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Biomedical subjects

Francesco Violi

Publications and source records attributed to Francesco Violi.

At least 19 recordsLinked to original sources
PubMed2006

Anti-inflammatory and anti-atherogenic effects of cathechin, caffeic acid and trans-resveratrol in apolipoprotein E deficient mice.

A strong negative correlation between polyphenols consumption and coronary heart disease has been extensively documented. These results prompted investigations on the mechanisms responsible for polyphenols effects in cardiovascular disease. The aim of this work was to investigate in apoE KO mice the effect of P183/1 (a mixture of cathechin, caffeic acid and resveratrol) on atherosclerosis and gene expression patterns in the vascular wall. ApoE KO mice were fed a diet supplemented with P183/1, 40 and 160 mg/kg body weight/day for 8 weeks. The supplementation with the high dose of P183/1 significantly reduced the presence of atherosclerotic plaque by 40 and 36% in the aortic sinus and in the ascending aorta, respectively. This reduction was associated with a reduced expression of markers for macrophages, lymphocytes (both Th1 and Th2) and of MCP-1, MIP-1alpha, MIP-1beta, CCR1, CCR2 and ET1 in the vascular wall. In conclusion, P183/1 supplementation significantly decreases atherosclerosis in ApoE KO mice by affecting inflammatory cells recruitment and expression of pro-inflammatory chemokines in the vascular wall.

Animals↗
PubMed2006

Imbalance between nitric oxide generation and oxidative stress in patients with peripheral arterial disease: effect of an antioxidant treatment.

BACKGROUND: Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is reduced in patients with peripheral arterial disease (PAD), but the mechanism has not been fully elucidated. Because NO is rapidly inactivated by superoxide anion, we speculated that enhanced oxidative stress could lower NO generation. The aim of our study was to investigate if an imbalance between oxidative stress and NO does exist in patients with PAD and if an increase of NO formation could be achieved by an antioxidant treatment. METHODS: In a first study, serum levels of nitrite and nitrate (NOx), markers of NO generation, and 8-hydroxy-2-deoxyguanosine (8-OHdG), a marker of oxidative stress and maximal walking distance (MWD), were measured in 40 PAD patients and 40 controls. In a second study, 10 PAD patients were randomly allocated in a crossover design to intravenous propionyl-L-carnitine (6 g/day) or placebo for 7 days, with a washout of 30 days between the two phases of the trial. Serum levels of NOx and 8-OHdG were measured before and after the study. RESULTS: Compared with controls, serum levels of 8-OHdG (mean +/- SD) were significantly increased in PAD patients (4.4 +/- 3.1 ng/mL vs 2.4 +/- 1.2 ng/mL; P < .001), and serum levels of NOx were significantly decreased (11.6 +/- 6 microM vs 17 +/- 6.1 microM; P < .001). Levels of 8-OHdG and NOx were inversely correlated (r = -0.879; P < .001). Serum levels 8-OHdG were inversely correlated with MWD (r = -0.48, P = .002). The interventional trial showed no changes in the patients given placebo. Patients treated with propionyl-L-carnitine showed a significant increase of MWD from 101 +/- 31 meters to 129 +/- 35 meters (P = .007) and in NOx from 14.5 +/- 4.5 microM to 17.1 +/- 3.8 microM (P = .007). A significant decrease of 8-OHdG from 3.6 +/- 1.1 ng/mL to 2.6 +/- 1 ng/mL was also found (P = .005.) CONCLUSIONS: This study suggests that in PAD patients, the reduction of NO generation could be dependent upon enhanced oxidative stress.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2006

Aspirin resistance: is this term meaningful?

PURPOSE OF REVIEW: To review data for and against the existence of 'aspirin resistance', a term coined to indicate aspirin-treated patients having ex-vivo tests of platelet activation insensitive to aspirin treatment and recurrence of cardiovascular disease. RECENT FINDINGS: 'Aspirin resistance' defined by ex-vivo tests of platelet activation yielded values ranging from 21 to 78%, indicating that such tests do not provide a useful measurement. In long-term aspirin-treated patients, studies demonstrated small but functionally relevant platelet thromboxane A2 formation that was responsible for an enhanced platelet activation in response to platelet agonist. These studies, however, did not fully exclude that aspirin compliance may be implicated in such phenomena. Two trials performed in patients with coronary artery disease demonstrated that laboratory evidence of aspirin resistance was no longer detectable when aspirin compliance was accurately monitored. SUMMARY: Given the multifactorial nature of atherothrombosis, recurrence of cardiovascular events in aspirin-treated patients does not necessarily suggest 'drug failure'. A cause-effect relationship between platelet insensitivity to aspirin and cardiovascular recurrence has not been defined overall because aspirin compliance has been scarcely considered. Until this information is taken into account, the existence of 'clinical resistance' to aspirin should be reconsidered.

