A nitric oxide-donor pravastatin hybrid drug exerts antiplatelet and antiatherogenic activity in mice

Aim of the present study was to compare the lipid-lowering, antithrombotic and antiatherogenic properties of NCX-6550, nitropravastatin, a nitric-oxide donating derivative of pravastatin, with those of pravastatin in hypercholesterolemic mice. LDL receptor-deficient mice (LDLR–/–) on a normal diet (ND) showed enhanced cholesterol levels as compared to wild type (WT) mice (6.8±1.2 mmol/L and 2.8±0.82 mmol/L, respectively). High fat diet (HFD) induced a large enhancement of cholesterolemia in LDLR–/– mice (23.7±5.7 mmol/L, p<0.0001 vs LDLR–/– ND and WT mice. Treatment with NCX 6550 (48 mg/kg), but not with equimolar pravastatin, reduced cholesterol in LDLR–/–HFD. Platelet adhesion to collagen under high shear rate (3000 sec–1) was significantly higher in LDLR–/– than in normal mice, and further enhanced in LDLR–/–HFD (-27%, p<0.0001 vs untreated). NCX 6550 (48 mg/kg), but not pravastatin, reduced platelet adhesion, especially in LDLR–/–HFD. U46619-induced platelet aggregation ex vivo was also inhibited by NCX 6550 (48 mg/kg) but not by the parent compound. Finally, photochemically-induced acute (1 hr) femoral artery thrombosis and delayed (21 days) intimal thickening was assessed. Thrombus size was larger in LDLR–/– on HFD than in normocholesterolemic mice (0.46±0.04 vs 0.18±0.08 mg) and it was reduced by NCX 6550 (48 mg/kg) (0.08±0.02 mg, p<0.0001), but not by pravastatin (0.4±0.01 mg p=NS). Intimal thickening was greater in hypercholesterolemic than in normal mice (I/M normal=0.53±0.16, LDLR–/–=1.1±0.15, LDLR–/–HFD=1.75 ±0.25). Both NCX 6550 and pravastatin reduced intimal thickening in normal (-95% and -74.5%, respectively) and LDLR–/– mice (-98% and -91%), while in strongly hyperlipidemic animals (LDLR–/–HFD) NCX 6550 was more effective than pravastatin (-98% vs -65%, p<0.0001). NCX 6550 shows greater antithrombotic and antiatherogenic activity than pravastatin in highly hypercholesterolemic mice

Endothelial dysfunction in patients with spontaneous venous thromboembolism

Background and Objectives A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism.Design and Methods Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age-(±5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured.Results Twenty-eight cases (8 females; mean age 59±15 years) and 28 controls (8 females; mean age 58±15) were studied. Flow-mediated vasodilation was 3.5±0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7±0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls.Interpretation and Conclusions Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis

Blood lipid, homocysteine, uric acid and vitamins in clinically stable Multiple Sclerosis patients

A decrease of antioxidants, of neuroprotective and immunoregulatory vitamins and an increase of total-Homocysteine, Cholesterol, HDL-cholesterol, and of cellular stress markers [1] was reported in patients affected by Multiple Sclerosis. Recently, considering their unreliability, mainly due to the variability of the samples investigated, the attention focused on clinical relapse that results associated to a decrease of Uric acid and an increase of Cholesterol and stress markers. Aim. To identify the biochemical status during Multiple Sclerosis (MS) in a phase of clinical stability (PCS), we compared the blood levels of Urico acid (UA), Folic acid (FA), vitamins B12, A, and E, total-Homocysteine (t-Hcy), total Cholesterol (CHL) , HDL-CHL, and Triglycerides (TG) in 20 MS stable patients with those of 40 healthy controls. Methods. Consecutive MS patients, with relapsing-remitting or secondary-progressive courses, in a (PCS), were included. Plasma t-Hcy levels were determined by Ubbink method [1]. Technicon Immuno autoanalyser was used for serum FA and vitamin B12 assays. HPLC and fluorometry were used for UA, vitamin A and E, CHL, HDL-CHL, and TG assays. The ratio of E/CHL was valued. Results and Discussions. We found that MS patients in a PCS have higher blood levels of vitamin B12, t-Hcy, CHL, and HDL-CHL and lower blood levels of vitamin E and of the ratio E/CHL. The blood level of UA, FA, vitamin A, and TG do not differ from controls during this phase of MS. The increased level of CHL could be expression of both an its increased synthesis by neural cells and a chronic damage of myelin and axons. HDL-CHL concentration might arise to counteract the increase of CHL and assure its transport to the liver. Plasma levels of vitamin E, the major hydrophobic chain-breaking antioxidant, are decreased and our data confirm and support the view that it is consumed to counterbalance MS chronic neurodegeneration. Also, the increased levels of t-Hcy and vitamin B12 match previous studies performed in MS patients outside relapse. No significant differences in UA, FA, vitamin A, and TG levels appeared, making unprobable their involvement in the degenerative process of the stable phase of MS

