(Circulation. 1996;93:529-536.)
© 1996 American Heart Association, Inc.
Articles |
Inhibition of Neointimal Proliferation With Low-Dose Irradiation From a ß-Particle–Emitting Stent
From the Cardiology Service, Walter Reed Army Medical Center, Washington, DC; The Armed Forces Institute of Pathology, Washington, DC; Boston Scientific Corporation, Watertown, Mass (S.H.N.); IsoStent Inc, Dayton, Md (R.E.F., D.R.F.); and the Division of Cardiology, Vanderbilt University School of Medicine, Nashville, Tenn (T.A.F.).
Correspondence to John R. Laird, MD, Cardiology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001. E-mail 73354.3062@compuserv.com.
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Abstract |
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Background Restenosis after successful percutaneous transluminal coronary angioplasty is the major factor limiting the long-term effectiveness of this procedure. Neointimal proliferation in response to arterial injury is an important contributor to restenosis. The use of radiation for the treatment of malignant and benign proliferative conditions has been well established. External beam irradiation and endovascular irradiation by use of an after-loading technique have been shown to inhibit neointimal proliferation in experimental models of restenosis. The objective of this study was to investigate whether low-dose irradiation from a ß-particle–emitting stent would inhibit neointimal proliferation after placement in porcine iliac arteries.
Methods and Results Fourteen titanium-mesh stents were implanted in the iliac arteries of nine NIH miniature swine. There were seven ß-particle–emitting radioisotope stents (32P, activity level 0.14 µCi) and seven control stents (31P, nonradioactive). Treatment effect was assessed by angiography and histomorphological examination of the stented iliac segments 28 days after implantation. There was a significant reduction in neointimal area (1.76±0.37 mm2 versus 2.81±1.22 mm2, P=.05) and percent area stenosis (24.6±2.9% versus 36.0±10.7%, P=.02) within the ß-particle–emitting stents compared with the control stents. Neointimal thickness, which was assessed at each wire site, was also significantly less within the treatment stents (0.26±0.04 mm versus 0.38±0.10 mm, P=.012). Scanning electron microscopy was performed on sections from four stents. This demonstrated endothelialization of both the treatment and control stents. There was no excess inflammatory reaction or fibrosis in the media, adventitia, or perivascular space of vessels treated with the ß-particle–emitting stent compared with control vessels. At 28 days, there was no difference in smooth muscle cell proliferation as measured by the proliferating cell nuclear antigen index.
Conclusions A local, continuous source of low-dose endovascular irradiation via a ß-particle–emitting stent inhibits neointimal formation in porcine arteries. This low dose of local irradiation did not prevent endothelialization of the stents. This novel technique offers promise for the prevention of restenosis and warrants further investigation.
Key Words: restenosis • ß-particle • radiation • stents
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Restenosis occurs in approximately 30% to 50% of cases after successful PTCA and is the major factor limiting the long-term effectiveness of this procedure.1 2 3 4 5 There is clinical and experimental evidence to suggest that restenosis results from a complex interaction between early elastic recoil, arterial remodeling, and neointimal formation. Neointimal formation is an important contributor to this process, particularly after intracoronary stent placement, and results from the migration and rapid proliferation of a subset of predominantly medially derived SMCs. These cells proliferate as a response to catheter-induced mechanical injury and stimulation by a variety of growth factors and cytokines.6 7 8 9 Experimental models of arterial injury have demonstrated that these cells begin proliferating within the first week after injury and return to baseline levels of proliferation within 1 to 2 months.10 11 12 13 This early proliferation is followed by the elaboration of an extracellular matrix that further contributes to neointimal formation and ultimately results in narrowing of the arterial lumen.
Numerous trials in humans with a variety of pharmacological agents have
failed to demonstrate a reduction in the incidence of
restenosis.8 The use of radiation for the
treatment of malignant and benign proliferative conditions has been
well established. Low-dose external beam irradiation has been shown
to inhibit keloid formation after
surgery14 15 16 17 and
heterotopic ossification after total hip
arthroplasty.18 19 20 This safe and
effective use of
radiation therapy for benign proliferative conditions has led several
investigators to test whether local irradiation might inhibit SMC
proliferation after arterial injury. A single dose of
external beam irradiation has been tested and was shown to be effective
in two different experimental models of
restenosis.21 22 Several investigators have
demonstrated that gamma irradiation by use of an endovascular
after-loading technique can successfully inhibit
neointimal proliferation in a porcine coronary
injury model.23 24 25 These investigators
used a
192Ir source to deliver an endovascular dose from 350 to
2500 cGy either immediately before, after, or within a few days of
balloon injury. A dose-response relationship was demonstrated, with
the greatest effect seen at higher doses (
1400 cGy).
