Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Therapeutic angiogenesis for management of refractory angina

Michael Simons, MD
Section Editor
Bernard J Gersh, MB, ChB, DPhil, FRCP, MACC
Deputy Editor
Gordon M Saperia, MD, FACC


Advances in medical therapy and mechanical revascularization have significantly improved outcomes and the quality of life in patients with angina pectoris. In addition, the widespread application of drug-eluting stents has greatly expanded the ability of percutaneous coronary intervention (PCI) to treat patients with complex coronary anatomy. (See "Stable ischemic heart disease: Overview of care" and "Stable ischemic heart disease: Indications for revascularization" and "Revascularization in patients with stable coronary artery disease: Coronary artery bypass graft surgery versus percutaneous coronary intervention".)

Despite these advances, there are patients with angina that is refractory to medical therapy who are not candidates for traditional revascularization (PCI or coronary artery bypass graft surgery [CABG]) because of the inability to achieve complete revascularization or the high risk of CABG [1].

Such patients provide part of the rationale for novel therapeutic strategies to improve both prognosis and the quality of life. Therapeutic angiogenesis is one such option and will be reviewed here [2,3]. This approach is also being investigated for treatment of patients with peripheral artery disease, including both intermittent claudication and critical limb ischemia. (See "Treatment of chronic lower extremity critical limb ischemia", section on 'Stimulation of angiogenesis'.)

Other investigational strategies, such as transmyocardial laser revascularization and new medications, are discussed separately. (See "Transmyocardial laser revascularization for management of refractory angina" and "New therapies for angina pectoris".)


