Luigi Di Pino

High circulating levels of cytokines (IL-6 and TNFa), adhesion molecules (VCAM-1 and ICAM-1) and selectins in patients with peripheral arterial disease at rest and after a treadmill test:

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that is associated with systemic inflammation. The aim of our study was to assess whether plasma markers of inflammation increased after exercise in patients with PAD. The study was conducted on two groups of 20 subjects each: one group (mean age 68.4 6 5.09 years) was affected by PAD with claudication, while the other group consisted of healthy controls (66.9 6 6.1 years). Concentrations of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNFa) were determined in plasma, in supernatants and in cells stimulated with 1 mg lipopolysaccharide in all patients. E-selectin (ES), L-selectin (LS) and P-selectin (PS) concentrations and plasma concentrations of VCAM-1 and ICAM-I were also determined. All determinations were performed in patients at rest and after the treadmill exercise. Resting values of soluble mediators were greater in PAD patients than in controls. They increased in both groups after the treadmill test, even if post-treadmill concentrations were signifi cantly higher in PAD patients (PAD p < 0.001 or 0.0001, controls p < 0.05 or 0.001). These results confi rm that white blood cell activation is characteristic of systemic atherosclerosis and that these inflammation markers increase in conditions of hemodynamic stress.

Plasma levels and zymographic activities of matrix metalloproteinases 2 and 9 in type II diabetics with peripheral arterial disease

Deregulation of matrix metalloproteinases (MMPs) is an important factor contributing to the development of vascular lesions. Plasma levels and zymographic activities of MMP-2 and MMP-9 were investigated in type II diabetics with (n = 51) or without (n = 42) peripheral artery disease (PAD) and in normal volunteers (n = 23). Plasma MMP-2 levels were higher in type II diabetics with (p < 0.01) or without (p < 0.05) PAD in comparison with normal volunteers. Similarly, type II diabetics with (p < 0.0001) or without (p > 0.05) PAD had higher plasma MMP-9 levels than normal volunteers. Plasma zymographic activities of both MMP-2 and MMP-9 were positively correlated with their plasma levels. Plasma MMP-2 zymographic activity was higher in type II diabetics with PAD than type II diabetics without PAD (p > 0.05). Plasma MMP-9 zymographic activity was higher in type II diabetics with (p < 0.0001) or without (p < 0.0001) PAD in comparision with normal volunteers. Together, these results indicate that increased plasma levels and zymographic activities of MMP-2 and MMP-9 may contribute to PAD in type II diabetics. In particular, plasma MMP-9 may be a useful marker for the development of vascular disease in type II diabetics.

Duration of menopause and behavior of malondialdehyde, lipids, lipoproteins and carotid wall artery intima-media thickness

AIM our study assessed whether minor or major hormonal deficiency influenced oxidative status and vascular wall structure in menopausal women. METHODS the study series was made up of 62 non hypertensive non diabetic menopausal women (mean age 52.3+/-4.7 years) divided into two groups depending on duration of menopause (group 1 duration 0-5 years; group 2 duration over 5 years). Total cholesterol (TC), LDL cholesterol (LDL-C), HDL-cholesterol (HDL-C), triglycerides (TG), malondialdehyde (MDA) and common carotid artery wall intima-media thickness (IMT) were determined in the entire series. RESULTS mean TC, LDL-C, TG, MDA and IMT values were higher in group 2 than group 1. The intergroup difference between MDA (P<0.007) and IMT values (P<0.006) values was statistically significant. CONCLUSIONS the study revealed a close temporal correlation between plasma oxidative stress and carotid wall IMT, jeopardizes vascular wall status as menopause proceeds.

A randomised, controlled clinical trial evaluating changes in therapeutic efficacy and oxidative parameters after treatment with propionyl L-carnitine in patients with peripheral arterial disease requiring haemodialysis.

ObjectiveWe explored the efficacy of intravenous therapy with propionyl L-carnitine in patients with both peripheral arterial disease (PAD) and chronic renal insufficiency requiring haemodialysis.MethodsThe trial was a randomised, double-blind, placebo-controlled trial. Sixty-four patients on haemodialysis (32 per treatment arm) with chronic renal insufficiency and PAD were assigned to receive either intravenous propionyl L-carnitine 600mg or placebo 3 times weekly for 12 months. The main outcome measures were the ankle/brachial index (ABI), plasma malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) concentrations, and the plasma nitrite/nitrate ratio (NO2/NO3); these were measured at baseline and at 6 and 12 months.ResultsSignificant increases in ABI were observed in the propionyl L-carnitine group, whereas in the placebo group the reverse trend was seen. In patients treated with propionyl L-carnitine, significant progressive decreases were seen in plasma MDA, 4-HNE and the NO2/NO3 ratio from baseline. In the placebo-treated group, only weakly significant or no differences were seen.ConclusionIntravenous administration of propionyl L-carnitine to haemodialysis patients with PAD improves both haemodynamic flow and the oxidative profile.

