Clinical trials in coronary angiogenesis: issues, problems, consensus: An expert panel summary.

The rapid development of angiogenic growth factor therapy for patients with advanced ischemic heart disease over the last 5 years offers hope of a new treatment strategy based on generation of new blood supply in the diseased heart. However, as the field of therapeutic coronary angiogenesis is maturing from basic and preclinical investigations to clinical trials, many new and presently unresolved issues are coming into focus. These include in-depth understanding of the biology of angiogenesis, selection of appropriate patient populations for clinical trials, choice of therapeutic end points and means of their assessment, choice of therapeutic strategy (gene versus protein delivery), route of administration, and the side effect profile. The present article presents a summary statement of a panel of experts actively working in the field, convened by the Angiogenesis Foundation and the Angiogenesis Research Center during the 72nd meeting of the American Heart Association to define and achieve a consensus on the challenges facing development of therapeutic angiogenesis for coronary disease.

[1]  P. D’Amore,et al.  Vascular Development: Cellular and Molecular Regulation , 2022 .

[2]  M. Fujita,et al.  Recent insights into coronary collateral circulation. , 1992, Circulation.

[3]  J. Ware,et al.  Angiogenesis and cardiovascular disease , 1999 .

[4]  W. Schaper,et al.  Angiogenesis but not collateral growth is associated with ischemia after femoral artery occlusion. , 1997, The American journal of physiology.

[5]  R. Deyo,et al.  Generic and Disease-Specific Measures in Assessing Health Status and Quality of Life , 1989, Medical care.

[6]  K. Sueishi,et al.  Angiogenic processes in the pathogenesis of human coronary atherosclerosis. , 1993, Current topics in pathology. Ergebnisse der Pathologie.

[7]  M. Post,et al.  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. , 1999, Circulation.

[8]  R. D'Amato,et al.  New activity of spironolactone. Inhibition of angiogenesis in vitro and in vivo. , 1996, Circulation.

[9]  J. Folkman.  Angiogenesis in cancer, vascular, rheumatoid and other disease , 1995, Nature Medicine.

[10]  V. Perry,et al.  Variation in the immune response to adenoviral vectors in the brain: influence of mouse strain, environmental conditions and priming , 1999, Gene Therapy.

[11]  D. Neglia,et al.  Microvascular dysfunction in collateral-dependent myocardium. , 1995, Journal of the American College of Cardiology.

[12]  P. Libby,et al.  Cytokines Regulate Vascular Functions Related to Stability of the Atherosclerotic Plaque , 1995, Journal of cardiovascular pharmacology.

[13]  G. Karakiulakis,et al.  Inhibition of angiogenesis, tumour growth and metastasis by the NO‐releasing vasodilators, isosorbide mononitrate and dinitrate , 1995, British journal of pharmacology.

[14]  H. Lassmann,et al.  Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials , 1999, Nature Medicine.

[15]  M. Bergner,et al.  Health status measures: an overview and guide for selection. , 1987, Annual review of public health.

[16]  J. Pearlman,et al.  Coronary angiogenesis: detection in vivo with MR imaging sensitive to collateral neocirculation--preliminary study in pigs. , 2000, Radiology.

[17]  T. Hollon.  Researchers and regulators reflect on first gene therapy death , 2000, Nature Medicine.

[18]  O. Volpert,et al.  Captopril inhibits angiogenesis and slows the growth of experimental tumors in rats. , 1996, The Journal of clinical investigation.

[19]  J. Pearlman,et al.  Magnetic resonance mapping demonstrates benefits of VEGF–induced myocardial angiogenesis , 1995, Nature Medicine.

[20]  P. Briand,et al.  Transient expression of genes transferred in vivo into heart using first-generation adenoviral vectors: role of the immune response. , 1995, Human gene therapy.

[21]  N. Alpert,et al.  Effects of dobutamine at maximally tolerated dose on myocardial blood flow in humans with ischemic heart disease. , 1997, Circulation.

[22]  E. Edelman,et al.  Effect of controlled adventitial heparin delivery on smooth muscle cell proliferation following endothelial injury. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[23]  C. Naylor,et al.  The Canadian Cardiovascular Society Grading Scale for Angina Pectoris: Is It Time for Refinements? , 1992, Annals of Internal Medicine.

[24]  R. Tamargo,et al.  Angiogenesis inhibition by minocycline. , 1991, Cancer research.

[25]  E. Levin,et al.  Inhibition of angiogenesis by nonsteroidal anti-inflammatory drugs: Insight into mechanisms and implications for cancer growth and ulcer healing , 1999, Nature Medicine.

[26]  E. Gharehbaghi-Schnell,et al.  Expression of the angiogenic protein, platelet-derived endothelial cell growth factor, in coronary atherosclerotic plaques: In vivo correlation of lesional microvessel density and constrictive vascular remodeling. , 1999, Arteriosclerosis, thrombosis, and vascular biology.

[27]  M. Simons,et al.  Subxyphoid access of the normal pericardium: A novel drug delivery technique , 1999, Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions.

[28]  J. Isner,et al.  Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. , 1999, Circulation research.

