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Ann Thorac Surg 2002;74:25-30
© 2002 The Society of Thoracic Surgeons

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Original article: cardiovascular

Cardiomyocyte transplantation does not reverse cardiac remodeling in rats with chronic myocardial infarction

^a Department of Cardiovascular Surgery, Kyoto University, Graduate School of Medicine, Kyoto, Japan
^b Department of Internal Medicine, National Cardiovascular Center, Suita, Osaka, Japan

Accepted for publication March 12, 2002.

* Address reprint requests to Dr Komeda, Graduate School of Medicine, Department of Cardiovascular Surgery, Kyoto University, 54 Kawaharacho Shogoin Sakyo-ku, Kyoto, Japan, 606-8507
e-mail: masakom{at}kuhp.kyoto-u.ac.jp

	Abstract

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Background. Several reports have documented the potential benefits of cell transplantation as an alternative to cardiac transplantation. This study was designed to investigate whether cardiomyocyte transplantation is effective in rats with chronic myocardial infarction.

Methods. Syngeneic Lewis rats were used in this study. Chronic myocardial infarction was induced in rats by ligating the left anterior descending artery. Four weeks later, after left ventricular (LV) dysfunction with akinetic regions was confirmed by echocardiography, the rats were randomized into two groups: a group that received fetal cardiomyocyte transplantation (TX group; n = 11); and a group that received an intramyocardial injection of culture medium only (control group; n = 12).

Results. Four weeks after treatment, the TX group had smaller end-systolic dimension (LVDs) (7.5 ± 0.9 vs 8.9 ± 0.8 mm, p < 0.01) and better fractional shortening (FS) (26.2 ± 5.9 vs 17.7% ± 5.1%, p < 0.01) than the control group. However, there were no differences in LV end-diastolic dimension, LVDs, and FS between baseline and post-treatment values in the TX group. In addition, plasma levels of atrial natriuretic peptide were not significantly different between the two groups 4 weeks after treatment. In microscopic examination, small amounts of transplanted cardiomyocytes were found only in the periinfarct area, not in the center of scar area, and a thicker ventricular wall in the infract area was detected in the TX group.

Conclusions. Fetal cardiomyocyte transplantation prevented, but did not reverse, cardiac remodeling that was accompanied with heart failure in myocardial infarction rats. Further investigation is warranted for optimal clinical application to the failing heart.

	Introduction

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Cardiac transplantation is a definitive therapy for the majority of patients with end-stage heart failure. However, because of the shortage of donor hearts, only a small percentage of patients can receive the transplants, and many patients die without them. To overcome the problem, several treatment alternatives to cardiac transplantation have been advocated.

Cell transplantation is one treatment that does not require donor organs and that can be applied without external energy source or mechanical devices. Mature cardiomyocytes, however, have a very limited ability to proliferate, and the myocardium has no myogenic stem cells capable of regenerating lost cardiomyocytes. Therefore, many efforts have been made to find cells that have the abilities not only to proliferate in the left ventricular (LV) wall, but also to work there and to enhance LV motion. Recently, several studies have documented the feasibility of cell transplantation for failing hearts. Although some reported that the beneficial effect of cell transplantation was limited to attenuation of progressive LV remodeling [1], other researchers demonstrated an improvement of LV function by cell transplantation after myocardial infarction [2–5]. However, most of these intriguing studies have been based on LV injury models, which are not necessarily clinically relevant (eg, cryoinjury to the left ventricle) or which have evaluated cardiac function in an ex vivo fashion such as a Langendorff perfusion model [2–4]. They did not clearly reveal the global cardiac function in vivo.

To assess the efficacy and feasibility of cell transplantation in a more clinically relevant model, in this study we used a chronic animal model with myocardial infarction caused by ligation of the left anterior descending artery (LAD). We also evaluated LV function using an in vivo method and measured ANP as an indicator of general cardiac condition.

	Material and methods

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Experimental animals
Syngeneic Lewis rats were used in this study. The study protocol was approved by the ethics committee for animal research of Kyoto University. All animals received humane care in compliance with the "Principles of Laboratory Animal Care" formulated by the National Society for Medical Research and the "Guide for the Care and Use of Laboratory Animals" prepared by the Institute of Laboratory Animal Resources, National Research Council and published by the National Academy Press.

