(Circulation. 1999;100:1548-1554.)
© 1999 American Heart Association, Inc.
Basic Science Reports |
Dose-Response Effects of 32P Radioactive Stents in an Atherosclerotic Porcine Coronary Model
From the Cardiology Research Foundation, Washington Hospital Center (A.J.C., D.S., L.B.), Walter Reed Army Medical Center (T.H.), and the Armed Forces Institute of Pathology (R.J., R.V.), Washington, DC.
Correspondence to Andrew J. Carter, DO, Cardiology Research Foundation, Washington Hospital Center, 110 Irving St NW, Suite 4B-1, Washington, DC, 20100. E-mail ajc2{at}mhg.edu
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Abstract |
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Background—Experimental studies have demonstrated that 32P radioactive stents reduce neointimal formation at 28 days in porcine iliac and coronary arteries. Our objective was to determine the long-term dose-response effects of 1.0- to 12.0-µCi 32P radioactive stents in a porcine atherosclerotic coronary model.
Methods and Results—Control (n=19) and 1.0- to 12.0-µCi
32P radioactive (n=43) stents (total, n=62) were implanted
in the coronary arteries of 31 miniature swine at 28 days after
creation of a fibrocellular plaque by overstretch balloon injury and
cholesterol feeding. Angiography and histomorphometry were
performed at 6 months. Stent thrombosis occurred in 3 radioactive
(7.7%) and no control stents (P=0.54). On histology,
the mean neointimal area and the percent in-stent
stenosis correlated positively with increasing stent activity
(r=0.64, P<0.001). The mean
neointimal area (mm2) for the stents with 
3.0
µCi 32P (3.57±1.21) was significantly greater than that
for the nonradioactive stents (1.78±0.68, P<0.0001).
The neointima of the stents with 3.0 µCi
32P was composed of smooth muscle cells, matrix
proteoglycans, calcification, foam cells, and cholesterol
clefts.
Conclusions—Continuous low-dose-rate irradiation delivered by high-activity 32P radioactive stents promotes the formation of an "atheromatous" neointima after 6 months in this experimental model. These data may be useful for predicting late tissue responses to radioactive stents in human coronary arteries.
Key Words: stents • restenosis • radioisotopes
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Radioactive stents have been proposed as a means to reduce in-stent restenosis by inhibiting neointimal formation.15 Presumably, continuous low-dose rate irradiation delivered by a radioactive stent may be sufficient to impair the ability of smooth muscle cells (SMCs) to proliferate after vascular injury after stent placement. Preliminary in vitro and short-term experimental studies in porcine iliac and coronary models suggest that low-dose-rate irradiation delivered by a 32P radioactive stent is indeed sufficient to reduce neointimal formation and in-stent stenosis compared with nonradioactive stents.
Experimental studies have demonstrated that stents ion-implanted with activities as low as 0.14 µCi of 32P reduce neointimal formation at 28 days in porcine iliac arteries.2 Hehrlein et al,5 however, reported a reduction in neointima after 12 weeks in rabbit iliac arteries after placement of radioactive stents with only 13 µCi 32P. Stents with 4 µCi of 32P were histologically similar to nonradioactive stents. In the porcine coronary restenosis model, we observed an unusual biphasic biological response to low- (0.5 µCi), intermediate- (1.0 µCi), and high- (>3.0 µCi) activity 7-mm-long 32P Palmaz-Schatz stents at 28 days.4 6 The low-activity 32P radioactive stents reduced neointimal formation to a degree similar to that reported in the porcine iliac model with 0.14-µCi 32P radioactive stents. The intermediate-activity stents, however, promoted the formation of a matrix proteoglycan-rich neointima, whereas the high-activity stents reduced neointimal formation but with histological evidence of delayed vascular repair. Thus, the present experimental data suggest important dose-, time-, species-, and model-dependent variations in the vascular response to 32P radioactive stents.
The purpose of this study was to determine the long-term dose-response effects of 32P ß-particle–emitting radioactive stents in a porcine atherosclerotic coronary model. A double-injury model of accelerated atherosclerosis was selected to mimic the geometric effects of plaque mass on radiation delivery to the arterial wall by a radioactive stent.