Multiple Sclerosis and CCSVI: A Population-Based Case Control Study

Background Chronic cerebrospinal venous insufficiency (CCSVI) has been associated to multiple sclerosis (MS). Objective To evaluate the possible association between CCSVI and MS, using a population-based control design. Methods A random cohort of 148 incident MS patients were enrolled in the study. We have also studied 20 patients with clinically isolated syndrome (CIS), 40 patients with other neurological diseases (OND), and 172 healthy controls. Transcranial (TCC) and Echo Color Doppler (ECD) were carried out in 380 subjects. A subject was considered CCSVI positive if ≥2 venous hemodynamic criteria were fulfilled. Results CCSVI was present in 28 (18.9%) of the MS patients, in 2 (10%) of CIS patients, in 11 (6.4%) of the controls, and in 2 (5%) of the OND patients. A significant association between MS and CCSVI was found with an odds ratio of 3.41 (95% confidence interval 1.63–7.13; p = 0.001). CCSVI was significantly more frequent among MS subjects with a disease duration longer than 144 months (26.1% versus 12.6% of patients with duration shorter than 144 months; p = 0.03) and among patients with secondary progressive (SP) and primary progressive (PP) forms (30.2% and 29.4, respectively) than in patients with relapsing remitting (RR) MS (14.3%). A stronger association was found considering SP and PP forms (age adjusted OR = 4.7; 95% CI 1.83–12.0, p = 0.001); the association was weaker with the RR patients (age adjusted OR = 2.58; 95%CI 1.12–5.92; p = 0.02) or not significant in CIS group (age adjusted OR = 2.04; 95%CI 0.40–10.3; p = 0.4). Conclusions A higher frequency of CCSVI has been found in MS patients; it was more evident in patients with advanced MS, suggesting that CCSVI could be related to MS disability.

Propionyl-L-Carnitine Therapy: Effects on Endothelin-1 and Homocysteine Levels in Patients with Peripheral Arterial Disease and End-Stage Renal Disease

Background/Aims: Recent data have addressed the issue of higher levels of homocysteine (Hcy) and endothelin-1 (ET-1) in end-stage renal disease (ESRD) that may be considered an independent predictor for cardiovascular disease. The prevalence of peripheral arterial disease (PAD) in patients with ESRD has been reported to be relevant, highlighting its clinical importance. We aimed to explore the therapeutic role of propionyl-L-carnitine (PLC) in hemodialysis patients with PAD by measuring ankle/brachial index (ABI), ET-1 and Hcy. Design: Randomized, double-blind, placebo-controlled trial. Methods: Sixty-four patients on hemodialysis with chronic renal insufficiency and PAD were assigned to receive either intravenous PLC (600 mg) or placebo 3 times weekly for 12 months. The ABI and plasma levels of ET-1 and Hcy were measured at baseline, 6 and 12 months. Results: In the PLC-treated group, progressive increases in ABI were observed, while in the placebo group the reverse trend was seen. Highly significant and progressive reductions in plasma levels of ET-1 and Hcy, compared to baseline, were also seen in the PLC-treated group. Conclusions: Hemodynamic flow, endothelial profile and Hcy levels were ameliorated by the administration of PLC in hemodialysis patients with ESRD and PAD.

Arterial Erectile Dysfunction and Peripheral Arterial Disease: Reliability of a New Phenotype of Endothelial Progenitor Cells and Endothelial Microparticles

The aim of this study was to evaluate whether the blood concentrations of a new immunophenotype of circulating late endothelial progenitor cells (EPC) and endothelial microparticles (EMP) varies in patients with arterial erectile dysfunction (aED) and abnormalities in other arterial districts. To accomplish this, cavernous artery peak systolic velocity (PSV), acceleration time (AT), and intima-media thickness (IMT) were determined after intracavernous administration of alprostadil by echo-color Doppler in 80 consecutive patients (age range, 50-75 years). Fifteen patients had aED alone (group A) and served as controls; 22 had aED plus atheroma plaques and/or increased IMT of the common carotid artery (group B); 20 had aED plus lower limb artery abnormalities (group C); and 23 had aED plus carotid and lower limb artery abnormalities (group D). EPC and EMP blood concentrations were evaluated by flow cytometry. Blood mononuclear cells with the immunophenotype CD45(neg)/CD34(pos)/CD144(pos) were defined as EPCs, whereas CD45(neg)/CD144(pos)/annexin V(pos) cells were defined as EMPs. Group B and C patients had a similar PSV, AT, and IMT at the level of the cavernous arteries. Their PSV values were significantly lower and mean values of AT and IMT significantly higher compared with group A patients. Patients of group D had a significantly lower PSV and significantly higher AT and IMT compared with all other groups. As far as serum concentrations of EPCs and EMPs, group D patients had significantly higher EPC and EMP mean values compared with all other groups. Group B and C patients had similar EPC and EMP values. This study showed that a more generalized peripheral atherosclerotic process is associated with a more severe penile artery insufficiency and endothelial dysfunction. Moreover, this study confirms the diagnostic reliability of the immunophenotype of EPCs and EMPs chosen in the clinical practice.

