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Ann Thorac Surg 2000;69:1155-1161
© 2000 The Society of Thoracic Surgeons

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ORIGINAL ARTICLES: CARDIOVASCULAR

Therapeutic angiogenesis with intramyocardial administration of basic fibroblast growth factor

^a Department of Surgery (I), Kanazawa University School of Medicine, Kanazawa, Japan

Address reprint requests to Dr Kawasuji, Department of Surgery (I), Kanazawa University School of Medicine, Takaramachi 13-1, Kanazawa 920-8641, Japan
e-mail: kawasuji{at}med.kanazawa-u.ac.jp

	Abstract

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Background. Basic fibroblast growth factor (bFGF) induces endothelial cell and smooth muscle cell proliferation and stimulates angiogenesis. This study was designed to evaluate the effects of intramyocardial administration of bFGF on myocardial blood flow, angiogenesis, and ventricular function in a canine acute infarction model.

Methods. Myocardial infarction was induced in 12 dogs by ligation of the left anterior descending coronary artery. Within 5 minutes after coronary occlusion, 100 µg of human recombinant bFGF in 1 mL of saline was injected into the infarct and border zone in 6 dogs, whereas saline alone was used in 6 control dogs. Myocardial blood flow was determined with colored microspheres before and immediately after coronary ligation and again 3, 7, 14, and 28 days after treatment and it was expressed as percent of normal. Angiogenesis was evaluated by immunohistochemical studies 28 days later. Cardiac function was evaluated by repeated echocardiographic measurement.

Results. Treatment with bFGF significantly increased the endocardial blood flow in the border zone (7 days after infarction, 75% ± 7% and 41% ± 7% in the bFGF and control groups, respectively, p < 0.01) as well as epicardial blood flow in the infarcted zone. Treatment with bFGF significantly increased the capillary density (39.7 ± 2.3 and 22.7 ± 1.1 vessels per visual field in the bFGF and control groups, respectively, p < 0.01) as well as arteriolar density in the border zone. Treatment with bFGF significantly reduced the change in ratio of thickness of the infarcted wall to the normal wall (44% ± 6% and 26% ± 5% in the bFGF and control groups, respectively, p < 0.05). It improved the left ventricular ejection fraction (7 days after infarction, 0.54 ± 0.02 and 0.37 ± 0.03 in the bFGF and control groups, respectively, p < 0.01).

Conclusions. Intramyocardial administration of bFGF increased the regional myocardial blood flow, reduced thinning of the infarcted region, and improved ventricular function in acute myocardial infarction. Intramyocardial administration of bFGF may be a new therapeutic approach for patients with acute myocardial infarction.

	Introduction

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Coronary artery bypass grafting has been well recognized to ameliorate angina pectoris, prevent myocardial infarction, and improve long-term survival in patients with atherosclerotic coronary artery disease. However, myocardial revascularization provides little or no benefit for patients with diffuse and extensive coronary arteriosclerosis. It is well known that coronary collateral vessels protect myocardial tissues from acute or chronic ischemia [1]. In addition to physiologic factors such as coronary perfusion pressure and flow, growth factors have become of major importance because they can induce angiogenesis [2, 3]. Induced angiogenesis consequently has drawn attention as a therapeutic modality for the ischemic myocardium.

Basic fibroblast growth factor (bFGF) is a single-chain peptide with a molecular size of 17 kD and is referred to as heparin-binding growth factor 2 because of its affinity for heparin [4]. Basic FGF induces endothelial and smooth muscle cell proliferation in vitro and elicits in vivo angiogenesis that includes the migration and proliferation of endothelial cells, vascular tube formation, and linkage to the preexisting vascular network [4, 5]. Existence of bFGF was confirmed in canine myocardial infarct tissues [6, 7]. In a canine experimental myocardial infarct model, intracoronary injection of exogenous bFGF increased the number of arterioles and capillaries in the infarct, reduced infarct size, and improved cardiac systolic function [7]. The mechanism of action of bFGF in acute myocardial infarction is unclear [8, 9]. The method of bFGF administration by intramyocardial injection into the infarcted area may be more widely applied irrespective or coronary anatomy. However, the effects of intramyocardial injection of bFGF on myocardial blood flow (MBF) and ventricular function in an infarcted heart have not been determined.

The purpose of the present study was to investigate the effects of intramyocardial administration of bFGF on MBF vascular density, and ventricular function in a canine model of acute myocardial infarction.

