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Expansion of the Multi-Link FrontierTM Coronary
Bifurcation Stent: Micro-Computed Tomographic
Assessment in Human Autopsy and Porcine Heart
Samples
Stefan Kralev1*, Benjamin Haag1, Jens Spannenberger1, Siegfried Lang1, Marc A. Brockmann2, Soenke
Bartling3, Alexander Marx4, Karl-Konstantin Haase5, Martin Borggrefe1, Tim Su¨selbeck1
1 I. Department of Medicine, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany, 2Department of Neuroradiology, Faculty of Medicine
Mannheim, University of Heidelberg, Mannheim, Germany, 3Department of Clinical Radiology and Nuclear Medicine, Faculty of Medicine Mannheim, University of
Heidelberg, Mannheim, Germany, 4Department of Clinical Pathology, Faculty of Medicine Mannheim, University of Heidelberg, Mannheim, Germany, 5 II. Department of
Internal Medicine, Hospital Steinberg, Reutlingen, Germany
Abstract
Background: Treatment of coronary bifurcation lesions remains challenging, beyond the introduction of drug eluting stents.
Dedicated stent systems are available to improve the technical approach to the treatment of these lesions. However
dedicated stent systems have so far not reduced the incidence of stent restenosis. The aim of this study was to assess the
expansion of the Multi-Link (ML) FrontierTM stent in human and porcine coronary arteries to provide the cardiologist with
useful in-vitro information for stent implantation and selection.
Methodology/Principal Findings: Nine ML FrontierTM stents were implanted in seven human autopsy heart samples with
known coronary artery disease and five ML FrontierTM stents were implanted in five porcine hearts. Proximal, distal and side
branch diameters (PD, DD, SBD, respectively), corresponding opening areas (PA, DA, SBA) and the mean stent length (L)
were assessed by micro-computed tomography (micro-CT). PD and PA were significantly smaller in human autopsy heart
samples than in porcine heart samples (3.5460.47 mm vs. 4.0460.22 mm, p = 0.048; 10.0062.42 mm2 vs. 12.8461.38 mm2,
p = 0.034, respectively) and than those given by the manufacturer (3.5460.47 mm vs. 4.03 mm, p = 0.014). L was smaller in
human autopsy heart samples than in porcine heart samples, although data did not reach significance (16.6661.30 mm vs.
17.3060.51 mm, p = 0.32), and significantly smaller than that given by the manufacturer (16.6661.30 mm vs. 18 mm,
p = 0.015).
Conclusions/Significance: Micro-CT is a feasible tool for exact surveying of dedicated stent systems and could make a
contribution to the development of these devices. The proximal diameter and proximal area of the stent system were
considerably smaller in human autopsy heart samples than in porcine heart samples and than those given by the
manufacturer. Special consideration should be given to the stent deployment procedure (and to the follow-up) of dedicated
stent systems, considering final intravascular ultrasound or optical coherence tomography to visualize (and if necessary
optimize) stent expansion.
Citation: Kralev S, Haag B, Spannenberger J, Lang S, Brockmann MA, et al. (2011) Expansion of the Multi-Link FrontierTM Coronary Bifurcation Stent: Micro-
Computed Tomographic Assessment in Human Autopsy and Porcine Heart Samples. PLoS ONE 6(7): e21778. doi:10.1371/journal.pone.0021778
Editor: Giuseppe Biondi-Zoccai, University of Modena and Reggio Emilia, Italy
Received January 22, 2011; Accepted June 11, 2011; Published July 21, 2011
Copyright: � 2011 Kralev et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: The authors have no support or funding to report.
Competing Interests: The authors have declared that no competing interests exist.
* E-mail: stefan.kralev@umm.de
Introduction
The presence of a bifurcation lesion in patients with coronary
artery disease (CAD) is a frequent morphology (8.5%). This
incidence was found by a recent study investigating a cohort of
6129 consecutive patients undergoing coronary stent implantation
[1]. In most lesion types, drug-eluting stents (DES) have reduced
the incidence of revascularization after percutaneous coronary
intervention (PCI [2,3]), but in the case of bifurcation lesions, rates
for adverse clinical events still remain high. A recent study
investigating bifurcation stenting with sirolimus eluting stents
reported in-stent restenosis rates in main vessel and/or side branch
of between 6.6% (culotte technique) and 12.1% (crush technique
[4]). Before that, main vessel and side branch restenosis rates of
.25% were reported [5–7], with side branch restenosis considered
as a main problem [8].
