JACC: CARDIOVASCULAR INTERVENTIONS
VOL. 7, NO. 3, 2014
ª 2014 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
PUBLISHED BY ELSEVIER INC.
ISSN 1936-8798/$36.00
http://dx.doi.org/10.1016/j.jcin.2013.05.034
Translational
Effect of the Endothelial Shear Stress
Patterns on Neointimal Proliferation
Following Drug-Eluting Bioresorbable
Vascular Scaffold Implantation
An Optical Coherence Tomography Study
Christos V. Bourantas, MD, PHD,* Michail I. Papafaklis, MD, PHD,y Anna Kotsia, MD,z
Vasim Farooq, MB, CHB,* Takashi Muramatsu, MD, PHD,* Josep Gomez-Lara, MD, PHD,*
Yao-Jun Zhang, MD, PHD,* Javaid Iqbal, PHD,* Fanis G. Kalatzis, MD, PHD,x
Katerina K. Naka, MD, PHD,z Dimitrios I. Fotiadis, PHD,x Cecile Dorange, MSC,k
Jin Wang, PHD,{ Richard Rapoza, PHD,{ Hector M. Garcia-Garcia, MD, PHD,*
Yoshinobu Onuma, MD,* Lampros K. Michalis, MD,z Patrick W. Serruys, MD, PHD*
Rotterdam, the Netherlands; Boston, Massachusetts; Ioannina, Greece; Diegem, Belgium; and
Santa Clara, California
Objectives This study sought to investigate the effect of endothelial shear stress (ESS) on neointimal
formation following an Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara,
California) implantation.
Background Cumulative evidence, derived from intravascular ultrasound–based studies, has
demonstrated a strong association between local ESS patterns and neointimal formation in bare-metal
stents, whereas in drug-eluting stents, there are contradictory data about the effect of ESS on the
vessel wall healing process. The effect of ESS on neointimal development following a bioresorbable
scaffold implantation remains unclear.
Methods Twelve patients with an obstructive lesion in a relatively straight arterial segment, who were
treated with an Absorb BVS and had serial optical coherence tomographic examination at baseline and
1-year follow-up, were included in the current analysis. The optical coherence tomographic data
acquired at follow-up were used to reconstruct the scaffolded segment. Blood flow simulation was
performed on the luminal surface at baseline defined by the Absorb BVS struts, and the computed ESS
was related to the neointima thickness measured at 1-year follow-up.
Results At baseline, the scaffolded segments were exposed to a predominantly low ESS environment
(61% of the measured ESS was <1 Pa). At follow-up, the mean neointima thickness was 113 45 mm,
whereas the percentage scaffold volume obstruction was 13.1 6.6%. A statistically significant inverse
correlation was noted between baseline logarithmic transformed ESS and neointima thickness at
1-year follow-up in all studied segments (correlation coefficient range 0.140 to 0.662). Mixed
linear regression analysis between baseline logarithmic transformed ESS and neointima thickness
at follow-up yielded a slope of 31 mm/ln(Pa) and a y-intercept of 99 mm.
Conclusions The hemodynamic microenvironment appears to regulate neointimal response following
an Absorb BVS implantation. These findings underline the role of the ESS patterns on vessel wall healing
and should be taken into consideration in the design of bioresorbable devices. (J Am Coll Cardiol Intv
2014;7:315–24) ª 2014 by the American College of Cardiology Foundation
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Shear Stress and Neointima Formation in BVS
Neointimal formation is modulated by several local factors,
including the vessel wall trauma caused during stent
deployment, the plaque burden, and the composition of the
underlying plaque, as well as local endothelial shear stress
(ESS) patterns (1–5). Several clinical and experimental
studies have provided evidence that local hemodynamic
factors, in particular low ESS, promote neointimal formation in bare-metal stents, whereas in drug-eluting stents, the
association between ESS and neointimal proliferation is
weak and appears to be affected by the mechanisms of action
and probably the release kinetics of the eluted drug (6–8).