Tolerability and Clinical Efficacy of Desmin in the Treatment of Superficial Thrombovaricophlebitis

Fifty-six patients with superficial thrombovaricophlebitis of the lower limbs were enrolled in an open and multicenter (4 centers) trial for a period of thirty days. Patients were randomly allocated to three treatment groups to receive a new low-molecular-weight dermatan sulfate (Desmin) at the dose, respectively, of 100 mg once daily by subcuta neous (SC) route, 100 mg twice a day SC, and 200 mg once daily by intramuscular (IM) route. The general and local tolerability and the clinical efficacy of the drug were evaluated by means of clinical, instrumental, and laboratory parameters. Desmin proved capable of effectively improving the symptoms of patients affected by thrombovari cophlebitis, inducing rapid regression by the tenth day of treatment. The daily dose of 200 mg (either SC or IM) was more effective than the 100 mg dose. The systemic toler ability of the drug, administered for the first time for one month, was extremely good, without significant variations in the relevant laboratory tests. Local tolerance (at the site of injection) of the drug was also good.

Three-Month Therapy with Calcium-Heparin in Comparison with Ticlopidine in Patients with Peripheral Arterial Occlusive Disease at Leriche-Fontaine IIb Class

Forty patients with a mean age of 62.6 ± 6 years, 36 men and 4 women, with peripheral arterial occlusive disease (PAOD) at Leriche-Fontaine IIb class, were randomly allocated to one of two treatment groups, receiving either 12,500 IU/ day of subcutaneous (sc) calcium-heparin (CAE) or 250 mg/day of oral ticlopi dine, each given for ninety days. The following parameters were evaluated be fore the start of the active treatment period and after thirty and ninety days of treatment: pain-free walking distance (PWD), maximum walking distance (WDmax), systolic and diastolic blood pressure (BP), posterior tibial arterial pressure and Winsor index at rest and after exercise (treadmill), transcutaneous oxygen and carbon dioxide pressures at rest (TcPO2 and TcPCO2 respectively), and time to 50% TcPo2 recovery after three-minute ischemia. Both treatments induced an improvement in PWD/WDmax, which, at the end of the study, were increased by 50.7/58.7% and 31.7/36.2%, respectively, for CAE and ticlopidine treatments, respectively. Statistical analysis did not show any difference between treatments, al though a statistically significant difference was found in comparison with basal measurements for both CAE and ticlopidine treatments (p < 0.01). Neverthe less, the effects determined by ticlopidine were, on the whole, less impressive than those of CAE. In fact, interestingly, although not in a statistically significant way, the CAE group walked longer in comparison with the ticlopidine group irrespective of the more critical baseline clinical conditions. Moreover, TcPo2 was favorably modified by CAE (p < 0.01) but not by ticlopidine treatment while the other parameters remained unchanged. In conclusion, CAE, given at the daily dose of 12,500 IU in patients with PAOD at the Leriche-Fontaine IIb class, showed beneficial clinical effects, which, in turn, could be due both to the removal of the thrombophilic im balance and to the restoration of the fibrinolytic-coagulatory hemostasis in the involved microvascular circulation.

Efficacy of L-Propionyl Carnitine in the Treatment of Chronic Critical Limb Ischaemia

ObjectiveTo compare the therapeutic benefits of L-propionyl carnitine (LPC) with those of pentoxifylline in the clinical treatment of patients with chronic critical limb ischaemia.DesignRandomised, single-blind study.Patients188 patients, 85 with a recent (within the previous 15 days) reduction in pain-free walking distance (PWD), 59 with rest pain lasting for ≥2 weeks, and 44 patients with skin ulcers that had appeared during the previous 15 days.InterventionsIntravenous infusion with LPC 1.2 g/day or pentoxifylline 1.2 g/day In both groups, patients also received calcium heparin 25 000 U/day (12 500U twice daily) subcutaneously. Treatment duration was 2 weeks.Main Outcome Measures and ResultsWith both treatments, an increase in the PWD, a reduction in the use of analgesics for pain relief and a reduction in the diameter (in cm) of skin ulcers were observed; all changes were significant versus baseline for both groups. However, a statistically significant difference was observed between the results obtained with LPC and those obtained with pentoxifylline, which was in favour of LPC. Mean PWD increased by 78% in the LPC group vs 30% in the pentoxifylline group (p < 0.001), mean pain score decreased by 83 vs 46% (p < 0.001), and mean ulcer size decreased by 48 vs 25% (p < 0.001).ConclusionsLPC, which has already been shown to produce beneficial effects in the treatment of the chronic phase of peripheral vascular disease, was also found in this study to have greater effects in delaying disease progression than pentoxifylline, a drug that has been extensively tested for this indication. LPC, therefore, appears to be a promising treatment option in patients with peripheral arterial disease and should be further explored in large randomised, long-term controlled trials.