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Biomedical subjects

P Menasché

Publications and source records attributed to P Menasché.

At least 19 recordsLinked to original sources
PubMed2002

[Myocardial implantation of muscle cells].

THE DEVELOPMENT OF CELL THERAPY: The stakes in the management of heart failure have become such that new therapeutic strategies have to be developed. Among the cell, molecular and genetic approaches aimed at reinforcing the deficient heart muscle by restoring its functional potential, cell therapy is the favored option in clinical application perspectives. IN THE FIELD OF ISCHEMIC HEART FAILURE: All the experimental data have shown that implantation of contractile cells in the post-infarction areas led to improved cardiac function. INTERESTING PRELIMINARY RESULTS: For ethical and immuno-biological reasons, the successful transplantation of autologous skeletal myoblasts has led our team to conduct a phase I clinical trial. Although the results of this study are preliminary with regard to cardiac function, they suggest the validity of the cell transplantation concept and allow one to hope that this new treatment method will have its place among the therapeutic arms of heart failure.

Heart Failure↗
PubMed2001

Regeneration of the myocardium: a new role in the treatment of ischemic heart disease?

Intramyocardial cell grafting aims to limit the consequences of the loss of contractile function of a damaged left ventricle. Its functional efficacy is suggested by a wealth of experimental data using multiple evaluation techniques in different animal species. Intramyocardial injections of cultured fetal cardiomyocytes after infarction increase the ejection fraction. Cultured autologous skeletal myoblasts, which do not raise immunologic, ethical, tumorigenesis, or donor availability problems, improve ventricular function to a similar extent. The presence of connexin-43 is demonstrated between fetal (but not myoblast) grafted cells and host myocytes. Thus, the mechanisms of this beneficial effect (direct systolic effect, paracrine factors, passive girdling effect, and decrease in wall stress) remain controversial. These encouraging results have opened the way to the first clinical trial in patients with low ejection fractions, akinetic and nonviable postinfarction scars, and indications for coronary artery bypasses in remote, viable, and ischemic areas. Large-scale cell expansion allows a yield of >10(9) myoblasts from a single human muscular biopsy. Cultured autologous myoblasts are directly administered by multiple injections within and around the infarcted area during open-chest surgery. Preliminary postoperative observations show an improvement in ejection fraction, reappearance of a systolic thickening of the grafted scars, and a new-onset metabolic viability within this area. Thus, this new procedure might become a useful adjunct to current treatments of severe ischemic heart failure.

Animals↗
PubMed2001

Is skeletal myoblast transplantation clinically relevant in the era of angiotensin-converting enzyme inhibitors?

BACKGROUND: There is compelling experimental evidence that autologous skeletal muscle (SM) cell transplantation improves postinfarction cardiac function. This study assessed whether this benefit is still manifested in the clinically relevant setting of a treatment by ACE inhibitors. METHODS AND RESULTS: A myocardial infarction was created in 99 rats by coronary artery ligation. They were divided into 4 groups. Two groups did not receive any drug and were intramyocardially injected 7 days after the infarct with either culture medium alone (control rats, n=16) or autologous SM cells (2.3x10(6) myoblasts) previously expanded ex vivo for 7 days (myoblasts, n=24). Two other groups received the ACE inhibitor perindoprilat (1 mg. kg(-1). d(-1)), started the day of the infarct and continued uninterruptedly thereafter, and underwent time-matched procedures, that is, they were intramyocardially injected at 7 days after infarction with either culture medium alone (ACE inhibitors, n=22) or autologous SM cells (2.5x10(6) myoblasts) previously expanded ex vivo for 7 days (ACE inhibitors+myoblasts, n=37). Left ventricular function was assessed by 2D echocardiography. At the end of the 2-month study, left ventricular ejection fraction (%, mean+/-SEM) was increased in all groups (myoblasts, 37.4+/-1.2; ACE inhibitors, 31.6+/-1.7; ACE inhibitors+myoblasts, 43.9+/-1.4) compared with that in control rats (19.8+/-0.7) (P<0.0001). The improvement in ejection fraction was similar in the ACE inhibitor and the myoblast groups (31.6+/-1.7 versus 37.4+/-1.2, P=0.0636). However, in the ACE inhibitor+myoblast group, this improvement was greater than that seen in hearts receiving either treatment alone (43.9+/-1.4 versus 31.6+/-1.7 in the ACE inhibitor group and 43.9+/-1.4. versus 37.4+/-1.2 in the myoblast group, P<0.0001 and P=0.0084, respectively). CONCLUSIONS: These data provide further support for the clinical relevance of autologous SM cell transplantation in that its cardioprotective effects are additive to those observed with ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Myoblast transplantation for heart failure.

