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(Circulation. 1996;94:2364-2368.)
© 1996 American Heart Association, Inc.

Articles

Effects of Endovascular Radiation From a ß-Particle–Emitting Stent in a Porcine Coronary Restenosis Model

A Dose-Response Study

Andrew J. Carter, DO; John R. Laird, MD; Lynn R. Bailey; Timothy G. Hoopes, MD; Andrew Farb, MD; David R. Fischell, PhD; Robert E. Fischell, ScD; Tim A. Fischell, MD; Renu Virmani, MD

Hematology and Vascular Biology, Walter Reed Army Institute of Research Cardiology Service, Walter Reed Army Medical Center, and The Armed Forces Institute of Pathology, Washington, DC; and the Division of Cardiology, Vanderbilt University School of Medicine, Nashville, Tenn (T.A.F.).

Correspondence to Andrew J. Carter, DO, Cardiology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001.

	Abstract

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Background Neointimal formation causes restenosis after intracoronary stent placement. Endovascular radiation delivered via a stent has been shown to reduce neointimal formation after placement in porcine and rabbit iliac arteries. The objective of this study was to evaluate the dose-related effects of a ß-particle–emitting radioactive stent in a porcine coronary restenosis model.

Methods and Results Thirty-seven swine underwent placement of 35 nonradioactive and 39 ß-particle–emitting stents with activity levels of 23.0, 14.0, 6.0, 3.0, 1.0, 0.5, and 0.15 µCi of ³²P. Treatment effect was assessed by histological analysis 28 days after stent placement. Neointimal and medial smooth muscle cell density were inversely related to increasing stent activity. The neointima of the high-activity (3.0- to 23.0-µCi) stents consisted of fibrin, erythrocytes, occasional inflammatory cells, and smooth muscle cells with partial endothelialization of the luminal surface. In the 1.0-µCi stents, the neointima was expanded and consisted of smooth muscle cells and a proteoglycan-rich matrix. The neointima of the low-activity (0.15- and 0.5-µCi) stents was composed of smooth muscle cells and matrix with complete endothelialization of the luminal surface. At low and high stent activities, there was a reduction in neointimal area (low, 1.63±0.67 mm² and high, 1.73±0.97 mm² versus control, 2.40±0.87 mm²) and percent area stenosis (low, 26±7% and high, 26±12%) compared with control stents (37±12%, P.01). The 1.0-µCi stents, however, had greater neointimal formation (4.67±1.50 mm²) and more luminal narrowing (64±16%) than the control stents (P<.0001).

Conclusions The differential response to the doses of continuous ß-particle irradiation used in this experimental model suggests a complex biological interaction of endovascular radiation and vascular repair after stent placement. Further study is required to determine the clinical potential for this therapy to prevent stent restenosis.

Key Words: stenosis • stents • arteries

	Introduction

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Experimental and clinical studies have shown that stents prevent restenosis by more effectively dilating the lesion and inhibiting chronic vascular constriction.^{1 2 3 4 5} Stent restenosis, which occurs in 20% to 30% of patients after intracoronary placement, is due solely to neointimal proliferation.^{4 5 6} A systemic or local antiproliferative therapy used in conjunction with a stent to inhibit neointimal formation would further reduce the incidence of restenosis.

In previous experimental studies, several investigators have shown that endovascular radiation before stentplacement or delivered via a radioactive stent effectively inhibits neointimal formation.^{7 8 9} Waksman et al⁷ reported a reduction in neointimal formation after placement of oversized stents in porcine coronary arteries with low-dose radiation delivered from ¹⁹²Ir and ⁹⁰Sr/Y sources before stent implantation. Hehrlein et al⁸ showed that a stainless steel stent made radioactive in a cyclotron with a composition of the - and ß-particle–emitting radionuclides ^55,56,57Co, ⁵²Mg, and ⁵⁵Fe inhibits neointimal proliferation after implantation in nondiseased rabbit iliac arteries. We and others^{9 10} have demonstrated the efficacy of low-dose endovascular radiation via a ß-particle–emitting stent to inhibit neointimal formation after placement in porcine and rabbit iliac arteries. ß-Particle irradiation with ³²P offers the advantages of a short half-life (14.3 days) and shallow penetration (3 to 4 mm) to reduce the risk to surrounding nontarget tissue. The objective of the present study was to investigate the dose-response effects of ß-particle irradiation from a stent implanted with ³²P ions in a porcine model of coronary restenosis.

