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Ann Thorac Surg 1996;62:654-660
© 1996 The Society of Thoracic Surgeons
Division of Cardiovascular Surgery, Department of Clinical Biochemistry, and The Centre for Cardiovascular Research, The Toronto Hospital-General Division, University of Toronto, Toronto, Ontario, Canada
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Abstract |
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Methods. Scar tissue was produced in the left ventricular free wall of 15 rats (weight, 450 g) by cryoinjury. Seven animals had operation only and survived for 8 weeks (sham group). Four weeks after cryoinjury, cultured fetal rat cardiomyocytes or culture medium was injected into the scar tissue of transplantation (n = 5) and control (n = 5) animals, respectively. Five other rats were sacrificed for scar assessment. Eight weeks after cryoinjury heart function in the transplantation, control, and sham groups was measured using a Langendorff preparation. Histologic studies were performed to quantify the extent of the scar and the transplanted cells.
Results. Four weeks after cryoinjury, 36% ± 4% (mean ± 1 standard error) of the left ventricular free wall surface area was scar tissue. At 8 weeks, the scar size had increased (p < 0.01) to 55% ± 3% in the control group. Although the scar size (43% ± 2%) in the transplantation group at 8 weeks was not significantly different from that at 4 weeks, it was less (p < 0.05) than that in the control group. Hearts in the sham group had no scar tissue. The transplanted cardiomyocytes had formed cardiac tissue within the myocardial scar. Systolic and developed pressures in the transplantation group hearts were greater (p = 0.0001) than in the control group hearts but less (p < 0.01) than those in the sham group hearts.
Conclusions. The transplanted cardiomyocytes formed cardiac tissue in the myocardial scar, limited scar expansion, and improved heart function compared with findings in the control hearts.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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After a myocardial infarction, the damaged cardiomyocytes are gradually replaced by fibrous tissue with loss of regional contractile function. Ventricular remodeling results in wall thinning, which can cause aneurysm formation [1]. Heart failure may develop. The myocardial dysfunction is primarily due to the loss of cardiomyocytes. Cardiomyocyte transplantation into the ventricular scar offers the hope of restoring some ventricular function.
Transplanted cardiomyocytes have been shown to survive, proliferate, and connect with the host murine myocardium [2, 3]. We [4] demonstrated that fetal rat cardiomyocytes transplanted into the subcutaneous tissue of the adult rat leg formed cardiac tissue that contracted for the 3-month duration of the study. We have also shown that transplanted cardiomyocytes can survive in a rat myocardial scar (unpublished observation). To determine whether cardiomyocyte transplantation prevents heart failure, we transplanted fetal rat cardiomyocytes into scar tissue of the cryonecrosed left ventricular free wall (LVFW) of adult rat hearts. The transplanted cardiomyocytes limited the expansion of scar tissue and improved heart function.
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Material and Methods |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Cell Culture and Preparation for Transplantation
Cardiomyocytes from fetal rat hearts were isolated, purified, and cultured as previously described [4, 5]. The purified cardiomyocytes were transfected by the calcium phosphate coprecipitation technique [6] with pRSV-lacZ plasmid containing ß-galactosidase gene (a generous gift of Dr R. Chiu, Montreal General Hospital, Montreal, PQ, Canada) for identification of the transplanted cells in the myocardial scar tissue. Cultures of the cells were grown for 24 hours in Iscove's modified Dulbecco's medium containing 10% fetal bovine serum, 100 U/mL of penicillin, and 100 ug/mL of streptomycin at 37°C in 5% carbon dioxide and 95% air. The transfected cardiomyocytes were detached from the cell culture dish with 0.05% trypsin in phosphate-buffered saline solution. After centrifugation at 580 g for 3 minutes, the cell pellet was resuspended in culture medium at a concentration of 16 x 106 cells/mL. A 0.25-mL cell suspension was used for each transplantation.
