Skip to main content

Trials of Angiogenesis Therapy in Patients with Ischemic Heart Disease

  • Chapter
  • First Online:
Biochemical Basis and Therapeutic Implications of Angiogenesis

Part of the book series: Advances in Biochemistry in Health and Disease ((ABHD,volume 6))

Abstract

After initial success in in vitro and in vivo studies showing tremendous potential of angiogenic therapy, therapeutic angiogenesis has been studied in humans with ischemic heart disease (IHD) not responding to conventional treatments. Vascular endothelial growth factor, fibroblast growth factor, and granulocyte colony stimulating factor are among the most commonly tested cytokines in human trials. Delivery as a protein or vector with gene encoding for specific protein have been tested in these trials. In addition, multitude of delivery routes ranging from direct intramyocardial transfer to intracoronary infusion to systemic administration via subcutaneous route have been tried. Clinical, radiographic, and angiographic parameters have been used to gauge the effect of these therapies in human trials. While promising results were attained in small phase I studies, these salutary results have not been replicated in large phase II and III studies. Multitude of variables including duration of exposure, type of vector, and need for co-factor influence the process of angiogenesis. Further studies accounting for these variables are needed to fully determine the potential of therapeutic angiogenesis in IHD.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 179.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Schumacher B, Pecher P, von Specht BU, Stegmann T (1998) Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. Circulation 97:645–650

    Article  PubMed  CAS  Google Scholar 

  2. Sellke FW, Laham RJ, Edelman ER et al (1998) Therapeutic angiogenesis with basic fibroblast growth factor: technique and early results. Ann Thorac Surg 65:1540–1544

    Article  PubMed  CAS  Google Scholar 

  3. Laham RJ, Sellke FW, Edelman ER et al (1999) 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 100:1865–1871

    Article  PubMed  CAS  Google Scholar 

  4. Unger EF, Goncalves L, Epstein SE et al (2000) Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. Am J Cardiol 85(12):1414–1419

    Article  PubMed  CAS  Google Scholar 

  5. Laham RJ, Chronos NA, Pike M et al (2000) Intracoronary basic fibroblast growth factor (FGF-­2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study. J Am Coll Cardiol 36:2132–2139

    Article  PubMed  CAS  Google Scholar 

  6. Simons M, Annex BH, Laham RJ, Kleiman N, Henry T, Dauerman H et al (2002) Pharmacological treatment of coronary artery disease with recombinant fibroblast growth factor-2: double-­blind, randomized, controlled clinical trial. Circulation 105:788–793

    Article  PubMed  CAS  Google Scholar 

  7. Jang E, Albadawi H, Watkins MT et al (2012) Syndecan-4 proteoliposomes enhance fibroblast growth factor-2 (FGF-2)-induced proliferation, migration, and neovascularization of ischemic muscle. Proc Natl Acad Sci U S A 109:1679–1684

    Article  PubMed  CAS  Google Scholar 

  8. Kim JH, Jung Y, Kim SH et al (2011) The enhancement of mature vessel formation and cardiac function in infarcted hearts using dual growth factor delivery with self-assembling peptides. Biomaterials 32:6080–6088

    PubMed  CAS  Google Scholar 

  9. Hendel RC, Henry TD, Rocha-Singh K et al (2000) Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-­dependent effect. Circulation 101:118–121

    Article  PubMed  CAS  Google Scholar 

  10. Henry TD, Rocha-Singh K, Isner JM et al (2001) Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. Am Heart J 142:872–880

    Article  PubMed  CAS  Google Scholar 

  11. Henry TD, Annex BH, McKendall GR et al (2003) The VIVA trial: vascular endothelial growth factor in ischemia for vascular angiogenesis. Circulation 107:1359–1365

    Article  PubMed  CAS  Google Scholar 

  12. Kuethe F, Figulla HR, Herzau M et al (2005) Treatment with granulocyte colony-stimulating factor for mobilization of bone marrow cells in patients with acute myocardial infarction. Am Heart J 150:115

    Article  PubMed  CAS  Google Scholar 

  13. Seiler C, Pohl T, Wustmann K et al (2001) Promotion of collateral growth by granulocyte-­macrophage colony-stimulating factor in patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Circulation 104:2012–2017

