From Children's Hospital, Harvard Medical School, Boston, Mass.
Correspondence to Judah Folkman, MD, Children's Hospital, Harvard Medical School, Hunnewell 103, 300 Longwood Ave, Boston, MA 02115. (Circulation. 1998;97:628-629.)
The field of
angiogenesis research was initiated 27 years ago by a hypothesis that
tumors are angiogenesis-dependent.1 Shortly
thereafter, in the early 1970s, it became possible to passage vascular
endothelial cells in vitro for the first
time.2 Bioassays for angiogenesis were developed
subsequently throughout that decade. The early 1980s saw the
purification of the first angiogenic factors.3 4 5 6
By the mid-1980s, angiogenesis inhibitors began to be
discovered.7 8 9 Translation of these laboratory
findings to clinical application started in 1989, when interferon alfa
was first used for the treatment of life-threatening hemangiomas in
infants.10 11 12
Clinical applications of angiogenesis research are being pursued
along three general lines: (1) prognostic markers in cancer
patients,13 14 (2) antiangiogenic therapy (for
review, see Reference 1515 ), and (3) angiogenic therapy. The first
angiogenic therapy of ischemic vascular disease was the
administration of vascular endothelial growth factor
(VEGF)/vascular permeability factor to patients with severe
peripheral vascular disease in the lower
limbs.16
In a landmark paper, Schumacher and colleagues now report the first
angiogenic therapy of human coronary heart
disease.17 It is an important study, not only
because the authors describe how they produced their own recombinant
human fibroblast growth factor-1 (FGF-1, also called acidic fibroblast
growth factor) and tested it in vitro and in vivo but also because they
conducted a randomized controlled clinical trial. In 20 patients with
three-vessel coronary artery disease who underwent two or three
venous bypass grafts and one from the internal mammary artery, the
angiogenic protein FGF-1 was injected into the myocardium
close to the left anterior descending coronary artery and
distal to its anastomosis with the internal mammary artery. FGF-1 was
injected during extracorporeal surgery and again after completion of
the anastomosis. Transfemoral, intra-arterial digital
subtraction angiography 12 weeks later showed coronary artery
neovascularization extending out from the area of FGF-1 injection.
Stenoses distal to the anastomosis were bridged by
neovascularization. This was similar to the neovascularization observed
by the authors in rat hearts injected with FGF-1.
Histological sections of rat myocardium
showed a threefold increase in microvessel density. In 20 patients
undergoing similar coronary artery bypass surgery in whom
inactivated FGF-1 was injected, there was no evidence of
myocardial neovascularization on the 12-week angiogram.
An advantage of this approach is that it induces local angiogenesis and
appears to avoid high levels of circulating angiogenic activity that
could possibly stimulate plaque angiogenesis and secondary plaque
growth. Why does neovascularization persist for at least 12 weeks after
only a single set of intramyocardial injections of the angiogenic
protein? Perhaps persistent neovascularization was facilitated by
upregulation of VEGF and its receptors in hypoxic
tissue.18 Furthermore, basic FGF and VEGF are
synergistic mitogens for endothelial cells in
vitro.19 20 Also, FGF can increase expression of
(or mobilize) VEGF.21
This report uses primarily anatomic studies to demonstrate increased
myocardial neovascularization after angiogenic therapy. We look forward
to the follow-up of these patients to learn whether they have
significant functional improvement compared with the control group of
patients who received inactive FGF. It may be difficult to discriminate
the extent to which functional improvement is due to the angiogenic
therapy per se, despite use of a control group, because of the
concomitant internal mammary artery anastomosis and the relatively
small number of patients in this study. Nevertheless, the angiographic
documentation of myocardial revascularization
suggests that functional improvement should follow.
Although major therapeutic advances in cardiology have
been based on the general principles of control of blood pressure,
regulation of cardiac rhythm, enhancement of myocardial contractile
strength, increased diameter of narrowed coronary arteries, and
lysis of intravascular thromboses, the report by Schumacher et al
introduces a new modality, the regulation of blood vessel growth. If
angiogenic therapy of the myocardium continues to live up
to its potential as indicated by this report, we may witness novel
refinements in future years as the molecular biology of
endothelial cell and smooth cell growth is gradually
uncovered. For example, the therapeutic induction of coronary
arterial collaterals may someday be optimized by
administration of appropriate mixtures of molecules that target
different components of the vasculature, ie, the FGFs are
mitogenic for vascular endothelial cells
and smooth muscle, VEGF22 is
mitogenic primarily for endothelial cells,
angiopoietin-1 mediates the recruitment of smooth muscle cells to the
wall of new vessels,23 and angiopoietin-2 appears
to prevent or downregulate smooth muscle apposition to the walls of
microvessels.24 It is interesting that the
methodology to discover these different vascular cell growth proteins
emerged largely from investigations of mechanisms of tumor angiogenesis
in studies funded primarily by the National Cancer Institute over many
years. The report by Schumacher et al illustrates how unpredictable are
the clinical applications that may arise from basic research in a
different field.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
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© 1998 American Heart Association, Inc.
Editorials
Angiogenic Therapy of the Human Heart
Key Words: Editorials • angiogenesis • growth substances
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