Blood pressure variability within a single visit and all-cause mortality.

BACKGROUND: Within-visit variability of repeated sequential readings of blood pressure (BP) is an important phenomenon that may affect precision of BP measurement and thus decision making concerning BP-related risk and hypertension management. However, limited data exist concerning predictive ability of within-visit BP variability for clinical outcomes. Therefore, we aimed to investigate the association between the variability of three repeated office BP measurements and the risk of all-cause mortality, independent of BP levels. METHODS: Data collected through the National Health and Nutrition Examination Survey (NHANES) were analysed. NHANES is a program of studies designed to assess health and nutritional status of adults and children in the United States. A complete set of three sequential BP measurements, together with survival status, were available for 24969 individuals (age 46.8±;19.3 years, 49% males). Multivariable logistic regression models were used to determine the prognostic ability of the examined demographic, clinical, and haemodynamic indices. RESULTS: Among various examined indices of variability of systolic (SBP) and diastolic (DBP) blood pressure measurements, the standard deviation of DBP (DBPSD) was the stronger independent predictor of mortality (odds ratio 1.064, 95% Confidence Interval: 1.011-1.12) after adjustment for age, sex, body mass index, smoking, SBP, heart rate, history of hypertension, diabetes mellitus, hypercholesterolaemia, and cardiovascular events. CONCLUSION: Within-visit variability of three sequential office DBP readings may allow for the identification of high-risk patients better than mean SBP and DBP levels. The predictive value of within-visit BP variability and methods to improve its clinical application are worthy of further research.

Cardiotoxic Profile and Arterial Stiffness of Adjuvant Chemotherapy for Colorectal Cancer.

BACKGROUND AND PURPOSE: Even though new cancer therapies have improved the overall survival, in some cases they have been associated with adverse effects, including increased cardiotoxicity. The purpose of the present study was to assess the cardiovascular effects of adjuvant chemotherapy for colorectal cancer and mainly the impact on arterial stiffness indices. MATERIAL AND METHODS: A total of 70 patients with non-metastatic colorectal cancer who were treated either with FOLFOX (n=16) or with XELOX (n=54) adjuvant chemotherapy were included in the study. All patients were subjected to full cardiovascular evaluation at the beginning and the end of chemotherapy. Arterial stiffness was assessed by means of pulse wave velocity (PWV) and augmentation index (Aix) and full laboratory examinations were conducted prior to, and soon after, the termination of chemotherapy. RESULTS: Patients exhibited significantly higher levels of carotid-radial PWV, carotid femoral RWV and Aix post-chemotherapy (p<0.001); these findings remained significant when examined separately in each treatment subgroup (FOLFOX, XELOX). The observed changes were independent of treatment regimen and baseline patient characteristics. Univariate regression analyses showed that baseline PWVc-r and PWVc-f were the only factors associated with PWVc-r and PWVc-f change, while Aix change was independent of its baseline value. CONCLUSION: There is a clear burden in arterial stiffness indices post-adjuvant chemotherapy for colorectal cancer in both chemotherapy groups. This is a finding of important clinical significance, however more prospective studies are required in order to encode the possible mechanisms involved.

The effect of TNF-a antagonists on aortic stiffness and wave reflections: a meta-analysis.

