PubMed Health⌕ Search

Biomedical subjects

Philippe Menasché

Publications and source records attributed to Philippe Menasché.

At least 37 records · Page 2Linked to original sources
PubMed2005

The potential of embryonic stem cells to treat heart disease.

Cell therapy is currently receiving growing interest as a new means of repairing infarcted myocardium. Despite the encouraging experimental results yielded by autologous skeletal myoblasts and bone marrow-derived hematopoietic and mesenchymal stem cells, there is increasing evidence that the plasticity of these adult cells is more limited than initially thought and that, consequently, their conversion into cardiomyocytes is unlikely or, at best, quantitatively very limited. As the engrafted cells should electromechanically interact with host cardiac cells to form a functional syncytium, attention is now increasingly focused on cells that feature a true cardiomyogenic differentiation potential, enabling them to connect with the neighboring cardiomyocytes. In this setting, embryonic stem cells are particularly attractive, since they can be precommitted towards a cardiac lineage and complete their full maturation in vivo, possibly under the influence of host tissue-associated paracrine signaling pathways. Although a potential clinical use of embryonic stem cells is still fraught with difficulty (amplification, purification and immunogenicity), available experimental data suggest a consistent efficacy in repairing infarcted myocardium, which has stimulated efforts to address these issues.

Adult↗
PubMed2004

Does the functional efficacy of skeletal myoblast transplantation extend to nonischemic cardiomyopathy?

BACKGROUND: The benefits of skeletal myoblast (SM) transplantation on infarcted myocardium have been investigated extensively; however, little is known about its effects in nonischemic cardiomyopathy models. To address this issue, we tested SM transplantation in CHF147 Syrian hamsters, a strain characterized by a delta-sarcoglycan deficiency that phenotypically features the human setting of primary dilated cardiomyopathy. METHODS AND RESULTS: Cell culture techniques were used to prepare approximately 5x10(6) muscle cells from autologous tibialis anterior muscle, of which 50% were SMs (desmin staining). The cells were injected in 6 sites across the left ventricular wall (n=14). Control animals (n=12) received equivalent volumes of culture medium. Left ventricular systolic function was assessed in a blinded fashion from 2D echocardiographic left ventricular fractional area change, before transplantation, and 4 weeks later. Explanted hearts were processed for the detection of myotubes and quantification of fibrosis. Baseline functional data did not differ between the 2 groups. Four weeks after transplantation, 6 of the 10 surviving grafted hamsters were improved compared with 0 of the 8 survivors of the control group. This translated into a 6% decrease in fractional area change in controls compared with a 24% increase in cell-transplanted hamsters (P=0.001). Engrafted myotubes were consistently detected in all SM transplanted hearts by immunohistochemistry, whereas fibrosis was not worsened by cell injections. CONCLUSIONS: These data suggest that the functional benefits of SM transplantation might extend to nonischemic cardiomyopathy.

Animals↗
PubMed2004

Comparison of human skeletal myoblasts and bone marrow-derived CD133+ progenitors for the repair of infarcted myocardium.

OBJECTIVES: The present study was designed as a face-to-face functional comparison of human skeletal myoblasts (SMs) and CD133(+) bone marrow-derived hematopoietic progenitors in an animal model of semichronic myocardial infarction. BACKGROUND: Compared with SMs, bone marrow-derived cells have the advantage of plasticity and might more effectively regenerate ischemic cardiac tissue. However, few data exist on the comparative efficacy of these two cell types in semichronic infarcts. METHODS: A myocardial infarction was created by coronary ligation in 32 nude rats. Ten days later, rats received in-scar injections of human SMs, CD133(+) progenitors, or culture medium. Left ventricular function was assessed before and one month after transplantation by echocardiography and pressure-volume loops. Immunofluorescence, polymerase chain reaction, and in situ hybridization were used to detect cells grafted in the hearts. RESULTS: One month after transplantation, left ventricular ejection fraction decreased by 8 +/- 4% in controls, whereas it increased by 7 +/- 3% in CD133(+)-grafted hearts (p = 0.0015 vs. controls) and further by 15 +/- 5% in SM-treated hearts (p = 0.008 vs. controls). Systolic indices yielded by pressure-volume loops paralleled these data. Engrafted myotubes were identified in all SM-treated hearts by immunofluorescence, whereas in CD133(+)-grafted hearts, few human cells were only detected by polymerase chain reaction. CONCLUSIONS: In the setting of postinfarction scars, the transplantation of bone marrow-derived CD133(+) progenitors improves cardiac function, but this benefit is not superior to that afforded by myogenic cells.