	Methods

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Stent Preparation
Commercially available tubular slotted stainless steel stents 15 mm long (Palmaz-Schatz, Johnson & Johnson Interventional Systems) were carefully cut at the central articulation with microdissection scissors to create two 7-mm stents. The 7-mm stents were then made radioactive by direct implantation of ³²P ions beneath the surface of the metal (Forschungszentrum Karlsruhe).¹⁰ The control stents were fabricated in a manner similar to the radioactive stents except that they were not subjected to implantation of ³²P. The activity level of each stent was determined by comparison with standard ³²P sources of known activity by liquid scintillation counting methods. After ion implantation, the stents were placed in a sealed acrylic resin shield and sterilized by rays. The radiation levels at implantation were determined by methods previously described.¹⁰ The ß-particle–emitting stents were implanted at approximate activity levels of 23.0, 14.0, 6.0, 3.0, 1.0, 0.5, and 0.15 µCi. Fig 1 is a plot of the calculated lifetime radiation dose at radial distances of 0.1, 0.25, 0.5, 1.0, and 2.0 mm from the surface of a 0.5-µCi stent 3.5 mm in diameter and 7 mm long. At depths of 1.0 and 2.0 mm, a uniform dose is delivered to the vessel that is similar to the dose measured with GafChromic film¹¹ and calculated by the Prestwich model.¹² However, at depths of <0.5 mm, the radiation distribution is nonuniform, with 1800 cGy delivered by a 0.5-µCi-activity stent to the vessel 0.1 mm from the wires. The radiation dose delivered over the 28-day study was equivalent to three fourths of the dose that would be delivered over the lifetime of the ³²P stent.

View larger version (25K): [in this window] [in a new window]   Figure 1. Plot of the two-dimensional near-field dose model for a 0.5-µCi 32P Palmaz-Schatz stent 3.5 mm in diameter and 7 mm long.

Animal Model
The model used for these experimental studies was similar to previous investigations in our laboratory and those reported by others.^{13 14} Thirty-seven Yucatan miniature swine underwent placement of 74 stents (35 control, 39 ß-particle) in the left anterior descending, circumflex, or right coronary artery. Animals received aspirin 650 mg, nifedipine extended-release 30 mg, and ticlopidine 250 mg PO the evening before stent placement. Under general anesthesia, an 8F sheath was placed retrograde in the right carotid artery, and heparin 150 U/kg was administered to achieve an activated clotting time >300 seconds. Stents were manually crimped onto noncompliant angioplasty balloons 3.0 or 3.5 mm in diameter and 10 mm long (SCIMED). After completion of angiography, the 7-mm stents were implanted to obtain 10% to 20% oversizing compared with the baseline vessel diameter. Placement of the stent was completed with two balloon inflations at 12 to 14 atm for 30 seconds. Animals were allowed to recover and were returned to care facilities in which they received a normal diet and aspirin 81 mg daily. In addition, the animals were treated with ticlopidine 250 mg PO for 2 days after stent implantation. The animals were returned for coronary angiography at 28 days after implantation.

