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Ann Thorac Surg 2001;71:844-851
© 2001 The Society of Thoracic Surgeons
a Department of Cardiovascular Surgery, Hôpital Bichat, Paris, France
b INSERM U523, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtriére, Paris, France
c Department of Cardiology, Hôpital Boucicaut, Paris, France
Address reprint requests to Dr Menasché, Service de Chirurgie Cardiovasculaire B, Groupe Hospitalier Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris Cedex 18, France
e-mail: ccv-bloc.sec3{at}bch.ap-hop-paris.fr
Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.
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Abstract |
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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 106, 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.
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Introduction |
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Previous experimental studies have documented the efficacy of contractile cell transplantation in improving function of infarcted myocardium. Initial studies using fetal cardiomyocytes [3] and newborn skeletal myoblast [4] grafts have demonstrated an equivalent efficacy in restoring myocardial function of ischemically damaged hearts. However, in the prospect of a clinical application, autologous adult skeletal myoblast transplantation seems to be more relevant, in that it avoids immunosuppressive therapy, availability, and ethical issues. In this perspective, using a rabbit model of cryonecrosis, Taylor and coworkers [5] have shown the favorable impact of autologous skeletal myoblasts in terms of functional efficacy after intramyocardial delivery.
Nevertheless, factors that may influence the functional outcome of cell-transplanted hearts has not yet been determined. The purpose of this study was, therefore, to assess two of these factors, which are of particular clinical relevance. The first objective was to investigate the effect of the initial degree of functional impairment of infarcted myocardium. The second objective was to evaluate the effect of the number of injected myoblasts.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsCommentDiscussionReferences |
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Myocardial infarction model
Male Wistar rats, weighing 280 g, were anesthetized with ketamine (50 mg/kg, intraperitoneally) and xylazine (10 mg/kg, intraperitoneally) and tracheally ventilated. They underwent a left lateral thoracotomy and after exposure of the heart, the myocardial infarction was created by ligation of the left coronary artery with a 7-0 polypropylene snare (Ethicon, Inc, Somerville, NJ).
Functional assessment
One week after myocardial infarction, and 1 and 2 months after transplantation, left ventricular function was studied by two-dimensional echocardiography.
Under general anesthesia with ketamine (50 mg/kg, intraperitoneally) and xylazine (10 mg/kg, intraperitoneally), the chest were shaved and a layer of accoustic coupling gel was applied to the thorax. Two-dimensional (and M-mode) measurements were performed with a commercially available 15 MHz (15L8) linear-array transducer system (Sequoia, Acuson Corp, Mountain View, CA) allowing a 160-Hz maximal frame rate. Parasternal long-axis views were obtained, making sure that the mitral and aortic valves and the apex were well visualized, and were then recorded.
Measurements of maximal left ventricular (LV) long-axis lengths (L) and endocardial area tracings (a), using the leading edge method [6], were performed from digital images captured on cine loops. Left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV) were calculated using the single plane area–length method [7]: 
. Left ventricular ejection fractions (LVEF) were then computed from the formula: 
. All measurements were made from at least three beats and involved two investigators who were blinded to the treatment group.
Cell culture methodology
During the myocardial infarction procedure, the right and left tibialis anterior muscles were dissected and harvested to remove the tendon and the aponeurotic tissue from the muscle tissue. Then, they were minced, weighed, and enzymatically dissociated using collagenase IA (2 mg/mL; Sigma Chemical Co, St. Louis, MO) for 1 hour and also trypsin-EDTA (0.25%, GIBCO BRL, Gaithersburg, MD) for 20 minutes.
The cells were collected by sedimentation (7 minutes at 1,200 rpm) and the enzyme reaction was arrested by adding 10% fetal bovine serum (HyClone Laboratories, Logan, UT). After passage through a 100-µm sieve (Cell Strainer Nylon; Becton Dickinson, Franklin Lakes, NJ) and centrifugation, the supernatant was discarded and the cells were resuspended in the culture medium composed of F12(HAM) with 20% fetal bovine serum (vol/vol), 1% (vol/vol) penicillin–streptomycin (10,000 UI/mL to 10,000 µg/mL; GIBCO BRL), and 5 ng/mL basic fibroblast growth factor (Sigma Chemical Co.). Initial plating was realized in 75-cm2 tissue culture flasks (Falcon; Becton Dickinson) and cells were grown in humid air with 5% CO2.
The day of the transplantation, at the end of the 7-day culture process and after echocardiographic baseline functional evaluation had been performed, the cells were harvested by trypsinization, washed, and the viability was assessed using trypan blue (0.4% GIBCO BRL). A sample was plated onto 12-well dishes in 0.2 mL of culture medium to be counted (see technique infra). The cells were washed in the injection medium (culture medium + 0.5% bovine serum albumin, Fraction V; Sigma Chemical Co) and kept on ice before transplantation. The cells were then pelleted, suspended in 150 µL of injection medium, and delivered intramyocardially into the infarcted area.
