HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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): Richard D. Weisel Vivek Rao Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, R.-K. Articles by Jia, Z.-Q. Search for Related Content PubMed PubMed Citation Articles by Li, R.-K. Articles by Jia, Z.-Q. Related Collections Myocardial infarction

Ann Thorac Surg 2001;72:1957-1963
© 2001 The Society of Thoracic Surgeons

---

Original article: cardiovascular

Optimal time for cardiomyocyte transplantation to maximize myocardial function after left ventricular injury

^a Division of Cardiac Surgery, Toronto Hospital Research Institute, and Laboratory Medicine and Pathobiology, Toronto General Hospital and the University of Toronto, Toronto, Ontario, Canada

Accepted for publication August 7, 2001.

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

	Abstract

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Background. This study was designed to determine the optimal time for cell transplantation after myocardial injury.

Methods. The left ventricular free wall of adult rat hearts was cryoinjured and the animals were sacrificed at 0, 1, 2, 4, and 8 weeks for histologic studies. Fetal rat cardiomyocytes (transplant) or culture medium (control) were transplanted immediately (n = 8), 2 weeks (n = 8), and 4 weeks (n = 12) after cryoinjury. At 8 weeks, rat heart function, planimetry, and histologic studies were performed.

Results. Cryoinjury produced a transmural injury. The inflammatory reaction was greatest during the first week but subsided during the second week after cryoinjury. Scar size expanded (p < 0.01) at 4 and 8 weeks. Cardiomyocytes transplanted immediately after cryoinjury were not found 8 weeks after cryoinjury. Scar size and myocardial function were similar to the control hearts. Cardiomyocytes transplanted at 2 and 4 weeks formed cardiac tissue within the scar, limited (p < 0.01) scar expansion, and had better (p < 0.001) heart function than the control groups. Developed pressure was greater (p < 0.01) in the hearts with transplanted cells at 2 weeks than at 4 weeks.

Conclusions. Cardiomyocyte transplantation was most successful after the inflammatory reaction resolved but before scar expansion.

	Introduction

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
After a myocardial infarction, injured cardiomyocytes are removed and replaced by scar tissue. Cardiac dysfunction is proportional to the extent of cardiac muscle cell loss and the extent of scar expansion. The feasibility of myocyte transplantation into an injured myocardial region has been demonstrated [1–4]. Recently patients have benefited from skeletal myoblast transplantation after an extensive myocardial infarction [5]. Myocyte transplantation may prevent heart failure after an extensive infarct. In a previous study we found that fetal rat cardiomyocytes transplanted into myocardial scar tissue 4 weeks after cryoinjury engrafted within the injured region formed cardiac tissue and limited scar expansion [6]. Heart function improved compared with media-injected control animals. The heart function was only 65% of sham-operated normal hearts.

After a myocardial infarction or cryoinjury, first an acute and then a chronic inflammatory reaction occurs. During this process injured cardiac cells are replaced with fibrous tissue and ventricular remodeling progresses [7, 8]. The acute inflammatory reaction could also have remove the transplanted cells which would limit the benefits of cell transplantation. Cell transplantation after significant scar expansion may also be of limited benefit. The present study investigated the optimal time for cell transplantation after myocardial injury.

	Material and methods

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Experimental animals
Experimental animals used were male Sprague-Dawley rats (Lewis; Charles River Canada Inc, Quebec, Canada) weighing 450 g. Cardiomyocytes obtained from 18-day gestational rat hearts were cultured before transplantation. All procedures were approved by the Animal Care Committee of Toronto General Hospital and performed in accordance with 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 (revised 1996).

Myocardial scar generation and evaluation
A myocardial scar was generated as described previously [6]. Briefly, rats were anesthetized with intramuscular ketamine injection (22 mg/kg body weight) followed by an intraperitoneal injection of pentobarbital (30 mg/kg body weight). 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; Southnatick, MA). The rat heart was exposed through a 2-cm left lateral thoracotomy. Cryoinjury of the left ventricular free wall (LVFW) was produced with a liquid nitrogen probe. Ten applications of the cryoprobe for 60 seconds were required to ensure a uniform transmural injury. The muscle layer and skin were closed with 5-0 Vicryl sutures. The rats were monitored for 4 hours postoperatively. Penlog XL (benzathine penicillin G 150,000 U/mL and procaine penicillin G 150,000 U/mL) were given intramuscularly (0.25 mL/rat) after surgery and buprenorphine (0.01 to 0.05 mg/kg body weight) was administrated subcutaneously after surgery.

