(Circulation. 2000;101:812.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Stent and Artery Geometry Determine Intimal Thickening Independent of Arterial Injury
From the Department of Medicine (Cardiac Catheterization Laboratory and Coronary Care Unit, Brigham and Women’s Hospital), Harvard Medical School, Boston, Mass (J.M.G., E.R.E., C.R.); the Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Mass (E.R.E., J.C.S., P.S., C.R.); and Medtronic/Arterial Vascular Engineering, Santa Rosa, Calif (M.S.W.).
Correspondence to Joseph Garasic, MD, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail jmgarasic{at}bics.bwh.harvard.edu
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Abstract |
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Background—Clinical trials show that larger immediate postdeployment stent diameters provide greater ultimate luminal size, whereas animal data show that arterial injury and stent design determine late neointimal thickening. At deployment, a stent stretches a vessel, imposing a cross-sectional polygonal luminal shape that depends on the stent design, with each strut serving as a vertex. We asked whether this design-dependent postdeployment luminal geometry affects late neointimal thickening independently of the extent of strut-induced injury.
Methods and Results—Stainless steel stents of 3 different configurations were implanted in rabbit iliac arteries for 3 or 28 days. Stents designed with 12 struts per cross section had 50% to 60% less mural thrombus and 2-fold less neointimal area than identical stents with only 8 struts per cross section. Sequential histological sectioning of individual stents showed that immediate postdeployment luminal geometry and subsequent neointimal area varied along the course of each stent subunit. Mathematical modeling of the shape imposed by the stent on the artery predicted late neointimal area, based on the re-creation of a circular vessel lumen within the confines of the initial stent-imposed polygonal luminal shape.
Conclusions—Immediate postdeployment luminal geometry, dictated by stent design, determines neointimal thickness independently of arterial injury and may be useful for predicting patterns of intimal growth for novel stent designs.
Key Words: stents • restenosis • angioplasty • pathology
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Introduction |
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The advantages of stents over angioplasty include larger acute gains in luminal diameter and better long-term patency and clinical outcomes.1 2 Nevertheless, stents provoke greater absolute late luminal loss than angioplasty1 3 4 5 and carry the additional risk of thrombosis.6 Better understanding of mechanical and biological contributors to thrombosis has prompted changes in clinical practice.7 In contrast, no strategy has been proved clinically effective at reducing the neointimal hyperplasia of in-stent restenosis.8 A central element in understanding in-stent restenosis is how stent design may affect neointimal growth. One aspect of stent-induced damage is strut-imposed vascular injury, which dictates the extent of intimal thickening in experimental animals.9 10 Design alterations that limit injury modulate neointimal hyperplasia.11 12 Meanwhile, clinical evidence suggests that larger immediate postdeployment dimension is the primary predictor of late luminal area, independent of stent design.3 4 5
At deployment, stent struts provide a frame over which the lumen is stretched, assuming a polygonal shape, with each strut marking a vertex. The geometry depends on stent design and varies along the length of a single stent. To test the hypothesis that acute stent-imposed luminal geometry affects vascular repair, stents were constructed to alter luminal geometry with minimal effect on deep injury. Using sequential histological sectioning, we examined whether initial stent-imposed lumen shape affects regional neointimal thickening. A mathematical model was constructed to examine whether these effects occurred in a predictable fashion. Elucidating effects of stent design on initial stent-imposed luminal geometry and biological sequelae may allow novel strategies for device design and use. Furthermore, the plethora of stent designs now available makes understanding and modeling of precise interactions between stent and artery essential.
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Methods |
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Surgical Procedure
New Zealand White rabbits (Covance Products, Denver, Pa), 3.5 to 4 kg, were fed rabbit chow and water. Aspirin (0.07 mg/mL, Sigma Chemical Co) was added to the drinking water 1 day before surgery for a dosage of
5 mg ·
kg-1 · d-1 and was
maintained throughout the postoperative period. Animals were
anesthetized with ketamine (35 mg/kg IM, Fort Dodge
Laboratories) and xylazine (5 mg/kg IM, Miles Inc). As previously
described,12 13 we performed bilateral iliac artery
denudation using a 3F embolectomy catheter (Baxter HealthCare Corp). A
stent mounted on a 3-mm angioplasty balloon (Arterial
Vascular Engineering) was passed retrogradely into each iliac artery
and expanded (15 seconds, 8 atm). Iliac arteries of rabbits in this
weight range are 2.5 to 2.75 mm in diameter, yielding
balloon:artery ratios of 1.1 to 1.2:1.12 13 14 At the time
of stent deployment, rabbits received a single bolus of heparin (100
U/kg, Elkin-Sinn Inc). All animal care was in accordance with
institutional guidelines.
