Antithrombotic drugs in acutely ill medical patients: review and meta-analysis of interventional trials with low-molecularweight heparin and fondaparinux

Venous thromboembolism (VTE) represents a severe complication for acutely ill hospitalized medical patients. Despite several guidelines suggesting that prophylactic measures significantly reduce the risk of VTE, there is a scarce tendency to use antithrombotic drugs in these patients. We performed a meta-analysis of the interventional trials with antithrombotic drugs (low-molecular-weight heparin and fondaparinux) to oversee the clinical effectiveness and bleeding complications. A total of eight randomized controlled trials, including 16,524 patients, were analyzed. This meta-analysis suggests that in acutely ill medical patients, compared with controls, prophylaxis with antithrombotic drugs may be of clinical benefit in VTE (odds ratio [OR]: 0.512; 95% CI: 0.41–0.64; p < 0.001) and deep venous thrombosis (OR: 0.520; 95% CI: 0.41–0.67; p < 0.001); furthermore, there is no effect on pulmonary embolism, VTE‑related death and death from any other cause, and significant enhancement of hemorrhages (OR: 1.465; 95% CI: 1.2–1.79; p < 0.001). Future clinical trials should better define the risk factors for VTE in order to provide the optimal care for acutely ill medical patients

Serum Levels of Vitamin E Are Associated With Early Recurrence of Atrial Fibrillation After Electric Cardioversion

Background—Oxidative stress is suggested to play a role in favoring the occurrence of atrial fibrillation (AF). We analyzed whether vitamin E, a known antioxidant, or markers of oxidative stress are associated with AF recurrence in patients undergoing electric cardioversion. Methods and Results—A total of 144 patients (83 men; mean age, 71.1±5.4 years) underwent successful biphasic electric cardioversion of nonvalvular persistent AF. At baseline, urinary 8-isoprostaglandin F2α and serum soluble NOX2-derived peptide (sNOX2-dp), high-sensitivity C-reactive protein (hs-CRP), and vitamin E levels were measured in each patient. All patients underwent 3 months of clinical follow-up, including an office visit with ECG every week or in cases of symptom recurrence. During the follow-up, 94 patients maintained sinus rhythm, whereas 50 experienced AF recurrence. In unadjusted analysis, left atrial diameter and levels of urinary isoprostanes and serum sNOX2-dp and hs-CRP were significantly higher and serum vitamin E lower in patients with AF recurrence. In multivariable Cox analysis, serum vitamin E (hazard ratio, 0.734; 95% CI, 0.605–0.891; P<0.001) and, to a lesser extent, hs-CRP (P=0.047) remained significantly associated with AF recurrence. Urinary isoprostanes and serum sNOX2-dp levels were inversely correlated with serum vitamin E level (r=−0.626, P<0.001, and r=−0.460, P<0.001, respectively). Conclusions—The study shows that low serum vitamin E levels are associated with AF recurrence in patients who underwent cardioversion. Because vitamin E inversely correlated with oxidative stress, the findings reinforce the hypothesis of an interplay between oxidative stress and AF

Oxidative stress is associated with arterial dysfunction and enhanced intima-media thickness in children with hypercholesterolemia: The potential role of nicotinamide-adenine dinucleotide phosphate oxidase

