Hybrid intravascular imaging: current applications and prospective
potential in the study of coronary atherosclerosis
Christos V. Bourantas,¶ MD, PhD; Hector M. Garcia-Garcia,¶,* MD, PhD;
Katerina K Naka,† MD, FESC; Antonios Sakellarios,‡ BSc; Lambros Athanasiou,‡ BSc;
Dimitrios I. Fotiadis,‡ PhD; Lampros K. Michalis,† MD, MRCP, FESC;
Patrick W. Serruys¶,* MD, PhD, FESC, FACC
¶
ThoraxCenter, Erasmus Medical Center, Rotterdam, The Netherlands
†
‡
Dept. of Cardiology, University of Ioannina, Greece
Unit of Medical Technology and Intelligent Information Systems, Dept. of Materials Science
and Engineering University of Ioannina, Greece
*Address for correspondence
Patrick W. S. Serruys, MD, PhD
ThoraxCenter, Erasmus MC ‘s-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands
Tel: +31 10463 5260; Fax: +31 10436 9154
e-mail: p.w.j.c.serruys@erasmusmc.nl
Hector M. Garcia Garcia
Thoraxcenter, Erasmus MC, z120 Dr Molerwaterplein 403015 GD Rotterdam, the Netherlands
Tel: +31 10 206 28 28
email: h.garciagarcia@erasmusmc.nl
Currently available and emerging intravascular imaging modalities
a)
Intravascular ultrasound
Intravascular ultrasound (IVUS) is currently the most widely used intravascular imaging
modality. It requires the insertion of a catheter with a transducer on its tip that emits ultrasound
signal perpendicular to its axis at a frequency of 20-70MHz. The reflections of the emitted signal
are received by the transducer and are analyzed to generate cross sectional images of the vessel
which allow identification of the luminal and media-adventitia borders, evaluation of the plaque
burden and characterization of its composition (1). The ability of grayscale IVUS to detect the
composition of the plaque is moderate according to histology based studies, a limitation that has
been addressed, to a certain extent, with the radiofrequency analysis of the IVUS backscatter
signal (RF-IVUS) (2). Although this approach has increased the sensitivity and specificity of
IVUS for plaque characterization, recent reports have casted doubts about its reliability in
assessing the plaque type especially in stented segments and behind calcium deposits (3-4). Other
significant limitations of IVUS are the noise and artifacts that it contains and its moderate radial
resolution which does not allow detection of features associated with an increased risk of plaque
rupture (e.g. microcalcifications, neovascularization, plaque erosion, etc) (5). Further to that,
IVUS cannot provide any information regarding the longitudinal 3 dimensional (3D) vessel
morphology and gives only indirect information about the distribution of the plaque onto the
vessel.
b)
Optical coherence tomography
Optical coherence tomography (OCT) is the optical analogous of IVUS. It has a higher axial
resolution (12-18μm) and thus permits visualization of details which cannot be seen by IVUS
including all vessel wall layers (provided that there is no disease in the intima), the presence of
macrophages, neovascularization, microcalcifications, the type of thrombus and it allows
estimation of the thickness of the fibrous cap (6-7). Histology based studies have demonstrated
that OCT is a reliable technique in detecting the type of the plaque although some reports have
raised concerns about its ability to discriminate calcific from lipid-rich plaques (8-10). These
qualities have rendered OCT as one of the most relevant methods for the identification of the
vulnerable plaques. Limitations of OCT imaging are: i) its inability to penetrate lipid-rich cores
and ii) its general limited tissue penetration (range: 2-3mm) which often inhibits the visualization
of the whole atheroma. Moreover, similarly to IVUS, OCT fails to portray the longitudinal 3D
morphology of the vessel and provides limited information about the distribution of the plaque
onto the artery.
