Search

SummaryThere are limited prospective data evaluating the role of urinary F2-IsoP and NOX2 as predictive markers in atrial fibrillation (AF). The aim of this study was to analyse the role of urinary prostaglandin PGF2alpha (8-iso-PGF2α) and NOX2, markers of systemic oxidative stress, in predicting cardiovascular (CV) events and mortality in anticoagulated non-valvular AF patients. This was a prospective study including 1,002 anticoagulated AF patients, followed for a median time of 25.7 months (interquartile range: 14.8–50.9). All major CV events, CV deaths and all-cause deaths were considered as primary outcomes of the study. CV events included fatal/nonfatal ischaemic stroke, fatal/ nonfatal myocardial infarction (MI), cardiac revascularisation and transient ischaemic attack (TIA). Oxidative stress biomarkers, such as urinary 8-iso-PGF2α and serum sNOX2-dp, a marker of NOX2 activation, were measured. A CV event occurred in 125 patients (12.5 %); 78 CV deaths and 31 non-CV deaths were registered. 8-iso-PGF2α and sNOX2-dp were correlated (Rs=0.765 p> 0.001). A significant increased cumulative incidence of CV events and CV deaths was observed across tertiles for 8-iso-PGF2α and sNOX2-dp. An increased rate of all-cause death was observed across tertiles of urinary 8-iso-PGF2α.In Cox or Fine and Gray models, 8-iso-PGF2α predicted CV events and CV and non-CV deaths. The addition of tertiles of 8-iso-PGF2α to CHA2DS2-VASc score improved ROC curves for each outcome and NRI for CV events (0.24 [0.06–0.53] p=0.0067). The study shows that in AF patients 8-iso-PGF2α and NOX2 levels are predictive of CV events and total mortality. F2-IsoP may complement conventional risk factors in prediction of CV events.Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief. Clinical Trial Registration: ClinicalTrials.gov NCT01882114.

Some evidences suggest that the use of digoxin may be harmful inatrial fibrillation (AF) patients. The aim of the study was to investigate in a "real world" of AF patients receiving vitamin K antagonists (VKAs), the relationship between digoxin use and mortality.Prospective single-center observational study including 815 consecutive non-valvular AF patients treated with VKAs. Total mortality was the primary outcome of the study. We also performed a sub-analysis considering only cardiovascular (CV) deaths. Time in therapeutic range (TTR) was used for anticoagulation quality.Median follow-up was 33.2months (2460 person-years); 171 (21.0%) patients were taking digoxin. Compared to those without, patients on digoxin were older (p=0.007), with a clinical history of HF (p0.001) and at higher risk of thromboembolic events (p0.001). No difference in TTR between the two groups was registered (p=0.598). During the follow-up, 85 deaths occurred: 47 CV and 38 non-CV deaths; 35 deaths occurred in digoxin users (20.6%). A significant increased rate of total mortality was observed in digoxin-treated patients (p0.001). Multivariable analysis showed that digoxin was associated with total mortality (hazard ratio [HR]: 2.224, p0.001) and CV death (HR: 4.686, p0.001). A propensity score-matched analysis confirmed that digoxin was associated with total mortality (HR: 2.073, p=0.0263) and CV death (HR: 4.043, p=0.004).In AF patients on good anticoagulation control with VKAs, digoxin use was associated with a higher rate of total and CV mortality.

To investigate the association between adherence to the Mediterranean Diet (Med-Diet), cardiometabolic disorders and polypharmacy.Cross-sectional study.Geriatrics outpatient clinic, Policlinico Umberto I, Sapienza University of Rome.508 patients (219 male, 289 female) aged 50 to 89 who were evaluated for cardiovascular and metabolic disorders.Patients underwent a comprehensive medical assessment including medical history and the use of medications. Adherence to Med-Diet was assessed using the validated Med-Diet 14-item questionnaire; for the analysis, patients were divided in high (≥8) and medium-low (8) adherence. Polypharmacy was defined as taking ≥5 medications.476 patients completed the study. Mean age was 70.4 years; 58% female. Median Med-Diet score was 8 (interquartile range, 6-9). Patients with medium-low adherence had higher body mass index (p=0.029) and higher prevalence of arterial hypertension (p0.001), previous coronary (p=0.002) and cerebrovascular events (p=0.011), diabetes, (p0.001) and dyslipidemia (p=0.001) compared to those at high adherence. Med-Diet score decreased with the number of cardiometabolic disorders (p0.001). The prevalence of polypharmacy was 39%. Consumption of olive oil (p=0.005), vegetables, (p0.001), wine (p=0.017), legumes (p=0.028), fish (p=0.046) and nuts (p=0.045) were all inversely associated with the overall number of medications. In a multivariable regression model, medium-low adherence to Med-Diet was independently associated to polypharmacy (O.R.:1.859; 95% CI 1.142 to 3.025; p=0.013), after adjusting for possible confounding factors.Med-Diet was inversely associated with cardiometabolic disorders and with polypharmacy, suggesting that improved Med-Diet adherence might potentially delay the onset of age-related health deterioration and reduce the need of multiple medications.

Oxidative stress plays an important role in chronic respiratory diseases where the use of non-invasive ventilation seems to reduce the oxidative damage. Data on acute respiratory failure are still lacking. The aim of the study is to investigate the interplay between oxidative stress and acute respiratory failure, and the role of non-invasive ventilation in this setting. We enrolled 60 patients suffering from acute respiratory failure (PaO2/FiO2 ratio