Anesthesia and Postoperative Care of Rats
Adult rats were anesthetized with intramuscular administration of ketamine hydrochloride (22 mg/kg) followed by an intraperitoneal injection of sodium pentobarbital (30 mg/kg). The anesthetized rats were intubated, and positive-pressure ventilation was maintained with room air supplemented with oxygen (6 L/min) using a Harvard ventilator (model 683). The rats were monitored for 4 hours postoperatively. Penlong XL (penicillin G benzathine, 150,000 U/mL, and penicillin G procaine, 150,000 U/mL) was given intramuscularly (0.25 mL per rat) every 3 days for 1 week after operation, and buprenorphine hydrochloride (0.01 to 0.05 mg/kg) was administered subcutaneously every 8 to 12 hours for the first 48 hours after operation.
Myocardial Scar Formation
Under general anesthesia, the adult rat heart was exposed through a 2-cm left lateral thoracotomy. For the animals having a sham operation (sham group) (n = 7), the surgical incision was then closed with 5-0 Vicryl sutures. Cryoinjury was produced in 15 animals with a metal probe 8 x 10 mm in diameter cooled to -190°C by immersion in liquid nitrogen and then applied to the LVFW for 1 minute. This procedure was repeated four times. The muscle layer and the skin incision were then closed with 5-0 Vicryl sutures. Antibiotics and analgesics were given as already described. The 15 cryoinjured animals were randomly divided into three equal groups: pretransplantation, control, and transplantation.
Cardiomyocyte Transplantation
Four weeks after cryoinjury, the pretransplantation hearts (n = 5) were harvested for histologic and planimetric studies. Under general anesthesia, the hearts in the control (n = 5) and transplantation (n = 5) groups were exposed through a midline sternotomy. A fetal rat cardiomyocyte suspension (0.25 mL, 4 x 106 cells) was injected once into the center of the scar tissue in the transplantation group using a tuberculin syringe, and 0.25 mL of cell culture medium was injected into the scar tissue in the control group. The chest was closed with 5-0 Vicryl sutures. The rats in the sham group (n = 7) underwent the same procedure without injection. Antibiotics and analgesics were given as previously described. Cyclosporin A, 5 mg • kg-1 • d-1, was administered subcutaneously to the control and transplantation groups. The rats were housed in cages with filter tops.
Myocardial Function Studies
Eight weeks after cryoinjury, heart function in the sham, control, and transplantation groups was measured using a Langendorff preparation [7]. The rats were anesthetized, and heparin sodium (200 units) was administered intravenously. The hearts were quickly isolated and perfused in a Langendorff apparatus with filtered Krebs-Henseleit buffer (mmol/L:NaCl, 118; KCl, 4.7; KH2PO4, 1.2; CaCl2, 2.5; MgSO4, 1.2; NaHCO3, 25; and glucose, 11; pH 7.4) equilibrated with 5% carbon dioxide and 95% oxygen. A latex balloon was passed into the left ventricle through the mitral valve and connected to a pressure transducer (model p10EZ; Viggo-Spectramed, Oxnard, CA) and a transducer amplifier and differentiator amplifier (model 11-G4113-01; Gould Instrument System Inc, Valley View, OH).
After 30 minutes of stabilization, the coronary flow of the heart was measured in triplicate by timed collection in the empty beating state. The balloon size was increased in 0.02-mL increments from 0.04 to 0.46 mL by the addition of saline solution. The systolic and diastolic pressures were recorded at each balloon volume, and developed pressure was calculated as the difference between the systolic and diastolic pressures.
The heart was weighed and the size measured by water displacement.
Measurement of LVFW Remodeling
The epicardial and endocardial surface areas of the normal and scar tissue in the LVFW were measured by the techniques of Pfeffer and associates [8] and Jugdutt and Khan [9]. Briefly, the hearts were fixed in distention (30 mm Hg) with 10% phosphate-buffered formalin solution and then cut into sections 3 mm thick. For each section, the areas of normal tissue, scar tissue, and transplanted tissue in the LVFW were traced onto a transparency and quantified using computed planimetry (Jandal Scientific Sigma-Scan, Corte Madera, CA). The lengths of the LVFW and the scar tissue on both the endocardial and epicardial surfaces of each section were measured. The surface areas of the epicardial and endocardial scar tissue and the LVFW were measured as the sum of the endocardial length and epicardial length times the section thickness (3 mm). The surface area percentage of scar tissue in the LVFW was calculated as follows:
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To calculate the percentage of the surface area in the scar tissue occupied by "cardiac tissue," the cardiac tissue length in the scar tissue of each section times the section thickness (3 mm) was added and then divided by the total scar area times 100.
