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 mug 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 mm(2) in 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. (J Am Coll Cardiol 2002; 39:1686-91) (C) 2002 by the American College of Cardiology Foundation.

Purpose: Intracoronary radiation has shown the potential to inhibit neointimal proliferation in porcine models of restenosis. The objective of this study was to determine whether intracoronary radiation using a new coiled wire of tungsten-188 (W-188), a pure beta emitter (half-life 69.4 days) is safe. In addition, a dose of 0 Gy, 18 Gy, or 25 Gy prescribed to 2 mm from the center of the source and delivered intraluminally Is sufficient to prevent restenosis and free from adverse effects.Methods and Materials: Ten domestic swine underwent 13-mm stent implantation (SI) into two arteries, left anterior descending plus either the left circumflex or right coronary artery. After SI, a closed-end lumen radiation catheter was inserted to the treated artery and a 40-mm coiled W-188 source was manually delivered to cover the stented segment and its margins. A total of 20 arteries were randomized to treatment with a radiation dose of 0, 18 Gy, or 25 Gy delivered to 2 mm depth from the center of the source. Four weeks after the procedure, the swine underwent angiography and intravascular ultrasound using automated pullback at 0.5 mm/s. before being killed and the arteries perfusion fixed. Histopathologic and histomorphometric analyses were performed at 28 days after injury and radiation.Results: Irradiation with 1138 W at a dose of 25 Gy after SI significantly inhibited neointima formation (intimal area: 1.05+/-0.64 vs. 2.75+/-0.99 mm(2), p<0.01) and at an 18 Gy dose of radiation (intimal area: 1.73 +/- 0.49 vs. 2.75 +/- 0.99 mm(2)), as compared to controls. One artery receiving 18 Gy and two arteries receiving 25 Gy were totally occluded at follow-up due to thrombus formation but no edge stenosis was observed in any of the irradiated arteries.Conclusions: Intracoronary radiation therapy using a new coiled wire of W-188 source delivered after SI appeared to be safe and well tolerated. The radiation doses demonstrated efficacy in reducing neointima formation in the porcine coronary stent injury model. (C) 2002 Elsevier Science Inc.

Background: The major limitation of coronary stenting remains in-stent restenosis, due to the development of neointimal proliferation. Radioactive stents have demonstrated the ability to reduce this proliferation in the healthy nonatherosclerotic porcine animal model. However, inhibition of tissue proliferation in the in-stent restenotic lesion in a porcine model is not well characterized. The objective of this study was to examine the efficacy and safety of the P-32 radioactive stent for the treatment of in-stent restenosis in a double stent injury model of the porcine coronaries.Methods and Materials: Eighteen coronary arteries in 9 pigs underwent nonradioactive stent (8 mm in length) implantation. Thirty days after the initial stent implantation, a 32P radioactive stent (18 mm in length) with an activity of 0 and 18 mu Ci was implanted to cover the initial stent. The swine were killed 30 days after the second stent implantation. Histomorphometric analysis was performed for vessel area (VA), stent strut area (SSA), intimal area (IA), and lumen area (LA).Results: Injury scores, VA, SSA, and LA were similar among the control and radiated groups. Neointimal formation was significantly reduced after placement of radioactive stents as compared to control in both the overlapped (0.93 +/- 0.12 vs. 1.31 +/- 0.51 mm(2), p < 0.05) and nonoverlapped segments (1.14 +/- 0.21 vs. 1.91 +/- 1.04 mm(2), p < 0.05). The smooth muscle cell index in the neointima was reduced. Intimal fibrin was increased in the radiated group as compared to the control (p < 0.01 respectively).Conclusions: P-32 radioactive stents may be safe and effective in reducing neointimal formation leading to in-stent restenosis. Longer follow-up will be required to examine whether these positive findings can be maintained. (C) 2001 Elsevier Science Inc.

BACKGROUND:Intracoronary radiation has shown the potential to reduce formation of neointima in porcine models of restenosis. OBJECTIVE:To investigate the feasibility, safety, and efficacy of a new 'deployable-balloon' device with radioisotope 32P integrated into the balloon material. METHODS:Ten swine were subjected to balloon-overstretching injury in 20 coronary arteries and were randomly allocated to receive a radiation dose of 0, 15, or 20Gy prescribed to 1 mm from the surface of the radioactive balloon material. The animals were killed 4 weeks after the procedure. Their coronaries were perfusion fixed and stained. Vessel parameters (area of intima and length of fracture) and area of thrombus area were analyzed by computer-aided histomorphometry. RESULTS:Radiation treatment with the new 32P balloon device was performed without complications. The lengts of fracture for the three groups were similar (NS). Formation of neointima after balloon injury was less in members of the radiated groups than it was in controls (area of intima/length of fracture was 0.70 +/-0.12 mm for controls, 0.08+/-0.13mm with 15 Gy, and 0.07+/-0.17 mm with 20 Gy; P < 0.001). Vessels treated with 20 Gy had a greater total area of thrombus (0.00+/-0.00 versus 0.51+/-0.98 mm2, P< 0.01). CONCLUSIONS:Intracoronary radiation therapy using a new 32P deployable-balloon system is feasible and safe. A radiation dose of 15 Gy was sufficient to inhibit neointimal response in the porcine coronary-balloon-injury model.