    Article  PubMed  CAS  Google Scholar 

  14. Zbinden S, Zbinden R, Meier P et al (2005) Safety and efficacy of subcutaneous-only granulocyte-­macrophage colony-stimulating factor for collateral growth promotion in patients with coronary artery disease. J Am Coll Cardiol 46:1636–1642

    Article  PubMed  CAS  Google Scholar 

  15. Valgimigli M, Rigolin GM, Cittanti C et al (2005) Use of granulocyte-colony stimulating factor during acute myocardial infarction to enhance bone marrow stem cell mobilization in humans: clinical and angiographic safety profile. Eur Heart J 26:1838–1845

    Article  PubMed  CAS  Google Scholar 

  16. Zohlnhofer D, Ott I, Mehilli J et al (2006) Stem cell mobilization by granulocyte colony-­stimulating factor in patients with acute myocardial infarction: a randomized controlled trial. JAMA 295:1003–1010

    Article  PubMed  Google Scholar 

  17. Kang HJ, Kim HS, Zhang SY et al (2004) Effects of intracoronary infusion of peripheral blood stem-cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: the MAGIC cell randomised clinical trial. Lancet 363:751–756

    Article  PubMed  CAS  Google Scholar 

  18. Kang HJ, Kim HS, Koo BK et al (2007) Intracoronary infusion of the mobilized peripheral blood stem cell by G-CSF is better than mobilization alone by G-CSF for improvement of cardiac function and remodeling: 2-year follow-up results of the myocardial regeneration and angiogenesis in myocardial infarction with G-CSF and intra-coronary stem cell infusion (MAGIC cell) 1 trial. Am Heart J 153:237.e1–e8

    Google Scholar 

  19. Belardinelli R, Belardinelli L, Shryock JC (2001) Effects of dipyridamole on coronary collateralization and myocardial perfusion in patients with ischaemic cardiomyopathy. Eur Heart J 22:1205–1213

    Article  PubMed  CAS  Google Scholar 

  20. Losordo DW, Vale PR, Symes JF et al (1998) Gene therapy for myocardial angiogenesis: Initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. Circulation 98:2800–2804

    Article  PubMed  CAS  Google Scholar 

  21. Rosengart TK, Lee LY, Patel SR et al (1999) Angiogenesis gene therapy: phase I assessment of direct intramyocardial administration of an adenovirus vector expressing VEGF121 cDNA to individuals with clinically significant severe coronary artery disease. Circulation 100:468–474

    Article  PubMed  CAS  Google Scholar 

  22. Symes JF, Losordo DW, Vale PR et al (1999) Gene therapy with vascular endothelial growth factor for inoperable coronary artery disease. Ann Thorac Surg 68:830–836; discussion 836–837

    Google Scholar 

  23. Vale PR, Losordo DW, Milliken CE et al (2000) Left ventricular electromechanical mapping to assess efficacy of phVEGF(165) gene transfer for therapeutic angiogenesis in chronic myocardial ischemia. Circulation 102:965–974

    Article  PubMed  CAS  Google Scholar 

  24. Sarkar N, Ruck A, Kallner G et al (2001) Effects of intramyocardial injection of phVEGF-A165 as sole therapy in patients with refractory coronary artery disease—12-month follow-up: angiogenic gene therapy. J Intern Med 250:373–381

    Article  PubMed  CAS  Google Scholar 

  25. Rosengart TK, Lee LY, Patel SR et al (1999) Six-month assessment of a phase I trial of angiogenic gene therapy for the treatment of coronary artery disease using direct intramyocardial administration of an adenovirus vector expressing the VEGF121 cDNA. Ann Surg 230:466–470; discussion 470–472

    Google Scholar 

  26. Stewart DJ, Hilton JD, Arnold JM, Gregoire J et al (2006) Angiogenic gene therapy in patients with nonrevascularizable ischemic heart disease: a phase 2 randomized, controlled trial of AdVEGF(121) (AdVEGF121) versus maximum medical treatment. Gene Ther 13:1503–1511

    Article  PubMed  CAS  Google Scholar 

  27. Giordano FJ, Ping P, McKirnan MD et al (1996) Intracoronary gene transfer of fibroblast growth factor-5 increases blood flow and contractile function in an ischemic region of the heart. Nat Med 2:534–539

    Article  PubMed  CAS  Google Scholar 

  28. Laitinen M, Hartikainen J, Hiltunen MO et al (2000) Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty. Hum Gene Ther 11:263–270