Bioresorbable scaffold is a new technology introduced to
overcome the long-term implications of metallic caging,
because these devices have the unique ability to disappear
after implantation, allowing restoration of vessel physiology
(9). The first clinical studies provided evidence about the
safety and efficacy of these devices and revealed a gradual
increase of the neointima tissue, which, however, was
accommodated by the expanding scaffold and did not appear
to affect luminal dimensions (10). We have recently
demonstrated that neointima tissue has an asymmetric distribution around the circumferAbbreviations
ence of the vessel wall, indicating
and Acronyms
that local factors (i.e., vessel wall
trauma, increased plaque in3D = 3-dimensional
flammation, and local hemodyESS = endothelial shear
namics) are likely to be involved
stress
and regulate this process (11).
IVUS = intravascular
ultrasound
The aim of the present analysis was to investigate the impact
NT = neointimal thickness
of ESS on neointima proliferaOCT = optical coherence
tion following an Absorb biotomographic/tomography
resorbable vascular scaffold (BVS)
(Abbott Vascular, Santa Clara, California) implantation. In
contrast to previous reports, we utilized optical coherence
tomographic (OCT) data to reconstruct the surface of the
scaffolded segment at baseline, simulate blood flow, and assess
vessel wall healing. The high resolution of this imaging
technique allows more detailed reconstruction of luminal
morphology and evaluation of the hemodynamic microenvironment and its impact on neointimal growth.
Methods
Included patients and study design. We analyzed data from
the patients recruited in the second group of the ABSORB
From the *Department of Interventional Cardiology, Erasmus University Medical
Centre, Thoraxcenter, Rotterdam, the Netherlands; yCardiovascular Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, Massachusetts;
zDepartment of Cardiology, Medical School, University of Ioannina, Ioannina,
Greece; xDepartment of Materials Science and Engineering, University of Ioannina,
Ioannina, Greece; kAbbott Vascular, Diegem, Belgium; and {Abbott Vascular, Santa
Clara, California. The ABSORB Cohort B study was sponsored and financially
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Cohort B Trial (A Clinical Evaluation of the Everolimus
Eluting Bioresorbable Vascular Scaffold System in the
Treatment of Patients With De Novo Native Coronary
Artery Lesions; NCT00856856). The study design has
already been described in detail by Serruys et al. (12). In
brief, 101 patients with single- or 2-vessel de novo coronary
disease implanted with an Absorb BVS (dimensions 3.0
18 mm) were included in this prospective multicenter trial.
The studied population was divided into 2 groups. Both
groups had serial angiographic, grayscale intravascular ultrasound (IVUS), IVUS virtual histology, and OCT evaluation at 3 time points. The first group (B1) had these tests at
baseline post-device implantation and at 6 months and 2
years follow-up, whereas the second group (B2) had these
investigations at baseline, 1-year, and 3-year follow-up.
Thus the current analysis included only the patients from
Cohort B2 who had received an Absorb BVS in a relatively
straight coronary segment and had undergone OCT evaluation at baseline and 1-year follow-up.
The ABSORB Cohort B study was approved by the
human research committee of the institutions that participated. Informed consent was obtained from all patients.
Computation of vessel angulation. Biplane coronary angiographic imaging that would allow accurate reconstruction of
coronary geometry was available only in 1 patient at 1-year
follow-up. Thus, coronary reconstruction was performed
using only the OCT data neglecting the vessel curvature. To
minimize the error introduced by this approximation, we
analyzed relatively straight arterial segments. The angulation
of the treated segments was assessed using a previously
described methodology (13). In brief, an expert observer
reviewed the angiographic images acquired at 1-year followup and selected an end-diastolic projection where there was
minimal foreshortening and overlapping of the scaffolded
segment. The angulation of the scaffolded segment was
defined as the angle formed by the tangents of the centerlines of the 5-mm proximal and distal parts of the segment.
To classify the scaffolded segments as straight or curved, we
estimated the curvature of the segments treated in the
Absorb Cohort B study during balloon inflation, assuming
that the balloon straightened the treated artery. The mean
2 SD (29 ) of the angulations measured during balloon
inflation was used as a cutoff value (13).
