Intravascular Coronary
Ultrasound and Beyond

CHAPTER

12

Teruyoshi Kume, Yasuhiro Honda, Peter J Fitzgerald

Chapter Outline
• Intravascular Ultrasound
–– Basics of IVUS and Procedures
–– Normal Vessel Morphology
–– IVUS Measurements
–– Tissue Characterization
–– Insights into Plaque Formation
and Distribution
–– Interventional Applications
–– Preinterventional Imaging
–– Balloon Angioplasty
–– Bare Metal Stent Implantation
–– Drug-eluting Stent Implantation
–– Safety
–– Future Directions
• Optical Coherence Tomography
–– Imaging Systems and Procedures
–– Image Interpretation

–– Clinical Experience
–– Detection of Vulnerable Plaque
–– Safety and Limitations

and unique insights into vascular biology as well.

INTRAVASCULAR ULTRASOUND
Basics of IVUS and Procedures

The IVUS imaging systems use reflected sound waves
to visualize the vessel wall in a two-dimensional format
analogous to a histologic cross-section. In general, higher
frequencies of ultrasound limit the scanning depth but improve
the axial resolution, and current IVUS catheters used in the
coronary arteries have center frequencies ranging 20–45 MHz.


434

Manual of Cardiac Diagnosis

There are two different types of IVUS transducer systems:
(i) the solid-state dynamic aperture system (the electronically
switched multi-element array system) and (ii) the mechanically
rotating single-transducer system (Table 1 and Figs 1A and B).
Several types of artifacts can be observed common or unique to
each system (Figs 2A to D). With both systems, still frames and
video images can be digitally archived on local storage memory
or a remote server using digital imaging and communications in
medicine (DICOM) Standard 3.0. Regardless of IVUS system
used in the patient, both require preprocedural administration
of intravenous heparin (5,000–10,000 U), or equivalent
anticoagulation along with intracoronary nitroglycerin (100–300
µg), to reduce the potential for coronary spasm.

Image quality

Artifacts

Solid-state dynamic
aperture system
An electronic solid state
catheter system with
multiple imaging elements
at its distal tip, providing
cross-sectional imaging
by sequentially activating
the imaging elements in a
circular way
One system is
commercially available
(Volcano Corporation,
Inc., Rancho Cordova,
CA)

Mechanically rotating
single-transducer system
A mechanical system that
contains a flexible imaging
cable which rotates a
single transducer at its tip
inside an echolucent distal
sheath

Several systems are

mechanical systems
have traditionally offered
advantages in image
quality compared with the
solid-state systems
The guidewire runs inside The guidewire runs
the IVUS catheter thereby outside the IVUS catheter,
preventing guidewire
parallel to the imaging
artifact
segment, resulting in
guidewire artifact
This system does not
This system requires
require flushing with
flushing with saline before
saline
insertion to eliminate
any air in the path of the
beam. Incomplete flushing
artifact may result in poor
image quality
Contd...

435


436

Manual of Cardiac Diagnosis

subtract this from the image
Short transducer-toThe pullback trajectory is
tip distance (10.5 mm)
stabilized and it reduces
facilitates visualization of the risk of a nonuniform
distal coronary anatomy
speed in a continuous
pullback

The relative echolucency of media compared with intima
and adventitia gives rise to a three-layered appearance
(bright-dark-bright), first described in vitro by Meyer and his
colleagues.3 Due to the lack of collagen and elastin compared
to neighboring layers, the media displays lower ultrasound
reflection. “Blooming”, a spillover effect, is seen in the IVUS
image because the intimal layer reflects ultrasound more strongly
than the media. This results in a slight overestimation of the
thickness of the intima and a corresponding under­estimation of
the medial thickness. On the other hand, the media/adventitia
border is accurately rendered, because a step-up in echo
reflectivity occurs at this boundary and no blooming appears.
The adventitial and periadventitial tissues are similar enough
in echoreflectivity that a clear outer adventitial border cannot
be defined.
Several deviations from the classic three-layered appearance
are encountered in clinical practice. The echoreflectivity
of the intima and internal lamina may not be sufficient to
resolve a clear inner layer in truly normal coronary arteries
from young patients. This is particularly true when the media
has a relatively high content of elastin. However, most adults

