Internacional Journal of Cardiovascular Sciences. 2016;29(3):223-232
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REVIEW ARTICLE
Clinical Applications and Methods of Intravascular Imaging of Atherosclerosis
Leonardo Silva Roever Borges1 e Cláudio Tinoco Mesquita2
Universidade Federal de Uberlândia – Departamento de Pesquisa Clínica1 – Uberlândia, MG, Universidade Federal Fluminense – Hospital Universitário
Antônio Pedro – Departamento de Medicina Clínica2 – Niterói, RJ – Brazil
Atherosclerosis is the leading cause of coronary
artery disease, stroke and peripheral artery disease.
The onset of atherosclerotic coronary lesions occurs
through accumulation and oxidation of low-density
lipoprotein (LDL). Oxidized LDL promotes the recruitment
and activation of leukocytes, as well as cell death
and generation of complex atherosclerotic plaques.
These plaques have high necrotic core content, a thin
fibrous inflamed layer, and intense accumulation of
macrophages. In the initial stage of the formation of
atheroma, remodeling of the vessel wall generally prevents
the plate from invading the lumen, thereby masking the
presence of atheroma in angiography. Advances have
contributed to the study of atherosclerosis by intravascular
imaging. Methods such as intravascular ultrasound,
optical coherence tomography, intravascular magnetic
resonance spectroscopy, infrared spectroscopy, Raman
spectroscopy, fluorescence spectroscopy, intravascular
magnetic resonance imaging and infrared fluorescence
have been used in the intravascular evaluation of
atherosclerosis. Intravascular ultrasound can assess the
extent of the disease in the axial and longitudinal plane and
contribute to the understanding of the pathophysiology
of coronary artery disease. This manuscript describes the
characteristics and clinical applications of the methods of
coronary intravascular imaging.
as the inability to provide information on the evaluation
of both the volume and the morphological characteristics
and the composition of plaques; the need for spatial
resolution for the identification of subtypes of lesions and
better understanding of the hemodynamic significance of
these lesions, as well as the evaluation of plaques with less
than 50% of stenosis that may have complications leading
to acute coronary syndromes, have led to the design and
development of new technologies to better assess not
only the luminal disease, but for a better quantitative and
qualitative analysis of the atherosclerotic plaque.1-4
Atherosclerosis is a complex disease characterized by
a chronic systemic inflammatory process that affects the
inner layer of the arteries, such as the coronary arteries,
the aorta, the carotid arteries and the peripheral arteries
of the lower limbs.5-9
In the pathophysiology of atherosclerosis, there is
an interaction between environmental risk factors,
genetic and psychological components, immune and
endocannabinoid system, hematological and endothelial
cells, clotting factors and inflammatory mediators.10-13
The characteristics of atherosclerotic plaques are
responsible for the form of presentation of clinical
events. Therefore, it is necessary to better understand
its histology and morphology, as well as its evolutionary
lesions, as described below:14-16
Introduction
Coronary angiography has been the gold standard
technique for the evaluation of coronary artery disease.
However, some limitations of coronary angiography such
Keywords
Atherosclerosis; Coronary artery disease; Diagnostic
imaging.
• Type I lesions (initial): these are characterized by
the presence of the first detectable lipid deposits in
the intima and the cellular reactions associated with
them. The initial histological changes at this stage
are minimal, with small groups of macrophages
containing lipid droplets known as foam cells;
• Type II lesions include fatty streaks. Microscopically,
they consist of laminated layers of foam cells
attached to smooth muscle cells with fat deposits.
T lymphocytes can also be found in this type of
lesion, but to a lesser extent than the macrophages;
Mailing Address: Leonardo Silva Roever Borges
Rua Rafael Rinaldi, 431 – Martins. Postal Code: 38400-384 – Uberlândia, MG – Brazil
E-mail: [email protected]
DOI: 10.5935/2359-4802.20160025
Article received on January 8, 2016; revised on February 29, 2016; approved on February 25, 2016.