Intramyocardial skeletal muscle transplantation has been shown experimentally to improve heart function after infarction. We report success with this procedure in a patient with severe ischaemic heart failure. We implanted autologous skeletal myoblasts into the postinfarction scar during coronary artery bypass grafting of remote myocardial areas. 5 months later, there was evidence of contraction and viability in the grafted scar on echocardiography and positron emission tomography. Although this result is encouraging, it requires validation by additional studies.

Aged↗
PubMed2001

Factors affecting functional outcome after autologous skeletal myoblast transplantation.

BACKGROUND: This study assessed the extent to which the initial degree of functional impairment and the number of injected cells may influence the functional improvement provided by autologous skeletal myoblast transplantation into infarcted myocardium. METHODS: One week after left coronary artery ligation, 44 rats received into the infarcted scar, autologous skeletal myoblasts expanded in vitro for 7 days (mean, 3.5 x 10(6), n = 21), or culture medium alone (controls, n = 23). Left ventricular function was assessed by two-dimensional echocardiography. RESULTS: When transplanted hearts were stratified according to their baseline ejection fraction, a significant improvement occurred at 2 months in the less than 25% (from 21.4% to 37%), 25% to 35% (from 29% to 43.8%), and in the 35% to 40% (from 37.2% to 41.7%) groups, compared to controls (p = 0.048, 0.0057, and 0.034, respectively), but not in the more than 40% stratum. A significant linear relationship was found between the improvement in ejection fraction and the number of injected myoblasts, both at 1 and 2 months after transplantation (p < 0.0001). CONCLUSIONS: Autologous myoblast transplantation is functionally effective over a wide range of postinfarct ejection fractions, including in the sickest hearts provided that they are injected with a sufficiently high number of cells.

Animals↗
PubMed2001

Backtable heat-enhanced preconditioning: a simple and effective means of improving function of heart transplants.

BACKGROUND: Cardiac harvest teams are usually committed to immediately transfer the explanted donor heart into its cold storage solution. We tested the opposite hypothesis that a brief prestorage episode of heat-enhanced ischemic preconditioning could be protective. METHODS: Fifty-three isolated isovolumic rat hearts underwent 4 hours of cold (4 degrees C) storage in the Celsior preservation solution and 2 hours of reperfusion. Control hearts were immediately immersed after arrest. In the 3 treated groups, 2 customized thermal probes were first applied onto the left ventricular free wall of the explanted heart at 22 degrees C, 37 degrees C or 42.5 degrees C for 15 minutes before immersion. Each of the selected temperatures were monitored at the probe-tissue interface by a thermocouple. RESULTS: Whereas base line end-diastolic pressure was set at = 8 mm Hg in all groups, it increased during reperfusion (mean +/- SEM) to 28+/-3, 27+/-3, 17+/-1, and 18+/-2 mm Hg in control, 22 degrees C, 37 degrees C and 42.5 degrees C-heated hearts, respectively (37 degrees C and 42.5 degrees C: p < 0.05 versus controls and 22 degrees C). Slopes of pressure-volume curves featured similar patterns. Likewise, reperfusion dP/dT (mm Hg/s(-1)) was significantly lower in control and 22 degrees C hearts (1,119+/-114 and 1,076+/-125, respectively) than in those undergoing prestorage heating to 37 degrees C and 42.5 degrees C (1,545+/-109 and 1,719+/-111, p < 0.05 and p < 0.01 versus controls and 22 degrees C, respectively). Western blot analysis of LV samples did not demonstrate any upregulation of HSP 72 in either group. Conversely, the involvement of preconditioning was evidenced by the loss of protection in the 42.5 degrees C-heated hearts when, in 2 additional groups, the storage solution was supplemented with either the protein kinase C and tyrosine kinase inhibitors chelerythrine (5 micromol/L) and genistein (50 micromol/L) or the mitochondrial K(ATP) channel inhibitor 5-hydroxydecanoate (200 micromol/L). CONCLUSIONS: A brief period of postexplant ischemia with enhancement by topical heating ("backtable preconditioning") could be a simple and effective means of improving the functional recovery of heart transplants.

