Therapeutic angiogenesis for coronary artery disease: clinical trials of proteins, plasmids, adenovirus and stem cells.

Therapeutic angiogenesis represents a molecular and cellular approach to the treatment of coronary artery disease that may be an alternative or additive to traditional pharmacology and interventional cardiology. The goal of angiogenic therapy is to activate endogenous angiogenic and arteriogenic pathways and stimulate revascularization of ischemic myocardial tissue. The feasibility of such a strategy has now been established through the results of studies over the past decade, and clinical trials involving more than 1000 patients have been implemented. In this review the results from these trials will be discussed, tracing the progression of the technology from the delivery of recombinant proteins to gene and stem-cell therapies. It is the opinion of the author that neither proteins nor genes delivered by transient expression vectors will provide an optimal therapy. Rather, the future of this approach lies with regulated genes delivered by permanent vector systems and possibly engineered into stem cells.

[1]  David A. Williams,et al.  Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts , 2004, Nature.

[2]  I. Weissman,et al.  Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium , 2004, Nature.

[3]  K. Park,et al.  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 , 2004, The Lancet.

[4]  Anindita Das,et al.  Cardioprotection with phosphodiesterase-5 inhibition--a novel preconditioning strategy. , 2004, Journal of molecular and cellular cardiology.

[5]  B. Gersh,et al.  Indications for Coronary Artery Bypass Surgery and Percutaneous Coronary Intervention in Chronic Stable Angina: Review of the Evidence and Methodological Considerations , 2003, Circulation.

[6]  C. Grines,et al.  Angiogenic gene therapy with adenovirus 5 fibroblast growth factor-4 (Ad5FGF-4): a new option for the treatment of coronary artery disease. , 2003, The American journal of cardiology.

[7]  S. Ylä-Herttuala,et al.  Evolving revascularization approaches for myocardial ischemia. , 2003, The American journal of cardiology.

[8]  Michael D. Schneider,et al.  Cardiac progenitor cells from adult myocardium: Homing, differentiation, and fusion after infarction , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Torella,et al.  Adult Cardiac Stem Cells Are Multipotent and Support Myocardial Regeneration , 2003, Cell.

[10]  J. Hartikainen,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) , 2003, Circulation.

[11]  James T. Willerson,et al.  Transendocardial, Autologous Bone Marrow Cell Transplantation for Severe, Chronic Ischemic Heart Failure , 2003, Circulation.

[12]  Brian H Annex,et al.  The VIVA Trial Vascular Endothelial Growth Factor in Ischemia for Vascular Angiogenesis , 2003 .

[13]  P. Bannon,et al.  Coronary artery bypass grafting (CABG) after initially successful percutaneous transluminal coronary angioplasty (PTCA): a review of 17 years experience. , 2003, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[14]  Rossella Fattori,et al.  Drug-eluting stents in vascular intervention , 2003, The Lancet.

[15]  Sankey V. Williams,et al.  ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). , 2003, Circulation.

[16]  Bernd Westphal,et al.  Autologous bone-marrow stem-cell transplantation for myocardial regeneration , 2003, The Lancet.

[17]  Hung-Fat Tse,et al.  Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation , 2003, The Lancet.

[18]  A. Ahmed.  American College of Cardiology/American Heart Association Chronic Heart Failure Evaluation and Management Guidelines: Relevance to the Geriatric Practice , 2003, Journal of the American Geriatrics Society.

[19]  G. Lip,et al.  Antithrombotic strategies in acute coronary syndromes and percutaneous coronary interventions , 2002, BMJ : British Medical Journal.

[20]  A. Gotto.  High-density lipoprotein cholesterol and triglycerides as therapeutic targets for preventing and treating coronary artery disease. , 2002, American heart journal.

[21]  M. Mann,et al.  Molecular approaches for the treatment of atherosclerosis. , 2002, Cardiology clinics.

[22]  P. Wernet,et al.  Repair of Infarcted Myocardium by Autologous Intracoronary Mononuclear Bone Marrow Cell Transplantation in Humans , 2002, Circulation.

[23]  H. Orskov,et al.  Cardiovascular disease and insulin-like growth factor I. , 2002, Circulation.

[24]  J. Ware,et al.  Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein. , 2002, The Journal of thoracic and cardiovascular surgery.

[25]  R. Hendel,et al.  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 , 2002, Circulation.

[26]  P. Carmeliet,et al.  Conditional switching of VEGF provides new insights into adult neovascularization and pro‐angiogenic therapy , 2002, The EMBO journal.

[27]  M. Yano,et al.  Therapeutic angiogenesis induced by local autologous bone marrow cell implantation. , 2002, The Annals of thoracic surgery.

[28]  C. Grines,et al.  Angiogenic Gene Therapy (AGENT) Trial in Patients With Stable Angina Pectoris , 2002, Circulation.

[29]  T. Henry,et al.  Pharmacological Treatment of Coronary Artery Disease With Recombinant Fibroblast Growth Factor-2: Double-Blind, Randomized, Controlled Clinical Trial , 2002, Circulation.

[30]  M. Seyfarth,et al.  Blocking caspase-activated apoptosis improves contractility in failing myocardium. , 2001, Human gene therapy.

[31]  R. Hendel,et al.  Intracoronary administration of recombinant human vascular endothelial growth factor to patients with coronary artery disease. , 2001, American heart journal.

[32]  A. Zeiher,et al.  Vitamin C Inhibits Endothelial Cell Apoptosis in Congestive Heart Failure , 2001, Circulation.

