(Circulation. 2000;102:1434.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
From the Thoraxcenter (I.P.K., M.S., M.A.C., K.K., M.A., W.J.v.d.G., A.J.W., J.M.R.L., P.W.S.) and the Daniel den Hoed Cancer Center (V.M.A.C., P.C.L.), Rotterdam, the Netherlands.
Correspondence to P.W. Serruys, MD, PhD, FACC, FESC, Professor of Interventional Cardiology, Department of Interventional Cardiology, Bd 418, Thoraxcenter, Academisch Ziekenhuis Rotterdam, PO Box 1738, Dr. Molewaterplein 40, 3000 DR Rotterdam, Netherlands. E-mail serruys{at}card.azr.nl
| Abstract |
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Methods and ResultsWe analyzed remodeling in 18 patients after conventional stent implantation, 16 patients after low-activity radioactive stent implantation, 16 patients after higher activity radioactive stent implantation, and, finally, 17 patients who underwent catheter-based radiation followed by conventional stent implantation. Intravascular ultrasound with 3D reconstruction was used after stent implantation and at the 6-month follow-up to assess remodeling within the stent margins and at its edges. Preprocedural characteristics were similar between groups. In-stent neointimal hyperplasia (NIH) was inhibited by high-activity radioactive stent implantation (NIH 9.0 mm3) and by catheter-based radiation followed by conventional stent implantation (NIH 6.9 mm3) compared with low-activity radioactive stent implantation (NIH 21.2 mm3) and conventional stent implantation (NIH 20.8 mm3) (P=0.008). No difference in plaque or total vessel volume was seen behind the stent in the conventional, low-activity, or high-activity stent implantation groups. However, significant increases in plaque behind the stent (15%) and in total vessel volume (8%) were seen in the group that underwent catheter-based radiation followed by conventional stent implantation. All 4 groups demonstrated significant late lumen loss at the stent edges; however, edge restenosis was seen only in the group subjected to high-activity stent implantation and appeared to be due to an increase in plaque and, to a lesser degree, to negative remodeling.
ConclusionsDistinct differences in the patterns of remodeling exist between conventional, radioactive, and catheter-based radiotherapy with stenting.
Key Words: stents remodeling radioisotopes angioplasty ultrasonics
| Introduction |
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Intracoronary radiation has been developed in an attempt to decrease restenosis after BA and stent implantation. Two parallel technologies, one using radioactive stents3 4 5 6 7 and the other using catheter-based radiation,8 9 10 have been the subject of both animal and human studies. Given the different dose rates and total doses delivered by each method, one may intuitively expect different patterns of remodeling subsequent to each approach.
Whereas the effect of catheter-based radiation after BA on vascular remodeling has been described,11 the response of the arterial wall to catheter-based radiation and subsequent stent implantation has not been described. Preliminary studies have reported the effect at the stent edge after radioactive stent implantation.4 However, these reports did not encompass the response behind the stent in the arterial wall.
The aim of the present study was to describe the response of the coronary artery to radiation and stenting by examining the stent and its edges after radioactive stent implantation and also after catheter-based radiation with stent implantation.
| Methods |
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Stents analyzed were from patients with singlenative-vessel coronary artery disease, normal left ventricular function, and objective evidence of ischemia. All groups were matched for patient baseline characteristics, vessel size, lesion, and stent length. Stents placed in the ostial position or adjacent to major side branches, such that the stent edges were unable to be analyzed, were excluded from analysis. Only patients who had completed 6-month angiographic and intravascular ultrasound (IVUS) follow-up were included.
Implantation Technique
The same group of cardiologists, using a similar technique,
implanted all stents. Predilation of the lesion was performed, followed
by stent implantation with use of either a premounted stent or the
Johnson & Johnson delivery system (Johnson & Johnson Interventional
Systems Co). A balloon shorter than the stent was then selected, and
high-pressure balloon inflation was performed within the stent to
ensure good stent apposition. Intravascular ultrasound was used to
ensure optimal stent deployment.