Histology
Immediately after angiography, the animals were euthanatized with a lethal dose of barbiturate. The hearts were then harvested, and the coronary arteries were perfusion-fixed with 10% neutral buffered formalin at 60 to 80 mm Hg for 30 minutes via the aortic stump. The stented coronary artery segments were carefully dissected from the epicardial surface of the heart. A central cross section was cut, and then the proximal and distal portions were longitudinally sectioned for examination of 20 stents in the first 14 hearts. One half of the proximal transverse section was used to take a hemi–cross section of the stent. The stent wires were then removed from this hemi–cross section under a dissecting microscope, and the tissue was processed for paraffin embedding after dehydration in a graded series of alcohols and xylene. These sections were examined by scanning electron microscopy according to previously described techniques.⁴ The central cross section of the stent, including the wires, was processed, embedded in methyl methacrylate, and then cut at 4 µm. The remaining 51 stents were each cut into two sections, processed, embedded in methyl methacrylate, and then cut at 4 µm. Histological sections were stained with hematoxylin-eosin and Movat pentachrome stains for qualitative analysis.

Studies of Vessel Morphometry and Cell Density
The cross-sectional area of each midstent section was measured with computer-assisted digital morphometry to determine the areas within the external elastic lamina, internal elastic lamina (IEL), or stent and the vessel lumen. The area within the IEL or stent was considered the normal reference lumen area. The percent area stenosis was then defined as [(IEL or stent area minus lumen area)/(IEL or stent area)] times 100. Neointimal area was determined by subtraction of the area of the lumen from the area within the stent wires. Neointimal thickness extending perpendicular from the stent to the lumen surface was measured at each wire site. The vessel injury score was determined by the method used by Schwartz et al.¹⁴ Neointimal and medial smooth muscle cell (SMC) densities were measured in all ß-particle–emitting and in 10 of the control stent sections. The total numbers of nuclei were counted in 12 randomly chosen 0.1-mm² regions of the media and neointima from each stented section with x100 (oil immersion) light magnification.

Statistical Analysis
Data are presented as mean±SD. The ß-particle–emitting stents were grouped into categories of low (0.15 to 0.5 µCi; tissue dose, <2000 cGy), intermediate (1.0 µCi; dose, 4000 cGy), or high (3 to 23.0 µCi; dose, >10 000 cGy) stent activity for comparison with nonradioactive stents. Lesion morphology, injury score, and cell density were compared for the control and radioactive stents by ANOVA with post hoc analysis for multiple comparisons. The stent activity and neointimal and medial cell densities were analyzed with a polynomial regression model. Significance was established at P.05. All statistics were calculated by use of Statview 4.5 (Abacus).

	Results

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Procedural and Postoperative
Seventy-three of 74 stents (98.6%) were successfully implanted in 37 swine. One animal died of balloon rupture during implantation of a control stent that resulted in severe coronary spasm and refractory ventricular arrhythmias. All other animals had a normal postoperative recovery and a stable or mild increase in body weight during the study (baseline, 29.2±5.1 kg versus 31.2±5.5 kg at 28 days, P<.001). One animal died on day 11 of thrombosis of a 23-µCi stent implanted in the left anterior descending coronary artery.

Histology
Vessel histology demonstrated dose-specific effects of endovascular radiation on the morphology of the neointima 28 days after placement of a ß-particle–emitting stent (Fig 2). The neointima of the high-activity stents was immature, with fibrin, erythrocytes, occasional polymorphonuclear cells, lymphocytes, and rare SMCs. The media in the vessels with high-activity stents was thinned, with areas of fibrinoid necrosis and loss of SMC nuclei, particularly in regions beneath the wire struts. SEM of the vessels with high-activity stents revealed partial endothelialization of the luminal surface. In the 1.0-µCi stents, the neointima was expanded by SMCs and a proteoglycan-rich matrix, with endothelialization of the luminal surface. Also, neovascular capillaries and extravascular red blood cells were present in the areas adjacent to the stent wires. The neointima of the low-activity stents was composed of a mature, organized layer of SMCs and matrix, with complete endothelialization of the luminal surface. The control stents had a neointima typical for 28 days after oversized implant in a porcine coronary artery.¹³

