients with or without cardiovascular events or subclinical atherosclerosis. Therefore, ADIPOQ rs266729 and rs1501299 polymorphisms do not seem to be associated with cardiovascular disease in RA.

Indoxyl Sulfate–Induced Endothelial Dysfunction in Patients with Chronic Kidney Disease via an Induction of Oxidative Stress

Recent data suggest indoxyl sulfate (IS), one of the uremic toxins that accelerate the progression of chronic kidney disease (CKD), may also be responsible for vascular disease via an induction of oxidative stress. The role of IS in endothelial dysfunction in CKD and potential mechanisms of IS-induced endothelial dysfunction were investigated. A prospective observational study in 40 CKD patients was performed. Flow-mediated endothelium-dependent vasodilatation (FMD) and its reaction time before and 24 weeks after an oral adsorbent of IS were evaluated. Plasma levels of IS and markers of oxidative stress were also measured. The proliferation, senescence, and production of nitric oxide and reactive oxygen species from human umbilical vein endothelial cells (HUVEC) were evaluated and the effect of antioxidants, N-acetylcysteine, rotenone, and apocynin was examined to explore the mechanism of IS-induced endothelial dysfunction. AST-120 treatment for 24 weeks resulted in a significant increase in FMD with a decrease in IS and oxidized/reduced glutathione ratio. The presence of diabetes and high-sensitivity C-reactive protein were the independent predictors for an improved FMD. IS induced a production of reactive oxygen species in HUVEC, and pretreatment with antioxidants ameliorated IS-induced inhibition of proliferation and nitric oxide production and inhibited a senescence of HUVEC. IS may play an important role in endothelial dysfunction via generation of oxidative stress with an induction of endothelial senescence. AST-120 improved endothelial dysfunction in patients with CKD associated with a decrease in IS and a restoration of antioxidant reserve.

Should we be on the fence or can we open the gate? Evidence that QRS gating in FMD analysis is not essential

the function of arterial endothelial cells is now recognized as an important factor in the pathogenesis of atherosclerosis. Almost two decades ago, Celermajer and colleagues ([2][1]) introduced a noninvasive assessment technique to evaluate endothelial function in humans. In this test, the magnitude

Flow-mediated dilatation has an additive value to stress ECG for the diagnosis of angiographically significant coronary atherosclerosis

The objective of this study is to determine if flow-mediated endothelial-dependent vasodilatation (FMD) performed after stress electrocardiogram (ECG) test has an additive value for the diagnosis of significant coronary artery disease (CAD). We studied 322 patients who underwent stress ECG test, coronary arteriography (CAG), and FMD evaluation. The pretest probability (preTP) for the presence of significant CAD (≥50% stenosis) was 73%. The probability for the disease after positive or negative ECG test (postTP) was 75% and 62%, respectively. A positive FMD response after a positive stress test resulted in 86% postTP with prevalence of advanced CAD in this subgroup −70.4%. A negative FMD response after a positive treadmill test decreased the postTP to 50% (prevalence of significant CAD 25.5%) and could change clinical behavior – additional tests before proceeding to CAG. After negative stress test the postTP increased to 78% when FMD was positive (prevalence of the disease 50%), necessitating the performance of CAG. It decreased to 36% after a negative FMD (prevalence of the disease 11.5%), directing to conservative behavior. In a group with a high pretest probability for the presence of advanced coronary atherosclerosis, FMD has an additive value to stress ECG for the diagnosis of significant CAD and could guide clinical behavior.

