Angiogenesis is the growth and development of supplemental collateral coronary vessels that will result in endogenous bypass arteries surrounding occluded coronary arteries.
Mechanism:
A complex process involving endothelial cell proliferation and migration, formation of new capillaries, attraction of macrophages, stimulation of smooth muscle cell proliferation and migration, formation of new vascular structures, and deposition of new matrix
Target population includes patients with chronic ischemia and anginal symptoms due to advanced coronary artery disease that is:
Refractory to antianginal medical therapy
Not amenable to percutaneous interventions
Not amenable to conventional coronary artery bypass grafting due to small, diffusely diseased distal target vessels
Found to have significant areas of viable, but underperfused myocardium
Not a candidate for cardiac transplantation
Typical candidate patient profile:
Elderly patient with class III or IV angina, mild to moderate reduction in ejection fraction, and multiple prior revascularization procedures
Most patients have had prior coronary bypass surgery within past 5–10 yr and have occluded most bypass grafts.
Patients frequently have small, diffusely diseased coronary arteries in association with long-standing DM.
The estimated annual mortality rate for these patients is 15%/yr.
Rationale is natural history of collateral vessels: Collateral vessels form from preexisting vascular structures in response to acute MI or chronic ischemia in order to bypass occluded coronary artery territories. This can improve oxygen supply to ischemic muscle:
Patients suffering AMI have less myocardial damage if collaterals are more abundant.
There are intra- and interspecies differences in the collateral response to ischemia; collateral development response in humans is intermediate compared with species such as cats and rabbits.
These differences in collateral development may relate to different levels of endogenous angiogenic factors that would promote this process.
The signaling for collateral development is upregulated in situations of ischemia and infarction. For example, fibroblast growth factor receptors will be increased in numbers in ischemic myocardium.
Endogenous angiogenic stimulants include fibroblast growth factors, vascular endothelial growth factors, platelet-derived growth factors, interleukin-8, and tumor necrosis factor b1.
Animal studies:
Canine and porcine models of acute coronary occlusion or chronic ischemia have been developed in order to assess the response of the coronary arteries to supplemental exogenous angiogenic factors to stimulate coronary collateral growth.
The following factors stimulate growth of coronary collateral vessels in these animal models:
Basic and acidic fibroblast growth factor (FGF)
Vascular endothelial growth factor (VEGF)
Transmyocardial laser channels inducing inflammation and angiogenesis
Methods:
Increased myocardial levels of angiogenic factors have been demonstrated by a variety of methods for the introduction of growth factors in animal models:
Treatment with genes, plasmids, or virus expressing the angiogenic protein factors rather than with the protein itself.
Ongoing Care⬆⬇
PROGNOSIS
Treatment results:
VIVA trial:
A randomized, placebo-controlled trial of combined IV and intracoronary infusions of VEGF in 180 patients with unstable angina
No adverse effects reported
Although exercise tolerance and anginal symptoms improved in the VEGF arm, they also improved in the placebo arm, thus making definite conclusions about the efficacy of VEGF coronary infusions difficult.
FIRST trial:
A randomized, placebo controlled trial of a 20-min intracoronary infusion of basic FGF in 337 patients with symptomatic, severe coronary artery disease:
Trial is based on earlier phase I open label trial of basic FGF in 66 patients with severe symptomatic coronary artery disease demonstrating safety, maximum tolerated dose, and improvement in symptoms and exercise tolerance.
Transmyocardial laser trials completed in 1999 and results published in 2002. The results did not show major benefit, overall, in patients treated with FGF.
2 randomized, nonblinded trials of transmyocardial laser revascularization in patients with refractory angina have reported improvement in symptoms and possible improvements in exercise tolerance.
The mechanism of benefit is unclear and may include formation of new myocardial blood channels, promotion of angiogenesis, and cardiac sympathetic denervation.
Results are controversial due to the possibility that a significant placebo effect may be present in patients undergoing surgical procedures.
Future Issues for therapeutic angiogenesis:
Proving efficacy vs. the placebo effect
Optimal route of delivery
Duration of benefit
Optimal method of angiogenesis: Laser, protein or gene therapy
Long-term safety concerns:
Neovascularization of nontargeted tissues
Tumorigenesis
Potential acceleration of atherosclerosis
Miscellaneous⬆⬇
CODES
ICD9
459.89 Other specified circulatory system disorders
SNOMED
251032001 coronary artery collaterals (finding)
Reference(s)⬆⬇
ADDITIONAL READING
Charney R, Cohen M. The role of coronary collateral circulation in limiting myocardial ischemia and infarct size. Am Heart J. 1993;126:937–945.
Engler DA. Use of vascular endothelial growth factor for therapeutic angiogenesis. Circulation. 1996;94:1496–1498.
Henry TD, Rocha-Singh K, Isner JM, et al. Results of intracoronary recombinant human vascular endothelial growth factor (rhVEGF) administration trial. J Am Coll Cardiol. 1998;31:65A.
Horrigan MC, MacIsaac AI, Nicolini FA, et al. Reduction in myocardial infarct size by basic fibroblast growth factor after temporary coronary occlusion in a canine model. Circulation. 1996;94:1927–1933.
Kornowski R, Epstein SE, Leon MB, eds. Handbook of myocardial revascularization and angiogenesis. London: Martin Dunitz, 2000.
Kornowski R, Hong MK, Leon MB. Current perspectives on direct myocardial revascularization. Am J Cardiol. 1998;81:44E–48E.
Laham RJ, Simons M, Pearlman JD, et al. Biosense catheter direct laser myocardial revascularization improves 30 day angina class, regional wall motion, and perfusion of the treated zone using MRI. J Am Coll Cardiol. 1998;31:333A.
Laham RJ, Hung D, Simons M. Therapeutic myocardial angiogenesis using percutaneous intrapericardial delivery. Clin Cardiol. 1999;22:6–9.
Laham RJ, Baim DS. Angiogenesis and direct myocardial revascularization. Totowa NJ: Humana Press, 2005.
Losordo DW, Vale PR, Symes JF, et al. Gene therapy for myocardial angiogenesis. Circulation, 1998;98:2800–2804.
Raizada MK, Paton JFR, Kasparov S, et al. eds. Cardiovascular Genomics. Totowa NJ: Humana Press, 2005.
Rubanyi GM, ed. Angiogenesis in health and disease. New York: Dekker, 2000.
Schofield PM, et al. Transmyocardial laser revascularization in patients with refractory angina: A randomised controlled trial. Lancet. 1999;353:519–524.
Sellke FW, Laham RJ, Edelman ER, et al. Therapeutic angiogenesis with basic fibroblast growth factor: Technique and early results. Ann Thorac Surg. 1998;65:1540–1544.
Simons M, Annex BH, Laham RJ, et al. Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: Double-blind, randomized, controlled clinical trial. Circulation. 2002;105:788–793.
Stegmann TJ. New vessels for the heart. Angiogenesis as new treatment for coronary heart disease: The story of its discovery and development. Henderson NV: CardioVascular BioTherapeutics Inc., 2004.
Ware JA, Simons M. Angiogenesis in ischemic heart disease. Nature Med. 1997;3:158–164.