Angiogenesis for Treatment of Ischemic Heart Disease: Should We Worry About Progression of Atherosclerosis?
To the Editor:
The data presented by Losordo and colleagues1 concerning direct myocardial gene transfer of vascular endothelial growth factor (VEGF) have significant clinical implications and add further support to the concept of using growth factors to stimulate neovascularization in patients with ischemic heart disease. The question that emerges at this stage of progress is whether we should be concerned about the possibility that these growth factors may accelerate the progression of atherosclerosis. This concern is based on the following:
1. In the absence of atherosclerosis, adult coronary arteries are normally devoid of a microvasculature except for a scant plexus of vasa vasorum in the adventitia and outer media.2
2. The formation of new microvessels in human atherosclerotic plaque is associated with high cellular proliferative activity in the plaque.3
3. The endothelial cells of intraplaque microvessels in advanced atherosclerotic lesions have a high level of VEGF expression. Furthermore, more intense VEGF expression was noted in totally occlusive lesions with extensive neovascularization.4
4. The relationship between vascular growth factors and atherosclerosis progression or neointimal hyperplasia does not appear to be unique to VEGF. A recent study suggest that bFGF (basic fibroblast growth factor) may incite aggressive vascular neointimal proliferation in ovariectomized female sheep.5
To investigate this possibility, planned clinical trials should include a quantitative assessment of atherosclerotic plaque volume by intravascular ultrasound to monitor the degree of progression of atherosclerosis, and the sample size of these trials should be sufficient to statistically establish that the growth factor tested does not increase the incidence of myocardial infarction and cardiac death.
- Copyright © 1999 by American Heart Association
Losordo DW, Vale PR, Symes JF, Dunnington CH, Esakof DD, Maysky M, Ashare AB, Lathi K, Isner JM. Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation. 1998; 98:2800–2804.
Inoue M, Itoh H, Ueda M, Naruko T, Kojima A, Komatsu R, Doi K, Ogawa Y, Tamura N, Takaya K, Igaki T, Yamashita J, Chun TH, Masatsugu K, Becker AE, Nakao K. Vascular endothelial growth factor (VEGF) expression in human coronary atherosclerotic lesions: possible pathophysiological significance of VEGF in progression of atherosclerosis. Circulation. 1998;98:2108–2116.
Selzman CH, Gaynor JS, Turner AS, Johnson SM, Horwitz LD, Whitehill TA, Harken AH. Ovarian ablation alone promotes aortic intimal hyperplasia and accumulation of fibroblast growth factor. Circulation. 1998;98:2049–2054.