Paolo Scacciatella

The CD133+ Cell as Advanced Medicinal Product for Myocardial and Limb Ischemia

Ischemic diseases are the major cause of death and morbidity in Western countries. In the last decade, cell therapy has been suggested to be a promising treatment both in acute/chronic myocardial and peripheral ischemia. Different cell lineages have been tested, including endothelial progenitor cells. A subpopulation of bone marrow-derived immature ECPs, expressing the highly conserved stem cell glycoprotein antigen prominin-1 or CD133 marker, was shown to possess pro-angiogenic and antiapoptotic effects on ischemic tissues. The mechanisms implicated in CD133+ cells ability to contribute to neovascularization processes have been attributed to their ability to directly differentiate into newly forming vessels and to indirectly activate pro-angiogenic signaling by paracrine mechanisms. A large body of in vivo experimental evidences has demonstrated the potential of CD133+ cells to reverse ischemia. Moreover, several clinical trials have reported promising beneficial effects after infusion of autologous CD133+ into ischemic heart and limbs exploiting various delivery strategies. These trials have contributed to characterize the CD133+ manufacturing process as an advanced cell product (AMP). The aim of this review is to summarize available experimental and clinical data on CD133+ cells in the context of myocardial and peripheral ischemia, and to focus on the development of the CD133+ cell as an anti-ischemic AMP.

Long-term outcomes of Percutaneous coronary interventions or coronary artery bypass grafting for left main coronary artery disease in octogenarians (from a drug-eluting stent for left main artery registry substudy)

Percutaneous coronary intervention (PCI) with drug-eluting stents is an accepted alternative to surgery for the treatment of unprotected left main coronary artery (ULMCA) disease, but the long-term outcome in elderly patients is unclear. Aim of our study was to compare the clinical outcomes of octogenarians with ULMCA disease treated either with PCI with drug-eluting stents or coronary artery bypass grafting (CABG). The primary study end point was the composite of death, cerebrovascular accident, and myocardial infarction at follow-up. A total of 304 consecutive patients with ULMCA stenosis treated with PCI or CABG and aged ≥80 years were selected and analyzed in a large multinational registry. Two hundred eighteen were treated with PCI and 86 with CABG. During the hospitalization, a trend toward a higher mortality rate was reported in PCI-treated patients (3.5% vs 7.3%, p = 0.32). At a median follow-up of 1,088 days, the incidence of the primary end point was similar in the 2 groups (32.6% vs 30.2%, p = 0.69). Incidence of target vessel revascularization at follow-up was higher in PCI-treated patients (10% vs 4.2%, p = 0.05). At multivariate analysis, left ventricular ejection fraction was the only independent predictor of the primary end point (hazard ratio 0.95, 95% confidence interval 0.91 to 0.98, p = 0.001). After adjustment with propensity score, the revascularization strategy was not significantly correlated to the incidence of the primary end point (hazard ratio 0.98, 95% confidence interval 0.57 to 1.71, p = 0.95). In octogenarians, no difference was observed in the occurrence of the primary end point after PCI or CABG for the treatment of ULMCA disease. However, the rate of target vessel revascularization was higher in the PCI group.

Antiplatelet theRapy after Genous EPC-capturing coroNary stenT implantatiOn The ARGENTO Study: a prospective, multicenter registry

BACKGROUND To investigate the safety and efficacy of Genous Bio-engineered R stent (GRS) with ≤ 15-day or >15-day dual antiplatelet therapy (DAT), in patients undergoing percutaneous coronary intervention (PCI), with known or expected low compliance to long-term DAT (Antiplatelet theRapy after Genous EPC-capturing coroNary stenT implantatiOn--ARGENTO study). METHODS Consecutive patients without ≤ 12-month revascularization history, known statins allergy, known hypersensitivity reaction or previous or concomitant monoclonal and/or recombinant antibodies therapy, treated with single- or multivessel PCI plus GRS, were prospectively enrolled, at four PCI centers. Major adverse cardiac events (MACEs), the composite of cardiac death, any myocardial infarction (MI) and target vessel revascularization (TVR), and stent thrombosis (ST) cumulative incidences were evaluated. RESULTS Between March 2008 and March 2010, 384 patients (70.3% male, 423 lesions) were enrolled. At follow-up (22.8 ± 13.6 months), 8.6% MACEs, 3.4% cardiac death, 3.4% any MI, 4.7% TVR and 2.3% overall ST (definite/probable ST 1.3%) rates were reported, without differences between ≤ 15-day and >15-day DAT groups. At Cox multivariable-adjusted regression analysis (Hosmer-Lemeshow statistic, p=0.50) female sex, diabetes, previous PCI history, <45% left ventricular ejection fraction at admission and lesion length were identified as independent MACE predictors. DAT time duration (hazard ratio 1.98; 95% confidence interval 0.57-6.80, p=0.27) was not independent risk factor for MACEs. CONCLUSIONS In consecutive, prospectively enrolled patients with PCI indication and known or supposed low compliance to long-term DAT, GRS implantation might be a safe and effective option regardless of DAT duration after stenting (≤ 15 days or >15 days).