Cell isolation and culture procedures
Ventricular cardiomyocytes were isolated from fetal rat hearts and cultured as previously described [6]. In brief, 20-day-old embryo hearts were removed and washed in phosphate-buffered saline (PBS) solution. The ventricles were minced and incubated in PBS solution containing trypsin (0.25%), collagenase (0.05%), and glucose (0.02%) at 37°C for 15 minutes. The cell suspension was transferred into culture medium supplemented with 10% fetal bovine serum, 100 U/mL of penicillin, and 100 µg/mL of streptomycin. Iscove’s modified Dulbecco’s medium (Gibco Laboratory, Life Technologies, Grand Island, NY) containing 0.1 mmol/L ß-mercaptoethanol was used as culture medium. Then the cells were cultured for 2 to 3 days. All cells were labeled using PKH 26 dye for general cell membrane labeling before transplantation. In advance, the purity of the cardiomyocytes in culture was evaluated by immunofluorescent staining with a monoclonal antibody against -sarcomeric muscle actin (DAKO A/S, Glostrup, Denmark).

Chronic myocardial infarction model
Male rats weighing 250 to 290 g were orally intubated after being anesthetized with ethyl ether gas. Anesthesia was maintained during the operation with 1% to 1.5% isoflurane. The LAD was proximally ligated with a 5-0 polypropylene suture [7, 8]. The ST elevations on electrocardiography and color changes in the left ventricular muscle were noted in all rats.

Experimental groups and protocol
Four weeks after LAD ligation, infarction size and cardiac function were evaluated by echocardiography [9, 10]. A total of 24 rats with moderate myocardial infarction were selected for this study. These rats were randomized into two groups: 12 rats received fetal cardiomyocyte transplantation (TX group), and the other 12 rats received an intramyocardial injection of serum free culture medium only (control group). Figure 1 illustrates the study protocol, including the operations and sampling points in both groups. Cardiac function in the study groups was compared with that in rats of the same age without LAD ligation (normal group).

View larger version (10K): [in this window] [in a new window]   Fig 1. Experimental protocol. (Blood sample = measurement of atrial natriuretic peptide in plasma;Cath. = measurement of left ventricular pressure and volume using a micromanometer-tipped catheter; Echo = echocardiography; LAD = left anterior descending artery;Treatment = culture medium injection or fetal cardiomyocyte transplantation.)

Assessment of the left ventricular function
Left ventricular function was assessed by echocardiography with a 10- to 12-MHz phased-array transducer (model 21380A with HP SONOS 5500 imaging system, Agilent Technologies, Andover, MA). Rats were anesthetized with 0.5% isoflurane during the assessment. Images were recorded from the left parasternal windows in the right lateral decubitus position. The following variables were derived from the M-mode tracing: LV end-diastolic dimension (LVDd; mm), LV end-systolic dimension (LVDs; mm), fractional shortening (FS; %), fractional area change (FAC; %) [11]. Infarction size was estimated by the percentage of the akinetic region divided by the LV endocardial circumference on a midventricular short axis view at end-diastole [12–14]. One day after the final echocardiographical evaluation, all rats had more precise assessment of global LV function before sacrifice. A 2F micromanometer-tipped catheter (Millar Instruments Inc, Houston, TX) was inserted into the LV through the right carotid artery, and a 3F occlusion balloon catheter for occluding the inferior vena cava (IVC) was inserted into the IVC through the right iliac vein. Two-dimensional echocardiography was also performed to determine the LVDd and LVDs. During caval occlusion, LV pressure and echocardiographic imagings were recorded simultaneously. Then, the LV maximum time-varying elastance (LV E_max; mm Hg/µL) and the time constant of isovolumic relaxation (; ms, = LV pressure at peak negative/-dp/dt) were calculated as an index of global systolic and diastolic function, respectively. Left ventricular end-diastolic pressure (LVEDP; mm Hg) was measured at the same time [9, 10].

Histologic study
After the final evaluation, all rats were sacrificed for histologic study. In each experimental group, half of the rat hearts were fixed with 10% formalin and stained with hematoxylin and eosin. The other half were cryopreserved and stained with PKH 26 red fluorescent dye to identify the transplanted cells. In each sample, the wall thickness was measured at three points in the infarct area and the values averaged.

Hormonal study
In all of the study rats (TX and control groups), 1 mL of blood was taken through the jugular vein for sampling before LAD ligation and 4 weeks after the second operation. In the 10 normal rats, the same volume of blood was collected for comparison. Plasma levels of ANP were measured with enzyme immunoassay using a high-sensitivity kit (EIAH9103, Peninsula Laboratories Inc, San Carlos, CA) and compared between the two points.

Statistical analysis
All values were shown as the mean value ± SD. Differences between echocardiographic measurements before and after transplantation were evaluated by paired t test (StatView; SAS Institute Inc, Cary, NC). Differences between the control and TX groups were compared by unpaired t test. Values of p less than 0.05 were considered to be statistically significant.

	Results

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Coronary artery ligation was performed fully in 40 rats; of these, 8 died within 1 week. Four weeks later, echocardiography was performed in the survivors. Among them, 3 had either no or small myocardial infarction (infarct size: < 20% [14]), and 5 had a large one (infarct size: > 40% [14]). The rats with moderate myocardial infarction (infarct size 20% to 40% [14]) in the anterior LV wall (n = 24) were enrolled in this study. One rat in the TX group died immediately after the second operation. The data from the 23 rats that survived the operations were used for analysis.