only a tiny percentage increase in the total area of the plaque.
The determination of the position of the imaging plane
within the artery is one important aspect of image interpretation.
For example, an IVUS beam penetrates beyond the coronary
artery, providing images of peri­vascular structures, including
the cardiac veins, myocardium and pericardium (Figs 4A to
C). These structures provide useful landmarks regarding the
position of the imaging plane because they have a characteristic
appearance when viewed from various positions within the
arterial tree. The branching patterns of the arteries are also

437


438

Manual of Cardiac Diagnosis

FIGURES 3A AND B: Cross-sectional format of a representative IVUS
image. The bright-dark-bright, three-layered appearance is seen in the
image with corresponding anatomy as defined. The “IVUS” represents
the imaging catheter in the vessel lumen. Histologic correlation with
intima, media and adventitia are shown. The media has lower ultrasound
reflectance owing to less collagen and elastin compared with neighboring
layers. Since the intimal layer reflects ultrasound more strongly than the
media, there is a spillover in the image, resulting in slight overestimation
of the thickness of the intima and a corresponding underestimation of
the medial thickness

distinctive and help to identify the position of the transducer.

Intravascular Coronary Ultrasound and Beyond

439


440

Manual of Cardiac Diagnosis

FIGURES 5A TO D: Pullback imaging sequence from mid to proximal
portion of the left anterior descending (LAD) artery: (A) The mid and
distal portions of the LAD often lie deeper in the sulcus than the proximal
LAD and myocardium may be observed. The pericardium is seen at the
opposite site of myocardium. (B and C) The septal branches emerge
opposite to the pericardium, but the diagonal branches take off more
superiorly. The angle between the septal and the diagonal branches
usually increases to as much as 180 degrees. (D) The left circumflex
artery emerges on the same side as the emergence of the diagonal
branches

by tracing the leading edge of the blood/intima border, whereas
vessel or external elastic membrane (EEM) area is defined as
the area enclosed by the outermost interface between media and
adventitia. Plaque area or plaque-plus-media area is calculated
as the difference between the vessel and lumen areas; the ratio
of plaque to vessel area is termed percent plaque area, plaque


Intravascular Coronary Ultrasound and Beyond


zed as hypoechoic plaque with ultrasound attenuation despite
little evidence of calcium has been reported (Figs 9A to C).
These specific plaques are more often seen in patients with
acute coronary syndromes than in those with stable angina and
are characterized by positive remodeling and nearby calcifica­
tion.5 Clinical studies have indicated that attenuated plaques
are associated with no reflow and creatine kinase-MB elevation
after PCI because of distal embolization.6,7 This novel defined
plaque may contain microcalcification, thrombus or cholesterol
crystals.8
Visual interpretation of conventional grayscale IVUS
images is limited in the detection and quantification of specific
plaque components. Therefore, computer-assisted analysis of
raw radiofrequency (RF) signals in the reflected ultrasound
beam has recently been developed (Figs 10A to C). Virtual
Histology™ (VH) IVUS (Volcano Corporation, Rancho

441


FIGURES 6A TO C: Examples of coronary calcification: (A) Superficial calcification is seen between 6 O’clock and 10 O’clock. The deeper vessel structure is
obscured by the shadowing of the calcium layer (acoustic shadowing: asterisk). (B) Deep deposit of calcium is seen in a rim of fibrous plaque. (C) There are
superficial and deep calcium deposits with acoustic shadowing

