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Heart DiseaseHeart DiseaseIn 1995: 481,000 deaths related to Coronary Artery Disease (CAD) 1,100,000 new or recurrent cases of CAD Estimated that 7.2 million people experienced angina to
some degree
Treatment 434,000 angioplasties performed 573,000 Bypasses performed
60,000-100,000 patients not good candidates for bypass/angioplasty(Possibly up to 250,000 patients a year)
Use of Vascular Endothelial Growth Factor (VEGF) as a Treatment for End Stage Coronary Artery Disease (CAD)
By: Jeremy GillisSenior…Biochemistry and Molecular Biology
Current Treatments for CADCurrent Treatments for CAD
Percutaneous Transluminal Coronary Angioplasty or PTCA (434,000)
Coronary Artery Bypass Graft (CABG) “cabbage” (573,000)
Vascular Stents (wire props for an artery)Rotational Atherectomy (much like a drill)
Problems with Current Problems with Current TreatmentsTreatments
Restenosis Graft disease Arterial puncture Coronary thrombosis
How can we help people who don’t respond well or are not good candidates for conventional treatments?
It is thought that VEGF is involved It is thought that VEGF is involved in Angiogenesisin Angiogenesis
Angiogenesis: the formation of new blood vessels (collaterals) from existing microvessels
Contributes to the preservation of ischemic tissue and myocardial pump function after myocardial infarction
Important in: Embryogenesis (called vasculogenesis) Wound healing Tumor growth and metastasization Rheumatoid arthritis Ischemic heart disease Ischemic peripheral vascular disease
Inducing AngiogenesisInducing Angiogenesis
1. Need a stimulusHypoxic tissue, Ischemic tissue, Mechanically damaged tissue
2. Need expression of angiogenic molecules to initiate angiogenesisVEGF, FGF, TGF, PDGF3. Need angiogenesis to occur1. Proliferation and migration of endothelial cells from the microvasculature2. Controlled expression of proteolytic enzymes3. Breakdown and reassembly of extracellular matrix4. Morphogenic process of endothelial tube formation
Mechanism of Angiogenesis not completely known
Why use VEGF to Promote Angiogenesis?Why use VEGF to Promote Angiogenesis?VEGF (vascular endothelial growth factor)Specific for only endothelial cellsMay inhibit smooth muscle growth…reduce restenosis
FGF (fibroblast growth factor)
Associated with tumor angiogenesisCan stimulate growth in other cells besides endothelial cellsNot as specific as VEGF
TGF- (transforming growth factor ß) Indirect angiogenesis effectPossibly induces VEGF expression (Protein Kinase C pathway)
PDGF (platelet derived growth factor)
Not well characterized in angiogenesis
Other VEGF CharacteristicsOther VEGF Characteristics
VEGF expressed by Macrophages, fibroblasts, smooth muscle cells, endothelial cells (all are present in the heart)
Action is direct because of the exclusive specificity for receptors (flt-1 and flk-1)
Receptors only found on endothelial cells
Causes activation of many other genes involved in angiogenic response
How to Deliver VEGFHow to Deliver VEGFProtein Therapy
Direct injection of protein Time delay delivery Local intercoronary bolus
Gene TherapyAdenovirus vector
Excellent specificity for endothelial cells Extended expression of VEGFDirect gene transfer
Involves direct injection of eukaryotic plasmid DNA containing VEGF cDNA
Should VEGF administration prove effective, it is likely that VEGF/VEGF DNA will be delivered on a catheter platform
Case StudiesCase Studies
Injection of naked VEGF cDNA contained in an Eukaryotic Expression Vector
Jeffery Isner et al. St. Elizabeth’s Medical Center
Phase I clinical trial…designed to assess safety and bioactivity of treatment methods
Limited sample…only 5 patients involved Prior Bypass and/or angioplasty Class 3-4 Angina No longer respond to additional treatment
Age Lifestyle Before Treatment Lifestyle After Treatment67 Angina from Mild activity ⟨ Angina virtually gone