Patients with rheumatoid arthritis (RA) have higher aortic stiffness and cardiovascular risk. Tumor necrosis factor alpha (TNF-a) antagonists reduce inflammation in RA and are indicated for the treatment of patients with severe active rheumatoid disease. However, it is debatable if they have favorable effects on cardiovascular health. The present meta-analysis evaluates the effect of TNF-a antagonists on aortic stiffness and wave reflections, predictors of cardiovascular events and mortality, in RA patients. A search of PubMed, Cohrane, and Embase databases was conducted to identify studies into the effect of TNF-a antagonists on aortic stiffness in RA patients. Aortic stiffness and wave reflections were assessed by aortic (carotid-femoral [cf]) pulse wave velocity (PWV) and augmentation index (AIx), respectively. cfPWV significantly improved following TNF-a antagonist treatment (mean change: -0.53 m/s, 95% CI: -0.833 to -0.218, p = 0.001), independently of age and clinical response to treatment. A more prominent reduction in cfPWV was associated with etanercept/adalimumab (mean difference: -0.62 m/s, 95% CI: -0.968 to -0.272 m/s, p < 0.001) versus infliximab (mean difference: -0.193 m/s, 95% CI: -0.847 to 0.462 m/s, p = 0.564). TNF-a antagonist treatment induced a significant improvement in AIx (mean change: -1.48%, 95% CI: -2.89 to -0.078%, p = 0.039), but this reduction was influenced by age and clinical response to treatment. The balance of evidence suggests that TNF-a antagonists may have a beneficial effect on aortic stiffness and, therefore, on cardiovascular risk. However, larger, longitudinal studies are warranted to confirm such findings.

Arterial aging mediates the effect of TNF-α and ACE polymorphisms on mental health in elderly individuals: insights from IKARIA study.

BACKGROUND: Aging is characterized by an insidious decline in cognitive function. Several genetic and lifestyle factors have been implicated in the increased risk or early onset of dementia. AIM: We sought to assess the role of tumor necrosis factor (TNF) and angiotensin-converting enzyme (ACE) polymorphisms on the development of impaired mental health in respect to indices of arterial aging in nonagenarian individuals. DESIGN: 178 consecutive subjects above 75 years that permanently inhabit in the island of IKARIA, Greece were recruited. METHODS: Aortic distensibility (AoD) was calculated and genetic evaluation was performed on the ACE Insertion/Deletion gene polymorphism (intron 16) and the G/A transition (position -308) of the TNF gene. Cognitive function was evaluated using the Mini-mental State Examination (MMSE). RESULTS: The DD genotype for ACE was independently associated ( b = -0.44, P = 0.007) with AD while AoD remained an independent determinant of mental status (OR = 1.82, P = 0.036). Interestingly though, when a combined genetic index (GI) was calculated for both genes (ACE and TNF), subjects being double homozygous (DD for ACE and GG for TNF) for these loci presented significantly decreased MMSE (adjusted OR = 0.259, P = 0.033). This GI independently associated with AD (beta coefficient = -0.785, P = 0.002). When AoD was included, GI lost its predictive role (OR = 0.784, P = 0.783) towards MMSE. AoD has marginal indirect mediating effect in the association of the GI with MMSE ( P = 0.07). CONCLUSION: Vascular aging may modulates the genetic substrate of elderly subjects on the risk for developing dementia.

Metabolic syndrome and 10-year cardiovascular disease incidence: The ATTICA study.

AIMS: To evaluate the influence of metabolic syndrome (MetS) as well as inflammatory and renal markers on cardiovascular disease (CVD) incidence. METHODS AND RESULTS: During 2001-2002, 1514 men and 1528 women (>18 y) without any clinical evidence of CVD or any other chronic disease, at baseline, living in greater Athens area, Greece, were enrolled. In 2011-2012, the 10-year follow-up was performed in 2583 participants (15% of the participants were lost to follow-up). Incidence of fatal or non-fatal CVD was defined according to WHO-ICD-10 criteria. MetS was defined using three definitions, provided by the National Cholesterol Education Program Adult Treatment panel III (revised NCEP ATP III), the International Diabetes Federation (IDF) or the Harmonized definition. Furthermore, the contributory predictive role of C-reactive protein (CRP), inteleukin-6, uric acid and estimated glomerular filtration rate in the aforementioned models was evaluated. History of MetS-NCEP was positively associated with CVD, adjusting for potential confounding factors (OR:1.83, 95%CI:1.24-2.72). Not statistically significant associations with CVD incidence were observed when using the IDF or the Harmonized definition. Additionally, none of the added inflammatory and renal function markers mediated the influence of MetS on CVD incidence (all p's from Sobel test >0.40). C-statistic values for the MetS definitions used exceeded 0.789 (CI:0.751-0.827), indicating fair-to-good predictive probability of the models. CONCLUSION: Results of the present work revealed the negative impact of MetS-NCEP, but not of the other MetS definitions, on CVD incidence, a key-point that may help in better understanding the role of IDF and Harmonized MetS definitions on CVD.