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Methods |
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Stent Preparation and Dosimetry
Commercially available 15-mm-long balloon-expandable stainless steel stents (Palmaz-Schatz, Cordis, a Johnson & Johnson Co) were rendered radioactive by direct ion implantation of 32P.5 The activity of the stent was determined, and stents were allowed to decay to desired 32P activities before the time of implantation.3 The dosimetry of 32P radioactive Palmaz-Schatz stents has previously been reported by Janicki et al.7 The estimated 1-month cumulative dose and initial dose rate at implantation for the 32P radioactive stents are shown in Table 1
.
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Animal Preparation
The animal work was completed after approval by the
institutional scientific review committee and conformed to the position
of the American Heart Association on animal research. Sixty-two stents
3.0 to 4.0 mm in diameter (19 control and 43 radioactive) were
implanted in the coronary arteries of 31 miniature swine at 28
days after creation of a fibrocellular plaque by overstretch injury
with a 10-mm-long angioplasty balloon and cholesterol
feeding. Animals were medicated with aspirin 650 mg, ticlopidine 250
mg, and nifedipine extended release 30 mg by mouth the
evening before stent placement. Under general anesthesia,
an 8F sheath was placed retrogradely in the right carotid artery, and
heparin (150 U/kg) was administered intra-arterially to
achieve an activated clotting time >300 seconds (Hemochron,
International Technidyne). After completion of angiography, the stent
was implanted at a site of balloon injury that was identified by an
anatomic landmark (such as a side branch) or the presence of luminal
narrowing. The stents were implanted with the guiding catheter used as
a reference to obtain a 1:1 stent-to-artery ratio compared with the
normal reference vessel diameter. Placement of the stent was completed
with a single balloon inflation at 10 to 14 atm for 30 seconds.
Angiography was completed after implantation to confirm patency of the
stent. Animals were allowed to recover and then returned to care
facilities, where they received a normal diet and were treated with
ticlopidine 250 mg/d for 28 days and aspirin 325 mg/d. After 6 months,
the animals were returned to the laboratory for coronary
angiography and were euthanized with a lethal dose of barbiturate.
Pathological Evaluation
The methods for tissue and stent processing have been
described in detail.4 Four sections from each stent were
evaluated for the presence of cholesterol clefts, foam
cells, calcification, and necrotic core within the intima. The
cross-sectional area of the proximal edge, proximal body, distal body,
and distal edge stent sections were measured with digital morphometry
to determine the areas within the adventitia (area of dense fibrous
tissue outside the external elastic lamina [EEL]), EEL, internal
elastic lamina (IEL), stent, and lumen. The area within the stent or
IEL was considered the normal reference lumen area. The percent area
stenosis was then defined as [(stent or IEL area - lumen
area)/(stent or IEL area)]x100. Neointimal area was
determined by subtracting the area of the lumen from the area within
the stent or IEL. The area of the plaque+media was determined by
subtracting the area of the stent or IEL from the EEL.
Neointimal thickness extending perpendicularly from the
stent to the lumen surface was measured at each strut. The extent of
vessel wall injury induced by the stent was determined by the methods
of Schwartz et al.8 The morphometry parameters
and injury score were measured for each of the 4 sections, and an
average for each stent was then calculated.
Quantitative Angiography
The baseline, postimplantation, and 6-month minimal lumen
diameter within the stent were measured from nonoverlapped and
nonforeshortened views, with the guiding catheter used as a standard
(CMS, Medis, Inc). The poststent percent diameter stenosis,
short-term stent-to-artery ratio (minimal stent balloon-inflated
diameter/reference lumen diameter), and 6-month percent diameter
stenosis were calculated from these data for each vessel.
Statistical Analysis
The angiographic parameters were compared by
paired t test. The mean morphological data for each stent
were compared by ANOVA with Scheffé's F tests for multiple
comparisons. Angiographic late lumen loss, injury score,
neointimal area, percent in-stent stenosis, and
stent activity were analyzed with linear regression to
determine relations. Significance was established by a value of
P
0.05. Data are expressed as mean±SD. All statistics were
calculated by use of Statview 4.5 (Abacus).
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Results |
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General
Sixty of 62 stents (96.8%) were successfully implanted into the coronary arteries of 31 swine. Two stent implantations were complicated by ventricular fibrillation that was refractory to medical therapy and DC cardioversion. Twenty-five of 29 animals (86.2%) survived after stent implantation for the duration of the study. One animal was euthanized 2 months after stent implantation because of an inner ear infection refractory to antibiotic therapy. This animal received a 1.0-µCi 32P stent and a nonradioactive stent. The histological data from this animal were excluded from analysis, although each stent was patent on microscopic analysis, with similar cellular appearance and degree of neointimal formation.
