overview by c. michael gibson
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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
• ~ 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
Scope of Coronary Artery Disease
Therapeutic Angiogenesis
Current Therapeutic OptionsMedical• Antianginals• Antiplatelet Agents• Lipid Lowering
Agents• Anticoagulants• Vasodilators
Interventional• PTCA• CABG• TMR/PMR• Cardiac
Transplantation• PVD: Amputation
New Therapeutic Option
Therapeutic Angiogenesis: DefinitionsAngiogenesis• 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
Angiogenic Growth Factors
• Basic fibroblast growth factor (bFGF)
• Acidic fibroblast growth factor (aFGF)
• Angiogenin• Angiotropin• Insulin-like growth factor• Interleukin-8• Platelet activating factor
(PAF)
J. Battegay: J. Mol Med; 1995
• Platelet-derived growth factor (PDGF)
• Proliferin• Transforming growth factor-• Transforming growth factor-• Tumor necrosis factor-• Vascular endothelial growth
factor (VEGF)
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
Augustin-Voss et al.
0
200
400
600
800
1000
1200
5 15 25 35 45
Control +bFGF
Passage Number
End
othe
lial C
ell M
igra
tion
(m
72
hour
s)
Bovine Endothelial Cell Migration
0
200
400
600
800
1000
1200
Control +bFGF
Prol
ifera
tion
% /
48 h
r
Augustin-Voss et al.
Impact of bFGF on Bovine Endothelial Cell Proliferation
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
M. Cohen: J Mol Cell Cardiol; 1994
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
Demonstration of Endogenous Tissue Production of bFGF: Canine LAD Occlusion Model
Time Following Canine LAD Occlusion
Isch
emic
/Nor
mal
Myo
card
ial b
FGF
ratio
0
0.5
1
1.5
2
2.5
3
2 Hours 1 Week 2 Weeks 8 Weeks
*
*
Cohen et al: J Mol Cell Cardiol; 1994
Endogenous bFGF production assayed in ischemic and adjacent normal cardiac tissue bFGF production rose as early as 2 hours
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
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
0
10
20
30
40
50
60
Base 1 Week 2 Weeks 4 Weeks
ControlbFGF
Time Following Hind Limb Arterial Occlusion
Col
late
ral F
low
(ml /
min
/ 10
0g) * *
H. Yang et al, Circ. Res.; 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Peripheral 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
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Base 30 min. 1 month
SalineHeparinbFGFHep+bFGF
Time Following Arterial Occlusion
Ejec
tion
Frac
tion
**
Y. Uchida: Am Heart J; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
0
5
10
15
20
25
30
Saline Heparin bFGF Hep +bFGF
Infa
rcte
d W
eigh
t (%
of L
V)
‡
*
Y. Uchida et al, Am Heart J; 1995
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
0123456789
Saline Heparin bFGF Hep+bFGF
Noninfarct Zone
Infarct Zone
Cap
illar
y N
umbe
r 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
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 Weeks 4 Weeks
SalineHeparinbFGF 30bFGF 200bFGF 2000
Circ
umfle
x F
low
(m
l / m
in /
g)*
**
Time Post Drug Administration
M. Simmons, personal communication; 1997
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
0
5
10
15
20
25
30
Saline Heparin bFGF 30
bFGF200
bFGF2000
Del
ayed
Con
tras
t Arr
ival
Ext
ent (
%)
*
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
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
D. Lazarous: Circulation; 1996
Lazarous et al: Data Following 7 Day Infusions
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
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
Baseline 30 Min. 1 Week
SalinebFGF
Ejec
tion
Frac
tion *
A. Yanagisawa-Miwa: Science; 1992
Time post Infarction
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
0
5
10
15
20
25
bFGF Saline
Infa
rct w
eigh
t / L
V w
eigh
t (%
) *
A. Yanagisawa-Miwa et al, Science; 1992
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
0
10
20
30
40
50
60
70
80
90
100C
apill
ary
Num
ber /
Uni
t Are
a*
A. Yanagisawa-Miwa et al, Science; 1992
0
2
4
6
8
10
12
14
16
Control bFGF
*
Art
erio
le N
umbe
r / U
nit A
rea
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
Control bFGF
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
0
5
10
15
20
25
30
Vehicle bFGF
Infa
rct S
ize
(% a
rea
at ri
sk)
*
M. Horrigan et al, Circulation; 1996
Ischemic Angiogenesis & Exogenous Growth Factors : Cardiac Models
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 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
Study Design
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