OxLDL- and HSP-60 antigen-specific CD8(+) T lymphocytes are detectable in the peripheral blood of patients suffering from coronary artery disease.

Inflammatory and immunologic mechanisms are important for the initiation and the progression of atherosclerotic lesions. OxLDL and HSP-60 antigens are involved in the pathogenesis of atherosclerotic disease by triggering immune cells within the plaques. Through the MHC pentamer assays, we investigated the presence of OxLDL- and HSP-60-specific CD8(+) T lymphocytes in twenty HLA-A2-positive patients suffering from coronary artery disease (10 NSTEMI and 10 stable angina). Similarly, 10 age- and sex-matched healthy subjects were enrolled as controls. Biological samples were collected within 6 h of admission to hospital, at 30 days and at 180 days. OxLDL- and HSP-60-specific CD8(+) T lymphocytes were never detectable in the peripheral blood from all the healthy controls. On the contrary, at each scheduled time point, both of these specific cells could be detected in peripheral blood from all enrolled patients. More in detail, the flow cytometric analysis of MHC-1 pentamer OxLDL-specific CD8(+) T lymphocytes revealed a sharp and significant increase at the hospital admission, within 6 h from the chest pain onset, followed by an evident decline to lower levels at 30 days and at 180 days from the enrollment in the study. On the contrary, although MHC-1 pentamer HSP-60 CD8(+) T lymphocytes were detectable in enrolled patients, almost no variance could be detectable during the follow-up scheduled evaluations. On the whole, this finding indicates that HSP-60- and OxLDL-specific CD8(+) T lymphocytes could play a role in the maintenance or worsening of the atherosclerotic coronary disease.

[Selection of candidates for cardiac resynchronisation therapy and prediction of their response.]. / Selezione dei candidati alla terapia di resincronizzazione cardiaca e predizione della loro risposta.

AIMS: Cardiac resynchronization therapy is currently used in selected patients with end-stage heart failure. However, 30% of patients do not respond to CRT. The aim of our study was to find echocardiographic (TDI), electrocardiographic (QRS interval and electric distance between right and left catheter), clinical (6MW test) or autonomical (HRV) parameters able to predict responsiveness to CRT. MATERIALS AND METHODS: 47 patients (mean age 74+/-10 years) with end-stage heart failure, symptomatic, with left ventricular (LV) ejection fraction less than 35% and QRS 120 ms, underwent CRT. RESULTS: At thirteen months follow up, all clinical and echocardiographic parameters significantly improves (EF p<0.001; LVED volume p<0.001; 6MWT p<0.001; max delay TDI p<0.001; HRV p<0.05; Right-left distance p<0.05). A positive response was documented in 31/47 (67.4%) patients who presented an increase in LVEF > or = 5 units. There was a significant difference of LVED diameter (p<0.05) and HRV (p<0.05) between responders and non responders. Receiver-operating curve analysis showed that a positive response to CRT may be predicted in patients with LVED diameter <67 mm (with a sensitivity of 77% and a specificity of 88%). CONCLUSIONS: Our results confirm the clinical improvement obtained by CRT in end-stage heart failure patients as well as the limited value of QRS duration and intraventricular dyssynchrony as predictor of clinical recovery after CRT. While a most-advanced clinical stage of disease (HRV) without an advance left ventricular remodeling (LVED diameter) demonstrated to predict response to CRT, with sensitivity of 77% and specificity of 88%.

Pro-proliferative FoxM1 is a target of p53-mediated repression.