AC133 Antigen↗
PubMed2004

Myoblast transfer in heart failure.

In conclusion, myoblast transfer has now reached a stage where large randomized trials such as the one we are initiating (300 patients) are mandatory to thoroughly assess the efficacy of the procedure. It is important that the design of these studies complies with the stringent methodologic guidelines commonly used in drug trials, as this is the only means of accurately assessing whether and to what extent skeletal myoblast transfer can really impact the outcome of patients with advanced left-ventricular ischemic dysfunction.

Cell Transplantation↗
PubMed2004

Cellular transplantation: hurdles remaining before widespread clinical use.

PURPOSE OF REVIEW: The last few years have witnessed a growing interest in regenerative therapy of the failing heart by cell transplantation. Special emphasis has been put on skeletal myoblasts and bone marrow-derived stem cells, with a flurry of experimental studies generating overall positive but occasionally conflicting results. It is thus appropriate to review the most important of these studies in light of the major issues that still impede widespread clinical use of cell therapy. RECENT FINDINGS: Recent laboratory data demonstrate the ability of autologous skeletal myoblasts to engraft into scarred myocardium and improve its function. Equally successful results have been reported with bone marrow-derived cells which, in contrast to myoblasts, are credited with a plasticity that might allow their transdifferentiation into cardiac or endothelial cells in response to organ-specific cues. However, some major questions remain unanswered; they include the choice of the optimal cell type in relation with the target patient population, the strategies for enhancing cell survival and functional integration, the clarification of the mechanisms of improvement, and the means of reducing invasiveness of cell delivery. SUMMARY: Although laboratory research attempts to overcome these persisting hurdles, the accumulated body of evidence warrants implementation of clinical trials. The earliest ones have now documented the feasibility of cell therapy. It is now appropriate to conduct safety and efficacy studies which, if carefully done, should allow assessment of the extent to which this concept of regenerative therapy can be made a clinical reality.

Bone Marrow Transplantation↗
PubMed2004

Skeletal myoblast transplantation for cardiac repair.

Cell transplantation is gaining interest as a potentially new means of improving function of the failing heart through replacement of lost cardiomyocytes with new contractile cells. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also being considered, particularly bone marrow stem cells which are credited for a plasticity that might allow them to change their phenotype in response to environmental cues. Several key issues still need to be addressed including: the comparative efficacy of different donor cell lineages in relation to the patient's clinical condition (i.e., ischemia vs. heart failure, the mechanism by which cell engraftment improves cardiac function, the enhancement of cell survival and functional integration within the recipient tissue, and the development of minimally invasive cell delivery techniques. In parallel to these laboratory studies, clinical trials are now being implemented to generate efficacy data. Altogether, these efforts should allow the assessment of whether and to what extent cell transplantation may ameliorate function of the failing heart.

Animals↗
PubMed2003

Efficacy of chordal cutting to relieve chronic persistent ischemic mitral regurgitation.

