Culture and Use of Mesenchymal Stromal Cells in Phase I and II Clinical Trials

Present in numerous tissues, mesenchymal stem cells/multipotent stromal cells (MSCs) can differentiate into different cell types from a mesoderm origin. Their potential has been extended to pluripotency, by their possibility of differentiating into tissues and cells of nonmesodermic origin. Through the release of cytokines, growth factors and biologically active molecules, MSCs exert important paracrine effects during tissue repair and inflammation. Moreover, MSCs have immunosuppressive properties related to non-HLA restricted immunosuppressive capacities. All these features lead to an increasing range of possible applications of MSCs, from treating immunological diseases to tissue and organ repair, that should be tested in phase I and II clinical trials. The most widely used MSCs are cultured from bone marrow or adipose tissue. For clinical trial implementation, BM MSCs and ADSCs should be produced according to Good Manufacturing Practices. Safety remains the major concern and must be ensured during culture and validated with relevant controls. We describe some applications of MSCs in clinical trials

Impact of intracoronary bone marrow cell therapy on left ventricular function in the setting of ST-segment elevation myocardial infarction: a collaborative meta-analysis

Aims The objective of the present analysis was to systematically examine the effect of intracoronary bone marrow cell (BMC) therapy on left ventricular (LV) function after ST-segment elevation myocardial infarction in various subgroups of patients by performing a collaborative meta-analysis of randomized controlled trials. Methods and results We identified all randomized controlled trials comparing intracoronary BMC infusion as treatment for ST-segment elevation myocardial infarction. We contacted the principal investigator for each participating trial to provide summary data with regard to different pre-specified subgroups [age, diabetes mellitus, time from symptoms to percutaneous coronary intervention, infarct-related artery, LV end-diastolic volume index (EDVI), LV ejection fraction (EF), infarct size, presence of microvascular obstruction, timing of cell infusion, and injected cell number] and three different endpoints [change in LVEF, LVEDVI, and LV end-systolic volume index (ESVI)]. Data from 16 studies were combined including 1641 patients (984 cell therapy, 657 controls). The absolute improvement in LVEF was greater among BMC-treated patients compared with controls: [2.55% increase, 95% confidence interval (CI) 1.83-3.26, P < 0.001]. Cell therapy significantly reduced LVEDVI and LVESVI (−3.17 mL/m², 95% CI: −4.86 to −1.47, P < 0.001; −2.60 mL/m², 95% CI −3.84 to −1.35, P < 0.001, respectively). Treatment benefit in terms of LVEF improvement was more pronounced in younger patients (age <55, 3.38%, 95% CI: 2.36-4.39) compared with older patients (age ≥55 years, 1.77%, 95% CI: 0.80-2.74, P = 0.03). This heterogeneity in treatment effect was also observed with respect to the reduction in LVEDVI and LVESVI. Moreover, patients with baseline LVEF <40% derived more benefit from intracoronary BMC therapy. LVEF improvement was 5.30%, 95% CI: 4.27-6.33 in patients with LVEF <40% compared with 1.45%, 95% CI: 0.60 to 2.31 in LVEF ≥40%, P < 0.001. No clear interaction was observed between other subgroups and outcomes. Conclusion Intracoronary BMC infusion is associated with improvement of LV function and remodelling in patients after ST-segment elevation myocardial infarction. Younger patients and patients with a more severely depressed LVEF at baseline derived most benefit from this adjunctive therap

La thérapie cellulaire en cardiologie (approche réglementaire, essais cliniques, limites et perspectives)

La thérapie cellulaire est une nouvelle thérapeutique encore en évaluation. La réglementation des essais cliniques la concernant a été modifiée par la directive européenne 2001/20/CE. En cardiologie, la recherche dans ce domaine est bien engagée. De nombreuses cellules semblent intéressantes pour la réparation myocardique, aussi bien des cellules embryonnaires et fœtales que des cellules souches adultes. De même, plusieurs voies d'administration sont évaluées, qu'il s'agisse de l'implantation directe dans le myocarde ou de l'injection vasculaire, essentiellement coronaire. Ainsi de nombreux essais cliniques ont été menés ou sont en cours, évaluant principalement les cellules souches adultes de moelle osseuse et les myoblastes squelettiques. Ils ont permis d'identifier non seulement des problèmes propres à la thérapie cellulaire et les premiers effets indésirables, mais aussi les premiers résultats.TOULOUSE3-BU Santé-Centrale (315552105) / SudocSudocFranceF