Int J Cardiovasc Sci. 2016;29(3):223-232
Review Article
• Type III lesions: those with chemical and
morphological composition intermediate to
type II and to atheroma. They are also known as
transitional or pre-atherosclerotic lesions. They are
histologically characterized by the presence of lipid
accumulation in the extracellular medium;
• Type IV lesions or atheroma: dense and extracellular
content of lipids uniformly located in the intima,
known as lipid cores. These lesions have arterial
wall thickening characteristics without causing
luminal narrowing, considering its eccentric
growth characteristic;
• Type V lesions: these are characterized by the
formation of fibrous connective tissue which,
associated with the lipid core, comprises the
fibroatheroma type Va lesion. If the lesion calcifies, it is
known as type Vb lesion and in cases where the lipid
core is absent or scarce, it is then type Vc. Such lesions
can cause clinically relevant luminal narrowing;
• Type IV or type V lesions that undergo disruption,
hematoma or hemorrhage and thrombosis are
called complicated lesions and are classified as type
VIa, VIb, VIc, respectively.
Vascular remodeling in atherosclerosis
Vascular remodeling of the coronary artery implies
geometric changes in vessel dimensions and evolves with
the progression and regression of the atherosclerotic process.
This includes a broad spectrum of presentations that may
vary from expansive remodeling, in which the dimensions
of the coronary artery increase as plaque accumulates,
and constricting remodeling in which there is a relative
contraction of the vessel wall, which affects the lumen.17-22
Alternatively, the vascular remodeling can be
classified as adaptive (compensatory, suitable for
hemodynamic stimulus), or maladaptive (inadequate
dysfunctional). The direction and scale of remodeling
are coordinated by the production of endothelial growth
factors, proteases and cell adhesion molecules in response
to the changes detected in blood flow. Degradation of
the matrix involved in this process enables the rupture
of atherosclerotic plaques, thereby increasing the risk of
acute coronary syndromes.23-25
Imaging modalities of coronary atherosclerosis
There is great advancement in imaging modalities of
coronary arteries. This study provides a more accurate
Borges e Mesquita
Intravascular Imaging of Atherosclerosis
assessment of coronary atherosclerosis, as well as
scientific advances in the pathophysiology, prevention
and treatment.26
The intimal layer of the arterial wall is between the
endothelium and internal elastic lamina and has, in its
borders, a subendothelium formed by smooth muscle
cells and fibroblasts arranged in a matrix of connective
tissue. The middle layer is composed of smooth muscle
cells arranged in a matrix with a small amount of elastic
and collagen fibers with an average thickness of 200 μm
and separated from the adventitia by the external elastic
lamina. The thickness of the adventitia, the outermost
layer of the arterial wall, ranges from 300-500 μm and
is composed of fibrous tissue (collagen and elastin)
and incorporates the vasa vasorum, nerves and lymph
vessels.
This manuscript describes the main types of
intravascular imaging of coronary atherosclerosis, as
well as the comparison between intravascular ultrasound
(IVUS) and optical coherence tomography (OCT) and
their applications27 (Chart 1).
– Intravascular Ultrasound (IVUS)
Intracoronary ultrasound is the intravascular imaging
most used today. This modality requires inserting a
catheter with a transducer at its tip, which emits an
ultrasound signal perpendicular to its axis with a
frequency of 20-70 MHz.
Detection of the intimal layer on intravascular
ultrasound depends on its thickness. The minimum
measurement of 160 μm is required for its definition.
The thickness of the intimal layer increases with age,
despite the absence of atherosclerotic lesions. Reflections
of the signals emitted are received by the transducer
and analyzed to generate cross-sectional images, which
enables the identification of luminal borders and media
and adventitia layer. It is also possible to evaluate
the atherosclerotic plaque load and characterize its
composition.28,29
The IVUS ability to detect the composition of the
plaque surface is moderate according to studies based on
the histology of atherosclerotic plaque.30 Recent studies
are skeptical about the reliability of evaluating the type
of plaque, especially in segments with stent and calcium
deposits31,32 as well as significant limitations of IVUS that
do not allow the detection of characteristics associated
with increased risk of plaque rupture (microcalcifications,
neovascularization, plaque erosion, etc.).33
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Intravascular Imaging of Atherosclerosis
Chart 1
IVUS and OCT and their applications
Specifications
IVUS
TCO
Axial resolution (µm)
100-150
10-20
Lateral resolution (µm)
150-300
25-40
Recoil velocity (mm/s)
0,5-2,0
0,5-2,0
Scanning diameter (CV) (mm)
8-10
6.8
Tissue penetration (mm)
4-8
1-2
Frame rate per second
30
15-20
Applications
– Evaluation of atherosclerotic plaque
– Evaluation of stent coverage and position
– PCI guide
• Evaluation of stenosis severity
– Allows better understanding the various
stages of atherosclerotic disease and vascular
response to treatment.
