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Ann Thorac Surg 2000;70:859-865
© 2000 The Society of Thoracic Surgeons

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Original articles: cardiovascular

Autologous smooth muscle cell transplantation improved heart function in dilated cardiomyopathy

^a Division of Cardiovascular Surgery and the Centre for Cardiovascular Research, Department of Surgery, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada

Address reprint requests to Dr Ren-Ke Li, Toronto General Hospital, CCRW 1-815, 200 Elizabeth St, Toronto, ON M5G 2C4, Canada
e-mail: renke.li{at}uhn.on.ca

Presented at the Thirty-sixth Annual Meeting of The Society of Thoracic Surgeons, Fort Lauderdale, FL, Jan 31–Feb 2, 2000.

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. Transplantation of myocytes into scarred myocardium has been shown to inhibit ventricular remodeling and maintain myocardial contractility. However, the effect of cell transplantation on hearts with global rather than regional dysfunction is unknown. Therefore, we evaluated the effect of transplantation of autologous smooth muscle cells on the morphometry and function of dilated cardiomyopathic hearts.

Methods. Smooth muscle cells were isolated from the ductus deferens of 13-week-old BIO 53.58 hamsters with dilated cardiomyopathy, and cultured for 4 weeks before transplantation. Smooth muscle cells (4 x 10⁶ cells) or culture medium were injected into 17-week-old animals in the transplantation and control groups (n = 12 each), respectively. Prelabeling of the smooth muscle cells with 5-bromo-2'-deoxyuridine was performed before transplantation in a group of transplanted hamsters. Another group (sham, n = 12) underwent the operation but did not receive an injection either of smooth muscle cells or of culture medium. Four weeks after transplantation, heart function was evaluated in a Langendorff preparation.

Results. Musclelike tissue, labeled with 5-bromo-2'-deoxyuridine, was found at the site of transplantation in the cell-transplanted animals. The cell-transplanted hearts were smaller (p < 0.001), and had greater developed pressures and maximum rate of increase of left ventricular pressure (both p < 0.001) than control and sham hearts. Control hamsters injected with culture medium did not differ from sham-operated animals.

Conclusions. Transplantation of autologous smooth muscle cells prevented cardiac dilatation and improved ventricular function in hamsters with dilated cardiomyopathy.

	Introduction

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Idiopathic dilated cardiomyopathy is one of the most prevalent causes of significant congestive heart failure [1], and the most common indication for cardiac transplantation [2]. Although cardiac transplantation can be an excellent therapy for patients with end-stage heart disease, the chronic shortage of donor organs and late sequelae of immunosuppression and rejection still limit the applicability and efficacy of this therapy [3, 4].

Transplantation of cells, rather than the entire organ, has undergone extensive investigation in recent years [5–10] as a potential novel therapy for patients with severe congestive heart failure. These investigations have focused, however, on improving the function of hearts in which myocardial infarction or cryoinjury has resulted in regional ventricular dysfunction. Little is known about the effect of cell transplantation on the contractile function of globally dysfunctional hearts, such as those with dilated cardiomyopathy. Scorsin and coworkers [11] studied cell transplantation in a model of doxorubicin-induced dilated cardiomyopathy, transplanting 1 x 10⁶ cardiomyocytes into the left ventricle. Although improved fractional shortening was noted, by echocardiography, in the cell-transplanted hearts compared to the control hearts, the transplanted cells were not detected in the host myocardium. These investigators attributed the improvement in contractility to the secretion of growth factors from the transplanted cells.

In our present study, we evaluated the effect of transplantation of smooth muscle cells on the histology and function of the hearts of adult hamsters with a hereditary dilated cardiomyopathy, to determine whether engraftment of the transplanted cells could be demonstrated, and their effect on the contractility of the globally dysfunctional heart.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Experimental animals
The experimental animals used were male BIO 53.58 hamsters (BIO Breeders, Fitchburg, MA) weighing approximately 100 g. All procedures on these hamsters were approved by the Animal Care Committee of the Toronto General Hospital, and carried out in compliance with the "Guide to the Care and Use of Experimental Animals" of the Canadian Council on Animal Care and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985).