Intraarterial beta irradiation at a dose of 1800 cGy
has also been shown to be effective in a model of
hypercholesterolemic rabbit
restenosis.26 Hehrlein et al27 28
showed that a radioactive stent can inhibit neointimal
proliferation after implantation in nondiseased rabbit iliac arteries.
They used a stainless steel stent (Palmaz-Schatz, Johnson & Johnson
Interventional Systems) made radioactive by proton bombardment in a
cyclotron with a resulting array of gamma- and
ß-particle–emitting radionuclides 55,56,57Co,
52Mg, and 55Fe. These radionuclides have a
half-life between 17.5 hours and 2.7 years. At 4 and 12 weeks after
stent implantation, there was almost complete inhibition of
neointimal proliferation in this model.
The previously described techniques suffer somewhat from impracticality as well as questions of safety regarding the use of gamma irradiation and radionuclides of such long half-life. ß-Particle irradiation with 32P offers the advantages of no associated gamma radiation, a short half-life (14.3 days), and limited range of the ß-particles in tissue (3 to 4 mm). This should essentially eliminate the risk to catheterization laboratory personnel and minimize the exposure of surrounding cardiac and pulmonary tissue to ionizing radiation. The objective of the current study was to investigate whether low-dose ß-particle irradiation from a 32P-impregnated stent could inhibit neointimal proliferation after implantation in porcine iliac arteries.
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Methods |
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Stent Preparation
The stents used in the present study are a modification of the Strecker Stent (Boston Scientific Corp). The design consists of a single filament of polished titanium wire, 0.125 mm in diameter, woven into a flexible mesh tube. The stents were 20 mm in length with an expanded diameter of 5 mm. After stent fabrication, the nonradioactive element 31P was ion-implanted beneath the outer surface of the titanium wire (Spire Corp). Ion implantation was accomplished by placing the 31P into a special vacuum apparatus, then vaporizing, ionizing, and accelerating the ions with a high voltage so that the 31P atoms became buried beneath the surface of the titanium wire.
The stents were then made radioactive by placement in the core of an experimental nuclear reactor at the Massachusetts Institute of Technology. They were exposed for several hours to a flux of slow neutrons. Neutron irradiation caused approximately 1 of every 100 000 31P atoms to be converted into 32P, the pure ß-particle emitter with a maximum energy of 1.709 MeV, an average energy of 0.695 MeV, and a half-life of 14.3 days. The reaction is given by the simple equation 31P+N=32P, where N indicates neutron. This technique results in even distribution of 32P within the stent wire, which ensures uniform delivery of ß-particle irradiation into the vessel wall. After a period of approximately 10 days, the radiation from other short-lived isotopes created by neutron bombardment of the titanium base metal becomes undetectably low. Spectroscopic measurements indicated that no other long-lived radionucleotides were created. The radioactive stents were mounted onto balloon catheters (Boston Scientific Corp). The assembly was then packaged and gamma-ray sterilized in the conventional manner. The control stents were fabricated in a manner identical to the radioisotope stents except that they were not placed in a reactor, so that no atoms of 31P were converted to 32P.
After each radioactive
stent was placed over the deflated balloon of
the balloon angioplasty catheter, a cylindrical acrylic resin radiation
shield with an OD of 16 mm, an ID of 2.2 mm, and a wall thickness of
6.9 mm was placed over the stent. Radiation detectors placed outside
each shield indicated no increase in radiation activity above
background levels. The shield was designed so that its distal end could
be advanced into the elastomer gland of a Tuohy-Borst "Y"
adapter. With the shield in place, the stent could be advanced through
the Tuohy-Borst adapter into the guiding catheter without exposing the
operator to any radiation from the stent (Fig 1
).