A Meta‐Analysis of Sex‐Related Differences in Outcomes After Primary Percutaneous Intervention for ST‐Segment Elevation Myocardial Infarction

INTRODUCTION The increasing use of primary percutaneous coronary intervention (pPCI) has improved clinical outcome in ST-segment elevation myocardial infarction (STEMI) patients, but the impact of sex on early and mid-term outcomes remains to be defined. METHODS Medline, Cochrane Library, Biomed Central, and Google Scholar were searched for articles describing differences in baseline, periprocedural, and midterm outcomes after pPCI, by sex. The primary end point was all-cause mortality at early and mid-term follow-up. Secondary endpoints included in-hospital bleeding and stroke. RESULTS Sixteen studies were included. Women were older, had more frequent hypertension, diabetes mellitus, and hypercholesterolemia, as well as longer ischemia time and more shock at presentation. Men were more likely to have had a previous myocardial infarction. Female sex emerged as independently associated to early mortality (OR 1.1; 95%CI, 1.02-1.18) but not to mid-term mortality (OR, 1.01; 95%CI, 0.99-1.03). The pooled analysis showed a significantly higher risk of in hospital stroke (OR, 1.69; 95%CI, 1.11-2.56) and major bleeding (OR, 2.04; 95%CI, 1.51-2.77) in women. CONCLUSIONS As compared to men, women undergoing pPCI have more bleedings and strokes, and a worse early, but not mid-term mortality. These findings may allow a better risk stratification of pPCI patients.

Ex vivo-expanded bone marrow CD34+ for acute myocardial infarction treatment: in vitro and in vivo studies

BACKGROUND AIMS Bone marrow (BM)-derived cells appear to be a promising therapeutic source for the treatment of acute myocardial infarction (AMI). However, the quantity and quality of the cells to be used, along with the appropriate time of administration, still need to be defined. We thus investigated the use of BM CD34(+)-derived cells as cells suitable for a cell therapy protocol (CTP) in the treatment of experimental AMI. METHODS The need for a large number of cells was satisfied by the use of a previously established protocol allowing the expansion of human CD34(+) cells isolated from neonatal and adult hematopoietic tissues. We evaluated gene expression, endothelial differentiation potential and cytokine release by BM-derived cells during in vitro culture. Basal and expanded CD34(+) cells were used as a delivery product in a murine AMI model consisting of a coronary artery ligation (CAL). Cardiac function recovery was evaluated after injecting basal or expanded cells. RESULTS Gene expression analysis of in vitro-expanded cells revealed that endothelial markers were up-regulated during culture. Moreover, expanded cells generated a CD14(+) subpopulation able to differentiate efficiently into VE-cadherin-expressing cells. In vivo, we observed a cardiac function recovery in mice sequentially treated with basal and expanded cells injected 4 h and 7 days after CAL, respectively. CONCLUSIONS Our data suggest that combining basal and expanded BM-derived CD34(+) cells in a specific temporal pattern of administration might represent a promising strategy for a successful cell-based therapy.

Real time triplane echocardiography in aortic valve stenosis: validation, reliability, and feasibility of a new method for valve area quantification.