Medication
Patients received 250 mg aspirin and 10 000 IU heparin at the
initiation of the procedure, and the activated clotting time
was maintained at >300 seconds. All patients received aspirin (80 mg
daily) indefinitely and ticlopidine (250 mg BID) for 2 weeks (C group)
or clopidogrel (75 mg daily) for 12 weeks (LA, HA, and CBS groups)
after stent implantation.
Radioactive Stents
The BX stent (Isostent Inc) was the
only radioactive stent implanted in this trial. It was 15 mm in
length and available in diameters of 3.0 and 3.5 mm. The
BX stent was made radioactive by
32P. The initial activity of the stents was
measured; thereafter, it was calculated at the date on which the
activity had decreased to 0.75 to 1.5 µCi or 6 to 12 µCi, levels
suitable for implantation.
Catheter-Based Radiation Delivery System
The Beta-Cath System (Novoste Corp) was used to deliver
localized ß-radiation
(90Sr/90Y) to a depth of
2 mm from the center of the source at the site of coronary
intervention. The device consisted of 3 components: (1) the transfer
device that stored the radiation source train and allowed the
positioning of these sources within the catheter; (2) the delivery
catheter, which was a 5F multilumen over-the-wire noncentered catheter
that used saline solution to send and return the radiation source
train; and (3) the radiation source train, which consisted of a series
of 12 independent cylindrical seeds that contained the radioisotope
90Sr sources and was bordered by 2 gold
radiopaque markers separated by 30 mm. Other device and procedural
details have been previously published by this
group.11
Definitions
Stent Edges
Stent edges were defined as those volumes axially 5 mm
proximal and distal to the final stent strut. An edge
restenosis was defined as an angiographic restenosis
>50% at 6-month follow-up located at either stent edge. An edge
effect was defined as any stent-edge renarrowing.
Patients with balloon-injured edges that failed to receive radiation in the catheter-based radiation group were excluded. In other words, no stents implanted in areas of geographical miss were included in the present study.
IVUS Image Acquisition Analysis
After the final balloon inflation and administration of
intracoronary nitrates, ECG-gated IVUS pullback was performed.
This was repeated at the 6-month follow-up.
The segment subjected to 3D reconstruction was examined with a mechanical IVUS system (ClearView, CVIS) with a sheath-based IVUS catheter incorporating a 30-MHz single-element transducer rotating at 1800 rpm. The IVUS transducer was withdrawn through the stationary imaging sheath by an ECG-triggered pullback device with a stepping motor.12 IVUS images coinciding with the peak of the R wave, which eliminates the artifacts caused by the movement of the heart during the cardiac cycle, were acquired. After each image acquisition, the transducer was withdrawn 0.2 mm to acquire the next image coincident with the R wave. The ECG-gated image acquisition and digitization was performed by a workstation designed for the 3D reconstruction of echocardiographic images12 (EchoScan, Tomtec). A Microsoft Windowsbased contour detection program, developed at the Thoraxcenter, Rotterdam, was used for the automated 3D analysis of up to 200 IVUS images.13 The feasibility, reproducibility, and interobserver and intraobserver variability of this system have been previously validated in clinical protocols.11
Quantitative IVUS Analysis
At the stent edges, the area encompassed by the lumen-intima and
media-adventitia boundaries defined the luminal volume (LV) and the
total vessel volume (TVV), respectively. The difference between LV and
TVV defined the plaque volume. TVV, stent volume,
neointimal hyperplasia (NIH), plaque behind the stent
(TVV-stent volume), and LV were obtained within the axial boundaries
of the stent.
The assessment of TVV in stented patients has previously been reported.14 Although in the previous report the delineation of TVV was not possible in some patients because of stent shadowing, in the present study the delineation of the TVV boundary was possible in all stented patients. When the TVV boundary was not visible in a single cross-sectional view, the computer extrapolated it from the contours of the previous and subsequent cross sections. In addition, the use of 3D reconstruction with multiple longitudinal views facilitates the visualization of vessel structures outside the stent.