Background and objectives: Retinal vein occlusion (RVO), one of the most relevant causes of vision loss, still represents an open issue in ophthalmology and vascular medicine. Its epidemiology and management approach have not been clearly characterized yet, with several grey zones requiring investigation. Significance of RVO on cardiovascular prognosis is also unclear. “High focused Evaluation of Atherosclerotic risk profile in Retinal Thrombosis: Vascular events Incidence, Sex involvement and Interventional outcomes assessed by Ophthalmologists and internists Network” (HEART VISION) is a longitudinal, prospective, multi-center study which aims at determining the epidemiology, potentially modifiable risk factors and the determinants of RVO in an Italian-based cohort. Methods: Enrollment of all the eligible patients presenting to recruiting centers (i.e. ophthalmology emergency room and thrombosis centers) with suspect of RVO. At baseline, all patients will undergo an opthalmologic evaluation and further investigations about cardiovascular co-morbidities and risk factors. Recruited patients will be followed for a 2-year period. Outcome measures: Data about adverse cardiovascular events and eye-related outcomes will be recorded. Discussion: HEART VISION will present data on prevalence and will inform on the prognosis of RVO in an Italian-based cohort. Characterization and prospective evaluation of these patients will be useful in developing novel strategies for management of RVO and their cardiovascular-related risk factors. Ethics and dissemination: This study protocol (n. 1.0, 01.07.2014) was approved by the Sapienza-University of Rome, Ethics Board (Protocol No. 1076/14). This study will be performed in accordance with the Declaration of Helsinki. Dissemination plans include presentations at scientific conferences and publication in scientific journals. Trial registration: ClinicalTrials.gov Identifier: NCT02257333 on October 6, 2014.

Objectives Extra virgin olive oil (EVOO) supplementation is associated with a significant reduction in cardiovascular disease but the underlying mechanism is still unclear. Methods In platelets that were taken from healthy subjects (n = 5), agonist-induced hydrogen peroxide (H 2 O 2 ) production and NADPH oxidase 2 (NOX2) activation in the presence of or without catalase, which catabolizes H 2 O 2 , were investigated. Platelet H 2 O 2 production, NOX2 activation, EVOO vitamin E, and total polyphenols as well as EVOO's ability to scavenge H 2 O 2 were also measured. Results Platelet NOX2 activation and H 2 O 2 production were significantly inhibited in catalase-treated platelets and platelets that were incubated with five different EVOOs. The EVOO content of vitamin E was 53 to 223 mg/kg and total polyphenols 145 to 392 mg/L Gallic acid equivalent. EVOOs quenched in vitro H 2 O 2 by 39 to 62%, which is an effect that is significantly correlated with vitamin E and total polyphenol concentrations ( R = 0.688; P R = 0.541; P Conclusions This in vitro study provides the first evidence that EVOO downregulates platelet H 2 O 2 and in turn NOX2 activity via H 2 O 2 scavenging.

ummary An enhanced risk of cardiovascular mortality has been observed after pneumonia. Epidemiological studies have shown that respiratory tract infections are associated with an increased risk of thrombotic-related vascular disease such as myocardial infarction, ischemic stroke and venous thrombosis. Myocardial infarction and stroke have been detected essentially in the early phase of the disease (i.e. within 48 h from hospital admission), with an incidence ranging from as low as 1% to as high as 11%. Age, previous cardiovascular events and high pneumonia severity index were independent predictors of myocardial infarction; clinical predictors of stroke were not identified. Deep venous thrombosis and pulmonary embolism may also occur after pneumonia but incidence and clinical predictors must be defined. The biological plausibility of such an association may be deduced by experimental and clinical studies, showing that lung infection is complicated by platelet aggregation and clotting system activation, as documented by up-regulation of tissue factor and down-regulation of activated protein C. The effect of antithrombotic drugs has been examined in experimental and clinical studies but results are still inconclusive.

SummaryOral anticoagulation is pivotal in the management of thromboembolic risk in non-valvular atrial fibrillation (NVAF) patients. Effective anticoagulation is important to avoid major adverse events and medication adherence is central to achieve good anticoagulation control. Non-vitamin K antagonist oral anticoagulants (NOACs) are as effective and safe as vitamin K antagonist (VKAs) in NVAF patients. Due to the absence of routine anticoagulation monitoring with NOACs treatment, concerns have been raised about patient’s adherence to NOACs and real-life data demonstrates variability in adherence and persistence. A multi-level approach, including patients’ preferences, factors determining physicians’ prescribing habits and healthcare system infrastructure and support, is warranted to improve initiation and adherence of anticoagulants. Adherence to NOACs is paramount to achieve a clinical benefit. Implementation of educational programs and easy-to-use tools to identify patients most likely to be non-adherent to NOACs, are central issues in improving the quality of NVAF anticoagulation management.Note: The review process for this manuscript was fully handled by C. Weber, Editor in Chief.

Statins are a main curbstone in the prevention of cardiovascular disease (CVD), pandemic in 21st century. CVD displays evident sex and gender differences, not only in clinical manifestation and outcomes but also in pharmacological treatment. Whether statin therapy should be differentially prescribed according to sex is a matter of debate. Aside a different pharmacological action, statins are not proven to be less effective in one gender comparing to the other, nor to be less safe. Nevertheless, up to date evidence shows that statins have not been adequately tested in women, especially in primary prevention trials. Since data-lacking, making a treatment decision on women is potentially harmful, although female individuals represent the majority of the population and they have a greater lifetime CVD risk. Therefore, adequately powered randomized control trials with longer follow-up are warranted to establish if a benefit on CV events and mortality prevention exists in both sexes. The aim of the present review is to summarize the sex and gender differences in statin use: it raises concerns and updates perspectives towards an evidence-based and sex-tailored prevention of CVD management.

Habitual physical activity has beneficial effects on cardiovascular risk reduction by improving vascular function but the underlying mechanism is still unclear. To address this issue, we performed a cross-sectional study comparing 50 physically active (PA) adults with 50 sedentary controls matched for age, sex, and cardiovascular risk factors. PA subjects had significantly higher flow-mediated dilation (FMD) than controls and higher serum levels of nitrite/nitrate, a marker of nitric oxide generation. In addition, PA subjects showed lower levels of urinary isoprostanes, a marker of reactive oxygen species (ROS) production, and lower serum levels of sNox2-dp, a validated assay to measure Nox2 activity, one of the most important enzymes producing ROS in the blood cells. FMD was independently correlated with sNox2-dp, after adjusting for possible confounding factors. Our observation leads to the hypothesis that, in adults, regular exercise preserves artery dilation through Nox2 decreased activity. Antioxid. Redox Signal. 28, 1576-1581.