c)
Near infrared spectroscopy
Near infrared spectroscopy (NIRS) relies on the principle that different organic molecules absorb
and scatter NIRS light to different degrees and at various wavelengths. The spectral analysis of
the reflected NIRS light allows evaluation of the chemical composition of the plaque and
identification of the lipid component. The ability of NIRS to detect lipid-rich plaques has been
evaluated using histology as gold standard, while the SPECTroscopic Assessment of Coronary
Lipid (SPECTACL) trial examined in vivo the feasibility of a NIRS catheter and demonstrated
that it is safe and provides reliable information regarding the lipid component in 83% of the
studied vessels (11-12). In contrast to RF-IVUS, NIRS is restricted to the identification of
superficial (cap thickness <450μm), wide lipid cores (circumferential extent >60o, plaque
thickness >200μm) but it appears more reliable for the detection of lipid-rich plaques located
behind calcific deposits (13-14). Other significant limitations of NIRS are its inability to visualize
the lumen and outer vessel wall, to quantify the atheroma burden and to portray plaque
characteristics associated with increased vulnerability such as the fibrous cap thickness, its
integrity and the presence of thrombus or neovascularisation.
d)
Intravascular magnetic resonance spectroscopy
Intravascular magnetic resonance spectroscopy involves the advancement of a catheter with a
magnetic resonance probe on its tip. The magnetic field generated by the probe creates a field of
view with a radial sector of 60ο that allows identification of the lipid component in 2 zones: the
superficial (depth: 0-100μm) and the deeper (depth 100-250μm) plaque. Image acquisition is time
consuming and requires a side balloon to stabilize the probe against the vessel wall and prevent
distal blood flow. The designed catheter has a large diameter (5.2F) and does allow visualization
of the lumen, vessel wall and plaque morphology (Online Fig. 1.A). Although small scale studies
have confirmed the feasibility of this modality the abovementioned limitations have restricted its
applications in the clinical and research arena (15-16).
e)
Intravascular magnetic resonance imaging
Intravascular magnetic imaging is likely to become a useful tool in the study of atherosclerosis as
it has a better penetration than OCT and, in contrast to IVUS, it allows visualization of the plaque
behind calcific tissue. Significant limitations of this technology such as the noise introduced by
movements, the heating produced during imaging and the increased time needed for image
acquisition have not allowed its implementation in humans yet. Recent advances in intravascular
magnetic resonance technology have permitted real time high resolution (80μm) in vivo imaging
(Online Fig. 1.B). However, further improvements in coil design (the current coil has a diameter
9F) are required before this modality being applied in clinical setting (17).
f)
Raman spectroscopy
Raman spectroscopy is an emerging intravascular modality that relies on the spectral analysis of
the Raman scattering by a tissue after this being illuminated with a laser beam. The Raman effect
involves the scattering of the light between molecules that finally change the energy of the
photons and modify the frequency of the backscattered light. The Raman spectra is unique for a
given molecule and therefore it can be used to identify the chemical composition of the plaque
(18). Numerous experimental studies have demonstrated that this modality provides accurate
characterization of different plaque types and, in contrast to the other techniques, detailed
analysis of their chemical composition and detection of different constituents such as elastin,
collagen, calcium, esterified and non-esterified cholesterol (19-21). Van de Poll et al. showed that
Raman spectroscopy permits quantification of the effect of treatment on the composition of the
plaque while Montz et al. studied specimens obtained from carotid and femoral human arteries
and showed that Raman spectroscopy not only allows accurate tissue characterization but also
identification of the vulnerable plaques with a high sensitivity and specificity (79% and 85%
respectively) (22-23). However, this modality has failed to progress mainly because of the
difficulty to acquire high quality signal for analysis as the noise, generated within the fibers of the
imaging catheters, interferes with the Raman spectra. High-wave number Raman spectroscopy
and new developments in catheter design are likely to address this pitfall and permit its use in
clinical setting (24-25) (Online Fig. 1.C). Other limitations of this modality are its inability to
visualize the lumen, vessel wall and plaque morphology and measure their dimensions.
