Current applications of optical coherence tomography for coronary intervention
Giuseppe Ferrantea, Patrizia Presbiteroa, Robert Whitbournb,c, Peter Barlisc,d,⁎
aDepartment of Interventional Cardiology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy
bDepartment of Cardiology, St Vincent's Hospital, Melbourne, Australia
cDepartment of Medicine, Faculty of Medicine, Dentistry & Health Sciences, The University of Melbourne, Victoria, Australia
dDepartment of Cardiology, Northern Health, Victoria, Australia
a b s t r a c ta r t i c l ei n f o
Received 24 March 2011
Received in revised form 30 January 2012
Accepted 4 February 2012
Available online 8 March 2012
Optical coherence tomography
Optical coherence tomography (OCT) is the ‘new kid on the block’ in coronary imaging. This technology offers
clinicians a high resolution (approximately 15 μm), that is ten times higher than the currently accepted gold
standard of intravascular ultrasound and has emerged as the ideal imaging tool for the assessment of superficial
components of coronary plaques and stent struts. Novel OCT systems can perform quick and safe scanning of
coronary arteries with a non-occlusive technique. A brief summary containing the key physical principles of
OCT technology with particular attention to the novel Fourier domain system is presented. This review will
focus on clinical and research applications of OCT in interventional cardiology. The two main fields of OCT in
vivo: coronary atherosclerosis assessment and the study of vessel wall response to stent implantation in terms
of strut coverage and apposition will be delineated. Limitations and future perspectives of the technique are
© 2012 Elsevier Ireland Ltd. All rights reserved.
(PCI) becomes the mainstay invasive therapy for patients with coronary
artery disease. Stents themselves have accounted for a significant reduc-
tion in adverse events compared to balloonangioplasty alone [1–4] with
the spectrum of stent types continuing to change. Drug-eluting stents
(DES) have dramatically reduced restenosis rates . However, a new
cation remains rare, however considerable mortality results [7–11].
with DES, but to study these very rare complications would require trials
with many thousands of patients and follow-up extending over numer-
ous years. Such follow-up would often exceed the product life cycle of
stents with refinements in design, platform and drug-elution continuing
at a rapidly advancing pace. Hence, a surrogate marker of stent safety
would be anattractive optionand this is indeed where novel intracoron-
ary imaging is positioning itself.
The ‘new kid on the block’ in coronary imaging is optical coherence
tomography (OCT). This technology offers clinicians a high resolution
(15 μm) and is ten times higher than the currently accepted gold stan-
dard of intravascular ultrasound (IVUS). OCT use is growing across
many catheterization laboratories worldwide and has already been
used extensively to examine strut coverage following stenting both in
registry studies [12–14] and in large, randomized trials [15–17]. The
attractive aspect of this device is that it is well positioned to detect
lialization has been linked to cases of stent thrombosis in post-mortem
series [18–20] and is therefore seen to be a key predictor of long-term
stent failure. This review will detail the principles of OCT imaging
within the coronary artery and explore the keyapplicationsin coronary
intervention that should propel this technology ahead of IVUS as the
new gold standard for stent imaging.
2. Optical properties of light-based imaging
OCT is an imaging modality that emits a near infrared light that
from the sample at a certain depth is measured using the principle of
low coherence interferometry, with a short coherence length of the
source of radiation [21,22]. The intensity of the interferometric signal
is converted to a color-scale or gray-scale to produce cross section
ation OCT systems, known as Time domain (TD) OCT [21–23], and
second generation systems, known as Fourier domain (FD) OCT
[24–26] that differ mainly with regard to the method used to calculate
the electric field amplitude. TD-OCT uses a broadband light source in
the 1280–1350 nm band, performs multiple scanning of reference
delay distance, and directly measures the electric field amplitude. By
contrast, FD-OCT uses a monochromatic laser whose wavelength
and is detected at all depth points simultaneously. Multiple terms are
International Journal of Cardiology 165 (2013) 7–16
⁎ Corresponding author at: Department of Cardiology, Northern Health, The Univer-
sity of Melbourne, 185 Cooper Street, Epping, Victoria 3076, Australia. Tel.: +61 3 8405
8554; fax: +61 3 8405 8405.
E-mail address: email@example.com (P. Barlis).
0167-5273/$ – see front matter © 2012 Elsevier Ireland Ltd. All rights reserved.
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International Journal of Cardiology
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currently in use for FD-OCT such as spectral radar and spectral-domain
OCT for those systems using a spectrometer and swept-source OCT, fre-
quency domain OCT, or optical frequency domain imaging (OFDI) for
systems with a wavelength-swept laser, the latter type being the most
commonly used in the setting of interventional cardiology [24–27].
OCT systems have a higher sensitivity than IVUS (Table 1), with
10–20 μm tissue axial resolution, 20–30 μm lateral resolution, although
the emitted light has a lower depth penetration than IVUS. TD-OCT
systems have a lower pullback, with a maximum of 3 mm/s, and a
frame rate that varies from 15.6 to 20 frames/s, while FD-OCT systems
have a higher pullback speed, up to 2 cm/s (Table 1). Therefore, FD-
OCT systems can perform intracoronary imaging with a non-occlusive
technique, thus avoiding ischemia-induced complications, and signifi-
cantly reducing the time for image acquisition. These features have
been responsible for the quick and growing widespread use of FD-OCT
inmodern catheterizationlaboratories worldwide. However, a common
limitation to both TD and FD-OCT systems is the need for intracoronary
contrast injection during image acquisition, to achieve adequate
displacement of red blood cells that limit the penetration of the emitted
light toward the target structures in the vessel wall, although the
volume of contrast injected is enormously minimized with FD-OCT.