The existence of an ostial and bifurcation lesion itself is – besides
long stents, overlapping stents, suboptimal stent results, stenting of
small vessels, existence of multiple lesions, etc – a predictor for late
stent thrombosis and restenosis [9,10]. The high rates of restenosis
were one of the reasons for the development of dedicated stent
systems (DSS) but according to current guidelines for PCI [11], so
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far there is no recommendation for the use of DSS. Angiographic
success, clinical outcome and development of DSS for coronary
bifurcation lesions still remain a challenge and the European
Bifurcation Club concluded in a recent state-of-the-art paper that
the role of DSS is still the subject of debate, awaiting the ‘‘magic’’
device [12]. Micro-CT has been utilized to investigate oversized
postdilation of DES [13], but no micro-CT data are available
regarding DSS.
The aim of this study was to assess the expansion of the DSS
Multi-Link (ML) FrontierTM (Abbott Vascular, Santa Clara, CA,
USA) in human and porcine coronary arteries to provide the
cardiologist with useful in-vitro information for stent implantation
and selection, contributing to the development of these devices
and the treatment of coronary bifurcation lesions.
Methods
The study was performed in accordance with federal laws and
regulations, international accreditation standards, institutional
policies and the local ethics committee (Medical Ethic Commission
II, Faculty of Medicine Mannheim, University of Heidelberg).
Written informed consent was obtained from all patients by the
Department of Anatomy, University of Heidelberg, and data were
analyzed anonymously.
Investigation background
In this in vitro study, seven autopsy heart samples from human
subjects with known CAD and five porcine heart samples were
appropriated. Human and porcine heart samples were immedi-
ately preserved with static cold flush with crystalloid solution [14].
Nine stents were implanted in human non-stenotic bifurcations
24–48 h after explantation and five stents were implanted in fresh
vascular porcine bifurcation tissue 24 h after excisement (Figure 1).
All heart samples were routinely processed for cardiac catheter-
ization with standard 5, 6 or 7F guiding catheters and 0.014-inch
floppy guide wires. Because of anonymization no detailed
information about the CAD status was available.
Stent implantation
In total, 14 ML FrontierTM stents with a nominal size of
3.0 mm618 mm were successfully implanted in appropriate
bifurcations under fluoroscopic control. Coronary intervention
was performed each time using high-pressure stent deployment as
recommended by the manufacturer (14 atm, duration 30–35 s).
Angiography was then performed and the coronary perfusion was
graded according to the Thrombolysis in Myocardial Trial (TIMI)
classification [15]. The proximal and distal reference luminal
diameters of the main vessels and the side branches were assessed
before stent implantation by quantitative coronary angiography
(QCA) and the stent/artery ratios were calculated.
Micro-CT
The stented segments were each prepared in a conical 50 ml
polypropylene tube (BD FalconTM Tube, Becton Dickinson,
Franklin Lakes). Micro-CT was performed using an industrial
micro-CT system (Yxlon Y.Fox, Yxlon International GmbH,
Hamburg, Germany). A total of 1200 projections were acquired
within 40 s of scan time (262 binning of the detector; 9446704
pixel; 360u rotation; 90 mA; 160 kV). Proprietary scanner control
software was used to monitor the scanning process, and to save
projection data. Standard cone-beam CT reconstruction was
performed using a filtered back-projection algorithm (Reconstruc-
tion Studio Version 1.2, Comet GmbH, Garbsen, Germany) with
Shepp-Logan filter applied. The reconstructed volumes (512
Matrix) were reviewed in multiplanar reformation (MPR) as well
as in a 3D volume rendering mode using OsiriX-software (v3.5.1).