The p53 tumor suppressor protein acts as a transcription factor to modulate cellular responses to a wide variety of stresses. In this study we show that p53 is required for the downregulation of FoxM1, an essential transcription factor that regulates many G2/M-specific genes and is overexpressed in a multitude of solid tumors. After DNA damage, p53 facilitates the repression of FoxM1 mRNA, which is accompanied by a decrease in FoxM1 protein levels. In cells with reduced p53 expression, FoxM1 is upregulated after DNA damage. Nutlin, a small-molecule activator of p53, suppresses FoxM1 levels in two cell lines in which DNA damage facilitates only mild repression. Mechanistically, p53-mediated inhibition of FoxM1 is partially p21 and retinoblastoma (Rb) family dependent, although in some cases p21-independent repression of FoxM1 was also observed. The importance of FoxM1 to cell fate was indicated by the observation that G2/M arrest follows FoxM1 ablation. Finally, our results indicate a potential contribution of p53-mediated repression of FoxM1 for maintenance of a stable G2 arrest.

Hypoadiponectinemia in lipodystrophic HIV individuals: a metabolic marker of subclinical cardiac damage.

BACKGROUND AND AIM: To evaluate cardiovascular abnormalities in highly active antiretroviral therapy (HAART) treated HIV patients with no signs or symptoms of cardiovascular impairment, and to assess the relative role of multiple concomitant risk factors. METHODS AND RESULTS: Forty-four consecutive HIV subjects (mean age 41+/-6 yrs) were enrolled. Inclusion criteria were HIV infection, CD4+cell count>150/ml, HAART treatment for at least 4 years. Metabolic serum levels, morphological and functional echocardiographic parameters were assessed in all subjects. Sixteen healthy age and sex matched subjects with no cardiovascular risk factors were recruited as controls. HIV patients showed increased left ventricular mass index with reduced mid-wall fractional shortening (mFS) when compared to controls (50.2+/-10.5 vs. 38.6+/-14.4, p=0.05 and 18.3+/-0.6 vs. 21.9+/-0.7, p<0.05, respectively). Twenty-nine patients were lipodystrophic (LD) and showed a longer HAART period (p=0.0004) and greater use of protease inhibitors (PI) (p=0.001). Coronary flow reserve (CFR) was significantly reduced in HIV patients as compared to controls (p<0.0001), as it was in LD subjects when compared to non-lipodystrophic ones (NLD) (p<0.001). Adiponectin concentrations were found to be significantly lower in LD subjects than in NLD ones (7.8+/-0.8 vs. 13.8+/-1.2 microg/ml, p=0.01), and showed a direct correlation with CFR. In multiple regression analysis, insulin, HDL and adiponectin accounted for 63% of CFR variations. CONCLUSIONS: Left ventricular hypertrophy, depressed mFS and reduced CFR represent the main signs of subclinical cardiac damage in HIV subjects treated with HAART. Hypoadiponectinemia in these subjects seems to be a metabolic risk factor of cardiovascular impairment.

Prognostic relevance of metabolic approach in patients with heart failure.

Progressions in acute cardiac care have improved survival after acute myocardial infarction, but in contraposition with this, there has been an increase in mortality because of heart failure. For this reason congestive heart failure is an increasingly widespread, costly and deadly disease, frequently named as epidemic of the XXI century. Despite advancement in modern treatment, mortality rate in heart failure patients remains high. In these patients more importance was attributed in the management of the left ventricle dysfunction. In fact, the heart failure patients have still a poor prognosis due to the ineluctable progression of contractile dysfunction and ventricular remodeling. The classical management of left ventricle dysfunction includes the pharmacological treatment with beta-blockers, ACE-inhibitors and aldosterone antagonists, and various surgical or electrophysiological interventions. Emerging evidence suggests that myocardium dysfunction is also due to substrate metabolism alterations. In particular, there is evidence that, in the failing heart, shifting metabolism away from a preference for fatty acids towards more carbohydrate oxidation could recover contractile function. Trimetazidine has been shown to improve symptoms and ventricular function and to have a beneficial effect on the inflammatory profile and endothelial function in these patients. Recently, it has been suggested that trimetazidine could also reduce ventricular remodeling, slowing down the progression of pump failure, and improve prognosis. These results suggest that trimetazidine is a useful adjunct to our current armamentarium for the treatment of heart failure patients.

Primary percutaneous transluminal coronary angioplasty in the setting of multivessel disease.