Aspirin↗
PubMed2005

99mTc-interleukin-2 scintigraphy for the in vivo imaging of vulnerable atherosclerotic plaques.

PURPOSE: Several histopathological studies have demonstrated that vulnerable plaques are enriched in inflammatory cells. The aims of this study were: (1a) to test the ability of 99mTc-labelled interleukin-2 (99mTc-IL2) to bind to IL2R-positive (IL2R+) cells in carotid plaques and (1b) to correlate the plaque uptake of 99mTc-IL2, measured in vivo, with the number of IL2R+ cells within the plaque, measured ex vivo by histology (transversal study, TS), and (2) to evaluate changes in 99mTc-IL2 uptake in plaques, before and after treatment with a statin or a hypocholesterolaemic diet (longitudinal study, LS). METHODS: Ultrasound scan was performed for plaque characterisation and localisation. Fourteen patients (16 plaques) eligible for endoarterectomy were recruited for the TS and underwent 99mTc-IL2 scintigraphy before surgery. Nine patients (13 plaques) were recruited for the LS; these patients received atorvastatin or a standard hypocholesterolaemic diet and 99mTc-IL2 scintigraphy was performed before and after 3 months of treatment. RESULTS: The degree of 99mTc-IL2 uptake was expressed as the plaque/background (T/B) ratio. In patients from TS, T/B ratios correlated with the percentage of IL2R+ cells at histology (r = 0.707; p = 0.002) and the number of IL2R+ cells at flow cytometry (r = 0.711; p = 0.006). No correlations were observed between ultrasound scores and either scintigraphic or histological findings. In patients from the LS, the mean 99mTc-IL2 uptake decreased in statin-treated patients (1.75+/-0.50 vs 2.16+/-0.44; p = 0.012), while it was unchanged in the patients on the hypocholesterolaemic diet (2.33+/-0.45 vs 2.34+/-0.5). CONCLUSION: 99mTc-IL2 accumulates in vulnerable carotid plaques; this accumulation is correlated with the amount of IL2R+ cells and is influenced by lipid-lowering treatment with a statin.

Aged↗
PubMed2005

Indobufen inhibits tissue factor in human monocytes through a thromboxane-mediated mechanism.

OBJECTIVE: To assess whether indobufen, a reversible inhibitor of platelet cyclooxygenase (Cox) activity, affects tissue factor (TF) in human monocytes and to investigate the relationship between Cox-derived products and TF. METHODS: TF was evaluated in isolated adherent monocytes, both resting and lipopolysaccharide (LPS)-stimulated, in terms of procoagulant activity, protein, and mRNA levels. The expression of TF surface antigen was determined in LPS-stimulated whole blood monocytes by flow cytometry. The levels of the stable thromboxane A2 (TxA2) metabolite, TxB2, and of prostaglandin E2 (PGE2) were measured in monocyte supernatant by immunoenzymatic techniques. Cox-1 and Cox-2 protein level, tyrosine phosphorylation, and mitogen-activated protein kinase (MAP-kinase) activation were determined by Western blot analysis. RESULTS: Indobufen prevents TF expression and activity both in isolated and in whole blood monocytes. Reduction of TxA2 synthesis, coupled with a lack of effect on PGE2 levels and prevention of ERK1/2 phosphorylation are highlighted as the mechanisms through which indobufen negatively affects TF. CONCLUSIONS: Data show that indobufen down-regulates TF in monocytes. This novel activity, coupled with the antiplatelet effect of the drug, may add benefit for its use in the management of atherothrombosis.

Cells, Cultured↗
PubMed2005

Tumor necrosis factor-alpha as trigger of platelet activation in patients with heart failure.

The clinical history of patients with heart failure (HF) is complicated by arterial thromboembolism. Platelet activation is reported in this population, but the underlying mechanism has not been clarified. Forty-two patients with HF scored according to New York Heart Association (NYHA) classification had higher levels of collagen-induced platelet aggregation, platelet tumor necrosis factor-alpha (TNF-alpha) receptor expression, and serum thromboxane B2 and higher circulating levels of TNF-alpha than 20 healthy subjects. Coincubation of platelets from HF patients with an inhibitor of TNF-alpha receptors significantly reduced collagen-induced platelet aggregation. In vitro study demonstrated that TNF-alpha amplified the platelet response to collagen; this effect was inhibited by TNF-alpha receptor antagonist and inhibitors of arachidonic acid metabolism. This study showed that TNF-alpha behaves as a trigger of platelet activation through stimulation of the arachidonic acid pathway.

Aged↗
PubMed2005

Vitamin C inhibits platelet expression of CD40 ligand.