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After
removal from the reactor, each stent had an activity level of
approximately 0.4 µCi. The activity level of each stent was measured
with a gas-filled proportional-counting device. This detection
system has been well described previously.29 The stents
were implanted 20 days after removal from the reactor when the
radiation level had decreased to an average value of 0.14 µCi for all
the stents. The radiation levels at implantation were determined by
calculations that used the known half-life for 32P
(14.3 days) and the following equation:
At=A0x2-t/
,
where At is the activity level at the time t (µCi),
A0 is the initial activity level (µCi), t is time (days),
and is the half-life of the radioisotope (days). The use of a
5-mm-diameter stent with an activity level of 0.14 µCi resulted
in a calculated total radiation dose at the surface of the stent wires
(over the lifetime of the isotope) of approximately 300 cGy. The
radiation dose delivered over the 28-day study period was equivalent to
three fourths of the total radiation dose. The dose to tissue versus
radial distance outward from the stent wires (both total and 28-day
dose) is plotted in Fig 2. The calculations of dose
distribution were performed by use of the dose-point-kernel
method, which has been described previously.30 This method
uses several assumptions, including the assumption that the source is a
uniform cylinder. A calculated dose was compared with a directly
measured dose for an unexpanded, 2.1-µCi, 2.2-mm-diameter,
2-cm-long titanium-mesh stent (Fig 3). There was
good correlation between the directly measured and calculated radiation
doses.
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Animal Preparation
The animal work was approved by the
institutional scientific
review committee and conformed with the position of the American Heart
Association on animal research. Fourteen stents (seven control, seven
32P-impregnated) were implanted in the right and/or left
external iliac arteries of nine NIH miniature swine (weight, 20 to 30
kg) fed a normal chow diet. The animals were medicated with aspirin
(650 mg) and extended-release nifedipine (30 mg)
(Pfizer Laboratories Division) by mouth the evening before stent
placement. Ketamine (20 mg/kg IM) and xylazine (4 mg/kg IM)
were used for induction of anesthesia. General
anesthesia was maintained by use of an
intravenous fentanyl infusion (Elkins-Sinn) at a rate of 40
µg/kg per hour. A 9F sheath was placed retrograde in the right
carotid artery. A bolus of heparin (150 U/kg) was administered
intraarterially. The activated clotting time
(Hemochron, Intl Technidyne) was measured to ensure a minimal value of
300 seconds for stent placement. Distal aortic and iliac angiography
with 66% meglumine diatrizoate and 10% sodium diatrizoate
(Hypaque-76, Sanofi Winthrop) was performed with a 9F multipurpose
guiding catheter placed at the aortic bifurcation. The proximal iliac
artery was engaged with the guiding catheter. A 0.014-in
high-torque floppy guide wire (Advanced
Cardiovascular Systems) was advanced to the femoral
artery under fluoroscopy. The guiding catheter was used as a reference
for stent sizing in an attempt to achieve a balloon (stent) to artery
ratio just >1.0. Placement of the titanium-mesh stent (5.0 mm
diameter, 20 mm length) was completed, after advancing the
prosthesis over the guide wire to the desired site, with two
balloon inflations at 8 atm for 30 seconds. This procedure was then
repeated for stent placement in the opposite iliac artery. Angiography
was completed after placement to confirm patency. The animals were
allowed to recover and were returned to care facilities. All animals
remained on a normal laboratory diet and received aspirin (81 mg) daily
by mouth. The animals were returned to the research
catheterization laboratory for angiography 28 days
after implantation. After completion of follow-up angiography, the
animals were euthanatized with a lethal dose of a barbiturate.
Pathological Evaluation
The iliac arteries were isolated and
perfusion fixed with an
ethanol-based fixative (Histochoice; Amresco) at 60 to 80 mm Hg for
30 minutes via a catheter positioned in the distal aorta. The distal
aorta and iliac vessels were then carefully removed and placed in
fixative. The stented arterial segments were sectioned
transversely into 2-mm segments. Sections from the proximal, mid, and
distal portion of the stent were embedded in paraffin and cut with a
carbide knife at 4 to 5 µ. The sections were stained with
hematoxylin-eosin and Movat pentachrome stains. The
cross-sectional area of each section was measured with digital
morphometry to determine area within the external elastic lamina, the
IEL, the media, and the residual vessel lumen. The area within the IEL
was considered the normal lumen area. The percent area stenosis
was then defined as: [(IEL area-residual lumen area)/IEL
area]x100. Neointimal area was determined by subtracting
the area of the residual lumen from the area within the IEL. A mean
value for each area within the stented arterial segment was
derived from the proximal, mid, and distal measurements.