Purity and labeling of cultured fetal cardiomyocytes
The purity of the cultured cardiomyocytes derived from fetal rat heart, defined as the ratio of the cells with positive immunohistochemical staining for -sarcomeric muscle actin, was more than 95.8% ± 3.1% (n = 6) just before transplantation. The efficiency of labeling with PKH26 dye was almost 100% (n = 2).

Echocardiographical functional study
Table 1 summarizes the echocardiographic data in the study groups 4 weeks after LAD ligation. Compared with values in normal rats, the LVDd and LVDs increased and the FS and FAC decreased in both groups. No differences in any variables were observed between the control and TX groups before treatment. The infarction size varied from 20% to 36%. Four weeks after treatment, the TX group had significantly smaller LVDs and better FS and FAC than the control group. The LVDd in the TX group was smaller than in the control group, but the difference did not reach statistical significance. However, there were no significant changes in any variables between the values at base line and posttreatment in the TX group. In the control group, there were small increases in LVDd and LVDs and small decreases in FS and FAC, (Table 1, Fig 2 A through D), although these changes were not significant.

View larger version (31K): [in this window] [in a new window]   Fig 2. (A through D) Results of cardiac function by echocardiography between fetal cardiomyocyte transplantation (TX) and control groups before and after treatment. There were no significant differences in each group before versus after treatment. The TX group had smaller left ventricular (LV) end-systolic dimension and higher fractional shortening and fractional area change. (E) Scar thickness. The ventricular wall in infarct area was thicker in the TX group. (F) Plasma levels of atrial natriuretic peptide (ANP; pg/mL) between the two groups before and after treatment. No significant differences were shown before versus after treatment in each group, or between the groups in each time point. (NS = not significant.)

Histologic study
Severe myocardial necrosis and fibrosis were noted in the LV anterior wall. The infarct LV wall was very thin compared with the noninfarct area. Four weeks after the second operation, transplanted cardiomyocytes were detected in all host hearts, and cardiomyocytes labeled by PKH 26 red fluorescent dye were detected in all samples (Fig 3). Most of the transplanted cells were either in or near the periinfarct region, not in the center of the scar in the TX group. In the TX group, a small amount of transplanted cardiomyocytes made an island formation in the periinfact area around the infarct. The typical myofibril seen in the normal myocardium was not found in those islands (Fig 3). Compared with the control group, more progressive fibrosis, some of which was labeled by PKH dye, were found in the infarct area. The wall thickness in the infarct was then significantly thicker in the TX group (control vs TX, 0.67 ± 0.065 vs 0.86 ± 0.14 mm, p < 0.01) (Fig 2E).

View larger version (96K): [in this window] [in a new window]   Fig 3. Photomicrographs of transplanted fetal cardiomyocytes in the periinfarct area of the left venticular free wall in the transplantation group 4 weeks after the second operation (magnification: A, x40; B, x200), and transplanted cardiomyocytes labeled by PKH26 red fluorescent dye (magnification: C, x40; D, x100). Panel B is enlargement of inset in A; panel D is enlargement of inset in C.

	Comment

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The present model, in which myocardial infarction was created by the proximal LAD ligation, simulated a clinical setting of chronic heart failure with infarction. Although echocardiography was technically demanding in this study because of the small animal model, modern echocardiographic technology (eg, high-frequency transducers) enabled us to precisely measure the LV geometry in rats. We also conducted a more sophisticated and precise method to measure LV function by simultaneous recordings of instantaneous LV pressure and volume. Moreover, we measured plasma levels of ANP, which have been demonstrated to reflect well a general condition of left ventricular function because they are localized in secretory granules of the atria and are released into the circulation as a result of atrial distension in left ventricular failure. These physiologic evaluations in vivo were clinically relevant and reproducible.