Adherence to Mediterranean diet and 10-year incidence (2002-2012) of diabetes: correlations with inflammatory and oxidative stress biomarkers in the ATTICA cohort study.

BACKGROUND: The purpose of this work was to investigate the links between oxidative stress, inflammation and coagulation and their effect on Mediterranean diet-diabetes relationship. METHODS: In 2001-2002, a random sample of 1514 men (18-87 years old) and 1528 women (18-89 years old) was selected to participate in the ATTICA study, where Athens is the major metropolis. A validated questionnaire was used to assess lifestyle and dietary factors. Adherence to Mediterranean diet was recorded using MedDietScore. Among others, oxidative stress and inflammatory biomarkers were recorded. During 2011-2012, the 10-year follow-up was performed. Diabetes incidence was defined according to the American Diabetes Association criteria. RESULTS: A total of 191 incident cases of diabetes were documented, yielding an incidence of 12.9% (13.4% in men and 12.4% in women). Medium and high adherence was found to decrease diabetes risk by 49% (95% CI: 0.30, 0.88) and 62% (95% CI: 0.16, 0.88), respectively, compared with low adherence. A logarithmic trend between Mediterranean diet and diabetes incidence was also revealed (p for trend = 0.042). Individuals with abnormal waist circumference (>94 for men, >80 for women) were benefited the most. Wholegrain cereals, fruits and legumes had the greatest predictive ability. The anti-diabetic effect of Mediterranean diet correlated with measurements of tumour necrosis factor-α, homocysteine and total antioxidant capacity. CONCLUSIONS: The reported results support the role of Mediterranean diet as a promising dietary tool for the primary prevention of diabetes, by attenuating inflammation and fostering total antioxidant capacity. This dietary pattern may have therapeutic potential for many cardiometabolic disorders associated with inflammation and/or oxidative stress.

Differences in arterial stiffness and target organ damage between native Greek patients and immigrants from Eastern European countries with essential hypertension.

AIM: The variance in hypertension-related sequelae between different ethnic groups is highly related to differences in socioeconomic conditions and lifestyle habits, but also to disparities in the awareness and treatment of the disease. In the present study, we sought to evaluate the target organ damage in a vulnerable hypertensive population, such as the Eastern European immigrants. METHODS: The study population consisted of 128 hypertensive patients: 67 immigrants from Eastern Europe and 61 native inhabitants. Anthropometric, biochemical and echocardiographic data were derived from both groups. Both groups underwent fundoscopic examination and pulse wave velocity (PWV) measurements for assessment of arterial stiffness. RESULTS: Although immigrants had lower body mass index compared to native inhabitants (P<0.001), they had significantly increased arterial stiffness (P=0.003). In multivariate analysis, higher carotid-femoral PWV was significantly associated with immigration status [ß (SE)=0.935(0.443), P=0.041], after adjustment for smoking status. Moreover, immigrants had increased left atrial volume index (LAVI) (P<0.001), left ventricular mass index (P<0.001) and higher rates of left ventricular diastolic dysfunction (p=0.047). In multivariate analysis, LAVI was significantly associated with immigration status (ß (SE)=5.17(1.93), P=0.01) after adjustment for serum glucose levels and age. Finally, immigrants had significantly higher levels of sodium urinary excretion (p=0.007) and lower glomerular filtration rate (P<0.001). CONCLUSION: Our findings suggest that hypertensive immigrants exhibit an aggravated arterial stiffness profile and increased risk of target organ damage. These findings could be attributed to differences in socioeconomic conditions and dietary habits.

Flavonoids in atherosclerosis: an overview of their mechanisms of action.