Optical coherence tomography. OCT image acquisition was
performed at baseline (immediately after scaffold implantation) and at 1-year follow-up using a C7XR Fourier Domain
supported by Abbott Vascular. Dr. Bourantas is funded by the Hellenic Cardiological Society. Dr. Dorange is an employee of Abbott Vascular. Drs. Wang and
Rapoza are employees of and hold stock in Abbott Vascular. All other authors have
reported that they have no relationships relevant to the contents of this paper to
disclose.
Manuscript received February 20, 2013; revised manuscript received April 26, 2013,
accepted May 9, 2013.
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system (LightLab Imaging, Westford, Massachusetts). The
data acquired at baseline were analyzed by 2 expert observers
blinded to patients’ procedural and clinical characteristics,
who reviewed the scaffolded segment and identified in each
frame the embedded, the protruded, and the malapposed
struts. Embedded struts were struts where the surface was
>50% impacted in the vessel wall; struts were considered
protruded when they were in contact with the vessel wall but
with <50% of their surface being impacted in the vessel wall;
and malapposed when the struts’ abluminal surface was not
in contact with the vessel wall. The feasibility of this classification has previously been tested in our department, and
the reported results have shown a high interobserver agreement (kappa index 0.75) (14).
The data acquired at 1-year follow-up were used to
reconstruct 2 surfaces: 1) the luminal surface at baseline
post-scaffold implantation; and 2) the luminal surface at
1-year follow-up. In each follow-up OCT examination, the
observers identified the frames portraying the scaffolded
segment and analyzed 1 frame at every 0.4-mm interval in
the non-scaffolded segment and 1 frame at 0.2-mm intervals
in the scaffolded segment. The luminal morphology at
baseline was approximated by the luminal borders in the
non-scaffolded segment at 1-year follow-up. In the scaffolded segment, the observers identified corresponding struts
between baseline and follow-up OCT examinations, and in
the case where the baseline struts were embedded, the
baseline luminal borders were defined by splines connecting
the adluminal sides of the struts (portrayed at the frames
acquired at 1-year follow-up), whereas in the case where the
baseline struts were protruded or malapposed, the baseline
luminal borders were defined by the adluminal sides of the
struts (portrayed at the frames acquired at 1-year follow-up)
and between struts by the segment connecting the abluminal
sides of adjacent struts (Fig. 1). For the struts where it was
not possible to identify correspondence between baseline and
follow-up examinations, we assumed that these struts were
protruded because the majority of the struts were protruded
at the baseline examination (14).
The luminal surface at follow-up was constructed by the
luminal borders in the scaffolded segment defined by the
endoluminal borders of the neointima. Malapposed struts at
1-year follow-up were not taken into consideration, and in
these segments, the baseline luminal border was approximated by the endoluminal border of the neointima (Fig. 1).
Segments exhibiting extensive malapposition (malapposition
seen in >25% of the frames portraying the scaffolded
segment) were excluded from the analysis.
Reconstruction of coronary anatomy. The vessel centerline
was approximated by a straight line with a length equal to the
length of the studied coronary artery. The center of mass of
the luminal borders in native segments, and of the scaffold
borders (defined by the abluminal side of the scaffold) in
scaffolded segments, were estimated, and these borders were
Bourantas et al.
Shear Stress and Neointima Formation in BVS
317
Figure 1. Segmentation of the OCT Data Acquired at 1-Year Follow-Up
Optical coherence tomography (OCT) image acquired at baseline (A) and the
corresponding frame at 1-year follow-up showing the distal end of a scaffolded segment (the distal marker is located at 11 o’clock) (B). The green line
in C corresponds to the luminal border at baseline, as defined in the follow-up
frame, and the blue line corresponds to the scaffold perimeter. Four corresponding struts were identified in the baseline and follow-up frames, 2 of
which (struts 3 and 4) were embedded at baseline. It was not possible to
identify correspondence for 4 struts (indicated with an asterisk). The area
between the luminal border at baseline and follow-up (red line) corresponds
to the neointima tissue portrayed in D in a semi-transparent fashion. In the
second case example, strut malapposition (strut 1) was noted in 2 corresponding OCT images acquired at baseline (E) and 1-year follow-up (F). In this
location, the baseline and follow-up luminal border and the scaffold perimeter
are defined by the endoluminal side of the neointima (G and H).
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Bourantas et al.
