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(Circulation. 1996;94:610-613.)
© 1996 American Heart Association, Inc.

Articles

Elevated Basic Fibroblast Growth Factor in Pericardial Fluid of Patients With Unstable Angina

Masatoshi Fujita, MD; Masaki Ikemoto, MD; Masamichi Kishishita, MD; Hideo Otani, MD; Ryuji Nohara, MD; Terumitsu Tanaka, MD; Shun-ichi Tamaki, MD; Ario Yamazato, MD; Shigetake Sasayama, MD

the College of Medical Technology (M.F., M.I., M.K.) and the Third Department of Internal Medicine (H.O., R.N., S.S.), Kyoto University, and Takeda Hospital (T.T., S.T., A.Y.), Kyoto, Japan.

Correspondence to Masatoshi Fujita, MD, College of Medical Technology, Kyoto University, 53 Kawaharacho, Shogoin, Sakyo-ku, Kyoto 606-01, Japan.

	Abstract

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Background Collateral growth is induced by chemical signals from the ischemic myocardium. We hypothesized that angiogenic growth factors are produced by cardiac tissue; they are diffusible, more concentrated in pericardial fluids, and are increased by myocardial ischemia.

Methods and Results With the use of an enzyme-linked immunosorbent assay, we measured the concentrations of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in pericardial fluids of 12 patients with unstable angina (group 1) and of 8 patients with nonischemic heart diseases (group 2). The levels of protein in pericardial fluids were quite comparable between the two groups (34±2 versus 32±4 mg/mL). The concentration of bFGF in pericardial fluids in group 1 was 2036±357 pg/mL, significantly (P<.001) higher than the 289±72 pg/mL in group 2. The amount of bFGF per milligram of protein was also significantly (P<.05) higher in group 1 than in group 2 (67±15 versus 12±4 pg/mg). The concentration of VEGF in pericardial fluids tended to be higher in group 1, but the difference was statistically insignificant (39±7 versus 22±6 pg/mL). The amount of VEGF per milligram of protein was 1.2±0.3 pg/mg in group 1, similar to the 0.8±0.4 pg/mg in group 2.

Conclusions This finding provides new evidence that bFGF plays an important role in mediating collateral growth in humans.

Key Words: ischemia • growth substances • collateral circulation

	Introduction

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Recently, a growing body of evidence has accumulated favoring a significant functional role of coronary collateral circulation in patients with coronary artery disease.¹ As a result, the study of growth adaptation of the collateral circulation appears to be of value because an understanding of these evolving mechanisms might be indispensable to the establishment of a new therapeutic modality promoting collateral development. Collateral growth is considered to be induced by a chemical signal from the ischemic myocardium, which triggers the events leading to DNA synthesis and to mitosis in collateral vessels.² Angiogenic growth factors have been isolated from human cardiac tissue^{2 3 4 5} and were extracted in larger quantities in the presence of myocardial ischemia.^{3 4} We hypothesized that angiogenic growth factors are produced by cardiac tissue; they are diffusible, more concentrated in pericardial fluids than in blood, and are increased by myocardial ischemia. Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) are candidates for such growth factors. Accordingly, our study was designed to determine whether concentrations of bFGF and VEGF in pericardial fluids relate to anginal episodes indicative of myocardial ischemia.

	Methods

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Study Patients
This study comprised 20 patients undergoing open heart surgery. Group 1 consisted of 12 patients with unstable angina, and group 2 consisted of 8 patients with nonischemic heart disease. The assessment of type of unstable angina was based on Braunwald's classification.⁶ The diagnosis of myocardial infarction was made according to World Health Organization criteria.

Coronary Angiography
All patients of group 1 were referred for selective coronary angiography to evaluate coronary atherosclerotic lesions and collateral circulation. A significant coronary stenosis was defined as 75% narrowing of a major coronary artery branch. Collateral circulation was graded on a scale of 0 to 3, depending on the degree of opacification of the occluded vessel.⁷

Collection and Analysis of Pericardial Fluid
Immediately after incision of the pericardium, undiluted samples of pericardial fluid were obtained before heparinization. The samples were collected in sterile tubes, placed immediately on ice, clarified by centrifugation at 3000g for 10 minutes at 4°C, and rapidly frozen at -80°C.

