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The aims of this study were to investigate the interrelationships between endothelial progenitor cells (EPCs), peripheral arterial disease (PAD), and atherosclerotic risk factors, as only limited data are available regarding the EPCs in patients with PAD. The authors studied the number of EPCs by different methods in a carefully selected group of 45 patients with PAD along with 24 healthy subjects (HS). In patients with PAD, by utilizing the dual-binding method, the number of EPCs was significantly increased compared to HS (M +/- SD, PAD: 73 +/- 33, HS: 52 +/- 20 EPCs/high power field; p < .001). On the contrary, both CD34(+) cell count and CD133(+) cell count were significantly decreased compared to HS. Colony-forming units were significantly increased in PAD compared to HS (median and 25th and 75th percentiles, PAD: 7, 1, 9; HS: 1, 1, 4 CFU/well, respectively; Mann-Whitney, p = .006). In patients with PAD, the number and proliferative activity of circulating EPCs are increased with respect to HS even though EPC count by flourecence-activated cell sorting (FACS) analysis provided different results and this may explain the discrepancy in data collected using different methods. The regulation of the number and biological activity of EPCs in PAD remains unclear.

Cardiovascular disease is the leading cause of mortality and morbidity in Western countries. Despite its remarkable medical and social consequences, the prevalence of peripheral arterial disease (PAD) is often underestimated among atherosclerotic disorders. So far, little is known about the behavior of traditional and emerging markers of ischemic heart disease that should allow the reliable identification of PAD patients at increased risk of developing myocardial ischemia and heart failure or dysfunction. To investigate this topic, we measured cardiac troponin T (cTnT), ischemia-modified albumin (IMA) and NT-prohormone-brain natriuretic peptide (NT-proBNP) in 35 consecutive patients with clinically ascertained PAD (stage 2-4, according to Lériche-Fontaine) asymptomatic for chest pain and current heart failure, and 20 controls displaying moderate to high cardiovascular risk factors (hypertension, diabetes, hyperlipidemia), but with no clinical evidence of PAD. Although the concentrations of cTnT and IMA were not statistically increased in PAD patients, NT-pro-BNP values were substantially higher in PAD patients than in controls (62.6 vs. 7.4 pmol/L, p<0.0001). The percentage of subjects displaying values exceeding the specific NT-proBNP diagnostic threshold (>14.8 pmol/L) was also significantly different between PAD patients and controls (74% vs. 10%, p<0.001). After excluding PAD patients exceeding the 0.01 ng/mL cTnT cutoff value indicative of current ischemic cardiac involvement, the median concentration of NT-proBNP remained statistically increased (28.0 vs. 5.8 pmol/L, p<0.0001). Taken together, these results indicate that NT-proBNP, but not IMA, is substantially increased in PAD patients. This finding suggests that such patients, even though asymptomatic, might develop myocardial dysfunction, and thus warrant further investigation.

The progressive increase of deaths and morbidity from cardiovascular disease (CVD) in most developed societies has led to the formulation of preventive strategies and application of several diagnostic guidelines. However, there is emerging evidence that most panels and algorithms are inadequate and require urgent revision and updating. Therefore, the aim of this study was the evaluation of a wide cardiovascular risk profile in elderly male patients with acute myocardial infarction (AMI) or peripheral occlusive disease (POD). The risk profile was assessed by measuring conventional serum lipid and lipoprotein levels and emerging parameters: lipoprotein(a) (Lp[a]), homocysteine (Hcy), and C-reactive protein (CRP). The concentration of triglycerides, Lp(a), Hcy and the total cholesterol/high-density lipoprotein (TC/HDL) ratio were significantly higher in both classes of patients than in a population of matched healthy controls and, similarly, patients with CVD displayed lower plasma values of HDL. No significant differences were observed for TC, low-density lipoprotein (LDL), and CRP. Patients with POD exhibited a marked atherogenic profile, as attested by substantially increased values of Hcy, Lp(a), triglycerides, and TC/HDL ratio. The frequency distributions of Lp(a) and Hcy concentrations were markedly shifted toward upper values in both classes of patients than in controls. In multivariate regression analysis, Lp(a) and Hcy were the best predictors for AMI, whereas Lp(a), Hcy, and the TC/HDL ratio were the best predictors for POD. Taken together, these data suggest that Lp(a) and Hcy excesses might exert a central role in the development of atherosclerotic disease in elderly male patients. Thereby, the inclusion of those tests, along with the TC/HDL ratio and other more conventional analyses in panels for the evaluation of the cardiovascular risk might be profitable in terms of effectual prevention.