	Material and methods

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Fifteen adult mongrel dogs weighing 11 to 16 kg were studied. The animals were anesthetized with an intramuscular administration of ketamine hydrochloride (20 mg/kg) and intravenous sodium pentobarbiturate (30 mg/kg) and were mechanically ventilated with a volume respirator. The dogs received humane care in compliance with the "Principles of Laboratory Animal Care" (National Society for Medical Research) and the "Guide for the Care and Use of Laboratory Animals" published by the National Institutes of Health (NIH publication 85-23, revised 1985). A small left thoracotomy through the fourth intercostal space was performed using a sterile technique. A silicone elastomer catheter was positioned in the left atrial appendage for microsphere blood flow determination. Lidocaine (1 mg/kg) was given intravenously before coronary occlusion. Acute myocardial infarction was made by ligation of the left anterior descending coronary artery distal to its first diagonal branch. Within 5 minutes after coronary occlusion, dogs were divided into two groups. In the bFGF group, human recombinant bFGF (Kaken Pharmaceutical, Tokyo, Japan), a total of 100 µg in 1 mL of saline, was injected using a thin needle into the myocardium at eight points of the ischemic area of the left ventricular wall (Fig 1). There were no changes in blood pressure or heart rate associated with the injection of bFGF, and no obvious adverse effects, such as anaphylactic reaction, in dogs throughout the experiment. In control dogs, the same volume of saline was injected in the same manner. After hemodynamic stability the pericardium and chest were closed, and the dogs were allowed to recover. The left atrial catheter was flushed daily with heparinized saline to maintain patency.

View larger version (17K): [in this window] [in a new window]   Fig 1. Experimental model used to make myocardial infarction by ligation of the left anterior descending coronary artery (LAD) and provide direct administration of basic fibroblast growth factor or placebo into the myocardium. The left atrial catheter was positioned for administration of colored microspheres. After all blood flow measurements, the heart was cut into short-axis slices and the left ventricle was divided into eight segments. (LCX = left circumflex coronary artery; RCA = right coronary artery.)

Echocardiographic studies were performed in each animal during the sedation period. Cardiac function was measured before treatment and 3, 7, 14, and 28 days after treatment using parasternal two-dimensional echocardiography (SSS-118F, Fukuda Electronic, Tokyo, Japan). Left ventricular end-diastolic and end-systolic volumes were measured by the single-plane area-length method and left ventricular ejection fraction was calculated. Left ventricular end-diastolic and end-systolic volumes were normalized for the baseline values before coronary occlusion.

On the final day the dogs were killed and the hearts were excised. A central short-axis slice of 1.5 cm was cut from the left ventricle and was divided into eight circumferential segments that were further subdivided into endocardial and epicardial portions (Fig 1). Segment 5, in the territory of the left anterior descending coronary artery, was defined as the infarct area. Segment 6, neighboring the infarct area, was defined as the border zone. Segments 1, 2, 7, and 8 were defined as normal areas. Each portion was used for microsphere blood flow analysis. The tissue samples and reference blood samples were digested with sodium hydroxide, and microspheres were reclaimed for measurement. Regional MBF (Qm, mL · min^-1 · g^-1) was calculated by the following equation:

where Cm is the number of microspheres in 1 g of myocardial tissue, Cr is the number of microspheres in reference blood sample, and Qr is the withdrawal rate of blood (mL/min). The ratio of ischemic area to normal area blood flow was normalized for the baseline blood flow before coronary occlusion and myocardial blood flow was expressed as percent of normal (%MBF).

A second slice to the base of the central slice was used for estimation of the myocardial infarct size and for the study of left ventricular morphology. Left ventricular dilatation was assessed by expansion index, which was defined as the ratio of endocardial length of infarction-containing area to normal area without infarction. The degree of thinning of the infarcted area was assessed by thinning ratio, which was defined as the ratio of thickness of infarcted anterior to normal posterior ventricular wall [10]. Then the hearts were fixed in 10% buffered formalin and transmural sections of the myocardium were embedded in paraffin and cut into 5 µm sections. These were stained using the hematoxylin-eosin method and Masson’s trichrome method. Blood vessels were highlighted by staining endothelial cells for von Willebrand factor, applying the avidin-biotin peroxidase complex method (Fig 2). Given the assumption that the tissue stimulus for angiogenesis would be intense in tissues adjacent to the infarct zone, five portions were randomly taken from the border zone (segment 6) and the assessment of vascular density was carried out in x200 field (x20 objective lens, x10 eye lens, 0.442 mm² per field). Vessels smaller than 25 µm were considered to be capillaries, and vessels larger than 25 µm and smaller than 100 µm were considered to be arterioles.

View larger version (71K): [in this window] [in a new window]   Fig 2. Heart tissue in the border zone of infarct in a dog treated with basic fibroblast growth factor (bFGF) (A) and a control dog (B). Vessels were expressed by staining endothelial cells using a monoclonal antibody against von Willebrand factor. Increased capillaries and arterioles were noted in an infarct-adjacent region of a bFGF-treated dog. (x200.)