Association between endothelial dysfunction and hyperuricaemia

We used high-resolution peripheral vascular ultrasound imaging to assess endothelial function in hyperuricaemic patients. Hyperuricaemia was defined as a serum uric acid concentration of > 7.7 mg/dl in men or > 6.6 mg/dl in women. Measurements of endothelium-dependent flow-mediated vasodilation (FMD) and endothelium-independent nitroglycerin-mediated vasodilation were performed in 46 hyperuricaemic patients and an equal number of healthy age- and gender-matched normal controls by high-resolution two-dimensional ultrasonographic imaging of the brachial artery. The serum levels of glucose, creatinine, alanine aminotransferase (ALT), lipid profiles and high-sensitivity CRP were measured for both the study groups. The serum uric acid levels averaged 9.24 (1.16) and 6.18 (0.99) mg/dl in the hyperuricaemic and control groups, respectively. Body weight and BMI were significantly higher in the hyperuricaemic group than in the control group. The serum levels of creatinine, ALT, triglyceride and high-sensitivity CRP were significantly different between the two groups. The FMD values were significantly lower in the hyperuricaemic patients than in the controls [4.45% (3.13%) vs 7.10% (2.48%); P < 0.001]. The FMD values were negatively associated with serum uric acid levels (r = -0.273; P = 0.009). Multivariate regression analysis showed that the presence of hyperuricaemia (β = -0.384; P < 0.001) and body weight (β = 0.215; P = 0.017) were independent determinants of low FMD values. Hyperuricaemia is associated with endothelial dysfunction. Decreased nitric oxide bioavailability may be the main reason.

Rapid effect of single-dose rosiglitazone treatment on endothelial function in healthy men with normal glucose tolerance: data from a randomised, placebo-controlled, double-blind study

Antidiabetic thiazolidinediones (TZDs) improve endothelial function in patients with or without type 2 diabetes. The present randomised, placebo-controlled, double-blind study examined the time course of a single dose of rosiglitazone on flow-mediated endothelium-dependent vasodilation (FMD), metabolic parameters, and its effect on inflammatory markers in non-diabetic men. Forty non-obese, healthy men with normal glucose tolerance were randomised to a single dose of rosiglitazone (8 mg) or placebo, and FMD was assessed at baseline as well as after 6 h and 24 h. Rosiglitazone did not significantly affect blood glucose and insulin levels or lipid parameters after 6 and 24 h compared with placebo. Treatment with rosiglitazone significantly increased FMD after 6 h from 4.3% (3.3; 4.9) to 7.6% (5.6; 9.2) (p<0.0001 vs. baseline) resulting in a highly significant effect compared with placebo (p<0.0001 for difference between groups). After 24 h FMD was still significantly higher in the rosiglitazone group compared with baseline (p=0.001), but the effect was no longer statistically significant versus placebo (p=0.171). Our study shows a very rapid effect of single dose rosiglitazone treatment on endothelial function in non-diabetic healthy men, underscoring the hypothesis that TZDs may exhibit direct effect in the vasculature independent of their metabolic action.

Association between Endothelial Function and Chronotropic Incompetence in Subjects with Chronic Heart Failure Receiving Optimal Medical Therapy

Impairment of flow-mediated, endothelium-dependent vasodilatation (FMD) of the brachial artery identifies peripheral endothelial dysfunction in subjects with chronic congestive heart failure (CHF) and is associated with increased morbidity and mortality. To further elucidate the interaction of peripheral and central mechanisms in the syndrome of CHF, we examined the association between endothelial function and chronotropic incompetence, an emerging prognostic marker in CHF. Thirty subjects with stable New York Heart Association (NYHA) functional class II-III CHF were studied. A vascular ultrasound study was performed to measure brachial artery FMD. The percentage of age-adjusted maximal predicted heart rate (MPHR) reached during cardiopulmonary exercise tolerance testing (CPETT) was used to assess the degree of chronotropic competence. All patients received ACE inhibitors and beta-adrenoceptor blockers. Brachial artery FMD averaged 1.3 +/- 2.4% and age-adjusted % MPHR 74.1 +/- 11.7%. FMD correlated with % MPHR among all patients (r = 0.60, P = 0.01). FMD and resting heart rate (RHR) did not significantly correlate (r = 0.13, P = 0.55). FMD, a measure of peripheral endothelial dysfunction, and % MPHR, a central determinant of cardiac output, are moderately correlated in heart failure patients receiving optimal medical therapy. Whether a cause-effect relationship underlies this association remains to be investigated.