Experimental groups
Forty-four rats were included in the study. All were reoperated at 1 week after myocardial infarction, under general anesthesia and tracheal ventilation, through an inferior midline ministernotomy. All rats received 150 µL of injection medium delivered to the infarcted area by means of a 30-gauge needle. In the control group (n = 23), the rats received the injection medium alone. The myoblast group (n = 21) was injected with the myogenic cultured cell suspension. A flow chart of the protocol is depicted in Figure 1.
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Immunochemical and histochemical studies
The day after transplantation, the cells plated on the 12-well dishes were fixed in methanol cooled at -20°C for 5 minutes. Nonspecific labeling was neutralized using a mixture of 5% horse serum and 5% fetal bovine serum in phosphate-buffered saline solution for 20 minutes. The cells were incubated with desmin mouse antihuman antibody (1/200, DAKO AS, Glostrup, Denmark) for 1 hour and then with Cy3-conjugated antimouse antibody (1/200, Jackson Immuno Research Laboratories, Inc, West Grove, PA) for 1 hour in darkness.
The cells were studied under phase contrast and fluorescent illumination using an inverted microscope (Olympus Optical Co, LTD, Tokyo, Japan). Photographs of several fields were then taken randomly. The proportion of myoblasts was calculated by dividing the number of desmin-positive cells counted on immunofluorescent pictures by the total number of cells counted on phase contrast pictures.
Within 3 days of the last echocardiography (ie, 2 months after transplantation), hearts were harvested from rats sacrificed with an overdose of ketamine and xylazine. The ventricles were isolated by trimming away the atria and the valves and were cross-sectioned at the midpoint of the long axis. Both parts were frozen in isopentane cooled with nitrogen. Eight-micrometer-thick sections were prepared using a cryostat and standard histologic studies were carried out with hematoxylin and eosin staining. For immunohistologic studies, the slides were rinsed in phosphate-buffered saline, fixed with cold methanol for 5 minutes, and the nonspecific labeling was neutralized using the blocking serum. They were incubated with the primary antibody for 1 hour and, after several washes, with the Cy3-conjugated immunoglobulin antibodies. The slides were mounted in phosphate-buffered saline/glycerol (1:1). The transplanted myoblasts were detected with the mouse monoclonal antibody directed against the embryonic myosin heavy chain (pure, kind gift of Dr Gillian Buttler-Browne, Paris, France) or against the fast skeletal myosin heavy chain (1:400, clone My 32, Sigma Chemical Co). The cardiac tissue was localized using the mouse monoclonal antibody directed against the rat cardiac 
-myosin heavy chain (1:1000, clone BA-G5, kind gift of Dr Schiaffino, Padua, Italy).
Statistical analysis
All data are reported as mean ± 1 SEM. All analyses were performed with an appropriate software (StatView 5.0; SAS Institute Inc, Cary, NC). The critical -level for these analysis was set at p less than 0.05.
Comparisons of continuous variables among control and myoblast groups and within each risk category were studied by one-way analysis of variance followed by a post hoc test (Scheffé). Longitudinal studies comparing echocardiographic data within each group, before, 1 and 2 months after intramyocardial injections, were achieved using paired t tests.
To assess the strength of the relationships between the number of injected myoblasts and cardiac function after transplantation, two variables have been created: 1-month LVEF/baseline LVEF and 2-month LVEF/baseline LVEF. The link was studied by calculation of the F ratio for analysis of variance regression and the adjusted R2 determination coefficient for linear regression analyses.
In addition, intraobserver variability in echocardiographic assessment was assessed from two sets of baseline measurements in 10 randomly selected rats using a Bland and Altman analysis [8].
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Results |
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Functional assessment
Baseline echocardiographic measurements were not significantly different between the two groups (32.6 ± 1.8 in controls and 30.3 ± 1.7 in the myoblast group, p = 0.087). In contrast, when results were analyzed as a whole, the patterns of changes after transplantation were markedly divergent. Thus, in the myoblast group, heart function improved, as assessed by LVEF, whereas a dramatic decrease was noticed in the control group (Fig 2).
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-myosin heavy chain were surrounding the scar tissue (Fig 7).