Isolation, culture, and identification of the smooth muscle cells
At 13 weeks of age all animals underwent laparotomy to remove the ductus deferens, from which the cultured smooth muscle cells were obtained. The hamsters were anesthetized with ketamine (20 mg/kg, intramuscular), followed by an intraperitoneal injection of pentobarbital (30 mg/kg). The anesthetized hamsters were ventilated by mask with oxygen-supplemented room air. The ductus deferens was exposed through a 3-cm transverse lower abdominal incision and excised after ligation of both ends. After abdominal closure, the hamsters were recovered from operation, electrocardiographically monitored for 4 hours, and given Penlong XL (benzathine penicillin G 150,000U/mL and procaine penicillin G 150,000 U/mL, 0.2 mL intramuscularly) every 3 days and buprenorphine (0.01 to 0.05 mg/kg subcutaneously) every 8 to 12 hours for the first 48 hours after operation.

The excised ductus deferens was washed with phosphate-buffered saline and the surrounding connective tissue was removed. The ductus was then minced and incubated in 10 mL of phosphate-buffered saline containing 0.2% trypsin, 0.1% collagenase, and 0.02% glucose for 30 minutes at 37°C [12]. The supernatant, containing the suspended cells, was transferred into 20 mL of Iscove’s modified Dulbecco’s medium (Gibco Laboratory, Life Technologies, Grand Island, NY) containing 10% fetal bovine serum, 0.1 mmol/L ß-mercaptoethanol, 100 U/mL penicillin, and 100 µg/mL streptomycin. This suspension was centrifuged at 600 g for 5 minutes at room temperature. The cell pellet was resuspended in cell culture medium and plated on one 10-cm diameter dish. The cells were cultured and passaged once, over a 4-week period.

The cultured smooth muscle cells were identified immunohistochemically, using a monoclonal antibody against -smooth muscle actin (Sigma, St. Louis, MO) as previously described [6, 10].

Identification of the transplanted smooth muscle cells
To facilitate identification of the transplanted smooth muscle cells in the recipient myocardium, cultured smooth muscle cells at 50% confluence were labeled with 25 µL of a 0.4% solution of the thymidine analog 5-bromo-2'-deoxyuridine (BrdU) (Zymed Lab Inc, South San Francisco, CA) for 72 hours before transplantation (n = 2). BrdU labeling efficiency was confirmed by staining two randomly selected dishes for BrdU. The BrdU-labeled cells were transplanted and identified as described below. Four weeks after transplantation, the hamsters were sacrificed and the hearts were examined. BrdU-labeled cells in the regions of transplantation were identified by immunohistochemical staining as previously described [10].

Preparation and transplantation of smooth muscle cells
Cultured smooth muscle cells were detached by the addition of 0.05% trypsin in phosphate-buffered saline to the culture dish for 2 minutes. After adding 10 mL of culture medium, the cell suspension was then centrifuged at 580 g for 3 minutes. The cell pellet was resuspended in culture medium at a concentration of 100 x 10⁶ cells/mL, and 0.04 mL of cell suspension or culture medium was used for subsequent transplantation into transplanted or control hearts, respectively.

At 17 weeks of age, the BIO 53.58 hamsters were again anesthetized as previously described. The anesthetized animals were intubated and ventilated with oxygen-supplemented room air with a Harvard ventilator (model 683; Harvard Instruments, South Natick, MA) at a rate of 60 breaths per minute and a tidal volume of 1.5 mL. The heart was exposed through a 3-cm left lateral thoracotomy. The smooth muscle cell suspension (transplantation, n = 12) or culture medium (control, n = 12) was injected with a tuberculin syringe into a single site on the anterior aspect of the left ventricular free wall. Sham operated animals (n = 12) underwent thoracotomy without injection. After chest closure, the animals were recovered from the procedure and were treated with antibiotics and analgesics as previously described.