Steel stents of 3 designs were used. Stents were of a simple
multicrowned configuration with either 8 (Figure 1A
) or 12 (Figure 1B) struts per
cross section. Stents of the 12-strut design were 8 mm long (four
2-mm segments), and stents of the 8-strut design were 9 mm long
(three 3-mm segments). Variations in strut thickness were tested as
well, with stent struts of the 12-strut design being either 125 or
200 µm thick. Struts of the 8-strut design were 200 µm
thick. In vitro expansion of all 3 stent designs showed an outer
dimension of 3.4 mm for 200-µm-thick stents of either design and
3.3 mm for 125-µm-thick 12-strut stents.
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Tissue Processing
Four stents of each design were implanted for 3 days, and 4 each
for 28 days. To label proliferating cells, all animals received
bromodeoxyuridine (BrdU) (50 mg/kg IV, Sigma) 1 hour before they were
euthanized. Under anesthesia with pentobarbital sodium,
inferior vena caval exsanguination was followed by
perfusion with Ringer’s lactate solution via left
ventricular puncture. Both iliac arteries were excised and
fixed by immersion in Carnoy’s solution (60% methanol, 30%
chloroform, and 10% glacial acetic acid). Intact stented
arterial segments were embedded in a modified methacrylate
resin formulation (Sigma Chemical Co) polymerized at -20°C. Before
sectioning, high-resolution radiographs of embedded stented arteries
were taken in 2 orthogonal views with a mammography unit, and the
external stent diameter was measured at the proximal end, the middle,
and the distal end with digital calipers. Cross-sectional planes were
then sawed out and sectioned at 5-µm thickness with a tungsten
carbide knife as previously described.15 16 Cross sections
were taken from each end and the middle of each stented artery.
To study neointimal hyperplasia along the length of a single stent subunit, sequential 5-µm sections from the middle of two 8-strut stents were taken at 100-µm intervals. This allowed study of neointimal responses along one half of 3-mm segments, with the subsequent half (1.5 mm) being a mirror image of the studied segment.
Histological Analysis
Histological sections were stained with
Verhoeff’s tissue elastin stain or hematoxylin and eosin. Areas of
neointima, adherent mural thrombus, lumen, internal elastic
lamina (IEL), and external elastic lamina were measured by
computer-assisted digital planimetry as previously
described.12 Stent-induced injury score was graded for
each cross section.9 10
Cellular responses 3 and 28 days after stent implantation were also studied. In proximal, middle, and distal sections of each stented artery, mononuclear inflammatory cells adherent to the lumen were counted.12 15 16 Macrophages were identified immunohistochemically with a species-specific antibody (RAM-11, Dako Co).15 16 Proliferating neointimal cells were quantified by BrdU incorporation (anti-BrdU, Dako Co). Sections were incubated with primary antibody and then biotinylated species-specific secondary antibody (Vector Laboratories Inc). Positive cells were detected by avidin-biotin-peroxidase or –alkaline phosphatase kits (Vector Laboratories Inc). Immunohistochemically identified monocytes/macrophages or proliferating cells were counted and their densities calculated.
Mathematical Modeling
When a stent is initially deployed, its struts provide a
scaffold over which the intima is tightly stretched. The lumen
therefore initially assumes the geometric shape of a polygon, with the
struts marking each vertex. We sought to determine whether eventual
lumen shape and the area of neointimal growth late after
stent implantation is a function of the shape of this polygon and the
largest circular lumen that can be inscribed within it.