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Comment |
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Left ventricular functional assessment was performed in vivo by two-dimensional echocardiography using a numeric machine allowing to record more than 20 heart scans at a rate of 400 beats per minute. Rat ventricular geometry has been previously studied [9] and postmortem examination findings have demonstrated the elliptical shape of rat ventricles. Because ventricular remodeling after myocardial infarction is a heterogeneous process, left ventricular geometry and function have been previously validated in the coronary artery ligation model of myocardial infarction in the rat [10]. In the present study, we used the single plane area–length method because two-dimensional measurements are more appropriate than those performed in the M-mode. Indeed, it is recognized that the most accurate way to calculate left ventricular volume in an asymmetric chamber is to use the Simpson’s rule as shown in human infarcted hearts [7]. The single plane model for volume calculation was chosen in preference to the biplane method, which has not been yet validated in rat myocardial infarction and is difficult to perform because of ventricular remodeling and heterogeneous cavity dilation after large anterior infarction. Because of its technical characteristics, the 15-MHz transducer used in this study allowed precise identification of end-systolic and end-diastolic frames on two-dimensional echocardiograms, which fully justifies our volume estimation based on the elliptical model.
In a previous study [11], we have shown that intramyocardially transplanted allogeneic newborn skeletal myoblasts were as effective as fetal cardiomyocytes in improving postinfarct left ventricular function. Not unexpectedly, the present data demonstrate that this improvement is also seen with autologous adult myoblasts, which obviously strengthens the clinical applicability of the procedure because of the potential of using these cells as autografts. The present data also extend the functional benefits of skeletal myoblast transplantation previously established by Taylor and associates [5] in a rabbit model of cryonecrosis to the more clinically relevant infarct model of coronary artery ligation. The mechanism of the improvement afforded by skeletal myoblasts remains, however, elusive. A first hypothesis is that they may limit infarct expansion owing to their elastic properties. This possibility is supported by recent data of Atkins and coworkers [12] showing that the primary effect of autologous skeletal myoblast transplantation after cryoinjury is to improve diastolic function, with an additional beneficial effect on systolic performance being seen only in hearts that demonstrate the greatest degree of cellular engraftment. In contrast, the findings of the present study show that the extent of postinfarct left ventricular remodeling was not different between control and transplanted hearts. These divergent results might be from differences in infarct models or methods used for assessing left ventricular function. Indeed, the improvement in ejection fraction seen in our myoblast-injected groups was found to be related to a decrease in end-systolic left ventricular volumes, thereby raising the possibility of a direct synchronous contribution of the grafted myoblasts to heart contractility. Theoretically, this would require that transplanted cells have established some form of functional coupling with the host cardiomyocytes. However, although Chiu and co-workers [13] have postulated that intramyocardially injected myoblasts could undergo a milieu-induced differentiation that would make them look like cardiac cells, previously we [14] failed to show a positive staining for connexin-43, a marker of cardiac-specific gap junctions, between grafted skeletal myoblasts and the surrounding cardiomyocytes of the host myocardium. Again, in the present study, we were unable to identify these junctions. Nevertheless, this may not necessarily exclude an inotropic involvement of the grafted cells if one assumes that they are mechanically stimulated by the surrounding host cardiomyocytes. A last mechanism whereby transplanted myoblasts could improve function is the stimulation of angiogenesis by locally released growth factors. Studies are underway in our laboratory to address this issue.
In a clinical perspective, it is important to evaluate to what extent the residual postinfarct left ventricular function affects the ultimate functional outcome after myoblast transplantation and whether the procedure may benefit patients with the most severely depressed ejection fractions. A well-known feature of the rat model of coronary artery ligation is that even when the vessel is consistently occluded at the same site (which was the case in this study), the resulting infarct may vary in size, which, in turn, is reflected by a scattering of the postinfarct ejection fractions. We took advantage of this heterogeneity to stratify transplanted rats into four risk groups so as to yield fairly comparable sample sizes. Not unexpectedly, rats with relatively small infarcts and consequently well-preserved ventricular functions (LVEF > 40%) did not improve further at 1 and 2 months after myoblast transplantation. Those hearts that were in the two intermediate risk categories (25% to 35% and 35% to 40%) were found to have significantly increased ejection fractions compared to baseline at the 1-month study point and this improvement was then sustained over time with ejection fraction values plateauing between 1 and 2 months. In contrast, the sickest hearts (LVEF < 25%) had not increased their ejection fraction at 1 month after myoblast injections and it was not until the second month that a significant improvement in function could be readily demonstrated. These findings suggest that patients with severely compromised left ventricular functions, who may not be amenable to a conventional heart transplantation might benefit from autologous skeletal myoblast injections, but that the functional improvement is likely to be delayed. Alternatively, it is conceivable that this improvement could occur earlier if these hearts are initially grafted with a greater number of cells.