The greater sensitivity of OCT systems than IVUS, has made OCT
the ideal imaging tool for the assessment of superficial components
of coronary plaques and stent struts.
3. Plaque assessment
The feasibility of OCT to image atherosclerotic plaque morphology
has been shown in early ex-vivo studies on explanted human aorta
and coronary arteries [28–30], and in subsequent in vivo studies in
animals [31,32]. A landmark post-mortem study has shown the ability
of OCT to characterize human atherosclerotic plaques compared to
histology . In this study, 357 atherosclerotic segments from 90
were established on 50 segments, allowing the identification of three
types of histological plaques: 1) fibrous, 2) fibrocalcific, 3) lipid-rich.
Fibrous plaques were defined as homogeneous, highly backscattering
(i.e., signal-rich) plaque interiors free of OCT signal-poor regions.
Fibrocalcific plaques presented signal-poor regions with sharply
delineated upper and/or lower borders. Lipid-rich plaques showed
lying signal-rich bands, corresponding to fibrous caps. A sensitivity and
specificity of 96% and 97% for calcific lesion, 90% and 92% for lipid-rich
plaques, 79% and 97% for fibrous plaque were obtained with OCT
compared to histology. The inter and intra-observer agreements for
plaque characterization by OCT were k=0.88 and 0.91, respectively.
pathology. In addition to identifying the same atherosclerotic compo-
nents detected by IVUS, such as fibrous plaque, and calcifications, OCT
allowed the identification of intimal hyperplasia, the internal and
external elastic lamina, and echolucent regions difficult to assess by
IVUS. Further, OCT was able to identify the position of calcium within
the vessel wall due to the lack of saturation and shadowing artifacts of
calcium deposits, therefore enabling the visualization of adjacent
tissues. OCT allowed the detection of the fibrous cap as strong contrast
between lipid-rich cores and fibrous regions and the quantitative mea-
This launched OCT as an imaging tool for the detection of the thin-cap
fibroatheroma (TCFA) that is considered the prototype of vulnerable
plaque and precursor of plaque rupture. Other studies confirmed the
ability of OCT to assess in vivo coronary plaque morphology, enrolling
patients with acute coronary syndromes . Furthermore, the OCT
signal variance derived parameter, known as normalized standard
deviation (NSD), showed a good correlation with CD68-positive cells
assessed by immunohistochemical analysis in postmortem specimens
superficial portion of atherosclerotic plaque . This parameter has
been successfully used for the measurement of macrophage densities
also in vivo . In another study of 108 coronary arterial segments of
40 consecutive human cadavers Kume et al.  showed that OCT can
correctly discern between red and white thrombi, on the basis of the
attenuation width of signal intensity, with the 1/2 attenuation width
of the signal intensity curve being significantly higher in red than in
white thrombi (324±50 vs 183±42, pb0.0001), and no significant
differences in peak intensity of OCT signal. Red thrombi appeared as
high-backscattering protrusions inside the lumen of the artery, with
signal-free shadowing, and white thrombi as low-backscattering
projections. Kubo et al.  assessed culprit lesion morphology in 30
patients with acute ST elevation myocardial infarction (STEMI) by
OCT, IVUS and coronary angioscopy. OCT detected fibrous cap disrup-
tion with a higher prevalence (73%) compared to coronary angioscopy
(47%, p=0.035) and IVUS (40%, p=0.009). The prevalence of plaque
erosion differed among techniques (23%, 3%, and 0% in OCT, coronary
angioscopy, and IVUS, respectively; p=0.003), with OCT reporting a
angioscopy, but it was identified only in 33% by IVUS (pb0.001). Inaddi-
tion, only OCT could estimate the fibrous cap thickness. Intraobserver
variability yielded acceptable concordance although interobserver vari-
ability showed slightly lower concordance. Other studies have used
OCT as imaging tool to study in vivo the mechanisms of acute coronary
syndromes, therefore limiting the effect of selection bias, typical of
of the culprit lesion, classifying the ruptured plaque as with rupture as at
the shoulder or in the central portion of the fibrous cap by OCT. They
investigated the relation between the morphology of plaque rupture
with the type of patient activity at the onset of symptoms (i.e. exertion
or rest) . This study found that patients with exertion triggered
acute coronary syndrome usually present with shoulder type plaque
rupture, while those with rest acute coronary syndrome onset show a
ruptured plaque in the central portion of the fibrous cap. Another study
que rupture or plaque erosion with luminal thrombi and systemic levels
of inflammatory biomarkers, such as myeloperoxidase and C-reactive
protein, in 25 consecutive patients with acute coronary syndrome .
This studyshowed thatpatients withplaque erosionpresentwithsignif-
while the levels of C-reactive protein did not significantly differ between
the two groups. Other studies have shown that OCT can monitor the
change in plaque fibrous cap thickness over time in response to drug
Physical characteristics of OCT vs IVUS.
Energy sourceNear-infrared lightNear-infrared
15 μm (axial)
100–200 μm (axial)
200–300 μm (lateral)
15 μm (axial)
40 μm (lateral)
1.5–2 mm2 mm10 mm
Modified from Eur Heart J. 2010 Feb;31(4):401–15.
aBased on specification of the LightLab M2/M2-X OCT systems.
bBased on specification of the C7XR OCT System.
cBased on specification of Volcano, Boston Scientific IVUS systems.