SummaryThe effect of lipopolysaccharide (LPS) on platelet aggregation is still controversial. We performed in vitro and ex vivo studies in controls and in patients with community-acquired pneumonia (CAP) to assess the effect of LPS on platelet activation (PA). LPS (15–100 pg/ml) significantly increased PA only if combined with sub-threshold concentrations (STC) of collagen or ADP; this effect was associated with increased platelet H2O2 production, Nox2 activation, PLA2 phosphorylation, thromboxane (Tx)A2 and 8-iso-PGF2α-III, and was inhibited by aspirin, TxA2 receptor antagonist or by Toll-like receptor 4 blocking peptide (TLR4bp). Analysis of up-stream signalling potentially responsible for Nox2 and PLA2 activation demonstrated that LPS-mediated PA was associated with phosphorylation of AKT, p38 and p47phox translocation. In 10 consecutive CAP patients serum endotoxins were significantly higher compared to 10 controls (145 [115–187] vs 18 [6–21] pg/ml; pSupplementary Material to this article is available online at www.thrombosis-online.com

Platelet activation seems to be implicated in the cardiovascular events occurring in patients with community-acquired pneumonia (CAP) but the underlying mechanism is still unclear. Aim of the study was to assess the mechanism involved in platelet activation in CAP patients.Two-hundred-seventy-eight consecutive patients hospitalized for CAP were recruited and followed-up until discharge. Hospitalized patients matched for sex, age and comorbidities but without acute infectious diseases were used as controls.At hospital admission patients disclosed enhanced plasma levels of sP-selectin, a maker of in-vivo platelet activation, serum sNOX2-dp, a marker of NADPH-oxidase activation, serum Lipopolysaccharide (LPS) and serum zonulin, a marker of gut permeability, compared to controls (p 0.001). Baseline sP-selectin was independently associated to serum LPS, sNOX2-sp and Pneumonia Severity Index score (p 0.001). Plasma sP-selectin, serum sNOX2-dp, LPS and zonulin coincidentally decreased at hospital discharge (p 0.001). An in vitro study showed that LPS, at concentration similar to that found in CAP patients, induced sP-selectin release by agonist-activated platelets, a phenomenon that was counteract by treating cells with gp91ds-tat, a specific inhibitor of NOX2.CAP patients display enhanced platelet activation, which is related to LPS-mediated NOX2 activation. Enhanced gut permeability seems be implicated in enhancing circulating levels of LPS.

Community-acquired pneumonia (CAP) is associated with an increased risk of arterial and venous thrombosis but the underlying pathophysiological mechanisms are still unclear. We investigated if, in patients with CAP, a pro-thrombotic state does exist and its relationship with serum levels of endotoxins.A total of 104 consecutive patients with CAP were prospectively recruited and followed up until discharge. At admission and at discharge, serum endotoxins, systemic markers of clotting activation and zonulin, a marker of gut permeability, were analysed. Hospitalized patients matched for gender, age and comorbidities but without infections were used as control.At admission, CAP patients showed higher plasma levels of F

Supplemental Digital Content is available in the text, Diabetes mellitus is a frequent comorbid conditions among patients with pneumonia living in the community. The aim of our study is to evaluate the impact of hospitalization for pneumonia on early (30 day) and late mortality (1 year) in patients with type 2 diabetes mellitus. Prospective comparative cohort study of 203 patients with type 2 diabetes hospitalized for pneumonia versus 206 patients with diabetes hospitalized for other noninfectious causes from January 2012 to December 2013 at Policlinico Umberto I (Rome). Enrolled patients were followed up to discharge and up to 1 year after initial hospital admission or death. Overall, 203 patients with type 2 diabetes admitted to hospital for pneumonia were compared to 206 patients with type 2 diabetes admitted for other causes (39.3% decompensated diabetes, 21.4% cerebrovascular diseases, 9.2% renal failure, 8.3% acute myocardial infarction, and 21.8% other causes). Compared to control patients, those admitted for pneumonia showed a higher 30-day (10.8% vs 1%, P

Background. Oxidative stress is enhanced in metabolic syndrome (MetS) and believed to contribute to accelerated atherosclerosis. Weight loss is associated with lowered oxidative stress. Methods. We performed a cross-sectional study in 92 consecutive patients with metabolic syndrome and 80 without. A dietary intervention with moderately low-calorie diet (600 calories/day negative energy balance) was carried out in 53 of metabolic syndrome patients. Oxidative stress, assessed by sNOX2-dp and urinary 8-iso-PGF2α, and antioxidant status, assessed by serum levels of vitamin E and adiponectin, were measured before and after 6 months. Results. Serum vitamin E/cholesterol ratio was significantly lower in metabolic syndrome compared to controls () and decreased by increasing the number of metabolic syndrome components (). After six months, 23 and 30 patients showed >5% (group A) or α (−39.0%), serum sNOX2-dp (−22.2%), adiponectin (+125%), and vitamin E/cholesterol ratio (+129.8%) significantly changed only in A group. Changes in body weight and in serum adiponectin were independent predictors of vitamin E/cholesterol ratio variation. Conclusion. Our findings show that in metabolic syndrome moderate weight loss is associated with multiple health benefits including not only oxidative stress reduction but also enhancement of antioxidant status.

Tumor necrosis factor (TNF) α may contribute to the deterioration of cardiovascular function in heart failure (HF) through various mechanisms, including the generation of reactive oxygen species (ROS). NADPH oxidase is the major source of ROS in the vascular system, but the interplay between TNFα and NADPH oxidase activation is elusive. As platelets possess NADPH oxidase enzyme, they represent an important tool to investigate the interplay between NADPH oxidase and TNFα in patients with HF. Serum gp91phox (NOX2), the catalytic core of NADPH oxidase, and serum TNFα were measured in 120 HF patients and in 60 healthy subjects. Compared with healthy subjects, HF patients had higher blood levels of NOX2 and TNFα with a progressive increase from NYHA I to NYHA IV classes. NOX2 levels in blood were independently associated with TNFα in HF patients. An in vitro study, performed on platelets from a subgroup of HF patients, shows that TNFα, at concentrations commonly found in HF patients' peripheral circulation, activates platelet NOX2. Thus, TNFα increases ROS production and the extracellular levels of NOX2. These phenomena are inhibited by the NOX2-specific blocking peptide gp91ds-tat. The study provides evidence that circulating NOX2, as well as the activation of NOX2 on platelets, is increased in HF likely as a consequence of the underlying inflammatory process.