The LVFW of 35 animals were cryoinjured. Immediately after cryoinjury and at 1, 2, 4, and 8 weeks after injury, 7 animals chosen at random were sacrificed under general anesthesia. The hearts were then fixed in distension (30 mm Hg) with 10% phosphate-buffered formalin solution for 48 hours and then cut into 3-mm thick sections [9]. The sections were used to assess viable myocardium and scar size. The scar was easily identified because it was white and stiff (Fig 2). For each section, the area of scar and the LVFW were traced onto transparencies and quantified using computerized planimetry (Jandal Scientific Sigma Scan, Fairfield, CT). Scar length was the average of endocardial scar length and epicardial scar length. The scar area was the scar length multiplied by section thickness (3 mm). The total scar area was the sum of the scar area in each section. The LVFW myocardial size was calculated as the sum of endocardial and epicardial ventricular muscle areas for each section. The percentage of the LVFW occupied by scar was calculated as scar size divided by LVFW size multiplied by 100.

View larger version (90K): [in this window] [in a new window]   Fig 2. Photomicrographs of hematoxylin and eosin-stained heart sections (magnification x 5) at (A) 1, (B) 2, (C) 4, and (D) 8 weeks after cryoinjury of the LVFW. The size of the scar tissue (arrows) increased with time after injury.

Cell culture and preparation for transplantation
Cardiomyocytes from fetal rat hearts were isolated, purified, and cultured as previously described [2, 6, 10]. Briefly, the cells were cultured for 24 hours in Iscove’s modified Dulbecco’s medium containing 10% fetal bovine serum, 100 U/mL penicillin, and 100 ug/mL streptomycin at 37°C, 5% CO₂, and 95% air. The cultured cardiomyocytes were detached from the cell culture dish with 0.05% trypsin in phosphate-buffered saline (PBS). After centrifugation at 580 g for 3 minutes, the cell pellet was resuspended in culture medium at a concentration of 16 x 10⁶ cells per mL. A 0.25-mL cell suspension was used for each transplantation.

Cardiomyocyte transplantation
The LVFW of 56 adult rat hearts were cryoinjured as described above. The animals were randomly divided into 3 groups. In group one, 8 animals were transplanted with cultured cardiomyocytes (transplant) and 8 animals were transplanted with cultured medium (control) immediately after myocardial injury. In group two, animals were transplanted with cells or cultured medium (n = 8 each) 2 weeks after myocardial injury. In group three, media-control and cell-transplanted animals (n = 12 each) were injected 4 weeks after myocardial injury.

Under general anesthesia, the hearts were exposed through a midline sternotomy. A fetal rat cardiomyocyte suspension (0.25 mL, 4 x 10⁶ cells) or culture medium (0.25 mL) was injected once into the center of the scar tissue of the transplanted and control animals, respectively, using a tuberculin syringe with a 27-gauge needle. The injection site was sealed with cryoprecipitate. The chest was closed with 5-0 Vicryl sutures. Antibiotics and analgesics were given as described above, in the myocardial scar generation and evaluation section. Cyclosporin A, at a dose of 5 mg/kg body weight daily, was administered subcutaneously to the control and transplanted rats. The rats were housed in cages with filter tops.

Myocardial function studies
At 8 weeks after myocardial injury, the heart function of control and transplanted animals at 0, 2 and 4 weeks after myocardial injury was assessed using a Langendorff perfusion apparatus [6, 11]. The rats were anesthetized and heparin (200 U) was administered intravenously. The hearts were quickly isolated from rats and perfused in a Langendorff apparatus with filtered Krebs Heinseleit buffer (in mmol/L: NaCl 118, KCl 4.7, KH₂PO₄ 1.2, CaCl₂ 2.5, MgSO₄ 1.2, NaHCO₃ 25, glucose 11; pH 7.4) equilibrated with 5% CO₂ and 95% O₂. 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), an amplifier and differentiator amplifier (Model 11-G4113 to 01, Gould Instrument System Inc, Valley View, Ohio). After 30 minutes of stabilization the balloon size was increased by the addition of saline in 0.02 mL increments from 0.04 mL to the volume at which the end diastolic pressure was 30 mm Hg. 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.