Animals↗
PubMed2001

The systemic factor: the comparative roles of cardiopulmonary bypass and off-pump surgery in the genesis of patient injury during and following cardiac surgery.

There is compelling evidence that off-pump coronary artery bypass operations are associated with reduced circulating levels of inflammatory mediators. Whereas complement activation and release of acute-phase reactants such as interleukin-6 are still expected to occur as consequences of a nonbypass-related general surgical trauma, a major feature of off-pump surgery seems to be a decreased production of interleukin-8, which may have important practical implications because of the participation of this cytokine in neutrophil trafficking and myocardial injury. The scarcity of carefully controlled, randomized trials precludes firm conclusions regarding the extent to which these biological changes translate into meaningful improvements in clinical outcomes. The problem is further complicated by the fact that the adverse effects of cardiopulmonary bypass largely depend on a genetically controlled balance between proinflammatory and antiinflammatory mediators. Currently, it is still impossible to predict, in a given patient, the side toward which this balance will be shifted. Nevertheless, accumulating experience identifies patient subgroups who may greatly benefit from avoiding extracorporeal circulation. These subsets include patients with severe extracardiac comorbidities (in particular, renal failure) and, possibly, patients with advanced left ventricular dysfunction, who may poorly tolerate superimposed, bypass-related, inflammatory tissue injuries.

Cardiopulmonary Bypass↗
PubMed2001

Pressure-adjusted antegrade brain perfusion for surgery of the aortic aneurysm.

Determining cerebral blood flow during circulatory arrest in patients undergoing surgery for aortic aneurysms has been traditionally based on body weight. We report the use of per-aortic antegrade cerebral perfusion regulated by perfusion pressure using a triple lumen cardioplegia catheter thus optimising cerebral flow.

Aortic Aneurysm, Thoracic↗
PubMed2001

Ischemic preconditioning with opening of mitochondrial adenosine triphosphate-sensitive potassium channels or Na/H exchange inhibition: which is the best protective strategy for heart transplants?

OBJECTIVE: This study was designed to compare ischemic preconditioning with opening of mitochondrial adenosine triphosphate-sensitive potassium channels and Na(+)/H(+) exchange inhibition in an isolated heart model of cold storage, simulating the situation of cardiac allografts. METHODS: Sixty-seven isolated isovolumic buffer-perfused rat hearts were arrested with and stored in Celsior solution (Imtix-Sangstat) at 4 degrees C for 4 hours before a 2-hour reperfusion. Group I hearts served as controls and were arrested with and stored in Celsior solution. In group II, hearts were preconditioned by two 5-minute episodes of global ischemia, each separated by 5 minutes of reperfusion before arrest with Celsior solution. Group III hearts were arrested with and stored in Celsior solution supplemented with 100 micromol/L of the mitochondrial adenosine triphosphate-sensitive potassium channel opener diazoxide. In group IV, hearts received an infusion of diazoxide (30 micromol/L) during the first 15 minutes of reperfusion. Group V hearts underwent a protocol combining both interventions used in groups III and IV. In group VI, hearts were arrested with and stored in Celsior solution supplemented with 1 micromol/L of the Na(+)/H(+) exchange inhibitor cariporide. Group VII hearts received an infusion of cariporide (1 micromol/L) during the first 15 minutes of reperfusion. In group VIII, hearts underwent a protocol combining both interventions used in groups VI and VII. Group IX hearts were ischemically preconditioned as in group II, and sustained Na(+)/H(+) exchange inhibition during both storage and early reperfusion was used as in group VIII. RESULTS: On the basis of comparisons of postischemic left ventricular contractility and diastolic function, coronary flow, total creatine kinase leakage, and myocardial water content, values indicative of improved protection were obtained by combining ischemic preconditioning with Na(+)/H(+) exchange inhibition by cariporide given during storage and initial reperfusion. The endothelium-dependent vasodilatory postischemic responses to 5-hydroxytryptamine or acetylcholine and endothelium-independent responses to papaverine were not affected by these interventions. CONCLUSIONS: These data suggest that cardioprotection conferred by the Na(+)/H(+) exchange inhibitor cariporide is additive to that of ischemic preconditioning and might effectively contribute to improve donor heart preservation during cardiac transplantation.

