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Ann Thorac Surg 2006;81:160-167
© 2006 The Society of Thoracic Surgeons

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Original article: Cardiovascular

Hybrid Surgical Angiogenesis: Omentopexy Can Enhance Myocardial Angiogenesis Induced by Cell Therapy

Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine, Kanazawa, Japan

Accepted for publication July 5, 2005.

^_* Address correspondence to Dr Kanamori, Department of General and Cardiothoracic Surgery, Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa, 920-8641, Japan (Email: kintaro{at}ruby.ocn.ne.jp).

	Abstract

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
BACKGROUND: The conditions at the injection site are important in cell transplantation for severe ischemic heart disease. The omentum is both a well-vascularized tissue and a source of angiogenic factors. We examined the effectiveness of autologous bone marrow-derived mononuclear cells (BM-MNCs) with or without omentopexy in a large animal model.

METHODS: Myocardial infarction was generated in the lateral wall by ligation of coronary artery branches in miniswine. Animals received BM-MNC injection with or without omentopexy. Controls received saline only. Three weeks after surgery, regional myocardial blood flow and contractility were measured, and density of arterioles was evaluated immunohistologically. Angiography and postmortem examinations were performed to determine collateral communication.

RESULTS: Regional myocardial contractility was significantly improved by BM-MNC transplantation both with and without omentopexy (0.29 ± 0.02 vs 0.11 ± 0.03, p < 0.01, 0.30 ± 0.02 vs 0.12 ± 0.01, p < 0.01, respectively). Relative regional myocardial blood flow in the combined omentopexy group was significantly higher than the controls both at rest (1.05 ± 0.11 vs 0.57 ± 0.07, p < 0.01) and under stress (1.09 ± 0.08 vs 0.40 ± 0.10, p < 0.01). The number of arterioles (< 50 µm) in both groups were higher than the controls (88.1 ± 5.00 vs 38.1 ± 8.99, p < 0.01 and 109.2 ± 9.91 vs 38.1 ± 8.99, p < 0.01, respectively). The number of large arterioles (> 50 µm) in the combined omentopexy group was significantly higher than in both BM-MNC alone (26.9 ± 2.4 vs 17.6 ± 1.8, p = 0.011) and controls (26.9 ± 2.4 vs 10.0 ± 1.3, p < 0.01). Collateral communication between the omentum and myocardium was demonstrated by angiography and postmortem injection.

CONCLUSIONS: The BM-MNC transplantation may attenuate cardiac contractile dysfunction, and omentopexy may enhance angiogenesis induced by BM-MNC transplantation.

	Introduction

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Cell transplantation has come of age as a promising novel treatment option for severe ischemic heart disease [1–3]. Recent experimental studies and clinical reports have demonstrated the safety, efficacy, and feasibility of cell transplantation [4–7]. The conditions at the site of injection are among the most important considerations determining the effectiveness of cell therapy. If cells were injected into infarcted myocardium it may be difficult for them to survive due to limitations in the blood supply with regard to both oxygen and nutrients [8]. Moreover, sufficient continuous blood supply to enhance angiogenesis may not be available from surrounding normal vessels, which may be far from the target area. The development of a new external blood flow source will be necessary for cells to survive and to allow angiogenesis to develop in the infarcted myocardium.

In the present study, we utilized the omentum as a new blood supply source. Historically, cardio-omentopexy had been demonstrated as a surgical technique for myocardial revascularization for ischemic heart disease induced by autologous outside tissue [9–13]. We developed a new hybrid surgical angiogenesis procedure induced by transplantation of autologous bone marrow-derived mononuclear cells (BM-MNCs) combined with omentopexy, and tested the effectiveness of cell transplantation with or without omentopexy in a large animal model.

	Material and Methods

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Experimental Animals
Nineteen healthy miniswine (25.1 ± 1.9 kg) were used for this study. All animals received humane care in compliance with the "Principles of Laboratory Animals 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 and published by the National Institutes of Health, revised in 1996. All protocols were approved by the Animal Use and Care Committee of Kanazawa University, and we complied with the regulations of this Committee completely.

Preparation of BM-MNCs
All surgical procedures were performed under general anesthesia, which was induced by intramuscular administration of ketamine hydrochloride (20 mg/kg), and maintained with 1% halothane. After intratracheal intubation, all animals were ventilated with a volume-regulated ventilator (KMA-1300IIS, Acoma Medical Industry, Tokyo, Japan). Continuous arterial pressure and electrocardiography were monitored during all procedures.