BACKGROUND: Mitral regurgitation (MR) conveys adverse prognosis in ischemic heart disease. Leaflet closure is restricted by tethering to displaced papillary muscles, and is, therefore, incompletely treated by annular reduction. In an acute ischemic model, we reduced such MR by cutting a limited number of critically positioned chordae to the leaflet base that most restrict closure but are not required to prevent prolapse. Whether this is effective without prolapse, recurrent MR, or left ventricular (LV) failure in chronic persistent ischemic MR, despite greater LV remodeling, remains to be established. Therefore, we studied 7 sheep with chronic inferobasal infarcts known to produce progressive MR over 2 months. In all of those sheep, after a mean of 4.1 months, the 2 central basal (intermediate) chordae were cut at the chronic ischemic MR stage. 3-Dimensional echo quantified MR, LV function, and valve geometry. Five other sheep were followed for a mean of 7.8+/-1.2 months after inferobasal infarction with chordal cutting. RESULTS: All 7 of the sheep with chronic ischemic MR (increased from 1.4+/-0.4 to 11.1+/-0.5 mL/beat, regurgitant fraction=39.0+/-4.2%, P<0.0001) showed anterior leaflet angulation at the basal chord insertion. Although end-systolic volume had doubled, cutting the 2 central basal chordae significantly decreased the MR to baseline (P<0.0001) without prolapse or decline in EF (41.1+/-1.5% to 42.6+/-1.6%, P=not significant [NS]). The five sheep with long-term follow-up showed no prolapse or MR, and no significant post-infarct decrease in LV ejection fraction (EF; 38.9+/-2.4% to 41.4+/-1.2%, P=NS). CONCLUSIONS: Cutting a minimum number of basal (intermediate) chordae can improve coaptation and reduce chronic persistent ischemic MR without impairing LVEF. No adverse effects were noted long-term after chordal cutting at the time of infarction.

Animals↗
PubMed2003

Transplantation of autologous fresh bone marrow into infarcted myocardium: a word of caution.

BACKGROUND: As the benefits of extemporaneous transplantation (Tx) of fresh (unfractionated) autologous bone marrow (BM) have been primarily studied in the setting of acute myocardial infarction, we assessed whether this approach could be effective for regenerating chronically infarcted myocardium. METHODS AND RESULTS: Myocardial infarction was created in 18 sheep by ligation of circumflex arterial branches. Three weeks later, BM was aspirated from the iliac crest, washed, labeled with the fluorescent dye Dil and reinjected (mean: 422 x 10(6) cells in 3 mL) in 10 sites across the infarcted area through the reopened thoracotomy (n=9). Nine controls received culture medium. Left ventricular (LV) function was assessed before and 2 months after Tx by two-dimensional echocardiography whereas transmural velocity gradients were measured using M-mode tissue Doppler imaging at the center of the infarcted/grafted area. Formalin-fixed hearts were processed for the detection of grafted cells and angiogenesis. LV ejection fraction deteriorated similarly in the Tx and control groups (from 42+/-5% to 30+/-4% and from 40+/-4% to 31+/-1%, respectively; P=0.86). Likewise, BM Tx failed to prevent LV dilatation and impairment of the global wall motion score. The decrease in regional systolic velocity gradients (s(-1)) featured a similar pattern (Tx group: from 0.77+/-0.11 to 0.31+/-0.07; control group: from 0.73+/-0.10 to 0.50+/-0.07; P=0.06). Histologically, there was neither BM tissue engraftment, except for a few scattered Dil-positive macrophages in the infarcted fibrotic areas nor transdifferentiation of BM cells into endothelial cells. CONCLUSIONS: These data caution against the functional efficacy of extemporaneous Tx of fresh unfractionated BM into postinfarction scars.

Animals↗
PubMed2003

Skeletal muscle satellite cell transplantation.

Cell transplantation is currently gaining a growing interest as a potential new means of improving the prognosis of patients with cardiac failure. The basic assumption is that left ventricular dysfunction is primarily caused by the loss of a critical number of cardiomyocytes and that their replacement by new contractile cells could functionally 'regenerate' postinfarction scars in which these cells are implanted. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also considered, particularly bone marrow stem cells which are attractive because of their autologous origin and their purported cardiomyocyte/endothelial transdifferentiation potential in response to cues present in the target organ. However, several key issues still need to be addressed including (1) the optimal type of donor cells, (2) the mechanism by which cell engraftment improves cardiac function, (3) the optimization of cell survival, and (4) the potential benefits of cell transplantation in nonischemic dilated cardiomyopathies. In parallel to the experimental studies designed to address these issues, clinical trials are underway and their results should hopefully allow the assessment of to what extent cellular therapy may improve the outcome of patients with heart failure.

