(Circulation. 2000;101:1970.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Endovascular Irradiation From ß-Particle–Emitting Gold Stents Results in Increased Neointima Formation in a Porcine Restenosis Model
From the I. Medizinische Klinik und Poliklinik (C.S., C.N., C.A., R.A.H., E.A.), the Nuklearmedizinische Klinik und Poliklinik (I.W.), the Institut für Medizinische Statistik und Epidemiologie (K.U.), Klinikum rechts der Isar, and the Institut für Radiochemie (R.H., X.L.), Technische Universität München, Munich; and the Institut für Strahlenschutz (C.H., W.P., D.F.R.), GSF-Forschungszentrum für Umwelt und Gesundheit, Neuherberg, Germany.
Correspondence to Eckhard Alt, MD, I. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Ismaningerstraße 22, 81675 München, Germany. E-mail alt{at}med1.med.tu-muenchen.de
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Abstract |
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Background—Recent studies have shown that ionizing radiation reduces neointima formation after balloon angioplasty and stent implantation in experimental models of restenosis and first clinical trials. The objective of this study was to determine the dose distribution of a new ß-particle–emitting radioactive gold stent and to evaluate the dose-dependent vascular response in the coronary overstretch pig model.
Methods and Results—Sixteen Göttinger minipigs underwent placement of 11 nonradioactive and 36 ß-particle–emitting stents with activity levels of 10.4±0.6, 14.9±2.4, 22.8±1.3, 35.8±2.8, and 55.4±5.3 µCi of 198Au. Three months after implantation, the percent area stenosis, neointimal thickness, neointimal area, and vessel injury were analyzed by quantitative histomorphometry. The lifetime radiation doses at a depth of 1 mm were 3.3±0.2, 4.7±0.5, 7.2±0.4, 11.4±0.9, and 17.6±1.7 Gy for the different activity groups. No dose-response relationship was observed in the radioactive stents with respect to percent area stenosis (P=0.297), mean neointimal thickness (P=0.82), or mean neointimal area (P=0.65). Significantly lower neointima formation and less luminal narrowing was seen in the control group than in the ß-particle–emitting stents (P<0.001). Multilinear regression analysis revealed that only radioactivity made a significant independent contribution to the degree of percent area stenosis (P<0.001).
Conclusions—Neointima formation in pigs is markedly increased by ß-particle–emitting stents with 198Au as the radioisotope. This study provides evidence that dosages of 3 to 18 Gy of low-dose-rate ß-particle irradiation via endovascular stents cause pronounced luminal narrowing in the animal model at 3 months.
Key Words: coronary disease • stenosis • stents • radioisotopes
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Introduction |
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Coronary stent placement is increasingly used to improve the early outcome1 and reduce late restenosis after PTCA.2 3 However, substantial expansion of the arterial lumen comes at the expense of a potent stimulus for neointimal proliferation leading to stent restenosis, which occurs in 20% to 40% of patients after intracoronary stent placement.1 2 3 A systemic or local antiproliferative therapy used in conjunction with a stent is thought to function by inhibiting the neointima formation that causes late lumen loss after stent implantation. The concept of using local radiation to control neointima formation is based on the assumption that ionizing radiation suppresses smooth muscle cell proliferation and thereby inhibits neointima formation. This therapy has been applied to benign situations such as keloid4 or heterotopic bone formation.5 In general, 2 different strategies can be followed in terms of intravascular brachytherapy, using either high-dose-rate catheter-based systems with ß- (eg, 90Y)6 or
- (eg, 192Ir)7 8 emitters or
low-dose-rate irradiation with radioactive stents (eg,
32P).9 10 The benefits of using
ß-emitters include their ease of use and practical integration into
current catheterization laboratory procedures.