After general anesthesia, autologous BMCs were aspirated (96.5 ± 11 mL) from the iliac crest using a bone marrow aspiration needle. The BM-MNCs were fractionated using a bone marrow processing filter (Terumo, Tokyo, Japan), and finally concentrated to a density of 3.0 x 10⁷ cells/mL; total 1.2 x 10⁸ cells. The bone marrow processing filter was a porous polyurethane material whose separation mechanism was performed by pore sizes changing when it was compressed and released thereafter [14]. After priming with washout solution (0.5% human serum albumin added saline), the filter was compressed while BM cells were draining in and filtering. Red blood cells (RBC), granulocytes, and platelets passed through a porous filter into the waste bag. After tube rinsing, the filter was depressed and the remaining cells were rinsed and flowed back up to the collection bag. Finally, volume was reduced to 20 mL by centrifugation. In this experiment, the recovery of BM-MNCs was 92.8 ± 7.5% and the RBC depletion was 96.4 ± 1.0%. The processing was simple to perform; filtration time was 322 ± 86 seconds, and total working time was 490 ± 99 seconds. Before cells centrifugation, BM-MNCs were prelabeled with PKH26 red fluorescence cell linker (Sigma, St. Louis, MO) to detect transplanted cells, as previously described [15].

Myocardial Infarction
Minimal left thoracotomy and pericardiotomy were performed in the left fifth intercostal space. Myocardial infarction at the lateral wall area was generated by direct ligation of the first and second obtuse marginal branches of the circumflex artery and the distal site of the first diagonal branch with 5-0 polypropylene sutures. To prevent fatal arrhythmia, lidocaine (2 mg/kg/hour) was administered intravenously to all animals. After ligation, animals were monitored carefully for 60 minutes to stabilize blood pressure and arrhythmia. In all animals, persistent ST-segment elevation on electrocardiographic monitor and color change of myocardium were observed.

Preparation of Omental Flap
Sixty minutes after ligation, upper midline laparotomy was performed in all animals. The omental flap measuring approximately 5 x 5 cm was prepared carefully using a harmonic scalpel to protect the left gastroepiploic artery and vein as its blood supplying conduit. At this time, fifteen animals survived and they were randomly divided into three groups: saline injection only (control group, n = 5), autologous BM-MNC injection (BM group, n = 5), autologous BM-MNC injection and omentopexy (BM+Oment group, n = 5).

BM-MNC Implantation and Omentopexy
Cell implantation was performed in the BM and BM+Oment group. The BM-MNCs (a total 1.2 x 10⁸ cells, 6.0 x 10⁶ cells/0.2 mL/site x 20 sites) were injected directly into the myocardium using a 26-gauge needle, including the infarct area and peri-infarct area taking a width of approximately 1 cm from the borderline (Fig 1). The same volume (0.2 mL/site x 20 sites) of saline was injected in the control group. After injection in the BM+Oment group, the pedicled omental flap was passed through the diaphragm into the pericardial space and wrapped directly around the lateral wall into which BM-MNCs had already been injected. It was fixed with 6-0 polypropylene sutures. Prior to wrapping with the omental flap, the epicardium of the wrapped area was abraded carefully using a circular scalpel [12]. The thoracic and abdominal incisions were closed, and animals were allowed to recover in their cages.

View larger version (61K): [in this window] [in a new window]   Fig 1. Experimental model. After myocardial infarction at the lateral wall area was generated, bone marrow-derived mononuclear cells (total 1.2 x 108 cells, 6.0 x 106 cells /0.2 mL/site x 20 sites) were injected directly into the myocardium including the infarct area and peri-infarct area with a width of approximately 1 cm from the borderline. After injection, epicardiectomy was performed and the omental flap passed through the diaphragm was wrapped directly around the injected area.

RFS = (LVDD – LVSD)/LVDD.

Angiographic Study
Three weeks after treatment, gastroepiploic angiography was performed to determine communication between the arteries in the omental flap and coronary arteries. After relaparotomy under general anesthesia, the left gastroepiploic artery (GEA) pedicle was identified and directly cannulated with an 18G catheter. Contrast medium (15 mL) was injected through the catheter into the left GEA at a continuous rate by hand for 10 seconds. Several angiograms of arteriovenous phase were taken in each animal.