The vessel injury score was determined by the method used by Schwartz et al.31 In brief, the degree of injury at each wire site was assessed as follows: grade 0, IEL intact with media compressed; grade 1, IEL lacerated with media compressed; grade 2, IEL and media lacerated with the external elastic lamina intact; and grade 3, external elastic lamina lacerated. Neointimal thickness was measured at each wire site. The mean injury score for each arterial segment was calculated by dividing the sum of injury scores at each wire site by the total number of wires from the midstent sections. In addition to the mean injury score, the degree of stent oversizing (stent to artery ratio) was determined with quantitative angiography.
Quantification of SMC Proliferation
Stent wires were carefully removed from adjacent tissue sections
of each arterial segment. The segments were dehydrated in
graded series of alcohol and embedded in paraffin, and multiple
sections were cut at 4 to 5 µ. The sections were stained with
monoclonal antibodies to 
-smooth muscle actin and PCNA. In
brief, slides were deparaffinized and pretreated with antigen
pretreatment solution (BioGenex Labs) for 5 minutes. The slides were
then incubated with 10% normal horse serum followed by incubation with
mouse anti-human PCNA antibody (Dako), 1:40 dilution, for 60
minutes. Biotinylated horse anti-mouse IgG was used as the
secondary antibody, and the detection system used was the Vectastain
Elite ABC kit (Vector Labs, Inc). Slides were counterstained lightly
with hematoxylin. A section of tonsil served as a positive control for
each series of immunohistochemical staining for PCNA. The total number
of cells and the number of PCNA-positive cells per high-power field
were counted from three randomly selected regions of each section. Only
cells with distinct nuclear PCNA staining were considered positive. At
least 50 cells per high-power field were manually counted for a
minimum total of 150 cells per section to derive a PCNA index
(percentage of PCNA positive cells=number of PCNA positive cells/total
number of cellsx100%). Actin staining followed the same procedure as
above with mouse anti-human -smooth muscle actin antibody
(Sigma Chem Co) in a 1:5000 dilution.
Scanning Electron Microscopy
Segments were selected from four
control and four
ß-particle–stented arteries, sectioned longitudinally,
rinsed in three changes of sodium phosphate for 15 minutes each, then
fixed in 1% osmium tetroxide for 1 hour and rinsed in distilled water.
The specimens were then dehydrated in a series of graded ethanols (50%
to 100%) for 15 minutes. After critical point drying, the specimens
were mounted, placed in a vacuum coater, and coated with a 30- to 40-nm
layer of gold for scanning electron microscopy.
Quantitative Angiography
The angiograms were analyzed with
electronic digital
calipers with use of the guiding catheter as a reference standard. The
baseline and postimplant artery diameters (data expressed in
millimeters) were measured at midstent from nonoverlapped and
nonforeshortened views. The acute stent to artery ratio (midstent lumen
diameter/baseline lumen diameter) was calculated from these data for
each vessel to provide an estimate of stent oversizing as a measure of
arterial injury.
Statistical Analysis
For each of the 14 arterial segments in
the study,
the stent to artery ratio, mean injury score, neointimal
thickness, neointimal area, medial area, and percent area
stenosis were determined. All data are expressed as mean±SD.
Lesion morphology and PCNA index scores were compared for the control
and radioactive stents by use of ANOVA with Scheffé's F test for
multiple comparisons. A value of P<.05 was considered
significant. All statistics were calculated with Statview 4.0
(Abacus).
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Results |
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Fourteen titanium stents were placed in the external iliac arteries of nine pigs (Table 1
). There were 7 control
stents and 7 treatment stents. All 14 stents were deployed without
complication and each of the animals survived to 28 days. Follow-up
angiography demonstrated 100% patency of the stents. The radioactive
stents had an activity of 0.14 µCi at the time of implantation, with
a calculated total dose over the lifetime of the isotope of
approximately 300 cGy delivered at the surface of the stent wires. The
dose delivered during the 28-day study period was equivalent to three
fourths of the total lifetime dose.