–Pre-intervention:
Advantages
• accurate evaluation of the lesion length;
• accurate evaluation of the vessel size;
– Detects arterial structures and helps
determining different histological constituents.
• better evaluation for direct stent implant.
–Post-intervention:
– Distinguishes different degrees of
atherosclerotic changes and various
• accurate evaluation of the apposition of
stent struts;
types of plaques.
– Allows extraordinary evaluation of the
• avoid gaps (implanting > 2 stents).
characteristics and thickness of the fibrous cap.
– Evaluates the neointimal coverage, tissue
patterns for stent strut and apposition.
- Invasive test.
Disadvantages
- Limits the study of the microstructure,
resulting in a sensitivity of only 37% for the
detection of plaque rupture.
– Invasive test.
– Its low axial penetration (1.5-2.0 mm) does
not provide optimal view of the arterial wall,
especially in large vessels, in which the outer
layers of the artery cannot be identified.
IVUS: intravascular ultrasound; OCT: optical coherence tomography; VF: vision field; PCI: percutaneous coronary intervention.
The main indications for the use of intravascular
ultrasound are: a) evaluation of moderate coronary
lesions; b) evaluation of ambiguous lesions in the left main
coronary artery; c) detection of unstable plaques; d) the
guide method in the implant of coronary stents (bare-metal
and/or drug-eluting stents). Figure 1 shows the image of
a normal coronary artery by the IVUS.34 Chart 2 shows the
differences in the IVUS modes of operation.
IVUS with virtual histology
The IVUS with radiofrequency, also called virtual
histology, allows the evaluation of the plaque
dimensions and detailed tissue characterization of the
atherosclerotic lesion.35-37
The four basic components of the plaque are defined
by this method: fibrolipidic tissue (light green), fibrous
tissue (dark green), calcium (white) and the areas of
inflammatory activity and necrosis (red).35-37 The IVUS
with virtual histology demonstrates plaque components
that can be quantified in relation to their corresponding
areas and the percentage occupied by each component
of the total plaque volume.35-37
Based on the percentage composition of the plaque and
the location of necrotic and calcium contents in relation to
the vascular lumen, the following classification of lesions
is obtained by virtual histology:38-39
• fibrotic plaque: predominant fibrotic tissue without
confluent areas of necrotic or calcium tissue;
Int J Cardiovasc Sci. 2016;29(3):223-232
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Intravascular Imaging of Atherosclerosis
Figure 1
IVUS image showing the trilaminate appearance of the normal coronary artery wall.
Source: adapted from Dash et al.34 IVUS: intravascular ultrasound.
• calcified fibroatheroma: presence of calcium
confluent areas (> 10% of the plaque area percentage)
in three or more consecutive sections;
• fibroatheroma: presence of confluent areas of
necrotic tissue (> 10% of the percentage of plaque
area) in three or more consecutive sections;
• thin cap fibroatheroma (TCFA): presence of confluent
areas of necrotic tissue (> 10% of the percentage of
plaque area) in three or more consecutive sections
and in direct contact with the lumen.
Figure 2 represents the morphology of the atheroma
plaque.40 Figure 3 shows the types of images that can be
viewed from the atherosclerotic plaque41 and Figure 4
shows the types of plaques.42
– Optical coherence tomography (OCT)
Optical coherence tomography (OCT) has an
axial resolution (12-18 μm) that delivers a detailed
intravascular view, including all layers of the vessel wall
(provided that there is no disease in the intima) and,
in the presence of macrophages, neovascularization,
microcalcifications and thrombi, it allows estimating the
fibrous cap thickness.42-45
Histology-based studies have shown that this is a
reliable technique to detect the plaque type, although
some studies have been concerned with their ability
to discriminate calcified plaques and plaques rich in
lipids. 44-46 Its imaging limitations are: incapacity to
penetrate the lipid-rich cores and tissue penetration
(interval: 2-3 mm), which repeatedly inhibits the image of
the entire atheroma plaque; limitations in portraying the
longitudinal 3D morphology of the plaque on the artery.
