Author + information
- Received March 12, 2001
- Revision received February 21, 2002
- Accepted February 27, 2002
- Published online May 15, 2002.
- Nicholas N Kipshidze, MD, PhD, FACC*,* (, )
- Han-Soo Kim, MD, FACC†,
- Patrick Iversen, PhD‡,
- Hamid A Yazdi, MD†,
- Balram Bhargava, MD†,
- Gishel New, MD, FACC*,
- Roxana Mehran, MD, FACC*,
- Fermin Tio, MD§,
- Christian Haudenschild, MD∥,
- George Dangas, MD, PhD, FACC*,
- Gregg W Stone, MD, FACC*,
- Sriram Iyer, MD, FACC*,
- Gary S Roubin, MD, PhD, FACC*,
- Martin B Leon, MD, FACC* and
- Jeffrey W Moses, MD, FACC*
- ↵*Reprint requests and correspondence:
Dr. Nicholas Kipshidze, Lenox Hill Heart and Vascular Institute, 130 East 77th Street, Black Hall-9th Floor, New York, New York 10021.
Objectives We evaluated the long-term influence of intramural delivery of advanced c-myc neutrally charged antisense oligonucleotides (Resten-NG) on neointimal hyperplasia after stenting in a pig model.
Background Neointimal hyperplasia after percutaneous coronary interventions is one of the key components of the restenotic process. The c-myc is a critical cell division cycle protein involved in the formation of neointima.
Methods In short-term experiments, different doses (from 500 μg to 5 mg) of Resten-NG or saline were delivered to the stent implantation site with an infiltrator delivery system (Interventional Technologies, San Diego, California). Animals were euthanized at 2, 6 and 18 h after interventions, and excised vessels were analyzed for c-myc expression by Western blot. In long-term experiments, either saline or a dose of 1, 5 or 10 mg of Resten-NG was delivered in the same fashion, and animals were euthanized at 28 days after the intervention.
Results Western blot analysis demonstrated inhibition of c-myc expression and was dose dependent. Morphometry showed that the intimal area was 3.88 ± 1.04 mm2in the control. There was statistically significant reduction of intimal areas in the 5 and 10 mg groups (2.01 ± 0.66 and 1.95 ± 0.91, respectively, p < 0.001) but no significant reduction in the 1 mg group (2.81 ± 0.56, p > 0.5) in comparison with control.
Conclusions This study demonstrated that intramural delivery of advanced c-myc neutrally charged antisense morpholino compound completely inhibits c-myc expression and dramatically reduces neointimal formation in a dose dependent fashion in a porcine coronary stent restenosis model, while allowing for complete vascular healing.
☆ These studies were supported in part by a research grant from the Medical Research Fund at Lenox Hill Hospital (New York, New York), AVI BioPharma (Portland, Oregon) and Cook Cardiology (Broomfield, Colorado).
- Received March 12, 2001.
- Revision received February 21, 2002.
- Accepted February 27, 2002.
- American College of Cardiology Foundation