Shear Stress and Neointima Formation in BVS
then placed perpendicularly onto the centerline in their
corresponding locations with their center of mass being
positioned on the vessel centerline. This approach is likely to
distort the anatomy of eccentric lesions located proximally or
distally to the scaffold; however, it is expected to provide a
more accurate representation of the coronary morphology in
the scaffolded segment and eliminate the wave-like artifacts
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introduced by the movement of the catheter (during the
cardiac circle) that can affect the ESS measurements (Fig. 2).
The final outcome of this process is 2 non-uniform,
rational B-spline surfaces: the first representing the luminal
surface at baseline (constructed by the luminal borders in the
non-scaffolded segment and by the scaffold borders in
the scaffolded segment), and the second representing the
Figure 2. 3D Reconstruction of a Scaffolded Segment
Longitudinal optical coherence tomographic (OCT) view of a coronary segment implanted with an Absorb bioresorbable vascular scaffold (BVS) (A). The red arrows
indicate the changes in the position of the OCT catheter with respect to the lumen wall as a result of the 3-dimensional (3D) geometry of the vessel, and the vessel
motion during the cardiac circle, while the white arrow indicates a protruded plaque into the lumen. (B) The reconstructed artery with the endothelial shear stress
(ESS) portrayed in the baseline 3D surface with the use of a color-coded map. The model in panel C was obtained after positioning the detected borders on the vessel
centerline using their gravitational centers. The change in vessel geometry affected ESS distribution, especially in segments with eccentric-protruded plaques and
increased curvature (white arrow). As shown in the magnified panels, the morphology of the baseline luminal surface (F) resembles the luminal morphology
portrayed in the high-resolution 3D volume–rendered frequency domain OCT image obtained immediately after device deployment (E) and the electron microscopy
photo (D) acquired from a rabbit artery 2 weeks after Absorb BVS implantation.
Bourantas et al.
Shear Stress and Neointima Formation in BVS
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 7, NO. 3, 2014
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luminal surface at 1-year follow-up (constructed by the
luminal borders in the scaffolded segment).
Blood flow simulation. The obtained geometries were
further processed with computational fluid dynamics techniques for the generation of a finite volume mesh. Anisotropic meshes with unstructured tetrahedral elements were
generated for each baseline surface using an automated mesh
generation program (ICEM CFD version 11, ANSYS,
Canonsburg, Pennsylvania). To capture the detailed characteristics of the hemodynamic microenvironment, mesh
density was increased around the stent struts and within the
boundary layer of the flow field, and had a maximum
element edge equal to approximately one-fourth of the BVS
strut thickness (i.e., w40 mm). Blood flow simulation was
performed by solving the 3-dimensional (3D) Navier-Stokes
equations (CFX 11, ANSYS). Blood was considered as a
homogeneous, Newtonian fluid with a dynamic viscosity of
0.0035 Pa$s and a density of 1,050 kg/m3. Blood flow was
considered to be steady, laminar, and incompressible, and a
flat velocity profile was imposed at the inlet of the entire
reconstructed arterial segment. Coronary blood flow for each
artery was estimated by measuring in 2 angiographic projections, obtained at baseline post-scaffold implantation, the
number of frames required for the contrast agent to pass
from the inlet to the outlet of the reconstructed segment, the
volume of the segment at baseline, and the cine frame rate
(6). The arterial wall was considered to be rigid, and no-slip
conditions were applied at the baseline luminal surface,
whereas zero-pressure conditions were imposed at the outlet.
ESS at the baseline luminal surface was calculated as the
product of blood viscosity and the gradient of blood velocity
at the wall.
Data analysis and statistics. In the scaffolded segment, the
lumen volume at baseline and 1-year follow-up was estimated, and the neointimal volume was defined as: the lumen
volume at baseline minus the lumen volume at follow-up,
whereas the percentage volume obstruction was defined as:
100 times the neointima volume divided by the lumen
volume at baseline. Neointima thickness (NT) was calculated as the distance between the luminal surface at baseline
and the luminal surface at follow-up using an in-house–
developed algorithm implemented in Visual Fortran 6.5
(Compaq Computer Corporation, Houston, Texas) (15).