Polyphenols are composed of a wide variety of molecules that are classified into several categories, according to their chemical type such as phenolic acids, flavonoids, stilbenes, and lignans. Many studies have proven the beneficial effects of flavonoids in atherosclerosis progression and cardiovascular disease. Dietary flavonoids reduce oxidative stress and exert anti-inflammatory actions. Moreover, flavonoids have the ability to avoid the thrombus formation, improve endothelial function, modify lipid levels and regulate glucose metabolism. In the context of this evidence in this review article we summarize the so far acquired knowledge of the most important mechanisms of action of flavonoids in atherosclerosis progression.

Clinical utility of biomarkers in premature atherosclerosis.

Atherosclerosis is a very complex procedure responsible for the development of coronary artery disease which is the leading cause of death in the civilized world. The obvious pandemic character of atherosclerosis augments the need to discover an ideal biomarker, which will be able to facilitate the clinical diagnosis of the atherosclerosis from the physicians especially in the early stages of the atherosclerotic process. Among the biomarkers that are already used there are classical ones, such as c-reactive protein, interleukins, tumour necrosis factor, apolipoproteins, fibrinogen, homocysteine, and novel promising ones such as lipoprotein-associated phospholipase, asymmetric dimethylarginine, myeloperoxidase, cathepsins and cystatin C. The possibility of combining circulating biomarkers with other methods such as non-invasive and invasive imaging is clinically attractive because this could contribute to the improved diagnosis and understanding of premature atherosclerosis pathogenesis.

Monitoring calcific aortic valve disease: the role of biomarkers.

Calcific aortic valve disease is a common disease in the elderly associated with significant morbidity and mortality. It was once described as a passive degenerative process during which serum calcium attaches to the valve surface and binds to the leaflet. However, during the last decade mounting evidence demonstrated that this disease has an active biologic process with numerous signaling pathways. The histological hallmarks seem to be inflammation, oxidized lipids-also detectable in aortic valve lesions-and a remodeling of the extracellular matrix leading to bone formation. Over the years, growing evidence has indicated the risk factors for calcific aortic stenosis including lipids, hypertension, male gender, renal failure, and diabetes. Additional monitoring tools, such as molecular imaging, could improve risk stratification, while assessment of severity and prognosis of patients with chronic aortic regurgitation, is desirable. Also, several studies have investigated the role of biomarkers regarding their utility in the screening of calcific aortic valve disease and their putative clinical value, though their role still remains undetermined.

Circulating endothelial progenitor cells as biomarkers for prediction of cardiovascular outcomes.

Experimental studies suggest that bone marrow-derived endothelial progenitor cells (EPCs) play an important role in the maintenance of endothelial integrity and hemostasis. The number of circulating EPC has been shown to be inversely correlated with cardiovascular risk factors and vascular function and to predict cardiovascular events independent of both traditional and non-traditional risk factors. Thus, EPCs provide a clinical advantage over the use of other biomarkers as their measurement is directly associated with endothelial function, and available evidence suggests that they are consistently and significantly associated with a spectrum of cardiovascular complications, such as acute coronary syndromes and coronary artery disease. However, many issues in the field of EPC isolation and identification, particularly in regards to the effective and unequivocal molecular characterization of these cells still remain unresolved. In addition, simple EPC counts do not adequately describe cardiovascular disease risk. This limitation is attributable to variation in the definition of EPCs, the number of existing cardiovascular risk factors in different patients as well as a difference in the interaction between EPCs and other hematopoietic progenitor, inflammatory cells or platelets.

Effects of atorvastatin on endothelial function and the expression of proinflammatory cytokines and adhesion molecules in young subjects with successfully repaired coarctation of aorta.