Platelet function and levels of vascular adhesion molecule-1 (VCAM-1) were investigated in 24 patients with peripheral arterial disease at Fontaine stage II undergoing a 2 weeks treatment with iloprost (0.5-2 ng/kg/h i.v. infused, 6 h/day) or a 2 weeks supervised physical training, randomly assigned. Patients were studied before (T0) and after (T14) treatments and 10 days later (T24). The adhesion of washed platelets to fibrinogen coated microwells was reduced after treatment both with iloprost (1.9+/-0.4 vs 6.8+/-0.7%; T24 vs T0; M+/-SEM; p<0.05) and physical exercise (3.0+/-1.0 vs 6.7+/-0.7; p<0.05) while adhesion to human plasma coated microwells was reduced only after treatment with iloprost (1.9+/-0.8 vs 5.8+/-0.9; p<0.05). The expression of fibrinogen receptor (glycoprotein IIb/IIIa) on platelets, measured by flow-cytometry was also reduced after iloprost treatment (17.1+/-1.5 vs 31.8+/-4.8 AU; p<0.05) and physical exercise (14.6+/-1.5 vs 34.0+/-3.3; p<0.05). Theurinaryexcretion of platelet thromboxane A2 metabolite 2,3-dinor-thromboxane B2 decreased only in patients treated with iloprost (154.7+/-97.9 vs 256.2+/-106.4 pg mg creatinine(-1); p<0.05). Similarly plasma VCAM-1 was lower in patients who were treated with iloprost (827.7+/-77.4 vs 999.0+/-83.8 ng ml(-1); p<0.05). In conclusion, both iloprost and physical exercise seem to act on reversible phenomena such as the expression of adhesion molecules or ex vivo adhesion, whereas only iloprost reduces thromboxane A2 biosynthesis in vivo. This anti-platelet activity seems to be extended in time and to be associated with an improvement in vascular function.

The effects of 14-day physical exercise or iloprost treatment (0.5-2 ng/Kg/min) on endogenous nitric oxide production and neutrophil adhesion were evaluated in 20 patients with peripheral arterial occlusive disease (Fontaine Stage II). Peripheral venous blood samples and 4-h urine samples were collected before, immediately after 14 days of therapy and 7-10 days after therapy in order to evaluate neutrophil adhesion, nitrite/nitrate and cGMP excretion rates. A longer pain free walking distance was observed after exercise, compared to iloprost (>500 m in 3/10 subjects). Urinary nitrite/nitrate, as well as cGMP concentrations, significantly increased after exercise. Nitrite/nitrate excretion rate inversely correlated to neutrophil adhesion. No variations were observed in these parameters in iloprost treated patients. The improvement in claudication and the transient increase in urinary nitrite/nitrate suggest a possible nitric oxide-dependent mechanism for the clinical efficacy of physical exercise. The results from the present and previous observations indicate that, besides pharmacological treatments, a regular aerobic exercise improves peripheral arterial occlusive disease.

