Abstract
Background: Therapeutic angiogenesis, if combined with primary percutaneous transluminal coronary angioplasty or stent placement, could improve the outcome of patients suffering from multifocal coronary disease.
Hypothesis: Because of the concern that angiogenic growth factors might promote restenosis, we studied the effect of a single intracoronary administration of recombinant fibroblast growth factor (rFGF)‐2 on restenosis after balloon angioplasty and stent placement in a pig model of coronary atherosclerosis.
Methods: In 24 Yucatan minipigs, coronary lesions were induced by arterial injury and 3 months of atherogenic diet. After 3 months, repeat catheterization was performed with balloon dilation or stent placement at the injured sites, with a follow‐up of 6 weeks. Results were monitored using quantitative angiography, intravascular ultrasound (IVUS), and histomorphometry.
Results: Intracoronary rFGF‐22 μg/kg did not affect neoin‐tima formation or remodeling in this model. A small but significant aggravation of late lumenloss was observed in the reference segments of the rFGF‐2‐treated group. Angiographic and echographic late lumen loss, intimal hyperplasia, and arterial remodeling, as well as histologic neointima were all similar in the rFGF‐2‐ and the vehicle‐treated group. Confirming earlier studies from our group and those of others, stented arteries compared with balloon‐dilated arteries had increased angiographic late lumen loss, a trend toward increased intimal hyperplasia and decreased remodeling.
Conclusion: We conclude that rFGF‐2 does not aggravate restenosis after balloon dilation or stenting in this pig model of coronary atherosclerosis. Future combinations of angioplasty and therapeutic angiogenesis in a single session should be pursued as a feasible and safe strategy.
Keywords: angiogenesis, pig, balloon angioplasty, stent, restenosis, growth factors, coronary disease
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References
- 1. Isner JM, Asahara T: Angiogenesis and vasculogenesis as therapeutic strategies for postnatal neovascularization. J Clin Invest 1999; 103: 1231–1236 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Laham R, Leimbach M, Chronos N, Vansant J, Pearlman J, Pettigrew R, Guler H, Whitehouse M, Hung D, Baim D, King S, Simons M: Intracoronary administration of recombinant fibroblast growth factor‐2 (rFGF‐2) in patients with severe coronary artery disease: Results of Phase I (abstr). J Am Coll Cardiol 1999; 33: 383A [Google Scholar]
- 3. Ware JA, Simons M: Angiogenesis and Cardiovascular Disease, p. 360 New York: Oxford University Press, 1999. [Google Scholar]
- 4. Ware JA, Simons M: Angiogenesis in ischemic heart disease. Nat Med 1997; 3: 158–164 [DOI] [PubMed] [Google Scholar]
- 5. Henry T, Annex B, Azrin M, McKendall G, Willerson J, Hendel R, Giordano F, Klein R, Gibson M, Berman D, Luce C, McCluskey E: Final results of the VIVA trial of rhVEGF Human Therapeutic Angiogenesis. Circulation 1999; 100:I–476 [Google Scholar]
- 6. Laham RJ, Chronos NA, Pike M, Leimbach ME, Udelson JE, Pearlman JD, Pettigrew RI, Whitehouse MJ, Yoshizawa C, Simons M: Intracoronary basic fibroblast growth factor (FGF‐2) in patients with severe ischemic heart disease: Results of a phase I open‐label dose escalation study (in process citation). J Am Coll Cardiol 2000; 36: 2132–2139 [DOI] [PubMed] [Google Scholar]
- 7. 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 [DOI] [PubMed] [Google Scholar]
- 8. Schwartz SM, deBlois D, O'Brien ER: The intima. Soil for atherosclerosis and restenosis. Circ Res 1995; 77: 445–465 [DOI] [PubMed] [Google Scholar]
