European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism

The presence of a patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions; however, the subject remains controversial and no official statements have been published. This interdisciplinary paper, prepared with involvement of eight European scientific societies, aims to review the available trial evidence and to define the principles needed to guide decision making in patients with PFO. In order to guarantee a strict process, position statements were developed with the use of a modified grading of recommendations assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements of particular management options were weighed and graded according to predefined scales. Despite being based often on limited and non-randomised data, while waiting for more conclusive evidence, it was possible to conclude on a number of position statements regarding a rational general approach to PFO management and to specific considerations regarding left circulation thromboembolism. For some therapeutic aspects, it was possible to express stricter position statements based on randomised trials. This position paper provides the first largely shared, interdisciplinary approach for a rational PFO management based on the best available evidence

Linking cell function with perfusion : insights from the transcatheter delivery of bone marrow-derived CD133+ cells in ischemic refractory cardiomyopathy trial (RECARDIO)

Background: Cell therapy with bone marrow (BM)-derived progenitors has emerged as a promising therapeutic for refractory angina (RA) patients. In the present study, we evaluated the safety and preliminary efficacy of transcatheter delivery of autologous BM-derived advanced therapy medicinal product CD133(+) cells (ATMP-CD133) in RA patients, correlating perfusion outcome with cell function. Methods: In the phase I "Endocavitary Injection of Bone Marrow Derived CD133(+) Cells in Ischemic Refractory Cardiomyopathy" (RECARDIO) trial, a total of 10 patients with left ventricular (LV) dysfunction (ejection fraction <= 45%) and evidence of reversible ischemia, as assessed by single-photon emission computed tomography (SPECT), underwent BM aspiration and fluoroscopy-based percutaneous endomyocardial delivery of ATMP-CD133. Patients were evaluated at 6 and 12 months for safety and preliminary efficacy endpoints. ATMP-CD133 samples were used for in vitro correlations. Results: Patients were treated safely with a mean number of 6.57 +/- 3.45 x 10(6) ATMP-CD133. At 6-month follow-up, myocardial perfusion at SPECT was significantly ameliorated in terms of changes in summed stress (from 18.2 +/- 8.6 to 13.8 +/- 7.8, p = 0.05) and difference scores (from 12.0 +/- 5.3 to 6.1 +/- 4.0, p = 0.02) and number of segments with inducible ischemia (from 7.3 +/- 2.2 to 4.0 +/- 2.7, p = 0.003). Similarly, Canadian Cardiovascular Society and New York Heart Association classes significantly improved at follow-up vs baseline (p = 0.001 and p = 0.007, respectively). Changes in summed stress score changes positively correlated with ATMP-CD133 release of proangiogenic cytokines HGF and PDGF-bb (r = 0.80, p = 0.009 and r = 0.77, p = 0.01, respectively) and negatively with the proinflammatory cytokines RANTES (r = -0.79, p = 0.01) and IL-6 (r = -0.76, p = 0.02). Conclusion: Results of the RECARDIO trial suggested safety and efficacy in terms of clinical and perfusion outcomes in patients with RA and LV dysfunction. The observed link between myocardial perfusion improvements and ATMP-CD133 secretome may represent a proof of concept for further mechanistic investigations

Combined administration of G-CSF and GM-CSF stimulates monocyte-derived pro-angiogenic cells in patients with acute myocardial infarction

Mobilization of endothelial progenitor cells has been suggested to contribute to neo-vascularization of ischemic organs. Aim of this study was to investigate whether the combination of granulocyte colony stimulating factor (G-CSF) and granulocyte-macrophage (GM)-CSF may influence the expansion of circulating KDR+ cells in patients with acute myocardial infarction (AMI). KDR+ cells significantly increased in peripheral blood of AMI patients treated with G-CSF and GM-CSF compared to untreated patients. This KDR+ cells population was CD14+ but not CD34+ or CD133+. CD14+/KDR+ cells were also obtained in vitro by culturing mononuclear cells from healthy donors in a Rotary Cell Culture System in the presence of G-CSF + GM-CSF, but not of the individual growth factors. CD14+/KDR+ cells, obtained from patients or from in vitro culture, co-expressed hematopoietic (CD45, CD14) and endothelial markers (CD31, CD105, and VE-cadherin). CD14+/KDR+, but not CD14+/KDR- cells, stimulated the organization of human microvascular endothelial cells into capillary-like structures on Matrigel both in vitro and in vivo. The combination of G-CSF and GM-CSF induced a CD14+/KDR+ cell population with potential pro-angiogenic properties

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

Concurrent G-CSF and GM-CSF administration for the induction of bone marrow-derived cell mobilization in patients with acute myocardial infarction: a pilot study evaluating feasibility, safety and efficacy

AIMS: To verify feasibility and safety of bone marrow stem cells (BMC) mobilization in patients (pts) with acute myocardial infarction (AMI) and to monitor the clinical effects of BMC mobilization in terms of myocardial perfusion and function. METHODS AND RESULTS: Eight male pts (median age: 50.5 years) treated with a primary PTCA were enrolled. The mobilization regimen consisted of G-CSF 5 microg/kg/12 h from day 0 to day +2 and GM-CSF 2.5 microg/kg/24 h. All pts underwent coronary angiography, intracoronary doppler flow study, echocardiography, and nuclear thallium scan before treatment and at 6 months. All pts showed increased values of WBC and circulating CD34+ following cytokine administration. No patient died. All patients completed a 6-months follow-up: target lesion revascularization rate was 12,5%, target vessel revascularization rate was 37.5%, angiographic mean ejection fraction increased from 49.8+/-11.9 to 55.4+/-8.7 (p=NS), mean coronary flow reserve from 1.63+/-0.42 to 2.5+/-0.4 (p=0.001), mean Thallium uptake raised from 55.56+/-16.42% to 67.56+/-13.66% (p=0.01), and normally perfused segments from 16% to 52% (p=0.01). CONCLUSION: Cytokine-induced BMC mobilization is feasible in AMI pts. Improvements of myocardial perfusion can be expected after PTCA associated with G-CSF and GM-CSF induced mobilization. Further studies are required to define the role of BMC-mobilization and the most effective cytokine combination

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)