442
Manual of Cardiac Diagnosis


Intravascular Coronary Ultrasound and Beyond



FIGURES 10A TO C: Color-mapped images of the coronary plaque.
Conventional grayscale IVUS images (left). (A) Virtual Histology ™ shows
a distinct color for each of the fibrous, necro­tic, calcific and fibro-fatty.
(B) Integrated Backscatter-IVUS can provide a quantitative visual readout
as four types of plaque composition: calcification, fibrous, dense fibrosis
and lipid pool. (C) iMap™ allows identification of four different types of
plaque components (fibrotic, necrotic, lipidic and calcified tissue) with
a confidence level assessment of each plaque component. (Source:
Figure A Dr Kenji Sakata)

four types of plaque composition: calcification, fibrosis, dense
fibrosis and lipid pool.10 Similar to these RF-based tissue
characteriza­tion techniques, iMap™ (Boston Scientific Inc,
Natick, Massachusetts) has recently been introduced as an upto-date tissue characterization method that is compatible with the
latest 40-MHz mechanical IVUS imaging system (as opposed

445


446

Manual of Cardiac Diagnosis

to VH-IVUS with 20-MHz solid-state IVUS system). The
iMap allows identification and quanti­fication of four different
types of atherosclerotic plaque components: fibrotic, necrotic,
lipidic and calcified tissues with accuracies at the high level
of confidence (95%, 97%, 98% and 98% for fibrotic, necrotic,
lipidic and calcified tissues, respectively).11 Recently, multiple

negative remodeling, or constriction, in the area of lumen
stenosis (Figs 12A and B).14 One important issue in evaluating
this heterogeneous process by IVUS is the methodology used
to quantify and categorize arterial remodeling. Although
remodeling was originally conceptualized as a change in
vessel size in response to plaque accumu­lation over time, most
histomorphometric or IVUS studies have relied on measure­
ments of reference sites as a surrogate for the size of the
vessel before it became diseased. Therefore, results can vary
distinctly accord­ing to the choice of reference site as well as


FIGURES 11A AND B: Angiographically silent disease: (A) An angiogram of the left coronary artery suggests minimal disease. (B) IVUS images show
significant eccentric plaque. The lumen is well preserved, round and regular, accounting for the benign angiographic appearance

Intravascular Coronary Ultrasound and Beyond

447


448

Manual of Cardiac Diagnosis

FIGURES 12A AND B: IVUS images showing remodeling: (A) Positive
remodeling with localized expansion of the vessel in the area of plaque
accumulation. (B) Negative remodeling or shrinkage where the lesion has
a smaller media-to-media diameter than the adjacent less diseased sites

the manner of addressing vessel tapering.15 Theoretically, the

Although the predictive values of these parameters in the context
of stenting have not been established with certainty, preinter­
ventional IVUS may identify lesions with significant positive
remodeling, providing triage information for increased risk of
unfavorable outcomes and possible need of adjunctive biologic
modalities for antirestenosis therapy in specific patients.

Interventional Applications
According to the 2005 American College of Cardiology/
American Heart Association/Society for Cardiovascular
Angiography and Interventions (ACC/AHA/SCAI) 2005
Guideline Update for PCI, it is reasonable to use IVUS: (a) to
assess the adequacy of coronary stent deploy­ment, including
the extent of apposition and minimum luminal diameter within
the stent; (b) to determine the cause of stent restenosis and
guide selection of appropriate therapy; (c) to evaluate coronary
obstruction in a patient with a suspected flow-limiting stenosis
when angiography is difficult because of location and (d) to
assess a suboptimal angiographic result after PCI.20 In addition,
not only after PCI but also before PCI, IVUS is a useful
application to assess lesion characteristics.

Preinterventional Imaging
Preinterventional IVUS has been used to clarify situa­tions
in which angiography is equivocal or difficult to interpret
(especially in ostial lesions or tortuous segments in which the
angiogram may not lay out the vessel well for interpretation).
In addition, intermediate coronary lesions identified by
angiography (40–70% angiographic stenosis) represent a
challenge for revascularization decision-making. Although

the circumferential and longitudinal extent of plaque as well as
the character of the tissue involved. This can lead to a change
in interventional strategy in 20–40% of cases.26,27 In particular,
the presence, location and extent of calcium can significantly
affect the results of balloon angioplasty, atherectomy and stent
deployment. The amount and distribution of plaque can be
accurately determined and may favor atheroablative procedures
as primary or adjunctive treatment. Precise measure­ments of
lesion length and vessel size can guide the optimal sizing of
devices to be employed. Detailed assessment of target lesion
anatomy in the coronary tree is also useful to prevent major
side branch encroach­ment by intervention.