Primary percutaneous coronary intervention of the culprit lesion is the treatment of choice for acute myocardial infarction, while treatment of the severe non culprit lesion is not indicated in the guidelines (Class III indication). More aggressive strategies that include initial treatment of the severe non culprit lesion may reduce the incidence of delayed occlusions in specific clinical settings. The two cases we describe support our point of view.

Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy.

OBJECTIVE: To investigate the long term effects of trimetazidine in patients with dilated ischaemic cardiomyopathy. The effects of trimetazidine on left ventricular function as well as its tolerability profile and potential anti-inflammatory effects were studied. DESIGN: 61 patients were randomly assigned either to receive trimetazidine (20 mg thrice daily) in addition to their conventional treatment or to continue their usual drug treatment for 18 months. Patients were evaluated at baseline and at 6, 12, and 18 months with a clinical examination, echocardiography, and biochemical analysis (C reactive protein). RESULTS: Trimetazidine added to the usual treatment significantly improved the patients' functional status (assessed by New York Heart Association functional class). The functional improvement of trimetazidine treated patients was associated with a significant increase in left ventricular ejection fraction (30 (6)%, 32 (8)%, 38 (7)%, and 37 (6)% v 31 (8)%, 30 (7)%, 28 (6)%, and 26 (9)% in control patients at baseline and at 6, 12, and 18 months, respectively) and with a significant effect on ventricular remodelling. C reactive protein plasma concentrations remained stable throughout the study in patients receiving trimetazidine (2.5 (1.0), 2.7 (2.0), 2.7 (3.0), and 3.0 (2.0) mg/l at baseline and at 6, 12, and 18 months, respectively) but increased significantly in the control group (2.4 (1.0), 3.4 (1.2), 6.0 (4.0), and 7.0 (5.0) mg/l, respectively). No significant adverse event or changes in clinical or biochemical parameters were detected. CONCLUSION: Treatment with trimetazidine added to the usual treatment for up to 18 months was well tolerated and induced a functional improvement in patients with dilated cardiomyopathy. Trimetazidine treatment was associated with a significant improvement of left ventricular function and the remodelling process. Results also suggest that the inflammatory response was limited in patients treated with trimetazidine.

Left ventricular myocardial mass determination by contrast enhanced colour Doppler compared with magnetic resonance imaging.

OBJECTIVE: To assess the feasibility of using contrast enhanced colour Doppler echocardiography to determine left ventricular (LV) mass and to compare its accuracy with LV mass obtained by magnetic resonance imaging (MRI). METHODS: Images were acquired in the short axis plane of the heart, derived from coronal and sagittal scout views and double oblique angulation. The LV mass was calculated by two methods: Simpson's rule and the area-length method. Levovist (Schering AG, Berlin, Germany) 2.5 g was given by slow intravenous bolus or infusion over about 45 seconds for contrast imaging. LV images were captured in the apical two chamber, four chamber, and three chamber views. Each contrast harmonic colour Doppler image was converted to a cavity-only image by simple image mathematics. RESULTS: 27 (77.1%) of the patients (mean (SD) age 66.2 (8.9) years) were men. There was a mean (SD) interval of 6.6 (8.6) days (range 0-27 days) between echocardiography and MRI. The mean (SD) LV mass determined by MRI Simpson's rule method was 171.0 (52.4) g (range 105.1-318.7 g). The mean LV mass (SD) determined by the echocardiographic Simpson's rule method was 178.2 (47.0) g (range 112.6-307.6 g). The mean (SD) MRI area-length LV mass was 187.3 (64.5) g (range 109.0-393.6 g). The linear regression correlation between LV mass determined by MRI Simpson's and echocardiographic Simpson's methods was excellent (y = 1.022x, R2 = 0.986) with a mean (SD) difference of 7.20 (20.9) g. The linear regression correlation between the MRI area-length LV mass and MRI Simpson's LV mass was excellent (y = 1.101x, R2 = 0.989) with a mean (SD) difference of 16.3 (22.3) g. CONCLUSIONS: LV mass may be obtained reliably by contrast enhanced colour Doppler and two dimensional echocardiography. The contrast Doppler method accurately determines LV mass with excellent agreement with the MRI technique.