Positive values corresponded to areas of neointimal hyperplasia. NT was measured along the axial direction per
0.2 mm and around the vessel circumference per 5 for each
cross section, and was associated with ESS at the corresponding location. A part of the scaffolded segment at the
entrance and exit of the scaffold, covering a length of
2.5 mm, was excluded from the analysis. Segments within
the scaffold located at the origin of side branches and their
adjacent segments with length equal to the diameter of the
side branch were also excluded from the analysis; the
branches were not included in the 3D reconstruction, as the
319
ESS assessment in these areas is not considered to be
reliable.
Continuous variables are presented as mean SD,
whereas categorical variables are presented as counts and
percentages. Pearson correlation coefficient and linear
regression analyses were implemented to investigate the
association between the baseline ESS or the logarithmic
transformed ESS (lnESS) and the estimated NT at followup. To control for patient effect, a mixed model with random
intercept and slope was used to estimate the overall association between lnESS and NT. In this mixed model, the
autoregressive covariance structure was utilized to take into
consideration the nested structure of cross sections within
subjects.
The interobserver agreement in the identification of corresponding struts between baseline and follow-up examination was evaluated with the use of the Cohen’s kappa test.
A p value <0.05 was considered statistically significant.
Statistical analysis was performed with the SPSS statistical
software package (version 18.0 for Windows, SPSS, Chicago, Illinois) and SAS software (version 9.2, SAS Institute,
Cary, North Carolina).
Results
Patient characteristics. Twenty-one patients (22 lesions)
from Cohort B2 were investigated with OCT at baseline
and 1-year follow-up. In 14 patients (14 arteries), the treated
segments had an angulation <29 . Two cases were excluded
from the analysis: the first because of extensive malapposition and the second because of poor OCT image quality.
Table 1. Baseline Characteristics of the Studied Population (N ¼ 12)
Age, yrs
61 9
Male
8 (67)
Hypertension
8 (67)
Hypercholesterolemia
7 (58)
Diabetes mellitus
0 (0)
Current smoking
4 (33)
Prior percutaneous coronary intervention
1 (8)
Prior myocardial infarction
2 (17)
Stable angina
10 (83)
Unstable angina
1 (8)
Silent ischemia
0 (0)
Treated vessel
Left anterior descending artery
9 (75)
Left circumflex artery
2 (17)
Right coronary artery
1 (8)
Ramus intermedius
0 (0)
Medications
Beta-blockers
Renin-angiotensin aldosterone inhibitors
Statins
Values are mean SD or n (%).
9 (75)
9 (75)
10 (83)
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Thus, 12 segments were reconstructed. The baseline characteristics of the studied population are shown in Table 1.
Most of the patients had hypercholesterolemia (58%) and
hypertension (67%), and 83% were treated for stable angina.
Coronary reconstruction analysis. The length of the reconstructed segments was 47.6 10.5 mm, whereas the length
of the scaffolded segment was 19.6 0.8 mm. Neointimal
proliferation was evident in all treated segments, which
resulted in a percentage scaffold volume obstruction of 13.1
6.6% (Table 2). The mean NT derived from the measurements in the 12 patients (scaffold level analysis) was 113
45 mm (range 72 to 200 mm).
Shear stress analysis. In the 12 patients (scaffold-level
analysis), the mean ESS measured in the scaffolded segments at baseline was 1.10 0.35 Pa. Sixty-one percent
of the ESS estimations in the 12 scaffolded segments were
<1 Pa. In native segments, the ESS values were higher (2.53
1.24 Pa, p < 0.0001); only 21% of the ESS estimations
were <1 Pa. As shown in Figure 3, the protruded struts
created a rough luminal surface at baseline that affected the
local hemodynamic microenvironment. Flow recirculation
zones were noted proximally and distally to the protruded
struts, resulting in low ESS in these regions and relatively
high ESS on top of the struts (Fig. 4). The low ESS noted
in these areas appeared to have affected neointima formation
with increased tissue formation proximally and distally to the
scaffold struts and with limited neointima formation on top
of the struts (Figs. 3 and 4).