Regional Myocardial Blood Flow
After angiography, regional myocardial blood flow (RMBF) was measured using the colored microsphere method based on the arterial reference sample technique in all animals [16]. Color-labeled microspheres 15 µm in diameter (E-Z Trac Inc, Los Angeles, CA) were injected into the left atrium while reference arterial samples were withdrawn from the left femoral artery. Postexperimental myocardial tissue and reference blood samples were analyzed with a spectrophotometer (U-1100; Hitachi, Tokyo, Japan). Color-labeled microspheres were injected at rest and under dobutamine stress (at a dose of 25 µg/kg/minute intravenously, for 3 minutes). Tissue samples were taken from the lateral wall area (infarcted wall area) and the septal wall area (normal wall area) in all animals. The RMBF was calculated as follows: RMBF (mLl/minute/gram) = (Ct / Wt) x (Fr / Cr), where Ct and Cr are the absorbance from dispersed microspheres in the tissue and the reference blood sample, respectively, Fr is the reference rate, and Wt is the total weight of the tissue sample in grams. The RMBF was evaluated as the absolute value and a relative RMBF index as follows: relative RMBF index = RMBF of the lateral wall/RMBF of the septal wall [17].

Histologic Study
At the end of the experimental procedures, all animals were euthanized and the hearts (and omental flaps) were removed. To provide the evidence of communication between the omental flap and the myocardium, a postmortem carbon injection test was performed prior to fixation. Diluted carbon medium was injected directly by hand from the proximal end of the left GEA, through the vessels of the omental flap to the myocardium for the subsequent histologic study.

Some parts of the tissue samples were cryopreserved in liquid nitrogen and cut in 5-µm thick sections with cryostat to detect the implanted BM-MNCs prelabeled with PKH26 red fluorescence cell linker. Sections were stained for alkaline phosphatase to detect capillary endothelial cells with 5-bromo-4-chlorl-3-indolyl phosphatase /nitro blue tetrazolium (Sigma, St. Louis, MO) for 45 minutes at 37°C, and then counterstained with eosin.

The other parts were fixed in neutralized 10% formaldehyde. Paraffin sections 4-µm thick were deparaffinized and intrinsic peroxidase activity was inhibited, and nonspecific binding was blocked. Antialpha smooth muscle actin (Dako, Carpinteria, CA) was used as the primary antibody, diluted 1:100, and incubated with the tissue sections for 24 hours at 4°C. Histofine Simple Stain MAX-PO(R) (Nichirei, Tokyo, Japan) was incubated with the tissue sections for 30 minutes at room temperature as the secondary antibody. Sections were stained with 0.2 mg/mL of 3,3'-diaminobenzidine tetrahydrochloride (Wako Pure Chemical Industries, Osaka, Japan), and then counterstained with hematoxylin. Between each step, the sections were washed with distilled water or 10 mmol/L phosphate-buffered saline (pH 7.2). To estimate the density of arterioles, the number of arterioles was counted in five fields chosen at random in the peri-infarct region of each section. The density of arterioles was defined as the number of arterioles per mm² containing smooth muscle cells detected by immunohistochemical staining and had round or elliptical structures (< 50 µm and > 50 µm in diameter) [7]. All quantitative analyses were performed in a blinded manner.

Statistical Analysis
All data are expressed as the means ± standard error. The RFS values were compared within each group using the paired Student's t test. One-way analysis of variance followed by Scheffe's test was used to compare RFS, RMBF, and the number of arterioles among the three groups. Data were considered significant at a value of p less than 0.05. All analyses were performed with SPSS 10.01 (SPSS Japan Inc, Tokyo, Japan).

	Results

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
Procedural Outcome
Ventricular fibrillation occurred as a fatal complication during surgery in four of the nineteen animals treated according to our protocol despite the intravenous administration of lidocaine (2 mg/kg/hour). In the fifteen surviving animals, echocardiography was performed before injection. Similar severe deterioration of the RFS was observed in all animals (preinfarction 0.36 ± 0.02 vs before injection 0.12 ± 0.02, p < 0.01) (Fig 2), and there were no significant differences in RFS before injection among the three groups (p = 0.63). Subsequently, no life-threatening infections or fetal arrhythmias were observed in any animals during the three weeks after surgery.