Nine years' experience of telecardiology in primary care.

The ITMS telecardiology network started in April 1995. Over nine years, about 7000 peripheral medical users (mainly general practitioners), who were experienced in using transtelephonic electrocardiography and who were spread throughout Italy, conducted teleconsultations with the Telecardiology Centre. A total of 106,942 patients were evaluated. Teleconsultation was carried out for non-cardiac symptoms or routine control for 30,444 patients (28%) and for symptoms suggestive of heart disease for 76,498 (72%). After teleconsultation, 61,908 patients (58%) were reported to have no heart disease, 27,947 patients (26%) had their drug dose adjusted and remained at home, 11,503 patients (11%) were sent to their cardiologist for further investigations and 5584 patients (5%) were urgently hospitalized. Among the hospitalized patients, the echocardiogram demonstrated an ST-elevation coronary syndrome in 1785 patients (32%), a non-ST-elevation coronary syndrome in 2236 (40%) and a life-threatening arrhythmia in 1354 (24%). Telecardiology improves the decision making of general practitioners, avoids unnecessary hospitalizations, reduces the time before treatment in cardiac emergencies, rationalizes health-care costs and promotes home care.

Reduction of cardiovascular morbidity and mortality in type 2 diabetes. A rational approach to hypoglycemic therapy.

Type 2 diabetes mellitus is the single most important risk factor for the development of coronary artery disease. Unfortunately, the traditional therapeutic strategies for the treatment of hyperglycemia have proven to be ineffective in preventing cardiovascular complications. In recent years the number of available hypoglycemic agents has increased and considerable progress has been made regarding the comprehension of the pathophysiology of diabetes and its vascular complications. In the present article we firstly present benefits and risks of intensive vs standard hypoglycemic intervention, and the pros and cons of therapy targeted to postprandial hyperglycemia. Secondly, we discuss the cardiovascular effects of sulfonylurea agents and insulin, focusing on the role of intensive insulin treatment in the context of acute coronary syndromes. Thirdly, we review the epidemiological, clinical and experimental evidence linking insulin resistance and cardiovascular disease. Finally, we present the rationale and the role of metformin and thiazolidinedionetherapy in the prevention of cardiovascular complications. We conclude that the optimal use of the full spectrum of hypoglycemic agents has the potential to play a key role in the prevention of diabetes-related macrovascular complications.

Blunted coronary flow reserve in systemic sclerosis.

OBJECTIVES: We investigated whether the non-invasive determination of coronary flow reserve (CFR), as evaluated by transthoracic Doppler echocardiography, might be a potential method to detect early dysfunction of cardiovascular system in patients affected by systemic sclerosis (SSc) without clinical signs or symptoms of cardiac impairment. The possible correlations between the CFR values and the duration of the disease, specific autoantibodies and cutaneous involvement subsets were investigated. METHODS: Forty-four consecutive patients affected by SSc were analysed. The CFR was detected in the distal left anterior descending coronary artery by contrast-enhanced transthoracic second harmonic Doppler in all SSc patients and in 16 healthy controls. CFR was assessed at rest and during hyperaemia induced by administration of adenosine at 0.14 mg/kg/min over 5 min. The CFR was calculated as the ratio between hyperaemic (peak adenosine infusion) and resting peak diastolic velocity (PdvCFR) and resting velocity time integral (VtiCFR). Past medical history was carefully investigated. RESULTS: Both PdvCFR and VtiCFR were significantly reduced in SSc patients when compared with controls (P<0.0001). In particular, both PdvCFR and VtiCFR were significantly lower in patients with dSSc when compared with patients affected by lSSc (P<0.02 and P<0.04 respectively). No statistically significant correlation was found between CFR values and history of smoking, serum levels of cholesterol or triglycerides, blood pressure, age of patients, duration of SSc and serum autoantibody positivity for ANA, ACA and Scl70. CONCLUSIONS: CFR is often reduced in SSc patients. CFR was lower in patients with dSSc than in those affected by lSSc. A reduced CFR value should be considered an indirect sign of heart involvement in scleroderma, but its clinical and prognostic implications need to be clarified.