A negative correlation coefficient (average 0.385, statistically different from 0; p < 0.001) was noted between
the baseline ESS and the NT at 1-year follow-up in all of
the studied scaffolded segments. The correlation coefficient
was higher after the logarithmic transformation of the
baseline ESS (average 0.451; p < 0.001). Table 3 provides the correlation coefficients between baseline lnESS
and NT for each subject, as well as the estimated slopes and
y-intercepts after applying linear regression analysis for
each subject (Fig. 5). The linear mixed effects model
yielded an overall slope of 31 mm/ln(Pa) and y-intercept
of 99 mm.
Table 2. Quantitative Analysis of the Scaffolded Segment in the
3D Reconstructed Arteries (N = 12)
Baseline mean lumen area, mm2
6.70 1.35
Follow-up mean lumen area, mm2
5.85 1.43
Mean neointima tissue area, mm2
0.85 0.38
Mean neointima thickness, mm
113 45
Lumen volume at baseline, mm3
130.9 25.7
Lumen volume at follow-up, mm3
114.6 28.2
Neointima tissue volume, mm3
16.4 6.9
Percentage volume obstruction, %
13.1 6.6
Values are mean SD.
3D ¼ 3-dimensional.
Interobserver agreement in identifying corresponding struts
in OCT examinations. The reliability of the 2 observers in
identifying corresponding struts between baseline and the
follow-up examinations was examined in 100 frames
randomly selected from 8 patients. The Kappa index was
0.79, indicating a good agreement.
Discussion
In this study, we used for the first time serial OCT data and
computational fluid dynamics techniques to evaluate the
effect of the hemodynamic microenvironment on neointimal
formation post-Absorb BVS implantation. We found that:
1) the thick protruded struts (strut thickness 156 mm) of the
implanted scaffold create a rough surface that causes flow
disturbance and recirculation zones resulting in low ESS;
and 2) the reported low ESS contributed to neointimal
formation because there was a negative correlation in all of
the scaffolded segments between ESS and NT.
Several computational experimental and clinical reports in
the past have examined the effect of stent implantation on
local hemodynamics and the association between ESS and
neointimal formation. In silico blood flow simulation studies
have underscored the effect of stent design on local hemodynamic patterns: the stents that have thick, rectangularshaped struts cause flow disruption and lead to a low ESS
environment, whereas the devices with thin, circular-shaped
struts appear to minimally influence the local flow and ESS
(16–19). The connection of the struts seems also to affect
ESS patterns: strut connectors that are parallel to the flow
direction have a minimal effect on ESS, whereas strut
connectors that have a perpendicular arrangement to the
flow direction influence considerably the ESS distribution
and increase the in-stent areas exposed to low ESS (20).
Clinical studies in 3D models obtained from patient data
have shown an inverse correlation between ESS and NT in
bare-metal stents, whereas in drug-eluting stents, there are
conflicting reports (6,7,21,22). Gijsen et al. (22) demonstrated an inverse relation between ESS and neointimal formation in patients treated with sirolimus-eluting stents,
whereas Suzuki et al. (21) found that ESS had no impact
on neointimal development in diabetic patients implanted
with the same type of stent. Papafaklis et al. (6) evaluated
the association between neointimal formation and ESS
in 10 patients implanted with paclitaxel-eluting stents and
10 patients treated with sirolimus-eluting stents, and found an
inverse correlation between ESS and NT in the paclitaxel arm,
but no significant association in the group of patients
implanted with sirolimus-eluting stents, advocating that these
findings are due to the different pathophysiological effect
of each drug on vessel wall healing and the pro-restenotic
ESS-related biological pathway. However, a significant
limitation of the aforementioned studies is the fact that neointimal formation was measured assuming that stent struts
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Bourantas et al.
Shear Stress and Neointima Formation in BVS
321
Figure 3. Distribution of the ESS and of the NT in a Scaffolded Segment
(A) Endothelial shear stress (ESS) patterns in the scaffolded segment portrayed in a color-coded map and (B) the corresponding neointima thickness (NT). The dashed
lines in the reconstructed segment in A and B indicate the location of the optical coherence tomographic images in 1 and 2. 10 and 20 show the ESS distribution at
baseline across the circumference of the vessel wall, and in 10 0 and 20 0 , the neointima thickness is portrayed in a semi-transparent fashion. As shown in i, ii, and iii, the
ESS is low in the between-strut areas and high on top of the struts. The neointima tissue appears to be increased in segments with low ESS and reduced in segments
with high ESS values.
were well apposed post-device implantation and that coronary
reconstruction was based on IVUS, an imaging modality with
a limited radial resolution that cannot accurately evaluate the
lumen surface irregularities caused by the stent struts and the
modest neointima proliferation in drug-eluting stents.