Subacute Stent Thrombosis
Three of 29 animals (10.3%) with successful stent placement
had sudden death secondary to subacute thrombosis of a stent.
Subacute stent thrombosis occurred in 3 of 39 radioactive stents
(7.7%) and none of the nonradioactive stents (P=0.54).
Stent thrombosis occurred on days 4, 27, and 28 after implantation. The
radioactive stents with subacute thrombosis were in the 6.0-µCi
32P activity group at the time of
implantation.
Quantitative Angiography
Quantitative analysis of the coronary angiograms
at implantation and at 6 months is summarized in Table 2. The stent-to-artery ratio (1.04±0.02)
was similar for the radioactive and nonradioactive stents
(P=0.48). Linear regression analysis demonstrated a
dose-dependent increase in the late lumen loss (r=0.72,
P<0.001).
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Pathology
Morphology of In-Stent Lesions After Sudden Death
Histology of the coronary arteries from the animal
with sudden death on day 4 revealed an occlusive thrombus distal to a
6.0-µCi 32P stent implanted in the left
anterior descending coronary artery. Focal compression of the
plaque and media was present without deep vessel wall injury within
the stent. Analysis of the proximal and distal reference
sections failed to identify a cause for stent thrombosis, such as a
medial dissection. The nonradioactive stent in the left circumflex
coronary artery was patent and had a thin neointima
consisting of an organized fibrin thrombus with inflammatory cells and
SMCs. Focal necrosis of the plaque and media underneath the struts was
more prominent for the radioactive than the nonradioactive stent.
The histology of the stents from the animals with sudden death on days
27 and 28 revealed a large organizing thrombus in one case and mural
thrombus associated with neointimal proliferation in the
other case. In the animal with sudden death on day 27, a 6.0-µCi
32P stent implanted in the left anterior
descending coronary artery had a fibrin-rich thrombus with 80%
luminal narrowing (Figure 1). This animal
did not have a nonradioactive stent for comparison. The animal with
sudden death on day 28 had abundant neointimal formation in
a 6.0-µCi 32P radioactive stent implanted in
the right coronary artery. The neointima consisted
of a proteoglycan-rich matrix with occasional SMCs and fibrin adjacent
to the struts resulting in >75% luminal narrowing. A mural thrombus
was present in this case, but without evidence of complete
occlusion of the lumen. A nonradioactive stent implanted in the left
anterior descending coronary artery was patent, with mild
neointimal thickening and evidence of surface
endothelialization on light microscopy.
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Dose-Response Effects on Arterial Morphology
The results of vessel morphometry are summarized in Table 3. The area of the plaque plus media
(mm2) was similar for the control (1.88±0.52)
and radioactive (1.73±0.53, P=0.12) stents. The mean
neointimal area (mm2) for the stents
with 3.0 µCi 32P (3.57±1.21) was
significantly greater than the nonradioactive stents (1.78±0.68,
P<0.0001), resulting in greater in-stent stenosis
(53±14 versus 28±9, P<0.0001). The mean
neointimal area and the percent in-stent stenosis
correlated positively with increasing stent activity
(r=0.64, P<0.001). The neointimal
area correlated with the injury score for the control stents
(r=0.33, P=0.009) but not the radioactive stents
(r=0.02, P=0.86).
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The neointima of the nonradioactive stents consisted of
well-organized SMCs within a collagen matrix. Neovascularization was
present adjacent to the strut wires. The adventitia contained
collagen, fibroblasts, and neovascular capillaries. The
neointima of the radioactive stents with 1.0 µCi of
32P appeared similar to that of the
nonradioactive stents (Figure 2).
Occasional regions of cholesterol-rich macrophages
were identified adjacent to the stent struts. Neovascularization of the
neointima and adventitia was also similar to that in the
nonradioactive stents.
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The morphology of the high-activity stents was somewhat variable.
The neointima contained areas of SMCs in a
proteoglycan-collagenous matrix localized primarily in the region of
the struts, with other areas rich in macrophages, necrotic
debris, cholesterol clefts, and giant cells (Figures 3 and 4).