The stents we considered can be closely modeled in a straight vessel as
a series of linked diamonds as shown in Figure 2. The strut locations for this design at
any given cross section are uniquely determined by 3 variables: the
number of diamonds, N, needed to traverse the lumen circumference (N=4
in Figure 2 and in the 8-strut stents used in this study, N=6 in
the 12-strut stents used in this study); the balloon radius,
Rb; and the longitudinal position 
of the
cross section. The strut configuration in Figure 2 across
section A stretches the lumen into the shape of a square; across
section C into an octagon; and between these regions, at section B,
into an 8-sided shape consisting of 4 grouped pairs of vertices. The
distance from A to C is measured with the normalized variable ,
which is given the value 0 at cross section A and 1 at cross section C.
Because the paired strut groupings between A and C are the same as
between C and the following A with a 90° rotation, analysis
was completed only on the region from A to C.
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One can derive the equations governing predicted neointimal
area for any N, Rb, and from examination of
Figure 2
. A stent whose circumference is spanned by N
circumferential diamond-shaped elements will have 2N struts showing at
each cross section, (with an exception at =0, where strut pairs
join). These 2N struts are separated by 2 angles, the larger
1 and the smaller 2
(Figure 2). At =0, 1=2
/N and
2=0. At =1,
1=2=/N. The area
of the polygon inscribed by the stent struts (Ap)
can then be calculated as follows:
 | (1) |
 | (2) |
can be
calculated as acute lumen area (Equation 1) minus eventual luminal area
(Rl2):
 | (3) |
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, within a stent for any
N and Rb, Equation 3 can be integrated over
all values of , yielding
 | (4) |
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We hypothesized that stent-induced neointimal formation
reflects geometric issues analyzed in this article as well as
nongeometric issues, such as underlying vessel composition, stent
material, and the extent of deep injury. These nongeometric issues do
not change in a regular graded fashion along the length of a single
stent and thus contribute a constant baseline term to the equation of
predicted neointimal area on which geometrically determined
fluctuations are imposed. We therefore offset the predicted
neointimal areas obtained from Equation 3 when plotting the
resultant modeled data against our experimentally obtained
sequential-section data.
Statistics
All data are presented as mean±SEM. Comparisons between
treatment groups used ANOVA with Bonferroni-Dunn correction for
multiple comparisons.
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Results |
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Stent Dimensions
Measurement of external stent diameter for all specimens before sectioning showed full expansion at proximal, middle, and distal segments for all 3 stent designs and no differential recoil or end-tapering in any design over time (Table 1
).
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Vascular Injury
Deep injury to the arterial wall at the time of stent
deployment is known to correlate closely with late
neointimal thickening in experimental
models.9 10 12 Our experiments were designed to minimize
differences in stent-imposed arterial injury, allowing
isolated study of luminal shape as a factor in repair. Measured injury
scores were low and did not differ significantly between stent designs
(Table 2).
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Thrombosis and Mural Thrombus Burden
No stents were found to be completely thrombosed at harvest.
Variable amounts of adherent mural thrombus were present after 3
days, localized around stent struts. Despite similar degrees of
vascular injury, 3-day mural thrombus burden (Figure 3A) was reduced 50% to 60% by
increasing strut number from 8 to 12 (mural thrombus area:
1.34±0.04 mm2 for 8-strut stent;
0.54±0.19 mm2 for 12-strut 125-µm stent,
P<0.004 compared with 8-strut; 0.67±0.19
mm2 for 12-strut 200-µm stent,
P<0.001 compared with 8-strut, P=NS compared
with 12-strut 125-µm).
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Neointimal Hyperplasia
Neointimal hyperplasia was examined for stents of
different strut number and thickness but similar arterial
injury scores. Twelve-strut stents displayed 2-fold less
neointima (Table 2, Figures 3A and 4) than 8-strut stents (intimal area:
1.54±0.13 mm2 for 8-strut stents;
0.87±0.15 mm2 for 12-strut 125-µm stents,
P<0.005 compared with 8-strut; 0.80±0.08
mm2 for 12-strut 200-µm stents,
P<0.002 compared with 8-strut, P=NS compared
with 12-strut 125-µm; Table 2, Figures 3A and 4). Lumen areas followed a pattern inverse to
neointimal areas (Table 2). Furthermore, there was a
trend toward greater IEL areas in 12-strut stents, reflecting the
greater circumference inscribed by a 12-strut stent than an 8-strut
stent for any fixed stent diameter (Table 2). From Equation 4,
the predicted ratio for neointimal hyperplasia between
8-strut and 12-strut stents was 0.50. The same ratio calculated with
measured values of neointimal area was 0.52 (Figure 3B).