View larger version (162K): [in this window] [in a new window]   Figure 2. High-power photomicrographs of porcine coronary arteries after placement of (A) nonradioactive, (B) 0.5-µCi, (C and D) 1.0-µCi, and (E and F) 23-µCi ß-particle–emitting stents. In the control stent (A), note normal appearance of media with mild compression at stent wire site. Neointima consists of smooth muscle cells in a proteoglycan-rich matrix. B, Low-dose (0.5-µCi) ß-particle–emitting stent with a normal-appearing media and mild neointimal formation. C and D, Note increase in neointimal formation with this intermediate-dose ß-particle–emitting stent. Higher-power magnification (D) of the same vessel demonstrating intimal hemorrhage at the stent wire sites and medial compression without evidence of inflammation. E and F, High-dose (23-µCi) ß-particle–emitting stent with severe medial necrosis and a stent strut penetrating the external elastic lamina. F, Higher-power photomicrograph of same vessel showing an immature neointima consisting of fibrin, erythrocytes, and rare cell nuclei. Bar=100 µm.

A reduction in neointimal and medial cell density was present in arteries with ß-particle–emitting compared with nonradioactive stents (Fig 3). Neointimal cell density progressively and significantly declined with increasing stent activities (r=.84, P<.00001). Also, a reduction in medial SMC density was present for activities of 0.15 to 1.0 µCi. However, there was no further reduction in medial cell density at stent activities 1.0 µCi (P=.42). The vessel morphometry for the ß-particle–emitting (n=39) and nonradioactive (n=26) stents is summarized in the Table. Five control stents were excluded from this analysis because of excessive arterial injury (injury score, 2.0). None of the ß-particle–emitting stents were excluded from analysis. At low and high stent activities, a modest reduction (30%) in neointimal formation resulted in less luminal narrowing than with nonradioactive stents (Table). The intermediate-activity stents, however, had greater neointimal formation and more luminal narrowing than the control stents (P<.0001).

View larger version (32K): [in this window] [in a new window]   Figure 3. Radiation dose effect of a ß-particle–emitting stent on neointimal and medial smooth muscle cell density. Reduction in medial cell density (50%) was similar for 1.0-, 3.0-, 6.0-, 14.0-, and 23.0-µCi-activity stents (P=.42).

View this table: [in this window] [in a new window]   Table 1. Summary of Vessel Morphometry 28 Days After Placement of High-Activity (3.0- to 23.0-µCi), Intermediate-Activity (1.0-µCi), and Low-Activity (0.15- to 0.5-µCi) ß-Particle–Emitting and Nonradioactive Stents in Pig Coronary Arteries

	Discussion

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The present study describes the dose-response effects of a ß-particle–emitting metallic stent in an experimental model of restenosis. The vascular response to low-activity (0.15- to 0.5-µCi), intermediate-activity (1.0-µCi), and high-activity (3- to 23-µCi) ³²P stents was evaluated at 28 days after placement in normal porcine coronary arteries. The stents were oversized 10% to 20% greater than the vessel diameter to induce a moderate neointimal response.

The cell density of the neointima and media was reduced at all stent activities evaluated in the present study compared with nonradioactive control stents. The reduction in neointimal and medial cell density indicates that a continuous source of endovascular radiation via a ß-particle–emitting stent with activities as low as 0.15 µCi is lethal to vascular SMCs in normal pig coronary arteries. Interestingly, the magnitude of reduction in neointimal cellularity (60% to 90%) was greater than the decrease in medial cellularity (40%) observed at stent activities >1.0 µCi. Therefore, in this model, neointimal SMCs appear to be more sensitive to the effects of endovascular ß-particle irradiation than the medial SMCs. Alternatively, the inhibition of SMC migration from the media into the neointima by the ß-particle–emitting stent could explain the reduction in neointimal cellularity.

The biological response of normal porcine coronary arteries to the doses of endovascular irradiation used may be related to the extent of radiation-induced medial SMC damage. The histological appearance of the neointima in the high-activity stents demonstrates that endovascular radiation at doses >10 000 cGy profoundly inhibits neointimal SMC proliferation, but these doses in normal porcine coronary arteries impair endothelialization and promote fibrin-thrombus deposition. These higher doses of radiation induced a greater reduction in medial cell density than stent activities <1.0 µCi. Recent experimental studies have suggested that medial SMCs produce substances such as nitric oxide in response to arterial injury, which could limit thrombus deposition and promote endothelialization.¹⁵ Thus, radiation damage to the media might adversely affect the normal arterial response to a stent.