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Histopathology
As previously described, attempts were made to
size the stents
just >1:1 to the treatment vessel. There was no difference in the
stent to artery ratio between the treatment and control stents
(1.01±0.03 versus 1.02±0.08, P=.86). Review of
the
histological sections revealed no difference between
the treatment and control groups with regard to vessel injury (grade 0
for all sections). The IEL was intact in each case.
There was a
statistically significant reduction in
neointimal area (1.76±0.37 mm2 versus
2.81±1.22 mm2, P=.05) and percent area
stenosis (24.6±2.9% versus 36.0±10.7%, P=.02) in
the ß-particle emitting–stents compared with control stents.
There was a trend toward an increase in lumen area in the treatment
group (5.38±0.75 mm2 versus 4.68±0.55
mm2, P=.07) (Table 2).
Neointimal thickness was assessed at each wire site, and
the mean neointimal thickness was also significantly less
within the ß-particle–emitting stents compared with the
control stents (0.26±0.04 mm versus 0.38±0.10 mm,
P=.01).
There was no difference in the size of the vessels as measured by the
area within the external elastic lamina and IEL (Fig 4).
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Review of the histological sections from both the
treatment and control stents demonstrated neointimal
proliferation with a predominant population of spindle-shaped cells
staining positive for -actin. These SMCs were haphazardly
arranged near the stent wires with abundant extracellular matrix. At
the lumen surface, the SMCs were more circumferentially organized and
had a higher cellular density compared with cells adjacent to the stent
wires (Fig 5). The IEL was intact in all sections,
indicating an absence of deep vessel wall injury. There was mild
compression of the media with minimal medial SMC necrosis. Scattered
inflammatory cells were present adjacent to stent wires (Fig 5B
and 5D). The degree of inflammatory reaction was minimal and
similar at the
site of ß-particle and control stent wires. There was no excess
fibrosis in the media, adventitia, or perivascular space of the vessels
treated with a ß-particle–emitting stent compared with
control vessels.
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The percentage of PCNA-positive cells was measured in a midstent section from each stent at 28 days. The mean cell proliferation index was similar for the treatment and control stents (2.15±0.91% versus 3.95±4.21%, P=.44). Cell density was also measured within the same sections and was similar between the two groups (362±42 versus 349±45 cells per high-power field, P=.46).
Scanning electron microscopy demonstrated
complete
endothelialization of all control and treatment stents
except at the proximal and distal ends of the stents over protruding
wire loops. The stents were covered with a population of immature,
cobblestone-shaped endothelial cells (Fig 6).
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Discussion |
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The rationale for use of irradiation to inhibit neointimal proliferation is based on the enhanced sensitivity of actively proliferating cells to the lethal effects of ionizing radiation. When the cell nucleus is exposed to ionizing radiation, DNA mutations and chromosome aberrations can occur. The ability of the cells to replicate is impaired, and ultimately cell death results. Radiation has been shown to inhibit benign "hyperplastic" responses such as keloid formation after surgery, fibroblast-mediated obliteration of filtering blebs after glaucoma surgery, and heterotopic ossification after total hip arthroplasty.14 15 16 17 18 19 20 32 More recently, several investigators showed that external beam x-irradiation and endovascular gamma irradiation with an after-loading technique can inhibit neointimal proliferation in experimental models of restenosis.21 22 23 24 25 There was also one clinical study33 that demonstrated a beneficial effect of endovascular irradiation on restenosis in the peripheral circulation after stenting. Only one experimental study34 failed to show a beneficial effect of radiation on the restenotic process. Schwartz et al34 found that x-irradiation actually modestly increased the neointimal proliferation seen after oversized stent placement in porcine coronary arteries. This negative result possibly was due to methodological differences, which included the use of relatively low radiation doses in the setting of more extensive vessel injury.
In the current study, we have shown that low-dose irradiation from a ß-particle–emitting stent inhibits neointimal proliferation after stent placement in porcine iliac arteries. There was a 37% reduction in neointimal area and a 32% reduction in percent area stenosis for ß-particle–emitting stents compared with control stents at 28 days in this model.
