Intramural delivery of recombinant apolipoprotein A-I Milano/phospholipid complex (ETC-216) inhibits in-stent stenosis in porcine coronary arteries. The study examined the effects of a single local intramural delivery of ETC-216 on luminal narrowing following coronary stent injury in pigs. Results showed that ETC-216 significantly reduced neointimal formation and luminal loss compared to controls, demonstrating its potential to prevent in-stent restenosis through local inhibition of intimal hyperplasia.
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Intramural delivery of recombinant
1. Intramural Delivery of Recombinant
Apolipoprotein A-I Milano
/Phospholipid
Complex (ETC-216) Inhibits In-stent
Stenosis in Porcine Coronary Arteries
Sanjay Kaul, Vladimir Rukshin, Raul Santos, Babak Azarbal,
*Charles L. Bisgaier, *Jan Johansson, Vivian T. Tsang, Kuang-Yuh
Chyu, James Mirocha, Bojan Cercek, Prediman K. Shah
Atherosclerosis Research Center, Cedars-Sinai Burns & Allen
Research Institute, Division of Cardiology, Cedars-Sinai Medical Center
and *Esperion Therapeutics
2. • Mutant Apo A-I
• Arginine to cysteine substitution at 173 position
• Transmitted as an autosomal dominant trait by a
single mating couple in Italy in the 18th century
• Confers protection from vascular disease despite
elevated triglycerides and low HDL levels
• Associated with longevity
Apolipoprotein A-IMilano
3. • Antiatherogenic effects
Inhibits progression of atherosclerosis and promotes regression
of atherosclerosis in atherosclerosis-susceptible transgenic
mice, the apo E null mice (Shah et al, Circulation. 1998; 97: 780–5)
• Vascular response to injury
Reduction in neointimal hyperplasia in balloon-injured
ileofemoral arteries of cholesterol-fed rabbits (Ameli et al, Circulation.
1994;90:1935-41)
• After repeated systemic administration of Apo A-IMilano
50 mg/kg IV in rabbits (5 injections every other day)
20-80 mg/kg IV in apo E null mice (18 injections every other day)
Vasculoprotective Effects of Apo A-IMilano
4. • Utilizing a local intramural drug delivery approach via
the Infiltrator catheter, we sought to examine the
effects
of recombinant apolipoprotein A-IMilano/1-palmitoyl,2-
oleoyl phosphatidylcholine complex (ETC-216)
on luminal narrowing in a porcine coronary artery stent
Aim of the Study
5. • Intramural delivery into the coronary vessel wall provides
for enhanced delivery efficiency, minimizes agent loss
into the systemic circulation, thereby resulting in lower
doses, longer duration of activity, and improved overall
effectiveness in modulating coronary arterial response to
Hypothesis
6. Experimental Protocol
• Coronary Stent Overstretch Injury
3.0-4.0 x 15 mm GFX Stent inflated at 8-12 atm x3 (S:A ~ 1.3:1)
• Animal Groups (Adult farm swine: 25-30 kg)
Group I: apo A-1M (n=6, 12 arteries)
Group II: vehicle control (n=6, 12 arteries)
• Histomorphometry
Perfusion-fixation, H&E and special stain, computerized morphometry
Day 0 28
Intramural local
drug delivery
Angio
Coronary
Injury Angio
Histomorphometry
12. • A single intramural administration of very low-
dose ETC-216 produced a significant reduction
in injury-induced luminal narrowing in the
porcine coronary stent overstretch injury model
through inhibition of intimal hyperplasia
Conclusion
13. Implication
•The data show that local intracoronary
delivery of ETC-216 may be useful to
prevent restenosis after coronary stenting