G. Ferrante et al. / International Journal of Cardiology 165 (2013) 7–16
Recently OCT was used to report differences in culprit lesion
morphology in patients with STEMI and non ST-elevation acute coro-
nary syndromes (NSTE-ACS) [43,44]. Ino et al.  assessed culprit le-
sion morphology in 89 consecutive patients (STEMI N=40; NSTEACS
N=49). The authors reported a higher incidence of plaque rupture,
thin-cap fibroatheroma, and red thrombus in STEMI patients com-
pared with NSTEACS (70% vs. 47%, p=0.033, 78% vs. 49%, p=0.008,
and 78% vs. 27%, p=0.001, respectively). OCT allowed the measure-
ment of the area of ruptured cavity, showing that this was significant-
ly larger in STEMI compared with NSTEACS (2.52±1.36 mm2vs. 1.67±
1.37 mm2, p=0.034). Further, OCT showed that a ruptured plaque with
an aperture open-wide against the direction of coronary flow was more
frequent in STEMI compared with NSTEACS (46% vs. 17%, p=0.036). In
another study, Toutouzas et al.  selected 55 patients with myocardial
infarction and documented culprit plaque rupture by OCT (N=30 with
STEMI; N=25 with NSTEMI). The authors reported that the site of pla-
que rupture was the minimal lumen in only 34.5% of patients, whereas
69% of the ruptures occurred at theplaqueshoulder.In 96% of cases, the
ruptured cap thickness was ≤90 μm. Patients with NSTEMI presented
with a greater minimal luminal area (pb0.001), less lipid content
(p=0.01), and lower rupture length (pb0.001) and length of missing
fibrous cap (pb0.05) compared with patients with STEMI.
The need for standardization of terminology for the appropriate use
and report of OCT imaging yielded to the publication of the “Expert
review document on methodology, terminology, and clinical applica-
tions of optical coherence tomography” . A complete description
of OCT and IVUS appearance of the atherosclerotic components has
been reported with details in this document, and remains beyond the
scope of this review. However, it is our aim to underscore the existing
limitations and pitfalls of OCT for the study of the biology of coronary
atherosclerosis in vivo, in particular in comparison with IVUS. Figs. 1
and 2 demonstrate some of the characteristic plaque appearances.
4. Pitfalls and limitations
Specifically, despite the higher resolution of OCT compared to
IVUS, sometimes non-protruding red thrombi can be misinterpreted
for necrotic lipid pool due to the similar OCT signal pattern of the
two plaque components . The visualization of the underlying
plaque may be affected by the presence of fresh, large or red thrombi,
the latter leading to typical signal free shadowing, thus making diffi-
cult the assessment of morphological characteristics such as plaque
rupture, that can otherwise be usually detected by OCT as a disconti-
nuity of the fibrous cap, leading to a communication between the
inner core of the plaque and the lumen. A frame by frame scanning
of OCT cross-sections acquired within the coronary segment with
thrombus may help the identification of sites where vessel wall and
plaque morphology can be assessed . Another main limitation of
OCT is the reduced depth penetration of the incident light beam
into the vessel wall compared to IVUS (Table 1). The identification
of atherosclerotic plaque components by OCT depends on such
depth penetration. This varies from lowest values for thrombotic
material to intermediate values for calcium and lipid tissue to the
highest values for fibrous tissue. Therefore in the majority of lesions
an accurate measurement of a total lipid pool cannot be performed
and the thickness of calcific deposits can be determined only in
their most superficial part. Similarly the assessment of vessel remo-
deling often cannot be performed by OCT. With respect to the latter
IVUS appears superior to OCT, and the use of IVUS virtual histology
may allow the characterization of plaque composition in vessels
with positive remodeling in an accurate manner . Furthermore,
although OCT has been shown to have the potential to identify eroded
plaques in vivo, by detecting plaques without signs of rupture and
with overlying thrombus [39,41], OCT does not allow to image directly
the luminal endothelial layer, as its sensitivity, albeit high, falls below
the size of individual endothelial cells. However a new form of OCT,
termed micro-OCT, with a resolution of 2 μm×2 μm×1 μm (x, y, z) in
tissue, improved by an order of magnitude has been recently reported
. In this study OCT images of fresh human coronary arteries from
explant (donor) hearts and from endothelial cell cultures as well as
swine coronary arteries, reproduced cellular and subcellular features
associated with atherogenesis, thrombosis and responses to interven-
Fig. 1. Panel A: Optical coherence tomography of the mid left circumflex artery show-
ing the normal 3 layered appearance of the coronary artery (intima, media and adven-
titia). Between 7 and 9 o'clock, an epicardial vein is seen. Panel B: An example of a
calcified plaque (arrow). This is characteristically poorly reflective and has sharply de-
marcated borders. Panel C: A concentric fibrous plaque is illustrated characterized by a
bright, highly light reflective appearance that is causing lumen constriction. Panel D:
Anexample of a lipid-richplaque (arrow) characterized by a poorly reflective appearance
with diffuse borders. Overlying the plaque is a bright thin rim of tissue characteristic of a
thin-cap fibroatheroma (red arrow). Lipid-rich plaques are differentiated from calcified
plaques by the nature of their borders, namely calcific plaques have sharply demarcated
edges compared to lipid rich plaques.
Fig. 2. Demonstrates the characteristic appearance of lipid-rich plaque (highlighted in
red on the right panel). OCT shows a poorly reflective region with diffuse borders.
Overlying this plaque is a bright thin rim of tissue indicating the thin fibrous cap. In
this example, the thin-cap fibroatheroma has ruptured (white solid arrow) with a
small protruding mass of tissue within the lumen consistent with thrombus (dashed
arrow). This plaque is pathognomonic of an acute coronary syndrome with rupture
of the vulnerable plaque. Rupture tends to occur in shoulder regions of plaques as in
G. Ferrante et al. / International Journal of Cardiology 165 (2013) 7–16
may occur. The Z-offset may undergo manual calibration using the
catheter diameter as reference, with the 4 marks aligning to fit the
In these cases the 4 marks should align the vessel wall using a frame
where the catheter is in contact with the vessel wall. With FD-OCT
systems, an automatic calibration is usually enabled. For a 1% change
in Z offset a 12% to 14% error in area measurements may occur
We report the list of artifacts that may affect the production of
optimal quality OCT images [48,49].
