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Explore the latest concepts in therapeutic angiogenesis for coronary artery disease, including definitions, growth factors, functions, and clinical applications. Learn about the potential of angiogenic growth factors in promoting tissue repair and cardiac health.
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Current Concepts In Therapeutic Angiogenesis C. Michael Gibson M.S., M.D.
Scope of Coronary Artery Disease • ~ 15 - 20 million Americans have a history of MI, angina, or both • Cardiovascular disease is the number one cause of death in the US • ~ 500,000 deaths per year • 1,500,000 new or recurrent MI’s per year AHA Databank
Scope of Coronary Artery Disease • ~ 10 million Americans have angina • ~ 350,000 new cases of angina diagnosed each year • ~ 1.5 million coronary angiograms per year • ~ 500,000 PTCA per year • ~ 500,000 CABGs per year AHA Databank
Medical Antianginals Antiplatelet Agents Lipid Lowering Agents Anticoagulants Vasodilators Interventional PTCA CABG TMR/PMR Cardiac Transplantation PVD: Amputation Current Therapeutic Options New Therapeutic Option • Therapeutic Angiogenesis
Therapeutic Angiogenesis: Definitions Angiogenesis • The formation of new capillary blood vessels from existing microvessels by sprouting, i.e. cellular outgrowth Vasculogenesis • The formation of new blood vessels of all types from blood islands, i.e. committed stem cells, in early embryogenesis Growth Factor • Polypeptide which acts as a regulator of cellular function, including proliferation, migration, differentiation, and survival/apoptosis
Basic fibroblast growth factor (bFGF) Acidic fibroblast growth factor (aFGF) Angiogenin Angiotropin Insulin-like growth factor Interleukin-8 Platelet activating factor (PAF) Platelet-derived growth factor (PDGF) Proliferin Transforming growth factor- Transforming growth factor- Tumor necrosis factor- Vascular endothelial growth factor (VEGF) Angiogenic Growth Factors J. Battegay: J. Mol Med; 1995
Basic Fibroblast Growth Factor (bFGF) • 154 amino acids, MW 18 kD • Additional higher MW forms exist • Post-translational modification may yield a shorter form • Present in almost all cells • Present from embryogenesis to adult cells • Released from extracellular sites by heparin and various proteolytic enzymes
bFGF Receptors • The cell receptor is a transmembrane tyrosine kinase • Found on numerous cell types • Receptor expression upregulated by injury (PTCA & ischemia) • bFGF Binds to heparin which protects it from degradation • Seperate binding sites for bFGF receptor and heparin
Functions of Growth Factors • Embryogenesis:Stimulates proliferation & differentiation of a variety of cells • Wound Healing:Stimulates migration and proliferation of connective tissue • Cytoprotection: CNS, vascular smooth muscle and endothelial cells • Angiogenesis:Ischemic & Non-Ischemic • Active at 0.1 to 1.0 ng/ml
Bovine Endothelial Cell Migration Augustin-Voss et al. Endothelial Cell Migration (m 72 hours) Passage Number
Impact of bFGF on Bovine Endothelial Cell Proliferation Proliferation % / 48 hr Augustin-Voss et al.
Functions of bFGF Non-ischemic Angiogenesis • Promotes endothelial cell migration and tube formation • Stimulates the production of collagenases and plasminogen activator necessary for basement membrane remodeling M. Klagsbrun: Progress Growth Factor Research; 1989
Ischemic Angiogenesis • Endogenous bFGF production in the presence of ischemia • Impact of exogenous bFGF on ischemic tissues
Ischemic Angiogenesis Longitudinal Changes in Myocardial Basic Fibroblast Growth Factor (FGF-2) Activity Following Coronary Artery Ligation in the Dog Michael V. Cohen et al. Albert Einstein College of Medicine M. Cohen: J Mol Cell Cardiol; 1994
Demonstration of Endogenous Tissue Production of bFGF: Canine LAD Occlusion Model • Endogenous bFGF production assayed in ischemic and adjacent normal cardiac tissue • bFGF production rose as early as 2 hours * * Ischemic/Normal Myocardial bFGF ratio Time Following Canine LAD Occlusion Cohen et al: J Mol Cell Cardiol; 1994
Production of Growth Factors in Ischemia: Other Indirect Evidence • Fujita et al measured the bFGF levels in the pericardial fluid of patients undergoing open heart surgery for unstable angina (CABG) versus those undergoing surgery for non-ischemic causes • Elevated bFGF levels found in the pericardial fluid of patients with unstable angina M. Fujita et al, Circulation; 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Peripheral Models Baffour et al. • Rabbit model of hind limb ischemia (ligated main arteries in staged procedure over 2 weeks) • Compared two weeks of IM bFGF to saline • Results: • bFGF groups had angiographically improved collaterals • bFGF groups had greater capillary density (per mm and per muscle fiber) • bFGF groups had greater muscle viability R. Baffour et al, J Vasc Surg; 1992
