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- bFGF, basic fibroblast growth factor
- ELISA, enzyme linked immunosorbent assay
- VEGF, vascular endothelial growth factor
Growth factors are currently emerging as a new therapeutic tool in coronary heart disease.1 Endogenous expression patterns of a number of angiogenic growth factors have been described in the chronically ischaemic and collateralised hearts.2 Through their proven experimental angiogenic effect, the administration of vascular endothelial growth factor (VEGF)3 and basic fibroblast growth factor (bFGF)1 have been explored as a means of increasing the degree of collateralisation in patients with end stage coronary heart disease. Questions remain however on the optimal dose, duration of administration, and monitoring of these agents1–3 as well as on the magnitude of risk posed by angiogenic cytokine treatment for accelerating atherosclerosis,4,5 partly because of the paucity of data on local growth factor concentrations and changes in living man. Patients with total coronary artery occlusions are known to have more developed collateral circulation compared to patients with stenosis and consequently, we hypothesised, that they may represent the ideal human model to examine endogenous, local growth factor production in vivo.
Endogenous VEGF and bFGF concentrations were prospectively examined in the coronary circulation and periphery of 14 male patients (seven with mean (SEM) diameter stenosis 83 (6)% , mean age 63 (2.4), and a further seven with total coronary artery occlusion, mean age 64 (4.4)) undergoing elective left coronary system intervention. Local (coronary sinus) and systemic (femoral) venous samples were obtained before coronary intervention and blood samples were centrifuged, plasma separated and stored at −80° C for further analysis. The concentrations of VEGF and bFGF in the plasma was then determined using an enzyme linked immunosorbent assay (ELISA) (R&D Systems Europe Ltd, UK). All data were analysed using the GraphPad Prism statistical software package (GraphPad Software, San Diego, California, USA). The non-parametric Mann-Whitney U test was used. Two tailed values of p < 0.05 were considered significant.
There was a difference between local and systemic concentrations of VEGF in the whole cohort of patients (251.8 (94.8) v 93.6 (14.1) pg/ml, respectively, p = 0.07). The difference was chiefly attributable to a fourfold increase in local VEGF concentrations in the occlusion group (400.2 (176.7) v 111.9 (22.9) pg/ml, p = 0.07) compared to the stenosis group (103.3 (19.8) v 75.2 (15.1) pg/ml, p = 0.5). The basal VEGF concentrations were significantly higher in the coronary sinus samples of patients with occlusions compared to those with stenoses (400.2 (176.7) v 103.3 (19.8) pg/ml, p = 0.026) (fig 1A). In contrast, no significant differences between local and systemic concentrations of bFGF for either the whole cohort of patients (15.7 (1.7) v 12.7 (1.0) pg/ml, respectively, p = 0.17), patients with occlusions (16.3 (2.5) v 12.5 (1.0) pg/ml, p = 0.26), or patients with stenoses (15.1 (2.5) v 12.9 (1.7) pg/ml, p = 0.54) were observed. The basal bFGF concentrations were not different in the coronary sinus samples of patients with occlusions compared to those with stenoses (16.3 (2.5) v 15.1 (2.5) pg/ml, p = 0.53) (fig 1B).
Our study provides the first direct evidence for increased local VEGF but not bFGF production in the diseased coronary circulation. The high concentrations of local, endogenous production and secretion of VEGF in patients with total coronary occlusions suggest a potential paracrine role for this growth factor in pathophysiologic collateral formation and supports its use as a therapeutic tool for angiogenesis, particularly in patients with inoperable coronary heart disease. The lack of any increase in local concentrations of bFGF could be attributed to impaired secretion caused by the absence of signal peptide in this growth factor and/or its restricted participation in local angiogenesis as compared to VEGF. In addition our methodology can potentially be extended to provide further insight into the dose, duration of administration, side effects, and long term monitoring of this promising method of treatment for end stage coronary heart disease.