[33]  D. Shum-Tim,et al.  The coronary delivery of marrow stromal cells for myocardial regeneration: pathophysiologic and therapeutic implications. , 2001, The Journal of thoracic and cardiovascular surgery.

[34]  A. Kosaki,et al.  Implantation of Bone Marrow Mononuclear Cells Into Ischemic Myocardium Enhances Collateral Perfusion and Regional Function via Side Supply of Angioblasts, Angiogenic Ligands, and Cytokines , 2001, Circulation.

[35]  Federica Limana,et al.  Mobilized bone marrow cells repair the infarcted heart, improving function and survival , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[36]  K. Hamano,et al.  The induction of angiogenesis by the implantation of autologous bone marrow cells: a novel and simple therapeutic method. , 2001, Surgery.

[37]  J. Isner,et al.  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 , 2001, Circulation.

[38]  David M. Bodine,et al.  Bone marrow cells regenerate infarcted myocardium , 2001, Nature.

[39]  S. Homma,et al.  Neovascularization of ischemic myocardium by human bone-marrow–derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function , 2001, Nature Medicine.

[40]  J. Pearlman,et al.  Intracoronary basic fibroblast growth factor (FGF-2) in patients with severe ischemic heart disease: results of a phase I open-label dose escalation study. , 2000, Journal of the American College of Cardiology.

[41]  V. Dilsizian,et al.  Therapeutic Angiogenesis With Recombinant Fibroblast Growth Factor-2 Improves Stress and Rest Myocardial Perfusion Abnormalities in Patients With Severe Symptomatic Chronic Coronary Artery Disease , 2000, Circulation.

[42]  A. Quyyumi,et al.  Effects of a single intracoronary injection of basic fibroblast growth factor in stable angina pectoris. , 2000, The American journal of cardiology.

[43]  U. Lendahl,et al.  Generalized potential of adult neural stem cells. , 2000, Science.

[44]  B. Schumacher,et al.  Angiogenesis in ischemic human myocardium: clinical results after 3 years. , 2000, The Annals of thoracic surgery.

[45]  P. Carmeliet.  Mechanisms of angiogenesis and arteriogenesis , 2000, Nature Medicine.

[46]  J. Pearlman,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. , 1999, Circulation.

[47]  P. Kligfield,et al.  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. , 1999, Annals of surgery.

[48]  Deepak L. Bhatt,et al.  Direct myocardial revascularization and angiogenesis--how many patients might be eligible? , 1999, The American journal of cardiology.

[49]  J. Isner.  Manipulating angiogenesis against vascular disease. , 1999, Hospital practice.

[50]  K. Webster.  Molecular switches for regulating therapeutic genes , 1999, Gene Therapy.

[51]  T. Asselah,et al.  Prevalence of Hepatitis C Virus Infection in Patients Hospitalized for Hepatitis A , 1999, Annals of Internal Medicine.

[52]  J. Isner,et al.  Age-dependent impairment of angiogenesis. , 1999, Circulation.

[53]  J. Isner,et al.  Gene therapy for myocardial angiogenesis: initial clinical results with direct myocardial injection of phVEGF165 as sole therapy for myocardial ischemia. , 1998, Circulation.

[54]  K Walsh,et al.  Constitutive expression of phVEGF165 after intramuscular gene transfer promotes collateral vessel development in patients with critical limb ischemia. , 1998, Circulation.

[55]  B. V. von Specht,et al.  Induction of neoangiogenesis in ischemic myocardium by human growth factors: first clinical results of a new treatment of coronary heart disease. , 1998, Circulation.

[56]  K. Webster,et al.  Regulated expression of a foreign gene targeted to the ischaemic myocardium. , 1997, Cardiovascular research.

[57]  B. Lewis,et al.  Angiogenesis by gene therapy: a new horizon for myocardial revascularization? , 1997, Cardiovascular research.

[58]  M. Capogrossi,et al.  Gene therapy for collateral vessel development. , 1997, Cardiovascular research.

[59]  Takayuki Asahara,et al.  Isolation of Putative Progenitor Endothelial Cells for Angiogenesis , 1997, Science.

[60]  J. Isner,et al.  Direct intramuscular gene transfer of naked DNA encoding vascular endothelial growth factor augments collateral development and tissue perfusion. , 1996, Circulation.

[61]  E. Jones,et al.  The importance of completeness of revascularization during long-term follow-up after coronary artery operations. , 1996, The Journal of thoracic and cardiovascular surgery.

[62]  Peipei Ping,et al.  Intracoronary gene transfer of fibroblast growth factor–5 increases blood flow and contractile function in an ischemic region of the heart , 1996, Nature Medicine.

[63]  K. Webster.  Therapeutic angiogenesis , 2007, Cardiovascular Toxicology.

[64]  M. Weitzman,et al.  Gene delivery to the mammalian heart using AAV vectors. , 2004, Methods in molecular biology.

[65]  Y. Kan,et al.  Adeno-associated viral vector-mediated gene transfer of VEGF normalizes skeletal muscle oxygen tension and induces arteriogenesis in ischemic rat hindlimb. , 2003, Molecular therapy : the journal of the American Society of Gene Therapy.

[66]  K. Webster.  Therapeutic angiogenesis: a case for targeted, regulated gene delivery. , 2000, Critical reviews in eukaryotic gene expression.

[67]  R. Hendel,et al.  Myocardial Perfusion : Evidence for a Dose-Dependent Effect Effect of Intracoronary Recombinant Human Vascular Endothelial Growth Factor on , 1999 .