(Circulation. 2000;102:3117.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Effects of ß–-Emitting 188Re Balloon in Stented Porcine Coronary Arteries
An Angiographic, Intravascular Ultrasound, and Histomorphometric Study
From the Division of Cardiology and the Research Institute at Cedars-Sinai Medical Center and the UCLA School of Medicine (R.M., H.H., J.H., F.L., N.L.E.), the Division of Medical Physics at Cedars-Sinai Medical Center (J.W., A.L.), and the Department of Pathology at UCLA School of Medicine (M.C.F.), Los Angeles, Calif, and the Oak Ridge National Laboratory (F.F.K.), Oak Ridge, Tenn.
Correspondence to Neal Eigler, MD, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA 90048. E-mail IB1surfdoc{at}aol.com
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Abstract |
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Background—Restenosis within stents may be prevented by ionizing radiation from an intravascular source.
Methods and Results—A liquid ß- radiation (188Re) balloon was evaluated in a randomized and blinded porcine coronary model of stent restenosis. Group A pigs (n=17) received 0,16, 22, or 29 Gy at 0.5-mm depth, followed by stenting. Restenosis was quantified by angiography, ultrasound, and histomorphometry at 30 days. Group B (n=7) was stented first and then treated with 0 or 29 Gy with follow-up at 60 days. There was a measurable effect at 16 Gy, which improved with increasing doses. At 29 Gy, the histological stenotic area was reduced by 67% (22% versus 66% in controls, P<0.001). Radiation after stenting was equally effective; the stenotic area was reduced (21% versus 65%, P<0.001). At 16 Gy, the vessel just distal to the stent was significantly smaller than control vessels because of intimal thickening (P=0.003). Radiated vessels had distinctive histology consisting of neointimal fibrin and reduced smooth muscle cells and matrix (P<0.0001).
Conclusions—188Re balloon brachytherapy in porcine coronary arteries results in dose-dependent and injury-independent inhibition of stent restenosis for up to 60 days. Restenosis at the borders of the irradiated zone is a potential limitation and may be related to underdosing. Brachytherapy with the 188Re balloon appears to be safe and feasible for clinical studies.
Key Words: balloon • restenosis • angioplasty • stents
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Restenosis within stents has high rates of recurrence and morbidity.1 Restenosis may be prevented by ionizing radiation delivered from an intravascular source. A variety of devices and sources, including radionuclide-coated stents and catheters containing radioactive wires or seeds, are being developed. This report describes the initial experience with a ß–emitting liquid-filled 188Re balloon in a porcine model of coronary stenting. The effects of dose, stent attenuation, location with respect to the irradiated field, and duration of effect up to 2 months were examined by quantitative angiography (QCA), intravascular ultrasound (IVUS), and histology.
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Methods |
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Radiation Delivery System
The radiation delivery system (Radiant, US Surgical, Inc) (Figure 1
) consisted of a balloon catheter coupled to
a liquid radiation source contained in a shielded isolation and
transfer device (ISAT). The catheters were modified
rapid-exchange–type polyethylene PTCA balloons with dual radiopaque
markers, puncture resistant walls, and self-sealing connectors.
Balloons achieved nominal diameter at 3 atm.
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Sterile 188Re perrhenate
(NaReO4) with activity concentrations ranging
from 50 to 150 mCi/mL was produced by eluting a
188W-188Re
generator (Oak Ridge National Laboratory). The half-life is 17 hours,
and the maximum ß- energy is 2.1 MeV. 
emissions (16%) facilitate calibration and leak detection while
contributing a negligible dose to the arterial wall.
The ISAT contains a smaller syringe filled with isotope coupled to the balloon by redundant self-sealing connectors. A 1-cm-thick leaded acrylic shield surrounds the isotope. The isotope syringe plunger is coupled back to back with the plunger of a saline-containing syringe that, in turn, is connected to a standard PTCA inflation device by 30-in tubing and a pressure-limiting (4-atm) valve. Operation of the inflation device transfers the isotope between ISAT and the balloon.
Treatment time depends on the prescribed dose at 0.5 mm
radial to the balloon surface, balloon diameter, isotope activity
concentration, and isotope decay. Negligible radiation is delivered
during balloon deflation. Thus, the balloon can be cycled as many times
as necessary to deliver the dose permitting intermittent perfusion.
Dose to the operator is limited to bremsstrahlung and
emissions.
Figure 2 shows isotope depth-dose plots for the long
axis of the balloon. Without a stent, the radiation fields are highly
uniform at depths from contact to 2.0 mm. When stents are positioned
over the balloon, a pattern of strut attenuation creates shadows that
are visible at contact but are absent at 0.5-mm
depth.