Caloric restriction (CR) retards aging in laboratory rodents. No information is available on the effects of long-term CR on physiologic markers of aging and longevity in humans. Heart rate variability (HRV) is a marker for cardiac autonomic functioning. The progressive decline in HRV with aging and the association of higher HRV with better health outcomes are well established. Heart rate variability assessment is a reliable tool by which the effects of CR on autonomic function can be assessed. Time- and frequency-domain analyses compared 24-h HRV in 22 CR individuals aged 35-82 years and 20 age-matched controls eating Western diets (WD). The CR group was significantly leaner than the WD group. Heart rate was significantly lower, and virtually, all HRV values were significantly higher in the CR group than in the WD group (P < 0.002). Heart rate variability in the CR individuals was comparable with published norms for healthy individuals 20 years younger. In addition, when differences in heart rate (HR) and HRV between CR and WD were compared with previously published changes in HRV induced in healthy adults given atenolol, percent differences in each measure were generally similar in direction and magnitude and suggested declines in sympathetic and increases in parasympathetic modulation of HR and increased circadian variability associated with CR. These findings provide evidence that CR has direct systemic effects that counter the expected age-associated changes in autonomic function so that HRV indexes in CR individuals are similar to those of individuals 20 years younger eating WDs.

Aspirin modestly influences cardiovascular events in patients with type 2 diabetes mellitus (T2DM), but the reason is unclear. The aim of the study was to determine whether in T2DM patients aspirin enhances platelet isoprostanes, which are eicosanoids with proaggregating properties derived from arachidonic acid oxidation by platelet NOX2, the catalytic subunit of reduced NAD phosphate oxidase. A cross-sectional study was performed comparing T2DM patients, treated (n = 50) or not treated (n = 50) with 100 mg/day aspirin, with 100 nondiabetic patients, matched for age, sex, atherosclerosis risk factors, and aspirin treatment. A short-term (7 days) treatment with 100 mg/day aspirin also was performed in 36 aspirin-free diabetic and nondiabetic patients. Higher platelet recruitment, platelet isoprostane, and NOX2 activation was found in diabetic versus nondiabetic patients and in aspirin-treated diabetic patients versus nontreated patients (P < 0.001). Platelet thromboxane (Tx) A2 (P < 0.001) was inhibited in all aspirin-treated patients. In the interventional study, aspirin similarly inhibited platelet TxA2 in diabetic and nondiabetic patients (P < 0.001). Platelet recruitment, isoprostane levels, and NOX2 activation showed a parallel increase in diabetic patients (P < 0.001) and no changes in nondiabetic patients. These findings suggest that in aspirin-treated diabetic patients, oxidative stress–mediated platelet isoprostane overproduction is associated with enhanced platelet recruitment, an effect that mitigates aspirin-mediated TxA2 inhibition.

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 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 r =−0.460, P 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.

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 (sNOX2dp)) 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 mM. Platelets from smokers (n¼5), but not from HS (n¼5), showed lower p47 phox translocation to platelet membrane and higher NOx when incubated with 0.1e10 mM epicatechin. Conclusion Results suggest that in smokers, cocoa enhances artery dilatation by lowering of NOX2 activation.

Reduction of body temperature has been proposed to contribute to the increased lifespan in calorie restricted animals and mice overexpressing the uncoupling protein-2 in hypocretin neurons. However, nothing is known regarding the long-term effects of calorie restriction (CR) with adequate nutrition on body temperature in humans. In this study, 24-hour core body temperature was measured every minute by using ingested telemetric capsules in 24 men and women (mean age 53.7 ± 9.4 yrs) consuming a CR diet for an average of 6 years, 24 age- and sex-matched sedentary (WD) and 24 body fat-matched exercise-trained (EX) volunteers, who were eating Western diets. The CR and EX groups were significantly leaner than the WD group. Energy intake was lower in the CR group (1769 ± 348 kcal/d) than in the WD (2302 ± 668 kcal/d) and EX (2798 ± 760 kcal/d) groups (P0.0001). Mean 24-hour, day-time and night-time core body temperatures were all significantly lower in the CR group than in the WD and EX groups (P ≤ 0.01). Long-term CR with adequate nutrition in lean and weight-stable healthy humans is associated with a sustained reduction in core body temperature, similar to that found in CR rodents and monkeys. This adaptation is likely due to CR itself, rather than to leanness, and may be involved in slowing the rate of aging.

Aims Statins inhibit oxidative stress, but the interplay between cholesterol lowering and antioxidant vitamins is still unclear. Aims of the study were to assess if statins inhibit oxidative stress independently from cholesterol lowering, to assess the behaviour of vitamin E simultaneously with the changes of oxidative stress, to determine in vitro if atorvastatin was able to directly influence platelet-mediated LDL oxidation and vitamin E consumption. Methods and results In 30 hypercholesterolaemic patients (HC) and 20 healthy subjects (HS), urinary isoprostanes and plasma vitamin E were determined. The HC were randomized to diet or diet plus atorvastatin 10 mg/day. Compared with HS, HC had higher isoprostanes and lower vitamin E levels. The statin-allocated group showed a reduction of isoprostanes after only 3 days (-18.8%, P < 0.01); after 30 days, a stronger reduction of isoprostanes was noted (-37.1%, P < 0.01) whereas an increase of vitamin E (+42%, P < 0.01) and a reduction of cholesterol (-24.9%, P < 0.01) were observed. The diet-allocated group showed a weak decrease of cholesterol after 30 days. In vitro study showed that atorvastatin dose-dependently inhibited platelet-mediated LDL oxidation and isoprostane formation with a mechanism involving NADPH-oxidase. Conclusion The study provides the first evidence that atorvastatin exerts an early antioxidant effect that could contribute to enhancing circulating vitamin E.

