Cardiovascular mortality in patients with acute and chronic coronary syndrome: insights from the clinical evidence on ticagrelor.

OBJECTIVE: The purpose of this review is to discuss cardiovascular mortality as clinical outcome in the setting of both acute and chronic coronary syndromes (ACS and CCS) with a focus on the clinical evidence supporting the mortality benefit of ticagrelor across multiple subpopulations. MATERIALS AND METHODS: Papers considered for this review were retrieved from a PubMed search, using different combinations of keywords (e.g., mortality AND coronary syndrome AND dual antiplatelet therapy AND ticagrelor), without limitations in terms of publication date and language. RESULTS: Prevention of ischemic events and death is of outmost relevance in patients with ACS and CCS, given the high rate of recurrence of such events and fatalities. Owing to the evolving nature of patients with CCS, characterized by a broad spectrum of clinical presentations and previous medical history, as well as the advances in the therapeutic and invasive management of ACS, greater attention to the rate of hard clinical outcomes, improvement in the long-term prognosis, and reduction in the residual risk of recurrent events are increasingly reported among cardiologists. Dual antiplatelet therapy (DAPT) is the cornerstone of antithrombotic therapy aimed at lowering the rate of ischemic events and death in patients treated both conservatively and invasively after ACS, as well as improving prognosis in patients with CCS. Significant differences are emerging among oral P2Y12 inhibitors with regards to mortality benefit. CONCLUSIONS: Ticagrelor is an effective and well-tolerated option to attain a meaningful and clinically relevant reduction in cardiovascular mortality in both acute and chronic settings across a broad range of high-risk patient subpopulations with an acceptable payoff in terms of bleeding risk.

Association of peripheral venous disease with arterial endothelial dysfunction: a proof-of-concept study.

The objective of the study was to evaluate the association between peripheral venous disease (PVD) and arterial endothelial dysfunction (ED). Arterial and venous diseases have been always considered as two completely different entities, but the recent discovery of a relationship between arterial and venous thrombosis have challenged this assumption. ED, considered to be an early process in the pathophysiology of atherosclerotic disease, could represent a common pathogenetic background. We studied 39 healthy volunteers (median age: 34 years; men: 25.6%). PVD was diagnosed using ultrasound examination, arterial ED using flow-mediated dilation (FMD) and FMD normalized for the peak shear rate (nFMD). Compared with controls, participants with PVD had a lower FMD (15.2 versus 23.4%, P < 0.001) and nFMD (12.7 × 10(-3) versus 19 × 10(-3)/second, P < 0.001). People with the most clinically evident disease had the worst endothelial function. In conclusion, our findings, if confirmed in larger population, might corroborate the idea that venous and arterial disease could have common causes.

Excimer laser ablation in the treatment of total chronic obstructions in critical limb ischaemia in diabetic patients. Sustained efficacy of plaque recanalisation in mid-term results.

This prospective study aims to evaluate the impact of the excimer laser technology as the first-line endovascular treatment of critical limb ischaemia (CLI) in diabetic patients. The protocol allowed the use of laser ablation of obstructive lesions when conventional endoluminal guidewire crossing of the plaque was unsuccessful. We extrapolate the data of consecutive patients treated, who completed at least 12 months of follow-up, extending the observation to a 26-month time frame. During this period, 67 diabetic patients with CLI were brought to the Cath Lab for 'operative angioplasty' and to be treated with endovascular techniques. Of the 67 cases, laser was used on 35 patients to treat 51 lesions. All patients had type C or D occlusive lesions, according to the TACS II classification, showing a single type D plaque or multiple tandem C/D occlusive plaques ranging from 4 to 23 cm in length. The immediate clinical success, defined as restored direct arterial flow to the foot, was 88.2%. The lesions were successfully crossed by laser in 45 out of 51 attempts. Stents were required in 25% of the patients with 21% lesions. Patency rates were assessed using the Kaplan-Meier survival curves. The patency rates of the successfully treated lesions (freedom from target lesion revascularisation) were 96.6% at 12 months and 82.7% at 24 months. Limb-salvage rate at 12 and 24 months were 100% and 94%, respectively. Our study showed that the excimer laser-assisted angioplasty, when feasible, is effective in granting event-free survival in CLI patients with diabetes, and that endoluminal-driven atherectomy allows long-term success in reducing the need of stents in the lower limb arteries.