Calcification was observed in some cases. Neovascularization was more
prominent in the neointima than in the control and
1.0-µCi 32P stents. The media was compressed
beneath the stent struts, and in other locations the media was of
normal thickness and appearance. Only rare areas of severe medial
disruption were observed. At other sites near the stent struts, the
neointima was markedly hypocellular and consisted of a
loose proteoglycan matrix with occasional SMCs and some condensation of
SMCs near the lumen. The adventitia was significantly thickened,
without any inflammatory infiltrate in the stents with 6.0 µCi of
32P (Table 3
).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Radioactive stents have been proposed as a means to reduce in-stent restenosis by inhibiting neointimal formation. We evaluated the long-term dose-response effects of radioactive stents ion-implanted with activities of 1.0 to 12.0 µCi of 32P in a porcine atherosclerotic coronary model. A double-injury model of accelerated atherosclerosis was selected to more closely mimic the geometric effects of plaque mass on radiation delivery to the arterial wall by a radioactive stent. Histological analysis demonstrated a dose-dependent increase in neointimal area and the percent in-stent stenosis with increasing stent 32P activity. The neointima of the stents with
3.0 µCi 32P was composed of SMCs
and a proteoglycan matrix with calcification, foam cells, and
cholesterol clefts. Therefore, the main finding of the
present study is that continuous low-dose rate irradiation
delivered by 3.0-µCi 32P radioactive stents
promotes the formation of an atheromatous
neointima in this experimental model.
Long-Term Effects of Continuous Low-Dose-Rate Endovascular
Irradiation
The present study, unlike previous 28-day studies in the
porcine coronary model of restenosis, failed to
demonstrate a significant reduction in neointimal formation
for low-activity (0.5 to 1.0 µCi 32P)
radioactive stents at 6 months in atherosclerotic pig coronary
arteries.3 4 The lack of efficacy at 6 months in this
model for the low-activity 32P stents suggests
inadequate cumulative radiation dose, dose rate, or delayed
neointimal growth after 28 days, although the higher injury
score observed in the 0.5- to 1.0-µCi 32P group
suggests that stent-induced arterial trauma may have
contributed to the failure at this activity. Importantly, a
dose-dependent increase in neointimal formation was
observed with increasing activity of 32P on the
stent at the time of implantation.
The histological features of the 3.0- to 12.0-µCi
32P radioactive stents observed in the
present study are consistent with radiation-induced
arteriopathy.9 10 11 Experimental studies in canine and
rabbit models indicate that external-beam irradiation of the aorta or
vascular grafts causes intimal hyperplasia and accelerated
atherosclerosis after 6 months with single doses >30
Gy.9 10 11 12 Hoopes et al12 reported that large
single intraoperative doses of radiation (60 Gy) delivered to the
canine aorta resulted in decreased or delayed intimal proliferation and
lumen narrowing compared with lower fractionated doses. Our data
suggest that the cumulative dose delivered by a 3.0-µCi
32P radioactive stent exceeds vascular tissue
tolerance in this model. The estimated lifetime cumulative tissue dose
at a distance of 0.5 mm from the surface of a 3.0- to 12.0-µCi
radioactive stent is 
20 to 125 Gy. Importantly, the lifetime
cumulative near-field (0.1 mm from the stent surface) dose for a
3.0-µCi 32P stent is >125 Gy. Therefore, the
arterial tissue immediately adjacent to the struts of a
permanently implanted 3.0-µCi 32P stent
receives a lifetime cumulative dose nearly 5-fold greater than a single
dose of irradiation known to induce an arteriopathy.
Several experimental and initial clinical trials have demonstrated efficacy in preventing restenosis after stenting by treatment with 8 to 30 Gy irradiation given in a single dose via a high-dose-rate (1200 to 5000 cGy/h) 192Ir catheter-based system.13 14 In the present study, the 28-day cumulative dose (10 Gy) or initial dose rate (3 cGy/h at implantation) delivered by a 1.0-µCi 32P radioactive stent was insufficient to reduce neointimal formation and in-stent stenosis at 6 months. The arterial morphology of the 1.0-µCi 32P radioactive stents did not exhibit the pathological features identified in the 3.0- to 12.0-µCi 32P radioactive stents consistent with a radiation-induced arteriopathy. Together, these preliminary data suggest that dose rate may be a critical factor in predicting efficacy for the prevention of restenosis with endovascular irradiation, whereas the cumulative dose predicts toxic radiation–induced late tissue responses.
