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Ann Thorac Surg 2003;75:549-554
© 2003 The Society of Thoracic Surgeons

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Original article: cardiovascular

Growth factors improve latissimus dorsi muscle vascularization and trophicity after cardiomyoplasty

^a Department of Cardiovascular Surgery, Broussais and Pompidou Hospitals, Paris, France

Accepted for publication August 22, 2002.

* Address reprint requests to Dr Chachques, Department of Cardiovascular Surgery, European Hospital Georges Pompidou, 20 Rue Leblanc, 75015 Paris, France.
e-mail: j.chachques{at}brs.ap-hop-paris.fr

	Abstract

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BACKGROUND: Dynamic cardiomyoplasty consists of wrapping the electrostimulated latissimus dorsi muscle (LDM) around the failed heart. Partial ischemia followed by atrophy of the middle and distal part of the LDM were observed in 30% of clinical cases after LDM flap elevation from its origin. In the current study, we hypothesized that local administration of growth factors at the LDM/epicardial interface could improve muscle vascularization and trophicity.

METHODS: In 24 sheep, dynamic cardiomyoplasty was performed using the left LDM. A multiperforated catheter was positioned at the LDM/epicardial interface for a weekly administration, during a 1-month period, of the following factors: basic fibroblast growth factor (bFGF, n = 6), vascular endothelial growth factor (VEGF, n = 6), and regenerating agent (RGTA, n = 6). Six sheep injected with phosphate-buffered saline (used for dilution of the growth factors) were used as a control group. At 3 months, angiographic, histologic, and histomorphometric studies were performed.

RESULTS: Angiographic studies of the animals treated with growth factors demonstrated hypervascularization due to the development of new vessels. Histomorphometric and histologic studies showed a significant increase in the number of capillaries and arterioles (100 fields/muscle) in the groups treated with bFGF (443.0 ± 101.2, p < 0.01), RGTA (293.2 ± 29.3, p < 0.05), and VEGF (246.5 ± 45.9, p < 0.05), as compared with the control group (81.5 ± 11.4). A significantly lower atrophy score was observed in the groups treated with bFGF (1.4 ± 0.18, p < 0.05), RGTA (1.59 ± 0.17, p < 0.05), and VEGF (1.96 ± 0.14, NS), as compared with the control group (2.48 ± 0.16).

CONCLUSIONS: Local administration at the heart/muscle interface of growth factors increases muscle vascularization and avoids muscle atrophy in an experimental cardiomyoplasty model, both of which are advantageous to the contracting LDM. The local growth factors delivery system used in this study appears efficient, easy to implant, and manipulate and safe.

	Introduction

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Severe chronic heart failure refractory to pharmacological therapy can be treated by several surgical procedures. Among them, cardiomyoplasty, a surgical procedure in which the electrostimulated latissimus dorsi muscle (LDM) is wrapped around the heart, has the advantages of not requiring a heart donor and of small financial costs.

Several reports on cardiomyoplasty (CMP) demonstrated good long-term results in approximately 70% of cases [1–5]. In the remaining 30%, it appears that the efficacy of the procedure is reduced due to several causes. The most important is partial ischemia of the distal part of the LDM, observed during surgery due to the elimination of the arterial supply arising from the intercostal arteries, resulting in partial atrophy of the LDM. In our study, we created an experimental CMP model in order to evaluate and compare the effects on the LDM of basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and regenerating agent (RGTA), administered at the heart/muscle interface. Growth factors are polypeptides that stimulate the proliferation, the migration, and the differentiation of cells. The aim of this study was to evaluate the effects of local administration of these exogenous factors through a port chamber, placed at the heart/muscle interface after a cardiomyoplasty.