Radiation energy from ß-sources diminishes rapidly with distance and
therefore does not require special radiation shielding in the
catheterization laboratory. Endovascular radiation
therapy from radioactive sources has been shown to effectively inhibit
neointima formation under experimental
conditions9 10 11 12 13 and in first clinical
studies.8 Hehrlein et al13 described the use
of intra-arterial radioactive Palmaz-Schatz stents produced
by particle bombardment in a cyclotron. His results clearly indicated
that low-dose radioactive stents potently inhibit smooth muscle cell
proliferation. In a subsequent study, these results were confirmed with
a pure ß-particle–emitting stent.10 Others were able to
demonstrate the efficacy of ß-particle–emitting stents to reduce
neointima formation in a porcine coronary
restenosis model.9 Coronary stents with a 5-µm-thick gold coating have recently been introduced in routine clinical practice. Through neutron irradiation, 197Au can be converted to 198Au, a ß-particle emitter that can be used for endovascular brachytherapy.
The objective of the present study was to investigate the dose-response effects of ß-particle irradiation from a 198Au stent with respect to neointima formation using the coronary overstretch pig model.
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Methods |
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Stent Preparation
Stainless steel stents 8 mm long, with a 5-µm-thick gold coating and multicellular design (InFlow Dynamics) (Figure 1
), were activated by irradiation
in the Forschungsreaktor München (Technische Universität
München, Garching, Germany). The irradiation time varied
according to the required 198Au activity. Neutron
beam radiation caused 197Au atoms to be converted
into 198Au by the reaction
197Au+n=198Au. The nuclide
198Au has a half-life of 2.7 days and decays by
ß-particle emission, with the following major emissions: ß
(98.6%), with 0.96 MeVmax and 0.314
MeVmean; and (95.5%), with 0.412 MeV. The
activity of each stent was calculated by measuring the
198Au 412-keV -line with a Ge(Li) detector
coupled to a Canberra GENIE -ray spectroscopy system. The
198Au stents were implanted at mean activity
levels of 10.4, 14.9, 22.8, 35.8, and 55.8 µCi. The control stents
were identical to the radioactive stents, except that they were not
subjected to neutron irradiation. Staff and implanting physicians
always used protective goggles during implantation, and contact time
between the stent and the gloved hands of the physician was kept at a
minimum (<20 seconds).
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Dosimetry Measurement Using Radiochromic Films
Depth doses for soft tissue equivalent to the material
surrounding an activated stent were measured by means of
radiochromic films (Gafchromic Dosimetry Media, type MD-55, ISP
Technologies Inc). These films acted as dosimeters and
simultaneously as an absorbing medium. The total thickness
amounted to 0.25 mm. To obtain a dose-calibration curve, films
were irradiated with 137Cs -radiation with
doses from 5 to 80 Gy and 90Sr ß-radiation with
doses from 5 to 40 Gy. Calibration and measuring films were scanned by
means of a CCD flatbed scanner (Ultrascan 5000, Vexcel) with a pixel
size of 20x20 µm and 16-bit data depth. The measuring films
were evaluated along the gray-value-versus-dose-calibration curve. The
depth-dose distribution was measured with a stack of 10 layers of
radiochromic films placed in a U-shaped formation around the stent.
Consequently, the dose values given later are to be considered mean
values averaged over a thickness of 0.25 mm in distances to the
stent surface of 0.125, 0.375, 0.625 mm, etc.
Surgical Procedure
This study was performed with Göttinger minipigs (32 to 57
kg, Ellegaard Göttingen Minipigs ApS, Dalmose, Denmark). Animal
research was conducted according to guidelines of the institutional
review board and animal use committees. A total of 16 Göttinger
minipigs underwent random placement of 48 gold stents in the left
anterior descending, left circumflex, or right coronary artery.