Rationale for Use of a ß-Particle–Emitting Stent
The use of a ß-particle–emitting stent to deliver
low-dose irradiation to the vessel wall offers several advantages
over previously described techniques for endovascular irradiation. Use
of a radioactive stent couples the radiation therapy to a platform with
a known benefit for the prevention of
restenosis.35 36 Mechanical factors such as
ineffective dilatation, early elastic recoil, and chronic remodeling
contribute to restenosis and would not likely be affected
by the radiation therapy alone. Endovascular after-loading
represents an alternative method for intravascular irradiation.
This technique requires that a special radioactive catheter or wire be
advanced across the lesion before PTCA, immediately after PTCA, or
within a few days of the procedure to deliver the 192IR
source. This might result in significant ischemia if performed
before PTCA and in dissection or vessel trauma if performed sometime
after the dilatation. Because the delivery catheter may not always be
centered within the vessel lumen, there will be nonuniformity of dose
delivery into the vessel wall. This may range from 0.6x to 2.9x
the
prescribed dose.24 In addition, these after-loading
devices are costly, require handling of highly radioactive sources (0.2
to 10 Ci), and may require isolation of patients when gamma radiation
is used.
ß-particles have a limited effective range in tissue
(
95% of
the particles are absorbed within 3 to 4 mm) and thus minimize the risk
of radiation exposure to surrounding cardiac or pulmonary
tissue. The radiation exposure to the interventionist implanting such a
device and to technicians in the catheterization
laboratory will be essentially zero. The total dose of radiation
required from a 32P source to inhibit
neointimal proliferation appears to be small. Previous in
vitro work has shown that ß-particle irradiation from a
32P-impregnated stent wire with an activity as low as 0.006
µCi/cm of wire results in complete inhibition of SMC proliferation
within 6.0 mm of the wire in cell culture.29 In the
current study, stents with an activity of 0.14 µCi, resulting in a
28-day tissue dose of approximately 210 cGy at the stent surface,
proved effective in inhibiting neointimal proliferation. On
the basis of prior published in vivo studies, it is likely that higher
doses of radiation from a ß-particle–emitting stent could
provide further inhibition of neointimal
proliferation.24
Endovascular Radiation to Inhibit Neointimal
Formation
Various factors affect the radiation damage in a cell and
hence
the cell survival curve. The total dose, dose rate, linear energy
transfer of the radiation, presence of chemical molecules, and stage of
the cell cycle all affect the survival curve.37 The total
radiation dose delivered in this model was low relative to previous
models and in a range that might not be expected to result in cell
death. Also, the dose rate was very low. Why then was this low-dose
ß-particle irradiation effective in decreasing
neointima formation? The radiation was delivered constantly
over a period of time during which it is known that SMCs in the intima
and media are undergoing rapid proliferation. Thus, although a lethal
dose of radiation is not given, this constant, low-dose radiation
therapy may impair cell proliferation (static effect) without producing
cell death (lethal effect) in all SMCs. In addition, this low-dose
radiation may have other, unknown effects. Fischell et
al29 demonstrated that ß-particle irradiation from
32P-impregnated wire resulted in a zone of inhibition of up
to 10.6 mm when placed in a cell culture of proliferating SMCs. Since
very few ß-particles could reach a range of 8 to 10 mm in
cell culture, it is conceivable that very low (sublethal) doses of
ß-particle irradiation may also inhibit SMC migration.
An important question regarding the use of radiation to inhibit neointimal hyperplasia is whether reendothelialization of the stents will also be inhibited. A delay in reendothelialization could, theoretically, adversely affect the risk of subsequent stent thrombosis. In cell culture, proliferating bovine endothelial cells are less sensitive to the effects of ß-particle irradiation than are rat or human SMCs.29 In the current study, endothelialization of the radioactive stents was evident by scanning electron microscopy 4 weeks after stent implantation. There was no noticeable difference with regard to endothelial cell growth within the treatment stents compared with control stents. Importantly, there was no stent thrombosis in the present study. Our data are consistent with preliminary work by Hehrlein et al,27 who showed nearly complete inhibition of neointimal hyperplasia, endothelial regrowth at 4 weeks, and no increase in thrombotic complications after implantation of radioactive stents.