	Material and methods

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Twenty-four sheep (mean weight of 34 ± 5.5 kg) underwent a cardiomyoplasty procedure. All procedures were performed under general anesthesia. Animals were premedicated with 5 mg/kg IM acepromazine, and anesthesia was induced with 8 mg/kg IV propofol and maintained with isoflurane 1% to 2% followed endotracheal intubation. A CMP was performed using the left LDM through a left thoracotomy (fourth intercostal space). The LDM was wrapped in clockwise fashion, with the deep LDM fascia positioned in contact with the epicardium. Postoperatively, the LDM was electrostimulated using two intramuscular electrodes (models SP 5548-35 and ST 5591-500-90; Medtronic, Maastricht, NL) implanted in proximity to the neurovascular pedicle. To obtain a synchronous systolic LDM contraction, a third electrode for R wave detection was positioned into the left ventricular wall (model SP 6917A-53T). The electrodes were then connected to a cardiomyostimulator (Medtronic model SP 1005) in a subcutaneous position. LDM electrostimulation was started 2 weeks after the cardiomyoplasty, after a progressive and sequential protocol [3]. The electrostimulation protocol, similar to that used in humans after cardiomyoplasty, started at the third week after surgery at a frequency of 2 Hz, and was progressively increased each week up to 30 Hz. As in previous studies [1], the target muscle pacing protocol at 6 weeks was a burst of six pulses, a pulse amplitude of 5 V, and a heart to muscle stimulation ratio of 2:1. Postoperatively, growth factors were delivered weekly, over a 1-month period, starting on the first postoperative day. Growth factor administration was performed using a subcutaneous chamber connected to a multiperforated catheter with five injection holes (Polysites 1007 ISP; LPI, Bornel, France), positioned during surgery between the LDM and the epicardial surface just over the left ventricle (Fig 1). Growth factors were injected into the subcutaneous chambers on postoperative days 1, 7, 14, and 21. To assess correct product administration and satisfactory dispersion over the heart-muscle interface, in 3 sheep, we injected a radio-opaque product through the port chamber at postoperative day 7. After this injection, it was possible to observe diffusion of contrast media over most of the muscle/cardiac interface. The quantity of each growth factor administered was calculated for optimal efficacy related to the mean weight of sheep LDM (220 ± 26 g). The volume of injection was 5 mL for each sheep, and the dose administered was 80 µg of bFGF, 120 µg of VEGF, and 480 µg of RGTA. In the control group, phosphate-buffered saline (PBS), used for dilution of the growth factors, was administered in an identical manner as described for growth factor administration.

View larger version (126K): [in this window] [in a new window]   Fig 1. The growth factors delivery catheter was placed between the epicardium and the latissimus dorsi muscle. A sensing epicardial electrode was inserted in the left ventricular wall.

Image assessment was conducted by two independent observers blinded to the treatment administered. Neovessels were defined as helical and tortuous vessels with no or little bifurcations. A semiquantitative scale was used to create the following score: grade 0, no neovessels; grade 1, some neovessels; and grade 2, numerous neovessels. The visualization of a tissue blush on the late phase was evaluated using the following tissue perfusion score: grade 0, nonblush; grade 1, mild blush; and grade 2, major blush. Blush refers to capillaries that are below the spatial resolution of the system and cannot be seen as individual vessels, but reflects increased tissue perfusion. For statistical analysis, the mean between the two observers was considered as the final value and used for the comparisons between the groups.

Histopathological studies
After these studies, all animals were euthanized after injecting heparin, papaverine, and formaldehyde (into the left ventricular cavity). In addition, a 4% formaldehyde solution was perfused into the LDM mass through the thoracodorsal artery, at the animal in vivo calculated main blood pressure. This procedure was used to obtain a physiologic opening of vessels, in order to better quantify vascularization and more objectively compare the animals.

After in situ formaldehyde perfusion, the LDM and heart were excised and put in a 10% formaldehyde solution for further fixation. After fixation, the LDM was separated from the heart and cut with seven equally distant slides from the mid part to the distal part of the muscle, so that the same part of the muscle was examined in all animals. The seven slides were embedded in paraffin. Each paraffin bloc was cut into three, 3-µm thigh sections and stained with hematoxylin-eosin-saffron (HES), Gordon Sweets, and orcein. HES is a stain routinely used to visualize cells and collagen network, Gordon Sweets is used for reticulin fibers surrounding cells and vessels, and orcein is used to detect elastin fibers present in vessels.

Histomorphometry was used to count the numbers of vessels and to quantify the area occupied by muscle cells in each histologic slide.

Histologic slides were examined under blind conditions by a cardiovascular pathologist (PF). We analyzed 14 or 15 fields per histologic slide at a x250 magnification (ie, a total of 100 fields for the seven slides per sheep). Fields were contiguous. The number of fields was chosen to obtain a thorough examination of the muscle, from its mid to distal part.

Muscular atrophy is defined in pathology by the decrease in size of muscle cells (myocytes) with time resulting in their loss. These lost cells are progressively replaced by fibrosis or adipocytes. Grossly, the process results in the decrease in the muscle thickness and physiologically by the decrease in its performance. To quantify the atrophic process, we evaluated the relative area occupied by myocyts in each slide (%). A score of 0 to 3 was attributed according to the degree of atrophy. As for the vessels counts, the seven slides were analyzed, and the mean of the degree of atrophy was calculated. The following muscle atrophy score was created: 0, no atrophy; 1, when the relative area occupied by myocytes per slide was more than two-thirds; 2, between two-thirds and one third; and 3, when myocytes occupied less than one-third of the total slide area.