Evaluation of left ventricular function
Four weeks after cell transplantation, the hamsters were anesthetized and heparin sodium (100 U) was administered intravenously. The heart was quickly excised and perfused in a Langendorff apparatus with filtered Krebs-Henseleit buffer (NaCl, 118 mmol/L; KCl, 4.7 mmol/L; KH₂PO₄, 1.2 mmol/L; CaCl₂, 2.5 mmol/L; MgSO₄, 1.2 mmol/L; NaHCO₃, 25 mmol/L; glucose, 11 mmol/L; pH 7.4) equilibrated with 5% carbon dioxide and 95% oxygen. A latex balloon was passed into the left ventricle across the mitral valve and connected to a pressure transducer (model p10EZ; Viggo-Spectramed, Oxnard, CA and differentiator amplifier (model 11-G4113-01; Gould Instrument System Inc, Valley View, OH). Coronary flow was measured in triplicate by timed collection in the empty beating heart. After 30 minutes of stabilization, balloon volume was increased in 0.005-mL increments from 0.005 to 0.025 mL by the stepwise addition of saline. Heart rate, systolic and diastolic left ventricular pressures, and maximum rate of increase of left ventricular pressure +dp/dt and -dp/dt were recorded at each balloon volume. Developed pressure was calculated as the difference between the systolic and diastolic pressures. After completion of all measurements, the hearts were arrested in diastole by perfusion with 5 mL of a 20% KCl solution. Passive left ventricular diastolic pressures were recorded over a range of balloon volumes from 0.005 to 0.035 mL, in 0.005-mL increments, and the hearts subsequently weighed.

Measurement of left ventricular chamber volume
Left ventricular chamber volume was measured by the technique of Pfeffer and associates [13]. Briefly, the hearts were fixed in left ventricular distension (30 mm Hg) with 10% phosphate-buffered formalin solution for 2 days and then cut into 1-mm slices. Each heart yielded six slices. The cross-sectional area of the left ventricle on the apical and basal faces of each section was traced onto a transparency, quantified by computerized planimetry (Jandal Scientific Sigma-Scan, Corte Madera, CA), and the mean left ventricular cross-sectional area of the section calculated. Total left ventricular chamber volume was calculated as the sum of the mean areas per section and multiplied by 1 mm.

Histology
Heart sections were fixed in 5% glacial acetic acid in methanol, embedded in paraffin, and cut into 10-µm thick sections. The sections were stained with hematoxylin and eosin as described in the manufacturer specifications (Sigma Diagnostics, St. Louis, MO). Sections also underwent immunohistochemical staining [10] for BrdU and -smooth muscle actin.

Statistical analysis
Data are presented as the mean ± standard deviation unless otherwise indicated. Statistical analysis was carried out with the SAS software package (SAS Institute, Cary, NC). Comparison of continuous variables between more than two groups were performed by a one-way analysis of variance. If the F ratio was significant, differences were specified by Duncan’s multiple-range t test. A p value of less than 0.05 was considered to be statistically significant.

Left ventricular function was evaluated by analysis of covariance, with intraventricular volume as the covariate and systolic, diastolic, and developed pressures, and dp/dt as dependent variables. Main effects were group, volume, and interaction between group and volume. When analysis of covariance indicated a significant effect group or interactive effect, differences were specified by multiple pair-wise comparisons.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Purity and labeling of cultured smooth muscle cells
The purity of the cultured smooth muscle cells, defined as positive immunohistochemical staining for -smooth muscle actin, was 87.8% ± 3.4% (n = 6) just before transplantation (Fig 1). The efficiency of labeling with BrdU was 48.6% ± 6.5% (n = 2).

View larger version (73K): [in this window] [in a new window]   Fig 1. Photomicrograph of cultured smooth muscle cells (A) (100x) that stained positively for -smooth muscle actin (B) (200x).