Animals↗
PubMed2003

Temporal patterns of bone marrow cell differentiation following transplantation in doxorubicin-induced cardiomyopathy.

OBJECTIVE: Recent studies have suggested benefits of bone marrow cell transplantation for the regeneration of ischemic cardiac tissue. To extend the potential of cell transplantation, we assessed this treatment in a mouse model of acute nonischemic doxorubicin-induced cardiomyopathy. METHODS: To allow detection of engrafted cells, we used transgenic mice expressing the nuclear-located LacZ under the control of either desmin or vimentin promoters, which identify muscle lineage and mesenchymal cells, respectively. All transplanted cells were also labeled with the fluorescent dye DIL. One week after the administration of doxorubicin (15 mg/kg), mice were intramyocardially injected with either allogeneic unpurified bone marrow cells (6 x 10(6) in 30 microl, n=59) or purified sca-1(pos) cells (4 x 10(5) in 30 microl, n=22). In parallel, control normal mice received only unpurified bone marrow cells (n=28). Hearts were harvested at serial intervals until 2 weeks after transplantation and analyzed by immunohistochemistry to assess the degree of engraftment and transplanted cell differentiation. RESULTS: In control mice, no differentiation of bone marrow cells was detected. In contrast, unpurified bone marrow cells grafted into diseased myocardium featured two successive phases of cell differentiation. The first yielded cells with a mesenchymal phenotype (44.1+/-10.1 cells/3 x 10(-2) mm(3) at 2 days), was transient and lasted 1 week. The second phase was characterized by cells with a muscular phenotype detected in a small number of cells (5.6+/-2.3 cells/3 x 10(-2) mm(3) at 7 days). Two weeks after transplantation, some of these cells appeared phenotypically close to cardiomyocytes, as evidenced by morphology and positive staining for myosin binding protein C, vinculin and myosin heavy chain. In sca-1(pos) hematopoietic progenitor grafted mice hearts, no transdifferentiation into cardiac cells was detected at any time point. CONCLUSION: These data support the hypothesis of the potential for a myogenic differentiation of bone marrow cells following engraftment in a nonischemic model of global cardiomyopathy. Bone marrow-derived cells amenable to cardiac differentiation are present in total unpurified bone marrow but not in the sca-1(pos) hematopoietic progenitor cell population. However, the very small number of transdifferentiated cells raises concerns over their functional efficacy.

Animals↗
PubMed2003

Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction.

OBJECTIVES: This phase I trial was designed to assess the feasibility and safety of autologous skeletal myoblast transplantation in patients with severe ischemic cardiomyopathy. BACKGROUND: Experimentally, myoblast grafting into postinfarction myocardial scars improves left ventricular function. METHODS: Ten patients were included on the basis of the following criteria: 1) severe left ventricular dysfunction (ejection fraction < or = 35%); 2) the presence of a postinfarction akinetic and nonviable scar, as assessed by dobutamine echocardiography and 18-fluorodeoxyglucose positron emission tomography; and 3) an indication of coronary bypass in remote areas. Skeletal myoblasts were grown from a biopsy taken at the thigh. RESULTS: An average of 871 x 10(6) cells (86% of myoblasts) were obtained after a mean period of 16 days and implanted uneventfully across the scar at the time of bypass. Except for one patient whose early death was unrelated to the cell transplantation, all patients had an uncomplicated postoperative course. Four patients showed delayed episodes of sustained ventricular tachycardia and were implanted with an internal defibrillator. At an average follow-up of 10.9 months, the mean New York Heart Association functional class improved from 2.7 +/- 0.2 preoperatively to 1.6 +/- 0.1 postoperatively (p < 0.0001), and the ejection fraction increased from 24 +/- 1% to 32 +/- 1% (p < 0.02). A blinded echocardiographic analysis showed that 63% of the cell-implanted scars (14 of 22) demonstrated improved systolic thickening. One noncardiac death occurred 17.5 months after transplantation. CONCLUSIONS: These preliminary data suggest the feasibility and safety of autologous skeletal myoblast transplantation in severe ischemic cardiomyopathy, with the caveat of an arrhythmogenic potential. New-onset contraction of akinetic and nonviable segments suggests a functional efficacy that requires confirmation by randomized studies.