- 9. Lindner V, Reidy MA: Expression of basic fibroblast growth factor and its receptor by smooth muscle cells and endothelium in injured rat arteries: An en face study. Circ Res 1993; 73: 589–595 [DOI] [PubMed] [Google Scholar]
- 10. Hanna AK, Fox JC, Neschis DG, Safford SD, Swain JL, Golden MA: Antisense basic fibroblast growth factor gene transfer reduces neointimal thickening after arterial injury. J Vasc Surg 1997; 25: 320–325 [DOI] [PubMed] [Google Scholar]
- 11. 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 [DOI] [PubMed] [Google Scholar]
- 12. Parish MA, Grossi EA, Baumann FG, Asai T, Rifkin DB, Colvin SB, Galloway AC: Effects of a single administration of fibroblast growth factor on vascular wall reaction to injury. Ann Thorac Surg 1995; 59: 948–954 [DOI] [PubMed] [Google Scholar]
- 13. de Smet BJ, van der Zande J, van der Helm YJ, Kuntz RE, Borst C, Post MJ: The atherosclerotic Yucatan animal model to study the arterial response after balloon angioplasty: The natural history of remodeling. Cardiovasc Res 1998; 39: 224–232 [DOI] [PubMed] [Google Scholar]
- 14. Gal D, Rongione AJ, Slovenkai GA, DeJesus ST, Lucas A, Fields CD, Isner JM: Atherosclerotic Yucatan microswine: An animal model with high‐grade, fibrocalcific, nonfatty lesions suitable for testing catheter‐based interventions. Am Heart J 1990; 119: 291–300 [DOI] [PubMed] [Google Scholar]
- 15. Reitman JS, Mahley RW, Fry DL: Yucatan miniature swine as a model for diet‐induced atherosclerosis. Atherosclerosis 1982; 43: 119–132 [DOI] [PubMed] [Google Scholar]
- 16. Kuntz RE, Safian RD, Carrozza JP, Fishman RF, Mansour M, Baim DS: The importance of acute luminal diameter in determining restenosis after coronary atherectomy or stenting. Circulation 1992; 86: 1827–1835 [DOI] [PubMed] [Google Scholar]
- 17. Harada K, Friedman M, Lopez JJ, Wang SY, Li J, Prasad PV, Pearlman JD, Edelman ER, Sellke FW, Simons M: Vascular endothelial growth factor administration in chronic myocardial ischemia. Am J Physiol 1996; 270: H1791–1802 [DOI] [PubMed] [Google Scholar]
- 18. Hariawala MD, Horowitz JR, Esakof D, Sheriff DD, Walter DH, Keyt B, Isner JM, Symes JF: VEGF improves myocardial blood flow but produces EDRF‐mediated hypotension in porcine hearts. J Surg Res 1996; 63: 77–82 [DOI] [PubMed] [Google Scholar]
- 19. Banai S, Jaklitsch MT, Casscells W, Shou M, Shrivastav S, Correa R, Epstein SE, Unger EF: Effects of acidic fibroblast growth factor on normal and ischemic myocardium. Circ Res 1991; 69: 76–85 [DOI] [PubMed] [Google Scholar]
- 20. Lopez JJ, Edelman ER, Stamler A, Hibberd MG, Prasad P, Thomas KA, DiSalvo J, Caputo RP, Carrozza JP, Douglas PS, Sellke FW, Simons M: Angiogenic potential of perivascularly delivered aFGF in a porcine model of chronic myocardial ischemia. Am J Physiol 1998; 274: H930–936 [DOI] [PubMed] [Google Scholar]
- 21. Harada K, Grossman W, Friedman M, Edelman ER, Prasad PV, Keighley CS, Manning WJ, Sellke FW, Simons M: Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. J Clin Invest 1994; 94: 623–630 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22. Lopez JJ, Edelman ER, Stamler A, Hibberd MG, Prasad P, Caputo RP, Carrozza JP, Douglas PS, Sellke FW, Simons M: Basic fibroblast growth factor in a porcine model of chronic myocardial ischemia: A comparison of angiographic, echocardiographic and coronary flow parameters. J Pharmacol Exp Ther 1997; 282: 385–390 [PubMed] [Google Scholar]
- 23. Giordano FJ, Ping P, McKirnan MD, Nozaki S, DeMaria AN, Dillmann WH, Mathieu‐Costello O, Hammond HK: Intracoronary gene transfer of fibroblast growth factor‐5 increases blood flow and contractile function in an ischemic region of the heart (see comments). Nat Med 1996; 2: 534–539 [DOI] [PubMed] [Google Scholar]