View larger version (56K): [in this window] [in a new window]   Fig 2. Photomicrograph of control (A; 40x) and cell transplanted hearts (B; 100x) of 21-week-old cardiomyopathic hamsters (hematoxylin and eosin). The cardiomyopathic host myocardium shows severe focal necrosis (N) and fibrosis (F). The transplanted smooth muscle cells formed musclelike tissue (T), in which multiple small-caliber blood vessels were noted (arrow).

View larger version (159K): [in this window] [in a new window]   Fig 3. Photomicrograph of transplanted smooth muscle cells in the transplanted hearts. Sections from hearts transplanted with 5-bromo-2'-deoxyuridine-prelabeled cells were stained with hematoxylin and immunohistochemically for 5-bromo-2'-deoxyuridine (100x). Musclelike tissue, which stained positively for 5-bromo-2'-deoxyuridine (arrows), was found in the smooth muscle cell-transplanted hearts but not in the control or sham-operated hearts.

View larger version (164K): [in this window] [in a new window]   Fig 4. Photomicrograph of the musclelike tissue formed by the transplanted smooth muscle cells, stained immunohistochemically for -smooth muscle actin (arrows) (100x).

Evaluation of left ventricular function in our Langendorff apparatus demonstrated significantly greater systolic (p < 0.001) and developed pressures (p < 0.001) (Fig 5 ) in smooth muscle cell-transplanted hearts, compared to control and sham-operated hearts. Maximum +dp/dt was also significantly greater in the cell-transplanted animals (p < 0.001) (Fig 6A). No difference between control and sham-operated animals was noted in these measurements of systolic function.

View larger version (13K): [in this window] [in a new window]   Fig 5. Peak systolic (A) and developed left ventricular pressures (B) in the transplanted, control, and sham-operated hearts over a range of intraventricular balloon volumes (mean ± standard deviation). Peak systolic and developed pressures in the transplantation group were significantly higher than in the control and sham-operated groups (p < 0.001). There were no significant differences between control and sham-operated hearts.

View larger version (14K): [in this window] [in a new window]   Fig 6. Maximum left ventricular +dp/dt (A) and -dp/dt (B) in the transplanted, control, and sham-operated hearts over a range of intraventricular balloon volumes (mean ± standard deviation). Maximum +dp/dt was significantly higher, and maximum -dp/dt was significantly lower, in the transplantation group than in the control and sham operated groups (p < 0.001). There were no significant differences between control and sham-operated hearts.

View larger version (12K): [in this window] [in a new window]   Fig 7. Active (A) and passive (B) left ventricular diastolic pressures in the transplanted, control, and sham-operated hearts over a range of intraventricular balloon volumes (mean ± standard deviation). Diastolic pressures in the transplanted hearts were significantly higher, at any intraventricular balloon volume, than in the control and sham-operated groups (p < 0.001). There were no significant differences between control and sham-operated hearts.

	Comment

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Since the initial studies in which cultured AT-1 and fetal cardiomyocytes were transplanted into syngeneic mouse hearts [14, 15], significant progress has been achieved in the field of cell transplantation. Transplantation of cultured fetal and neonatal cardiomyocytes [5–7], skeletal muscle satellite cells [8, 9], and smooth muscle cells [10] has been shown to improve the function of scarred and infarcted hearts. Previously, we have evaluated the effect of allotransplantation of heart cells in BIO 53.58 cardiomyopathic hamsters, and showed that 4 weeks later, the transplanted heart cells formed cardiac-like tissue, limited left ventricular dilatation, and improved systolic function [16]. The cardiaclike tissue gradually decreased in size with time, which we attributed to chronic rejection despite immunosuppression with cyclosporine. Cell autotransplantation, therefore, appeared to be an ideal way to achieve the beneficial effects of cell transplantation without stimulating a chronic immune response. However, autotransplantation of already cardiomyopathic cardiomyocytes may be futile. In addition, the risk of harvesting cardiomyocytes by percutaneous biopsy for expansion in culture may be elevated in patients with dilated, thinned hearts. Autotransplantation of skeletal myocytes is an alternative, but the necessary satellite progenitor cells have been difficult to harvest and isolate in clinically useful numbers. Therefore, we chose to study the effects of autotransplantation of smooth muscle cells on globally dysfunctional cardiomyopathic hamster hearts.