g)
Photoacoustic imaging
Intravascular photoacoustic (IVPA) imaging is based on the analysis of the sound produced by
the thermal expansion of irradiated tissues. The photoacoustic response of different tissues
depends on the absorption characteristics of their constituents and seems to allow identification of
different plaque components. Several experimental studies have demonstrated that IVPA is
capable to differentiate lipid rich plaques from fibrous tissue and detect the presence of
neoangiogenesis (Online Fig. 1.D) (26-28). In addition, markers with high optical absorption
coefficients can be used, during IVPA imaging, to detect cells (e.g. macrophages) or molecules
that are involved in the atherosclerosis process and plaque inflammation (e.g. metalloproteinases,
selectins, etc) and thus to evaluate more accurately the atherosclerotic evolution (29). The
feasibility of this potential was examined ex vivo by Wang et al. who utilized gold nanoparticles
to label macrophages that were injected in the aorta of a rabbit. IVPA imaging was then
performed and it was found that it allowed accurate identification of the location of the injected
macrophages (30). Other significant advantages of IVPA imaging are its ability to visualize stent
morphology and its high penetration and lateral and axial resolution that permit detailed and
complete evaluation of vessel wall (30-31). Although several experimental studies have provide
evidence about the value of this modality in the study of atherosclerosis IVPA imaging has not
have clinical applications as its safety has not been confirmed yet.
h)
Near infrared fluorescence imaging
Near infrared fluorescence (NIRF) imaging is a rapidly evolving imaging modality that has been
recently introduced in the study of atherosclerosis. It relies on the injection of agents that have the
ability to bind molecules and fluoresce when they imaged with a near infrared light. This
modality was implemented for the first time 10 years ago by Chen et al. to visualize cathepsin B
accumulation in mice models (32). Since then advances in molecular biology have permitted the
development of several NIRF markers that can label different molecules such as thrombin, matrix
metalloproteinase 2 and 9, cathepsin K, D and S (33-37). Numerous in vitro and in vivo
experimental studies have tested the feasibility and accuracy NIRF and provided evidence that it
can be used to study plaque biology and detect inflammation and neo-vascularization (38).
For the in vivo NIRF imaging of coronary artery pathology an intravascular catheter has been
recently constructed that allows real time study of the whole circumference of the vessel wall and
consists of an optical fiber which is able to emit a 750nm laser light and collect the NIRF
emissions. Validation of the catheter in experimental models demonstrated its capability to detect
plaque inflammation and highlighted the potentialities of this modality in the study of plaque
biology (Online Fig. 1.E) (39). However, further evaluation of the safety profile of the used
agents is required before NIRF being applied in humans.
i)
Time resolved fluorescence spectroscopy
Time resolved fluorescence spectroscopy (TRFS) relies on the assessment of the time required to
resolve the fluorescence emitted after molecules being excited by light. Several experimental
studies have showed that TRFS is able to discriminate different grades of atherosclerotic lesions
and detect the presence of macrophages while a recent report conducted in specimens obtained
from carotid endarterectomy (65 patients) demonstrated that TRFS can be used to differentiate
plaque types (intima thickening, fibrous/fibrocalcific plaques and high risk – inflamed and
necrotic rich – plaques) with a high sensitivity and specificity (range between 73-94%) (40-42).
TRFS is unable to provide information about the luminal and vessel wall morphology and plaque
distribution and has restricted field of view which does not allow study of the whole
circumference of the vessel. New technological advancements and the construction of
fluorescence lifetime imaging microscopy (FLIM) systems facilitated the analysis of a large
amount of TRFS data, increased the field of imaging (4mm diameter surface) and enhanced the
applicability of this modality in the study of atherosclerosis (Online Fig. 1.F) (43-44). The
feasibility of the proposed approach was examined by Phipps et al. in histological sections
obtained from the aortas of 11 deceased humans (45). Forty one regions of interest were
evaluated and it was found that FLIM permits detection of different plaque types (elastin rich,
collagen rich, lipid rich and elastin and macrophage rich plaque) with a moderate sensitivity
(range between 50-86%) but high sensitivity (range between 89-92%). A significant limitation of
TRFS and FLIM is the poor penetration of the excited light (250μm) which requires the catheter
to be in contact with the vessel wall rendering challenging its use in the imaging of coronary
pathology (46).