- 24. Devlin GP, Fort S, Yu E, Cusimano RJ, Wei K, Rakowski H, Butany J, Richards JA, Sole MJ, Schwartz L: Effect of a single bolus of intracoronary basic fibroblast growth factor on perfusion in an ischemic porcine model. Can J Cardiol 1999; 15: 676–682 [PubMed] [Google Scholar]
- 25. Laham RJ, Sellke FW, Edelman ER, Pearlman JD, Ware JA, Brown DL, Gold JP, Simons M: Local perivascular delivery of basic fibroblast growth factor in patients undergoing coronary bypass surgery: Results of a phase I randomized, double‐blind, placebo‐controlled trial. Circulation 1999; 100: 1865–1871 [DOI] [PubMed] [Google Scholar]
- 26. Udelson JE, Dilsizian V, Laham RJ, Chronos N, Vansant J, Blais M, Galt JR, Pike M, Yoshizawa C, Simons M: Therapeutic angiogene‐sis with recombinant fibroblast growth factor‐2 improves stress and rest myocardial perfusion abnormalities in patients with severe symptomatic chronic coronary artery disease (in process citation). Circulation 2000; 102: 1605–1610 [DOI] [PubMed] [Google Scholar]
- 27. de Smet BJ, Pasterkamp G, van der Helm YJ, Borst C, Post MJ: The relation between de novo atherosclerosis remodeling and angioplasty‐induced remodeling in an atherosclerotic Yucatan micropig model. Arterioscler Thromb Vasc Biol 1998; 18: 702–707 [DOI] [PubMed] [Google Scholar]
- 28. Post MJ, de Smet BJ, van der Helm Y, Borst C, Kuntz RE: Arterial remodeling after balloon angioplasty or stenting in an atherosclerotic experimental model. Circulation 1997; 96: 996–1003 [DOI] [PubMed] [Google Scholar]
- 29. Bjornsson TD, Dryjski M, Tluczek J, Mennie R, Ronan J, Mellin TN, Thomas KA: Acidic fibroblast growth factor promotes vascular repair. Proc Natl Acad Sci USA 1991; 88: 8651–8655 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Lindner V, Majack RA, Reidy MA: Basic fibroblast growth factor stimulates endothelial regrowth and proliferation in denuded arteries. J Clin Invest 1990; 85: 2004–2008 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31. Rutherford C, Martin W, Salame M, Carrier M, Anggard E, Ferns G: Substantial inhibition of neo‐intimal response to balloon injury in the rat carotid artery using a combination of antibodies to platelet‐derived growth factor‐BB and basic fibroblast growth factor. Atherosclerosis 1997; 130: 45–51 [DOI] [PubMed] [Google Scholar]
- 32. Chen C, Mattar SG, Hughes JD, Pierce GF, Cook JE, Ku DN, Hanson SR, Lumsden AB: Recombinant mitotoxin basic fibroblast growth factor‐saporin reduces venous anastomotic intimal hyper‐plasiain the arteriovenous graft. Circulation 1996; 94: 1989–1995 [DOI] [PubMed] [Google Scholar]
- 33. Kumamoto M, Nakashima Y, Sueishi K: Intimal neovascularization in human coronary atherosclerosis: Its origin and pathophysiological significance. Hum Pathol 1995; 26: 450–456 [DOI] [PubMed] [Google Scholar]
- 34. Kennedy SH, Rouda S, Qin H, Aho S, Selber J, Tan EM: Basic FGF regulates interstitial collagenase gene expression in human smoothmuscle cells. J Cell Biochem 1997; 65: 32–41 [PubMed] [Google Scholar]
- 35. Post MJ, Borst C, Kuntz RE: The relative importance of arterial remodeling compared with intimal hyperplasia in lumen renarrowing after balloon angioplasty. A study in the normal rabbit and the hypercholesterolemic Yucatan micropig (see comments). Circulation 1994; 89: 2816–2821 [DOI] [PubMed] [Google Scholar]
- 36. Simons M, Post MJ: Coronary artery disease: Vascular endothelial growth factor and fibroblast growth factor. Curr Interv Cardiol Rep 2001; 3: 185–191 [PubMed] [Google Scholar]