Adult↗
PubMed2003

Long-term (1 year) functional and histological results of autologous skeletal muscle cells transplantation in rat.

BACKGROUND: Several studies have demonstrated the short-term benefits of autologous skeletal muscle cell transplantation on postinfarction left ventricular function. The present experiments were designed to assess the long-term effects of the procedure. METHODS AND RESULTS: Thirteen Wistar rats that had undergone skeletal muscle cell transplantation (n=6) or injection of control culture medium (n=7) in isoforms areas after myocardial infarction created by coronary artery ligation and survived for 1 year were functionally assessed by combining echocardiography and pressure-volume loops. At 1 year after transplantation, both contractile and relaxation indices were significantly improved in the skeletal muscle cell-grafted group compared with controls. One-year echocardiographic measurements of ejection fraction were similar to those recorded 2 months after the procedure. The stability of the functional outcome contrasted with a decrease in the number of histologically detectable skeletal myotubes over time. However, the proportion of the slow and composite (fast and slow) myosin isoforms expressed by skeletal muscle fibers still present after 1 year was greater than that found in animals sacrificed after 2 months. CONCLUSION: The functional benefits of autologous skeletal muscle cell transplantation are sustained over time and are associated with either selection, preservation or an increased expression of slow myosin heavy chain isoforms. The discrepancy between maintenance of this improvement and the decay in the engrafted myotubes suggests protective mechanisms operative from the early post-transplantation stage and possibly involving modulation of extracellular matrix remodelling or paracrinally induced maturation of putative cardiac resident stem cells.

Animals↗
PubMed2003

Viability and differentiation of autologous skeletal myoblast grafts in ischaemic cardiomyopathy.

Autologous skeletal myoblast transplantation might improve postinfarction ventricular function, but graft viability and differentiation (ie, proof of concept) has not been shown. A 72-year-old man had autologous cultured myoblasts from his vastus lateralis injected to an area of transmural inferior myocardial infarction in non-reperfused scar tissue. He showed improvement in symptoms and left-ventricular ejection fraction. When he died 17.5 months after the procedure, the grafted post-infarction scar showed well developed skeletal myotubes with a preserved contractile apparatus. 65% of myotubes expressed the slow myosin isoform and 33% coexpressed the slow and fast isoforms (vs 44% and 0.6%, respectively, in skeletal muscle). Myoblast grafts can survive and show a switch to slow-twitch fibres, which might allow sustained improvement in cardiac function.

Aged↗
PubMed2003

Cell transplantation in myocardium.

Cell transplantation is gaining a growing interest as a potential new means of improving the prognosis of patients with cardiac failure. The basic assumption is that left ventricular dysfunction is largely due to the loss of a critical number of cardiomyocytes and that it can be partly reversed by implantation of new contractile cells into the postinfarction scars. Primarily for practical reasons, autologous skeletal myoblasts have been the first to undergo clinical trials but other cell types are also considered, particularly bone marrow stem cells, which are attractive because of their autologous origin and their purported cardiomyocyte/endothelial transdifferentiation potential in response to cues provided by the target organ. However several key issues still need to be addressed including (1) the optimal type of donor cells, (2) the mechanism by which cell engraftment improves cardiac function, (3) the optimization of cell survival, and (4) the potential benefits of cell transplantation in non-ischemic heart failure. In parallel to the experimental studies designed to address these issues clinical trials are under way and should hopefully allow assessing to what extent cell transplantation may improve the outcome of patients with heart failure.