Concentrations of bFGF in pericardial fluids were measured by an enzyme-linked immunosorbent assay with a murine monoclonal antibody specific for bFGF (Quantikine, R&D Systems, Minneapolis, Minn).⁸ This assay was performed with the use of the quantitative sandwich enzyme immunoassay technique. The aforementioned antibody had been coated onto the microtiter plate. Standards and samples were pipetted into the wells, and any bFGF present was bound by the immobilized antibody. The wells were covered with the provided adhesive strip and incubated for 2 hours at room temperature. After washing away any unbound proteins three times with a 25-fold concentrated solution of buffered surfactant, we added an enzyme-linked polyclonal antibody specific for bFGF to the wells to sandwich the bFGF immobilized during the first incubation. The wells were incubated again for 2 hours at room temperature. After a wash to remove any unbound antibody-enzyme reagent in the same manner as in the first step, a substrate solution of hydrogen peroxide and tetramethylbenzidine was added to the wells and color-developed in proportion to the amount of bFGF bound in the initial step. The color development was stopped by adding 2N sulfuric acid, and the intensity of the color was measured with a spectrophotometer at 450 nm. A curve had been prepared, plotting the optical density versus the concentration of recombinant human bFGF in the seven standard wells. By comparing the optical density of the samples with this standard curve, the concentration of the bFGF in the unknown samples then could be determined. Concentrations of VEGF in pericardial fluids were measured with the similar method as in bFGF. A monoclonal antibody specific for VEGF and an enzyme-linked polyclonal antibody specific for VEGF were used for the quantitative sandwich enzyme immunoassay technique (Quantikine, R&D Systems). Finally, to verify that the recovery in pericardial fluid was accurate and consistent, the measurement of concentrations of bFGF and VEGF was repeated on a different day with the use of another Quantikine kit. The difference in values between two measurements was within ±10%. Concentrations of tumor necrosis factor- (TNF) in pericardial fluids were also measured with a similar method as in bFGF and VEGF (Quantikine, R&D Systems).

Concentrations of total protein in pericardial fluids were measured with the use of the biuret reagent (Hitachi 7150). The amount of fibrin in pericardial fluids was determined visually.

Statistical Analysis
All values are expressed as mean±SEM. The differences between the groups were analyzed with the Mann-Whitney U test. P<.05 was considered statistically significant.

	Results

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Patient Characteristics
Of 12 group 1 patients (8 men, 4 women; mean age, 70±3 years), 3 had class III unstable angina (Braunwald's classification) and the remaining 9 had class II unstable angina. The duration of rest angina was 12±2 days, ranging from 2 to 28 days. Seven patients had old myocardial infarction, but none had acute or recent myocardial infarction by the diagnosis criteria described in "Methods." Levels of MB creatine kinase (CK) were above normal ranges (0 to 7 IU/L) in 2 patients. There were no serial ECG changes compatible with acute myocardial infarction in these 2 patients. Seven of 12 patients had severe three-vessel disease, 4 had two-vessel disease, and the remaining patient had left main trunk lesion. The average collateral index was 2.2±0.3. Six patients had well-developed collateral circulation with the index 3, whereas the remaining 6 had poor collateralization with the index 0 to 2. In all 12 patients with unstable angina, there were no clinical and echocardiographic signs of pericarditis.

Of 8 group 2 patients (3 men, 5 women; mean age, 62±4 years), 3 had atrial septal defect and 5 had valvular heart disease.

Pericardial Fluids
Pericardial fluids from all 20 patients were not hemorrhagic. The amount of fluid obtained was 4±1 mL in both groups of patients. In 3 patients of group 1, the fluids were rich in fibrin; in 2 patients the fluids were abundant in fibrin, but the remaining 4 had little or no fibrin in the pericardial fluids. The levels of protein in pericardial fluids were quite comparable between the two groups (34±2 versus 32±4 mg/mL). The concentration of bFGF in pericardial fluids in group 1 was 2036±357 pg/mL, significantly (P<.001) higher than the 289±72 pg/mL in group 2 (Fig 1). The amount of bFGF per milligram of protein was also significantly higher (P<.05) in group 1 than in group 2 (67±15 versus 12±4 pg/mg). The concentration of VEGF in pericardial fluids tended to be higher in group 1, but the difference was statistically insignificant (39±7 versus 22±6 pg/mL) (Fig 1). The amount of VEGF per milli-gram of protein was 1.2±0.3 pg/mg in group 1, similar to the 0.8±0.4 pg/mg in group 2. There was no correla-tion between the concentrations of bFGF and VEGF (y=0.00645x+24.4, n=20, r=.36, P=NS) (Fig 2). The concentration of bFGF in patients with good collaterals was 2558±584 pg/mL, higher than the 1513±329 pg/mL in those with poor collaterals (P=NS). The concentration of VEGF in both groups was not different in terms of collateral development (45±14 versus 34±5 pg/mL, P=NS). The concentrations of bFGF and VEGF were also comparable between subgroups with and without elevated serum CK isoenzyme values, which was the case in terms of the extent and duration of unstable angina. The concentration of TNF in both groups was not different (7.9±1.7 pg/mL [group 1, n=5] versus 8.0±1.7 pg/mL [group 2, n=5], P=NS).