View larger version (16K): [in this window] [in a new window]   Fig 2. Regional fractional shortening (RFS) at three periods (preinfarction, before injection, three weeks after injection) is shown. Before injection, severe deterioration of the RFS was observed in all animals. Three weeks after injection, the RFS of the bone marrow (BM) group and the BM+Oment group were significantly improved as compared with those before injection each. There was no significant difference between BM group and BM+Oment group. *p < 0.01 vs RFS before injection. (Oment = omentopexy.)

Regional Myocardial Blood Flow
There were no significant differences in absorbed value of RMBF at rest and under stress among the three groups (Table 1). The relative RMBF index of the BM+Oment group was significantly higher than that of the control group at rest (1.05 ± 0.11 vs 0.57 ± 0.07, p < 0.01); however, there was no significant difference between the BM+Oment and the BM group. Relative RMBF index of the BM group and the BM+Oment group were significantly higher than that in the control group under stress (0.93 ± 0.11 vs 0.40 ± 0.10, p < 0.01, and 1.09 ± 0.08 vs 0.40 ± 0.10, p < 0.01, respectively) (Fig 3).

View larger version (21K): [in this window] [in a new window]   Fig 3. Relative regional myocardial blood flow (RMBF) at rest (left) and under stress (right) is shown. Relative RMBF index was defined as RMBF of the infarcted (lateral) wall/RMBF of the normal (septal) wall. At rest, relative RMF index of the BM+Oment group was significantly higher than that of the control group. There was no significant difference between the BM+Oment and the BM group. Under stress, relative RMBF index of the BM group and the BM+Oment group were significantly higher than that in the control group. *p < 0.01 vs the control group. (BM = bone marrow; Oment = omentopexy.)

View larger version (91K): [in this window] [in a new window]   Fig 4. (A) The density of arterioles was evaluated by immunohistochemical staining with anti-alpha-smooth muscle actin antibody (right: BM group, Left: BM+Oment group). (B) The number of arterioles per mm2 were counted (< 50 µm and > 50 µm in diameter). The numbers of arterioles (< 50 µm) were significantly increased in both the BM group and BM+Oment group as compared with the control group. The number of arterioles (> 50 µm) in the BM+Oment group was higher than those of both the BM group and the control group. *p < 0.01 vs the control group and **p = 0.011 vs the BM group. (BM = bone marrow; Oment = omentopexy.)

View larger version (158K): [in this window] [in a new window]   Fig 5. Representative immunohistochemical fingings in myocardium in BM+Oment group three weeks after injection (original magnification [A] 100x, [B] 400x). A great number of isolated transplanted cells detected with PKH26 red fluorescence cell linker were observed in the myocardium, and some corresponded to capillaries, which were detected with alkaline phosphatase staining. (BM = bone marrow; Oment = omentopexy.)

View larger version (129K): [in this window] [in a new window]   Fig 6. Representative gastroepiploic angiographic findings in BM+Oment group 3 weeks after surgery is shown. Rich collaterals are created from the branches of the left gastroepiploic artery (Lt GEA) in the omental flap to the myocardial capillary beds (small arrow), and retrograde contrast of the coronary artery flow through collaterals is observed (large arrow). (BM = bone marrow; Oment = omentopexy.)

View larger version (74K): [in this window] [in a new window]   Fig 7. Representative postmortem carbon injection test findings in the BM+Oment group. Diluted carbon medium injected from the left gastroepiploic artery was seen filling the arteries of the omental flap and laying within the coronary arterioles in the transmural myocardium. (BM = bone marrow; Oment = omentopexy.)

	Comment

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

While various kinds of angiogenic factors, such as members of the fibroblast growth factor and vascular endothelial growth factor families, were evaluated, autologous BMC transplantation is a relatively simple procedure for clinical application because there is no risk of immunologic rejection as the cells used are the patient's own and there are no problems with their availability. Moreover, BMCs have multipotential mechanisms for angiogenesis because of the secretion of various kinds of cytokines to stimulate other angiogenic factors or each other and differentiation into endothelial cells. Kamihara and colleagues [7] demonstrated the safety of intramyocardial BM-MNCs containing cells of various lineages without any side effects. In our procedure, there were very few risks of infection because we did not culture cells. Moreover, BM-MNCs could be obtained simply and in only ten minutes using bone marrow processing filters. This procedure was simple, safe, and cost-effective, making it suitable for clinical application.