Community-acquired pneumonia (CAP) is complicated by cardiac events in the early phase of the disease. Aim of this study was to assess if these intrahospital cardiac complications may account for overall mortality and cardiovascular events occurring during a long-term follow-up. Three hundred one consecutive patients admitted to the University-Hospital, Policlinico Umberto I, with community-acquired pneumonia were prospectively recruited and followed up for a median of 17.4 months. Primary end point was the occurrence of death for any cause, and secondary end point was the occurrence of cardiovascular events (cardiovascular death, nonfatal myocardial infarction [MI], and stroke). During the intrahospital stay, 55 patients (18%) experienced a cardiac complication. Of these, 32 had an MI (29 non-ST-elevation MI and 3 ST-elevation MI) and 30 had a new episode of atrial fibrillation (7 nonmutually exclusive events). During the follow-up, 89 patients died (51% of patients with an intrahospital cardiac complication and 26% of patients without, p0.001) and 73 experienced a cardiovascular event (47% of patients with and 19% of patients without an intrahospital cardiac complication, p0.001). A Cox regression analysis showed that intrahospital cardiac complications, age, and Pneumonia Severity Index were significantly associated with overall mortality, whereas intrahospital cardiac complications, age, hypertension, and diabetes were significantly associated with cardiovascular events during the follow-up. In conclusion, this prospective study shows that intrahospital cardiac complications in the early phase of pneumonia are associated with an enhanced risk of death and cardiovascular events during long-term follow-up.

Oxidative stress seems to play a key role in the pathogenesis of atherosclerosis. Agents that protect low-density lipoprotein from oxidation have been shown in a range of in vitro and animal models to reduce the development and progression of atherosclerosis. These agents include antioxidant micronutrients such as vitamin E. They have gained wide interest because of the potential for prevention of atherosclerotic vascular disease in humans. In the last decade, many trials with antioxidants have been carried out in patients with cardiovascular disease, but the results are equivocal. The reason for the disappointing findings is unclear, but one possible explanation is the lack of identification criteria of patients who are potential candidates for antioxidant treatment. This review analyses the data reported so far to determine whether they clearly support the premise that patients at risk of cardiovascular disease may be candidates for antioxidant treatment.

Aims It is unclear if atrial fibrillation (AF) patients treated with oral vitamin K antagonists (VKAs) must follow a specific diet to avoid interference with anticoagulation. The aim of this study was to assess if Mediterranean diet (Med-Diet) may affect quality of anticoagulation, as expressed by the time in therapeutic range (TTR). Methods and results A prospective observational study including 553 non-valvular AF patients. Time in therapeutic range was calculated for all patients treated with VKAs, and adherence to Med-Diet was evaluated with a validated nine-item dietary questionnaire. Cardiovascular events (CVEs), such as cardiovascular death and fatal/non-fatal stroke or myocardial infarction, and bleedings were recorded. The median follow-up was 31.6 months. The median number of international normalized ratios for each patient was 63.0 (35.0–98.0) and 38 730 blood samples were analysed. In the whole cohort, the mean TTR was 65.5 ± 17.8%. The mean Med-Diet score was 5.19 ± 1.6, with frequent use of olive oil (90.1%), fruits (88.4%), and vegetables (69.3%) and low meat intake (71.2%). There were no differences among tertiles of Med-Diet score regarding TTR. A multivariable linear regression analysis showed that diabetes ( β : −0.105, P = 0.015) and the use of angiotensin converting enzyme inhibitor/angiotensin receptor blockers ( β : 0.153, P < 0.001) were associated with TTR. Compared with those without, AF patients with a CVE had significantly lower TTR (65.9 ± 17.9 vs. 59.6 ± 15.9, P = 0.029) and Med-Diet score (5.2 ± 1.5 vs. 4.4 ± 1.9, P = 0.004). A reduction of CVE was observed for each point of the Med-Diet score (hazard ratio 0.790, P = 0.017). Conclusion In our cohort of AF patients, Med-Diet is not associated with changes in TTR, and thus can be recommended for AF patients who are taking VKAs.

Background Pneumonia is complicated by high rate of mortality and cardiovascular events (CVEs). The potential benefit of aspirin, which lowers platelet aggregation by inhibition of thromboxane A2 production, is still unclear. The aim of the study was to assess the impact of aspirin on mortality in patients with pneumonia. Methods and Results Consecutive patients admitted to the University‐Hospital Policlinico Umberto I (Rome, Italy) with community‐onset pneumonia were recruited and prospectively followed up until discharge or death. The primary end point was the occurrence of death up to 30 days after admission; the secondary end point was the intrahospital incidence of nonfatal myocardial infarction and ischemic stroke. One thousand and five patients (age, 74.7±15.1 years) were included in the study: 390 were receiving aspirin (100 mg/day) at the time of hospitalization, whereas 615 patients were aspirin free. During the follow‐up, 16.2% of patients died; among these, 19 (4.9%) were aspirin users and 144 (23.4%; P P =0.040). The Cox regression analysis showed that pneumonia severity index ( PSI ), severe sepsis, pleural effusion, and PaO 2 /FiO 2 ratio P =0.029) for total mortality. Conclusions This study shows that chronic aspirin use is associated with lower mortality rate within 30 days after hospital admission in a large cohort of patients with pneumonia.