Animals were medicated with aspirin 500 mg and amiodarone 150
mg IV. Under general anesthesia, a 7F sheath was placed
retrogradely in the left carotid artery, and heparin 100 U/kg IV was
administered. The stents were implanted according to the randomization
protocol with the guiding catheter used as a reference to obtain a
1.2:1 balloon-to-vessel ratio compared with the baseline vessel
diameter. The implanting physician was blinded to the type of stent
radioactivity. The stents were hand-crimped on PTCA balloons as used
for coronary angioplasty (Cruiser II, Nycomed Amersham, or
Viva, Boston Scientific Corp), with balloon diameters applied from 2.5
to 3.5 mm. Placement was achieved with a single balloon inflation
at 6 to 18 atm for 30 seconds. Angiography was completed after
implantation to confirm patency of the stent and side branches as well
as to assess for stent migration and intraluminal filling defects.
Animals were allowed to recover and were returned to care facilities.
They underwent follow-up coronary angiography 12 weeks after
implantation, and were again deeply anesthetized, fully
heparinized, and euthanized with an overdose of pentobarbital.
Quantitative Angiography
Each angiogram was evaluated for evidence of stent migration,
intraluminal filling defects, side-branch occlusion, lumen narrowing,
and distal coronary flow characteristics by standard criteria
for quantitative coronary angiography. The baseline mean lumen
diameter, balloon-inflated stent, and postimplant and follow-up
coronary artery minimal lumen diameters (in mm) were
measured from within the stented segment in nonoverlapped and
nonforeshortened views with the guiding catheter used for image
calibration. The acute balloon-to-vessel ratio (minimal stent
balloon-inflated diameter/baseline lumen diameter) was calculated from
these data for each stented vessel.
Histological Evaluations
Immediately after euthanasia, the heart and ascending aorta were
excised and the coronary arteries were perfusion-fixed with 6%
neutral buffered formalin at 100 mm Hg for 15 minutes via the
aortic stump. The stented coronary arteries were dissected from
the epicardial surface, left in formalin overnight, and thereafter
embedded in methylmethacrylate. Sections 8 µm thick were
obtained from 5 different levels of the stented coronaries with a
stainless steel carbide knife and stained with hematoxylin-eosin and
van Gieson’s elastica stains. All segments were evaluated by
computer-assisted histomorphometry. The segment most narrowed was then
used for further calculations. Therefore, the data presented
are composed of the worst levels obtained from each individual stent.
The cross-sectional area of each section was measured with digital
morphometry (NIH Image 1.59 for quantitative analysis) to
determine the areas within the internal elastic lamina (IEL) and vessel
lumen. The percent area stenosis was then defined as IEL-lumen
area/IELx100. The area of the neointima was
determined by subtracting the area of the lumen from the IEL.
Neointimal thickness extending perpendicular to the lumen
was measured at each strut site. The severity of stent-induced vascular
injury was graded according to the method of Schwartz et
al.14 Neointimal and medial cell densities
were measured in 5 randomly chosen 0.1-mm2 areas
close to the stent struts of both the ß-particle–emitting and the
control stents at x200 light magnification. The number of
neocapillaries within the neointima was counted. The
density was determined as number of neovascularizations per
neointimal area and compared between radioactive and
control stents.
Statistical Analysis
Data are presented as mean±SD. Angiographic data at
stent implantation, cell densities for the control and radioactive
stents, and morphometric data between the different groups of
ß-particle–emitting stents were compared by the Kruskal-Wallis
nonparametric ANOVA test with post hoc test for multiple
comparisons. Percent area stenosis, neointimal
thickness, and neointimal area between all radioactive and
control stents were compared by Mann-Whitney rank sum test. Multiple
linear regression analysis was applied to assess the impact of
injury and radioactivity (taken as the independent variables) and
their interaction (injury score x radioactivity) on percent area
stenosis (taken as the dependent variable). Binary
variables (value 0 or 1) denoting radioactive treatment were added
to the regression equation to evaluate the significance of the
treatment. Significance was established at P<0.05, except
for Bonferroni-corrected Mann-Whitney tests (P<0.01
[0.05/5]).