BACKGROUND. Endothelial dysfunction and intima-media thickness are precocious manifestations of hypercholesterolemia, but the mechanism is unclear. OBJECTIVE. The aim of the study was to analyze the interplay among endothelial dysfunction, intima-media thickness, and oxidative stress in children with hypercholesterolemia. METHODS. We performed a cross-sectional study comparing flow-mediated dilation, intima-media thickness, lipid profile, urinary isoprostanes as markers of oxidative stress, and platelet expression of gp91(phox), the catalytic unit of nicotinamide-adenine dinucleotide phosphate oxidase, in a population of 50 children with hypercholesterolemia (mean age +/- SD: 10.0 +/- 3.7 years) and 50 children without hypercholesterolemia (mean age: 9.2 +/- 3.5 years). Four children with hereditary deficiency of gp91(phox) were studied also. RESULTS. Children with hypercholesterolemia had reduced flow-mediated dilation (mean +/- SD: 6.2 +/- 2.4 vs 9.2 +/- 2.5%) and enhanced intima-media thickness (0.45 +/- 0.07 vs 0.40 +/- 0.06 mm), urinary isoprostanes (86.9 +/- 51.6 vs 45.9 +/- 25.6 pg/mg creatinine), and gp91(phox) platelet expression (4.4 +/- 3.8 vs 2.0 +/- 1.7 mean fluorescence) compared with control subjects. At bivariate analysis, flow-mediated dilation was correlated with low-density lipoprotein cholesterol, intima-media thickness, urinary isoprostanes, and platelet gp(91phox). Stepwise multiple linear regression analysis showed that, in children with hypercholesterolemia, flow-mediated dilation and intima-media thickness were significantly associated with low-density lipoprotein cholesterol and urinary isoprostanes; also, gp91(phox) platelet expression was an independent predictor of urinary isoprostanes. Children with gp91(phox) hereditary deficiency showed downregulation of platelet gp91(phox) and reduced urinary excretion of isoprostanes. CONCLUSIONS. The study suggests that gp91(phox)-mediated oxidative stress may have a pathogenic role in the anatomic and functional changes of the arterial wall occurring in children with premature atherosclerosis

Dark chocolate inhibits platelet isoprostanes via NOX2 down-regulation in smokers

Background: Dark chocolate is reported to decrease platelet activation but the underlying mechanism is still undefined. Dark chocolate is rich in polyphenols that could exert an antiplatelet action via inhibition of oxidative stress. The aim of the present study was to assess if dark chocolate inhibits platelet reactive oxidant species (ROS) formation and platelet activation. Methods: Twenty healthy subjects (HS) and 20 smokers were randomly allocated to receive 40 g of dark (cocoa > 85%) or milk chocolate (cocoa < 35%) in a cross-over, single-blind study. There was an interval of 7 days between the two phases of the study. At baseline and 2 h after chocolate ingestion, platelet recruitment (PR), platelet ROS, platelet isoprostane 8-ISO-prostaglandin F2a (8-iso-PGF2a), Thromboxane (TxA2) and platelet activation of NOX2, the catalytic sub-unit of NADPH oxidase, and serum epicatechin were measured. Results: Compared with HS, smokers showed enhanced PR, platelet formation of ROS and eicosanoids and NOX2 activation. After dark chocolate, platelet ROS (-48%, P < 0.001), 8-iso-PGF2a (-10%, P < 0.001) and NOX2 activation (-22%, P < 0.001) significantly decreased; dark chocolate did not affect platelet variables in HS. No effect of milk chocolate was detected in both groups. Serum epicatechin increased after dark chocolate in HS (from 0.454 +/- 0.3 nm to 118.3 +/- 53.7 nm) and smokers (from 0.5 +/- 0.28 nm to 120.9 +/- 54.2 nm). Platelet incubation with 0.110 mu m catechin significantly reduced PR, platelet 8-iso-PGF2a and ROS formation and NOX2 activation only in platelets from smokers. Conclusions: Dark chocolate inhibits platelet function by lowering oxidative stress only in smokers; this effect seems to be dependent on its polyphenolic content