Adenosine Triphosphate↗
PubMed2001

Strategies to improve myocardial protection during extracorporeal circulation.

A recent survey of outcomes in 8,641 patients who underwent coronary artery bypass grafting (CABG) operations in northern New England indicates an overall mortality of 4.48%. (1) Importantly, 65% of all deaths could be directly attributed to postoperative heart failure. These data indicate that in spite of the dramatic improvements in myocardial protection that have been accomplished over the past decades, there is still room for improvement, in particular in high-risk patients who may poorly tolerate superimposition of perioperative ischemic damage on their underlying critical hemodynamic status. This paper reviews the major techniques in current clinical use with more emphasis on recent advances and possible perspectives. From a practical standpoint, a distinction can be made between strategies directly targeted at the myocardium and strategies that can indirectly enhance cardioprotection by attenuating the systemic inflammatory effects of cardiopulmonary bypass (CPB). These different approaches will thus be reviewed consecutively.

Cardiopulmonary Bypass↗
PubMed2000

Intramyocardial transplantation of autologous myoblasts: can tissue processing be optimized?

BACKGROUND: Autologous skeletal myoblast (SM) transplantation improves function of infarcted myocardium, but pretransplantation cultures remain a complex process. This study assessed whether it could be optimized by muscle preconditioning with the local anesthetic bupivacaine or even bypassed with the use of the so-called mince technique. METHODS AND RESULTS: Muscle preconditioning consisted of intramuscular injections of the tibialis anterior of rats, 2 days before harvest. After 7 days of culture, the number of available myoblasts was significantly increased compared with nonconditioned controls (1 683 147 versus 85 300, P:=0.0013). The mince technique was then assessed. A myocardial infarction was created in 66 rats by coronary artery ligation. One week later, rats were reoperated on and intramyocardially injected with culture medium alone (controls, n=23), autologous cultured SM (3.5 x 10(6), n=21), or autologous muscle minced into a fine slurry, which was immediately transplanted (n=22). All muscles had been preconditioned. Left ventricular function was assessed by 2D echocardiography. Whereas end-diastolic volumes expanded over time in all groups, left ventricular ejection fraction (%, mean+/-SEM) was increased only in the cultured SM-transplanted group at 1 (P:=0. 0006) and 2 months (P:=0.0008) versus baseline (37.52+/-1.92 and 40. 92+/-2.17 versus 30.34+/-1.74), with a significant additional benefit between 1 and 2 months (P:=0.0069). CONCLUSIONS: Cell culture remains mandatory for SM transplantation to be successful but, in a clinical perspective, this process can be made more expeditious by preharvest muscle conditioning with bupivacaine, which greatly enhances the baseline cell yield.

Animals↗
PubMed2000

Opening of mitochondrial potassium channels: a new target for graft preservation strategies?

BACKGROUND: This study was designed to assess the protective effects of the mitochondrial adenosine triphosphate-sensitive potassium channel (KATP) opener diazoxide as an additive to heart preservation solution. METHODS: Forty isolated isovolumic buffer-perfused rat hearts were divided into four groups. Groups I and III hearts were arrested with and cold-stored in Celsior solution for 4 hr and 10 hr, respectively. In Groups II and IV, hearts underwent a protocol similar to that used in Group I and III, respectively, except that Celsior was supplemented with 100 micromol/L of diazoxide. RESULTS: The protective effects of diazoxide were primarily manifest as a better preservation of diastolic function and a reduction of myocardial edema. The improvement of postischemic systolic function was observed only after prolonged exposure to diazoxide in Group IV, compared with Group III. The endothelium-dependent and endothelium-independent coronary flow postischemic responses were not affected by the supplementation of Celsior with diazoxide. CONCLUSIONS: Pharmacologic activation of mitochondrial KATP channels seems to be an effective means of improving preservation of cold-stored hearts, which is consistent with the presumed role of these channels as end effectors of the cardioprotective preconditioning pathway.