Metalloproteinases 2 and 9 are increased in plasma of patients with heart failure.

BACKGROUND: Progression of heart failure is associated with interstitial changes in the heart and in areas distant from the heart. Enhanced expression of metalloproteinases 2 and 9 and of metalloproteinases tissue inhibitors 1 and 2 have been found in ventricular tissue of patients with heart failure. Our aim was to determine whether increased activity of metalloproteinase-2, metalloproteinase-9 and of metalloproteinases tissue inhibitor-1 and metalloproteinases tissue inhibitor-2 were also present in plasma of patients with heart failure. DESIGN: Levels of metalloproteinase-2, metalloproteinase-9 and of metalloproteinase tissue inhibitor-1 and metalloproteinases tissue inhibitor-2 were measured in venous blood of 51 patients with heart failure, and were compared with levels of 52 control subjects. Samples collected from patients and control subjects were assayed for gelatinolytic activity (zymography) and for protein levels. RESULTS: Compared with the control subjects, the patients with heart failure had a significant increase in activity levels (mean +/- SE, ng mL(-1)) of prometalloproteinase-9 (95.1+/-11.2 and 38.9+/-4.5*), activ. metalloproteinase-9 (18.4+/-2.5 and 10.9+/-1.3*), and of prometalloproteinase-2 (571.4+/-26.1 and 456.8+/-21.1*) (respectively: patients and control subjects; *P<0.05). Metalloproteinases tissue inhibitor-1, but not metalloproteinases tissue inhibitor-2 protein values were higher in the patients. Among the patients, clinical status and New York Heart Association (NYHA) class did not correlate with the metalloproteinase concentrations. Positive correlations with left ventricular volumes, and negative correlations with lipid values were obtained for prometalloproteinase-2; positive correlations with total number of white cells and neutrophils were obtained for prometalloproteinase-9; and positive correlations with lactate dehydrogenase, serum fibrinogen, aspartate transaminases were found for activ. metalloproteinase-9. CONCLUSIONS: Regardless of the clinical phase of heart failure, elevated levels of activity and of circulating metalloproteinase protein levels suggest the presence of persistent extracellular remodeling in patients with heart failure.

[Treatment of severe intermittent claudication: ORACLE-PGE1 short term study. A randomised 40-week study. Evaluation of efficacy and costs]. / Trattamento della claudicatio intermittens severa: studio ORACLE-PGE1 short term. Registry e studio randomizzato a 40 settimane, valutazione di efficacia e costi.

BACKGROUND: The efficacy and cost of prostaglandin E1 (PGE1) in severe intermittent claudication was studied comparing a long-term protocol (LTP) with a short-term protocol (STP) in a randomised 40-week study. METHODS: Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. Treatment was performed with 2-hour infusions (60 micro g PGE1, 5 days each week for 4 weeks. In phase 3 (4-week interval period), PGE1 was administered twice a week (same dosage). In phase 4 (40 weeks), no PGE1 were used. In STP, phase 2 treatment was performed in two days by a 2-hour infusion (60 micro g PGE1 twice a day in 2 days). The same cycle was repeated every 4 weeks. A treadmill test was performed at inclusion, at the beginning of each phase and at the end of weeks 12, 16, 20 32 and 40. A progressive training plan (walking) and reduction in risk factors plan was used in both groups. RESULTS: Out of the 1276 included patients 1165 completed the study (606 in LTP group; 559 in the STP). Drop-outs were 111. The two groups were comparable in distribution, risk factors and smoking. Intention-to-treat analysis indicated an increase in pain free walking distance (PFWD). The absolute and percent increase in pain-free walking distance (PFWD) was comparable in both LTP and STP groups with a significative increase in TWD at 4 weeks. At 20 and 40 weeks increase was up to 219% in the LTP and 460% in the STP group (p<0.02). Comparable results concerning PFWD were obtained in the two groups. Both treatments were well tolerated. No side effect was observed. Local effects were observed in 8.5% of the treated subjects in the LTP and 4% in the STP. The average cost of the LTP protocol was 8786 Euro. For STP the costs was 946 (10.8% of LTP). For both protocols the cost of the infusion was 24% of the total for the LTP and 35% in the STP. Therefore 75% of the cost is not drug-related. CONCLUSIONS: In conclusion between-group-analysis favours STP considering walking distance and costs. Results indicate good efficacy and tolerability of PGE1 treatment particularly STP.