Incompletebloodclearance, i.e. the lack of adequate displacement of
red blood cells using contrast media injection may limit the penetra-
tion of the emitted light toward the target structures, thus resulting in
reduced brightness of the vessel wall, leading eventually to misinter-
pretation of residual blood as intravascular thrombotic material
Non-uniform rotational distortion consists in shape distortion of the
vessel wall as a result of non-uniform rotation of the fiber optic tube
that may be the consequence of vessel tortuosity or of imperfections
of the wire or the sheath.
Artifacts caused by discontinuity or sew-up artifact consist in the lack
of vessel wall continuity or misalignment of the lumen border caused
by rapid movements of the coronary artery or of the guidewire.
Saturation artifacts consist in signals produced by the reflection of
the light from specular surfaces that extend beyond the system's limit
of absorption. As a result the definition of the surface is reduced. A
typical example is imaging of stent struts.
Folding artifact is the distortion in the form of a “folded” vessel that
occurs when the light is reflected outside the system's penetration
field, such as side branches or large vessels. This artifact is more
common with FD-OCT systems.
Artifactsofeccentricityoftheguidewireintheartery. There are 2 types
of artifacts: 1) due to carrousel or merry-go-round phenomenon; 2)
due to sunflower phenomenon. Both usually occur with stent struts.
The first phenomenon causes a decrease of lateral resolution and
depends on imaging sweep speed. The second phenomenon is the
alignment of the reflections from the struts toward the image wire,
not coincident with the center of artery.
Bubble artifact leads to attenuation of the signal inside a region in
the vessel wall. It arises from the presence of small gas bubbles in the
silicon lubricant between the sheath of the optic fiber in TD-OCT
6. Vessel wall response to stent implantation
6.1. Strut apposition
OCT can adequately detect individual stent struts and characterize
their apposition to the vessel wall, with fewer artifacts and superior
contrast than IVUS . In IVUS studies incomplete “stent” apposition
was usually defined as the presence of 1 or more struts clearly sepa-
rated from the vessel wall with evidence of blood speckles behind
the strut in a vessel segment not associated with any side branches
. Therefore, by definition, IVUS studies were used to report the
number of stents with incomplete “stent” apposition and to compare
these with stents without evidence of incomplete “stent” apposition
[51,52]. OCT instead, due to its higher resolution, allows an accurate
measurement of the separation distance between the endoluminal
surface of individual struts and the vessel wall, thus quantifying the
number of struts, with incomplete apposition or malapposition, in
cross sections along the entire segment of interest. Therefore, stent
apposition is assessed at the strut level [48,53].
A detailed investigation in vivo of strut apposition in complex lesion
settings such as coronary bifurcation lesions has become feasible with
OCT. A recent study  enrolling 13 patients (17 bifurcation lesions)
treated with a simple strategy of stenting main vessel alone, and 14
patients (14 lesions) treated with the culotte technique, analyzed a
total of 8666 struts by OCT across four segments into the bifurcation
lesion: the bifurcation segment divided into 2 halves: toward and
oppositethe sidebranch, aproximalandadistalsegmenttothebifurca-
tion segment. This study showed that strut malapposition occurs most
frequently and is most severe toward the side branch origin. In another
study, OCT measured the performance of a novel dedicated stent for
bifurcation lesions . Fig. 4 demonstrates gross strut malapposition
8 months post stenting in an area of stent overlap.
6.2. Acute damage after stent implantation
OCT has been shown to detect disrupted intima, intraluminal throm-
bus and tissue prolapse during PCI [56,57]. Its higher resolution allowed
the visualization of the depth of balloon-induced dissections and cutting
OCT than with IVUS, and the extent of the tissue prolapse (mean±SD)
was 242±156 μm by OCT and 400±100 μm by IVUS . Gonzalo et
al.  have reported a systematic and quantitative classification of the
acute effects of stent implantation on the vessel wall, by OCT. In this
study enrolling 73 patients (80 lesions), tissue prolapse was detected in
97.5% of stents, the presence of thrombus in 45%, intra-stent dissection
in 87.5%, intrastent dissection flap in 86.2%, intrastent dissection cavity
Fig. 3. Panel A: High power view of cross section OCT image showing typical artifact
due to incomplete blood clearance with the swirling intraluminal appearance. This
can often be overcome by increasing the rate of contrast flush within the artery.
Fig. 4. Panel A. Left oblique angiographic view of the right coronary artery 8 months
following stenting of a long segment of disease with drug eluting stents from the prox-
imal to distal segment. Arrow marks the proximal stent. Panel B. Cross section OCT
image corresponding to arrow in A showing grossly malapposed stent struts that ap-
pear to be covered by a layer of tissue (curved line o' clock 12–6).
G. Ferrante et al. / International Journal of Cardiology 165 (2013) 7–16
in 68.8%, and edge dissection in 26% (see Fig. 5). In IVUS studies the
frequency of tissue prolapse after stent implantation was lower ranging
from 22% after BMS , to 16.6% in a study of diabetic patients , to
41% after sirolimus eluting stent implantation or 24% after paclitaxel
eluting stent implantation in another study , likely due to the lower
resolution of IVUS compared to OCT. Similarly, Kawamori et al. 
reported a higher prevalence of tissue prolapse, thrombus, edge dissec-
tion by OCT compared to IVUS after stent implantation. In a recent
study an association between procedural dissections and malapposed
and/or protruding struts at follow-up was reported by OCT . In an
IVUS study, patients with tissue prolapse presented higher values of
post-PCI CK-MB elevation, however tissue prolapse was not associated
with restenosis or clinical events . In the study of Gonzalo et al.,
no clinical events occurred during hospitalization, however periproce-
dural Troponin I or CK-MB or long term follow up was not reported
. Therefore the clinical meaning of these frequent OCT findings of
acute vessel damage after stent implantation remains to be established
in larger studies with longer follow up.
neointimal hyperplasia , or the effect of excimer laser on restenotic
tissue . Finally OCT has been reported to allow an accurate diagnosis
of stent fracture of sirolimus eluting stents .
