Angiogenesis
The therapeutic use of growth factors to stimulate angiogenesis has only recently been used to treat ischemia. Vascular Endothelial Growth Factor (VEGF) and Basic Fibroblast Growth Factor (bFGF), the main growth factors involved in the process of angiogenesis, appear to act by local upregulation of nitric oxide production1 and exhibit some synergism in their actions2. Hypercholesterolemia impairs angiogenesis3 by inhibiting the actions of nitric oxide. The beneficial effect of laser myocardial revascularisation (PMR or TMR) in relieving ischemia is also mediated through stimulation of angiogenesis4. Promotion of angiogenesis with intraarterial injection of naked VEGF cDNA to relieve ischemia in atherosclerotic peripheral vascular disease was the first successful application of these research advances5. Injection of VEGF cDNA directly into ischemic tissues has also been used successfully to reduce ischemia in both thromboangiitis obliterans6 and coronary artery disease7. Intracoronary injection of purified bFGF has also been used to reduce ischemia in coronary disease8. Both of these techniques have some potential disadvantages as direct injection into ischemic myocardium requires a limited thoracotomy while intracoronary injection means a most of injected material will not flow through the ischemic area. Other methods of delivery such as intrapericardial injection have had limited success prompting a search for the optimum way to deliver these potent therapeutic compounds. The recent identification of bone marrow progenitor cells which transform into endothelial cells and localise into the angiogenic network and augment growth factor stimulated angiogenesis provide further possibilities for this promising therapy9.
Most recently, early results from the VIVA trial10 were reported. 178 patients with refractory angina were randomized to: placebo, 17 ng/kg/min, or 50 ng/kg/min rhVEGF administered in two 10 minutes IC infusions followed by three 4-h IV infusions on days 3, 6, and 9. Endpoints at 60 days included: exercise treadmill time (primary), ejection fraction, SPECT, angina class, and quality of life (QOL). 120 day endpoints were not reported but include angina class, QOL and exercise time.
The results at 60 days showed no significant differences in the primary endpoint (+0.73 minutes in placebo, 0.43 min. for low-dose and 0.53 minutes for high-dose VEGF) as well as anginal class (-0.66 vs. –0.83 vs. –0.74, respectively). In addition, there were no significant differences in QOL between the untreated and treated groups.
Final results are pending from this trial.
Stanford is also currently involved in a trial with bFGF in patients with otherwise refractory angina.
References
1. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, Kearney M, Chen D, Symes JF, Fishman MC, Huang PL, Isner JM. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest. 1998; 101:2567-78.
2. Asahara T, Bauters C, Zheng LP, Takeshita S, Bunting S, Ferrara N, Symes JF, Isner JM. Synergistic effect of vascular endothelial growth factor and basic fibroblast growth factor on angiogenesis in vivo. Circulation. 1995; 92:II365-71.
3. Van Belle E, Rivard A, Chen D, Silver M, Bunting S, Ferrara N, Symes JF, Bauters C, Isner JM. Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines. Circulation. 1997; 96:2667-74.
4. Malekan R, Reynolds C, Narula N, Kelley ST, Suzuki Y, Bridges CR. Angiogenesis in transmyocardial laser revascularization. A nonspecific response to injury. Circulation. 1998; 98:II62-5; discussion II66.
5. Isner JM, Pieczek A, Schainfeld R, Blair R, Haley L, Asahara T, Rosenfield K, Razvi S, Walsh K, Symes JF. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet. 1996; 348:370-4.
6. Isner JM, Baumgartner I, Rauh G, Schainfeld R, Blair R, Manor O, Razvi S, Symes JF. Treatment of thromboangiitis obliterans (Buerger's disease) by intramuscular gene transfer of vascular endothelial growth factor: preliminary clinical results [In Process Citation]. J Vasc Surg. 1998; 28:964-75.
7. 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; 98:2800-4.
8. 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; 97:645-50.
9. Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997; 275:964-7.
10. Henry TD, Annex BH, Azrin MA, McKendall GR, Willerson JT, Hendel RC, Giordano FJ, Klein R, Gibson MC, Berman DS, Luce CA and ER McCluskey (1999). Double-blind, placebo controlled trial of recombinant human vascular endothelial growth factor. The VIVA Trial. JACC 33 (2: supp A): 384A.
Michael Ward, M.B.B.S.