Aims: The aim of the study was to validate a novel formula for aortic valve area (AVA) based on the principle of continuity equation, that substitutes Doppler‐derived stroke volume (SV) by SV directly measured with real time simultaneous triplane three‐dimensional echocardiography (RT3P). RT3P has proved accuracy for left ventricular volume calculation. So far, however, neither this potential has been applied to hemodynamic assessment, nor RT3P has succeeded in the evaluation of aortic valve disease. Methods and results: AVA was measured in 21 patients with aortic stenosis using Gorlins equation, Doppler continuity equation (two‐dimensional echocardiography), the novel RT3P method, and by substituting Doppler‐derived SV by SV measured with two‐dimensional stroke volume (2DSV). RT3P has the best linear association (R2= 0.61) and the best correlation with Gorlin of all noninvasive methods (even if not statistically significant). RT3P carries significantly lower mean differences with catheterization, as compared with 2D and 2DSV (Table 4). Standard deviations of mean differences between RT3P and catheterization and between the other echocardiographic methods are not statistically different, even if RT3P seems to be nearer to catheterization. Inter‐ and intraobserver variability were, respectively, 0.03 ± 0.11 cm2 and 0.02 ± 0.03 cm2, better than 2D and 2DSV. Conclusions: RT3P has revealed to be more accurate than two‐dimensional method in AVA quantification, with a better intraobserver agreement. In addition, it allows simple and fast image acquisition. (Echocardiography 2010;27:644‐650)

Sex-related differences in patients with ST-elevation myocardial infarction undergoing primary PCI: A long-term mortality study

OBJECTIVES To assess sex differences in clinical presentation, in-hospital and long-term outcome in ST-elevated myocardial infarction (STEMI) patients undergoing primary PCI (PPCI). BACKGROUND Several studies have shown higher rates of mortality in women. These differences are not always confirmed after adjusting for confounding variables. METHODS From January 2007 to December 2011, 325 consecutive patients (23.1% females and 76.9% males) were prospectively treated and retrospectively analyzed. Primary outcome was in-hospital and long-term mortality. RESULTS Women were older (71.8±11.7 vs. 62.5±12.6years; p<0.0001), presented more renal failure (45.3% vs. 20.8%; p<0.0001) and severe haemodynamic impairment (9.3% vs. 3.6%; p=0.04). In-hospital overall mortality (14.7% vs. 4.8%; p=0.003) and cardiac death (12% vs. 2%; p=0.002) were significantly higher in women. The multivariate analysis identified age (OR 1.07; 95% CI: 1.01-1.13), resuscitated cardiac arrest (CCA) and cardiogenic shock (CS) (OR 15.31; 95% CI: 4.30-61.75), renal failure (OR 0.20; 95% CI: 0.06-0.68), but not sex (OR 1.49; 95% CI: 0.53-4.22) as independent prognostic factors of in-hospital mortality. During a median follow-up of 46.5months (IQR range 32.7-63.1months), long-term overall mortality (24.2% vs. 11.0%; p=0.007) and cardiac death (4.8% vs. 1.7%; p=0.02) were significantly higher in women. The multivariate analysis identified age (HR 1.06; 95% CI: 1.02-1.11), previous AMI (HR 3.9; 95% CI: 1.63-9.35), renal failure (HR 5.21; 95% CI: 2.12-12.85), technical success (HR 0.35; 95% CI: 0.14-0.84) but not sex (HR 0.90; 95% CI: 0.42-1.94) as independent prognostic factors of long-term mortality. CONCLUSIONS Worse clinical presentation rather than sex may explain the excess of mortality in women with STEMI undergoing PPCI.

Fracture of coronary artery sirolimus eluting stent with formation of four aneurysms

Coronary stent fracture is a relatively rare but potentially serious complication of coronary artery stenting, in particular with sirolimus-eluting stents. It has been recognized as one possible cause of in-stent restenosis as well as acute stent thrombosis. The formation of coronary artery aneurysm is one of the critical complications after percutaneous coronary intervention and it has been described after a stent fracture too. We report here a case of formation of four coronary artery aneurysms associated with the fracture of a sirolimus-eluting stent.

Economy class syndrome complicated by stroke: a rare condition due to paradoxical embolism--a case report and review of the literature.

To the Editor. Venous thromboembolism (VTE) sustained by deep vein thrombosis (DVT) can occur during or immediately after long flights, as a result of prolonged immobilization. This clinical situation is called ‘economy class syndrome’ (ECS) [1]. However, it has also been reported in first-class travellers, airline pilots, and on train and highway journeys. Asymptomatic DVT after long-haul flights could be detected using ultrasound in many cases, however, symptomatic DVT occurs much less frequently, with passengers being at a four-fold risk for the following 4-week period after the air travel.

Culprit plaque characteristics in younger versus older patients with acute coronary syndromes: An optical coherence tomography study from the FORMIDABLE registry

Culprit plaque characteristics in young patients who experience an Acute Coronary Syndrome (ACS) evaluated by OCT (Optical Coherence Tomography) have to be defined. The OCT‐FORMIDABLE is a multicentre retrospective registry enrolling consecutive patients with ACS who performed OCT in 9 European centres.