6.3. Tissue coverage
OCT allows an accurate assessment in vivo of strut tissue coverage
and neointimal hyperplasia at follow up, providing quantitative
measurements of minimal lumen area, minimal stent cross section
area, percentage lumen obstruction and percent neointimal hyperpla-
sia, due to its ability to characterize lumen-vessel/stent interface .
Several OCT studies have reported a neointima hyperplasia at 6 to
12 months follow up after DES implantation with a median thickness
that falls below the sensitivity of IVUS (100 μm)in a large proportion of
lesions [67–69]. OCT studies have shown that DES struts may present
lack of tissue coverage even at 2 years after stent implantation 
and that the rate of covered struts differs across patients with different
clinical syndromes . Although the lack of detection of a thin layer of
tissue of 10 μm does not rule out the presence of strut coverage by
endothelial cells, OCT still has a far superior resolution to IVUS. This
has led to several studies addressing the process of strut healing in
different types of DES. In a subgroup of the LEADERS trial, a multi-
center, randomized comparison of a biolimus-eluting stent (BES) with
biodegradable polymer with sirolimus eluting stent (SES), OCT was
employed to assess the difference in percentage of uncovered struts at
9-month follow-up between BESs and SESs . Twenty patients in
the BES group (29 lesions with 4592 struts) and 26 patients in the SES
group (35 lesions with 6476 struts) underwent OCT. A total of 83 struts
were uncovered in the BES group and 407 struts were uncovered in the
SES group [weighted difference −1.4%, 95% confidence interval (CI)
23.7 to 0.0, p=0.04]. Three lesions in the BES group and 15 lesions in
the SES group that had ≥5% of all struts uncovered (difference
−33.1%, 95% CI −61.7 to −10.3, pb0.01).
Other studies have addressed strut healing at follow up in complex
and strut healing at follow up, reporting a tendency towards a less
pronounced strut coverage over malapposed and protruding struts, as
compared to apposed struts . In a substudy of the ODESSA trial,
focused on bifurcation lesions, Kyono et al. reported a variable pattern
of strut coverage in the bifurcation among different types of stents, with
a high percentage of paclitaxel eluting stents floating struts remaining
uncovered at 6 month follow-up . Recently, in an analysis of 178
DES implanted in 99 patients from 2 randomized trials, struts with
incomplete apposition and malapposed side-branch struts presented a
follow up . Furthermore strut tissue coverage and neointima hyper-
plasia assessed by OCT have become primary endpoints of randomized
trials comparing different types of stents [15,17]. Although the use of
such “intermediate” OCT endpoints has a pathophysiological interest, in
particular due to the relationbetweenstrut coverageand stent thrombo-
sis [18–20], these endpoints should not be considered as a substitute for
clinical endpoints on which clinical decision making should rely.
6.4. Restenotic tissue characterization
Fig. 6 demonstrates the OCT appearances ofin-stentrestenosis (ISR)
and the possible quantitative measurements able to be derived. Several
OCT studies have reportedthepresenceofseveralmaterials withdiffer-
ent optical properties inside the restenotic tissue after stent implanta-
tion, suggesting that different tissue constituents may contribute to
ISR, thus showing that OCT may be useful in studying the mechanisms
of ISR [73,75]. Gonzalo et al.  assessed the morphologic characteris-
tics of restenotic tissue by OCT in 24 patients (25 vessels) who pre-
sented with angiographically documented ISR. In addition to a
quantitative assessment of lumen and stent area measurement and cal-
culation of restenotic tissue area and burden, the authors performed a
Fig. 5. Panel. A High power view of cross section OCT image showing intra-stent dissec-
tion consisting in a disruption of the vessel luminal surface in the stented segment with
evidence of flap (arrow). Panel B. High power view of cross section OCT image showing
typical example of edge dissection defined as a disruption of the vessel luminal surface
in the stent edge region (5 mm proximal and distal to the stented region, no struts are
visible) with evidence of flap (arrow).
Fig. 6. Panel A. Left oblique angiographic view of the right coronary artery 4 years after
stenting with a bare metal stent. Panel A shows in-stent restenosis in the proximal seg-
ment with homogeneous appearance at 12–6 o'clock and a heterogeneous, layered ap-
pearance between 6 and 12 o'clock. Corresponding measurements of the restenosed
segment showed a minimum lumen area (MLA) of 1.63 mm2, stent diameter of
2.53 mm, and lumen diameter of 1.38 mm with an area stenosis (AS) of 68.4%.