Walking-induced endothelial dysfunction predicts ischemic cardiovascular events in patients with intermittent claudication

Endothelial dysfunction, evaluated by flow-mediated dilatation (FMD), predicts adverse cardiovascular events in patients with intermittent claudication (IC). IC is an example of repeated ischemia/reperfusion injury that may contribute to the progression of vascular disease by worsening endothelial function, a trigger for acute cardiovascular events. The predictive value of effort-induced endothelial dysfunction for cardiovascular events in patients with IC has not been studied previously. The objective of this study was to assess whether exercise-induced endothelial dysfunction is predictive of adverse cardiovascular outcome in IC. In 44 patients with IC, we measured brachial artery FMD by B-mode ultrasonography at rest and 10 minutes after a maximal treadmill exercise. Treadmill exercise halved the FMD (from 3.5 +/- 0.6% to 1.45 +/- 0.46%, p &lt; 0.05). After a follow-up period of 85 (72-98) months, a total of 20 major cardiovascular events occurred. In a multivariate analysis, a post-exercise reduction of brachial FMD &gt; 1.3% was predictive for cardiovascular events. Maximal exercise-induced endothelial dysfunction is predictive of cardiovascular events in patients with IC

Oncoplastic surgery in elderly patients with breast cancer: overtreatment or a goal worth pursuing?

Breast cancer is the most common cancer in women in Western countries, which increases with age. The improvement of reconstructive methods in light of the principles and techniques borrowed directly from cosmetic surgery has helped raise the quality in terms of aesthetic results in conservative treatment. This approach has reached results, which merits a more precise role of self-autonomy and the name of oncoplastic breast surgery. Today this approach is becoming, in the centers dedicated to the treatment of breast cancer, the gold standard in the surgical treatment of patients with this cancer. So if the role of oncoplastic in the surgical treatment of breast cancer is to be established, it remains crucial to have a selection of patients who could benefit from this approach: today, age is one of the determining factors in the selection of patients and, in fact, patients over 75 years, are often excluded from surgery of this type. In our opinion, after a multidisciplinary assessment, also the older women could be able to receive this type of surgical approach

Electrocardiogram-gated 16-multidetector computed tomographic angiography of the coronary arteries in dogs

The aims of this study were to assess if ECG-gated 16-multidetector CT (MDCT) provides sufficient temporal and spatial resolution to evaluate canine coronary arteries and provide a detailed description of their anatomy. A total of 24 dogs were included. Images were reviewed to assess: (1) coronary artery opacification and dominance; (2) choice of optimal R-R ECG reconstruction interval for both left coronary artery (LCA) and right coronary artery (RCA); (3) branching patterns of the left main coronary artery (LMCA); and (4) diameter and length of the LCA and RCA and classification of their branches by adapting a previously described segmental coding system. The degree of opacification of the coronary arteries was subjectively judged as excellent or good in five and 19 dogs, respectively. All hearts showed a left coronary dominance. The best R-R reconstruction interval for both LCA and RCA arteries was 75 per cent. Seven different subtypes of LMCA branching patterns were noted. The and were divided into three angiographic segments, and the and the RCA in two and three segments, respectively. ECG-gated 16-MDCT coronary angiography provides adequate resolution to assist the basic anatomy of the main coronary artery branches

Development of anti-matrix metalloproteinase-2 (MMP-2) nanobodies as potential therapeutic and diagnostic tools

Matrix metalloproteinase-2 (MMP-2) is an endopeptidase involved in cardiovascular disease and cancer. To date, no highly selective MMP-2 inhibitors have been identified for potential use in humans. Aim of our work was to apply the nanobody technology to the generation of highly selective inhibitors of human MMP-2 and to assess their effects on platelet function and their applicability as conjugated nanobodies. We constructed a nanobody library after immunising an alpaca with human active MMP-2 and identified, after phage display and screening, one MMP-2 inhibitory nanobody (VHH-29), able to hinder the effects of MMP-2 on platelet activation, and one nanobody not inhibiting MMP-2 activity (VHH-136) which, chemically conjugated to a fluorescent probe, allowed the detection of human MMP-2 by flow-cytometry and immune-cytochemistry. In conclusion, we have generated and characterized two new nanotechnological molecular tools for human MMP-2 which represent promising agents for the study of MMP-2 in cardiovascular pathophysiology.status: publishe