On the other hand, the omentum once played an active part in surgical revascularization for ischemic heart disease. The omentum was an attractive tissue for cardiac surgeons, because the omentum is not only a well-vascularized tissue providing oxygen and nutrients to solve cardiothoracic surgical problems, but also has been shown to be a source of angiogenic factors [21, 22]. In 1936, O'Shaughnessy [9] reported a cardio-omentopexy procedure in which pedicled omental grafts were attached to the surface of the ischemic heart through the diaphragm in humans. Subsequently, Vineberg and colleagues [13] introduced a modified omentopexy procedure with free (detached) omental grafts combined with implantation of the internal mammary artery into the left ventricular wall. This method was called the Vineberg operation, clinical application of which became widespread during the 1960s. However, these procedures have gradually fallen off use with the development of CABG and PCI, because it was thought that an effectiveness of revascularization was not given enough by omentopexy alone. Recently, Ueyama and colleagues [23] demonstrated that bypass from the GEA in the omentum to the coronary arteries could be achieved by administration of show-release basic fibroblast growth factor (bFGF), while omentopexy alone was not effective for revascularization. Ruel and colleagues [17] used a gastric submucosal patch for endogenous myocardial angiogenesis instead of an omental patch. They assumed that omentopexy alone was not as effective in terms of angiogenesis in the infarcted area. Therefore, we developed a new hybrid surgical angiogenesis induced by BM-MNCs transplantation combined with omentopexy, not as a main angiogenic factor but as an external blood flow source for the transplanted area to enhance transplanted cell survival, which results in more angiogenesis.

The results of the present study suggested that BM-MNC transplantation recovered regional cardiac function and omentopexy contributed to enhance the effectiveness of cell therapy. In vessel counting, the numbers of large arterioles (> 50 µm) in the BM+Oment group were significantly increased as well as those of small arterioles (< 50 µm). These results suggested that the combined therapy not only augmented angiogenesis but also may have caused maturation of new blood vessels, similarly to arteriogenesis, defined as the rapid proliferation of preexisting collateral arteries. It is possible that new blood vessels proliferated and were growing further, and formation of collateral circulation was developed, when new abundant blood flow supply from the omental flap was provided. Blood flow velocity and fluid shear stress were increased in the new vessels, which were assumed to act as new collateral vessels [24, 25]. As this process was effective between the omental flap and the infarcted area followed by enhancement of angiogenesis, the effect of revascularization may be developed and steady. In the present study, however, the process of revascularization was not confirmed in detail, such as cells survival, integration, and differentiation, and there were not significant differences in both increase of myocardial blood flow and functional study between, with, and without omentopexy groups. Further investigation, including survival, integration, and differentiation of the transplanted BM-MNCs and long-term effects of cell transplantation with omentopexy, will be needed to achieve the effectiveness of omentopexy in cardiac function.

This study had several limitations. First, our experiment was performed in an acute myocardial infarction model. From the viewpoint of clinical application, surgical cell therapy combined with CABG has been performed in patients scheduled for chronic myocardial infarction but not in emergency cases. Second, we did not investigate an infarcted size after each therapy. Those data would strengthen the data of the effect of therapies in this study. In the future we will prepare further investigations, including the assessment of infarcted size, with a long observation period in a chronic myocardial model. In addition, the development of a cell delivery method to ensure no leakage of injected cells is also needed to ensure as many implanted cells as possible are maintained and survive in the myocardium. In the present study, we performed epicardiectomy after cell injection to allow direct communication between the omentum and myocardium. Whether epicardiectomy causes leakage of cells remains to be resolved.

In conclusion, BM-MNC transplantation may attenuate cardiac contractile dysfunction after myocardial infarction, and hybrid therapy combined with omentopexy may enhance the effectiveness of angiogenesis induced by BM-MNC transplantation. This new strategy is expected to be safe, rapid, and cost-effective for clinical use, and be a novel option for surgical revascularization combined with CABG in patients with severe ungraftable coronary vessels.

	Acknowledgments

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 
This work was supported by the Terumo Corporation R&D Center, Japan. The authors are grateful to Yoshitaka Omura, Hazime Okaze, and Yutaka Imahori for their invaluable technical assistance.

	References

Top Abstract Introduction Material and Methods Results Comment Acknowledgments References

 

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