Comparison With Previous Studies of Radioactive Stents
Hehrlein et al5 also reported a series of experiments
with similar activities of 32P stents in rabbit
iliac arteries. In contrast to the porcine experiments, these authors
reported a dose-dependent reduction in neointimal
formation, with the maximal effect evident at 3 months after placement
of a 13.0-µCi 7-mm-long stent. The contrasting results with the doses
of continuous ß-particle irradiation used in these experimental
studies suggest a species- or model-dependent response to endovascular
irradiation delivered via a stent. Others have demonstrated species
differences in response to nonradioactive stent implantation that may
be related to endothelial cell regeneration or the
intrinsic fibrinolytic capacity of the animal.15 16
Studies are currently under way to examine species differences in the
response to stent-based irradiation that may have important
implications for the selection of animal models used to evaluate
radioactive stents.
The clinical phase 1 Isostent for Restenosis Intervention Study
(IRIS) demonstrated similar target-lesion
revascularization and angiographic
restenosis after 6 months for 0.5- to 1.5-µCi
32P Palmaz-Schatz stents compared with expected
late outcomes for a nonradioactive Palmaz-Schatz stent in patients with
focal native coronary arterial
lesions.17 Currently, dose-escalation trials are in
progress with stent activities of 3.0 to 24 µCi
32P to determine safe and potentially effective
irradiation doses delivered via a ß-particle–emitting stent to
reduce restenosis.
Limitations of the Study
Interpretation of the data obtained in the present study must
be made with caution, because the study involves the dose-response
effects of a radioactive stent in vessels with focal experimentally
induced atherosclerotic lesions. The atherosclerotic pig
coronary lesions created by balloon injury and
high-cholesterol diet differ from the complex
atherosclerotic lesions in humans in which focal plaque rupture,
necrosis, and calcification are often observed. The diet- and
injury-induced lesions in the porcine atherosclerotic coronary
model consist primarily of SMCs. The extent of atherosclerotic plaque
is substantially less in this model than that encountered when stents
are implanted in diseased human coronary arteries. These
factors will have significant effects on radiation dose distribution to
the vessel wall because of variations in tissue density and plaque mass
as well as uniformity of stent expansion. The present study,
however, clearly defines the late tissue responses to continuous
low-dose-rate irradiation delivered by a 0.5- to 12-µCi
32P radioactive stent in an experimental model of
restenosis. Therefore, these data may be useful for predicting
dose-dependent long-term effects of 32P
radioactive stents in human coronary arteries.
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Acknowledgments |
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This study was funded by a grant from Isostent, Inc, Belmont, Calif, through the Henry M. Jackson Foundation, Rockville, Md.
Received March 5, 1999; revision received May 25, 1999; accepted June 2, 1999.
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H.-S. Kim, R. Waksman, Y. Cottin, M. Kollum, B. Bhargava, R. Mehran, R. C. Chan, and G. S. Mintz Edge stenosis and geographical miss following intracoronary gamma radiation therapy for in-stent restenosis J. Am. Coll. Cardiol., March 15, 2001; 37(4): 1026 - 1030. [Abstract] [Full Text] [PDF]
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I. P. Kay, A. J. Wardeh, K. Kozuma, D. P. Foley, A. H. M. Knook, A. Thury, G. Sianos, W. J. van der Giessen, P. C. Levendag, and P. W. Serruys Radioactive Stents Delay but Do Not Prevent In-Stent Neointimal Hyperplasia Circulation, January 2, 2001; 103(1): 14 - 17. [Abstract] [Full Text] [PDF]
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K. Kozuma, M. A. Costa, M. Sabate, I. P. Kay, J. P. A. Marijnissen, V. L. M. A. Coen, P. Serrano, J. M. R. Ligthart, P. C. Levendag, and P. W. Serruys Three-Dimensional Intravascular Ultrasound Assessment of Noninjured Edges of {beta}-Irradiated Coronary Segments Circulation, September 26, 2000; 102(13): 1484 - 1489. [Abstract] [Full Text] [PDF]
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I. P. Kay, M. Sabate, M. A. Costa, K. Kozuma, M. Albertal, W. J. van der Giessen, A. J. Wardeh, J. M. R. Ligthart, V. M. A. Coen, P. C. Levendag, et al. Positive Geometric Vascular Remodeling Is Seen After Catheter-Based Radiation Followed by Conventional Stent Implantation but Not After Radioactive Stent Implantation Circulation, September 19, 2000; 102(12): 1434 - 1439. [Abstract] [Full Text] [PDF]
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