The reduction in neointimal formation for the low-activity (0.15- and 0.5-µCi) stents in the present study is similar to the effects demonstrated after placement in pig iliac arteries.⁹ In the present study, the low-activity stents were fully endothelialized and induced less medial SMC damage than the stents with activities 1.0 µCi. The results of the cell density studies indicate that the low-activity stents, which deliver 600 to 1800 cGy to the arterial wall directly subjacent to the stent wires, inhibit neointimal formation at least in part by producing cell death. These results differ from our data in porcine iliac arteries, in which a 0.15-µCi titanium mesh stent was used to deliver 300 cGy to the arterial wall. In these experiments, the cell density and the percentage of proliferating cell nuclear antigen–positive cells were similar for the ß-particle–emitting and nonradioactive stents, suggesting that ultralow-dose radiation impairs cell proliferation (static effect) or possibly migration.⁹

The 1.0-µCi stents had a more severe neointimal response and greater luminal narrowing than the nonradioactive stents. In the 1.0-µCi-activity stents, the reduction of medial SMC density was similar to that for stents with activities 3.0 µCi. It is possible that this level of endovascular radiation was insufficient to inhibit SMC proliferation at the luminal surface within the fibrin matrix 400 µm from the stent wires, thus resulting in a more severe neointimal response than the higher stent activities. Delayed endothelialization at this dose could also result in continued fibrin-platelet deposition that promotes SMC proliferation and matrix protein production. It is also possible that the 1.0-µCi level of radiation may induce a unique stochastic effect on matrix protein production by neointimal SMCs.

Limitations of the Study
The present study is limited by the evaluation of low numbers of stents at each activity and having follow-up only at 4 weeks. It is possible that late SMC proliferation could result in more neointimal proliferation and luminal narrowing that would be identified only by studies with long-term follow-up. The results observed in this experimental model may not be applicable to the treatment of human atherosclerotic lesions. The extent of cellular damage and the ability of atherosclerotic arteries to repair in response to endovascular radiation will probably be different from the response of normal artery tissue. There are also important radiobiological considerations regarding differences in tissue exposure and dose distribution after stent placement in normal coronary arteries versus atherosclerotic arteries. In atherosclerotic arteries, the media is often insulated by a layer of plaque that would substantially reduce the dose of radiation to this layer of the artery.¹⁶ The sensitivity of plaque SMCs to endovascular radiation may be different from that of normal medial SMCs. It is possible that activities >0.5 µCi will be required for inhibition of neointimal formation in atherosclerotic arteries.

In summary, the dose-dependent effects of endovascular radiation from a ß-particle–emitting stent suggests a complex biological interaction of endovascular radiation and vascular repair after placement in normal pig coronary arteries. In this porcine restenosis model, low-dose endovascular radiation via a ß-particle–emitting stent modestly reduces neointimal proliferation without impairing endothelialization. Increased medial damage and delayed endothelialization with stent activities 1.0 µCi promote fibrin and thrombus deposition, which requires higher levels of endovascular radiation (>3.0 µCi) to effectively inhibit SMC proliferation within this matrix. Further study is required to better determine the clinical potential for this therapy to prevent stent restenosis.

	Acknowledgments

 
This study was funded in part by the Department of Clinical Investigation, Walter Reed Army Medical Center, and by a grant from Isostent, Inc, San Carlos, Calif, through the Henry M. Jackson Foundation, Rockville, MD.

	Footnotes

 
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Drs David Fischell, Robert Fischell, and Tim Fischell are inventors of the ß-particle–emitting stent and have a financial interest in the device.

Received June 18, 1996; revision received August 14, 1996; accepted August 25, 1996.

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