Data sets were reviewed in MPR (OsiriX) and 3D volume
rendering using standard radiological equipment (I-View 3D
1.0.2.3, TeraRecon Inc., San Mateo, USA). After that, devices
were surveyed and proximal and distal stent diameters (PD, DD),
side branch diameters (SBD), mean stent length (L), as well as the
corresponding opening areas (PA, DA, SBA) were measured. The
measurements were carried out in MPR-mode. The stent length
(Figure 2, panel A), stent diameters and sidebranch diameters
(Figure 3, panel A and B) were measured aligning the z-axis with
the centreline of the stent looking exactly perpendicular into the
stent lumen. In the real world stent opening is not always exactly
circular, consequently the stent expansion cannot always be
assessed by measuring a diameter, and two orthogonal angio-
graphic views or IVUS (intravascular ultrasound, visualizing vessel
lumen and stent opening area) are recommended for evaluation of
stent expansion. As with IVUS, micro-CT also offers the
possibility of visualizing the stent opening area. Therefore, in this
Figure 1. ML FrontierTM stent in porcine coronary artery.
Immediately after excisement the ML FrontierTM stents were implanted
in fresh vascular bifurcation tissue in the porcine heart samples.
doi:10.1371/journal.pone.0021778.g001
Figure 2. Assessment of the stent length. 2D measurement (panel
A) and 3D visualization (panel B) of stent length by micro-CT.
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study, in all cases both the diameters and the opening areas were
measured and compared with the data given by the manufacturer.
The compliance chart of the manufacturer contains the diameters of
the stent, so the corresponding opening areas were calculated by
applying the circle area formula Area=pr2 with r describing the
radius of the circle, conforming to 1/2 the diameter. All opening
areas were first manually traced by the observer and then determined
by the software (Figure 3, panel C, sidebranch opening area).
Statistical analysis
Deviations from values given by the manufacturer were
evaluated by the one sample t test. Data are presented as mean
6 standard deviation (SD). Values of p,0.05 (two-tailed) were
considered statistically significant. The calculations were per-
formed using SPSS-Software (SPSS-Software GmbH, Mu¨nchen,
Germany).
Results
All DSS showed a successful angiographic result with a TIMI 3
flow. Detailed measurements of opening areas, corresponding
diameters, stent lengths, reference luminal diameters and stent-to-
artery ratios are presented in Table 1. The proximal stent
diameters assessed in human autopsy heart samples were
significantly smaller than in porcine heart samples (PD:
3.5460.47 mm human vs. 4.0460.22 mm porcine, p= 0.048)
and than those given by the manufacturer (PD: 3.5460.47 mm
human vs. 4.03 mm manufacturer, p= 0.014). The mean stent
length assessed in human autopsy heart samples was smaller than
in porcine heart samples (L: 16.6661.30 mm human vs.
17.3060.51 mm porcine, p = 0.32) and significantly smaller than
that given by the manufacturer (L: 16.6661.30 mm human vs.
18 mm manufacturer, p = 0.015). Measured values of the distal
stent diameter (DD: 3.2460.41 mm human vs. 3.26 mm porcine,
p = 0.91) and side branch diameter (SBD: 2.1560.44 mm human
vs. 2.2 mm porcine, p = 0.75) showed no significant difference
between human autopsy heart samples, porcine heart samples and
data given by the manufacturer (Figure 4).
Correspondingly, the proximal stent opening area was signifi-
cantly smaller than the area measured in porcine heart samples
(PA: 10.0062.42 mm2 human vs. 12.8461.38 mm2 porcine,
p = 0.034) and the area given by the manufacturer (PA:
10.0062.42 mm2 human vs. 12.76 mm2 manufacturer,
p = 0.009, calculated with the proximal diameter of the compli-
ance chart). The distal stent opening area (DA: 8.3962.06 mm2
human vs. 8.35 mm2 porcine, p = 0.96) and the side branch
opening area (SBA: 3.7761.40 mm2 human vs. 3.80 mm2
porcine, p = 0.94) did not differ significantly from areas measured
in porcine heart samples or data given by the manufacturer
(Figure 5).
Exact 2D measurement and 3D visualization of the stent length
is depicted in Figure 2, panels A and B. Adequate expansion of the
distal opening and the side branch opening is depicted in Figure 6,
panel A; inadequate expansion of the proximal opening is shown
in Figure 6, panel B.