Histologic Studies
The heart sections were fixed in 5% glacial acetic acid in methanol, embedded in paraffin, and sectioned to yield slices 10 µm thick. The slices were stained with hematoxylin and eosin as described in the manufacturer's specifications (Sigma Diagnostics, St. Louis, MO).
To stain for in vitro ß-galactosidase activity in the cultured fetal cardiomyocytes, the cells were washed three times with phosphate-buffered saline solution and fixed in 2% formaldehyde and 2% glutaraldehyde in phosphate buffer (0.15 mol/L NaCl and 0.015 mol/L NaH2PO4; pH 7.2) at 4°C for 5 minutes. After washing with phosphate buffer containing 2.0 mmol/L MgCl2, the cells were stained overnight at 37°C in a solution containing 1 mg/mL of 5-bromo-4-chloro-3-indolyl-beta-galactopyranoside (X-gal), 5 mmol/L K3Fe(CN)6, 5 mmol/L K4Fe(CN)6•3H2O, and 0.2 mmol/L MgCl2 in phosphate buffer (pH 7.2). The stained and nonstained cells (100 cells per dish) in six dishes were counted under a microscope to determine the percentage of cells containing ß-galactosidase activity.
To stain for ß-galactosidase activity in the transplanted cardiomyocytes, the heart sections were fixed in 2% formaldehyde and 2% glutaraldehyde in phosphate buffer at 4°C for 12 hours. The tissue was then stained for ß-galactosidase activity at 37°C for 24 hours as just described. The heart section was embedded in paraffin and sectioned to yield slices 10 µm thick. After removal of the paraffin using xylene and followed by clearing in 100%-95%-90%-85%-70% ethanol (3 minutes each), the stained cells were photographed.
Data Analysis
Data are expressed as the mean ± the standard error. Statistical Analysis System software was used for all analyses (SAS Institute, Cary, NC). Comparisons of continuous variables between more than two groups were performed by a one-way analysis of variance. If the F ratio was significant from the analysis of variance, a Duncan's multiple-range t test was employed to specify differences between groups. The critical 
-level for these analyses was set at a p value of less than 0.05.
Functional data were evaluated for the sham, control, and transplantation groups by an analysis of covariance using intracavitary balloon volume as the covariant-factor and systolic, diastolic, and developed pressures as dependent variables. Main effects were group, volume, and interaction between group x volume. If there was an overall difference in the analysis of covariance, multiple pairwise comparisons were performed to specify which groups were different. Because there were multiple pairwise comparisons, a Bonferroni correction was performed, and the critical level was set at 0.01 for the analysis of covariance.
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Results |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Four weeks after transplantation, the fetal cells had formed cardiac tissue in the myocardial scar tissue of the transplantation group (n = 5) (Figs 1, 2
). The transplanted cells stained positively for ß-galactosidase activity (see Fig 2a). The cells were elongated, contained organized sarcomeres, and were connected to each other by intercalated discs (Fig 3; see Figs 2b, 2c). Blood vessels were present in the transplanted tissue, and lymphocytes surrounded it. There was no cardiac tissue in the myocardial scar of the control animals (n = 5) (Fig 4; see Fig 1). The sham group had no LVFW scar tissue.