Measurement of left ventricular free wall remodeling
After the function measurements, the hearts were fixed, sectioned, and photographed. LVFW and scar sizes were quantified using computerized planimetry as described above, in the myocardial scar generation and evaluation section. The transplanted tissue size as a percentage of the scar size was similarly calculated.

Histological identification of transplanted muscle cells in the scar tissue
The fixed heart sections were then embedded in paraffin and sectioned to yield slices 10 µm thick. The slices were stained with hematoxylin and eosin as described above, in the histologic studies section.

The slices with transplanted cells were also stained for myosin heavy chain (monoclonal antibody specific for alpha and beta myosin heavy chain from Rougier Bio-Tech, Montreal, Quebec) using avidin-biotin-peroxidase complex technique as we described previously [12]. After deparaffined and rehydrated, the sample was incubated with a solution of 3% H₂O₂ in 70% methanol for 30 minutes to inhibit endogenous myocardial peroxidase. Triton X-100 (0.2%) was used to treat samples for 10 minutes to enhance cell permeability. After blocking nonspecific protein binding with 2% normal goat serum in 0.05 mol/L Tris buffer (pH 7.4) for 15 minutes, the primary antibodies against myosin heavy chain (1:1000) were added and the samples were incubated at 37°C for 30 minutes followed by an overnight incubation at 4°C. Negative control samples were incubated in PBS under the same conditions. After samples were washed with PBS, a biotin-labeled secondary antibody (1:250) was added and the samples were incubated at room temperature for 1 hour. The samples were rinsed with PBS and then reacted with an avidin-biotin complex conjugated with peroxidase at room temperature for 45 minutes. A diaminobenzidine solution (0.25 mg/mL in 0.05 Tris-HCl buffer containing 0.02% H₂O₂) was added and incubated with cells for 10 minutes to identify the positive cells. The cellular nuclei were counter-stained with hematoxylin for 1 minute. The samples were covered and photographed.

Data analysis
Data are expressed as the mean ± standard error. The Statistical Analysis System software was used for all analysis (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 ANOVA, a Duncan’s multiple-range t test was employed to specify differences between the groups. The critical -level for these analyses was set at p less than 0.05.

Functional data were evaluated by an analysis of covariance (ANCOVA) using intracavitary balloon volume as the covariate and systolic, diastolic, and developed pressure as dependent variables. The main effects were group (media or cell transplants) and pressure and the interaction between group and pressure.

	Results

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
Histologic and morphologic changes of the hearts after myocardial injury
Immediately after cryoinjury, 25% ± 3% of the LVFW was damaged transmurally. The cardiomyocytes were fragmented (Fig 1A). At 1 week after cryoinjury most of the injured cardiomyocytes were gone and a predominantly mononuclear inflammatory infiltrate was present in the affected area (Fig 1B). At 2 weeks the inflammatory infiltrate had almost disappeared and fibroblasts and collagen deposition were evident (Fig 1C). At 4 and 8 weeks the scar was composed of mature fibrous tissue (Fig 1D) that was less cellular. Lymphocytes were not observed.

View larger version (161K): [in this window] [in a new window]   Fig 1. Photomicrographs of hematoxylin and eosin-stained sections from the injured region sequentially after cryoinjury. (A) Immediately after cryoinjury (magnification x 200), the myocytes were fragmented immediately. (B) One week after cryoinjury (x 100), a predominantly mononuclear infiltrate was present and most of the necrosed cardiomyocytes had disappeared. (C) Two weeks after cryoinjury (x 100), fibroblasts and collagen were evident; the inflammatory infiltrate was almost gone. (D) Four weeks after cryoinjury (x 200), a transmural scar had formed.

Effect of transplanted cells on scar size
Eight weeks after cryoinjury the fetal rat cardiomyocytes transplanted into the injured region immediately after cryoinjury were not found in the injured region. (Figs 3 and 4). The scar area (53% ± 5%) of transplanted hearts was similar to that of the media-injected control group (55% ± 3% of the LVFW). No myocardial tissue was found in the scar in either the endocardial or epicardial regions. Cardiomyocytes transplanted at 2 weeks after cryoinjury engrafted in the injured region and formed cardiac tissue, which stained positively for myosin heavy chain in all sections studied. The newly formed cardiac tissue occupied 34% of the total scar area (11% ± 3% of the LVFW). Similarly cardiomyocytes transplanted at 4 weeks occupied 31% of total scar area (12% ± 2% of LVFW). The scar sizes for both the 2 and 4 week transplanted hearts were smaller (p < 0.01) than the scar size of the control hearts. The total scar size of the hearts transplanted at 2 weeks (32% ± 5%) was smaller (p < 0.01) than that of the hearts transplanted at 4 weeks (42% ± 2% of the LVFW).