Discussion
Micro-CT is an independent method capable of measuring stent
cells with high precision [13,16]. This is the first study that has
investigated a DSS by micro-CT, visualizing the deployment
behaviour and assessing expansion in different tissue models.
Proximal diameters of the devices implanted in human autopsy
hearts were significantly smaller than in porcine heart samples and
than the predicted diameter from the manufacturer’s compliance
chart. In comparison to the porcine heart samples, as in real world
stenting conditions, the human heart samples had atherosclerosis.
Atherosclerosis is associated with a higher vessel wall resistance
and this might have led to a suboptimal expansion of the stent in
comparison to the porcine heart samples and in comparison with
the data given by the compliance chart. Proximal vessel diameters
are generally larger than distal vessel diameters, which should
ideally also be factored in the stent-balloon design. But conical
ballons (proximal balloon ending larger than distal ballon ending)
are not available, so this might be a reason why suboptimal stent
expansion was observed mainly in the proximal stent part. Similar,
it must be taken in account that coronary arteries are not linear so
that vessel wall resistance in the curved part and/or shear forces of
the coronary arteries due to atherosclerosis might hinder complete
length expansion. Our results reflect findings of a previous study in
which intravascular ultrasound (IVUS) was used to investigate four
different stents demonstrating that the minimal stent diameters
measured by IVUS were significantly smaller than those predicted
by the manufacturers [17]. Regarding clinical data relating to the
ML FrontierTM, the FRONTIER stent registry [18] reported an
initial device success of 91%. At 6 month follow-up, the MACE
rate was 17.1% with a main branch in-stent restenosis (ISR) of
25.3%. Newer data evaluating the ML FrontierTM [19] reported a
Figure 3. Assessment of the stent opening diameters and areas. Diameters were measured by aligning the z-axis with the centreline of the
stent looking exactly perpendicular into the stent lumen (panel A, panel B). Panel C depicts the measurement of the side branch opening area (SBA).
Measurements were performed in multiplanar reformation (MPR) mode.
doi:10.1371/journal.pone.0021778.g003
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device success of 95% (postprocedural main vessel stenosis 19%)
with a follow-up ISR rate of 29% (in-stent late lumen loss
0.5260.44 mm). The results of the present study might contribute
to a better understanding of these clinical trials, suggesting that in
human heart samples with CAD the proximal part of the ML
FrontierTM shows a smaller expansion characteristic than in
porcine heart samples or in a water bath.
Our results are in accordance with the results of another study,
reporting an incomplete apposition also at the proximal edge of
the DSS AXXESS in two of 139 cases [20]. Although there is a
case report of the ML FrontierTM, showing an adequate proximal
stent apposition documented by IVUS [21]. On balance, we agree
with Bhalla et al., recommending careful stent deployment [22]
and propose special consideration of balloon inflation pressure and
duration, postdilation of the proximal stent part and final kissing
balloon technique, respecting the individual lesion type of the
patient to avoid stent malapposition.
Stent malapposition and its pathophysiological role in both ISR
and stent thrombosis is of major importance. One of the leading
sources of ISR is local vascular healing response associated with
intimal hyperplasia [23]. Main predictors of ISR are final minimal
luminal diameter, stent length and structural deformation of the
stents with suboptimal vessel wall coverage [24,25]. Insufficiently
enlarged stent cells may also cause thrombus formation [26,27].
Several important studies have demonstrated that stent under-
expansion/malapposition is one of the major reasons for stent
thrombosis [26,28–31]. Focusing on data for bifurcation stenting,
fewer data are available but similar mechanisms are thought to be
implicated. Good positioning of the stent struts against the vessel
wall, adequate stent openings and the stent length are – in addition
to other factors such as delta angle, etc – crucial factors for
successful bifurcation stenting [27,32–34]. The results of the
present study suggest that in human autopsy hearts with CAD the
stent length might be slightly smaller than expected. More micro-
CT studies with newer stent devices are needed to clarify this
point. We agree with Mortier et al. who recommend careful
selection of stent devices [16], and want to draw special attention
also to the stent length. Therefore, after complex PCI with heavy
calcification, need for multiple balloon inflation, etc, critical
observation of the angiographic result in two orthogonal
perspectives should be performed. In some cases IVUS, optical
coherence tomography (OCT) or X-ray visual enhancement [35]
might provide additional useful information, enabling optimiza-
tion of the stent deployment.