Analysis of Variance↗
PubMed2000

Is adenosine preconditioning truly cardioprotective in coronary artery bypass surgery?

BACKGROUND: The large number of experimental studies showing that adenosine "turns on" the protein kinase C (PKC)-mediated pathway that accounts for the cardioprotection conferred by ischemic preconditioning contrasts with the scarcity of clinical data documenting the preconditioning-like protective effect of adenosine during cardiac operations on humans. METHODS: Forty-five patients undergoing coronary artery bypass were randomized to receive, after the onset of cardiopulmonary bypass, a 5-minute infusion of adenosine (140 microg x kg(-1) x min(-1)) followed by 10 minutes of washout before cardioplegic arrest (n = 23) or an equivalent period (15 minutes) of prearrest drug-free bypass (controls, n = 22). Outcome measurements included troponin I release over the first 48 postoperative hours and activity of ecto-5'-nucleotidase, an admitted reporter of PKC activation, as assessed on right atrial biopsies taken before bypass and at the end of the preconditioning protocol (or after 15 minutes of bypass in control patients). RESULTS: Aortic cross-clamping times were not different between the two groups. Likewise, prebypass values of ecto-5'-nucleotidase (nanomoles/mg protein per minute) were similar in control (3.14+/-1.02) and adenosine-treated (2.66+/-1.08) patients. They subsequently remained unchanged in control patients (3.87+/-1.65) whereas they significantly increased after adenosine preconditioning (4.47+/-1.96, p<0.001 versus base line values). However, peak postoperative values of troponin I (microg/L) were not significantly different between control (4.8+/-2.8) and adenosine-preconditioned patients (5.9+/-6.6) nor were the areas under the curve. There were no adverse effects related to adenosine. CONCLUSIONS: Adenosine, given at a clinically safe dose, can turn on the PKC-mediated signaling pathway involved in preconditioning but this biochemical event does not translate into reduced cell necrosis after coronary artery surgery, suggesting that a preconditioning-like protocol may not be the best suited for exploiting the otherwise well-documented cardioprotective effetcs of adenosine.

Adenosine↗
PubMed2000

Comparison of the effects of fetal cardiomyocyte and skeletal myoblast transplantation on postinfarction left ventricular function.

OBJECTIVES: Transplantation of fetal cardiomyocytes improves function of infarcted myocardium but raises availability, immunologic, and ethical issues that justify the investigation of alternate cell types, among which skeletal myoblasts are attractive candidates. METHODS: Myocardial infarction was created in rats by means of coronary artery ligation. One week later, the animals were reoperated on and intramyocardially injected with culture growth medium alone (controls, n = 15), fetal cardiomyocytes (5 x 10(6) cells, n = 11), or neonatal skeletal myoblasts (5 x 10(6) cells, n = 16). The injections consisted of a 150-microL volume and were made in the core of the infarct, and the animals were immunosuppressed. Left ventricular function was assessed by echocardiography immediately before transplantation and 1 month thereafter. Myoblast-transplanted hearts were then immunohistologically processed for the expression of skeletal muscle-specific embryonic myosin heavy chain and cardiac-specific connexin 43. RESULTS: The left ventricular ejection fraction markedly increased in the fetal and myoblast groups from 39.3% +/- 3.9% to 45% +/- 3.4% (P =.086) and from 40.4% +/- 3.6% to 47.3% +/- 4.4% (P =.034), respectively, whereas it decreased in untreated animals from 40.6% +/- 4% to 36.7% +/- 2.7%. Transplanted myoblasts could be identified in all animals by the positive staining for skeletal muscle myosin. Conversely, clusters of connexin 43 were not observed on these skeletal muscle cells. CONCLUSIONS: These results support the hypothesis that skeletal myoblasts are as effective as fetal cardiomyocytes for improving postinfarction left ventricular function. The clinical relevance of these findings is based on the possibility for skeletal myoblasts to be harvested from the patient himself.

Animals↗