[Alexithymia and immunoendocrine parameters in patients affected by systemic lupus erythematosus and rheumatoid arthritis]. / Alessitimia e pathway immunoendocrino nel lupus eritematoso sistemico e nell'artrite reumatoide.

OBJECTIVE: Aim of this study was to evaluate the prevalence of alexithymia in patients affected by SLE or RA and to investigate the correlation between alexithymia and immunoendocrine parameters (PRL, hGH, IL-6 and TNF-alfa). METHODS: Twenty-five patients (12 and 13 affected by SLE and RA, respectively) were enrolled into the study. The Toronto Alexithymia Scale-20 (TAS-20) was administered. PRL, hGH, IL-6 and TNF-alfa levels were measured by commercially available ELISA kits. RESULTS: Alexithymia prevalence (TAS-20 > or = 51) was 54% in RA and 42% in SLE patients. hGH serum levels were 3.1+/-4.2 and 1.1+/-0.9 IU/ml in SLE and RA, respectively. PRL concentration was 18.4+/-6.5 ng/ml and 14.2+/-4.0 ng/ml in SLE and RA patients, respectively (p=0.03). In RA group, TNF-alpha was 20+/-36.2 whereas in SLE it was 4.9+/-12.8 pg/ml (p=0.03); IL-6 serum concentrations were 24.4+/-25.1 and 2.9+/-5.4 pg/ml, in RA and SLE respectively (p=0.004). The serum level of hGH showed slight increase in alexithymic group (A) compared to non alexithymic group (NA) in both SLE and RA patients. PRL serum levels in SLE-A patients was 26.7+/-17.3 ng/ml while in SLE-NA patients was 12.4+/-3.3 ng/ml (p=0.04). In RA patients increased values of IL-6 and TNF-alpha were present in the A group compared to NA group (IL-6: 35.3+/-28 pg/mL vs 3.5+/-3.9 pg/mL, p=0.01; TNF-alpha: 34.7+/-39 pg/mL vs 3.1+/-3.4 pg/mL, p=0.01). CONCLUSIONS: In this preliminary results we found an high prevalence of alexithymia and a correlation between immunoendocrine parameters and alexhytimic features in SLE and RA, suggesting that an immunomodulatory pathway could influence this cognitive style in patients with autoimmune disorders. Other studies should contribute to find a common biological pathway linking alexithymia and autoimmunity.

Alexithymia and neuroendocrine-immune response in patients with autoimmune diseases: preliminary results on relationship between alexithymic construct and TNF-alpha levels.

Alexithymia is conceptualized as a disorder of emotion regulation mechanisms, which involves a dissociation of emotional and physical responses to life events and bodily sensations. Our results might suggest a possible relationship between the alexithymic construct and TNF levels in RA patients. These preliminary findings corroborate the integrated bidirectional interactions between neuropsychological mechanisms and the neuroendocrine-immune system in patients affected by autoimmune diseases and contribute to finding a common biological pathway linking alexithymia and autoimmune-inflammatory diseases.

Validity and reliability of an Italian version of the revised Leeds disability questionnaire for patients with ankylosing spondylitis.

OBJECTIVE: The purpose of the present study was to produce an Italian version of the Revised Leeds Disability Questionnaire (LDQ) in a group of patients with ankylosing spondylitis, and to examine the psychometric properties of this version, evaluating its internal consistency, external validity and reliability. METHODS: The LDQ was administered to 60 Caucasian patients affected by ankylosing spondylitis (50 males, 10 females, mean age 46.1 +/- 14.2 yr, range 22-74, median disease duration 4.5 yr, range 1-24) together with the Italian version of the Stanford Health Assessment Questionnaire (HAQ), and anthropometric measurements. Thirty patients completed the questionnaire after a 10-day interval. Internal consistency was evaluated with Cronbach's alpha coefficient of reliability. Construct validity of the LDQ was evaluated using the correlation between the HAQ and anthropometric measurements. Test-retest reliability was assessed with the intraclass correlation coefficient. RESULTS: All patients completed the validation study. The questionnaire was internally consistent (alpha=0.90). A significant correlation was recorded between the LDQ and the HAQ score (rho=0.841, P<0.01) and the anthropometric measurements. Test-retest reliability showed a good correlation coefficient (intraclass correlation=0.97). CONCLUSION: The Italian LDQ is a valid and reliable instrument for detecting and measuring functional disability in patients with ankylosing spondylitis. Our results confirm the utility of this questionnaire as a valid and feasible functional measure for patients with ankylosing spondylitis.