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Inflammatory and Proliferative Indices
The presence of luminally adherent monocytes correlates with
neointimal thickening in this model of stent-induced
injury.12 15 16 17 At 28 days, few luminal monocytes were
present: 19±4 monocytes per section in 8-strut stents, 11±9 in
12-strut 200-µm stents, and 12±4 in 12-strut 125-µm stents
(P=NS for all comparisons). More RAM-11–positive
macrophages were identified among stents of the 12-strut
design: 0.47±0.17% in 8-strut stents; 1.07±0.44% in 12-strut
200-µm stents (P<0.04 compared with 8-strut); and
1.07±0.15% in 12-strut 125-µm stents (P<0.04 compared
with 8-strut). Increasing strut number from 8 to 12 was also associated
with more proliferating cells: BrdU positivity was 0.04±0.01% in the
8-strut group, 0.15±0.07% in the 12-strut 200-µm group
(P<0.02 compared with 8-strut), and 0.15±0.02% in the
12-strut 125-µm group (P<0.02 compared with 8-strut
200-µm). Most BrdU-positive cells were of monocyte-macrophage
lineage in the peristrut regions, explaining the slightly higher
numbers of these cells in 12-strut stents.
Sequential Sectioning and Mathematical Modeling
To examine a potential mechanism whereby strut-vessel geometric
interactions may modulate neointimal thickening, sequential
sections were taken at 100-µm intervals along two 8-strut stents
harvested after 28 days. This allowed examination of
neointimal thickening as strut configuration varied. Within
any stented segment, radial strut distribution varied depending on the
point at which the sections were taken. In sections taken near the
beginning of the stent segment, the IEL was stretched between the 4
cusps in a square design, and these sections showed a large amount of
neointimal hyperplasia (Figure 4A). Sections taken
at the other end of the segment near 8 equidistant, radially
distributed struts showed an octagonal IEL and markedly less
neointima (Figure 4B). These values and all in
between were measured and plotted as a function of distance along the
stent segment (Figure 5). Using Equation 3 above, we calculated predicted neointimal area for N=4
(Figure 5). These derived and measured values showed that
neointimal area fell and lumen size rose as struts became
more numerous and more evenly distributed. As the cycle then repeated
and struts again became less evenly spaced, neointimal area
rapidly began to rise again. In both sequentially sectioned stents, the
predicted neointimal area, derived by use of a geometric
model to inscribe a largest, best-fit circular lumen within
stent-imposed initial lumen geometry, closely approximated
histologically measured values (Figure 5).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Studies of neointimal thickening after vascular stenting have identified deep vessel laceration in animals9 10 11 12 and early gains in luminal dimension in humans3 4 5 as determinants of late luminal size. There has been debate as to whether these 2 paradigms are reconcilable. At deployment, a stent imposes on the lumen a polygonal shape that depends on stent design, with each strut at a vertex. We asked whether this design-dependent postdeployment luminal geometry affects late neointimal thickening independent of strut-induced injury. We present a new model of experimentally induced intimal thickening whereby immediate postdeployment 3D luminal geometry determines eventual lumen size. These data demonstrate how, even in the absence of deep arterial injury, stent design can markedly affect lumen shape and produce distinctly different degrees and patterns of intimal thickening.
With stents differing in strut number but imposing similar injury scores, isolated investigation of the effects of altering initial lumen shape was possible. Altering lumen shape by increasing the number of struts per cross section from 8 to 12 was associated with a 50% to 60% drop in mural thrombus burden after 3 days and a 2-fold reduction in neointimal thickening after 28 days. In contrast, changing only strut thickness from 125 to 200 µm had no significant impact on early luminal thrombus or late intimal thickening. There was no evidence of differential stent expansion or tapering. Computer-aided mathematical modeling used to inscribe a largest, best-fit circular lumen within the confines of different stent-imposed acute luminal configurations accurately predicted different degrees of neointimal thickening. Detailed sequential sectioning of 8-strut stent segments showed that as struts became more numerous and evenly distributed, neointimal area fell and lumen size rose in a completely predictable manner.