Figure 4 shows coronary OCT image. Chart 3 describes
the particularities of the OCT in different types of plaque.
– Magnetic resonance intravascular spectroscopy
Magnetic resonance intravascular spectroscopy
involves advancing the catheter with a magnetic
resonance probe at its tip, which creates a field of vision
with a 60o radial sector, which allows the identification of
the lipid component into two zones: superficial (0-100μm)
and deep (100-250 μm). This technique does not show the
lumen, the vessel wall and the plaque morphology.44-48
– Intravascular magnetic resonance imaging
Intravascular magnetic resonance imaging shows
the plaque behind the calcified tissue. Its limitations
include the noise introduced by the movements, the
heat generated during the imaging and increased time
required to acquire the images, which would limit its
application in humans. Recent advances in intravascular
magnetic resonance imaging enabled high-resolution
(80 μm) real-time study of the in vivo image.49
– Intravascular photoacoustics (IP)
Intravascular photoacoustic imaging allows
identifying many plaque components and is able to
differentiate plaques rich in fibrous tissue lipids and
detect the presence of neoangiogenesis.50,51 In addition,
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Intravascular Imaging of Atherosclerosis
Chart 2
IVUS: operating modes
Modes
Frequency of the ultrasound beam
Catheter size
Mechanic (rotation)
Electronic (solid state)
A single piezoelectric transducer at the
catheter tip, which rotates at 1800 rpm to
64 transducer elements in an annular
array is sequentially activated to generate
create the tomographic image
the cross-sectional image
30 – 45 MHz
~ 20 MHz
3.2 F (Atlantis SR, BSC)
3.5 F (Eagle Eye, Volcano)
Positive points
– Best image quality and easier to interpret.
Traps
– Requires saline washing to provide a
pathway for the ultrasound beam fluid
(air bubbles may degrade image quality).
– Slightly easier to set up.
– Simultaneous display of blood flow in
color, which facilitates the distinction
between lumen and wall limits.
– Artifacts and image can be problematic,
immediately adjacent to the transducer.
– It is necessary to use the closer field ring
down the subtraction.
IVUS: intravascular ultrasound.
Figure 2
Morphology of atheroma on IVUS. Soft (left), fibrous and calcified atheromas (center) and highly calcified mixed atheromas.
Source: adapted from Nissen et al.40 IVUS: intravascular ultrasound.
markers can be used to detect cells or molecules that are
involved in atherosclerosis and inflammation process
(macrophages, metalloproteinases, selectins).52,53
The significant advantages of IP imaging are the ability
to view the stent morphology and its high penetration
and lateral and axial resolution which allow a more
detailed and thorough assessment of the vessel wall.54
Figure 5 shows a coronary IP image.55
– Infrared fluorescence (IRF)
Infrared fluorescence imaging is a modality that
is rapidly evolving in the study of atherosclerosis.
This method is based on the injection of agents that have
the ability to attach molecules and cause fluorescence when
viewed with infrared light.
This modality has been implemented to view the
accumulation of cathepsin in rat models.56 Since then,
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Intravascular Imaging of Atherosclerosis
Figure 3
Intravascular imaging of atherosclerosis
From the radio frequency backscattering data, different types of information can be seen: (1) Virtual histology, (2) retinography, (3) integrated
backscattered image with intravascular ultrasound (4) iMAP.
Virtual histology can detect four types of tissues: necrotic core, fibrous tissue, fibrofatty tissue and dense calcium tissue. Plaque strain on retinography
is reported in strain values, which are further classified into four categories according to the Rotterdam classification. The tissues characterized by
integrated backscattered image with intravascular ultrasound are the lipid, fibrous and calcified tissues; iMAP detects the fibrous, lipid, necrotic and
calcified tissues.
Source: adapted from García-García et al.41
Figure 4
Measurement of the fibrous cap. Sample containing atherosclerotic plaque with different fibrous cap thicknesses. A and B: thin fibrous cap, measuring
40 μm. C and D: thick fibrous cap, measuring 250 μm.