The present study overcomes the aforementioned pitfalls
because it uses for the first time OCT to reconstruct the
coronary lumen. OCT, with its high radial resolution,
allows reliable evaluation of luminal morphology, detailed
assessment of strut apposition, and accurate estimation of
NT. In addition, the heterogeneous appearance of the
struts of the Absorb BVS in OCT permits us to find
corresponding struts at baseline and follow-up examinations
and use this information for more reliable reconstruction of
the baseline luminal surface (23). The high resolution of
OCT allowed us to confirm for the first time in vivo the
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Shear Stress and Neointima Formation in BVS
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Figure 4. Longitudinal Section of a Scaffolded Segment
The blood flow streamlines are shown with velocity color coding (map on the
right), whereas the endothelial shear stress (ESS) distribution along the
baseline luminal surface is portrayed according to the color-coded map (left).
The neointima thickness at 1-year follow-up is shown in a semi-transparent
fashion. Low ESS and recirculation zones are noted in the interstrut areas,
whereas ESS values are high on top of the struts. The ESS distribution appears
to affect neointimal formation, because there is increased neointima tissue in
the regions between the struts and minimal neointima over the struts.
findings of computational flow dynamic studies on theoretical models and demonstrate that the thick, protruded
struts disrupt flow, resulting in recirculation zones in front
of and especially behind the struts. These regions are
exposed to low ESS (ESS were <1 Pa in 61% of the
scaffolds’ surfaces), which appears to promote neointimal
growth (24).
In contrast to previous reports that showed that rapamycin
derivatives abrogate the effect of ESS on neointimal formation, we found a statistically significant correlation between
Table 3. Correlation Coefficient, Slope, and y-Intercept
Patient #
Correlation Coefficient
Slope (mm/(ln)Pa)
y-Intercept (mm)
1
0.480
30
116
2
0.412
37
181
206
3
0.140
35
4
0.426
26
57
5
0.386
28
84
6
0.488
29
85
7
0.533
31
69
8
0.590
34
65
9
0.662
39
122
10
0.410
24
58
11
0.428
33
72
12
0.455
30
68
The correlation coefficient, slope, and y-intercept were obtained after applying linear regression analysis between logarithmic transformed baseline endothelial shear stress (lnESS) and
neointima thickness at 1-year follow-up in each case.
Figure 5. Association Between ESS and NT
Regression curves showing the correlation between the endothelial shear
stress (ESS) (lnESS) at baseline and neointima thickness (NT) at follow-up in
the 12 segments included in the current analysis (A). Regression analysis
between lnESS and neointima thickness for a typical case (B).
ESS and NT in all studied segments implanted with an
everolimus-eluting BVS (6,8,21). This discrepancy should be
attributed to the more reliable evaluation of NT thickness
and baseline ESS patterns in the reconstructed by OCT data
segments, as well as to the longer follow-up period. In previous studies, the association between NT and ESS was
evaluated at 6 and 9 months follow-updonly 3 or 6 months
after the complete elution of the antiproliferative drug (25).
In Absorb BVS, 80% of the everolimus elution is released
within the first month and is completed 3 months after device implantation (26). It can be speculated that after the first
months, the low ESS promoted neointimal formation,
resulting in a negative association between ESS at baseline
and neointimal formation at 1-year follow-up.
In this analysis, we focused on the association between
ESS and NT at 1-year follow-up and not at other time
points (i.e., at 3 years follow-up or at 6 months or 2 years
follow-up using the data of the ABSORB Cohort B1 group)
for the following reasons: 1) one-half of the baseline OCT
examinations in the Cohort B1 group were performed by an
M-3 Time Domain system, which has different radial and
axial resolution and image quality from the C7XR Fourier
Bourantas et al.