The goal of therapeutic angiogenesis is the induction of new coronary arterial vessels that can effectively provide blood supply to the area of myocardium subtended by diseased or occluded native coronary arteries. These "native bypass" vessels could then relieve myocardial ischemia, improve regional and global left ventricular performance, lessen symptoms of angina, and potentially improve patient prognosis [4].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Dec 17, 2015.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Mukherjee D, Comella K, Bhatt DL, et al. Clinical outcome of a cohort of patients eligible for therapeutic angiogenesis or transmyocardial revascularization. Am Heart J 2001; 142:72.
  2. Khurana R, Simons M, Martin JF, Zachary IC. Role of angiogenesis in cardiovascular disease: a critical appraisal. Circulation 2005; 112:1813.
  3. Simons M. Angiogenesis: where do we stand now? Circulation 2005; 111:1556.
  4. Simons M, Ware JA. Therapeutic angiogenesis in cardiovascular disease. Nat Rev Drug Discov 2003; 2:863.
  5. Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood 2007; 109:1801.
  6. Pearson JD. Endothelial progenitor cells - hype or hope? J Thromb Haemost 2009; 7:255.
  7. Schaper W, Scholz D. Factors regulating arteriogenesis. Arterioscler Thromb Vasc Biol 2003; 23:1143.
  8. Heil M, Eitenmüller I, Schmitz-Rixen T, Schaper W. Arteriogenesis versus angiogenesis: similarities and differences. J Cell Mol Med 2006; 10:45.
  9. Helisch A, Schaper W. Arteriogenesis: the development and growth of collateral arteries. Microcirculation 2003; 10:83.
  10. Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9:669.
  11. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature 1996; 380:435.
  12. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature 1996; 380:439.
  13. Simons M. Integrative signaling in angiogenesis. Mol Cell Biochem 2004; 264:99.
  14. Arras M, Ito WD, Scholz D, et al. Monocyte activation in angiogenesis and collateral growth in the rabbit hindlimb. J Clin Invest 1998; 101:40.
  15. Simons M, Bonow RO, Chronos NA, et al. Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary. Circulation 2000; 102:E73.
  16. Tchaikovski V, Olieslagers S, Böhmer FD, Waltenberger J. Diabetes mellitus activates signal transduction pathways resulting in vascular endothelial growth factor resistance of human monocytes. Circulation 2009; 120:150.
  17. Simons M. Angiogenesis, arteriogenesis, and diabetes: paradigm reassessed? J Am Coll Cardiol 2005; 46:835.
  18. Simons M. Diabetic monocyte and vascular endothelial growth factor signaling impairment. Circulation 2009; 120:104.
  19. Keck A, Hertting K, Schwartz Y, et al. Electromechanical mapping for determination of myocardial contractility and viability. A comparison with echocardiography, myocardial single-photon emission computed tomography, and positron emission tomography. J Am Coll Cardiol 2002; 40:1067.
  20. Baklanov DV, de Muinck ED, Simons M, et al. Live 3D echo guidance of catheter-based endomyocardial injection. Catheter Cardiovasc Interv 2005; 65:340.
  21. Spertus JA, Winder JA, Dewhurst TA, et al. Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. J Am Coll Cardiol 1995; 25:333.
  22. Tirziu D, Moodie KL, Zhuang ZW, et al. Delayed arteriogenesis in hypercholesterolemic mice. Circulation 2005; 112:2501.
  23. Henry TD, Annex BH, McKendall GR, et al. The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis. Circulation 2003; 107:1359.
  24. Hedman M, Hartikainen J, Syvänne M, et al. Safety and feasibility of catheter-based local intracoronary vascular endothelial growth factor gene transfer in the prevention of postangioplasty and in-stent restenosis and in the treatment of chronic myocardial ischemia: phase II results of the Kuopio Angiogenesis Trial (KAT). Circulation 2003; 107:2677.
  25. Kastrup J, Jørgensen E, Rück A, et al. Direct intramyocardial plasmid vascular endothelial growth factor-A165 gene therapy in patients with stable severe angina pectoris A randomized double-blind placebo-controlled study: the Euroinject One trial. J Am Coll Cardiol 2005; 45:982.
  26. 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.
  27. Laham RJ, Sellke FW, Edelman ER, et al. 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.
  28. Ruel M, Laham RJ, Parker JA, et al. Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. J Thorac Cardiovasc Surg 2002; 124:28.
  29. 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.
  30. Grines CL, Watkins MW, Helmer G, et al. Angiogenic Gene Therapy (AGENT) trial in patients with stable angina pectoris. Circulation 2002; 105:1291.
  31. Grines CL, Watkins MW, Mahmarian JJ, et al. A randomized, double-blind, placebo-controlled trial of Ad5FGF-4 gene therapy and its effect on myocardial perfusion in patients with stable angina. J Am Coll Cardiol 2003; 42:1339.
  32. Henry TD, Grines CL, Watkins MW, et al. Effects of Ad5FGF-4 in patients with angina: an analysis of pooled data from the AGENT-3 and AGENT-4 trials. J Am Coll Cardiol 2007; 50:1038.
  33. Wright MJ, Wightman LM, Latchman DS, Marber MS. In vivo myocardial gene transfer: optimization and evaluation of intracoronary gene delivery in vivo. Gene Ther 2001; 8:1833.
  34. Seiler C, Pohl T, Wustmann K, et al. Promotion of collateral growth by granulocyte-macrophage colony-stimulating factor in patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Circulation 2001; 104:2012.
  35. Unger EF, Sheffield CD, Epstein SE. Heparin promotes the formation of extracardiac to coronary anastomoses in a canine model. Am J Physiol 1991; 260:H1625.
  36. Melandri G, Semprini F, Cervi V, et al. Benefit of adding low molecular weight heparin to the conventional treatment of stable angina pectoris. A double-blind, randomized, placebo-controlled trial. Circulation 1993; 88:2517.
  37. Barron HV, Sciammarella MG, Lenihan K, et al. Effects of the repeated administration of adenosine and heparin on myocardial perfusion in patients with chronic stable angina pectoris. Am J Cardiol 2000; 85:1.
  38. Drinane M, Mollmark J, Zagorchev L, et al. The antiangiogenic activity of rPAI-1(23) inhibits vasa vasorum and growth of atherosclerotic plaque. Circ Res 2009; 104:337.
  39. Tirziu D, Simons M. Angiogenesis in the human heart: gene and cell therapy. Angiogenesis 2005; 8:241.