Statistical analysis
Comparison of the mean number of capillaries and arterioles per group was carried out using an analysis of variances (ANOVA) parametric test, followed by the Newman-Keuls multiple comparison test. For the atrophy score and the angiographic grading, comparisons were made by the Kruskal-Wallis nonparametric test, followed by Dunnís multiple comparison test. Results are expressed as mean values (SEM).

	Results

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Angiographic studies
The neovascularisation was evaluated by a score of neovessels and a score of blush tissue. The mean neovessels scores were: for the bFGF group (1.83 ± 0.27, p < 0.05), for the RGTA group (1.66 ± 0.44, p < 0.05), for the VEGF group (1.64 ± 0.28, p < 0.05), and for the control group (0.33 ± 0.14).

The mean tissue blush scores were: for the bFGF group (1.68 ± 0.3, p < 0.05), for the RGTA group (1.56 ± 0.38, p < 0.05), for the VEGF group (1.16 ± 0.27, p < 0.05), and for the control group (0.16 ± 0.12).

All animals treated with growth factors (bFGF, VEGF, and RGTA) demonstrated hypervascularization due to neoangiogenesis. Neovascular structures, such as helical arteries or neoanastomoses, and tissue blush were observed. On the other hand, no hypervascularization was found in the control group (Fig 2).

View larger version (110K): [in this window] [in a new window]   Fig 2. Angiographic studies. (A) Control group. (B) Basic fibroblast growth factor group showing hypervascularization of thoracodorsal artery branches and helical arteries (neoangiogenesis). (Arrows show helical arteries.)

View larger version (62K): [in this window] [in a new window]   Fig 3. Histologic studies. (A) Control group showing atrophy in the distal portion of the latissimus dorsi muscle (LDM) (hematoxylin-eosin-saffron, magnification x40). (| = the borderline between the epicardium and the LDM.) (B) Basic fibroblast growth factor (bFGF) group showing a preserved LDM trophicity (hematoxylin-eosin-saffron, magnification x20). (C) bFGF group. A large number of neocapillaries (arrows) is observed between the LDM fibers (hematoxylin-eosin-saffron, magnification x400).

	Comment

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The purpose of this study was to preserve trophicity and to improve vascularization of the LDM by utilization of growth factors on an experimental cardiomyoplasty model. Another objective of the study was to select the most efficient growth factor so as to initiate human clinical evaluation.

VEGF, also called vascular permeability factor (VPF) or vasculotropin, is a glycoprotein of 45-kD "heparin binding." It is a well-known angiogenic factor that acts mainly on endothelial cells and plays a role in vessel development and endothelial repair. This factor also influences coronary artery relaxation and prevents intimal arterial hyperplasia [6].

Basic FGF (or FGF-2) was identified by Gospodarowicz in 1974, and is present in the majority of tissues. This factor is essential for the proliferation and differentiation of meso and neuro-ectodermic cells (endothelial cells, cardiomyocytes), and plays an important role in the regulation of vascularization. Experimentally, this factor can reduce the span and the consequence of ventricular infarcts in dog models by neoangiogenesis [7].

RGTA, derived from Dextran, possesses heparin or heparan sulfate properties (no anticoagulation effect) by protecting growth factors from pH, thermal, or proteolytic denaturation [8]. Consequently, RGTA increases the activity of growth factors. RGTA is not an endogenous growth factor but an original product, synthesized by successive substitution of a dextran molecule. "Heparin-heparan binding" growth factors may improve the action of FGF, VEGF, transforming growth factor (TGF), platelet-derived growth factor (PDGF), or bone morphogene protein (BMP) [9]. RGTA has demonstrated an ability to accelerate and optimize healing in different experimental models [10].

In recent clinical studies, growth factors have been applied in both cardiac [11] and plastic surgery [12]. In ischemic cardiomyopathies, bFGF injected around the distal anastomosis of coronary artery bypass grafts increased neoangiogenesis in the patient-treated group [11]. In another clinical study, bFGF was administered using a microcapsule, implanted in proximity of ischemic myocardial areas [13]. In an experimental porcine model of chronic myocardial ischemia, bFGF was injected in the pericardial sac. The results of this study demonstrated an improvement in myocardial perfusion and function in the ischemic territory and increased myocardial vascularity [14]. In chronic limb ischemia, a gene coding for the vascular endothelial growth factor (VEGF) has been injected intraarterially, increasing distal revascularization in a group of patients presenting arteriosclerothic disease [15]. In burn patients, local (topical) application of VEGF accelerated reepidermization [16], and in chronic wounds, several growth factors have been used with success [17].