Shear Stress and Neointima Formation in BVS
JACC: CARDIOVASCULAR INTERVENTIONS, VOL. 7, NO. 3, 2014
MARCH 2014:315–24
Domain system, and thus, it is not feasible to find corresponding struts between baseline and follow-up examinations; 2) our objective was not to compare our findings with
the results of the IVUS-based reconstruction studies in
metallic drug-eluting stents, but rather to examine the
midterm effect of ESS on NT where the antiproliferative
drug has been eluted and the effect of vessel wall injury has
dissipated; and 3) although it would be interesting to
compare the association between ESS and NT at 2 different
follow-up time points (i.e., at 1- and 3-year follow-up),
because it has been shown that neointimal tissue continues
to develop, the proposed analysis cannot be applied at 2- or
3-year follow-up because the scaffold loses its structural
integrity after 1 year and expands; thus we cannot approximate the baseline luminal surface in the scaffolded segment
based on the location of the struts at 2- or 3-year follow-up
(10,27). To our knowledge, this is the first study that
examines the effect of ESS on neointimal proliferation postbioresorbable scaffold implantation. We found that the early
depolymerization of the scaffold’s struts does not apparently
affect the mechanotransduction pathways that regulate the
response of the free (i.e., noncovered by struts) vessel wall to
the local hemodynamic microenvironment (28–30). Hence,
the current design (in-phase zigzag hoops linked with
bridges; strut thickness of 156 mm) and composition (polyL-lactic struts, covered by a thin layer of an amorphous
matrix of poly-D,L-lactide that controls the release of the
antiproliferative drug everolimus) of the Absorb BVS seems
to provide a template for the formation of a potentially
protective thin layer of neointimal tissue that without
restricting the luminal dimensions covers the underlying
plaque and the scaffold’s struts, minimizing the risk for late
scaffold thrombosis. Furthermore, the neointima tissue that
developed in the areas between the struts appears to smooth
the luminal morphology and normalize the ESS, creating in
the long term an athero-protecting environment (31).
Study limitations. A significant limitation of this analysis is
the use of the follow-up OCT data to reconstruct both the
baseline and follow-up luminal surface. This was done
because there were significant differences in corresponding
OCT frames, regarding the number of the portrayed struts
and their circumferential distribution, between baseline and
follow-up examinations (Fig. 1). Thus, it was not possible to
accurately associate the luminal surface derived from the
baseline OCT data with the luminal surface reconstructed at
follow-up so as to quantify the NT and examine the effect of
the baseline ESS on neointimal proliferation.
Another limitation of the current analysis is the lack of
biplane angiographic data that would allow accurate 3D
reconstruction of the coronary anatomy. To address this
drawback, we included in this analysis relatively straight
coronary arteries, assuming that they were totally straight
segments and that the scaffold was symmetrically expanded.
We have recently reported a high minimal luminal/maximal
323
luminal diameter ratio (0.85 0.08) in IVUS cross-sectional
images of segments implanted with an Absorb BVS 1.1, a
fact that indicates a symmetric expansion of the device (32).
However, potential asymmetries in scaffold expansion that
may have affected the estimated association between ESS
and NT cannot be excluded. The effect of malapposed struts
on local hemodynamics was not taken into account in this
analysis. Considering the overall low reported prevalence of
malapposed struts and the fact that we excluded segments
with extensive malapposition, it is unlikely for this approximation to have affected our results (14).
Conclusions
In this study, we used serial OCT data to reconstruct the
coronaries and evaluate the effect of the hemodynamic
microenvironment on neointimal formation after Absorb
BVS implantation. We found a statistically significant inverse association between ESS and NT in all of the studied
segments. These findings underscore the role of local
hemodynamic milieu on vessel wall healing and should be
taken into consideration in the design of bioresorbable
devices.
Reprint requests and correspondence: Dr. Patrick W. Serruys,
Interventional Cardiology Department, Erasmus Medical
Center, ‘s-Gravendijkwal 230, 3015 CE Rotterdam, the
Netherlands. E-mail: p.w.j.c.serruys@erasmusmc.nl.
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Key Words: bioresorbable scaffold - endothelial shear stress
- neointimal formation - optical coherence tomography.