Statistical Analysis
Quantitative data are presented as mean±SD. Volumetric
data derived from the 3D reconstruction of the IVUS imaging were
compared immediately after treatment and at follow-up by the 2-tailed
paired Student t test. Comparison between groups was
performed by 1-way ANOVA. A value of P<0.05 was considered
statistically significant.
The Medical Ethical Committee of the University Hospital Rotterdam approved the study, and all patients provided written informed consent before the procedure.
| Results |
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In-Stent Inhibition of NIH
Intrastent NIH was decreased after high-activity radioactive stent
implantation and catheter-based radiation followed by conventional
stent implantation (P=0.008). Lower activity radioactive
stents had an effect similar to that of conventional stent implantation
(see Table 4
and Figure 1
).
|
Behind Stent
The C, LA, and HA groups demonstrated an absence of remodeling
behind the stent, with no significant changes in TVV or plaque volumes.
This is in contrast to the CBS group, which demonstrated a significant
increase in plaque (immediately after treatment versus follow-up, 15%;
P=0.002) and an increase in TVV (after treatment versus
follow-up, 8%; P=0.003). Intergroup comparison showed that
this change was significant (Table 4
, P=0.01).
Further comparisons of changes within and between groups are
demonstrated in Figure 1
. No chronic recoil of the stent was
seen in any group.
Stent Edge
No significant difference between groups was seen at baseline
(after stent implantation). All groups demonstrated late lumen loss at
the stent edges. At the stent edges, remodeling is similar in the C and
LA groups. In these groups, there is evidence of a decrease in TVV,
with little change in plaque as a cause of late lumen loss (Figure 2
). In the HA group, a target segment
restenosis (angiographically >50%) was observed in 7 patients
at the stent edges. This was more common at the proximal edge (in 6 of
7 patients). The major mechanism of such a restenosis appears
to be due to an increase in plaque at the stent edge. In
nonrestenotic patients, the edge effect appears to be due to a
decrease in TVV and, to a lesser degree, an increase in plaque (Figure 3
).
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In the CBS group, the edge effect is largely due to an increase in plaque, with no negative remodeling seen (P=0.045 for plaque increase in CBS versus LA, HA, and C groups). No patient with edge restenosis after catheter-based radiation was seen in our series of patients.
Stent Activity and Dose Prescribed
Mean stent activity at implantation (LA group) was 1.1±0.3 µCi.
Mean stent activity at implantation (HA group) was 8.6±1.6 µCi. For
the CBS group, the mean dose prescribed was 16.7±2.0 Gy.
| Discussion |
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Neointimal Hyperplasia
In the present study, neointimal formation was
inhibited after higher dose radioactive stent implantation and after
catheter-based radiation plus stenting. The present study is in
contrasts to the recent study by Carter et al,16 who used
32P stents in the porcine model, but is in
keeping with earlier studies of Hehrlein et al,6 who used
the rabbit model, and recent reports by Albiero et al,4
who noted a dose-dependent inhibition of NIH.
Mechanism of Remodeling Behind the Stent
Catheter-Based Radiation
After conventional and radioactive stent implantation, little
positive or negative remodeling is witnessed behind the stent. In stark
contrast to this is the increase in plaque behind the stent and TVV
seen after catheter-based radiation and stenting. Part of the key to
understanding this process may be acquired from understanding the
healing process after BA. Wilcox and colleagues17 18
describe the presence of early proliferation of myofibroblasts
expressing contractile proteins in the adventitia surrounding the
porcine coronary artery after BA. Tracing studies have
indicated that the same cells migrate and form part of the
neointima. Wilcox and colleagues hypothesize that the
adventitial myofibroblasts constrict the artery at the angioplasty site
in much the same way as myofibroblasts participate in scar retraction
in dermal healing. The source of these myofibroblasts may be distant to
the immediate site of injury, including pericardial, adipose, and
intramyocardial layers.19
Radiation treatment of porcine coronary arteries after BA
upregulates p21 synthesis in adventitial cells, especially
myofibroblasts. Such induction is dose dependent and is sustained for
at least 7 days after radiation. Additionally, radiation inhibits the
expression of growth factors, reduces the proliferation of adventitial
myofibroblasts, and decreases the production of
-actin by
the adventitial myofibroblasts, preventing the formation of the
myofibroblast scar around the angioplasty site and negative vascular
remodeling.17 20 Data from Fareh and et al 21
suggest that inhibition of migration but not of cellular proliferation
may occur at lower doses of radiation. Therefore, cells may remain in
situ, unable to migrate but able to grow in the presence of a weakened
external elastic membrane. After 1 week, the effect of the radiation
diminishes, and cellular proliferation, possibly as a reaction to the
presence of the stent, continues behind the stent in the context of
positive vascular remodeling. In our cohort of patients, no cases of
stent malapposition were seen at follow-up, although our group has
described this as a risk of ongoing positive vascular
remodeling.22 23 A further concept to be explored is that
relating to the sharp drop-off in radiation seen with the ß-radiation
source, which may cause underdosing deep in the adventitia and
geographical miss24 in a radial sense rather than the more
commonly described longitudinal sense.