Balloon Angioplasty
The IVUS imaging of percutaneous transluminal coronary
angioplasty (PTCA) sites demonstrates plaque disruption or
dissection more often than angiography does (40–70% of
cases versus 20–40% by angio­graphy).28,29 The IVUS is able
to characterize the depth and extent of dissections created by
balloon inflation with relatively high accuracy. Although the
extent of dissections is relatively unpredictable, it is frequently
possible to predict where tears will occur, based on certain
morphologic features shown by IVUS. If a plaque deposit is
eccentric, tears usually occur at the junction between the plaque
and the normal wall (Figs 13A and B). This is presumably
because the non-diseased wall is more elastic than the plaque,
and, with balloon inflation, it stretches away from the plaque,
creating a cleavage plane running either within the media
or within the plaque substance, close to the media. Another
important factor in determining the location of tears is the

and media-to-media diameters for cases in which the plaques
were not extensively calcified. This led to an average 0.5 mm
“oversizing” of the balloon compared with sizing based on
standard angiographic criteria, and resulted in a significant
decrease in post-procedure residual stenosis (from 28% to
18%). Importantly, there was no increase in clinically significant
complications from this aggressive balloon sizing approach.
One-year follow-up of this trial showed a late adverse event
rate (death, myocardial infarction or target lesion revas­culari­
zation) of 22%.31 This IVUS-guided aggressive PTCA strategy
was expanded and confirmed by two single-center studies of
provisional stenting, wherein balloon sizing was performed
based on IVUS measure­ments of media-to-media diameter at
the lesion site.32,33 Angiographic or clinical follow-up of these

451


452

Manual of Cardiac Diagnosis

studies also showed long-term outcomes equivalent to those
of elective stenting.

Bare Metal Stent Implantation
The IVUS clearly visualizes stent struts as bright, distinct
echoes. Stents essentially provide a rigid scaffold against the
force of vessel recoil. During stent implantation, axial extrusion
of noncalcified plaque into the adjacent reference zones can

percentage of these stent deployment issues.35,36
After stent implantation, tears at the edge of the stent
(marginal tears or pocket flaps) occur in 10–15% of cases
(Figs 13A and B).37 These tears have been attributed to the
shear forces created at the junction between the metal edge
of the stent and the adjacent, more compliant tissue or to the
effect of balloon expansion beyond the edge of the stent (the
“dog-bone” phenomenon). Although minor nonflow-limiting
edge dissections may not be associated with late angiographic
in-stent restenosis, significant residual dissections can lead to
an increased risk of early major adverse cardiac events.38 The
current practice in our laboratory is to determine from the IVUS
image whether the tear appears to be flow-limiting (i.e. whether
there is an extensive tissue arm projecting into the lumen), and,
if so, an additional stent is placed to cover this region.
Over the past decade, a number of studies have shown that
IVUS-guided stent placement improves the clinical outcome
of bare metal stents.39–44 In the landmark trial, Multicenter
Ultrasound-guided Stent Implantation in Coronaries (MUSIC)
trial, three main IVUS variables were considered for assessing
optimal stent deployment: (1) complete stent apposition over
the entire stent length; (2) in-stent minimum stent area (MSA)
greater than or equal to 90% of the average of the reference
areas or 100% of the smallest reference area and (3) symmetric
stent expansion with the minimum/maximum lumen diameter
ratio greater than or equal to 0.7.45 This study highlights that
appropriate evaluation of stent deployment by IVUS impacts
restenosis rate.
A subacute thrombosis rate of less than 2% was believed
to represent a reduction compared with non­guided deployment,