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Results |
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Dose Measurements
-Ray spectroscopy revealed that >99.8% of the total
stent activity was due to 198Au. In addition,
51Cr, 187W, and
65Zn contributed to the total stent activity with
0.1%, 0.006%, and 0.008%, respectively, with half-lives of 7.7
(51Cr), 23.7 (187W), and
244.3 days (65Zn). 55Fe and
59Fe were not detectable.
Figure 2 is a plot of the calculated
lifetime radiation dose at radial distances of 0.125, 0.375, 0.625,
0.875, 1.125, and 1.375 mm from the surface of a 46.5-µCi
(1720x103-Bq), 3.3-mm-diameter stent. Minimum
(cell area) and maximum (strut intersections) doses were averaged over
6x6 pixels measured at 8 different positions. At depths of 0.625,
0.875, and 1.125 mm, a uniform dose is delivered to the vessel. At
depths <0.375 µm, however, the radiation distribution is highly
heterogeneous, with maximum and minimum doses of 
260 and
140 Gy, respectively, delivered to the vessel 0.125 mm from the
struts. At a distance 
1.375 mm outward from the stent, the
radiation dose was below the detection threshold of the dosimeter film.
On the basis of these results and the known activity of each stent at
implant, the lifetime radiation dose at a depth of 1 mm was
calculated for the different stent activity groups
(Table).
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Procedure
Forty-seven of 48 stents were successfully implanted in the left
anterior descending (n=16), left circumflex (n=16), and right (n=15)
coronary arteries of 16 pigs. One stent was lost in the aorta
before the stent was advanced into the coronary system. One
animal died of reasons unrelated to stenting at day 18. Another animal
developed pneumonia 10 weeks after stent implantation, returned at day
73 (10.4 weeks) for follow-up angiography, and was euthanized. The
remaining animals survived for 12.9±0.3 weeks (12.3 to 13.6 weeks)
without complications.
Angiography
Baseline mean lumen diameter and balloon-inflated and post–stent
inflation minimal lumen diameters were not significantly different
between the groups. Quantitative analysis of the
coronary angiograms at implantation revealed a mean
balloon-to-artery ratio of 1.16±0.11, with a range of 1.08 to 1.20.
There were no significant differences between the radioactive and
control stents. Typical edge effects were not observed within the group
of the radioactive stents.
Histological Evaluations
Coronary histology of the control stents demonstrated a
neointima that consisted of a dense, circumferentially
arranged population of smooth muscle cells on the lumen surface with
less well-organized spindle-shaped cells, rare multinuclear giant
cells, and some neovascularization in the region of the stent struts. A
neointima with haphazardly placed cells near the stent
struts and moderately increased extracellular matrix but appearance
otherwise similar to that of control stents was seen in almost all
radioactive stents. No reduction in neointimal
(P=0.179), medial (P=0.07), or adventitial
(P=0.159) cell density was seen in arteries with
ß-particle–emitting stents compared with control stents. There was
some inflammatory reaction at the site of both the ß-particle and
control stent struts. The inflammatory reaction consisted of groups of
histiocytic cells adjacent to the struts with occasional multinucleated
foreign-body giant cells. In contrast, eosinophils, plasma cells, and
neutrophils were not prominent. Quantitative differences within
different treatment groups were not observed. A considerably thickened
adventitia was observed in most of the radioactive stents. The vessel
morphometry for the ß-particle–emitting and control stents is
summarized in the Table
. Microscopic examination revealed
proliferative neointimal responses and lumen
stenosis of various magnitudes in all groups. Comparison of the
different ß-particle–emitting stent groups revealed no significant
differences for mean percent area stenosis (P=0.297,
Figure 3A), mean neointimal
thickness (P=0.82), and mean neointimal area
(P=0.65). In the control group, however, a significantly
lower neointimal formation and less luminal narrowing was
seen than in the ß-particle–emitting stents (P<0.001,
Figures 3B and 4, top and bottom).