Upon stimulation with agonists, platelets express CD40 ligand (CD40L), a transmembrane protein implicated in the initiation and progression of atherosclerotic disease. We have recently discovered that oxidative stress plays a major role in platelet CD40L expression. In this study, we sought to determine whether vitamin C, a known antioxidant, is able to influence platelet CD40L expression. In vitro experiments were done by stimulating platelets with collagen in the presence or absence of vitamin C (50-100 microM) or vehicle as control. An in vivo study was done in 10 healthy subjects who were randomized to intravenous infusion of placebo or 1 g vitamin C for 45 min in a crossover design. At the end of infusion platelet CD40L and O2- were measured. The in vitro study demonstrated that vitamin C dose dependently inhibited platelet CD40L expression without affecting agonist-induced platelet aggregation. In subjects treated with placebo no changes of platelet CD40L and O2- were observed; conversely, vitamin C infusion caused a significant and parallel decrease of platelet O2- (-70%, P < 0.001) and CD40L (-68%, P < 0.001). Platelet aggregation was not modified by either treatment. This study suggests that water-soluble antioxidants, which scavenge superoxide radicals, may reduce platelet CD40L expression.

Adult↗
PubMed2005

Short-term treatment with atorvastatin reduces platelet CD40 ligand and thrombin generation in hypercholesterolemic patients.

BACKGROUND: Soluble CD40L (sCD40L), a substance that maximally reflects in vivo platelet activation, is increased in patients with hypercholesterolemia. We investigated the relation between sCD40L and platelet CD4OL in hypercholesterolemic patients before and after a short-term treatment with atorvastatin. METHODS AND RESULTS: Collagen-induced platelet CD40L and plasma levels of sCD40L and prothrombin fragment F1+2, a marker of thrombin generation, were investigated in 30 hypercholesterolemic patients and 20 healthy subjects. Hypercholesterolemic patients were then randomized to either diet (n=15; group A) or atorvastatin 10 mg/d (group B); the aforementioned variables were measured at baseline and after 3 days of treatment. Compared with referents, hypercholesterolemic patients showed higher values of platelet CD40L (P<0.005), sCD40L (P<0.005), and F1+2 (P<0.003). Platelet CD40L was significantly correlated with sCD40L (P<0.001), and the latter was significantly correlated with F1+2 (P<0.001). The intervention trial showed no changes in group A but a significant decrease in platelet CD40L (P<0.01), sCD40L (P<0.002), and F1+2 (P<0.03) in group B. In vitro studies demonstrated that cholesterol enhanced platelet CD40L and CD40L-mediated clotting activation by human monocytes; also, atorvastatin dose-dependently inhibited platelet CD40L expression and clotting activation by CD40L-stimulated monocytes. CONCLUSIONS: This study shows that, in hypercholesterolemia, platelet overexpression of CD40L may account for enhanced plasma levels of sCD40L and F1+2. Atorvastatin exerts a direct antithrombotic effect via inhibition of platelet CD40L and CD40L-mediated thrombin generation, independently of its cholesterol-lowering effect.

Adenosine Diphosphate↗
PubMed2005

CD40 ligand enhances monocyte tissue factor expression and thrombin generation via oxidative stress in patients with hypercholesterolemia.

OBJECTIVES: We tested the hypothesis that CD40 ligand (CD40L) induces a prothrombotic state by enhancing oxidative stress. BACKGROUND: Patients with hypercholesterolemia show an ongoing prothrombotic state, but the underlying mechanism is still unclear. METHODS: Circulating levels of the soluble form of CD40L (sCD40L), prothrombin fragment (F1+2, a marker of thrombin generation), and 8-hydroxy-2'-deoxyguanosine (8-OHdG, a marker of oxidative stress) were measured in 40 patients with hypercholesterolemia and in 20 age- and gender-matched healthy subjects. RESULTS: Patients with hypercholesterolemia showed significantly higher levels of sCD40L (p <0.005), 8-OHdG (p <0.005), and prothrombin F1+2 (p <0.005), as compared with control subjects. Soluble CD40L significantly correlated with 8-OHdG (r=0.85, p <0.0001) and prothrombin F1+2 (r=0.83, p <0.0001); a significant correlation between 8-OHdG and prothrombin F1+2 was also observed (r=0.64, p <0.0001). An in vitro study demonstrated that CD40L-stimulated monocytes from patients with hypercholesterolemia expressed more tissue factor (TF) and prothrombin F1+2 than monocytes from controls; co-incubation of monocytes with either an inhibitor of NADPH oxidase or an inhibitor of phosphatidylinositol-3-kinase significantly reduced CD40L-mediated clotting activation. A marked inhibition of CD40L-mediated clotting activation was also observed in two male patients with hereditary deficiency of gp91 phox, the central core of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Finally, we demonstrated that CD40L-mediated clotting activation was significantly inhibited by vitamin C, a known antioxidant. CONCLUSIONS: This study indicates that in patients with hypercholesterolemia, CD40L over-expresses TF and increases the thrombin generation rate by an oxidative stress-mediated mechanism that requires the activation of NADPH oxidase.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2005

Evaluation of D-dimer and factor VIII in cirrhotic patients with asymptomatic portal venous thrombosis.

