Biomedical subjects

Philippe Menasché

Publications and source records attributed to Philippe Menasché.

42 records · Page 3Linked to original sources

PubMed2002

Is there a place for preconditioning during cardiac operations in humans?

BACKGROUND: Activation of the kinase cascade (protein kinase C (PKC), tyrosine kinase (TK), and mitogen-activated protein kinase (MAPK) is a key feature of the transduction pathway, elicited by preconditioning signals and mediating their cardioprotective effects. We assessed whether such an activation occurred during cardiac operations and could thus represent a target for cardioprotective strategies. METHODS: A total of 20 patients undergoing coronary artery bypass grafting surgery were studied. During the first 10 minutes of cardiopulmonary bypass (CPB), 10 were treated with sevoflurane (2.5 minimum alveolar concentration), an inhalational anesthetic that mimics preconditioning through a similar activation of the kinase cascade. Ten case-matched patients undergoing 10 minutes of sevoflurane-free CPB served as controls. Right atrial biopsies were taken before and 10 minutes after CPB and were then processed for the measurement of PKC, TK, and p38 MAPK activities by enzyme assay techniques. Troponin I was also monitored over the first 2 postoperative days. RESULTS: Compared with pre-CPB values, PKC and p38 MAPK activities (in nanomoles per milligram of protein per minute and arbitrary units, respectively) increased significantly and to the same extent in both groups: PKC, from 20.7+/-0.7 to 29.9+/-3.9 in controls (p = 0.037) and from 18.4+/-1.1 to 23.9+/-1.8 in sevoflurane (p = 0.016); p38 MAPK, from 88.6+/-8.5 to 312.9+/-66.2 in controls (p = 0.005) and from 114.6+/-14.7 to 213.4+/-51.8 in sevoflurane (p = 0.045). Conversely, sevoflurane triggered a significant increase in TK activity (from 68.5+/-1.4 to 83.7+/-2.9 picomoles per milligram of protein per minute p = 0.0015) which did not occur in controls (from 67.5+/-1.9 to 76.8+/-4.2 picomoles per milligram of protein per minute, p = 0.09). Likewise, the peak postoperative value of troponin I was not different between controls and sevoflurane-treated patients (3.4+/-0.6 vs 2.4+/-0.4, p = 0.21). CONCLUSIONS: Cardiopulmonary bypass triggers an activation of the kinase cascade that is mechanistically linked to opening of potassium channels. The direct opening of these channels by the anesthetic sevoflurane does not increase kinase activation further, nor does it improve markers of cell necrosis, thus suggesting that pharmacologically targeting potassium channels may overlap the preconditioning-like effects of CPB alone.

Anesthetics, Inhalation↗

PubMed2002

Cell therapy of heart failure.

Together with angiogenesis and gene therapy, cell transplantation is one of the newest treatments that have been proposed to improve the still grim outcome of patients with cardiac failure. The underlying rationale is that implantation of contractile cells into fibrous post-infarction scar can functionally 'regenerate' these areas. Primarily for practical reasons, autologous skeletal myoblasts have been the first to be tested in a clinical trial but other cell types can be considered, among which bone marrow stromal and hematopoietic stem cells are of particular interest because of their autologous origin and their purported transdifferentiation potential into cardiac and/or endothelial cells. However, several key issues still need to be addressed, including (i) the optimal type of donor cells, (ii) the mechanism by which cell engraftment improves cardiac function, actively (i.e., by increasing contractility) or passively (i.e. by limiting infarct expansion and remodelling), (iii) the optimisation of cell survival, and (iiii) the potential benefits of cell transplantation in non-ischaemic heart failure. Parallel to the numerous experimental studies designed to address these issues, initial clinical trials are underway or in preparation and, if properly designed and conducted, should allow to know whether the hopes raised by cellular therapy are met by clinically meaningful improvements in the outcomes of patients with heart failure.

Animals↗

PubMed2002

Cell transplantation for the treatment of heart failure.