Surgical treatment of persistent type 2 endoleaks, with increase of the aneurysm sac: indications and technical notes.

OBJECTIVE: Unsolved type 2 endoleaks and aneurysmal sac increasing after endovascular aneurysm repair (EVAR) can be fixed with surgical sacotomy, ligation of the patent backbleeding vessels and preservation of the endograft. The aim of the paper is to highlight the technique as a feasible procedure in alternative to the removal of the graft. MATERIALS AND METHODS: Four male patients whose aneurysm sac maximum transverse diameter had increased by 5 mm or more, without evidence of endoleak, migration or structural alteration of the endografts. The surgical access was by medial laparotomy in one case, flank incision in two cases and mini-laparotomy with laparoscopic assistance in the fourth case. Patients were followed with spiral CT and duplex ultrasound at discharge and at 6-12 months. RESULTS: All procedures were carried out, without complication. Two patients required intensive care unit (ICU) admission and the average post-operative hospital stay was 10 days (range 6-13). All patients are currently alive with a functioning endograft, at an average follow-up of 14.7 months. CONCLUSIONS: Sacotomy, leaving the endograft in place, appears to be a feasible therapeutic option, less invasive than conversion to open repair. This technique merits further study.

Gene therapy in peripheral artery disease.

In the last decade, studies of the biological mechanisms underlying angiogenesis, i.e. the development of a new vasculature from pre-existing blood vessels, have suggested a new approach to peripheral obstructive artery disease based on the treatment of ischemic tissues with angiogenic growth factors. As demonstrated by experimental studies in animal models, a therapeutic effect can be reached as the newly formed vascular network, functioning as a biologic by-pass, restores a normal blood supply to the ischemic territories. New techniques of gene therapy proved effective in reaching sustained concentrations of angiogenic factors in the target tissues. This review concerns the pre-clinical background and the results of the early clinical trials of angiogenic gene therapy, which have shown the safety and feasibility of this new approach.

Rational design of biologically active peptides: inhibition of T cell activation through interference with CD4 function.

In our laboratory we generated one synthetic cyclic peptide (Pep4) and tested it in human mitogen stimulation assays (MSA) and mixed lymphocytes reactions (MLR) generating dose-response curves showing a dose-dependent inhibition of MSA up to 80% and MLR up to 98%. MSA and MLR were repeated after pre incubation of the Pep4 with each separate responder cell subset and subsequent reconstitution: these experiments showed inhibition only when the peptide was present in culture. Pep4 showed species specificity since it was ineffective in inhibiting rat MLR. Combination effect analysis with Pep4 and cyclosporine showed a combination index > 1. This rationally designed peptide (Pep4) shows powerful inhibition of human T cell activation and, although the exact mechanism is still undefined, it seems to exert its major action on the T cell surface, interfering with co receptor interaction and disrupting the same activation signal pathway inhibited by cyclosporine A.

Transcriptionally active drugs improve adenovirus vector performance in vitro and in vivo.

Cytomegalovirus (CMV) promoter is often present in recombinant adenovirus vectors (AdVs) suitable for gene therapy, ensuring high levels of transgene production in a wide range of hosts. Despite this characteristic, the presence of the AdV genome in target cells and tissues typically lasts longer than transgene production that may be rapidly extincted by ill-defined silencing mechanisms. In the present article, it is reported that transcriptionally active drugs, retinoic acid (RA) and histone deacetylase inhibitor trichostatin A (TSA), enhance AdV transgene expression in infected cells and tissues. The association of RA and TSA increased more than seven-fold above control the activity of AdVs encoding for LacZ or VEGF165. This effect was, at least in part, mediated by the direct activation of retinoic acid receptors. Finally, administration of RA and TSA alone at days 0 and 5 after infection prolonged transgene production up to 21 days after infection versus 6-8 days in untreated controls. These results indicate that transcriptionally active drugs improve AdV function and may represent a novel strategy to more efficiently design AdVs for gene therapy interventions.

Induction of interleukin-1beta and interleukin-6 gene expression in hypoperfused skeletal muscle of patients with peripheral arterial disease.