Table 1. Micro-CT analysis of stent diameters, opening areas and stent length.
Heart/Stentn Stent diameter/opening area (mm/mm2) Stent length
Human autopsy hearts Proximal Distal Bifurcation strut
I/11 3.98/12.44 3.86/11.70 2.54/5.07 15.8
II/22 2.45/4.70 2.55/5.12 1.47/1.69 14.2
II/34 3.30/8.55 3.30/8.55 2.22/3.87 15.5
III/43 3.50/9.62 2.90/6.61 1.50/1.77 17.6
III/54 3.44/9.29 3.53/9.79 1.99/3.11 16.1
IV/64 3.70/10.75 3.42/9.19 2.61/5.35 17.5
V/72 3.67/10.58 2.81/6.20 2.42/4.59 17.8
VI/81 4.04/12.82 3.49/9.57 2.06/3.33 17.9
VII/91 3.78/11.22 3.34/8.76 2.55/5.11 17.5
RLD* 3.7360.28 3.1760.15 1.7960.30
Stent/artery ratio{ 1.08 : 1 1.03 : 1 1.23 : 1
Stent/artery ratio{ 0.95 : 1 1.02 : 1 1.20 : 1
Porcine heart model
I/101 4.23/14.05 3.24/8.23 2.28/4.07 18.0
II/112 3.86/11.70 3.19/8.01 2.29/4.12 17.4
III/124 3.79/11.31 3.33/8.72 2.12/3.53 17.2
IV/133 4.03/12.75 3.19/8.02 2.17/3.71 17.3
V/143 4.29/14.41 3.25/8.32 2.16/3.65 16.6
RLD* 2.9260.19 2.3160.17 1.4860.33
Stent/artery ratio{ 1.38 : 1 1.41 : 1 1.49 : 1
Stent/artery ratio{ 1.00 : 1 0.99 : 1 1.00 : 1
Manufacturer** 4.03/12.76 3.26/8.35 2.20/3.80 18.0
n= Location of bifurcation:
1left anterior descending (LAD)/ramus diagonalis (RD) I,
2LAD/RD II,
3LAD/left circumflex,
4right coronary artery: ramus interventricularis posterior/ramus posterolateralis dexter.
*Measured before stent implantation by QCA.
{Calculated with stent diameter given by manufacturer.
{Calculated with stent diameter assessed by Micro-CT.
**Opening area was calculated using the circle formula area = p radius2. RLD: reference luminal diameter; QCA: quantitative coronary angiography.
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Another conclusion of this study is that micro-CT is a feasible
tool to visualize and survey expansion of dedicated stent systems in
vitro. So far, only few data about micro-CT are available, but
micro-CT has already been described as an adequate tool for the
assessment of single wires, lumen, endo-luminal plaques, cell sizes
of stents [16,36,37], as well as for the assessment of complex
stenting strategies on silicone bifurcated vessel models [38].
Importantly, this study provides data on autopsy heart samples
from human subjects with CAD. Performing this investigation
strictly in accordance with the guidelines of the local ethics
Figure 5. Comparison of stent areas between autopsy hearts, porcine model and data given by the manufacturer. Proximal stent
opening areas (PA) were significantly smaller in autopsy human heart samples than in porcine heart samples and than those given by the
manufacturer. Side branch opening areas (SBA) and distal stent opening areas (DA) did not differ significantly.
doi:10.1371/journal.pone.0021778.g005
Figure 4. Comparison of stent dimensions between autopsy hearts, porcine model and data given by the manufacturer. Proximal
stent diameters (PD) were significantly smaller in human autopsy heart samples than in porcine heart samples (P = 0.048) and than those given by the
manufacturer (P = 0.014). The mean stent length was smaller in human autopsy hearts than in porcine heart samples (P = 0.32), and also significantly
smaller than that given by the manufacturer (P = 0.015). Side branch diameters (SBD) and distal stent diameters (DD) did not differ significantly.
doi:10.1371/journal.pone.0021778.g004
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