[29]  A. Bol,et al.  Mechanisms of Chronic Regional Postischemic Dysfunction in Humans New Insights From the Study of Noninfarcted Collateral‐Dependent Myocardium , 1993, Circulation.

[30]  E. Edelman,et al.  Perivascular and intravenous administration of basic fibroblast growth factor: vascular and solid organ deposition. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[31]  M. Coughlin.  Comparison of Transmyocardial Revascularization with Medical Therapy in Patients with Refractory Angina , 2001 .

[32]  I. Wiklund,et al.  The relationship between exercise tolerance and quality of life in angina pectoris , 1991, Clinical cardiology.

[33]  P. Carmeliet,et al.  PR39, a peptide regulator of angiogenesis , 2000, Nature Medicine.

[34]  R A Deyo,et al.  Development and evaluation of the Seattle Angina Questionnaire: a new functional status measure for coronary artery disease. , 1995, Journal of the American College of Cardiology.

[35]  C M Bloor,et al.  Coronary collateral development in swine after coronary artery occlusion. , 1992, Circulation research.

[36]  R. Timpl,et al.  Angiogenesis inhibitor endostatin is a distinct component of elastic fibers in vessel walls , 1999, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[37]  M. Perricaudet,et al.  Widespread long-term gene transfer to mouse skeletal muscles and heart. , 1992, The Journal of clinical investigation.

[38]  W Grossman,et al.  Basic fibroblast growth factor improves myocardial function in chronically ischemic porcine hearts. , 1994, The Journal of clinical investigation.

[39]  J. Spertus,et al.  Monitoring the quality of life in patients with coronary artery disease. , 1994, The American journal of cardiology.

[40]  C M Gibson,et al.  Angiographic methods to assess human coronary angiogenesis. , 1999, American heart journal.

[41]  L. Aiello,et al.  Vascular endothelial growth factor-induced retinal permeability is mediated by protein kinase C in vivo and suppressed by an orally effective beta-isoform-selective inhibitor. , 1998, Diabetes.

[42]  J. Ware,et al.  Angiogenesis in ischemic heart disease , 1997, Nature Medicine.

[43]  J. Pearlman,et al.  VEGF administration in chronic myocardial ischemia in pigs. , 1998, Cardiovascular research.

[44]  Robert D. Dowling,et al.  Comparison of transmyocardial revascularization with medical therapy in patients with refractory angina. , 1999, The New England journal of medicine.

[45]  S. Signoretti,et al.  Safety and efficacy of in vivo gene transfer into the porcine heart with replication-deficient, recombinant adenovirus vectors. , 1996, Gene therapy.

[46]  R. Hendel,et al.  Effect of intracoronary recombinant human vascular endothelial growth factor on myocardial perfusion: evidence for a dose-dependent effect. , 2000, Circulation.

[47]  M A Konerding,et al.  Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. , 1999, Circulation.

[48]  J. Hartikainen,et al.  Catheter-mediated vascular endothelial growth factor gene transfer to human coronary arteries after angioplasty. , 2000, Human gene therapy.

[49]  Hidehiro Ishii,et al.  Vascular Endothelial Growth Factor–Induced Retinal Permeability Is Mediated by Protein Kinase C In Vivo and Suppressed by an Orally Effective β-Isoform–Selective Inhibitor , 1997, Diabetes.

[50]  R. Roncucci,et al.  Preclinical and Clinical Studies with Recombinant Human Basic Fibroblast Growth Factor , 1991, Annals of the New York Academy of Sciences.

[51]  H. Dustan.  50th anniversary historical article. Hypertension. , 2000, Journal of the American College of Cardiology.

[52]  I. Buschmann,et al.  The pathophysiology of the collateral circulation (arteriogenesis) , 2000, The Journal of pathology.

[53]  R. MacLaren,et al.  Immunological Instability of Persistent Adenovirus Vectors in the Brain: Peripheral Exposure to Vector Leads to Renewed Inflammation, Reduced Gene Expression, and Demyelination , 1996, The Journal of Neuroscience.

[54]  F. Sellke,et al.  Hemodynamic effects of intracoronary VEGF delivery: evidence of tachyphylaxis and NO dependence of response. , 1997, The American journal of physiology.

[55]  J. Isner,et al.  VEGF contributes to postnatal neovascularization by mobilizing bone marrow‐derived endothelial progenitor cells , 1999, The EMBO journal.

[56]  P. Cuevas,et al.  Hypotensive activity of fibroblast growth factor. , 1991, Science.

[57]  Napoleone Ferrara,et al.  Clinical applications of angiogenic growth factors and their inhibitors , 1999, Nature Medicine.

[58]  J. Folkman,et al.  Increased Vascular Endothelial Growth Factor Levels in the Vitreous of Eyes With Proliferative Diabetic Retinopathy , 1995 .

[59]  R. Verrier,et al.  Persistent primary coronary dilation induced by transatrial delivery of nitroglycerin into the pericardial space: a novel approach for local cardiac drug delivery. , 1999, Journal of the American College of Cardiology.

[60]  W. Schaper,et al.  Vascular remodeling and altered protein expression during growth of coronary collateral arteries. , 1998, Journal of molecular and cellular cardiology.