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Study Design
The Institutional Animal Care and Use Committee
approved the experiments. Group A was involved in a dose-response study
in which arteries were irradiated before stenting. Juvenile farm pigs
(n=17, 25 to 30 kg) received 250 mg ticlopidine and 325 mg aspirin the
day before and for 7 and 30 days thereafter, respectively. Anesthesia
was maintained with isoflurane, followed by 5 mg/kg bretylium and
10 000 IU heparin intravenously. Coronary angiograms were performed
after 200 µg IC nitroglycerin.
Segments of the right coronary artery (RCA) and left anterior descending coronary artery (LAD) were irradiated with 3.5x20-mm balloons. Arteries were randomized to receive 0, 16, 22, or 29 Gy. One-minute inflation/deflation cycles were performed until the prescribed dose was administered. Balloon-vessel contact was confirmed by contrast injection. Blood samples were assayed for radioactive contamination. All study participants except the physicist (A.L.) were blinded to dose until the completion of data analysis.
A 4.0x17-mm nitinol stent (ACT-One, US Surgical, Inc) was deployed at 12 atm within the irradiated segment. At 30 days, QCA and IVUS were performed, followed by euthanasia under general anesthesia. The coronary arteries were perfusion-fixed and placed in formalin.
Of the 34 coronary arteries attempted, 1 RCA could not be cannulated with a guide catheter, and 1 LAD could not be successfully stented. One LAD receiving 22 Gy was occluded at follow-up. The results are included, but IVUS examination was not possible. Histology revealed organized occlusive stent thrombosis.
Group B was involved in irradiation after stent placement; follow-up was extended to 60 days. Pigs (n=7) received a 3.5x17-mm ACT-One stent, followed by irradiation with 0 or 29 Gy. Otherwise, the methodology was identical to that for group A. One radiated LAD was excluded because the stent migrated 10 mm proximal to the treated segment immediately after radiation delivery. A single additional pig was euthanized at 2 days to observe the early effects of brachytherapy.
Data Acquisition and Analysis
QCA parameters included the following: proximal and
distal reference diameters, minimum lumen diameter (MLD) and mean lumen
diameter, minimum and mean percent diameter stenosis, and mean and
maximal late loss. Ten IVUS frames (6 within the stent and 2 in the
5-mm segments proximal and distal to the stent) were selected at 2.5-mm
intervals for planimetry. Measurements included stent, lumen, and
intimal areas. Tissue blocks were embedded in methyl methacrylate and
cut into 4 cross sections at predetermined points to avoid sampling
bias. From proximal to distal, sections were taken at 2, 6, 9, and 15
mm within the stent. Stained sections (paragon
stain)2 were evaluated
by an experienced cardiovascular pathologist (M.C.F.).
Table 1 summarizes prospectively defined grades for
intimal, medial, and adventitial features. The circumferential extent
of media disrupted or absent was measured. The appearance of the vasa
vasorum and myocardium surrounding the artery were also systematically
evaluated. Histological sections were scanned at 9-µm resolution for
automatic edge detection and measurement of the areas constituting the
lumen, boundary of the stent struts, and neointimal thickness. Percent
area stenosis was calculated as 100x(stent area-lumen area)/stent
area. The mean injury score was measured as described by Schwartz et
al.3
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Statistical Analysis
Data are summarized as mean±SD. Comparisons were by
ANOVA and by ANCOVA, where the covariate variable was the injury score.
Post hoc testing was by the least significant difference method.
Comparison between ranks was by Kruskal-Wallis ANOVA. At
P<0.05, post hoc comparisons were by the Mann-Whitney
U test corrected for multiple comparisons. Comparisons
for nominal-scaled data were by 
2
analysis or by the Fisher exact test. Relationships between variables
were assessed by linear regression or by Spearman rank
correlation.
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Results |
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Irradiation Before Stenting
There were no radiation leaks. The total exposure outside the operator’s lead apron, exclusive of fluoroscopy, was <1 mR per treatment. Table 2
summarizes the quantitative results for group A.
QCA stent diameter and reference diameter did not differ among the dose
groups. The model created oversized stent injury with stent/artery
ratios averaging 1.21 to 1.28. There was dose-dependent improvement in
all parameters of stenosis severity (MLD, mean diameter, maximum and
mean percent stenosis, and late loss). MLD increased by 30%, 40%, and
90%, whereas mean late loss decreased by 37%, 56%, and 62% at 16,
22, and 29 Gy, respectively.