BACKGROUND: A growing amount of data supports the role of inflammation in the pathophysiology of atherosclerotic diseases but the cellular source of cytokines has not been clearly identified. Cytokines could be produced by inflammatory cells, activated endothelial and smooth muscle cells, and by the tissue exposed to recurrent ischemia. Accordingly, we evaluated whether hypoperfusion induces gene expression of interleukin (IL)-1beta and IL-6 in the skeletal muscle of patients with peripheral arterial disease and critical limb ischemia. METHODS: Skeletal muscle biopsies were obtained, during a femoral-distal bypass, from normoperfused (control) and hypoperfused skeletal muscles in 8 patients. Gene expression was assessed by semiquantitative reverse transcriptase-polymerase chain reaction, using glyceraldehyde-phosphate-deydrogenase mRNA levels as a normalization factor. RESULTS: In the hypoperfused biopsies, the level of IL-1beta gene expression was significantly higher in all but 2 patients (mean upregulation > 8.8 fold, p = 0.043), and the level of IL-6 gene expression was significantly higher in all but 1 patient (mean upregulation > 23.7 fold, p = 0.031). CONCLUSIONS: We report that IL-1beta and IL-6 gene expression is markedly upregulated in hypoperfused skeletal muscle of patients with critical lower limb ischemia. To our knowledge this is the first report of a local activation of the inflammatory cascade at the level of hypoperfused skeletal muscle. This activation, which could worsen symptoms and tissue viability and be involved in the pathophysiology of reperfusion injury, might be considered as a therapeutic target. It remains to be investigated whether our results may also apply to coronary artery disease.

Rational design of biologically active peptides: inhibition of T cell activation through interference with CD4 function. Transplant Int (2000) 13 [Suppl 1]: S306-S310.

In our laboratory we generated one synthetic cyclic peptide (Pep4) and tested it in human mitogen stimulation assays (MSA) and mixed lymphocytes reactions (MLR) generating dose-response curves showing a dose-dependent inhibition of MSA up to 80% and MLR up to 98%. MSA and MLR were repeated after pre incubation of the Pep4 with each separate responder cell subset and subsequent reconstitution: these experiments showed inhibition only when the peptide was present in culture. Pep4 showed species specificity since it was ineffective in inhibiting rat MLR. Combination effect analysis with Pep4 and cyclosporine showed a combination index > 1. This rationally designed peptide (Pep4) shows powerful inhibition of human T cell activation and, although the exact mechanism is still undefined, it seems to exert its major action on the T cell surface, interfering with co receptor interaction and disrupting the same activation signal pathway inhibited by cyclosporine A.

Synergistic immunosuppressive actions of cyclosporine with a mouse anti-rat alpha/beta-T cell receptor monoclonal antibody.

A mouse IgG1 mAb (R73) directed against the rat alpha/beta-TCR was documented not only to prolong the survival of allografts across major RT1 plus non-RT1 antigenic disparities, but also to display a synergistic immunosuppressive interaction with CsA. Heterotopic cardiac transplants from Buffalo (RT1b) rats survived significantly longer in Wistar-Furth (RT1u) hosts treated immediately after the operation with 0.25 mg/kg R73 i.v., with a mean survival time of 11.0 +/- 5.5 versus 6.8 +/- 1.2 days in the untreated group (P < 0.01). Administration of 0.5 or 5.0 mg/kg R73 displayed dose-dependent prolongation of survival to 17.0 +/- 8.3 days (P < 0.05) or 28.6 +/- 14.0 days (P < 0.01), respectively. One 0.5 mg/kg i.v. dose of R73 delivered to normal Wistar-Furth hosts produced peripheral T cell depletion that reversed after 16 days. Three injections of 0.5 mg/kg R73 on days 0, 2, and 4 prolonged allograft survival to 52.5 +/- 38.6 days compared with 17.0 +/- 8.3 days with a single dose (P < 0.01). Addition of 3 daily doses of 5 or 10 mg/kg CsA administered per oral gavage to a single dose of 0.05, 0.25, or 0.5 mg/kg R73 injected on day 0 produced a synergistic effect to prolong allograft survival, as determined by the rigorous median-effect analysis. The synergistic interaction, which may be explained by the inhibitory effect of CsA on Ca(2+)-dependent pathways triggered after activation of TCR, the target of R73, warrants clinical investigation in order to assess the potential impact of anti-alpha/beta-TCR mAb on CsA-based immunosuppressive regimens.