G. Ferrante et al. / International Journal of Cardiology 165 (2013) 7–16
qualitative assessment of the restenotic tissue structure, assessing the
backscattering and symmetry, the presence of visible microvessels,
lumen shape, and presence of intraluminal material. They classified
the restenotic tissue structure as layered in 52%, homogeneous in 28%,
are associated with different types of angiographically defined ISR as
heterogeneous and low scattering restenotic tissue was more frequent
in focal (45.5% and 54.5%, respectively) than in diffuse (0 and 11.1%)
and margin restenosis (0 and 0%) (p=0.005 for heterogeneous,
p=0.03 for low scattering). Furthermore they reported a higher preva-
lence of restenotic tissue with layered appearance (84.6% vs 16.7%,
p=0.003) in stents implanted ≤12 months earlier suggesting the
sis. Takano et al.  compared the restenotic tissue of ISR of 20 BMS
implanted b6 months earlier with that of ISR from 21 BMS at a follow
up ≥5 years, using OCT. The authors reported the lack of lipid-laden
intima in the early phase, with homogeneous proliferation of normal
neointima, while lipid-laden intima, intimal disruption, and thrombus
were more frequently detected in the late phase as compared to the
early phase (67% vs. 0%, 38% vs. 0%, and 52% vs. 5%, respectively;
pb0.05). Also intraintima neovascularization was more frequent in the
late phase than the early phase (62% vs. 0%, pb0.01) and in segments
with lipid-laden intima than in nonlipidic segments (79% vs. 29%,
p=0.026). Therefore the authors showed the dynamic change of the
restenotic tissue from neointima to atherosclerotic like appearance in
the same patients, over a late phase period of observation. Kang et al.
 have used OCT to investigate the mechanisms of DES failure. The
authors enrolled 50 patients (30 stable, 20 unstable angina) with 50
DES ISR lesions and intimal hyperplasia >50% of stent area that under-
went OCT and grayscale and virtual histology IVUS, at a median
follow-up time of 32.2 months. They reported at least 1 OCT-defined
in-stent TCFA containing neointima in 26 lesions (52%) and at least 1
in-stent neointimal rupture in 29 (58%). Patients presenting with unsta-
ble angina showed a thinner fibrous cap and had a higher incidence of
OCT-defined TCFA-containing neointima (75% versus 37%, p=0.008),
intimal rupture (75% versus 47%, p=0.044), thrombi (80% versus 43%,
p=0.010), and red thrombi (30% versus 3%, p=0.012) than stable pa-
tients. Of note DES ≥20 months after implantation had a higher inci-
dence of TCFA-containing neointima (69% versus 33%, p=0.012) and
red thrombi (27% versus 0%, p=0.007), compared with DES
b20 months after implantation.
6.5. Stent thrombosis
the features of very late stent thrombosis (VLST) after DES with OCT in
18 patients. The authors reported the presence of ruptured and lipid-
laden neointima inside DES without uncovered or malapposed stent
struts in 4 (22.2%) patients. Among the remaining 14 patients without
neointimal rupture, uncovered and malapposed struts were detected
in 9 and 7 seven patients, respectively, and lipid-laden neointima in 4
patients. Lipid-laden neointima was more frequent in patients with
neointimal rupture than in those without (100% vs. 28.6%, respectively,
p=0.023). The authors enrolled additional57 patients with neointimal
hyperplasia causing >40% diameter stenosis. Among these, those
(N=8) with lipid-laden neointima had a significant longer time to
OCT after DES implantation than those (N=49) without lipid-laden
neointima (45.5±17.7 months vs. 11.7±7.2 months, respectively,
pb0.001). The authors suggested that the presence of lipid-laden
neointima inside DES might represent the potential substrate for the
development of neointimal rupture. These findings are in agreement
with the results from another study by Lee et al.  who reported
the presence of neointimal rupture within the stent in 43.5% of 23 pa-
tients with DES-related VLST, using IVUS. However, OCT is superior to
IVUS in detecting neointimal rupture or lipid-laden neointima due to
its higher spatial resolution and is more sensitive in discriminating
thrombus from coronary artery structures.
6.6. Periprocedural myocardial damage
OCT has been employed to study the relation between culprit lesion
morphology and no-reflow or periprocedural myocardial damage after
PCI with stent implantation [78–81]. Tanaka et al.  assessed the
culprit lesion in 83 patients with NSTE-ACS undergoing emergent PCI
byOCT.Theyprovideda semi-quantitativemeasureof plaquelipid con-
tent by measuring the lipid arc, and defining a plaque as “lipid-rich”
when the lipid arc stretched for >90°. The authors reported a higher
prevalence of TCFA by OCT in patients who developed no-reflow, de-
fined as post-PCI TIMI flow b3 in the absence of a mechanical obstruc-
tion on angiograms, than in those who did not (50% vs. 16%, p=0.01).
They showed a positive relation between the rate of no-reflow and
the size of lipid arc at the culprit plaque, they reported that 46% of pa-
tients with lipid-rich plaque developed no-reflow after PCI, while no
case of no-reflow occurred among 34 patients without lipid plaques,
and that lipid arc alone was a significant, albeit weak, predictor of no-
reflow (odds ratio 1.018; CI 1.004–1.033; p=0.01) at multivariable lo-
gistic regressionanalysis. Yonetsu et al. , performed baselineOCT to
tients undergoing elective PCI with stent implantation. A higher
prevalence of TCFA and plaque rupture was detected in patients who
developed post-PCI increase in creatine kinase-myocardial band CK-
MB above the upper reference limit. Lipid quadrants and the length of
the lipid-rich plaque also showed significant associations with post-PCI
CK-MB elevation. At multivariable analysis, among OCT derived vari-
ables, the presence of TCFA [odds ratio (OR) 4.68, 95% CI 1.88–11.64,
p=0.001)] was associated with post-PCI CK-MB elevation. Lee et al.
with normal pre-PCI CK-MB levels (28 with unstable angina; 107 with
stable angina) with intravascular ultrasound and OCT before elective
stent implantation. They reported that plaques with echo attenuation
presented an association with the presence of TCFA, ruptured plaques,
greaterlipidcontentassessed by OCT. Theyalso found that bothplaques
with echo attenuation (OR 3.49, 95% CI 1.53 to 7.93; pb0.003) and the
presence of plaque rupture, assessed by OCT, (OR 2.92, 95% CI 1.21 to
7.06; p=0.017) were predictors of post-PCI CK-MB increase above the
upper reference limit at multivariable analysis. The same group of
authors, in a separate study , reported a significant association
between the presence of TCFA assessed by OCT and the occurrence of
post PCI elevations of Troponin I above 3 times the upper reference
sis (OR 10.47, 95% CI 3.74 to 29.28; p=0.001). Although these studies
provided an interesting and plausible pathophysiological association
between the presence of TCFA or lipid plaques and peri-procedural
myocardial or microvascular damage, thus suggesting that OCT may
be useful for risk stratification of patients undergoing PCI, the small
of multivariable analyses and thus the strength of such association.