OBJECTIVE: To investigate the effects of atorvastatin on endothelial function and low-grade systemic inflammation in subjects with successful surgery for aortic coarctation repair (SCR). DESIGN: Open-label study. SETTING: Outpatients visiting the adult congenital heart disease department of our hospital. PATIENTS: 34 young people with SCR. INTERVENTIONS: Patients with SCR received atorvastatin 10 mg/day (n=17) or no treatment (n=17) for 4 weeks. At baseline and at 4 weeks, endothelial function was assessed by flow-mediated dilatation (FMD) of the right brachial artery, and blood samples were obtained. Serum levels of interleukin (IL) 1b, IL-6 and soluble vascular cell adhesion molecule-1 (sVCAM-1) were determined by ELISA. MAIN OUTCOME MEASURES: Effects of treatment on FMD and serum levels of IL-1b, IL-6 and sVCAM-1. RESULTS: FMD in the atorvastatin group was significantly improved after 4 weeks (from 6.46±0.95% to 11.24±1.38%, p<0.01), while remaining unchanged in the control group (from 6.74±0.58% to 6.95±0.53%, p=NS). Even though atorvastatin had no effect on serum IL-6 levels (0.62 (0.37-0.88) pg/ml to 0.53 (0.28-0.73) pg/ml, p=NS), it significantly reduced circulating levels of IL-1b (from 1.17 (0.92-1.77) pg/ml to 1.02 (0.75-1.55) pg/ml, p<0.05) and sVCAM-1 (from 883.4 (660.3-1093.1) ng/ml to 801.4 (566.7-1030.2) ng/ml, p<0.05). No changes were seen in serum levels of IL-6, IL-1b and sVCAM-1 in the control group after 4 weeks compared with baseline (p=NS for all). CONCLUSIONS: Atorvastatin treatment for 4 weeks in subjects with SCR significantly improved endothelial function and suppressed systemic inflammatory status by decreasing circulating levels of IL-1b and sVCAM-1.

Divergent anti-inflammatory effects of different oil acute consumption on healthy individuals.

BACKGROUND/OBJECTIVES: Inter-cellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and tumor necrosis factor-α (TNF-α), are implicated in atherogenesis. In addition, several types of oil as part of different types of diet are associated with the initiation of atherosclerosis and consequently with the risk of cardiovascular disease. However, the exact role of oil consumption on vascular inflammation remains unknown. In this parallel study, we assessed the acute effects of extra virgin olive oil, soy oil, corn oil and cod liver oil on circulating soluble(s) forms of adhesion molecules and TNF-α. SUBJECTS/METHODS: In all, 67 healthy volunteers were randomized to receive 50 ml of oil. Soluble forms of VCAM-1, ICAM-1 and TNF-α were measured by enzyme-linked immunosorbent assay at baseline and at 3 h post oil consumption. RESULTS: All types of oil had no significant effect on soluble VCAM-1 levels (P=nonsignificant (NS) for all). On the contrary, all oil types decreased ICAM-1 levels (P<0.01). Olive oil (P<0.05), soy oil and cod liver oil (P<0.01 for both) reduced TNF-α levels significantly, in contrast to corn oil, which induced a nonsignificant decrease (P=NS). Moreover, there was a significant correlation between the absolute change in ICAM-1 and TNF-α levels (ρ=0.379, P<0.05), but not between the absolute changes in VCAM-1 and TNF-α levels (ρ=0.019, P=NS). CONCLUSIONS: Acute consumption of all types of oil decreased significantly ICAM-1 levels. In addition, olive oil, soy oil and cod liver oil decreased significantly TNF-α levels. Moreover, the absolute change in TNF-α levels was correlated with the absolute change in ICAM-1 levels. These findings indicate that acute consumption of specific types of oil is associated with specific significant anti-inflammatory effects.

The role of the cytochrome P450 polymorphisms in clopidogrel efficacy and clinical utility.