In our study, growth factors were delivered locally, at the heart/LDM interface. In a previous study on experimental cardiomyoplasty, Mannion and associates [18] showed that the administration of bFGF into the left subclavian artery preserves vascularization and trophicity of the LDM. We believe that intraarterial administration of growth factors, by increasing proliferation and migration of cells, represents an important risk with consequent systemic effects. Furthermore, successive intravascular administration is technically difficult and costly. In 1996, Isner and associates [19] administered VEGF through the femoral arteries in order to stimulate collateral circulation in patients presenting an obliterative arteriopathy of the lower limbs. Some patients developed painful and hemorrhagic angiomas, and for this reason, in the majority of recent clinical studies, growth factors are administered locally. Schumacher and associates [11] injected bFGF directly into the myocardium in order to revascularize ischemic areas around coronary anastomosis. Vale and associates [15] performed therapeutic angiogenesis using catheter-based myocardial gene transfer (encoding VEGF-2) guided by electromechanical mapping. More recently, in an experimental model, gene transfection for human hepatocyte growth factor (hHGF) combined with cellular cardiomyoplasty was used to regenerate the impaired myocardium [20]; the liposome-plasmid complex (including 15 µg of the human HGF cDNA) was injected directly into the infarcted area.

Concerning the dynamic cardiomyoplasty surgical technique, another interesting approach to improve LDM irrigation before CMP is to use a vascular delay or electrostimulation before harvesting the muscular flap, thus improving blood flow in the distal portion of the LDM [21–24]. The vascular delay procedure consists of ligation of the intercostal perforating vessels between the LDM and the chest wall, 1 month before complete elevation of the LDM. This experimental approach was also associated with intraarterial administration of growth factors [25].

To propose growth factors therapy for clinical CMP, our policy was to choose and test a mode of growth factor administration, using a multiperforated catheter positioned at the LDM/epicardial interface and connected to a subcutaneous port chamber. Histomorphometric studies permitted precise evaluation of the neoangiogenesis. An increased number of capillaries and arterioles was observed in all the groups treated with growth factors. Basic FGF and RGTA, which possess angiogenic and myogenic properties, were significantly more efficient in stimulating angiogenesis and in avoiding muscle atrophy than VEGF, which is only angiogenic. In cases of muscular atrophy, such as found in the control group, nerves were detected presenting a normal histology. This observation seems to prove that LDM atrophy is due to devascularization and not to denervation.

In summary, this study demonstrates that in an experimental dynamic cardiomyoplasty model, local administration of growth factors at the muscle-epicardial interface appears efficient. A statistically significant correlation between the number of capillaries and arterioles and the amount of muscular atrophy was observed. Basic FGF and RGTA were the most promising agents in preserving vascularization and trophicity of the LDM. (bFGF appears to be the most active factor).

Study limitations
The present study was performed in a normal heart model, without induction of ventricular failure. The heart vascularity was intact (myocardium normally perfused). Therefore, we believe that hemodynamic studies assessing ventricular function could be overlooked. Furthermore, histologic studies were performed only on the LDM samples. In future studies, it could be interesting to perform dynamic CMP procedures associated with angiogenic and myogenic growth factors in an ischemic cardiomyopathy model. The hemodynamic effects of CMP should be evaluated as well as the collateral circulation between the LDM and the infarcted myocardium. These aspects were not assessed in our study and require further investigation.

Conclusion
In our experimental model, preservation of LDM trophicity after cardiomyoplasty was due to the action of growth factors on neovascularization and myogenesis. These results presented above are promising for both muscle and myocutaneous flaps used in the clinical setting of cardiomyoplasty and plastic and reconstructive surgery. The local growth factor delivery system used in our study appears efficient, easy to implant, and manipulate and safe. In the future, we believe that this approach will improve muscle morphology and function, optimizing the functional results after cardiomyoplasty surgical procedures. Finally, in patients presenting with ischemic cardiomyopathy and an indication for cardiomyoplasty, growth factors could induce the development of collateral circulation between the LDM flap and the myocardium with beneficial effects.

	Acknowledgments

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We would like to acknowledge Jean Plouet, PhD, from the Laboratory of Molecular Eucaryotic Biology, University of Toulouse; and Jose Courty, PhD, and Jean-Pierre Caruelle, PhD, from the Laboratory CRRET, University of Paris 12. We are also grateful to Pantelis Argyriadis, MD, Nathalie Goussef, Martine Rancic, and Cyril Schneider-Maunoury from Broussais Hospital for their technical assistance.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Alain F. Carpentier Juan Carlos Chachques Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zakine, G. Articles by Chachques, J. C. Search for Related Content PubMed PubMed Citation Articles by Zakine, G. Articles by Chachques, J. C. Related Collections Cardiac - other