Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease.
Schumacher B, Pecher P, Specht BU, Stegmann T. Circulation. 1998; 97:645-50. [ see abstract below ]
Angiogenic therapy of the human heart. (Accompanying editorial)
Folkman J. Circulation. 1998; 97:628-29 No abstract available
The authors of this article remind us of the limitations of current revascularization of the heart: "For the cardiac surgeon who is attempting to treat CHD, the use of sections of autologous blood vessels as bypass material is subject to severe limitations. Autologous arterial conduits are in short supply, and segments of the saphenous vein do not remain patent for very long. Furthermore, 'complete' revascularization is limited if diffuse coronary arteriosclerosis is present and extensive, especially if there are additional peripheral stenoses."
The aim or these investigators was to evaluate the information on angiogenic growth factors in animals, and, if appropriate, to use human growth factor in the treatment of CHD. Pursuit of these ambitious aims required (1) production of the human growth factor FGF-1 (basic fibroblast growth factor) by genetic engineering, followed by its isolation, characterization and purification; (2) use of animal experiments to establish the angiogenic effects of FGF-1; and (3) clinical use of FGF-1 as an adjunct to coronary surgery to demonstrate neoangiogenesis in ischemic human myocardium. All of these strategies were carried out successfully. And in doing so, the authors appear to have demonstrated that the human growth factor FGF-1 does induce angiogenesis in the ischemic human heart, and may therefore prove efficacious in the treatment of CHD.
This important paper was accompanied by an editorial by the seminal leader of angiogenesis research, Dr. Judah Folkman. Dr. Folkman provided a unique perspective on the significance of findings of Schumacher et al, as well as the larger role of angiogenesis in biomedicine today. The potential clinical applications of angiogenesis - which have only come into public view as a result of the lay press' recent reporting on angiogenesis as a possible cure for cancer - extend from Dr. Folkman's 27-year-old hypothesis that tumors are dependent upon angiogenesis. Subsequent research based on that hypothesis has resulted in approaches to clinical applications along three general lines: (1) prognostic markers in cancer patients; (2) antiangiogenic therapy; and (3) angiogenic therapy.
The first angiogenic therapy in ischemic vascular disease involved the application of "vascular endothelial growth factor" (VEGF) to patients with severe peripheral vascular disease of the lower extremities. Dr. Folkman views the present paper by Schumacher et al, involving the use of FGF-1 in the correction of myocardial ischemia in humans, as "landmark" in nature, but appropriately cautions that that this work uses primarily anatomic studies to demonstrate increased myocardial neovascularization after angiogenic therapy, and that follow-up of these patients to confirm functional improvement, relative to controls receiving inactive FGF-1, is warranted.
If this work indeed offers proof of efficacy, as one is inclined to anticipate, it holds the promise of adding a novel treatment modality - the regulation of blood vessel growth - and of advancing the therapy of cardiac-related disease beyond control of blood pressure, regulation of cardiac rhythm, enhancement of myocardial contractile strength, dilation of narrowed coronary arteries, thrombolysis, and other relatively traditional measures.
Clearly, this paper heralds exciting new applications of contemporary biology research to the treatment of cardiovascular disease. And furthermore, it underscores just how important (and unpredictable) new discoveries in basic biology research can be to the advancement of clinical medicine.
ABSTRACT BACKGROUND: The present article is a report of our animal experiments and also of the first clinical results of a new treatment for coronary heart disease using the human growth factor FGF-I (basic fibroblast growth factor) to induce neoangiogenesis in the ischemic myocardium.
METHODS AND RESULTS: FGF-I was obtained from strains of Escherichia coli by genetic engineering, then isolated and highly purified. Several series of animal experiments demonstrated the apathogenic action and neoangiogenic potency of this factor. After successful conclusion of the animal experiments, it was used clinically for the first time. FGF-I (0.01 mg/kg body weight) was injected close to the vessels after the completion of internal mammary artery (IMA)/left anterior descending coronary artery (LAD) anastomosis in 20 patients with three-vessel coronary disease. All the patients had additional peripheral stenoses of the LAD or one of its diagonal branches. Twelve weeks later, the IMA bypasses were selectively imaged by intra-arterial digital subtraction angiography and quantitatively evaluated. In all the animal experiments, the development of new vessels in the ischemic myocardium could be demonstrated angiographically. The formation of capillaries could also be demonstrated in humans and was found in all cases around the site of injection. 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.
CONCLUSIONS: We believe that the use of FGF-I for myocardial revascularization is in principle a new concept and that it may be particularly suitable for patients with additional peripheral stenoses that cannot be revascularized surgically.