These findings may elucidate biological mechanisms of neointimal hyperplasia after vascular stenting. Restoration of luminal circularity may be driven by elements of arterial strain or flow characteristics. Stent-imposed strain for a vessel of any given size will increase as a function of increasing stent diameter. At the same diameter, stents with greater strut number will produce larger lumen circumferences and therefore increase chronic stent-imposed strain. This is suggested by data from our experiments, which show a trend toward greater IEL areas in 12-strut stents. Increasing vascular strain may affect cellular orientation and enhance cell proliferation.18 19 20 Thus, there was no reduction in chronic vascular strain with increasing strut number that would explain the reduction in neointimal thickening seen in the 12-strut stents. Conversely, for a vessel of fixed size, greater interstrut distances are associated with greater acute strain imposed on the vessel wall by the balloon during stent expansion.21
In contrast, altered stent-imposed fluid dynamics may well explain our findings. Several groups have examined the fluid dynamics governing blood flow through stented arteries.22 23 24 Their discoveries of regions of turbulence and/or stagnation in the immediate vicinity of stent struts provide a basis for the observation that restoring the lumen to a circular shape will optimize fluid flow characteristics at the blood/tissue interface. Platelet and inflammatory cell adhesion and activation may be less in settings of more laminar flow within the lumen of more circular stented vessels.
Our data show that less thrombus is present in stents of the 12-strut design than the 8-strut design and there is an accompanying decrement in neointimal thickening at 28 days. Several investigators have suggested that early thrombus deposition and late intimal thickening may be linked in experimental models.9 10 25 Alternatively, a common mechanism, most likely flow-mediated, may underlie both processes, driving thrombus deposition as well as intimal thickening at different phases of repair.
The trend toward fewer luminal monocytes among 12-strut stents versus 8-strut stents at 28 days correlates with the accompanying difference in neointimal thickening, as reported previously.12 13 15 16 In the present study, however, tissue macrophage numbers and proliferative indices were increased among stents of the 12-strut design. This apparent paradox may be explained by the observation that macrophages, monocytes, and giant cells cluster around stent struts. As strut number increases from 8 to 12, the proportion of neointima rich in tissue inflammatory cells increases. In contrast to luminally adherent cells, tissue cells reflect earlier recruitment and may not presage delayed neointimal thickening. Nevertheless, greater late neointimal growth, after 28 days, in the 12-strut stents cannot be ruled out from our experiments.
Altering stent strut configuration and number has practical effects on the clinical use of vascular stents. Increasing strut number and regularity of strut distribution provides a more circular vascular lumen and is associated with a smoother, more homogeneous arteriographic contour. Although our data suggest that variation in strut thickness within the range studied had no significant impact on the biological end points we investigated, in clinical use, thicker struts enhance radiopacity and radial strength, 2 favorable stent characteristics. It is possible that the beneficial effects of increased strut number and near-circular postdeployment lumen shape outweigh any detrimental effects of increased stent mass. There may be a limit, however, to the benefits of this biological effect, and the detrimental effects of increasing strut number or thickness may eventually overcome the beneficial effect of a circular postdeployment lumen shape.
Study Limitations
The stents studied differed in length by 1 mm (8 versus
9 mm) out of the necessity to achieve comparable hoop strength.
This difference is unlikely to have a significant biological
consequence, because these short stents were deployed in long,
nontapering vessels. Furthermore, we documented stent-vessel
interactions at various points along each stent, which would be
unaffected by minor differences in stent length. In mathematical
modeling, we made a simplifying assumption in the geometric derivations
for intimal area concerning the behavior of the arterial
wall. Because the arterial wall has some thickness, it may
not stretch into straight-line segments joining the strut vertices, as
we assumed. Instead, the media will resist compression by forcing the
interstrut luminal region to bow slightly inward. This effect
contributes negligible error when the thin-walled iliac vessels of the
rabbit model are used but may be more consequential in thicker muscular
coronary arteries or abnormal atherosclerotic vessels. Finally,
in vivo imaging of stent sizes was not obtained, although ex vivo test
expansions and postmortem measurement of explanted stents showed no
differences in diameters between designs.