that the predicted risk of restenosis decreases 19% for every
1 mm2 increase in MSA and suggested that stents with MSA
greater than 9 mm2 have a greatly reduced risk of restenosis.49
In the can routine ultrasound improve stent expansion
(CRUISE) trial, IVUS guidance by operator preferences
increased MSA from 6.25 mm2 to 7.14 mm2, leading to a
44% relative reduction in target vessel revasculari­zation at 9
months, compared with angiographic guidance alone.42 In the
angiography versus IVUS-directed stent placement (AVID)
trial, IVUS-guided stent implantation resulted in larger acute
dimensions (7.54 mm2) than angiography (6.94 mm2), without
an increase in complications, and lower 12-month target lesion
revascularization rates for vessels with angio­graphic reference
diameter less than 3.25 mm, severe stenosis at preintervention
(> 70% angiographic diameter stenosis), and vein grafts.51
However, some IVUS-guided stent trials produced controversial
results,52,53 presumably due to differing procedural end points
for IVUS-guided stenting, and the various adjunctive treatment
strategies that were used in these trials in response to suboptimal
results. Overall, a meta-analysis of nine clinical studies (2,972
patients) demonstrated that IVUS-guided stenting significantly
lowers 6-month angiographic restenosis [odds ratio = 0.75,
95% confidence interval (CI), 0.60–0.94; P = 0.01] and target
vessel revasculari­zation (OR = 0.62; 95% CI, 0.49–0.78; P =
0.00003), with a neutral effect on death and nonfatal myocardial
infarction, compared to an angiographic optimization.54
Insights into Long-term Outcomes
Intimal proliferation rather than chronic stent recoil primarily
causes in-stent restenosis. Growth of neoin­tima is usually
greatest in areas with the largest plaque burden,55 and the

a considerable reduction in angiographic and/or clinical
recurrence of in-stent restenosis in patients with diffuse instent restenosis treated with ablative therapies (directional
coronary atherectomy, rotational atherectomy or laser angio­
plasty) compared with PTCA alone.58–60

Drug-eluting Stent Implantation
In current clinical experience, IVUS observations of
antiproliferative drug-eluting stents (DES) have shown a
striking inhibition of in-stent neointimal hyperplasia (Fig. 15).
Thus, it comes as no surprise that since the introduction of DES,
both the rate of restenosis and need for repeat revascularization

455


456

Manual of Cardiac Diagnosis

have been dramatically reduced. Moreover, both statistical
and geographic distri­­butions of neointimal hyperplasia can be
signi­ficantly different between biologic (DES) and mechanical
(bare metal) stents, despite mechanical performances of DES
being similar to those of conventional bare metal stents.61 In
general, neointimal volume (as a percentage of stent volume)
within bare metal stents follows a near-Gaussian or normal
frequency distribution, with a mean value of 30–35%. The
standard deviation of this statistical distribution represents
biologic variability in vascular response to acute and/or chronic
vessel injury as a result of inter­ventions. In contrast, biologic

(Fig. 6). One important advantage of online IVUS guidance is
the ability to assess the extent and distance from the lumen of
calcium deposits within a plaque. For example, lesions with
extensive superficial calcium may require rotational atherectomy
before stenting. Conversely, apparently significant calcification


Intravascular Coronary Ultrasound and Beyond

on fluoroscopy may subsequently be found by IVUS to be
distributed in a deep portion of the vessel wall or to have a
lower degree of calcification (calcium arc < 180 degrees). In
these cases, stand-alone stenting is usually adequate to achieve
a lumen expansion large enough for DES deployment.
The stent deployment techniques on clinical outcomes of
patients treated with the cypher stent (STLLR) trial demons­
trated that geographic miss (defined as the length of injured or
stenotic segment not fully covered by DES) had a significant
negative impact on both clinical efficacy (target vessel and
lesion revascularization) and safety (myocardial infarction) at 1
year after sirolimus-eluting stent implantation.68 These findings
suggest that less aggressive stent dilation and complete coverage
of reference disease may be beneficial, as long as significant
underexpansion and incomplete strut apposition are avoided.
Another single center study showed optimal stent longitudinal
positioning of sirolimus-eluting stents using unique stepwise
IVUS criteria (mainly targeting the sites with plaque burden