Cor triatriatum sinistrum and persistent left superior vena cava: an original association.

Cor triatriatum sinistrum is a rare congenital heart disease usually diagnosed in symptomatic children. Symptoms depend on the degree of obstruction to pulmonary venous return with pulmonary hypertension and other associated abnormalities. Persistent left superior vena cava is quite a common congenital heart disease (about 0.5% in healthy populations). It should be suspected every time a dilated coronary sinus is detected at the echo examination. Transthoracic and transoesophageal examinations visualize the site and the size of the fibrous membrane as well as the degree of obstruction, and allow the evaluation of pulmonary pressures that are very important clues for prognosis and therapy. This case report describes the clinical signs and the diagnostic ultrasound findings evaluated in comparison with magnetic resonance imaging, a well-defined gold standard in heart disease of this uncommon congenital association.

High doses of atorvastatin do not affect activity of prothrombinase in patients with acute coronary syndromes.

Membrane-dependent coagulation processes play a key role in acute coronary syndromes (ACS), where the generation of thrombin depends on the complex of activated factors X and V (prothrombinase complex) assembled on activated platelets. The aim of the present study was to evaluate prothrombinase activity in patients with ACS and to examine the effect of treatment with 80 mg/day atorvastatin on prothrombinase activity. Blood samples were obtained at admission from 22 patients with ACS, and then again at 2 weeks and at 16 weeks after double-blind randomization to either placebo or atorvastatin. Prothrombinase activity was evaluated by measuring the generation of thrombin by in vitro reconstructed thrombi, and also by measuring plasma levels of prothrombin fragment F1 + 2. Twenty age-matched subjects with stable angina and 11 without coronary disease were used as controls. At admission, prothrombinase activity and F1 + 2 were significantly higher in ACS patients than in controls. Prothrombinase activity was still high at 2 weeks while it returned to normal levels at 16 weeks. F1 + 2 remained high both at 2 and at 16 weeks. Our data indicate that prothrombinase activity is high in patients with ACS, and that it is not affected by high-dose atorvastatin.

The role of telecardiology in supporting the decision-making process of general practitioners during the management of patients with suspected cardiac events.

We studied the role of telecardiology in reducing unnecessary hospital admissions of patients with suspected life-threatening cardiac events (CEs), evaluated by general practitioners (GPs). Over one month, 456 consecutive patients (mean age 65 years, SD 19) complaining of typical (10%) or atypical (42%) chest pain, palpitations (19%), dyspnoea (19%) or syncope (10%) were enrolled. Before teleconsultation, the GPs recorded their own opinion (based on clinical evaluation only) about the presence of a CE. Following transmission of the electrocardiogram (ECG), this opinion was compared with that of the cardiologist. In total there was agreement between the GP and cardiologist about the presence of a CE in 316 of the patients (69%) and disagreement in 140 patients (31%). This represents a specificity and sensitivity of the GPs' diagnosis of 76% and 47%, respectively. For 84 of 134 patients judged as having a CE by the GP, telecardiology avoided hospitalization; on the other hand, telecardiology identified a CE in 56 of 322 patients judged as not having a CE by the GP. Telecardiology is a useful tool with which to reduce unnecessary hospitalizations in patients with suspected life-threatening CEs.