Reduced endothelial progenitor cells and brachial artery flow‐mediated dilation as evidence of endothelial dysfunction in ocular hypertension and primary open‐angle glaucoma

This study aimed to assess vascular endothelial function in patients with ocular hypertension (OHT) or primary open-angle glaucoma (POAG) by measuring: (a) endothelium-dependent flow-mediated vasodilation (FMD) of the brachial artery, and (b) circulating endothelial progenitor cells, which are believed to support the integrity of the vascular endothelium. We enrolled 25 patients with OHT, 23 with POAG and 26 control subjects, all of whom were aged < 65 years and had no medical history of cardiovascular disease or cardiovascular risk factors. All subjects underwent a complete ophthalmological examination, biochemistry study, assessment of cardiovascular parameters, brachial artery ultrasound assessment of endothelium-dependent FMD, generic circulating progenitor cell (CPC) and circulating endothelial progenitor cell (EPC) count with the use of flow cytometry. Flow-mediated vasodilation values differed significantly in OHT (4.5 +/- 1.1%; p = 0.021) and POAG (4.0 +/- 0.9%; p = 0.003) patients compared with controls (7.7 +/- 0.8%). The CD34(+) KDR(+) EPC count was markedly lower in OHT (28.0 +/- 5.0; p < 0.001) and POAG (24.3 +/- 3.4; p < 0.001) patients compared with controls (73.1 +/- 8.1). Neither FMD not EPCs differed significantly between OHT and POAG patients. No significant differences in CPC count or cardiovascular parameters were found among OHT or POAG patients and controls. The levels of CD34(+) KDR(+) EPCs were directly correlated (p = 0.043) with FMD, and inversely correlated (p = 0.032) with baseline intraocular pressure in OHT and POAG patients. Both OHT and POAG patients without cardiovascular risk factors have previously unreported severely reduced circulating EPCs and reduced FMD, both of which are indicators of endothelial dysfunction and increased risk of cardiovascular events.

Effect of Exercise Intervention on Endothelial Function and Incidence of Cardiovascular Disease in Patients with Type 2 Diabetes

The effects of exercise intervention and to assess its long-term efficacy in preventing subsequent cardiovascular events in patients with type 2 diabetes were little known on randomized controlled trial. Thirty-eight type 2 diabetic patients (21 men and 17 women) were assigned to either the exercise group (n=21) or the control group without exercise training (n=17) by simple randomization. The exercise training group was scheduled for aerobic and resistance exercise programs for 3 months. After the 3-month, we investigated endothelial function, insulin resistance, adipocytokines and inflammatory markers. The endothelial function was evaluated by examining a flow-mediated endothelium-dependent vasodilatation (FMD). Furthermore, we followed the incidence of cardiovascular events for 24 months. After 3-month, HbA1C was decreased significantly in both groups. FMD was increased from 7.3+/-4.7% to 10.9+/-6.2% only in the exercise group (p<0.05). Long-term follow-up data showed that the control group developed cardiovascular events more frequently than did the exercise group (p<0.05). Exercise improves endothelial dysfunction independently of glycemic control and insulin sensitivity in patients with type 2 diabetes. The beneficial effects of 3-month exercise to reduce cardiovascular events persist for 24 months.

A1298C polymorphism in the MTHFRgene predisposes to cardiovascular risk in rheumatoid arthritis