Cumulative data are expressed as the mean ± the standard error of the mean. A repeated-measures analysis of variance model was used to examine the interaction between treatment and time in bFGF-treated and control groups. For blood chemistry, morphologic study, and histologic study, the Mann-Whitney U test was used to detect significant differences between measured variables. A value of p less than 0.05 was considered significant.

	Results

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Myocardial blood flow
There were no significant differences in hemodynamic parameters including heart rate, blood pressure, and left atrial pressure between the bFGF and control groups during the study period.

In the endocardial portion of the infarct area (segment 5), %MBF was markedly decreased immediately after coronary occlusion and was comparable in the bFGF and control groups (Fig 3). Thereafter, %MBF increased gradually in both groups, although there were no significant differences between the two groups. In the epicardial portion of the infarct area, %MBF was also markedly decreased immediately after coronary occlusion and was comparable in the bFGF and control groups. %MBF began to increase 3 days after treatment in the bFGF group, although it began to increase 14 days after coronary occlusion in the control group. Disparity between %MBF in the bFGF and control groups was significant (p = 0.029). Values of %MBF 7 days after treatment were 67.2% ± 8.7% and 35.7% ± 5.2% in the bFGF and control groups, respectively (p = 0.011).

View larger version (18K): [in this window] [in a new window]   Fig 3. Effect of basic fibroblast growth factor (bFGF) on myocardial blood flow, which is shown as percent of normal (%MBF). A marked increase in %MBF is evident in bFGF-treated dogs during the period from 3 to 7 days after infarction. (A) Endocardial portion of the infarcted area. (B) Epicardial portion of the infarcted area. (C) Endocardial portion of the border zone. (D) Epicardial portion of the border zone. (NS = not significant.)

Cardiac function
Left ventricular end-systolic volume was markedly increased 3 days after coronary occlusion and was comparable in the bFGF and control groups. Although left ventricular end-systolic volume in the control group was further increased 7 days after coronary ligation and contrarily, it was decreased in the bFGF group; this difference did not reach statistical significance. Left ventricular end-diastolic volume was also increased 3 days after coronary occlusion and was comparable in the bFGF and control groups. There was no significant difference in left ventricular end-diastolic volume between the two groups. Left ventricular ejection fraction was markedly decreased 3 days after coronary occlusion and was comparable in the bFGF and control groups (0.44 ± 0.05 and 0.42 ± 0.03, respectively, p = not significant [NS]). The disparity between left ventricular ejection fraction in bFGF and control groups was significant (p = 0.017), with a significant difference 7 days after treatment (0.54 ± 0.02 and 0.37 ± 0.03, respectively, p = 0.004) (Fig 4).

View larger version (21K): [in this window] [in a new window]   Fig 4. Effect of basic fibroblast growth factor (bFGF) on left ventricular function. Treatment with bFGF improved left ventricular ejection fraction 7 days after infarction. (LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic volume; NS = not significant.)

Histologic study
In the bFGF group, 3 dogs showed transmural infarction and 3 showed nontransmural infarction. In the control group, 5 dogs showed transmural infarction and 1 showed nontransmural infarction. Left ventricular thinning ratio was significantly higher in the bFGF group than in the control group (43.5% ± 6.3% and 26.4% ± 5.0%, respectively, p = 0.045). Left ventricular expansion index was similar in the bFGF and control groups (2.3 ± 0.1 and 2.2 ± 0.1, respectively, p = NS).

Vascular density was examined in the border zone of the infarct. Capillary density was significantly higher in the bFGF group than in the control group (39.7 ± 2.3 and 22.7 ± 1.1 vessels per visual field, respectively, p = 0.004). Arteriolar density was also significantly higher in the bFGF group than in the control group (4.5 ± 0.4 and 2.3 ± 0.3 vessels per visual field, respectively, p = 0.012) (Fig 5).

View larger version (27K): [in this window] [in a new window]   Fig 5. Numerical density of capillaries and arterioles in the border zone of infarct, expressed as vessels per visual field. Treatment with basic fibroblast growth factor (bFGF) increased the number of capillaries and arterioles.

	Comment

Top Abstract Introduction Material and methods Results Comment References

Yanagisawa-Miwa and coworkers [7] assessed the effects of bFGF in a canine acute infarction model in which the left anterior descending coronary artery was subjected to acute occlusion and bFGF was injected into the left circumflex coronary artery. Treatment with bFGF has been shown to increase the number of arterioles and capillaries in the infarct, reduce infarct size, and improve ventricular function. Unger and colleagues [8] reported that in a canine model of chronic myocardial ischemia, intracoronary administration of bFGF increased numerical density of distribution vessels and enhanced myocardial collateral flow. They raised a question regarding the mechanism of action of bFGF in the context of acute infarction: irreversible damage occurs in acutely ischemic myocardium within 4 to 6 hours of acute infarction [11], whereas true angiogenesis could only improve blood flow over the course of days [5].