Cell transplantation has been examined by many study groups as a potential treatment to repair damaged hearts [1–5, 15–17]. Li and coworkers [2, 6] have shown that fetal cardiomyocyte transplantation improved cardiac function in myocardial infarction rats produced by cryoinjury. Scorsin and associates [5] have also shown by echocardiographical assessment that fetal cardiomyocytes improved cardiac function in rats after acute myocardial infarction. Etzion and colleagues [1] have demonstrated that fetal cardiomyocyte transplantation has not reversed remodeling and not improved cardiac function compared with base line study and control animals. In our results, there were some significant differences in LV systolic functions between the control and TX groups 4 weeks after treatment. However, there were no significant differences in LV diastolic and systolic functions before versus after treatment in both groups. Moreover, although LV E_max in the TX group was higher than that in the control group, the value was too low compared with that of normal rats. These data indicated that cardiomyocyte trasplantation only inhibited the progress of cardiac remodeling in chronic myocardial infarction and did not improve cardiac function significantly. This finding was consistent with the ANP levels that were increased in both groups and not significantly different between both groups after treatment. In this point of view, our results compared favorably with Etzion’s report [1]. In our results, we found the trend of improvement in systolic function in the TX group, which was not shown in their report. This discrepancy may have been caused by the timing of cell transplantation. Although they performed it 1 week after coronary occlusion when cardiac remodeling was still progressive, we performed it 4 weeks after LAD ligation when infarction area was stable. Generally speaking, there is supposed to be more progressive remodeling in the hearts 1 week after the onset of myocardial infarction compared with those 4 weeks after. Therefore, such circumstances might have been disadvantageous for the survival of transplanted cardiomyocytes in their model.

Histologically, transplanted cells failed to replace the akinetic wall, and only small amounts of transplanted cardiomyocytes were observed in or around the peri-infarct area, not in the center of scar area remote from viable myocardium tissue. However, the ventricular wall of infarct area was thicker in the TX group. This response after transplantation may have been due to growth factors secreted from transplanted cells. In addition, some of the fibrosis consisted of transplanted fibroblasts, because the labeled cells by PKH dye were identified.

Whether or not the transplanted cells are continuously viable in the scar tissue has been controversial. Reinecke and coworkers documented that grafted fetal cardiomyocytes survived and proliferated in the impaired myocardium as well as in the normal myocardium [18]. On the contrary, Scorsin and colleagues reported that no transplanted cell was identified in the host myocardium of Doxorubicin-induced failing hearts [17]. In this study, transplanted cells were not observed in the center of the scar area but only in the border area of the infarction. We have identified the substantial amount of transplanted cells in the scar area 1 day after cell transplantation in a preliminary experiment. Disappearance of many transplanted cells in the host heart may be explained as follows. One reason is lack of blood flow with enough oxygen and nutrition for long-term cell survival. Another is that cardiomyocytes cannot tolerate ischemic condition compared with other immature cells such as stem cells [19]. In the present study, we injected the cells into the center of scar area, and they spread out to the circumference in a concentric circle. Therefore, it was considered that transplanted cardiomyocytes in the periinfarct area survived whereas those in the severely ischemic or infarct area soon died. Rejection of the cells was not likely because this study was performed in syngeneic rats.

These findings may show that direct contribution of the transplanted cardiomyocytes to contractility is not likely and that other factors are associated with the benefits of cell transplantation. Although the precise mechanisms by which transplanted cells improve cardiac function have not yet been elucidated, it may be likely that their elastic properties against mechanical stretching and the increase of wall thickness by themselves prevent LV dilation and remodeling. In addition, angiogenesis or revascularization induced in ischemic and preischemic regions by the transplanted cells may also ameliorate cardiac function in the failing heart.

In this study, transplanted cells were injected at one point in the LV free wall. Cardiac function may be further improved by multiple injections into the scar and the border area, although such procedures are not practical in a small heart. Although we used fetal cardiomyocytes, there are at least three hurdles to be overcome before they can be used clinically in treating ischemic heart disease. First, fetal transplantation is allotransplantation and is not free of rejection except in syngeneic settings. Second, using fetuses poses an ethical problem in itself. Third, cardiomyocytes may not be suitable for transplantation in infarcted hearts due to their intolerance of ischemia. Recently it was reported that autologous stem cells derived from bone marrow could differentiate to cardiomyocytes and survive in ischemic lesions [20, 21]. In addition, many researchers have reported the idea of producing angiogenesis to supply enough blood flow to the transplanted area [22, 23]. Therefore, it may be possible in the future that cardiomyocyte transplantation will be performed safely, and that the transplanted cells can survive in infarct regions and thus potentially improve cardiac function by furthering progress in the research.

In conclusion, this study demonstrated that fetal cardiomyocyte transplantation prevented LV function from deterioration in rats with chronic myocardial infarction. However, its benefit was limited, and its effectiveness was not enough to reverse the cardiac remodeling that accompanied the development of heart failure. Further investigation is warranted for optimal clinical application of cell transplantation to the failing heart.

	Acknowledgments

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We thank Dr Ren-Ke Li and Dr Richard D Weisel (the Division of Cardiac Surgery at the University of Toronto General Hospital, Canada) for technical advice. This research was supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Culture, Sports, Science and Technology, and by a "Research for the Future" Program from the Japan Society for the Promotion of Science.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Kazunobu Nishimura Masashi Komeda Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sakakibara, Y. Articles by Komeda, M. Search for Related Content PubMed PubMed Citation Articles by Sakakibara, Y. Articles by Komeda, M. Related Collections Myocardial infarction