7. Practical implications of OCT
Imola et al.  have reported data from a single center registry
enrolling 90 patients who underwent FD-OCT, for the assessment of
angiographically ambiguous/intermediate lesions (N=40) or of stent
adequacy after implantation (N=50). In this registry, the use of OCT
helped in thedecisionon a)whether to treat angiographically apparent
ambiguous/intermediate lesions with stent implantation, on the basis
of the presence of OCT detected thrombus and/or a minimal luminal
area(MLA)b3.5 mm2; b)whethertoperformfurther balloondilatation
ing criteria: 1) lack of optimal stent expansion defined according to the
previously reported IVUS based criteria in the MUSIC study ; 2)
G. Ferrante et al. / International Journal of Cardiology 165 (2013) 7–16
significant strut malapposition, defined as a distance between strut and
vessel wall greater than 200 μm and extending for a length of at least
600 μm; 3) significant intraluminal tissue-prolapse, (i.e. >100 μm); or
to perform further stent implantation in case of edge-dissection, defined
as disruption of the luminal vessel surface in the stent edge segments
(within 5 mm proximal and distal to the stent) extending beyond
200 μm. The use of OCT yielded to deferring PCI for ambiguous/
intermediate lesions in 40% patients, and to further balloon dilatation/
stent implantation in 32% patients with stented coronary segments.
Outcome at mean follow-up of 4.6 months was extremely good with
2.2% repeat revascularization and no stent thrombosis.
In a larger registry  enrolling 884 patients, IVUS guidance of PCI
with DES implantation yielded to a significant lower rate of definite
stent thrombosis at 30 days and 12-month follow-up, compared to a
propensity score matched population of patients undergoing angio-
graphic guided PCI with DES (0.5% vs. 1.4%, p=0.046 and 0.7% vs.
2.0%,p=0.014, respectively)and emergedasanindependentpredictor
of freedom from cumulative stent thrombosis at 12 months (adjusted
HR 0.5, CI 0.1–0.8; p=0.02). However, no major differences in major
adverse cardiovascular events at 12-month follow-up, rates of death
and Q-wave myocardial infarction, and target vessel revascularization
were observed between the groups.
Merits of the study by Imola et al.  are the use of quantitative
OCT criteria to guide PCI. From a theoretical standpoint the operator at-
tention moved from the IVUS based endpoints of optimal stent expan-
sion with respect to reference vessel diameter and optimal stent
symmetry to those aiming at improving the luminal area inside the
stented segments or at the stent margins, that can be better assessed
sumptions, yet to be proven, that the correction of OCT detected
significant strut malapposition or significant tissue prolapse by further
balloon dilatations, as far as the correction of edge dissections by addi-
stent thrombosis,thusyieldingto a better clinical outcome.OCTmaybe
when vessel size is large, due to its limited depth penetration, as we
mentioned in this review. Recently Tu et al.  have reported an inte-
grated three dimensional (3D) approach based on thecombinationof X
about vessel size and plaque size at every position along the vessel of
interest. This approach starts with standard quantitative coronary
angiography of the vessel of interest in the two angiographic views
(either biplane or two monoplane views). A 3D reconstruction of the
vessel of interest is then performed and registered with the corre-
sponding IVUS/OCT pullback series by a distance mapping algorithm.
This allows a more accurate interpretation of vessel dimensions per-
mitting the recognition of the exact position in the X ray images
where the stent should be deployed.
The use of an OCT MLA 3.5 mm2as cutoff to perform or defer PCI
needs validation in future studies. For long time an IVUS MLA
4 mm2cutoff has been chosen to defer PCI on the basis of the results
of a study , that enrolled 300 patients (357 lesions) and reported
that in 248 lesions with a minimum lumen area ≥4.0 mm2the rate of
death, myocardial infarction, target lesion revascularization (TLR)
was 4.4% and TLR rate was 2.8% at a mean follow up of 13 months.
However a single cross sectional area in a vessel is only one of several
factors limiting flow and producing ischemia, with different effects
depending of diameter vessel size .
Ina morerecentstudyenrolling150patients (170 lesions)who
underwent stress myocardial single-photon emission computed to-
mography (SPECT), the best cutoff value of IVUS MLA was ≤2.1 mm2
with an 86.7% sensitivity, a 50.4% specificity, a 38.6% positive predictive
value, and a 91.3% negative predictive value versus lesions with a
positive SPECT. The agreement between IVUS MLA criteria and SPECT
was poor, considering the kappa statistic of 0.27. Due to the high
negative predictive value, IVUS MLA could be considered useful to
defer PCI but its low positive predictive value limits its use for clinical
decision-making. In another study  enrolling 201 patients (236 le-
sions) the independent determinants of fractional flow reserve (FFR)
were the IVUS parameters of MLA, plaque burden, lesion length with a
lumen area b3.0 mm2and left anterior descending artery location.