⟨ Able to resume swimming⟨ Nitroglycerin (NTG) no longer needed
69 Angina after walking 10 yards ⟨ 30 days post needed very little NTG⟨ 60 days post could exercise for 30
minutes on a stationary bike
53 Angina after walking 50 yards ⟨ 60 days post could walk ? mile⟨ Claims to have felt beneficial effects
after only two weeks
71 Angina from walking 100 yards ⟨ 30 days NTG use decreased dramatically⟨ Returned to work part time
59 Daily Angina ⟨ 30 days later could walk up to ? milewithout pain
⟨ Less need for supplemental oxygen⟨ 2 episodes of angina/month
ResultsResults
Also notable:Also notable:
Nitroglycerin usage dropped from 7.7 pills per day to 1.4 per day for the group (60 days post)
Effective biological outcomes despite low transfection rates
Because of the condition of the patients in the study, the improvements to health were not likely random events
All 5 patients had remarkable gains in quality of life post procedure
Animal Data:Animal Data:
Charles Mack et al. New York Hospital-Cornell Medical Center
Administration VEGF gene through Adenovirus mediated gene therapy
Preclinical work to determine efficacy in an animal model of ischemia
Model:Model: Pig with a constrictor band around circumflex artery to
induce myocardial infarction and ischemia Eventually results in complete occlusion of circumflex
artery
Vector:Vector: Adenovirus vector in E1a-, partial E1b-, and partial E3-
mutations (makes them replication deficient) Adenovirus used because of the natural selectivity for
endothelial cells Minimal inflammation detected in animals 4 weeks post
therapy In vivo conformation of expression confirmed by ELISA 3
days after injection
ResultsResults
Treatment Resulted in significantly reduced ischemic area (area of oxygen starved tissue) and
Ischemic maximum (severity of ischemia) in treated animals
Strength of heartbeat returned in treated animals more than untreated animals
More vessels visible angiographically in treated animals vs. untreated animals
Treated animals seemed to route around the occlusion as demonstrated by the filling of branching arteries
Why it works?Why it works?
Placebo effect?VEGF stimulates growth of
“collateral” vessels?Microvessel growth due to physical
damage of heart?Real or perceived Angiogenesis?
Problems:Problems:
Doesn’t work as well on older patients with more advanced disease
VEGF may stimulate undetected cancer growth (tumors cannot be larger than a few mm3 without revascularization?
Limited number of trials and patients Treatment kills some patients? What are the effects on women? No placebo substance given for ethical reasons
ReferencesReferencesBattegay, E.J. Angiogenesis: mechanistic insights, neovascular diseases, and
therapeutic prospects. Journal of Molecular Medicine (1995) 73:333-346.Losordo, Douglas W., et al. Gene therapy for Myocardial Angiogenesis: Initial Clinical
Results With Direct Myocardial Injection of phVEGF165 as Sole Therapy for Myocardial Ischemia. Circulation (1998) 98:2800-2804.
Mack, Charles A., et al. Biologic Bypass With the Use of Adenovirus-Mediated Gene Transfer of the Complementary Deoxyribonucleic Acid for Vascular Endothelial Growth Factor 121 Improves Myocardial Perfusion and Function in the Ischemic Porcine Heart. Journal of Thoracic and Cardiovascular Surgery (1998) 115:168-77.
Li, Jian, et al. Stretch-induced VEGF Expression in the Heart. Journal of Clinical Investigation (1997) 100:18-24.
Seko, Yoshinori, et al. Serum levels of vascular endothelial growth factor in patients with acute myocardial infarction undergoing reperfusion therapy. Clinical Science (1997) 92:453-454.
Lopez, John J., et al. VEGF administration in chronic myocardial ischemia in pigs. Cardiovascular Research (1998) 40:272-281.
Metais, Caroline, et al. Effects of coronary artery disease on expression and microvascular response to VEGF. American Journal of Physiology (1998) 275:H1411-H1418.
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