    Article  PubMed  CAS  Google Scholar 

  29. Vale PR, Losordo DW, Milliken CE et al (2001) Randomized, single-blind, placebo-controlled pilot study of catheter-based myocardial gene transfer for therapeutic angiogenesis using left ventricular electromechanical mapping in patients with chronic myocardial ischemia. Circulation 103:2138–2143

    Article  PubMed  CAS  Google Scholar 

  30. Losordo DW, Vale PR, Hendel RC et al (2002) Phase 1/2 placebo-controlled, double-blind, dose-escalating trial of myocardial vascular endothelial growth factor 2 gene transfer by catheter delivery in patients with chronic myocardial ischemia. Circulation 105:2012–2018

    Article  PubMed  CAS  Google Scholar 

  31. Hedman M, Hartikainen J, Syvanne M et al (2003) 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 107:2677–2683

    Article  PubMed  CAS  Google Scholar 

  32. Kastrup J, Jorgensen E, Ruck A et al (2005) 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 45:982–988

    Article  PubMed  CAS  Google Scholar 

  33. Gyongyosi M, Khorsand A, Zamini S et al (2005) NOGA-guided analysis of regional myocardial perfusion abnormalities treated with intramyocardial injections of plasmid encoding vascular endothelial growth factor A-165 in patients with chronic myocardial ischemia: subanalysis of the EUROINJECT-ONE multicenter double-blind randomized study. Circulation 112(9 suppl):I157–I165

    PubMed  Google Scholar 

  34. Ripa RS, Jorgensen E, Wang Y et al (2006) Stem cell mobilization induced by subcutaneous granulocyte-colony stimulating factor to improve cardiac regeneration after acute ST-elevation myocardial infarction: result of the double-blind, randomized, placebo-­controlled stem cells in myocardial infarction (STEMMI) trial. Circulation 113:1983–1992

    Article  PubMed  CAS  Google Scholar 

  35. Stewart DJ, Kutryk MJ, Fitchett D et al (2009) VEGF gene therapy fails to improve perfusion of ischemic myocardium in patients with advanced coronary disease: results of the NORTHERN trial. Mol Ther 17:1109–1115

    Article  PubMed  CAS  Google Scholar 

  36. Kastrup J, Jorgensen E, Fuchs S et al (2011) A randomised, double-blind, placebo-controlled, multicentre study of the safety and efficacy of BIOBYPASS (AdGVVEGF121.10NH) gene therapy in patients with refractory advanced coronary artery disease: the NOVA trial. EuroIntervention 6:813–818

    Article  PubMed  Google Scholar 

  37. Grines CL, Watkins MW, Helmer G et al (2002) Angiogenic gene therapy (AGENT) trial in patients with stable angina pectoris. Circulation 105:1291–1297

    Article  PubMed  CAS  Google Scholar 

  38. Grines CL, Watkins MW, Mahmarian JJ et al (2003) 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 42:1339–1347

    Article  PubMed  CAS  Google Scholar 

  39. Henry TD, Grines CL, Watkins MW et al (2007) 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 50:1038–1046

    Article  PubMed  CAS  Google Scholar 

  40. Kukula K, Chojnowska L, Dabrowski M et al (2011) Intramyocardial plasmid-encoding human vascular endothelial growth factor A165/basic fibroblast growth factor therapy using percutaneous transcatheter approach in patients with refractory coronary artery disease (VIF-CAD). Am Heart J 161:581–589

    Article  PubMed  CAS  Google Scholar 

  41. Ruel M, Beanlands RS, Lortie M et al (2008) Concomitant treatment with oral L-arginine improves the efficacy of surgical angiogenesis in patients with severe diffuse coronary artery disease: the endothelial modulation in angiogenic therapy randomized controlled trial. J Thorac Cardiovasc Surg 135:762–770, 770.e1

    Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sandeep Singla M.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Singla, S., Mehta, J.L. (2013). Trials of Angiogenesis Therapy in Patients with Ischemic Heart Disease. In: Mehta, J., Dhalla, N. (eds) Biochemical Basis and Therapeutic Implications of Angiogenesis. Advances in Biochemistry in Health and Disease, vol 6. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-5857-9_17

Download citation

Publish with us

Policies and ethics