Myeloperoxidase overexpression in children with hypercholesterolemia

Background: Studies conducted in healthy children showed that biomarkers of oxidative stress decreased with increasing age from 1 to 11 years. No data have been reported concerning the behavior of age-related oxidative stress in hypercholesterolemic children. Objective: Aim of this study was to test if children with hypercholesterolemia have prolonged exposure to enhanced oxidative stress and to study the underlying mechanism. Methods: We performed a cross-sectional study comparing 8-hydroxy-2'deoxyguanosine, oxidized-LDL and myeloperoxidase plasma levels in 95 normocholesterolemic and 95 hypercholesterolemic children. Results: Compared to normocholesterolemic children, those with hypercholesterolemia had higher 8-hydroxy-2'deoxyguanosine, oxidized-LDL and myeloperoxidase plasma levels. A correlation analysis of the overall population showed that total cholesterol was directly correlated with 8-hydroxy-2'deoxyguanosine, oxidized-LDL and myeloperoxidase. Stepwise linear regression showed that only total cholesterol, 8-hydroxy-2'deoxyguanosine and myeloperoxidase levels predicted oxidized-LDL plasma levels. In normocholesterolemic children oxidized-LDL and myeloperoxidase plasma levels significantly decreased from first (1-5 years) to second (6-9 years) quartile of age. In hypercholesterolemic children 8-hydroxy-2'deoxyguanosine. oxidized-LDL and myeloperoxidase plasma levels did not show significant differences among quartiles of age. Conclusion: This study shows that an early and persistent oxidative stress is detected in hypercholesterolemic children and that myeloperoxidase up-regulation might play a role. (C) 2008 Elsevier Ireland Ltd. All rights reserved

NOX2-mediated arterial dysfunction in smokers: acute effect of dark chocolate

Background Cocoa seems to exert artery dilatation via oxidative stress inhibition but the mechanism is still unclear. Objectives To investigate whether in smokers, dark chocolate elicits artery dilatation via down-regulation of NOX2, the catalytic core of NADPH oxidase. Methods Flow-mediated dilatation (FMD), oxidative stress (as assessed by urinary isoprostanes excretion), nitric oxide generation (as assessed by serum levels of nitrite/nitrate (NOx)), NOX2 activity (as assessed by blood levels of soluble NOX2 derived peptide (sNOX2-dp)) and serum epicatechin were studied in 20 smokers and 20 healthy subjects (HS) in a crossover, single-blind study. Patients were randomly allocated to 40 g dark chocolate (>85% cocoa) or 40 g of milk chocolate (<= 35% cocoa). FMD, urinary isoprostanes, NOx and sNOX2-dp were assessed at baseline and 2 h after chocolate ingestion. Results Smokers had lower FMD and NOx and higher sNOX2-dp compared to HS. After dark chocolate intake, urinary isoprostanes and sNOX2-dp significantly decreased and FMD and NOx significantly increased in smokers but not in HS. No changes of the above variables were observed after milk chocolate intake. Multiple linear regression analysis showed that in smokers the only independent predictive variable associated with a change in FMD was a change in sNOX2-dp. Serum epicatechin increased in either group only after dark chocolate intake, reaching values higher than 0.1 mu M. Platelets from smokers (n=5), but not from HS (n=5), showed lower p47(phox) translocation to platelet membrane and higher NOx when incubated with 0.1-10 mu M epicatechin. Conclusion Results suggest that in smokers, cocoa enhances artery dilatation by lowering of NOX2 activation

Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis

Background Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. Aim To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. Methods In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (&gt;85% cocoa) or 40 g/day of milk chocolate (&lt;35% cocoa), for 2 weeks. sNOX2-dp, serum isoprostanes and CK-18 were assessed at baseline and after 2 weeks of chocolate intake. Results Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that Δ of sNOX2-dp was associated with Δ of serum isoprostane

Obesity and Hypercholesterolemia are Associated with NOX2 Generated Oxidative Stress and Arterial Dysfunction