An important finding of this study is that the functional outcome after tansplantation was linearly related to the number of injected myoblasts, both in the whole set of transplanted hearts and within each risk group. For sake of standardizing the protocol, this study was designed so that a fixed time interval elapsed between muscle harvest and the subsequent intramyocardial reimplantation of cells. This time point was set at 7 days after the infarct. By that time, the remodeling process from infarct healing is still under way, whereas the acute inflammatory response induced by coronary artery ligation, in this rat model, is terminated. Pfeffer and colleagues [15] have described the different postinfarct phases. The resolution of the acute inflammatory response is achieved within 2 days after coronary artery ligation. During the late postinfarct period, the formation of the scar tissue is achieved at day 26, and day 7 is considered as the beginning of this late postinfarct phase. Consequently, this time frame dictated the duration of in vitro cell expansion. Because the baseline cell yield and the kinetics of the in vitro expansion vary from one biopsy to the other, different amounts of myoblasts (from 700,000 to 6.5 x 106) were injected in the experimental animals in this fixed period of cell culture, thereby allowing us to study a dose–response relationship. The general conclusion that the greater the number of transplanted cells, the greater the functional benefits, is not unexpected in view of the previous clinical studies of myoblast transplantation in patients with Duchenne’s myopathy [14]. These reports have emphasized that this procedure triggers intense inflammatory and immune responses that cause the rapid death of a high proportion of the injected myoblasts. Assuming that the use of autologous cells eliminates the immune component of this attrition process, an inflammatory reaction is still likely to occur and it is sound to postulate that its destructive effects can only be overwhelmed by supplying large numbers of donor cells, even if the ideal number remains to be defined and still requires thorough dose–response studies. From a mechanistic standpoint, these findings provide additional evidence that the improvement of function after transplantation is truly from the presence of cells. This observation is important in view of recent experimental studies that have assessed the consequences of transmyocardial laser revascularization and concluded that mechanical punctures [16], by themselves, could induce an inflammatory reaction with angiogenesis potentially responsible for the purported clinical benefits of the laser procedure [17, 18]. Such a mechanism can be ruled out in the present study as no improvement of function was seen in control hearts that were subjected to injection-related mechanical injuries similar to those of transplanted hearts. These findings are actually consistent with those of Taylor and coworkers [5], who could only document a functional benefit after transplantation in the cryoinjured rabbit hearts where grafted cells were identified. Thus, the development of scale-up expansion techniques appears mandatory for the clinical implementation of intramyocardial myoblast transplantation to be successful.
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Discussion |
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DR POUZET: Between controls and transplantation?
DR FULLERTON: Or smooth muscle cells or myocytes.
DR POUZET: You mean the functional reasons?
DR FULLERTON: Yes.
DR POUZET: Probably the mechanisms involved are not unique but could likely include an increasing contractile effect of transplanted myoblasts as we have demonstrated, I hope, in this study. But previous studies of our group have also explained these effects by the elastic properties of the cells, which may limit the scar expansion, or the release of angiogenic and growth factors, which may induce neovascularization, thus also improving function.
DR FULLERTON: Does the phenotype of the cells change after it has been transplanted into the heart?
DR POUZET: In this set of experiments we did not use the multiple labeling, but in another set of experiments we used embryonic myosin heavy chain, ß-galactosidase and ß-myosin heavy chain labeling, and we were able to demonstrate that there was a graft conversion into slow twitch fibers attested by the presence of ß-myosin heavy chain, which is a hallmark of slow fiber phenotype, and thus this was consistent with possibly synchronous beating with the host myocardium.
DR RICHARD D. WEISEL (Toronto, Ontario, Canada): Perhaps, I could respond as well. Endothelial cell transplantation resulted in a tremendous angiogenic response but heart function was not improved. Fibroblast transplantation prevented the heart from expanding but did not improve function. Therefore, we would agree 100% with the concept that contractile elements are necessary to prevent thinning and dilatation. Contraction may not be necessary but the elasticity of the muscle cells is necessary to improve heart function. Do you agree?
DR MENASCHÉ: Yes.
DR AXEL HAVERICH (Hannover, Germany): On your histology did you find any intercalated disks between the transplanted cells and the natural muscle?
DR POUZET: No, actually we did not find intercalated disks. We performed labeling with connexin 43, which is a marker of gap junctions in the intercalated disks, and we were not able to demonstrate a connection between host myocardium and transplanted cells. But these results, which may look discrepant, are actually investigated by further studies.
DR MENASCHÉ: If I can just briefly follow up on Dr Pouzet’s comments, we have been very concerned about the connections between the injected cells and the host cardiomyocytes, and it turns out that every time you inject skeletal myoblasts, you definitely fail to see these connections. Now, on the other hand, previous studies from various groups, including ours, have shown that if you inject fetal cardiomyocytes, you get the connections between the graft itself and the host myocardium. Nevertheless, in spite of the fact that some cells establish connections and others do not, from a functional standpoint the results are equivalent. So we are not so sure that in contrast to the initial hypothesis, it is absolutely necessary that the graft itself establishes connections for functional improvement to occur. So the fact that there are no connections between the myoblasts and the other cells, at least connections that were identified, does not necessarily preclude that function can improve.
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