Quantitative differences with respect to neointimal
thickness, percent area stenosis, and neointimal
area within the different sections from 1 stent were <5%,
demonstrating a rather even vessel wall response to the stent
implantation. There was a trend toward greater neovascularization in
the radiated group (10.1±3.92 versus 14.01±10.08). However, this did
not reach the level of significance (P=0.504).
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To assess the contributions of injury score, radioactivity, and their interaction term (injury scorexradioactivity) to percent area stenosis, (dependent variable) multiple linear regression analysis was applied. According to this model, only radioactivity had a significant positive correlation to the percent area stenosis (P<0.001 for radioactivity, P=0.229 for injury score, and P=0.082 for the interaction term).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The aim of the study was to describe the dose-response effects of a low-dose-rate ß-particle–emitting 198Au stent in the coronary overstretch pig model. However, no dose-response relationship was found for stents implanted with activities ranging from 5 to 55 µCi with respect to a reduction of neointima formation, and all radioactive stents revealed more severe neointimal responses and greater luminal narrowing than the control stents.
Several other ß-emitters, such as 32P and 90Sr/90Y, have been used in different animal models and first clinical studies that revealed feasibility and efficacy to reduce neointima formation.6 9 10 In general, ß-emitters show a rapid dose falloff versus distance because of the large number of low-energy electrons in their respective spectra that have concomitant short ranges.15 32P has a maximum energy of 1.7 MeV and a mean energy of 0.69 MeV; the corresponding properties for 90Sr/90Y are 2.27 MeV and 0.97 MeV, respectively.15 Compared with these 2 isotopes, 198Au has far lower transition energies (0.96 MeV maximum energy and 0.312 MeV mean energy) and therefore has the greatest dose falloff. On the basis of the maximum energy and the dose measurements performed, the tissue range of 198Au ß-particles is <1.5 mm, compared with 5 to 6 mm with 32P.15 Taking these basic physical properties into consideration, the radioactive 198Au gold stent of the design used should fulfill the desired criteria for endovascular brachytherapy in the animal model to reach neointima, media, and adventitia with sufficient dose distribution.15
In the pig model, the greatest number of proliferating cells 2 to 3
days after angioplasty was found primarily in the adventitia
surrounding the injured artery.16 In the same model 1 week
after angioplasty, cell proliferation was reduced in the media and
adventitia, with the greatest number of proliferating cells found in
the neointima. Myofibroblasts in the adventitia proliferate
after angioplasty and may migrate into the neointima, where
they appear as smooth muscle cells.16 Thus,
hypothetically, intravascular irradiation is effective in inhibiting
neointima formation, if a significant reduction of
proliferating adventitial cells can be achieved.16 With
high-dose-rate brachytherapy, doses 
20 Gy targeted at a distance of
2 mm from the source18 appear to be efficacious in
lowering or even preventing restenosis.17 18 As a
rule in radiobiology, however, the biological effect of a given dose is
lowered if the dose rate is reduced and the overall exposure time is
increased.19 This implies that with low-dose-rate
endovascular irradiation via radioactive stents, the applied dosages
have to be considerably higher to be effective. Because a multicellular
stent design was used, the maximal distance from strut to strut for
vessel diameters 3 mm was 550 µm. On the basis of the
results from the dose measurements, this approach allowed application
of doses of 50 to 100 Gy to the adventitia and neointimal
tissue (mean distance from strut to adventitia, 200 to 400 µm)
in our highest-activity group. Thus, an effective prevention of
restenosis was expected, but the opposite effect was seen.
Because the implantation characteristics and vascular injury scores were comparable in all groups, these somewhat unexpected findings cannot be attributed to higher vascular injury in the irradiated groups. Furthermore, the results from the multiple linear regression analysis showed that only radioactivity made a significant independent contribution to the percent area stenosis. This lends additional support to the hypothesis that irradiation itself caused the pronounced neointima formation.