View larger version (17K): [in this window] [in a new window]   Figure 1. Concentrations of basic FGF (fibroblast growth factor) and VEGF (vascular endothelial growth factor) in pericardial fluids from patients with unstable angina (group 1) and nonischemic heart disease (group 2). Error bars indicate ±SEM.

View larger version (8K): [in this window] [in a new window]   Figure 2. Relationship of bFGF (basic fibroblast growth factor) to VEGF (vascular endothelial growth factor) in pericardial fluids from patients with unstable angina (closed circles) and nonischemic heart disease (open circles). The relationship between variables was fitted to a linear regression line (y=0.00645x+24.4, n=20, r=.36, P=NS).

	Discussion

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Recently, it has been demonstrated that bFGF mitogenic activity increases in ischemic myocardium after coronary artery ligation in the dog, and this increase parallels the increase in collateral blood flow.⁹ In our patients, the concentrations of bFGF in pericardial fluids from patients with ischemic heart disease were significantly higher compared with those from nonischemic patients. Since bFGF lacking a signal sequence may not be secreted, it must be released by alternative mechanisms.¹⁰ Cell lysis as a result of myocardial injury may be a mechanism for releasing bFGF. However, a general leakage of many growth factors as the result of cell lysis does not explain that CK isoenzyme values were within normal ranges in most patients with unstable angina, and concentrations of VEGF were not elevated definitely in these patients. Although bFGF lacks a typical hydrophobic signal peptide sequence as mentioned above, current evidence indicates that this factor can be secreted by a nonclassic pathway.¹¹ Thus, it appears to be likely that there is a distinctive upregulation of bFGF in response to ischemia. The origin of ischemia-induced bFGF in the cardiac tissue has not yet been documented precisely, although cardiac myocytes, monocyte/macrophages, smooth muscle cells, and pericardial cells are all candidates for bFGF sources.^{5 12} In canine experiments, it has been demonstrated that local^{13 14} or systemic¹⁵ administration of bFGF enhances collateral neovascularization, resulting in a reduction of infarct size.¹³

In this study there was no tight relation between collateral development and levels of bFGF. There are several explanations for this discordance. First, the timing of collateral development is unclear, particularly in patients with old myocardial infarction. Second, determination of the ischemia-related coronary artery may be difficult in patients with severe multivessel disease. Finally, the extent of collateral development may be underestimated in the absence of the pressure gradient across the collateral network as a result of the patent receiving coronary arteries of collateral circulation.⁷

It is tempting to speculate that VEGF also may contribute to ischemia-mediated coronary collateral vessel formation.¹⁶ This assumption derives from observations that hypoxia produced a significant increase in VEGF mRNA expression in rat cardiac myocytes.^{17 18} It also has been demonstrated that the levels of VEGF were increased in tumor tissue^{19 20} and ocular fluids,²¹ where angiogenesis was activated. However, the levels of VEGF in pericardial fluids from our patients with severe myocardial ischemia were not elevated definitely compared with nonischemic patients. In our patients, the expression of VEGF was not upregulated by the increased bFGF. This finding is not in agreement with an earlier report.²² These disparities may, at least in part, be explained by different species, organs, tissues, or cell types.

Recently, it has been reported that bolus injection of bFGF into the pericardial cavity is effective for collateralization and reducing infarct size in dogs with acute myocardial infarction.²³ It also has been demonstrated that bFGF administered into the pericardial space induces new vessel growth in a rabbit model, and ischemia facilitates bFGF-induced myocardial angiogenesis.²⁴ Our data give a theoretical basis for these therapeutic approaches because under ischemic conditions, cardiac tissue produces significant amounts of bFGF that are accumulated in pericardial fluids. Thus, angiogenic therapy for coronary artery disease would be promising also in the clinical setting.

	Acknowledgments

 
This study was supported by a Grant-in-Aid for Scientific Research ([c] 07670777) from the Ministry of Education, Science, and Culture, Tokyo, Japan.

Received April 2, 1996; revision received May 31, 1996; accepted June 13, 1996.

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