Clopidogrel, an antiplatelet agent, prevents platelet aggregation by inhibiting the adenosine disphosphate (ADP) P2Y12 receptor, which is located on the platelet surface. Although dual antiplatelet therapy appears to be efficient, a considerable number of patients continue to experience adverse cardiovascular events, such as stent thrombosis. The percentage of low response to antiplatelet therapy varies from 4% to 30% of patients depending on the cut-off values. In addition, several factors such as poor absorption, drug-to-drug interactions, inadequate dosing, elevated body mass index, insulin resistance and the nature of acute coronary syndromes have been implicated in low clopidogrel response. Recently, studies have focused on the role of genetic polymorphisms encoding enzymes that participate in clopidogrel hepatic metabolism or receptors involved in intestinal absorption and ADP induced platelet aggregation, which may affect the percentage of platelet inhibition after clopidogrel administration. The management of clopidogrel resistance remains a controversial issue and additional studies are required to evaluate the safety and efficacy of increased loading of clopidogrel or replacement with other new antiplatelet agents such as prasugrel.

Prognostic clinical and angiographic characteristics for the development of a new significant lesion in remote segments after successful percutaneous coronary intervention.

BACKGROUND: The majority of cardiovascular events in patients undergoing PCI arise from the progression of NCL during the long-term follow-up period. The purpose of the study was to investigate the clinical and angiographic factors related to the progression of non-culprit lesions (NCL) of patients undergoing percutaneous coronary interventions (PCI). METHODS: One hundred and seventeen patients that underwent two coronary angiograms with a time interval greater than 3 months were enrolled. All patients underwent PCI as a treatment for the culprit lesion. In the second coronary angiography we investigated whether they had a new culprit lesion clearly differentiated from the one of the first angiogram. The demographic characteristics, the clinical syndrome responsible for the first PCI and the procedural characteristics were recorded. Quantitative coronary angiography was performed at the culprit lesion of the second angiography and in the same lesion in the first angiography. RESULTS: Multivariate analysis showed that the independent variables for the development of a significant lesion at the follow-up requiring intervention were: the presence of complex lesion (53.78% vs 36.22%, p<0.001, OR=39.42), acute myocardial infarction (AMI) at the initial diagnosis (36.3% vs 32.4%, p<0.001, OR=3.9), and smoking (46.15% vs 53.84%, p=0.03, OR=0.29). CONCLUSIONS: Patients with AMI and complex morphology of NCL have increased risk for a new intervention after successful PCI. Smoking at the time of the follow up, was associated with fewer coronary interventions.

Independent association of circulating resistin with glomerular filtration rate in the early stages of essential hypertension.

Resistin, a newly discovered protein, promotes endothelial dysfunction and proinflammatory activation, contributing to subclinical atherosclerosis in different clinical settings. In this study we sought to investigate the relationship of increased resistin levels with estimated glomerular filtration rate (eGFR), the most established marker of kidney impairment, in hypertensive subjects. Our population consisted of 132 untreated non-diabetic subjects with stage I-II essential hypertension (49 males, mean age=54 years, office blood pressure (BP)=159/100 mm Hg). In all patients eGFR was assessed by the Modification in Renal Disease equation and venous blood sampling was performed for estimation of resistin concentrations. The distribution of resistin was split by the median (4.63 ng ml(-1)) and accordingly subjects were stratified into those with high and low values. Hypertensive patients with high (n=66) compared to those with low resistin (n=66) exhibited lower eGFR values (77.1+/-9.4 vs 89.1+/-12.2 ml min(-1) per 1.73m(2), P<0.0001), even after adjustment for established confounders. In the total population, resistin was associated with 24-h systolic BP (r=0.244, P<0.05), serum creatinine (r=0.311, P=0.007) and eGFR (r=-0.519, P<0.0001). Multiple regression analysis revealed that age (b=0.379, P=0.01), body mass index (b=0.158, P=0.022), 24-h systolic BP (b=0.284, P=0.006) and resistin (b=0.429, P<0.0001) were independent predictors of eGFR (R(2)=0.436, P<0.0001). In essential hypertensive subjects, higher resistin levels are associated with renal function impairment, as reflected by decreased eGFR. Moreover, the independent association of resistin with eGFR suggests involvement of resistin in the progression of kidney damage in the early stages of hypertension.