Online Figure 1. Upcoming intravascular imaging techniques. (A) Angiographic views of the
intravascular magnetic spectroscopy catheter (I-III) (M indicates the probe and B the balloon used
to prevent flow) and color coded display of the acquired data (the yellow corresponds to lipid
tissue and the blue to non-lipid tissue). (B) Intravascular magnetic resonance images (I-IV)
acquired in vitro from an atherosclerotic iliac artery. The dark patches at 9 (II, III) and 12 o’ clock
(IV) corresponds to calcific tissue. Histology and Van Kossa staining confirmed the presence of
calcium (V-VI) which can also be detected by micro-computed tomography (VII). (C) Output of
an intravascular Raman spectroscopy catheter. Panel (I) demonstrates in a color coded map the
distribution of the total cholesterol throughout the studied vessel (in the y-axis the number of the
sensors used to scan the vessel) with the yellow-red color corresponding to increased cholesterol.
Panel (II) provides the ratio of non-esterified cholesterol versus cholesterol ester measured when
the total cholesterol is >5%. (D) Intravascular photoacoustic images of a diseased (I) and a
normal (II) aorta. The special photoacoustic fingerprints of different tissues [e.g. lipid tissue (1),
normal vessel wall (2) and media-adventitia (3)] allow reliable characterization of the
composition of the plaque (III). (E) Fluorescence reflectance imaging (I) and the corresponding
near infrared fluorescence (NIRF) data acquired by an intravascular NIRF catheter in a stented
rabbit aorta (II). Before pull-back an activatable NIRF agent was used to mark the cysteine
protease activity. An increased activity was noted at the edges of the stent (indicated with a
white-yellow color) suggesting inflammation of the vessel wall. (F) Time resolve fluorescence
spectroscopic analysis of a carotid atherosclerotic plaque using a recently developed fluorescence
lifetime imaging apparatus which allows evaluation of the chemical composition of relatively
large surfaces. The final output is a biochemical map of the superficial plaque where the red
corresponds to fibrotic plaque, the yellow color to fibro-lipid and the cyan to normal endothelium.
Images were obtained with permission from Regar et al, Sathyanarayana et al., Sutter et al., Wang
et al., Jaffer et al. and from Sun et al. (15,17,27,39,44,47).
Online Figure 2. Co-registration of intravascular ultrasound (IVUS) and computed tomographic
coronary angiography (CTCA). Panel (A) shows a longitudinal CTCA view, panel (B) the
corresponding grayscale IVUS and (C) the radiofrequency IVUS backscatter analysis (RF-IVUS)
data. The CTCA cross-section with the minimum luminal area is shown in panel (D). The green
color corresponds to the lumen area, the yellow to calcified plaque and the purple to high density
non calcified plaque. The corresponding grayscale IVUS and RF-IVUS cross sections are
illustrated in panel E and F. A good matching noted between the type of the plaque detected by
CTCA and IVUS. The figure was modified and used with permission from Voros et al. (48).
Online Figure 3. Angiographic image showing the culprit lesion (arrow) in the distal right
coronary artery (A) and optical coherence tomographic image (C) illustrating the ruptured plaque
(arrow). The data from these modalities were fused to reconstruct the luminal surface of the
vessel (B) and identify the 3D location of the culprit lesion (arrow – brown area in the model).
Blood flow simulation was performed and the computed shear stress was portrayed in a color
coded map (D). Increased shear stress was found in the culprit lesion (arrow).
Online Figure 4. Fusion of intravascular ultrasound (IVUS) and optical coherence tomographic
(OCT) data. Panels (A), (B) and (C) portray corresponding cross sections obtained by IVUS,
OCT and IVUS radiofrequency backscatter analysis (RF-IVUS) respectively. The integration of
IVUS-OCT and especially of OCT and RF-IVUS allows more precise evaluation of the
composition of the plaque as these complement each other. Image obtained with permission from
Räber et al. (49).
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