Introduction: Non-Valvular Atrial Fibrillation (AF) patients show high residual cardiovascular risk despite oral anticoagulants. Urinary 11-dehydro-thromboxane B2 (TxB2) is associated with an increased risk of cardiovascular events, but its predictive value in anticoagulated AF patients is unknown. Hypothesis: Aim of this was to assess whether urinary 11-dehydro-TxB2 is a predictor of cardiovascular events in anticoagulated patients with AF. Methods: Prospective single-center cohort study, including 864 consecutive AF patients. Mean time of follow-up was 30.0 months yielding 2062 person-years of observation. Urinary 11-dehydro-TxB2 was measured at baseline. The primary end-point was the composite of myocardial infarction, ischemic stroke, cardiac revascularization, cardiovascular death and deaths from any cause. Results: Cardiovascular events occurred in 98 (11.3%), whilst 81 patients died (9.4%), including 55 from cardiovascular and 26 from non-cardiovascular causes. At baseline, urinary 11-dehydro-TxB2 levels were higher in patients who experienced a cardiovascular event (p Conclusions: Urinary 11-dehydro-TxB2 predicts residual risk of cardiovascular events in anticoagulated atrial fibrillation patients. Urinary 11-dehydro-TxB2 progressively increases with increasing CHA2DS2-VASc score suggesting that anticoagulated patients with high CHA2DS2-VASc score may need additional antithrombotic strategies.

Patients with nonvalvular atrial fibrillation (AF) show high residual cardiovascular (CV) risk despite oral anticoagulants. Urinary 11-dehydro-thromboxane B2 (TxB2) is associated with an increased risk of CV events (CVEs), but its predictive value in patients with anticoagulated AF is unknown.A prospective single-center cohort study, including 837 patients with AF, was conducted. Mean time of follow-up was 30.0 months, yielding 2,062 person-years of observation. Urinary 11-dehydro-TxB2 was measured at baseline. The primary end point was the occurrence of a CVE including fatal/nonfatal myocardial infarction and ischemic stroke, transient ischemic attack, cardiac revascularization, and CV death.Mean age of patients was 73.1 years, and 43.6% were women. Median 11-dehydro-TxB2 levels were 100 (interquartile range 50-187) ng/mg of urinary creatinine. Overall, the anticoagulation control was adequate (63.9% of mean time in therapeutic range). A CVE occurred in 99 (11.8%) patients, and 55 were CV deaths. At baseline, 11-dehydro-TxB2 levels were higher in patients with a CVE compared with those without (186 [107-400] vs 98 [52-170], P.001). An increased rate of CVEs (log-rank test, P.001) and CV deaths (P.001) was observed across tertiles of 11-dehydro-TxB2. Cardiovascular events were associated with age (hazard ratios [HR] 1.72 per 1 SD, 95% CI 1.33-2.21, P.001), diabetes mellitus (HR 1.89, 95% CI 1.20-2.96, P = .005), heart failure (HR 1.60, 95% CI 1.01-2.54, P = .044), history of stroke/transient ischemic attack (HR 1.96, 95% CI 1.25-3.06, P = .003), and 11-dehydro-TxB2 (HR 1.64 per 1 SD, 95% CI 1.42-1.89, P.001).Urinary 11-dehydro-TxB2 levels are associated with a residual risk of CVEs and CV mortality in patients with AF despite anticoagulant treatment.

Technetium-99m-tetrofosmin is a radiopharmaceutical employed for myocardial imaging, which has recently emerged as useful in the visualization of tumors. In this study technetium-99m-tetrofosmin was evaluated for its accuracy in differentiating malignant from benign pulmonary lesions, and in detecting mediastinal node metastasis due to lung cancer. Eighty-one patients with a solitary lung lesion on the chest radiograph and/or CT scan were submitted to chest single photon emission computed tomography after technetium-99m-tetrofosmin injection (740 MBq i.v.). The scintigraphic findings were correlated to the final histopathological diagnosis, demonstrating abnormal tracer accumulation in 51 of 54 malignant lesions (sensitivity 94%) and in 4 out of 27 benign conditions (specificity 85%), yielding an accuracy of 91%. Mediastinal lymph-node involvement was evaluated in 35 patients with non small cell lung cancer who underwent mediastinoscopy and/or surgery. Tetrofosmin accuracy (89%) was significantly higher than that of CT (69%, p0.05); the false negative scintigraphic results were in nodes sized less than 1 cm. In conclusion, technetium-99m-tetrofosmin imaging is useful in distinguishing malignant from benign pulmonary lesions, and in non-invasively assessing mediastinal node metastases from non small cell lung cancer, especially in patients with enlarged nodes by CT scan.

ReplyWe thank Dr Yildiz and Dr Soydinc for their interest and commentsonourrecentworkregardingtheassociationbetweentheuseofdigox-in and increased mortality in patients affected by atrial fibrillation (AF)[1].IntheirLettertotheEditor[2],Authorsraisemanyinterestingques-tions, suggesting that other factors, in addition to those reported in ourobservational study, may influence the incidence of cardiovascularoutcome in AF digoxin-treated patients.A crucialpointraisedby theAuthorsconcernsthe dosageof digoxinand blood concentrations, as these two factors contribute to the in-creasedriskofmortality[3].Digoxinserumlevelsabovethetherapeuticrangecanbefoundinapercentageofpatientsrangingfrom4to10%[4],and are known to be associated with cardiac toxicity and increasedmortality [5]. However, in a large cohort of 5100 patients in whichblood concentration of digoxin was measured, clinical toxicity attribut-ed to thepro-arrhythmic effectof digoxin havebeensuspected for only0.25% of total patients treated with digitalis [3].Renal dysfunction is another critical issue, which requires digoxintailoring to avoid toxicity; thus, 50%–70% of digitalis is excreted un-changed by the kidney [6].Noteworthy, in the large RIKS-HIA trial [7] including 1493 patientswith and 5540 without digoxin, the relative risk for death betweenpatients discharged with and without digoxin, after adjustment forpropensity score, was independent from baseline serum creatinine.Recent findings from the TREAT-AF study [8] confirmed that, in avery large cohort of 122,465 AF patients (353,168 person-years), theincreased mortality by digoxin was apparently independent from theestimated glomerular filtration rate (eGFR), the effect persisting alsoin the propensity-matched cohort.Inourpopulation,wefoundnodifferencesinrenalfunctionbetweenAF patients treated (n = 90, eGFR calculated by MDRD formula, 69.5[56.4–88.9] ml/min) or not (n = 426, eGFR 73.6 [59.5–87.3] ml/min,p = 0.601) with digoxin.Body mass composition did not apparently influence results fromour study, as at baseline no differences of body mass index (27.4 ±5.0 vs. 27.4 ± 4.7 kg/m