Interaction between cytokines and sCD40L in patients with stable and unstable coronary syndromes.

BACKGROUND: Evidence suggests that soluble CD40-ligand (sCD40L) is elevated in coronary artery disease (CAD) and is released from activated platelets during the acute myocardial infarction (AMI). Although sCD40L is part of immune response, the mechanisms regulating its release in different disease states remain unknown. MATERIALS AND METHODS: This study enrolled 596 subjects: 201 patients with stable CAD, 109 patients with AMI and 286 healthy controls. Circulating levels of sCD40L, interleukin-6 (IL-6), soluble vascular cell adhesion molecule-a (sVCAM-1) and soluble intercellular adhesion molecule-1 (sICAM-1) were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: Patients with AMI (n = 109) had higher levels of sCD40L and IL-6 compared to both CAD (n = 201) (P < 0.01) and controls (n = 286) (P < 0.01), while CAD also had higher levels of sCD40L and IL-6 compared to controls (P < 0.01). Similarly, sICAM-1 and sVCAM-1 levels were higher in CAD and AMI compared to controls (P < 0.05). IL-6 was the only parameter independently associated with sCD40L in healthy individuals [beta (SE):0.491(0.096), P = 0.0001]. However, in CAD or AMI, only diabetes mellitus [beta (SE): 2.689 (1.082), P = 0.044 and beta (SE): 10.406 (3.215), P = 0.002, respectively] and smoking [beta (SE): 3.470 (1.111), P = 0.002 and beta (SE): 9.694 (2.478), P = 0.0001, respectively] (but not IL-6), were independently associated with sCD40L levels. CONCLUSIONS: Both CAD and AMI are accompanied by increased levels of sCD40L in parallel with an elevation of proinflammatory cytokine IL-6 and adhesion molecules sVCAM-1 and sICAM-1. Diabetes mellitus and smoking (but not IL-6 or adhesion molecules) were the only factors independently associated with sCD40L levels in CAD and AMI patients.

Improvement of vascular endothelial function using the oral endothelin receptor antagonist bosentan in patients with systemic sclerosis.

OBJECTIVE: Increased endothelin activity may play a role in the pathogenesis of vascular injury, a primary feature of systemic sclerosis (SSc; scleroderma). Our goal was to test the hypothesis that treatment with the oral endothelin receptor antagonist bosentan might improve vascular endothelial function in SSc patients. METHODS: A 4-week, prospective, parallel-group study compared 12 SSc patients who did not receive bosentan treatment with 12 patients who did receive treatment (125 mg/day) for pulmonary hypertension and/or digital ulcers. There were no differences in demographic and clinical characteristics or medications between the 2 groups. Baseline endothelial dysfunction was documented by decreased brachial artery ultrasound-derived flow-mediated dilation (FMD%; <5.5). Pulse wave analysis, venous occlusion plethysmography, and measurement of serum vascular markers were performed in parallel. RESULTS: FMD%, the main end point, increased significantly from a mean +/- SD of 3.1 +/- 1.3% to 8.4 +/- 2.6% after 4 weeks of bosentan treatment (P < 0.001, compared with a change from 2.4 +/- 1.6% to 2.4 +/- 2.2% in control patients). Arterial blood pressure, endothelium-independent vascular function, augmentation index, peripheral flow reserve, as well as circulating intercellular adhesion molecule 1, E-selectin, vascular endothelial growth factor, and endothelin 1 were not significantly affected by bosentan treatment. In patients continuously treated for 4 months, during which the dosage of bosentan remained at 125 mg/day (n = 5) or increased to 250 mg/day (n = 5), the 4-week results remained unchanged. CONCLUSION: Small doses of bosentan improve endothelial function without affecting hemodynamic parameters or endothelial activation-related processes, thus supporting a direct, reversible effect of endothelin in SSc-associated vascular injury. A long-term, controlled trial to examine the potentially global clinical benefit of endothelin receptor blockade in patients with early SSc may be warranted.