In this study, we used BIO 53.58 Syrian hamsters [17–19], which develop a dilated cardiomyopathy with ventricular dilatation and thinning, and focal myocytolysis, leading to progressive congestive heart failure. Histologic changes begin at approximately 10 weeks of age, and the disease becomes clinically apparent at about 17 weeks. Abnormalities of the skeletal myocytes are also noted. We therefore used this strain in which to evaluate smooth muscle cell autotransplantation, and arbitrarily selected 4.0 x 10⁶ cultured smooth muscle cells, to be transplanted into single site on the left ventricular free wall.

We observed significant engraftment of the transplanted smooth muscle cells, which formed a musclelike tissue occupying almost one third of the left ventricular free wall. This tissue stained positively both for -smooth muscle actin, and for BrdU in hearts transplanted with BrdU-prelabeled smooth muscle cells. The engrafted tissue also contained numerous capillaries. Because smooth muscle cells can proliferate in vivo [10], some of the musclelike tissue observed may have been formed by postimplantation hyperplasia of the transplanted cells. The arrangement of the transplanted smooth muscle cells, however, was clearly disorganized. Effective contractility of the transplanted cells, therefore, seems unlikely. We attributed the changes noted in the diastolic function of transplanted hearts to the increased wall thickness, which would limit ventricular dilatation. The left ventricular diastolic pressure-volume relation appeared to be shifted to the right in the control and sham-operated animals, but not in the transplanted animals. This shift would also result in greater systolic and developed pressures in the transplanted hearts at equivalent ventricular volumes. The significantly greater maximum +dp/dt and -dp/dt in the transplanted hearts, however, suggests that cell transplantation favorably affected systolic shortening and active relaxation to a greater degree than can be explained purely by the change in the diastolic pressure–volume relation.

Modification of the contractility of myopathic native cardiomyocytes themselves by the process of cell transplantation is another perhaps less plausible mechanism by which left ventricular function was improved, but it is possible that the modest angiogenesis noted in the region of smooth muscle cell implantation may have improved regional perfusion and thereby augmented native cardiomyocyte contractility. There were, however, no apparent differences in the degree of myocytolysis in the surrounding myocardium between the transplanted, control and sham-operated groups. The release of growth factors from the transplanted cells, which was not assessed in this study, might potentially also have affected ventricular morphology and function.

Autologous smooth muscle cell transplantation may prove to be a clinically applicable therapeutic strategy. Smooth muscle cells can be obtained by laparoscopic biopsy from the ductus deferens, stomach, vermiform appendix, or uterus for expansion in culture before autotransplantation back into the heart of the same patient.

Although smooth muscle cell transplantation improved left ventricular function and limited ventricular dilatation in our hamster model of dilated cardiomyopathy, we did not evaluate the long-term survival of these animals. In addition, it is still unclear as to which characteristics of smooth muscle cells are responsible for the change in ventricular function. Smooth muscle cell contraction is extremely energy-efficient, compared to skeletal muscle, and despite the relatively few myosin filaments and the slow cycling time of the actin–myosin cross-bridge, the maximum force of contraction of smooth muscle is often even greater than that of skeletal muscle [20]. We are undertaking further studies of smooth muscle cell transplantation in a large animal model of dilated cardiomyopathy to further define the mechanisms by which smooth muscle cell transplantation exerts its effect.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
We thank Dev Olshansky and James C. Ho for the preparation and staining of the histologic materials and Drs Eung-Joong Kim and Shinji Tomita for surgical assistance. Ren-Ke Li is a Research Scholar of the Heart and Stroke Foundation of Canada. Richard D. Weisel is a Career Investigator of the Heart and Stroke Foundation of Ontario. This research was supported by Ren-Ke Li’s research grants from the Medical Research Council of Canada (MT-13665).

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

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