Several preclinical studies have demonstrated that
intracoronary radiation reduces neointima formation
when applied immediately after vessel injury.7 9 10 11 13
However, some found an accentuated neointima response after
radiation.20 21 Most of the studies showing
significant efficacy performed a 4-week follow-up, and rates of
proliferation of smooth muscle cells were usually not assessed. Only
limited data on long-term studies after radiation therapy are
available. At least 1 recently completed study, conducted by Virmani et
al,21 evaluated the long-term dose-response effects of
32P stents with activities of 0 to 12 µCi in a
proliferative double-injury pig model. For stents with activities 1
µCi, a significant increase was found in mean neointimal
area, percent restenosis, and neointimal thickness
compared with nonradioactive stents.21 Furthermore, for
stents with activities from 1 to 12 µCi, no dose-response
relationship was found.21 There are considerable
differences between our study and the double-injury
atherosclerosis model with 6 months of follow-up used
by Virmani et al. Despite these differences, the principle of an
increased proliferative response after endovascular irradiation using
low-dose-rate brachytherapy is seen in both studies. However, the
underlying mechanisms remain unclear. It is probable that the radiation
applied was insufficient to inhibit smooth muscle cell proliferation.
In addition, the irradiation-induced delay in
endothelialization facilitated fibrin-platelet
deposition, and the resulting thrombus promoted cell proliferation and
matrix protein production. This aspect is important in the
development of restenosis, especially in the porcine animal
model.
Catheters and radioactive stents deliver radiation at different dose
rates. Catheter studies using 192Ir or
90Sr/90Y delivered the dose
between 3 minutes and 1 hour, and dose rate varied from 0.2 Gy/h to
2.5 Gy/min.6 7 The dose-rate range of importance in
radiotherapy extends from 0.1 Gy/h to several Gy/min. In this range,
the fraction of cells killed by a given dose decreases as the dose-rate
is reduced, principally because of the repair of sublethal
damage.19 With radioactive stents, the dose rates are some
100-fold lower than high-dose-rate brachytherapy. However, Laird et
al11 demonstrated that 32P-labeled
stents with an initial activity as low as 0.14 µCi, which resulted in
a dose rate of <0.001 Gy/h, inhibited neointima formation
in porcine arteries. Thus, low-dose radiation may impair cell
proliferation without producing cell death. These results, in
conjunction with the present study, further point toward a complex
interaction between low-dose-rate ß-particle–emitting stents and
cellular wall vascular elements.
Study Limitations
The results observed in this experimental model may not
sufficiently reflect the pathological mechanisms that occur in human
restenosis after angioplasty. Because other experiments and
clinical trials using isotopes with different physical properties have
been shown to effectively reduce neointima formation, these
results cannot be applied toward low-dose-rate endovascular irradiation
in general. In our study, no antiplatelet or anticoagulation regime
was used after the initial injury and treatment procedure. Thus,
endovascular irradiation was insufficient to inhibit smooth muscle cell
proliferation, and an irradiation-induced delay in
endothelialization facilitated fibrin-platelet
deposition, promoting cell proliferation and matrix protein
production. Therefore, the contribution of insufficient
inhibition of smooth muscle cell proliferation and local thrombus
formation for increased neointima formation must be
considered.
Conclusions
Low-dose-rate ß-particle irradiation via endovascular stents
with activities from 5 to 55 µCi causes increased
neointima formation and greater luminal narrowing in an
experimental animal model of restenosis. This study provides
evidence for a complex interaction between radiation dose, dose rate,
and vessel wall cellular elements. These results suggest that
implanting radioactive 198Au gold stents, which
deliver dosages from 3 to 18 Gy to the coronary artery targeted
at a distance of 1 mm from the stent surface, provokes rather than
reduces neointima formation.
Received November 11, 1999; revision received February 14, 2000; accepted February 18, 2000.
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