We thank Drs. Savas and Kalay for their interest in our paper [(1)][1]. Epidemiological studies have shown that respiratory tract infections are associated with an increased risk for the development of artery thrombosis as shown by an increased risk of acute cardiovascular and cerebrovascular

In the present study, we tested the hypothesis that oxidative stress could be implicated in myocardial damage during the acute phase of pneumonia. NOX2 activation, the catalytic subunit of NADPH oxidase, and high-sensitivity cardiac troponin T (hs-cTnT) elevation have been analyzed in two hundred forty-eight consecutive patients hospitalized for community-acquired pneumonia. Serum NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, and 8-isoprostaglandin F2α (8-iso-PGF2α), a marker of oxidative stress, were measured upon admission; serum hs-cTnT and ECG were measured every 12 and 24 h, respectively. One hundred thirty-five patients (54%) showed elevated serum levels of hs-cTnT (>0.014 μg/L). A logistic regression analysis showed sNOX2-dp (p

To evaluate the early and long-term postoperative results of malabsorptive surgery in morbidly obese patients. Between 2000 and 2007, 102 morbidly obese patients were referred to the Department of Surgery “Pietro Valdoni”, “Sapienza” University of Rome, Policlinico “Umberto I°”, Rome, Italy for malabsorptive surgery. All patients underwent derivative biliodigestive surgery after they had been reviewed by a team of surgeons, physicians, dieticians, and psychologists. There were no intra-operative complications, but two patients suffered postoperative pulmonary embolisms, which resolved with medical treatment. The mean postoperative hospital stay was 7 days, with no early or late mortality. Maximum weight loss was reached 12–24 months after surgery, while the mean percentage excess weight loss at 3–5 years ranged from 45 to 64 %. Specific postoperative complications in the first 2 years after surgery were abdominal abscess (n = 2), gastroduodenal reflux (n = 4), and incisional hernia (n = 6). Diabetes resolved in 98 % of the diabetic patients within a few weeks after surgery and blood pressure normalised in 86.4 % of those who had had hypertension preoperatively. Obstructive sleep apnoea and obesity hypoventilation syndrome also improved significantly in 92 % of the patients. Morbidly obese patients can undergo biliodigestive surgery safely with good long-term weight loss and quality of life expectancy.

Background Urinary 8‐iso‐ PGF 2α, a marker of oxidative stress, is influenced by the activation of NOX 2. It is unclear if platelets 8‐iso‐ PGF 2α contribute to urinary 8‐iso‐ PGF 2α. Methods and Results In a cross‐sectional study, platelet, urinary, and serum 8‐iso‐ PGF 2α were determined in subjects with downregulation (X‐linked chronic granulomatous disease [ X‐CGD ], n=25) and upregulation (type II diabetic patients [T2D], n=121) of NOX 2 and 153 controls matched for sex and age. In diabetic patients (n=18), the above variables were repeated before and after 7 days treatment with 100 mg/day aspirin or 100 mg/day aspirin plus 40 mg/day atorvastatin. In vitro study was performed to see the contribution of blood cells to serum 8‐iso‐ PGF 2α. Compared with controls, X‐CGD patients had lower platelet, serum, and urinary 8‐iso‐ PGF 2α values; conversely, diabetic patients had higher values of 8‐iso‐ PGF 2α compared with controls. Urinary 8‐iso‐ PGF 2α significantly correlated with both platelet and serum 8‐iso‐ PGF 2α in the 2 cohorts. A parallel increase of platelet, serum, and urinary 8‐iso‐ PGF 2α by aspirin and a parallel decrease by aspirin plus atorvastatin were detected in the interventional study. In vitro study demonstrated that platelets contribute to 37% of serum 8‐iso‐ PGF 2α and that only 13% of it is of extravascular origin. Conclusions The study suggests that NOX 2 contributes to the formation of 8‐iso‐ PGF 2α in both platelets and urine. The direct correlation between platelet and urinary 8‐iso‐ PGF 2α suggests that, at least partly, urinary 8‐iso‐ PGF 2α reflects platelet 8‐iso‐ PGF 2α production. Analysis of serum 8‐iso‐ PGF 2α may represent a novel tool to investigate the production of 8‐iso‐ PGF 2α by blood cells including platelets. Clinical Trial Registration URL: ClinicalTrials.gov. Unique Identifier: NCT01250340 .

Objective Oxidative stress seems to play a role in impairing flow-mediated dilation (FMD) in patients with peripheral artery disease (PAD) but the underlying mechanism is still undefined. We evaluated whether NOX2, the catalytic core of NADPH oxidase, the most important producer of reactive oxidant species (ROS), is implicated in impairing FMD. Methods We measured FMD, urinary isoprostanes, a marker of oxidative stress, nitric oxide generation by serum levels of nitrite/nitrate (NOx), and serum levels of soluble NOX2-derived peptide (sNOX2-dp), a marker of NOX2 activation, in 50 PAD patients and 50 controls. Also, we performed an interventional cross-over study to assess if propionyl-l-carnitine (PLC) (6g/day), vs. placebo, was able to affect FMD via an oxidative stress-mediated mechanism. Results Compared to controls, patients with PAD had enhanced sNOX2-dp and isoprostanes and reduced NOx and FMD. Multiple linear regression analysis showed that FMD was independently associated with sNOX2-dp. After PLC infusion FMD increased while sNOX2-dp and isoprostanes significantly decreased; no changes were observed after placebo. In vitro study by incubating platelets or white cells with PLC demonstrated a significant inhibition of p47 phox translocation on cellular surface and ROS generated by NOX2 activation. Conclusion This study suggests that in PAD patients ROS generated by NOX2 contribute to reduce FMD and that the administration of an antioxidant is able to improve arterial dilatation via NOX2 inhibition.