IntroductionWe determined the contribution of the methylene tetrahydrofolate reductase (MTHFR) 677 C>T and 1298 A>C gene polymorphisms to the susceptibility to rheumatoid arthritis (RA). We also assessed whether these two MTHFR gene polymorphisms may be implicated in the development of cardiovascular (CV) events and subclinical atherosclerosis manifested by the presence of endothelial dysfunction, in a series of Spanish patients with RA.MethodsSix hundred and twelve patients fulfilling the 1987 American College of Rheumatology classification criteria for RA, seen at the rheumatology outpatient clinics of Hospital Xeral-Calde, Lugo and Hospital San Carlos, Madrid, were studied. Patients and controls (n = 865) were genotyped using predesigned TaqMan SNP genotyping assays.ResultsNo significant differences in allele or genotype frequencies for the MTHFR gene polymorphisms between RA patients and controls were found. Also, no association between the MTHFR 677 C>T polymorphism and CV events or endothelial dysfunction was observed. However, the MTHFR 1298 allele C frequency was increased in patients with CV events after 5 years (38.7% versus 30.3%; odds ratio = 1.45; 95% confidence interval = 1.00 to 2.10; P = 0.04) and 10 years (42.2% versus 31.0%; odds ratio = 1.62; 95% confidence interval = 1.08 to 2.43; P = 0.01) follow up. Moreover, patients carrying the MTHFR 1298 AC and CC genotypes had a significantly decreased flow-mediated endothelium-dependent vasodilatation (4.3 ± 3.9%) compared with those carrying the MTHFR 1298 AA genotype (6.5 ± 4.4%) (P = 0.005).ConclusionsOur results show that the MTHFR 1298 A>C gene polymorphism confers an increased risk for subclinical atherosclerosis and CV events in patients with RA.

Green tea consumption improves endothelial function but not circulating endothelial progenitor cells in patients with chronic renal failure

This study was designed to determine the effect of green tea consumption in patients with chronic kidney disease (CKD) on flow-mediated endothelium-dependent vasodilation (FMD) and the number of circulating endothelial progenitor cells (EPCs). Forty patients with CKD requiring chronic dialysis were enrolled. The patients were divided into two groups: the catechin group that consumed green tea (5 g/day for 1 month) and the control group that consumed water. The number of EPCs, inflammatory markers, oxidative stress, and FMD were determined at baseline and 4 weeks after green tea consumption. Clinical characteristics, oxidative stress, inflammatory markers, and circulating EPCs number were not significantly different. FMD was significantly improved after 4 weeks in the catechin group (from 5.68±2.67% to 8.66±3.46%, p=0.002). Short-term green tea consumption induced a rapid improvement in FMD, but did not improve circulating EPC levels in patients with CKD.

Abstract 5453: Endothelial Dysfunction Plays Important Roles on Development of Acute Coronary Syndrome and Fatal Events

Background and hypothesis: Endothelial dysfunction is thought to contribute to atherothrombogenic process, however we identify little about practical relationship between clinical evolution of acute coronary syndrome (ACS) and endothelial dysfunction. This study assessed hypothesis that endothelial dysfunction has clinical impact on development of ACS and the related prognosis. Methods: Endothelial dysfunction was graded by ultrasonic measured reactive changes in lumen diameter of right brachial artery following transient forearm occlusion for 5 minutes (FMD; flow-mediated endothelium-dependent vasodilation) in consecutive 518 patients with stable coronary artery disease. The enrolled patients were categorized into three groups according to the values of FMD, and their cardiovascular and other clinical events were prospectively followed-up for no less than 36 months. Results: For a mean follow-up period of 60 months with 100% follow-up, the patients with severe endothelial dysfunction (FMD&lt;4%; Group-L, n=174), far more frequently developed ACS, compared to those in Group-M with mild endothelial dysfunction (4%≤FMD&lt;8%, n=171) or Group-H with preserved endothelial function (FMD 8% or more, Group-H, n=173), [p&lt;0.001, by Kaplan-Meier analysis], while the patients in group-H remained free from ACS. More than two thirds of the patients with fatal events belonged to Group-L. Cox proportional hazard model analysis showed that severe endothelial dysfunction was the most powerful predictor for future development of ACS (hazard ratio=5.77, 95%confidential interval; 2.52–13.22, p&lt;0.001) and any fatal events (hazard ratio=5.87, 95%confidential interval; 1.26–72.25, p=0.009). Conclusion: These results certainly suggest endothelial dysfunction plays important roles on development of ACS or any fatal events in the near future and strategies based on practical status of endothelial function are required to prevent ACS or fatal clinical events. Relationship Between Incidence of ACS or Fatal Events and Endothelial Dysfunction