[61]  E. Edelman,et al.  Basic fibroblast growth factor in a porcine model of chronic myocardial ischemia: a comparison of angiographic, echocardiographic and coronary flow parameters. , 1997, The Journal of pharmacology and experimental therapeutics.

[62]  P. Seth,et al.  Recombinant, Replication-Defective Adenovirus Gene Transfer Vectors Induce Cell Cycle Dysregulation and Inappropriate Expression of Cyclin Proteins , 1998, Journal of Virology.

[63]  R. Doughty,et al.  Measuring health-related quality of life. , 1999, The New Zealand medical journal.

[64]  E. Nabel,et al.  Recombinant fibroblast growth factor-1 promotes intimal hyperplasia and angiogenesis in arteries in vivo , 1993, Nature.

[65]  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.

[66]  H. Fujiwara,et al.  Antithrombotic Effect of Ticlopidine on Occlusive Thrombi of Small Coronary Arteries in (NZWxBXSB)F1 Male Mice with Myocardial Infarction and Systemic Lupus Erythematosus , 1995, Journal of cardiovascular pharmacology.

[67]  R. Sexton.  Prognosis in congestive heart failure. , 1952, The Journal of the Tennessee State Medical Association. Tennessee State Medical Association.

[68]  G H Guyatt,et al.  How should we measure function in patients with chronic heart and lung disease? , 1985, Journal of chronic diseases.

[69]  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.

[70]  E. Edelman,et al.  Local perivascular administration of basic fibroblast growth factor: drug delivery and toxicological evaluation. , 1996, Drug metabolism and disposition: the biological fate of chemicals.

[71]  U. Gleichmann,et al.  Improvement in coronary flow reserve determined by positron emission tomography after 6 months of cholesterol-lowering therapy in patients with early stages of coronary atherosclerosis. , 1999, Circulation.

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

[73]  C. Tracy,et al.  Enhanced regional left ventricular function after distant coronary bypass by means of improved collateral blood flow. , 1989, Journal of the American College of Cardiology.

[74]  P. Dolan,et al.  Modeling valuations for EuroQol health states. , 1997, Medical care.

[75]  O. Frazier,et al.  Transmyocardial revascularization with a carbon dioxide laser in patients with end-stage coronary artery disease. , 1999, The New England journal of medicine.

[76]  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.

[77]  R. Bonow.  Contractile reserve and coronary blood flow reserve in collateral-dependent myocardium. , 1999, Journal of the American College of Cardiology.

[78]  W. Thompson,et al.  The clinical manipulation of angiogenesis: pathology, side‐effects, surprises, and opportunities with novel human therapies , 1999, The Journal of pathology.

[79]  L. Turka,et al.  Tissue-specific consequences of the anti-adenoviral immune response: implications for cardiac transplants , 1999, Nature Medicine.

[80]  S M Schwartz,et al.  Angiogenesis in human coronary atherosclerotic plaques. , 1994, The American journal of pathology.

[81]  D. Feeny,et al.  Multiattribute utility function for a comprehensive health status classification system. Health Utilities Index Mark 2. , 1996, Medical care.

[82]  K. Seibert,et al.  COX‐2 Inhibitors: A New Class of Antiangiogenic Agents , 1999, Annals of the New York Academy of Sciences.

[83]  J. Isner,et al.  Hypercholesterolemia attenuates angiogenesis but does not preclude augmentation by angiogenic cytokines. , 1997, Circulation.

[84]  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.

[85]  E. Brogi,et al.  Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischemic hind limb model. , 1994, The Journal of clinical investigation.

[86]  James P. Martucci,et al.  Short-term cholesterol lowering decreases size and severity of perfusion abnormalities by positron emission tomography after dipyridamole in patients with coronary artery disease. A potential noninvasive marker of healing coronary endothelium. , 1994, Circulation.

[87]  H. Atlan,et al.  Bumetanide and furosemide inhibited vascular endothelial cell proliferation , 1994, Journal of cellular physiology.

[88]  R Langer,et al.  Controlled and modulated release of basic fibroblast growth factor. , 1991, Biomaterials.

[89]  A. Dabrowska,et al.  Lovastatin and tumor necrosis factor‐α exhibit potentiated antitumor effects against Ha‐ras‐transformed murine tumor Via inhibition of tumor‐induced angiogenesis , 1999, International journal of cancer.

[90]  F. Sellke,et al.  Intracoronary and intravenous administration of basic fibroblast growth factor: myocardial and tissue distribution. , 1999, Drug metabolism and disposition: the biological fate of chemicals.

[91]  C. Jenkins,et al.  Coronary artery bypass surgery. Physical, psychological, social, and economic outcomes six months later. , 1983 .

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

[93]  N. Hara,et al.  Clarithromycin is a potent inhibitor of tumor-induced angiogenesis , 1997, Research in experimental medicine. Zeitschrift fur die gesamte experimentelle Medizin einschliesslich experimenteller Chirurgie.

[94]  P Lavie,et al.  Interindividual heterogeneity in the hypoxic regulation of VEGF: significance for the development of the coronary artery collateral circulation. , 1999, Circulation.