Animals↗
PubMed2003

Myoblast-based cell transplantation.

Cell transplantation is emerging as a new treatment designed tot improve the poor outcome of patients with cardiac failure. Its rationale is that implantation of contractile cells into postinfarction scars can functionally rejuvenate these areas. Primarily for practical reasons, autologous skeletal myoblasts have been the first to be tested clinically but bone marrow stromal and hematopoietic stem cells may represent an interesting alternative in select situations because of their autologous origin and their purported plasticity. However, several key issues still need to be addressed including (1) the optimal type of cells, (2) the mechanism by which cell engraftment improves cardiac function, i.e., increased contractility or limitation of remodeling, (3) the most effective strategies for optimizing cell survival, and (4) the potential benefits of cell transplantation in nonischemic heart failure. In parallel to the experimental studies designed to address these issues, initial clinical trials are underway and should hopefully allow to know whether the hopes raised by cellular therapy are met by clinically meaningful improvements in function and outcome in patients with severe left ventricular ischemic dysfunction.

Animals↗
PubMed2002

[Surgical treatment and transplantation in heart failure].

Cardiac transplantation still remains the only radical treatment of end-stage heart failure but organ shortage results in the lengthening of the waiting period during which hemodynamic decompensation may occur and then require temporary circulatory support. Improvement in these assist devices now allows to permanently implant some of them which then appear as true alternatives to cardiac transplantation when this technique is contra-indicated. In parallel to these "mechanical" options, "biological" strategies have been designed, which are primarily based on cell therapy. Thus, autologous skeletal myoblast transplantation has yet entered the clinical arena, on the basis of experimental data suggesting the functional efficacy of these cells once implanted into infarcted myocardium. However, the clinical benefits of this approach still need to be validated by randomized trials. Gene therapy appears more complex to implement clinically, because of the multiplicity of candidate genes and the persisting issues associated with vectors and gene transfection systems.

Graft Rejection↗
PubMed2002

Long-term efficacy of myoblast transplantation on regional structure and function after myocardial infarction.

BACKGROUND: Transplantation (Tx) of skeletal myoblasts (SM) within an infarcted myocardium improves global left ventricular (LV) function, although a direct systolic effect remains controversial. METHODS AND RESULTS: Global and regional LV functions were studied in a sheep model (n=16) of infarction before (baseline), and 4 (M4), and 12 (M12) months after in-scar injections of autologous SM or culture medium (CM). LV end-diastolic volume (EDV), ejection fraction (EF), wall motion score (WMS), and systolic myocardial velocity gradient (MVG) across the scar were measured by echocardiography with tissue Doppler imaging. Parameters were similar at baseline between groups. At M4, Tx of SM reduced the postinfarction increase in EDV (72+/-8 versus 105+/-13 mL in the CM group, P<0.05) and the decrease in EF (48+/-5 versus 33+/-3% in the CM group, P=0.006) although it improved WMS (5.4+/-1.2 versus 13+/-2.2 in the CM group, P<0.01) and SMVG (0.60+/-0.13 versus -0.04+/-.13 seconds(-1) in the CM group, P<0.05). Results were similar at M12. In-scar accumulation of myotubes and SM were detected in all Tx animals up to M12, with co-expression of fast and slow isoforms of the myosin heavy chain (MHC) (30% of the fibers versus 0% in the normal skeletal muscle) and decreased collagen density (30+/-2% versus 73+/-3%, P<0.0001). CONCLUSIONS: For up to 1 year, Tx of SM limits postinfarction EF deterioration and improves systolic scar function through colonization of fibrosis by skeletal muscle cells with expression of both MHC isoforms, which may confer to the graft the ability to withstand a cardiac-type workload.

Animals↗