D-dimer and factor VIII levels raise in advanced cirrhosis. We investigated the behavior and the diagnostic usefulness of D-dimer and factor VIII in cirrhotic patients with asymptomatic portal venous thrombosis. Factor VIII coagulant and D-dimer values were measured in 136 consecutive outpatients with stable cirrhosis divided according to Child-Pugh (CP) classification, who underwent color/power ultrasonography to detect portal thrombosis. Portal thrombosis was found in 33 patients (24.2%). In patients without thrombosis, factor VIII was significantly higher in CP class C compared with class A and B. Conversely, class C patients with portal thrombosis had lower factor VIII levels than those without thrombosis. In both groups, D-dimer was significantly increased in class C compared with class A and B. In class C, thrombotic patients showed higher D-dimer values than did patients without thrombosis. In class C, a D-dimer value > or = 0.55 microg/mL provided a sensitivity and a negative predictive value for portal thrombosis of 100%, and a factor VIII coagulant level < or = 80% showed a specificity and a negative predictive value of 76% and 84%, respectively. In class B, a D-dimer value > or = 0.225 microg/mL had a sensitivity of 89% and a negative predictive value of 82%. In conclusion, our study shows that factor VIII values increase in severe cirrhosis but significantly decrease in the presence of concomitant portal thrombosis, likely because of consumption during thrombosis; D-dimer is enhanced by both liver failure and portal thrombosis; in severe cirrhosis, normal D-dimer and factor VIII values may safely exclude the presence of asymptomatic portal thrombosis.

Aged↗
PubMed2005

The association between hyperhomocysteinemia and ischemic stroke in patients with non-valvular atrial fibrillation.

BACKGROUND AND OBJECTIVES: Atrial fibrillation is complicated by a high rate of ischemic stroke. Previous studies have shown that an increased level of circulating total plasma homocysteine (tHcy) is an independent predictor of stroke, but it is unclear whether it is also predictive of stroke in patients with atrial fibrillation. The objective of this study was to evaluate whether increased tHcy is an independent predictor of cardio-embolic stroke in patients with non-valvular atrial fibrillation. DESIGN AND METHODS: We studied 163 consecutive patients (77 males and 86 females; mean age 72.3+/-8.8 years) with permanent (n=118) or paroxysmal (n=45) atrial fibrillation of non-valvular origin hospitalized for cardiac reasons. Ischemic stroke, documented by nuclear magnetic resonance or computerized tomography imaging, had occurred at an average of 2 years before hospitalization in 40 patients (16 males and 24 females, mean age 74.8+/-8.8 years). Fasting tHcy levels were determined by high performance liquid chromatography. RESULTS: Multivariate analysis adjusting for traditional cardiovascular risk factors, thromboembolic risk factors and predictors of tHcy (glomerular filtration rate, uric acid, gender) and fibrinogen levels (age, alcohol intake) showed that total homocysteine (OR: 1.056; for each 1 micromol/L increase, 95% C.I.: 1.00-1.12; p=0.042) and fibrinogen (OR: 1.008 for each 1 mg/dL increase; 95% C.I.: 1.00-1.014; p=0.016) were independently associated with ischemic stroke. With respect to patients in the first quartile of the tHcy distribution (4.6-7.5 micromol/L), patients in the fourth quartile of the tHcy distribution (18.7-67.1 micromol/L) had a 2.73-fold increased probability of ischemic stroke INTERPRETATION AND CONCLUSIONS: In patients with non-valvular atrial fibrillation hospitalized for cardiac reasons, increased fasting tHcy levels are independently associated with a history of ischemic stroke.

Aged↗
PubMed2005

Antioxidants and cardiovascular disease.

Oxidative stress appears to play a key role in the pathogenesis of atherosclerosis. Agents that prevent the oxidation of low-density lipoprotein have reduced the development and progression of this disease in a range of in vitro experiments and animal models. In the last decade, many trials of antioxidants in patients with cardiovascular disease have been conducted, but the results have been ambiguous. The reason for the disappointing findings is unclear, but one possible explanation is the lack of identification criteria for patients who are potential candidates for antioxidant treatment. This review analyzes data reported to date, in order to determine whether these clearly support the premise that patients at risk of cardiovascular disease may be candidates for this therapeutic option.

Animals↗