Previous studies have shown that intracoronary administration of bFGF produced apparent increases in vascular density at 1 or 2 weeks after acute infarction; however, early effects of bFGF on MBF are unclear [7, 12]. The present study demonstrated that bFGF-treated dogs showed a significant improvement in regional MBF beginning 3 days after acute infarction. Whereas control dogs showed a progressive decrease in endocardial blood flow of the border zone up to 7 days after coronary occlusion, bFGF-treated dogs showed markedly higher levels of endocardial blood flow. In addition to angiogenic effects, bFGF has coronary and systemic vasodilatory properties [8, 13, 14]. Although the vasodilatory properties of bFGF may have contributed to the increase in MBF by acute dilatation of preexisting but nonfunctioning collaterals, its vasodilatory effect persists only a few hours [8]. Therefore, the increase in MBF we observed in the present study is likely mediated through the direct angiogenic effects of bFGF, supported by increases in vascular density within the border zone. Padua and associates [15] demonstrated that bFGF exerts a cardioprotective effect in perfused rat hearts, and the cardioprotective effect may represent the initial mechanism by which bFGF reduces myocardial damage during ischemia. In the present study, troponin-T levels after 24 hours in the bFGF group showed no difference compared with the control group, indicating that irreversible myocardial injury was similar in both groups. These results suggest that intramyocardial administration of bFGF led to an increase in MBF early after infarction, probably due to angiogenesis, but that this was not so rapid as to influence infarct size, expressed as the magnitude of myocardial necrosis.

Alterations in ventricular structure involving both the infarcted and noninfarcted areas are referred to as ventricular remodeling [16]. Infarct expansion, acute dilatation, and thinning of the infarct area not explained by additional myocardial necrosis occur as a consequence of ventricular remodeling after acute myocardial infarction [17]. Compared with control dogs, bFGF-treated dogs showed markedly higher blood flow in the infarct and border zone during the 1-week period after infarction. The early increase in MBF in the border zone may limit the extent of infarct expansion and reduce thinning of the infarcted region. Blood flow increases at a phase of infarct healing may promote scar formation. In the present study, intramyocardial administration of bFGF improved cardiac function without influencing infarct size. One possible explanation is that increased MBF protects the ischemic myocardium around the infarct and influences ventricular remodeling after infarction.

The growth factors that are potentially involved in the process of cardiac collateralization are bFGF, acidic FGF, vascular endothelial growth factor, insulin-like growth factor I, and platelet-derived growth factor. The vascular endothelial growth factor protein has a relatively short biologic half-life in the circulation [18], and most previous studies have required continuous administration or repetitive dosing of the vascular endothelial growth factor to achieve an angiogenic effect [19, 20]. Recent studies have used gene transfer technique for slow release of vascular endothelial growth factor [21]. Unlike vascular endothelial growth factor, the bFGF protein is protected against rapid breakdown and stimulates angiogenesis for a longer duration. Our choice of bFGF for this study is based on these findings. Another potential advantage of bFGF over the use of other growth factors with angiogenic properties is that bFGF is mitogenic for fibroblast, and thus theoretically improves healing of infarcted myocardium. It is possible to administer bFGF selectively into the infarcted and ischemic area, irrespective of the coronary anatomy. An advantage of intramyocardial administration of bFGF is that it induces local angiogenesis and seems to avoid high levels of circulating angiogenic activity that could possibly stimulate plaque angiogenesis or stimulate growth of concealed neoplasmas.

There are limitations in the extrapolation of these findings in a canine model to human coronary circulation because dogs have more native coronary collateral vessels compared with humans. This method can be applied as an additional therapeutic regimen to those patients who require emergency myocardial revascularization for acute infarction or who require surgical procedures for ventricular free wall or septal rupture. In the present study, bFGF was administered immediately after myocardial infarction was produced. In the clinical setting, most patients receive surgical procedures over the course of hours. It is necessary to confirm the efficacy of bFGF administered at a longer time after infarction. Intramyocardial administration of acidic FGF was reported to be effective in increasing collateral vessels in the clinical setting of chronic myocardial ischemia [22]. Sellke and coworkers [23] reported administration of bFGF using heparin-alginate slow-release devices in surgical patients. The present method of intramyocardial administration of bFGF can be extended to protect patients with angina pectoris by increasing collateral vessels with induced angiogenesis.

	Acknowledgments

 
The authors thank Kaken Pharmaceutical Co, Ltd for providing human recombinant bFGF.

	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): Michio Kawasuji Yoh Watanabe Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kawasuji, M. Articles by Watanabe, Y. Search for Related Content PubMed PubMed Citation Articles by Kawasuji, M. Articles by Watanabe, Y. Related Collections Related Article