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IVUS confirmed that stent area, diameter, and eccentricity did not differ among the dose subgroups. There was improvement in lumen area, intimal area, and percent area stenosis at each dose, but dose-dependent differences were less marked compared with QCA.
Injury score and histological stent area were similar
between dose subgroups. There was substantial injury in all groups
(injury scores 1.5 to 1.6). Lumen area, intimal area, area of stenosis,
and mean intimal thickness improved as a function of dose, with all
radiation groups significantly different from control groups. At 29 Gy,
there was a 150% increase in lumen area and a 67% decrease in
stenotic area (22% versus 66% in controls). Similar radiation effects
were seen in the LAD and RCA.
Figure 3 plots neointimal thickness and lumen area as a
function of injury score. ANCOVA testing showed that when
injury-related effects were accounted for, the dose-dependent effects
of radiation resulted in very strong statistical differences compared
with controls (P
0.0001 for all
doses).
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Irradiation After Stenting
Table 3 summarizes the quantitative analyses for group B.
All parameters of stenosis severity improved with radiation, and most
achieved statistical significance despite the small sample size. MLD
and mean lumen diameter increased by 31% and 37%, respectively. The
mean in-stent diameter remained 17% larger than the reference
diameter, and mean late loss decreased by 54%. IVUS showed 50% and
62% decreases in intimal area and percent area stenosis, respectively.
Histomorphometry yielded a 69% reduction in intimal area, a 170%
improvement in lumen area, and a 67% decrease in stenotic area (21%
versus 65% in controls).
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Edge Effects
When groups A and B were combined, there was a
significant difference in the distribution of angiographic stenosis
location (P=0.0002). Of 14 control arteries, 11 (78%)
had 
50% stenosis involving the entire stent, whereas only 3 (21%)
had <50% stenosis. Of 31 irradiated arteries, 2 (6%) had diffuse
stenosis, whereas 8 (26%) had focal edge stenosis, and 21 (68%) had
no stenosis
(Figure 4). Of the 8 edge stenoses, 5 were distal, 2 were
proximal, and 1 involved both edges. Also, in the edge stenosis cases,
the stent/artery ratio was higher for the distal reference segment than
for the proximal reference (1.46±0.28 versus 1.15±0.10, respectively;
P=0.013).
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Figure 5 shows serial pullback IVUS measurements. In
controls, the entire stent length was narrowed relative to the proximal
and distal reference segments. In irradiated vessels, all doses
inhibited intimal thickening within the stent. At 16 Gy, however, there
was a focal zone of narrowing adjacent and immediately distal to the
stent (P=0.003 versus controls). Focal edge stenosis
was approximately as severe as the worst in-stent narrowing in
controls. The major cause was increased neointimal area
(P=0.002), whereas no change in vessel size was
observed. There was no edge stenosis with higher dose
radiation.
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2.5-mm intervals. Data are shown as mean±SE.
*P<0.05 for all radiation doses vs control;
P<0.05 for 29 Gy vs control; and
P<0.005 for 16 Gy vs
control.
Histological Effects
Figure 6 shows representative histology sections.
Table 4 summarizes the scored histological features in
group A. Control vessel neointima was highly cellular and composed
predominantly of smooth muscle cells and extracellular matrix.
Radiation had a dose-dependent negative correlation with neointimal
cellularity. At 29 Gy, the neointima was acellular and free of matrix
in 18 (56%) of 32 sections. When cellular, the predominant cell type
resembled control smooth muscle cells. The most striking effect of
radiation was an increase in fibrin surrounding the struts
(P<0.0001). At 29 Gy, there was more medial absence
and necrosis. The media was replaced with fibrin similar to the
neointimal deposits. The adventitia also tended to be thicker in
radiation-treated arteries. No differences were seen in the severity of
the inflammatory response, and the vasa vasorum appeared normal. The
adjacent myocardium was free of fibrosis. Histological sections from
group B control and irradiated vessels after 2 months were
indistinguishable from respective group A sections. Sections 48 hours
after radiation showed widely patent stents with circumferential
acellular fibrin surrounding the struts and adhering to the adjacent
vascular wall. Media was absent for 30% to 50% of the circumference
consistent with balloon overstretch injury. The adventitia was
thickened and contained diffuse infiltration with acute and chronic
inflammatory cells.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present report evaluates a new liquid-filled 188Re balloon system in a porcine coronary oversized stent injury model using 3 independent analytical tools: QCA, IVUS, and histomorphometry. Radiation before stenting produced a dose-dependent reduction of intimal thickening at 4 weeks. Improvement was documented in every index of lumen patency, whether measured as an absolute dimension or a ratio indexed to a reference diameter or area. There was a measurable effect at 16 Gy that improved stepwise with higher doses. At 29 Gy, the stenotic area improved from a control of 66% to 22%. These data are consistent with the previously reported experience of Waksman et al,4 albeit at different dose prescriptions.