Along with angiogenesis and gene therapy, cell transplantation is one of the newest treatment modalities proposed to improve the outcome of patients with cardiac failure. Both experimental and clinical data have now established that implantation of contractile cells into fibrous postinfarction scars can allow them to regain some functionality. Primarily for practical reasons, autologous skeletal myoblasts have been the first to be tested in a clinical trial, but other cell types can be considered among which bone marrow stromal and hematopoietic stem cells are of particular interest because of their presumed pluripotentiality and the possibility to use them as autografts. However, several key issues still need to be addressed including: (1) the advantages and disadvantages of these different donor cells; (2) the extent to which cell engraftment affects cardiac function actively (ie, by increasing contractility) or passively (ie, by limiting infarct expansion and remodeling); (3) the development of strategies targeted at enhancing cell survival; and (4) the identification of cardiac diseases for which cell engraftment may be most beneficial. In parallel to the numerous experimental studies designed to address these issues, initial clinical trials are underway or in preparation and it is mandatory to design and conduct them in a careful manner so as to ultimately know whether cellular transplantation holds its promise as a means of improving the outcomes of patients with heart failure.

Animals↗

PubMed2002

Myoblast transplantation: feasibility, safety and efficacy.

Cell transplantation is emerging as a potentially new means of improving function in patients with advanced ischemic heart failure. Skeletal autologous myoblasts have been the first cells to be used clinically as they feature several advantages, but bone marrow stem cells might represent the second generation. Whereas the feasibility of myoblast transplantation is well established, the safety record appears equally satisfactory, with the caveat of a risk of arrhythmias which needs to be better characterized. Preliminary data regarding efficacy are encouraging, but need to be validated by large prospective randomized trials.

Arrhythmias, Cardiac↗

PubMed2002

[Cell therapy: myoblast autograft].

Transplantation of autologous skeletal muscle cells (myoblasts) into post-infarction scars is intended to restore some functionality in these akinetic areas. This concept is now validated by a large number of experimental studies and the preliminary results of a phase 1 human trial. Several issues however still need to be addressed: critical analysis of myoblasts in comparison with other cell types, in particular bone marrow stem cells; optimization of delivery techniques and cell survival following engraftment; mechanisms by which transplanted cells may affect overall cardiac function and possible extension of the indications to non ischemic cardiomyopathies. Only carefully controlled clinical studies, based on sound experimental data, will allow to address these questions and to define the place cell therapy may have within our armamentarium of techniques designed to ameliorate the prognosis of patients with severe heart failure.

Cell- and Tissue-Based Therapy↗

PubMedDate not supplied

Transplantation of cardiac-committed mouse embryonic stem cells to infarcted sheep myocardium: a preclinical study.

BACKGROUND: Heart failure develops after myocardial infarction and is a major cause of morbidity and mortality. The ability to direct differentiation of embryonic stem cells (ESC) towards a cardiomyogenic phenotype makes them an attractive therapeutic option for cardiac repair, but species-specific and individual-specific immunological imprinting remains a hurdle. Our aim was to ascertain whether the purported immune privilege of ESC allows for their cross-species engraftment in a clinically relevant large-animal model. METHODS: We studied engraftment and differentiation of cardiac-committed mouse ESC in 18 sheep in which a myocardial infarction had been induced; nine controls received medium and nine sheep (five of which were immunosuppressed) received ESC. The gain in myocardial function was measured by echocardiography 1 month after cell transplantation. FINDINGS: Cardiac-committed murine ESC engrafted in infarcted myocardium of immunosuppressed and immunocompetent sheep, and differentiated into mature cardiomyocytes that expressed connexins. Colonisation of the scar area by ESC was accompanied by a functional benefit of the damaged myocardium. Left-ventricular ejection fraction deteriorated in the control group by a median of 9.9% (range -20 to 0.3) relative to baseline (p=0.011) whereas in the treated group it improved by 6.6% (-5.7 to 50.8; comparison between groups p=0.002). INTERPRETATION: These findings obtained in a clinically relevant large-animal model of heart failure strengthen the potential therapeutic use of ESC to regenerate the severely dysfunctional myocardium and bring additional evidence for an immune privilege of these cells.

Animals↗