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). The hearts in the control and transplantation groups were larger (p < 0.01) than those in the sham group. Four weeks after cryoinjury, 36% ± 4% (mean ± 1 standard error) (n = 5) of the LVFW in the pretransplantation animals was replaced with a transmural scar (Fig 5). After 8 weeks, the scar tissue had expanded (p < 0.01) in the control group to 55% ± 3% (n = 5) of the free wall. The size of scar tissue (43% ± 2% of the LVFW) in the transplantation group (n = 5) 8 weeks after cryoinjury was not significantly different from that of the pretransplantation animals at 4 weeks and was less (p < 0.05) than the size in the control hearts at 8 weeks. The transplanted cardiomyocytes had formed cardiac tissue that occupied 37% ± 4% (n = 5) of the scar tissue (see Fig 5). The transplanted tissue contracted visibly. We were unsuccessful in measuring its contractility because of the contractions of the surrounding myocardium. After removing the hearts and separating the scar area, we found that the transplanted region continued to contract when stimulated. The transplanted cells, which had been injected into the middle of the scar, did not communicate with the host myocardium.
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illustrates the results of measurements of left ventricular function in the sham, transplantation, and control groups. Analysis of covariance demonstrated a significant (p = 0.0001) interaction between balloon volume and treatment group for systolic, diastolic, and developed pressures. Pairwise comparisons demonstrated a significant (p = 0.0001) depression in systolic and developed pressures in control animals compared with the sham group (normal hearts). The transplantation hearts had better (p = 0.001) function than the control hearts, although both systolic pressure and developed pressure were lower (p < 0.01) than those pressures in the sham group. Diastolic pressures were significantly lower in both the cryoinjured control and transplantation hearts than in the sham group hearts at higher balloon volumes because of the marked dilatation resulting from myocardial scar expansion.
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shows the differences in developed pressure at balloon volumes of 0.1 and 0.2 mL. The cryoinjured control group had lower (p = 0.0001) pressure than either the sham group normal hearts or the transplantation group hearts.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Transplantation of cultured cardiomyocytes is a possible technique of replacing scar tissue. Koh and associates [2] transplanted AT-1 cardiomyocytes (a cell line isolated from subcutaneous tumors derived from the left atrium of transgenic mice) into syngeneic mouse hearts and found that the transplanted cells survived and proliferated. Angiogenesis occurred in the transplant [10]. The same research group [3] found that the transplanted cardiomyocytes survived and formed gap junctions with host cardiomyocytes in the host myocardium. Because the clinical application of cardiomyocyte transplantation requires the transplanted cells to survive and function in fibrous tissue (myocardial scar tissue), we extended these observations. In previous studies, we [4] found that fetal rat cardiomyocytes transplanted into the subcutaneous tissue of the adult rat leg were viable and formed cardiac tissue, which contracted for the 3-month duration of the experiment. When fetal cardiomyocytes were transplanted into a homogeneous scar in adult rat hearts, the transplanted cells survived and formed cardiac tissue for the 2-month duration of the study (unpublished observations).
Coronary artery ligation is often used experimentally to produce a myocardial infarction and scar tissue. However, coronary ligation produces a wide spectrum of necrosis, scar tissue, and ventricular dysfunction in rats [8]. The extent and homogeneity of the scar is dependent on the amount of collateral perfusion, which is variable [11]. Although myocardial necrosis and scar formation resulting from cryoinjury are not clinically relevant, the transmural scar is more constant in size and myocardial dysfunction is less variable than seen after coronary ligation. In the present study cryoinjury generated a homogeneous scar occupying 36% ± 4% of the LVFW at 4 weeks and 55% ± 3% at 8 weeks. However, experiments using an animal model of myocardial infarction produced by coronary artery ligation will be necessary to determine whether our results have clinical relevance.
Four weeks after cryoinjury, a maturing scar was present. Fetal rat cardiomyocytes were transplanted at 4 weeks to avoid the inflammatory reaction that occurs in the ventricular wall immediately after cryoinjury. Four weeks after transplantation, the transplanted cardiomyocytes had survived and formed a cardiac tissue that stained positive for ß-galactosidase activity. The arrangement of the cardiomyocytes appeared to be disorganized compared with the arrangement in the host cells. The transplanted cells were connected to each other by intercalated discs. The tissue was more vascular than surrounding scar tissue. The presence of lymphocytes indicated rejection of the transplant despite cyclosporine treatment. The relative importance of cardiomyocyte hypertrophy and hyperplasia in forming the transplant in the scar is unknown.
