Human Basic Fibroblast Growth Factor Induces Angiogenesis in Hen Eggs and Rat Hearts
To the Editor:
In the February 24, 1998, issue of Circulation, Schumacher et al1 report on their work concerning the production of human basic fibroblast growth factor (FGF-1), 2 series of animal experiments using FGF-1, and the clinical use of the growth factor in patients undergoing CABG surgery. They have to be congratulated for their persistent effort of genetically producing, experimentally testing, and clinically applying an angiogenic growth factor in patients with coronary artery disease (CHD) for the first time. The authors themselves say at one point in the discussion that the possibility of inducing angiogenesis in the human heart “has been widely discussed for many years but never before attempted.”
There is complete agreement with Schumacher and coworkers that they were the first to attempt human myocardial neoangiogenesis. At the same time, the clinical data presented of the 20 patients treated with FGF-1 and of the 20 individuals subjected to inactivated FGF-1 are not at all convincing that the authors “established for the first time the efficacy of FGF-1 for the treatment of CHD, and were able to demonstrate that it can induce neoangiogenesis… .” The only thing the authors are able to demonstrate persuasively is that the area surrounding the bypassed left anterior descending coronary artery in their Figure 6A (digital subtraction angiography) is grayer than that in Figure 6B. To claim on the basis of this example that “the formation of capillaries could also be demonstrated in humans” is severely exaggerated, because the reader does not know anything about the timing of aquisition of those images with respect to the contrast injection. A difference of 250 ms (frequency of 4 images per second) between the image aquisition for Figure 6A and B and not the different treatment modalities could be the reason for the variable gray shades. The not completely intelligible sentence in the Results section that the angiograms of both treated and control groups “show comparable distances between the beginning of the injection and visualization of the medium” further raises the question of exactly where the contrast dye was injected and how much of it was injected in the 2 study groups. To state (in the Abstract) on the basis of Figure 7 that “[a] capillary network sprouting from the proximal part of the coronary artery could be shown to have bypassed the stenoses and rejoined the distal parts of the vessel” in response to FGF-1 treatment is equally speculative, because probably not even the authors know whether collaterals, if present, weren’t already there before bypass surgery and FGF-1 therapy.
To be able to assess the efficacy of the potentially very important new treatment modality of growth factors for ischemic heart disease, precise functional measurements of collateral flow have to be used.2 This is not only important because numerous growth factors can potentially be judged regarding their effect on collateral capillary vessels (angiogenesis) or larger, functionally more important conductance collaterals (arteriogenesis),3 it is also relevant because the effect of a collateral-promoting, angiogenic substance has to be characterized in light of its atherogenic potency.4
As a minor point, it has to be mentioned that the study by Yanagisawa-Miwa was performed in dogs and not in rabbits.5
- Copyright © 1999 by American Heart Association
Schumacher B, Pecher P, von Specht BU, Stegmann T. Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation. 1998;97:645–650.
Wulf DI, Arras M, Winkler B, Scholz D, Schaper J, Schaper W. Monocyte chemotactic protein-1 increases collateral and peripheral conductance after femoral artery occlusion. Circ Res. 1997;80:829–837.
Lazarous DF, Shou M, Scheinowitz M, Hodge E, Thirumurti V, Kitsiou AN, Stiber JA, Lobo AD, Hunsberger S, Guetta E, Epstein SE, Unger EF. Comparative effects of basic fibroblast growth factor and vascular endothelial growth factor on coronary collateral development and the arterial response to injury. Circulation. 1996;94:1074–1082.
Yanagisawa-Miwa A, Uchida Y, Nakamura F, Tomaru T, Kido H, Kamijo T, Sugimoto T, Kaji K, Utsuyama M, Kurashima C, Ito H. Salvage of infarcted myocardium by angiogenic action of basic fibroblast growth factor. Science. 1992;257:1401–1403.