View larger version (84K): [in this window] [in a new window]   Fig 3. Photomicrograph of hematoxylin and eosin-stained heart sections (magnification x 5) at 8 weeks after cryoinjury. (A) Control media-transplanted heart is shown. (B) Hearts transplanted with cultured fetal rat cardiomyocytes immediately after cryoinjury had no cardiac tissue in the myocardial scar tissue. Cardiomyocytes transplanted (C) 2 weeks and (D) 4 weeks after cryoinjury demonstrated cardiac tissue (arrows) in the scar.

View larger version (23K): [in this window] [in a new window]   Fig 4. Percentages of scar tissue and transplanted cardiac tissue in the left ventricular free wall at 8 weeks after cryoinjury. Fetal rat cardiomyocytes transplanted at 2 and 4 weeks after myocardial injury formed cardiac tissues that occupied 34% and 31% of the total scar area, respectively. The cardiac transplant limited scar expansion. Results are expressed as mean ± SE (n = 8, 12). (**Indicates p < 0.01, "a" versus "b.")

View larger version (24K): [in this window] [in a new window]   Fig 5. Cardiac function when the cardiomyocytes were transplanted 2 (A and B, n = 8) and 4 weeks (C and D, n = 12) after cryoinjury. Systolic and developed pressures of the transplanted rat hearts were significantly greater than those of media control hearts (p < 0.01, interactive effect of analysis of covariance). Results are expressed as mean ± SE.

View larger version (22K): [in this window] [in a new window]   Fig 6. Developed pressures in hearts transplanted at 2 and 4 weeks after cryoinjury. The developed pressures of hearts transplanted at 2 weeks (n = 8) were significantly (*p < 0.05, **p < 0.01) higher than those of the hearts transplanted at 4 weeks (n = 12). Results are expressed as mean ± SE.

	Comment

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
After a myocardial infarction the damaged myocardium undergoes both acute and chronic inflammatory reactions and myocardial fibrosis [13]. Ventricular pressure stretches and thins the healing area inducing ventricular dilatation [14]. The dilated heart may result in congestive heart failure. A ventricular aneurysm may form, further comprising heart function. The goal of all current treatments is to limit this remodeling process [15]. Prevention of infarct thinning and dilatation will reduce the signs and symptoms of congestive heart failure. The addition of muscle cells provides elasticity, stabilizing the injured region and preventing infarct thinning and preserving chamber size and ventricular function.

We previously demonstrated that fetal cardiomyocytes transplanted into a myocardial scar formed cardiac tissue and improved myocardial function [6]. In that study, transplantation was performed 4 weeks after myocardial cryoinjury when ventricular dilatation had already begun. Therefore we investigated the benefits of cell injection earlier than 4 weeks after cryoinjury. We found that cell transplantation immediately after cryoinjury resulted in cell loss during the acute inflammatory reaction and no improvement in myocardial function. We believed the activated neutrophils and macrophages in the inflammatory reaction indiscriminately removed the injured cardiomyocytes as well as the transplanted cells. Consistent with the histologic findings, the myocardial function of the hearts transplanted at 2 weeks was better than that of the hearts transplanted at 4 weeks. The improved myocardial function was due to less scar thinning and smaller ventricular volumes. Transplantation as soon as possible after disappearance of the acute inflammatory reaction in the infarcted myocardium should minimize ventricular remodeling and optimize myocardial function.