Radioactive Stent
The objective of using the radioactive stent is not to neutralize
myofibroblasts in the adventitia; it is the prevention of the migration
and invasion of myofibroblasts from the adventitia through the stent
struts and into the lumen. As is seen in the HA group, this is
accomplished by the continuous and low dose rate provided by the
radioactive stent. Because of the range of the "radioactive fence"
created, adventitial cells remain intact without upregulation of growth
factors and inhibition of contractile proteins. Consequently, no
remodeling is seen behind the radioactive stent at either activity
level.
Edge Remodeling
Hoffmann et al15 have previously described negative
remodeling at the stent edge after conventional stent implantation. In
the present study, we have been able to precisely describe the
decrease in TVV as the dominant contributor to nonrestenotic
lumen loss at the stent edge. Recent reports on radioactive stents
suggest that the edge effect and edge restenosis may be due to
an increase in plaque at the edge and to a component of negative
remodeling as one moves axially from the stent.4 The
contributing factors to radioactive stent edge restenosis have
been discussed in detail recently by Serruys and
Kay.25
It may be argued that stent-edge restenosis was not seen in the CBS group because no individuals with geographical miss were evaluated. However, our objective in the present study was to analyze the vascular response to appropriately applied catheter-based radiation, which necessitates the exclusion of all those in whom injury was not covered by radiation. Recent reports have suggested that the combination of suboptimal low-dose radiation and injury may make individuals with geographical miss vulnerable to edge restenosis.26
Study Limitations
This was a retrospective nonrandomized study of individuals who
had completed 6 months of follow-up and in whom IVUS examination was
possible. Individuals who had a total occlusion or in whom the IVUS
catheter could not be passed under acceptable clinical circumstances
were not included.
No edge restenosis was seen in the CBS group, unlike the HA group; however, both the CBS and the HA groups reflected the larger parent populations from which they were selected in all other features.
The dosimetry (catheter-based) described in the present study relates to prescribed doses only and does not necessarily reflect the dose delivered 2 mm from the source in the adventitia. Description of dosimetry is beyond the scope of the present study; however, previous work by the authors (Sabaté et al27 ), who used a similar radiation source and study population, suggests that delivered dose, residual plaque burden, and tissue composition play a fundamental role on the volumetric outcome at 6 months of follow-up after catheter-based ß-radiation therapy and BA.
Conclusions
Distinct differences in the patterns of remodeling exist between
conventional, radioactive, and catheter-based radiotherapy with
stenting. Users of radiation need to be alerted to edge
restenosis seen after higher activity radioactive stent
implantation and positive remodeling behind the stent seen after
catheter-based radiation and stenting. Radiation, whether it be
catheter or stent-based, has forced the interventional community to
look closely not only at effective inhibition of intimal proliferation
but also at the adverse response of the artery to the combination of
injury and radiation.
| Acknowledgments |
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Received December 30, 1999; revision received April 12, 2000; accepted April 14, 2000.
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P.W. Serruys and S.G. Carlier Brachytherapy in the Journal: European cardiologists have their own forum and should use it! Eur. Heart J., December 2, 2000; 21(24): 1994 - 1996. [PDF] |
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