The best cutoff value (with a maximal accuracy) of the MLA to predict
FFR b0.80 was b2.4 mm2, with a diagnostic accuracy of 68% (90% sensi-
tivity, 60% specificity). However, only 44 (37%) lesions with an MLA
b2.4 mm2had an FFR b0.80, therefore IVUS-derived MLA ≥2.4 mm2
could be useful to exclude FFR b0.80, but poor specificity limits its
value for physiological assessment of lesions with MLA b2.4 mm2.
On the basis of such IVUS data,an OCTMLA 3.5 mm2may not bethe
optimal cutoff for the identification of functional significant stenosis.
Further the agreement between OCT and IVUS for luminal measure-
ments is not perfect. In a multicenter registry enrolling 76 patients,
Yamaguchi et al.  reported measurements of minimal lumen
diameter and MLA by TD-OCT and IVUS. The authors found a good
agreement between the techniques assessed by Bland Altman plot.
The OCT intraobserver correlation coefficients for minimal lumen
diameter and MLA were 0.999 and 0.999, respectively, and the interob-
server correlation coefficients for minimal lumen diameter and MLA
were 0.997 and 0.998, respectively. However both measurements by
OCT were significantly smaller than those by IVUS (2.2±0.7 vs 2.3
±0.6 mm,p=0.008; 5.2±2.8
respectively). In another study, Suzuki et al.  compared TD-OCT,
IVUS, and histology for the assessment of in-stent neointima in 33
stents from 6 pigs at 1-month follow-up. Compared with histology
and TD-OCT, IVUS tended to overestimate lumen area and underesti-
mate percent area stenosis, however the agreement between the tech-
niques was not addressed by means of Bland Altman plot.
In a recent study, Stefano et al.  reported an initial experience of
complementary use of FD-OCT with FFR to guide decision-making in
complex clinical scenarios. Indeed, the authors enrolled a series of the
14 patients who underwent FFR of 18 target stenoses in addition to
FD-OCT. FD-OCT was used to guide decision to defer PCI in six patients
with acute coronary syndrome and FFR>0.80, by ruling out the
presence of plaque rupture, erosion and thrombosis and to guide PCI
strategy in tandem lesions with an FFRb0.80. However in this study
there was no significant correlation between FFR and morphologic
quantitative parameters by OCT. Indeed single stenoses with FFR b0.80
presented a wide range of MLA from 1.95 to 9.04 mm2.
Therefore although the use of FD-OCT may provide undoubtedly
clear morphological information in a quick and safe manner during
PCI, decisions regarding coronary intervention should be based on
objectiveevidenceof myocardialischemia andoffunctional significance
of coronary artery stenoses. With this respect the use of FFR is based on
large evidence [93,94].
8. Novel applications and future perspectives
OCT has been used to assess in vivo the bioabsorption process of
struts of bioresorbable vascular scaffolds, such as the everolimus-
eluting bioresorbable vascular scaffold (BVS; Abbott Vascular, Santa
Clara, CA, US) that was tested in the ABSORB study (N=30 patients)
[95,96]. OCT can distinguish the rectangular polymer BVS struts that
are optically transparent from the highly scattering vascular wall.
Changes in the strut optical appearance at follow-up were categorized
as: “preserved box” when an intact strut footprint was present, “open
box” that marks the first OCT change in the strut footprint, dissolved
“bright box”, and dissolved “black box” that designate struts with a
degraded footprint that merges into the artery wall . At 2 years,
OCT analysis showed that 34.5% of the struts were no longer identifi-
on thebasis ofhistological analysis,thatBVSstrutswithOCTappearance
of “preserved box” could be seen either in the presence of intact polymer
G. Ferrante et al. / International Journal of Cardiology 165 (2013) 7–16
struts or in case of complete resorption of the polymer with replacement
by proteoglycans, that the stent strut outline was preserved even when
the polymer is fully resorbed and replaced by proteoglycans, that struts
with OCT appearance of “dissolved” box corresponded to areas of cells
and/or connective tissue that replaced the struts. Therefore OCT was un-
able to characterize polymer content. However researchers from Harvard
Medical School, Boston , who have pioneered and made an outstand-
ing contribution to the development and use of OCT in the field of inter-
ventional cardiology with their innovative inventions, have suggested
that future OCT technology could be configured to allow a better distinc-
tion of polymer from proteoglycan, detecting differences in the physical
parameters of refractive index, dispersion, and/or birefringence between
new bio-absorbable devices that will intentionally incorporate a small
amount of scattering that canbe detected by OCT; thus allowing to quan-
tify polymer content from the OCT signal within the strut region.
For research purposes it would be of interest also to develop OCT
systems with the ability of cellular and molecular tagging toward the
constituents of coronary atherosclerotic plaques, endothelial cells and
inflammatory cells, in order to provide a functional assessment of the
vulnerable plaques and to help the characterization of the properties
of the tissue covering stent struts in vivo. The recently reported
micro-OCT , able to visualize key cellular and subcellular features,
with many of the capabilities of 3D histology and of scanning electron
ready ongoing [98–103]. Previous studies have experimented tissue
characterization software for a semi-quantitative measurement of pla-
que components on the basis of light coefficient attenuation and
backscattering properties [104,105]. Three dimensional image recon-
struction with FD-OCT systems has also been demonstrated and
may represent a useful application for the quantification and the
characterization of the pattern of strut malapposition and strut coverage
inside stented segments .
OCT is a high-resolution intravascular imaging technique permitting
the in vivo study of the pathophysiology of coronary atherothrombosis
nique that can also assess on a micrometer scale vessel wall response to
stent implantation, thus providing clinically useful information to the
interventional cardiologist. The undisputed clarity in imaging has
attracted considerable attention in cardiovascular circles and further
research will help to establish the clinical impact of this modality in
patients with heart disease.
The authors of this manuscript have certified that they comply
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