The explanation for improved heart function by cardiomyocyte transplantation was not determined in this study. Cardiomyocyte transplantation limited scar thinning and expansion. The smaller ventricle prevented overstretching of the host and transplanted cardiomyocytes, thus resulting in improved contractile force compared with control hearts. Four mechanisms are possible: (1) cardiomyocyte contractility; (2) cardiomyocyte elastic properties; (3) revascularization; and (4) a factor secreted by the transplanted cardiomyocytes. The transplanted tissue was contractile and occupied 37% of the scar. The transplanted tissue was unlikely to contract synchronously with the host myocardium because the cells were injected into the center of the scar and did not appear to be in contact with the host cardiomyocytes. Although the contribution of the transplant contractility to overall function is unknown, it was modest. Another possible mechanism of the beneficial effect of cardiomyocyte transplantation is the elastic properties of the contractile apparatus of the transplanted cardiomyocytes. These properties would prevent fibroblast stretching and ventricular enlargement. With each ventricular contraction, the elastic properties may have tended to restore the ventricular wall to its original size and shape. The development of angiogenesis may also have limited scar expansion and modified ventricular remodeling [12]. The increased blood supply in the scar may have facilitated fibroblast turnover and strengthening of the scar in response to ventricular stretch. Finally, the transplanted cardiomyocytes could secrete a factor that stimulates fibroblast turnover and prevents scar thinning and expansion.
Cardiomyocyte transplantation may have clinical applications. Transplantation early after an infarction at the time of coronary artery bypass grafting to treat persistent angina could prevent scar expansion, restore contractility of the infarcted region, and reduce the long-term morbidity and mortality after surgical revascularization. Late after a myocardial infarction, contractility could be restored by resecting the thin scar and reconstructing the normal geometry with a pericardial patch [13]. Cardiomyocytes could be placed on a pericardial patch used to reconstruct the ventricle. If the transplanted cardiomyocytes developed into contracting tissue that formed junctions with the host myocardium and contracted synchronously, cardiac function might be restored. A cardiac pacemaker would be required if the transplant did not beat synchronously with the heart.
Although human fetal cardiomyocytes could be transplanted into the infarcted heart, patients would require immunosuppressants to prevent rejection. We [14–16] have grown human cardiomyocytes from myocardial specimens obtained from children and adults undergoing cardiac operations. However, these cardiomyocytes did not beat spontaneously even though the cultured cells contained contractile proteins such as human ventricular myosin heavy chain, light chain, cardiac-specific troponin I isoform, T, and actin. If these inactive cardiomyocytes could be induced to contract, they could be used for transplantation.
Simpson and co-workers [17] found that exposing cardiomyocytes to mechanical stimuli could induce alignment of the contractile apparatus. In a pilot study, we transfected human pediatric cardiomyocytes with a plasmid containing ß-galactosidase gene and cultured them on top of confluent beating fetal rat cardiomyocytes. After 5 days, the cultured cells beat synchronously. Electron microscopy showed transfected human cardiomyocytes contained crystalloid inclusions produced by ß-galactosidase, and many myofilaments were lined up in the cytoplasm. If future research can develop the technology to stimulate the transplanted cardiomyocytes to reform their sarcomeres and to induce angiogenesis, ventricular cardiomyocytes obtained from transvenous endocardial specimens could be grown and autotransplantation could become a reality. The transplanted cells should form intercalated junctions with the host cardiomyocytes, beat synchronously, and improve infarcted heart function.
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Acknowledgments |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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We thank Judy Birth for assistance in the fetal rat heart preparation, Dr Guang Ming Li for help in the histologic examination, and Dr Frank Merante for cell transfection.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and MethodsResultsCommentAcknowledgmentsReferences |
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Address reprint requests to Dr Li, Toronto Hospital-General Division, CCRW 1-854, 200 Elizabeth St, Toronto, Ont, Canada M5G 2C4.
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