Background: Ticlopidine inhibits platelet aggregation by preventing the binding of fibrinogen to its platelet receptor. We examined whether this inhibition involved platelet transduction system such as Na+/H+ pump and platelet intracellular calcium., Methods: Platelet adhesion in 13 patients with peripheral vascular disease treated with ticlopidine, 250 mg b.i.d for 30 days, was measured in culture microplates before and after therapy. The microplate wells were coated with human plasma, fibrinogen or collagen, and platelet adhesion was studied in the resting condition and after stimulation with 1 and 10 microM ADP. At the same time, platelet intracellular calcium and ADP-induced calcium increases were measured with the fluorescent indicator Fura 2. In addition, intracellular pH and thrombin-induced pH variations were measured with the fluorescent probe BCECF., Results: Platelet adhesion to plasma and fibrinogen was significantly reduced (about 50%) after treatment with ticlopidine, while adhesion to collagen was not modified. Basal calcium and ADP-induced calcium increase were not significantly different before and after ticlopidine. Platelet basal intracellular pH was reduced (from 7.44+/-0.009 to 7.41+/-0.017, p<0.05), but agonist-induced alkalinisation was not significantly different. Early acidification, not dependent on Na+/H+ exchange, was also reduced (p<0.05)., Conclusions: These data do not seem to support the hypothesis that ticlopidine-induced reduction of platelet adhesion depends on alteration of the mechanisms determining signal transduction, at least as far as basal and post-stimulation intracellular calcium is concerned. On the contrary, the possibility that ticlopidine inhibits the Na+/H+ antiport remains open to consideration.

Background: Iloprost therapy for severe peripheral obstructive arterial disease (POAD) has demonstrated to be effective in reducing the need for amputation. However the feasibility of a 28-day infusion regimen in less severe stages of the disease is poor due to the length in hospital stay. A randomized, controlled, parallel-group pilot study was carried out with the aim to evaluate clinical and circulatory effects of Iloprost, a stable prostacyclin analogue, administered with two different infusion schedules to patients with POAD at Leriche Fontaine stage III., Methods: Twenty patients 16 males and 4 females, mean age 66 +/- 6 years) with objective signs of POAD, rest pain for at least two weeks and posterior tibial artery pressure > 50 mmHg, were randomized to either Iloprost i.v. infusion up to 2 ng/Kg/min for 6/h/day for 28 days (Group A) or to Iloprost i.v. infusion up to 1.5 ng/Kg/min for 16/h/day for 7 days (Group B). At baseline (before starting first infusion) after 7 days (for group B only, end of therapy) and after 28 days (end of therapy for Group A, end of study for Group B) the following parameters were evaluated: walking distance, rest pain and analgesic consumption, plethysmographyc parameters (first flow, peak flow and peak flow time) and laser Doppler parameters (rest flow, post ischemic flow)., Results: After 28 days, both Iloprost infusion schedules increased walking capacity (maximum walking distance/pain free walking distance +119/+84% +199/+85% respectively, for Group A and B respectively) reduced ischemic pain (-45% and -48% respectively for Group A and B) and analgesic consumption and improved plethysmographyc and laser Doppler parameters. Tolerability seemed to be better in Group B, suggesting that the lower dose and the shorter duration of the therapy period might result in reduced incidence of headache thus, in principle, increasing patient acceptability., Conclusions: The results of this pilot study, if confirmed by larger trials, could have important positive implications in terms of costs, patient comfort and management.

High lipoprotein(a) [Lp(a)] has been observed in patients with ischemic heart disease and cerebrovascular disease. Lp(a) is actually thought to be an independent risk factor for coronary disease. We therefore carried out a case-control study, evaluating plasma Lp(a) in 61 patients with angiographically documented peripheral arterial disease (PAD) and in 61 age- and sex-matched patients with no cardiovascular disease. General risk factors for vascular disease were also taken into account. Lp(a) was significantly higher in patients than controls (257.0 +/- 34.8 vs 146.5 +/- 23.5 mg/l p < 0.05), as were cigarette smoking, diabetes, cholesterolemia, fibrinogenemia and the waist-to-hip circumference ratio. Stepwise logistic regression analysis showed that, in addition to cigarette smoking, diabetes, cholesterol and fibrinogen, Lp(a) is a significant independent risk indicator for PAD. This result suggests that high plasma Lp(a) is associated with enhanced risk of PAD and must therefore be evaluated alongside traditional risk factors.