Conclusions
Clinical trials support the paradigm that a larger postdeployment
stent diameter provides greater ultimate luminal size, although an
effect of stent design on clinical restenosis has not been
proved. Animal data, conversely, show that arterial injury
as dictated by stent design affects late neointimal
thickening. We describe a new model of intimal thickening dependent
only on lumen size and shape as determined by stent design. Immediate
postdeployment 3D luminal geometry and recreation of a circular vessel
lumen within the confines of this initial stent-vessel shape determine
eventual lumen size. These data attest to the importance of stent
design as a predictor of biological outcomes and may serve to guide
future stent design and the choice between stents of differing designs
within the clinical arena.
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Acknowledgments |
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This work was supported in part by grants from the NIH (GM/HL-49039 and HL-60407 to Dr Edelman and HL-03104 to Dr Rogers). Dr Edelman is an Established Investigator of the American Heart Association. We are grateful to Cindy Richmond for expert technical assistance and to Dr Jeffrey J. Popma for critical review of the manuscript.
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Footnotes |
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M.S. Williams is an employee of Medtronic/Arterial Vascular Engineering, whose stents are the subject of this study.
Received June 1, 1999; revision received August 6, 1999; accepted August 26, 1999.
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J. F. LaDisa Jr., L. E. Olson, I. Guler, D. A. Hettrick, S. H. Audi, J. R. Kersten, D. C. Warltier, and P. S. Pagel Stent design properties and deployment ratio influence indexes of wall shear stress: a three-dimensional computational fluid dynamics investigation within a normal artery J Appl Physiol, July 1, 2004; 97(1): 424 - 430. [Abstract] [Full Text] [PDF]
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J. F. LaDisa Jr., D. A. Hettrick, L. E. Olson, I. Guler, E. R. Gross, T. T. Kress, J. R. Kersten, D. C. Warltier, and P. S. Pagel Stent implantation alters coronary artery hemodynamics and wall shear stress during maximal vasodilation J Appl Physiol, December 1, 2002; 93(6): 1939 - 1946. [Abstract] [Full Text] [PDF]
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J Gunn, N Arnold, K H Chan, L Shepherd, D C Cumberland, and D C Crossman Coronary artery stretch versus deep injury in the development of in-stent neointima Heart, October 1, 2002; 88(4): 401 - 405. [Abstract] [Full Text] [PDF]
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R. S. Schwartz, E. R. Edelman, A. Carter, N. Chronos, C. Rogers, K. A. Robinson, R. Waksman, J. Weinberger, R. L. Wilensky, D. N. Jensen, et al. Drug-Eluting Stents in Preclinical Studies: Recommended Evaluation From a Consensus Group Circulation, October 1, 2002; 106(14): 1867 - 1873. [Full Text] [PDF]
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R. Hoffmann, C. Jansen, A. Konig, P.K. Haager, G. Kerckhoff, J. Vom Dahl, V. Klauss, P. Hanrath, and H. Mudra Stent design related neointimal tissue proliferation in human coronary arteries; an intravascular ultrasound study Eur. Heart J., November 1, 2001; 22(21): 2007 - 2014. [Abstract] [PDF]
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A. Kastrati, J. Mehilli, J. Dirschinger, F. Dotzer, H. Schuhlen, F.-J. Neumann, M. Fleckenstein, C. Pfafferott, M. Seyfarth, and A. Schomig Intracoronary Stenting and Angiographic Results : Strut Thickness Effect on Restenosis Outcome (ISAR-STEREO) Trial Circulation, June 12, 2001; 103(23): 2816 - 2821. [Abstract] [Full Text] [PDF]
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E. R. Edelman, P. Seifert, A. Groothuis, A. Morss, D. Bornstein, and C. Rogers Gold-Coated NIR Stents in Porcine Coronary Arteries Circulation, January 23, 2001; 103(3): 429 - 434. [Abstract] [Full Text] [PDF]
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C.-W. Hwang and E. R. Edelman Arterial Ultrastructure Influences Transport of Locally Delivered Drugs Circ. Res., April 19, 2002; 90(7): 826 - 832. [Abstract] [Full Text] [PDF]
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