Neointimal thickness was proportional to local mechanical injury in controls. When the effects of injury were accounted for by ANCOVA testing, the radiation was more statistically differentiated from controls. Radiation was effective over the broad range of injury scores. Most irradiated sections had substantially less intimal thickening than did control sections; however, a minority of the irradiated sections were indistinguishable from the control sections, both morphometrically and histologically. We suspect that these irradiated proliferating segments received a lower dose because of the difficulty of positioning the 17-mm stent precisely in the middle of the 20-mm irradiated zone. This, along with the edge effects, may explain why maximum late loss was not reduced as impressively as mean late loss. Even so, the overall effects of radiation were strong, and the 3 analytical methods were in close agreement.
Irradiating after stent placement remains controversial.
Wiedermann et al5
showed that irradiating after stenting was less effective by use of a
source. Amols et
al6 showed that the
type of stent, its metallic composition, and design geometry modify
dosimetry. In group B, radiation after stenting with a moderately
radiopaque thick-walled stent did not interfere with the biologic
effect. According to
Figure 2
, the actual dose to tissue at a depth 0.5 mm from
the external surface of the stent was 23 Gy, or a 21% dose reduction
due to stent attenuation and standoff thickness of 0.008
inches.
The histological signature of successful radiation therapy was persistence of neointimal fibrin from early after stenting (2 days) to 30 and 60 days after stenting. Radiation had no effect on inflammatory cell infiltration or foreign body reaction around the struts. The vasa vasorum and adjacent myocardium appeared normal. Other histological correlates of radiation were medial fibrin and adventitial thickening.
The 32P Stent (Isostent) and the 90Sr BetaCath (Novoste) have been associated with restenosis at the ends of the radiation zone, creating a candy wrapper–like appearance.7 8 There are data in balloon-injured porcine arteries showing that lower dose radiation may promote proliferation, thus suggesting that border zone restenosis may be secondary to insufficient dose.9 10 11 The present study systematically evaluated the border zones by QCA and IVUS. With radiation, the smallest lumen diameter tended to be at the distal portion of the stents compared with diffuse in-stent restenosis seen in controls. Higher stent/artery ratios at the distal part of the stent may create more mechanical injury at the distal edge. At 16 Gy, a highly focal (<5-mm) segment just distal to the stent was significantly narrowed because of exaggerated intimal thickening. One hypothesis is that an insufficient radiation dose paradoxically enhances proliferation in the presence of severe vascular injury. These observations may also be an artifact of the short effective length of the irradiating balloon versus the stent (18 versus 17 mm) and any misalignment between these 2 zones. These data suggest that understanding the nature, severity, and mechanism of border zone phenomena will be an important area of future research.
Although the radiation delivery system was safe and
efficacious in an animal model, there are several limitations that
should lend caution to any inference about clinical efficacy. The
porcine coronary model has no atherosclerosis, there was severe
mechanical injury from oversized stenting, and the follow-up period was
short. These considerations notwithstanding, a
188Re balloon incorporates many of the
features that may enhance the feasibility and potentially clinical
efficacy compared with other brachytherapy systems. The high ß energy
and short half-life help achieve a low relative surface dose and short
treatment times. At 150 mCi/mL, 3 to 6 minutes of inflation is
required, depending on the balloon diameter. The emissions aid
calibration and detection of picocurie–sized leaks with a Geiger
counter. The isotope generator has a 2-month half-life and can be
automated, and per-patient costs can be kept low. Waste management
requires holding radioactive material for 1 week (10 half-lives) and
then discarding it as biohazard waste. The primary advantages of a
balloon-based system are precision dosimetry and ease of delivery. The
source is centered with respect to the lumen, and the dose distribution
is homogeneous in both axial and radial dimensions. Circumferential
wall contact minimizes stent strut shadows, and IVUS dimensioning is
not required to limit the dose to the nearest
target.12 The device
is 6F guide catheter compatible and is applicable in small, distal, and
tortuous vessels reachable with modern low-profile PTCA
balloons.