Source: adapted from Bezerra et al.42
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Intravascular Imaging of Atherosclerosis
Chart 3
OCT particularity in different types of plaques
OCT in different types of plaques
Lipid plaque
Fibrotic plaque
Calcified plaque
Low
High
Low
Homogeneous
Homogeneous
Non-homogeneous
Moderately delineated
Poor delineated
Well delineated
Light attenuation
High
Lowa
Low
Penetration depth
Low
High
High
Signal strength
Signal homogeneity
Plaque margins
OCT: optical coherence tomography.
Figure 5
In vivo IP/IVUS of lipids of the abdominal aorta of a rabbit. (1) IP imaging; (2) combined IP/IVUS. The location of lipid deposits on the vessel wall is
shown on the combined IP/IVUS image.
Source: adapted from Wang et al.55 IP: intravascular photoacoustics. IVUS: intravascular ultrasound.
advances in molecular biology have allowed the development
of several markers, such as thrombin, metalloproteinases 2
and 9, cathepsin K, D and S.57-62 A number of in vitro and
in vivo studies were tested for the feasibility and accuracy
of IRF, providing evidence that it can be used to study the
plaque biology, inflammation and neovascularization.63,64
– Fluorescence spectroscopy (FS)
Fluorescence spectroscopy is based on the evaluation of
the time needed to resolve the fluorescence emitted after the
molecules have been excited by light. Several experimental
studies have shown that FS is able to discriminate between
different degrees of atherosclerotic lesions and detect the
presence of macrophages.
A recent study on samples taken from carotid
endarterectomy showed that FS can be used to differentiate
types of plaque (intimal thickening, fibrous plaques/
fibrocalcified plaques, inflamed and necrotic plaques) with
high sensitivity and specificity.62,63 Among its limitations,
FS is not able to provide information on the vessel lumen,
wall and plaque morphology, and its field of vision does
not study the entire vessel circumference.65-68
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– Infrared spectroscopy (IS)
Infrared spectroscopy allows evaluating the
chemical composition of the plaque and the lipid
component. The IS ability to detect lipid-rich plaques
was evaluated and compared to histology. The result
was reliable in relation to the lipid component in 83%
of the vessels studied.69,70
The IS allows identifying the superficial plaque (cap
thickness < 450 μm) and the width of the lipid cores
(circumferential measurement > 60o, plaque thickness
> 200 μm) and detecting lipid-rich plaques located
behind calcified deposits.71,72 Its limitations include the
inability to view the lumen and the outer wall of the
vessel to quantify the atheroma load and retract plaque
characteristics associated with increased vulnerability,
such as fibrous cap thickness, integrity, the presence of
thrombi and neovascularization.
– Raman spectroscopy (RS)
Raman spectroscopy involves the scattering of light
through the molecules.43 A number of experimental
studies have shown that this method provides accurate
characterization of different types of plates, detailed
analysis of its chemical composition and the detection
of many constituents such as elastin, collagen, calcium,
esterified and non-esterified cholesterol.73-76
Intravascular Imaging of Atherosclerosis
vulnerable plaques with high sensitivity and specificity
(79% and 85%, respectively).77 Its limitations are the
inability to show the morphology of the vessel wall
lumen and the plaque and to measure their dimensions.
In summary, advances in intravascular imaging
modalities greatly contributes to the evaluation of
atherosclerosis, enabling high-resolution evaluation of
plaque characteristics with better characterization and
quantification of atherosclerosis. Randomized controlled
trials with large numbers of patients should be conducted
to better understand the real impact of their use in terms
of prevention and treatment.
Author contributions
Conception and design of the research: Borges LSR.
Acquisition of data: Borges LSR. Analysis and interpretation
of the data: Borges LSR. Writing of the manuscript: Borges
LSR, Mesquita CT. Critical revision of the manuscript for
intellectual content: Borges LSR, Mesquita CT.
Potential Conflicts of Interest
This study has no relevant conflicts of interest.
Sources of Funding
This study had no external funding sources.
Academic Association
RS allows quantifying the effect of treatment on
the composition of the plaque surface and identifying
This study is not associated with any graduate programs.
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