Ischemic Angiogenesis & Exogenous Growth Factors : Peripheral Models Yang et al • Rat model of hind limb ischemia • Compared one to four weeks of continuous intra-arterial bFGF (1 g/day) to heparinized saline control • Demonstrated improvement in: • Collateral blood flow by microspheres • Capillary density • Muscle performance by stimulated tension H. Yang et al, Circ. Res 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Peripheral Models * * Collateral Flow (ml / min / 100g) Time Following Hind Limb Arterial Occlusion H. Yang et al, Circ. Res.; 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models Uchida et al • Occluded canine LAD model • Compared intrapericardial bFGF, heparin, or both to saline control (drug given 30 minutes after occlusion) • Measured: • Ejection fraction • Capillary density • Infarct size Y. Uchida et al, Am Heart J; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * * Ejection Fraction Time Following Arterial Occlusion Y. Uchida: Am Heart J; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models ‡ Infarcted Weight (% of LV) * Y. Uchida et al, Am Heart J; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models ‡ * Capillary Number per 200 m Y. Uchida et al, Am Heart J; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models Ameroid constriction of porcine circumflex • Compared intrapericardial bFGF and/or heparin to saline control • Measured: • Angiographic collaterals • Microsphere blood flow • MRI Cardiac function • MRI collateral flow M. Simmons, personal communication; 1997
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * * * Circumflex Flow (ml / min / g) Time Post Drug Administration M. Simmons, personal communication; 1997
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * Delayed Contrast Arrival Extent (%) * * M. Simmons, personal communication; 1997
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models Lazarous et al. • Ameroid constriction of porcine circumflex • Daily systemic bFGF (4 to 9 weeks) vs saline control • Measured microsphere determinations of collateral blood flow D. Lazarous et al, Circulation; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models D. Lazarous et al, Circulation; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models Lazarous et al. Short Infusion Model • Ameroid constriction of porcine circumflex • Shorter duration of systemic bFGF (7 days) or VEGF to saline control • Measured microsphere determinations of collateral blood flow D. Lazarous et al, Circulation; 1996
Lazarous et al: Data Following 7 Day Infusions D. Lazarous: Circulation; 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models Yanagisawa-Miwa et al. • Acute occlusion of canine LAD • Compared two bolus circumflex injections of bFGF vs saline • Measured: • LV Function • Infarct size • Histologic assessment of collateral growth A. Yanagisawa-Miwa et al, Science; 1992
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * Ejection Fraction Time post Infarction A. Yanagisawa-Miwa: Science; 1992
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * Infarct weight / LV weight (%) A. Yanagisawa-Miwa et al, Science; 1992
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * * Arteriole Number / Unit Area Capillary Number / Unit Area Control bFGF A. Yanagisawa-Miwa et al, Science; 1992
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models Horrigan et al. • Four hour balloon occlusion of canine LAD • Compared two bolus LM injections of bFGF or vehicle • Measured: • Infarct size • Histologic assessment of collateral growth M. Horrigan et al, Circulation; 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models * Infarct Size (% area at risk) M. Horrigan et al, Circulation; 1996
Chiron Study Multi-Center, Single-Blind, Dose Escalation, Safety and Tolerability Study of Recombinant Fibroblast Growth Factor-2 (rFGF-2) in Subjects with Advanced Coronary Artery Disease
Study Objectives • Evaluate safety, tolerability and pharmacokinetics of short-term (20 min) intracoronary (IC) and intravenous (IV) single infusions of ascending doses of rFGF-2 • Determine maximum tolerated IC and IV doses • Measure preliminary efficacy data using nuclear stress imaging and cardiac MRI
Study Design • Study Agent • Recombinant protein produced in yeast • Differs from native human bFGF by only two amino acids • Essentially identical angiogenic properties • Enrollment • Screening physical exam and labs • Exercise or dipyridamole stress test with dual isotope imaging • Cardiac MRI with cardiac function and collateral flow determinations • Ophthalmologic exam • Quality of Life questionnaire
Inclusion Criteria • Severe CAD with inducible ischemia on stress test • No optimal revascularization option • Normal routine laboratory screening • Willingness and ability to complete all components of the study and its follow-up • Signed informed consent
Class IV CHF or EF < 20% MI < 3 months New or unstable angina < 3 wks CABG < 6 months PTCA or TMR < 6 months Significant arrhythmias Pacemaker or AICD LBBB Severe valvular heart disease Restrictive or hypertrophic cardiomyopathy Known AVMs TIA or CVA < 6 mths DM with end-organ damage Cr Cl < 80 ml/min or proteinuria Cancer within 10 years Exclusion Criteria
Drug Administration • Intracoronary Infusion • Left and Right heart catheterizations • 10 minute infusions of bFGF into the RCA and LM (or the major supplying bypass graft) • Intravenous Infusion • Left heart catheterization (if not done within 6 mths) • 10 minute infusion into a peripheral vein
Follow-Up Protocol • Clinic visits with routine blood tests at day 6, day 14 and at 1, 2, 6 and 12 months • Repeat stress test and MRI scans at 1 month • Subsequent exams only if indicated • Repeat Eye exams at 2 and 12 months • Repeat Quality of Life questionnaire at 2 months