Specific design features and methodology for use emphasize safety. Redundant seals prevent radiation leaks at the ISAT-catheter interface. The pressure-limiting valve restricts inadvertent overpressurization of the balloon to >4 SDs below the mean burst pressure of the balloon. The isotope has a short half-life, and urinary excretion can be enhanced by diuresis. Although perrhenate is concentrated 10- to 100-fold in the thyroid, stomach, large intestine, and bladder wall, treatment with oral perchlorate reduces these organ doses to average whole-body levels.13 14
Preliminary experience with a 188Re balloon intravascular brachytherapy device in a porcine coronary stent model suggests that radiation reduces restenosis in a dose-dependent fashion, as evaluated by QCA, IVUS, and histomorphometry. Radiation was equally effective when given before or after stent placement. Restenosis at the borders of the irradiated segment is a potential limitation. Persisting neointimal fibrin was associated with reduced cellular proliferation and matrix deposition. Radiation exposures were acceptable for day-to-day usage in the cardiac catheterization laboratory.
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Acknowledgments |
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This study was supported by a grant from United States Surgical, Inc.
Received November 23, 1999; revision received July 11, 2000; accepted July 13, 2000.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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-
Kastrati
A, Schömig A, Elezi S, et al. Predictive factors of restenosis
after coronary stent placement. J Am Coll
Cardiol. 1997;30:1428–1436.[Abstract]
-
Burns WA,
Bretschneider AM, Morrison AB. Embedding in large plastic blocks:
diagnostic light and potential electron microscopy on the same block.
Arch Pathol Lab Med. 1979;103:177–179.[Medline]
[Order article via Infotrieve]
-
Schwartz
RS, Murphy JG, Edwards WD, et al. Restenosis after balloon angioplasty:
a practical proliferative model in porcine coronary arteries.
Circulation. 1990;82:2190–2200.
[Abstract/Free Full Text]
-
Waksman
R, Robinson KA, Crocker IR, et al. Intracoronary radiation before stent
implantation inhibits neointima formation in stented porcine coronary
arteries. Circulation. 1995;92:1383–1386.
[Abstract/Free Full Text]
-
Wiedermann
JG, Marboe C, Amols H, et al. Intracoronary irradiation fails to reduce
neointimal proliferation after oversized stenting in a porcine model.
Circulation. 1995;92(suppl I):I-146.
Abstract.
-
Amols HI,
Trichter F, Weinberger J. Intracoronary radiation for prevention
of restenosis: dose perturbations caused by stents.
Circulation. 1998;98:2024–2029.
[Abstract/Free Full Text]
-
Albiero
R, Di Mario C, De Gregorio J, et al. Intravascular ultrasound (IVUS)
analysis of b-particle emitting radioactive stent implantation in human
coronary arteries: preliminary immediate and intermediate-term results
of the Milan study. Circulation. 1998;98(suppl
I):I-780. Abstract.
-
King SB
III, Klein JL, Bonan R, et al. The Beta Restenosis Trial: updated
results and subgroup analysis. Circulation.
1998;98(suppl I):I-651. Abstract.
-
Waksman
R, Robinson KA, Crocker IR, et al. Endovascular low-dose irradiation
inhibits neointima formation after coronary artery balloon injury in
swine: a possible role for radiation therapy in restenosis prevention.
Circulation. 1995;91:1533–1539.
[Abstract/Free Full Text]
-
Weinberger
J, Amols H, Ennis RD, et al. Intracoronary irradiation: dose response
for the prevention of restenosis in swine. Int J Radiat Oncol
Biol Phys. 1996;36:767–775.[Medline]
[Order article via Infotrieve]
-
Giedd
KN, Amols H, Marboe CC, et al. Effectiveness of beta-emitting
liquid-filled perfusion balloon to prevent restenosis.
Circulation. 1998;96(suppl I):I-220.
Abstract.
-
Teirstein
PS, Massullo V, Jani S, et al. Catheter-based radiotherapy to inhibit
restenosis after coronary stenting. N Engl J
Med. 1997;336:1697–1703.
[Abstract/Free Full Text]
-
Kotzerke
J, Fenchel S, Guhlmann A, et al. Pharmacokinetics of
99Tcm-pertechnetate and
188Re-perrhenate after oral administration
of perchlorate: option for subsequent care after the use of liquid
188Re in a balloon catheter. Nucl
Med Commun. 1998;19:795–801.[Medline]
[Order article via Infotrieve]
-
Hausleiter
J, Li A, Knapp FF, et al. Low body exposure in case of radioactive
balloon leakage: a biodistribution and elimination study of 188 Rhenium
in pigs. J Am Coll Cardiol. 1999;33(suppl
2):44A. Abstract.
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