Unfortunately, our study has limitations that should be recognized [1]. The rat completes the inflammatory response to cryoinjury within 2 weeks. Larger animals have an inflammatory response that lasts longer [14]. Therefore the optimal time for cell transplantation may be weeks after a myocardial infarction in large animals and humans [2]. Cryoinjury is not clinically relevant but this injury may be more similar to a transmural infarction in humans who have limited collaterals than to coronary ligation in the rat. A nontransmural infarct may preserve an epicardial rim of viable myocardium that resists thinning and dilatation. Cryoinjury produces a reproducible transmural injury producing uniform and consistent ventricular thinning and later dilatation [3]. Delayed cardiomyocyte transplantation permitted adhesion formation between the chest wall and the injured region. Dissecting the heart from the chest wall may have injured the heart when cell transplantation was performed at 2 and 4 weeks after injury. Function was better at 2 and 4 weeks than immediately after cryoinjury, however, suggesting that cardiac injury at reoperation was minimal [4]. Langendorff measurements of intraventricular volumes are difficult in the rat. The intraventricular balloon does not accurately measure the volume in the left ventricle but does accurately measure the increase in volume associated with the injection of saline into the balloon. Therefore the Langendorff perfusion technique permits a comparison between groups but does not accurately measure ventricular volumes [5]. Extrapolation of our results to humans should be performed with caution. The rats used in this study did not have coronary artery disease, valvular disease, or arrhythmias. Humans may have an adverse response to cell transplantation not seen in the rat. However, the recent clinical report of skeletal myoblast implantation in patients who had an extensive myocardial infarction documented improved perfusion and function of the infarct region, perhaps related to the cell transplantation [5].

The mechanism of improved heart function by myocyte transplantation has been incompletely studied. Taylor and colleagues [15] demonstrated increased elasticity of the cryoinjured region when skeletal myoblasts engrafted. The benefits of cell engraftment included angiogenesis [2, 6] and the maintenance of the elasticity of the scar by changes in the interstitial matrix.

In summary, transplantation of fetal cardiomyocytes forms cardiac tissue in scar tissue that limited scar thinning and ventricular dilatation. The optimal time for transplantation to improve myocardial function was after the acute inflammatory reaction has subsided and before significant ventricular dilatation had occurred.

	Acknowledgments

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 
This study was supported by the Medical Research Council of Canada (MT-13665, MT-10392). Ren-Ke Li is a career investigator of the Heart and Stroke Foundation of Canada. Richard D. Weisel is a career investigator of the Heart and Stroke Foundation of Ontario.

	References

Top Abstract Introduction Material and methods Results Comment Acknowledgments References

 

1. Leor L., Patterson M., Quinones M.J., Kedes L.H., Kloner R.K. Transplantation of fetal myocardial tissue into the infarcted myocardium of rat: a potential method for repair of infarcted myocardium?. Circulation 1996;94(Suppl II):332-336.
2. Li R.-K., Mickle D.A.G., Weisel R.D., Zhang J., Mohabeer M.K. In vivo survival and function of transplanted rat cardiomyocytes. Circ Res 1996;78:283-288.[Abstract/Free Full Text]
3. Scorsin M., Marotte F., Sabri A., et al. Can grafted cardiomyocytes colonize peri-infarct myocardial areas?. Circulation 1996;94(Suppl II):337-340.
4. Van Meter C.H., Claycomb W.C., Delcarpio J.B., et al. Myoblast transplantation in the porcine model: a potential technique for myocardial repair. J Thorac Cardiovasc Surg 1995;110:1442-1448.[Abstract/Free Full Text]
5. Menasche P., Hagege A.A., Scrosin M., et al. First successful clinical myoblast transplantation for heart failure. Lancet 2001;357:279-280.[Medline]
6. Li R.-K., Jia Z.-Q., Weisel R.D., et al. Cardiomyocyte transplantation improves heart function. Ann Thorac Surg 1996;62:654-661.[Abstract/Free Full Text]
7. Jugdutt B.I., Khan M.I., Jugdutt S.J., Blinston G.E. Combined captopril and isosorbide dinitrate during healing after myocardial infarction: effect on ventricular remodeling, function, mass and collagen. J Am Coll Cardiol 1995;25:1089-1096.[Abstract]
8. Roberts C.S., Maclean D., Braunwald E., Maroko P.R., Kloner R.A. Topographic changes in the left ventricle after experimentally induced myocardial infarction in the rat. Am J Cardiol 1983;51:872-876.[Medline]
9. Fletcher P., Pfeffer J., Pfeffer M., Braunwald E. Left ventricular diastolic pressure-volume relations in rats with healed myocardial infarction. Circ Res 1981;49:618-626.[Abstract/Free Full Text]
10. Li R.-K., Weisel R.D., Williams W.G., Mickle D.A.G. Method of culturing cardiomyocytes from human pediatric ventricular myocardium. J Tiss Cult Meth 1992;14:93-100.
11. Fremes S.E., Furukawa R.D., Zhang J., et al. Cardiac storage with University of Wisconsin solution and a nucleoside-transport blocker. Ann Thorac Surg 1995;59:1127-1133.[Abstract/Free Full Text]
12. Li R.-K., Li G., Mickle D.A.G., et al. Over-expression of transforming growth factor beta1, and insulin-like growth factor-I in patients with idiopathic hypertrophic cardiomyopathy. Circulation 1997;96:874-881.[Abstract/Free Full Text]
13. Fishbein M., Maclean D., Maroko P. Experimental myocardial infarction in the rat. Am J Pathol 1978;90:57-70.[Abstract]
14. Jugdutt B.I., Amy R.W.M. Healing after myocardial infarction in the dog: changes in infarct hydroxyproline and topography. J Am Coll Cardiol 1986;7:91-102.[Abstract]
15. Taylor D.A., Atkins B.Z., Hungspreugs P., et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998;4:929-933.[Medline]