MR evaluation of coronary stents with navigator echo and breath-hold cine gradient-echo techniques.

The aim of this study was to evaluate coronary artery stents with MR. Thirty-eight patients underwent MR imaging 48.1 +/- 6.6 days (range 38-60 days) after placement of 47 coronary stents of 11 different types, using navigator echo (NE) and cine gradient-echo (GE) techniques. For both sequences the low signal artifact was used to localize the stent, whereas the flow-related high signal before and distal to the stent was considered as a patency sign. Exercise electrocardiographic test (EET) had been performed 1-7 days before MR. No adverse event with possible relation to the MR examination was observed. All the stents were recognized as signal void with GE, and all but one with NE. Of the 2 patients with positive EET, the first one, with a stent on the left anterior descending coronary artery, presented low signal distal to the stent at both MR sequences, suggesting dysfunction [60% stenosis at conventional coronary angiography (CCA)]; the second one, with two sequential stents on the right coronary artery, presented lack of signal distal to the stents at both MR sequences, suggesting occlusion (97% stenosis at CCA). For the 44 remaining stents in 36 patients with negative EET, MR high signal before and distal to the stent suggested patency at both sequences. MR seems to be a safe and promising technique for non-invasive evaluation of coronary stents.

Treatment of severe intermittent claudication with pentoxifylline: a 40-week, controlled, randomized trial.

The efficacy, safety, and cost of pentoxifylline (PXF) in the treatment of severe intermittent claudication were studied comparing PXF and placebo in a randomized 40-week study. A treadmill test was performed at inclusion and at the end of weeks 20 and 40. A progressive training plan and the control of risk factors (with antiplatelet treatment) were used in both groups. Of the 200 included patients, 178 completed the study: 88 in the PXF group and 90 in the placebo group. There were 22 dropouts. The two groups were comparable for age, sex distribution, and for the presence of risk factors and smoking. There was a significant increase in pain-free walking distance (PFWD) in both groups. The absolute and percent increase in PFWD was significantly greater in the PXF group (p<0.05). At 20 weeks, the increase was 360.5% in the PXF vs 252% in the placebo group. At 40 weeks, the increase was 386% in the PXF and 369% in the placebo group (p<0.02). Total walking distance (TWD) increased at 20 weeks (up to 254%) and up to 329% at 40 weeks. In the placebo groups the increase was 158% at 20 weeks and 183% at 40 weeks. The excess increase produced by PXF treatment was 30% at 20 weeks and 38% at 40 weeks (p<0.02). Unwanted effects treatment was well tolerated. No serious drug-related side effects were observed. In summary, between-group analysis favors PXF considering walking distance and costs. Results indicate good efficacy and tolerability.

Verapamil reduces coronary endothelium damage and cardiomyocyte necrosis but not apoptosis after ischemia and reperfusion: ex-vivo study in rat hearts.

We tested the hypothesis of beneficial effects of the calcium-blocker verapamil in a model of ischemia-reperfusion, and investigated its effects against coronary microcirculation and cardiomyocyte apoptosis. Isolated working rat hearts were subjected to 15 min global ischemia and 22-180 min reperfusion in the presence or absence of verapamil (0.25 &mgr;M). We evaluated creatinephosphokinase (CK) in coronary effluent, heart weight changes, microvascular permeability (extravasation of fluoresceine-labeled albumin), ultrastructural alterations, and cardiomyocyte apoptosis (by 1.5% agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labelling technique). In this model, 0.25 &mgr;M verapamil significantly reduced myocardial damage, CK release and vascular hyperpermeability, concomitant with a reduction in endothelial and cardiomyocyte lesions; on the contrary, 0.25 &mgr;M verapamil was unable to reduce cardiomyocyte apoptosis. In conclusion, in the absence of perfusing granulocytes, the acute administration of a pharmacologically relevant verapamil concentration reduces ischemia-reperfusion injury and prevents coronary endothelial cell and cardiomyocyte necrotic cell death but it is unable to reduce apoptotic cell death in isolated working rat hearts.