Background— Statins exert an antithrombotic effect in patients at risk of or with acute thrombosis, but no study has investigated whether this effect is immediate and whether there is an underline mechanism. Methods and Results— Patients with hypercholesterolemia were randomly allocated to a Mediterranean diet with low cholesterol intake (2 , platelet Nox2, Rac1, p47 phox , protein kinase C, vasodilator-stimulated phosphoprotein, nitric oxide, and phospholipase A 2 , were determined at baseline and after 2, 24, and 72 hours and 7 days of follow-up. An in vitro study was also performed to see whether atorvastatin affects platelet oxidative stress and activation. The atorvastatin-assigned group showed a significant and progressive reduction of urinary isoprostanes and serum Nox2, along with inhibition of platelet recruitment, platelet isoprostanes, Nox2, Rac1, p47 phox , and protein kinase C, starting 2 hours after administration. Platelet phospholipase A 2 and thromboxane A 2 significantly decreased and vasodilator-stimulated phosphoprotein and nitric oxide increased after 24 hours. Low-density lipoprotein cholesterol decreased significantly after 72 hours and further declined after 7 days. No changes were observed in the Mediterranean diet group. In vitro experiments demonstrated that atorvastatin dose-dependently inhibited platelet Nox2 and phospholipase A 2 activation, along with inhibition of platelet recruitment, platelet isoprostanes, and thromboxane A 2 , and increased vasodilator-stimulated phosphoprotein and nitric oxide. Conclusions— The study provides the first evidence that atorvastatin acutely and simultaneously decreases oxidative stress and platelet activation by directly inhibiting platelet Nox2 and ultimately platelet isoprostanes and thromboxane A 2 . These findings provide a rationale for the use of statins to prevent or modulate coronary thrombosis. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01322711.

Background NOX2, the catalytic subunit of NADPH oxidase, is suggested to play a role in favouring the occurrence of atrial fibrillation (AF) after cardiac surgery via formation of reactive oxidant species. However, its role in spontaneous AF is still unclear. Objective To define the role of NOX2 and isoprostanes, a marker of oxidative stress, in the different settings of AF. Methods The study was performed on 174 patients with AF (82 with paroxysmal/persistent AF and 92 with permanent AF) and 90 controls matched for sex, age and atherosclerotic risk factors. Urinary isoprostanes and serum levels of soluble NOX2-derived peptide (sNOX2-dp) were measured in each patient. Results Urinary isoprostanes and sNOX2-dp concentrations were significantly higher in patients with paroxysmal/persistent AF than in those with permanent AF and controls. Compared with controls, patients with permanent AF showed a weak increase in sNOX2-dp and no difference in isoprostanes. Multivariable analyses demonstrated that baseline values of sNOX2-dp and urinary isoprostanes were independently associated with the type of AF (paroxysmal/persistent vs permanent; β=−224, p=0.007 and β=−231, p=0.005, respectively). A significant correlation between sNOX2-dp levels and urinary excretion of isoprostanes was also detected (R=0.707, p Conclusions This study provides evidence that NOX2 is upregulated only in patients with paroxysmal/persistent AF and is responsible for overproduction of isoprostanes. This finding warrants further study to see if inhibition of NOX2 may reduce the risk of paroxysmal/persistent AF.

Calorie restriction (CR) slows aging and consistently reduces circulating sex hormones in laboratory animals. However, nothing is known regarding the long-term effects of CR with adequate nutrition on serum sex-hormone concentration in lean healthy humans. In this study, we measured body composition, and serum total testosterone, total 17-beta-estradiol, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEA-S) concentrations in 24 men (mean age 51.5 +/- 13 years), who had been practicing CR with adequate nutrition for an average of 7.4 +/- 4.5 years, in 24 age- and body fat-matched endurance runners (EX), and 24 age-matched sedentary controls eating Western diets (WD). We found that both the CR and EX volunteers had significantly lower body fat than the WD volunteers (total body fat, 8.7 +/- 4.2%; 10.5 +/- 4.4%; 23.2 +/- 6.1%, respectively; P = 0.0001). Serum total testosterone and the free androgen index were significantly lower, and SHBG was higher in the CR group than in the EX and WD groups (Por = 0.001). Serum 17beta-estradiol and the estradiol:SHBG ratio were both significantly lower in the CR and EX groups than in the WD group (Por = 0.005). Serum DHEA-S concentrations were not different between the three groups. These findings demonstrate that, as in long-lived CR rodents, long-term severe CR reduces serum total and free testosterone and increases SHBG concentrations in humans, independently of adiposity. More studies are needed to understand the role of this CR-mediated reduction in sex hormones in modulating the pathogenesis of age-associated chronic diseases such as cancer and the aging process itself.

Objective— The inhibition of oxidative stress is among the most relevant pleiotropic effects of statins. The mechanism by which statins exert their antioxidant effect in vivo is still undefined. NADPH oxidase is among the most important sources of reactive oxygen species involved in atherosclerotic disease. Methods/Results— We developed an ELISA to evaluate serum levels of soluble-gp91 phox , the catalytic core of phagocyte NADPH oxidase. In a cross-sectional study performed in 30 hypercholesterolemic patients and in 20 controls, serum soluble-gp91 phox and urinary isoprostane, a marker of oxidative stress, were measured. The 2 variables were also measured in hypercholesterolemic patients, randomized to diet (n=15), or diet plus atorvastatin (10 mg daily, n=15) and followed for 30 days. Compared to controls, hypercholesterolemic patients had higher and significantly correlated ( R =0.71; P phox ( P P phox (−33%, P P P Conclusion— Our study demonstrates that statins exert an antioxidant effect via inhibition of soluble gp91 phox expression.

Statins have been shown to inhibit oxidative stress, however it is still unclear if they influence antioxidant status. We performed a retrospective analysis of oxidative stress, as assessed by serum levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and vitamin E, a known antioxidant, in patients with metabolic syndrome (n=112) treated (n=30) or not (n=82) with statins. Statin-treated patients showed higher levels of vitamin E (p=0.02) and lower 8-OHdG (p0.01) than statin-free patients. An inverse correlation between oxidative stress and vitamin E was observed (r=-0.670, p0.001). These preliminary data suggest that statins enhance the antioxidant status likely by inhibiting oxidative stress.