This article has been cited by other articles:

				M. Yousef, C. M. Schannwell, M. Kostering, T. Zeus, M. Brehm, and B. E. Strauer The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J. Am. Coll. Cardiol., June 16, 2009; 53(24): 2262 - 2269. [Abstract] [Full Text] [PDF]

				R. L Kao, W. Browder, and C. Li Cellular Cardiomyoplasty: What Have We Learned? Asian Cardiovasc Thorac Ann, January 1, 2009; 17(1): 89 - 101. [Abstract] [Full Text] [PDF]

				P. Farahmand, T. Y.Y. Lai, R. D. Weisel, S. Fazel, T. Yau, P. Menasche, and R.-K. Li Skeletal Myoblasts Preserve Remote Matrix Architecture and Global Function When Implanted Early or Late After Coronary Ligation Into Infarcted or Remote Myocardium Circulation, September 30, 2008; 118(14_suppl_1): S130 - S137. [Abstract] [Full Text] [PDF]

				Y.-J. Yang, H.-Y. Qian, J. Huang, Y.-J. Geng, R.-L. Gao, K.-F. Dou, G.-S. Yang, J.-J. Li, R. Shen, Z.-X. He, et al. Atorvastatin treatment improves survival and effects of implanted mesenchymal stem cells in post-infarct swine hearts Eur. Heart J., June 2, 2008; 29(12): 1578 - 1590. [Abstract] [Full Text] [PDF]

				J. Leor, S. Gerecht, S. Cohen, L. Miller, R. Holbova, A. Ziskind, M. Shachar, M. S Feinberg, E. Guetta, and J. Itskovitz-Eldor Human embryonic stem cell transplantation to repair the infarcted myocardium Heart, October 1, 2007; 93(10): 1278 - 1284. [Abstract] [Full Text] [PDF]

				X. Hu, J. Wang, J. Chen, R. Luo, A. He, X. Xie, and J. Li Optimal temporal delivery of bone marrow mesenchymal stem cells in rats with myocardial infarction Eur. J. Cardiothorac. Surg., March 1, 2007; 31(3): 438 - 443. [Abstract] [Full Text] [PDF]

				S. Wisel, S. M. Chacko, M. L. Kuppusamy, R. P. Pandian, M. Khan, V. K. Kutala, R. W. Burry, B. Sun, P. Kwiatkowski, and P. Kuppusamy Labeling of skeletal myoblasts with a novel oxygen-sensing spin probe for noninvasive monitoring of in situ oxygenation and cell therapy in heart Am J Physiol Heart Circ Physiol, March 1, 2007; 292(3): H1254 - H1261. [Abstract] [Full Text] [PDF]

				E. Shantsila, T. Watson, and G. Y.H. Lip Endothelial Progenitor Cells in Cardiovascular Disorders J. Am. Coll. Cardiol., February 20, 2007; 49(7): 741 - 752. [Abstract] [Full Text] [PDF]

				S. Jiang, H. Kh. Haider, N. M. Idris, A. Salim, and M. Ashraf Supportive Interaction Between Cell Survival Signaling and Angiocompetent Factors Enhances Donor Cell Survival and Promotes Angiomyogenesis for Cardiac Repair Circ. Res., September 29, 2006; 99(7): 776 - 784. [Abstract] [Full Text] [PDF]