Fibrinolyse préhospitalière versus angioplastie primaire dans l'infarctus du myocarde (suivi à court et long terme)

TOULOUSE3-BU Santé-Centrale (315552105) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Autologous bone marrow cells and ischemic cardiomyopathy.

International audienceEvaluation of: Williams AR, Trachtenberg B, Velazquez DL et al. Intramyocardial stem cell injection in patients with ischemic cardiomyopathy: functional recovery and reverse remodeling. Circ. Res. 108, 792-796 (2011). Transcatheter, intramyocardial injections of bone marrow-derived cells produce reverse remodeling in large animal models of ischemic cardiomyopathy. A variety of adult stem and progenitor cells from different sources have already been examined for their potential to promote cardiac repair and regeneration after myocardial infarction. This article reviews a recent study by Williams et al. who test the hypothesis that transcatheter, intramyocardial injections of autologous bone marrow progenitor cells (mononuclear or mesenchymal stem cells) in left ventricular scar and border zone improve regional contractility of a chronic myocardial scar and that these changes predict subsequent reverse remodeling. All patients tolerated the procedure with no serious adverse events. At 1 year, cardiac MRI demonstrated a decrease in end diastolic volume, a trend toward decreased end systolic volume, decreased infarct size and improved regional left ventricular function. This article focuses on the findings and limitations of the study and provides an insight for future promising clinical trials

An Alternative Approach to Alternative Beta

Hedge fund replication based on factor models is encountering growing interest. In this paper, we investigate the implications of substituting standard rolling windows regressions, which appear ad-hoc, with more efficient methodologies like the Kalman filter. We show that the copycats constructed this way offer risk-return profiles which share several characteristics with the ones posted by hedge funds indices: Sharpe ratios above buy-and-hold strategies on standard assets, moderate correlation with tandard assets, and limited drawdowns during equity downward trends. An interesting result is that the shortfall risk seems less important than with hedge fund indices and regressions-based trackers. We finally propose new breakdowns of hedge fund erformance into alpha, traditional beta, and alternative beta.hedge fund replication; alternative beta; Kalman filter

The properties of equally-weighted risk contributions portfolios

Minimum variance and equally-weighted portfolios have recently prompted great interest both from academic researchers and market practitioners, as their construction does not rely on expected average returns and is therefore assumed to be robust. In this paper, we consider a related approach, where the risk contribution from each portfolio components is made equal, which maximizes diversication of risk (at least on an ex-ante basis). Roughly speaking,the resulting portfolio is similar to a minimum variance portfolio subject to a diversification constraint on the weights of its components. We derive the theoretical properties of such a portfolio and show that its volatility is located between those of minimum variance and equally-weighted portfolios. Empirical applications confirm that ranking. All in all, equally-weighted risk contributions portfolios appear to be an attractive alternative to minimum variance and equally-weighted portfolios and might be considered a good trade-off between those two approaches in terms of absolute level of risk, risk budgeting and diversificationou

A Family History of Dilated Cardiomyopathy Induced by Viral Myocarditis

Myocarditis can lead to acute heart failure, cardiogenic shock, or sudden death and later, dilated cardiomyopathy (DCM) with chronic heart failure. We report the cases of two DCM induced by acute and past myocarditis in the same family and expressed by its two main complications within few weeks: an hemodynamic presentation as a fulminant myocarditis rapidly leading to cardiac tranplantation and a rythmologic presentation as an electrical storm leading to catheter ablation of ventricular tachycardia. These cases ask the question of the family predisposition to viral myocarditis leading to DCM

Meta-Analysis of Cell-based CaRdiac stUdiEs (ACCRUE) in Patients with Acute Myocardial Infarction Based on Individual Patient Data.

International audienc