Objective To analyze the interplay among oxidative stress, NOX2, the catalytic core of nicotinamide-adenine dinucleotide phosphate oxidase, and endothelial dysfunction in children with obesity and/or hypercholesterolemia. Study design We performed a cross-sectional study comparing flow-mediated arterial dilation (FMD), oxidized low-density lipoprotein, and urinary excretion of isoprostanes (8-iso-PGF2 alpha), as markers of oxidative stress, and NOX2 activity, as assessed by blood levels of soluble NOX2-dp (sNOX2-dp), in a population of 100 children, matched for age and sex, including 40 healthy subjects (HS), 20 children with hypercholesterolemia (HC), 20 obese children (OC), and 20 children with coexistence of hypercholesterolemia and obesity (HOC). Results HOC had higher sNOX2-dp and oxidized low-density lipoprotein levels compared with HS, HC, and OC. HC, OC, and HOC had lower FMD values compared with HS. Urinary 8-iso-PGF2 alpha excretion was higher in HOC compared with HS. FMD was inversely correlated with sNOX2-dp levels (r = -0.483; P < .001) and with the number of cardiovascular risk factors (r = -0.617; P < .001). Multiple linear regression analysis showed that the number of cardiovascular risk factors was the only independent predictive variable associated with FMD (beta: -0.585; P < .001; R-2 = 35%) and sNOX2-dp (beta: 0.587; P < .001; R-2 = 34%). Conclusion The study suggests that NOX2-generating oxidative stress may have a pathogenic role in the functional changes of the arterial wall occurring in HOC. (J Pediatr 2012;161:1004-9)

Relation of Nonalcoholic Fatty Liver Disease and Framingham Risk Score to Flow-Mediated Dilation in Patients With Cardiometabolic Risk Factors

Nonalcoholic fatty liver disease (NAFLD) has a high prevalence in the general population. Brachial artery flow-mediated dilation (FMD) is a surrogated marker of early atherosclerosis. Few data investigating the relation between FMD, NAFLD, and cardiovascular (CV) risk are available. We recruited 367 consecutive outpatients with cardiometabolic risk factors who underwent ultrasound scanning for liver steatosis and FMD. Mean age was 54.2 ± 12.2 years, and 37% were women. NAFLD was present in 281 patients (77%). Median FMD was 5.1%. FMD was significantly reduced in patients with NAFLD (p 20; FMD, 3.3% [1.7% to 4.5%]) risk, FMD significantly decreased across risk classes of FRS (p = 0.003). At multivariate regression analysis, both FRS (β, -0.129; p = 0.016) and NAFLD (β, -0.218; p <0.001) were variables independently associated with FMD. In conclusion, the presence of NAFLD and FRS inversely correlated with FMD

Impaired flow-mediated dilation in hospitalized patients with community-acquired pneumonia

Background Community-acquired pneumonia (CAP) is complicated by cardiovascular events as myocardial infarction and stroke but the underlying mechanism is still unclear. We hypothesized that endothelial dysfunction may be implicated and that endotoxemia may have a role. Methods Fifty patients with CAP and 50 controls were enrolled. At admission and at discharge, flow-mediated dilation (FMD), serum levels of endotoxins and oxidative stress, as assessed by serum levels of nitrite/nitrate (NOx) and isoprostanes, were studied. Results At admission, a significant difference between patients with CAP and controls was observed for FMD (2.1 ± 0.3 vs 4.0 ± 0.3%, p < 0.001), serum endotoxins (157.8 ± 7.6 vs 33.1 ± 4.8 pg/ml), serum isoprostanes (341 ± 14 vs 286 ± 10 pM, p = 0.009) and NOx (24.3 ± 1.1 vs 29.7 ± 2.2 μM). Simple linear correlation analysis showed that serum endotoxins significantly correlated with Pneumonia Severity Index score (Rs = 0.386, p = 0.006). Compared to baseline, at discharge CAP patients showed a significant increase of FMD and NOx (from 2.1 ± 0.3 to 4.6 ± 0.4%, p < 0.001 and from 24.3 ± 1.1 to 31.1 ± 1.5 μM, p < 0.001, respectively) and a significant decrease of serum endotoxins and isoprostanes (from 157.8 ± 7.6 to 55.5 ± 2.3 pg/ml, p < 0.001, and from 341 ± 14 to 312 ± 14 pM, p < 0.001, respectively). Conversely, no changes for FMD, NOx, serum endotoxins and isoprostanes were observed in controls between baseline and discharge. Changes of FMD significantly correlated with changes of serum endotoxins (Rs = − 0.315; p = 0.001). Conclusions The study provides the first evidence that CAP is characterized by impaired FMD with a mechanism potentially involving endotoxin production and oxidative stress