				T. Mizuno, T. M. Yau, R. D. Weisel, C. G. Kiani, and R.-K. Li Elastin Stabilizes an Infarct and Preserves Ventricular Function Circulation, August 30, 2005; 112(9_suppl): I-81 - I-88. [Abstract] [Full Text] [PDF]

				H. Piao, T.-J. Youn, J.-S. Kwon, Y.-H. Kim, J.-W. Bae, Bora-Sohn, D.-W. Kim, M.-C. Cho, M.-M. Lee, and Y.-B. Park Effects of bone marrow derived mesenchymal stem cells transplantation in acutely infarcting myocardium Eur J Heart Fail, August 1, 2005; 7(5): 730 - 738. [Abstract] [Full Text] [PDF]

				F. Fernandez-Aviles, J. A. San Roman, J. Garcia-Frade, M. E. Fernandez, M. J. Penarrubia, L. de la Fuente, M. Gomez-Bueno, A. Cantalapiedra, J. Fernandez, O. Gutierrez, et al. Experimental and Clinical Regenerative Capability of Human Bone Marrow Cells After Myocardial Infarction Circ. Res., October 1, 2004; 95(7): 742 - 748. [Abstract] [Full Text] [PDF]

				J. C. Chachques, C. Acar, J. Herreros, J. C. Trainini, F. Prosper, N. D'Attellis, J.-N. Fabiani, and A. F. Carpentier Cellular cardiomyoplasty: clinical application Ann. Thorac. Surg., March 1, 2004; 77(3): 1121 - 1130. [Abstract] [Full Text] [PDF]

				T. Siminiak and M. Kurpisz Myocardial Replacement Therapy Circulation, September 9, 2003; 108(10): 1167 - 1171. [Full Text] [PDF]

				A. Bel, E. Messas, O. Agbulut, P. Richard, J. L. Samuel, P. Bruneval, A. A. Hagege, and P. Menasche Transplantation of Autologous Fresh Bone Marrow Into Infarcted Myocardium: A Word of Caution Circulation, September 9, 2003; 108(90101): II-247 - 252. [Abstract] [Full Text] [PDF]

				G. H.L. Tang, P. W.M. Fedak, T. M. Yau, R. D. Weisel, A. Kulik, D. A.G. Mickle, and R.-K. Li Cell transplantation to improve ventricular function in the failing heart Eur. J. Cardiothorac. Surg., June 1, 2003; 23(6): 907 - 916. [Abstract] [Full Text] [PDF]

				P. Menasche Cell transplantation in myocardium Ann. Thorac. Surg., June 1, 2003; 75(90060): S20 - 28. [Abstract] [Full Text] [PDF]

				T. Reffelmann and R. A. Kloner Cellular cardiomyoplasty--cardiomyocytes, skeletal myoblasts, or stem cells for regenerating myocardium and treatment of heart failure? Cardiovasc Res, May 1, 2003; 58(2): 358 - 368. [Full Text] [PDF]

				M. Ruel, R. A. Kelly, and F. W. Sellke Therapeutic Angiogenesis, Transmyocardial Laser Revascularization, and Cell Therapy Card. Surg. Adult, January 1, 2003; 2(2003): 715 - 750. [Full Text]

				B. E. Strauer, M. Brehm, T. Zeus, M. Kostering, A. Hernandez, R. V. Sorg, G. Kogler, and P. Wernet Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans Circulation, October 8, 2002; 106(15): 1913 - 1918. [Abstract] [Full Text] [PDF]

				Y. Sakakibara, K. Tambara, F. Lu, T. Nishina, G. Sakaguchi, N. Nagaya, K. Nishimura, R.-K. Li, R. D. Weisel, and M. Komeda Combined Procedure of Surgical Repair and Cell Transplantation for Left Ventricular Aneurysm: An Experimental Study Circulation, September 24, 2002; 106(12_suppl_1): I-193 - I-197. [Abstract] [Full Text] [PDF]

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): Richard D. Weisel Vivek Rao Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Li, R.-K. Articles by Jia, Z.-Q. Search for Related Content PubMed PubMed Citation Articles by Li, R.-K. Articles by Jia, Z.-Q. Related Collections Myocardial infarction