The use of radiation to inhibit neointimal proliferation does not appear to only postpone the restenotic process. Both Wiederman et al38 and Waksman et al24 demonstrated that the beneficial effect of endovascular irradiation was well maintained at 6-month follow-up in the porcine coronary model. C. Hehrlein, MD, (personal communication) has obtained follow-up at 1 year after use of radioactive stents in rabbit iliac arteries; the initial beneficial effect of radiation therapy was still present at 1 year. Because the degree of vessel injury and the type and method of radiation delivery differ in the current study, further study is required to assess the long-term effect of irradiation with this model. The use of fractionated dosing, with a total tissue dose less than that given as a single dose with the after-loading technique, would be expected to result in improved long-term safety.37
In the current study, we used the PCNA index to quantify SMC proliferation at 28 days after stent implantation. There was no significant difference in PCNA index between the treatment and control groups. Although this is a single measurement at a single point in time, it demonstrates that there is no delayed (rebound) SMC proliferation at 28 days after implantation of a radioactive stent with a short-lived radioisotope.
Biocompatibility of Stents Modified to Deliver
Radiation
Modification of a metallic stent surface may alter the
mechanical
performance of the device or its blood and tissue
biocompatibility. Polymer-coated stents designed to reduce
thrombogenicity and provide a local method for drug delivery have been
limited by problems with chronic tissue compatibility. Severe
neointimal formation has been seen after implantation of
these devices in porcine coronary arteries.39 40
The ion implantation technique to render the stent radioactive is
highly desirable in that it does not require the use of a potentially
biologically active substance, such as a biodegradable polymer, to
deliver the endovascular radiation. The absence of a significant
foreign body reaction or evidence of a greater degree of vascular
injury by the ß-particle–emitting stent indicates acceptable
tissue compatibility. The present stent modification techniques may
alter the surface charge of the metal, thus affecting the risk for
thrombosis. Although stent thrombosis did not occur in this study,
further analysis of stent surface characteristics is
required.
Study Limitations
The present study is limited by the use of
a single radiation
dose and the small number of stents. Although the dose selected for
this study was based on prior in vitro analysis and
represented an effective dose to inhibit SMC proliferation
without preventing endothelial cell growth, additional
study is required to define an optimal in vivo dose. As previously
suggested, higher doses could provide more effective suppression of
neointimal growth.24 These stents were
implanted in normal arteries. In addition, stent placement was not
associated with any significant vessel injury. This model differs from
other models in which a proliferative response is invoked by more
severe damage to the vessel wall. The dose and duration of endovascular
radiation required to reduce neointimal formation in
atherosclerotic vessels or vessels with more severe, deep injury may be
different. The contribution of thrombus to the neointimal
response in this model is also unknown. Larger studies with
long-term follow-up will be required to confirm the persistence
of this inhibitory effect on neointimal
formation and to ensure the long-term safety of this technique.
Further studies of lesion formation and SMC proliferation after
coronary intervention are also necessary to enable selection of
the appropriate radioisotope and dose for clinical studies.
In summary, the present study demonstrates that a locally applied continuous source of low-dose endovascular radiation via a ß-particle–emitting stent inhibits neointimal formation after stent implantation in porcine arteries. This novel therapy may have a significant impact on stent restenosis and warrants further investigation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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The study was funded in part by a grant from IsoStent Inc, Dayton, Md, and from the Department of Clinical Investigation at Walter Reed Army Medical Center. The stents were provided by Boston Scientific Corporation, Watertown, Mass. The authors thank Lynn Bailey, Russ Jones, and Roger Hillhouse for their expert technical assistance in the research laboratory. Dennis M. Duggan, PhD, and Charles W. Coffey II, PhD, provided valuable assistance with dosimetry.
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Footnotes |
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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.
R.E.F., D.R.F., and T.A.F. are inventors of the concept of a ß-particle–emitting stent and have a financial interest in the device.
Received June 5, 1995; revision received August 10, 1995; accepted September 18, 1995.
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References |
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TopAbstractIntroductionMethods Results Discussion References |
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