virtual histology ivus2.pdf

8/11/2019 Virtual Histology IVUS2.pdf

1/17


2/17

Catheter designsThe IVUS equipment consists of a catheter incorporating a minia-

turized transducer and a console to reconstruct and display the

image (Figure 4). Current catheters range from 2.6 to 3.2 Frenchin size and can be introduced through conventional 6-French

guide catheters. Rotational, mechanical IVUS probes rotate a

single piezoelectric transducer at 1800 r.p.m. and operate at fre-

quencies between 30 and 45 MHz while electronic phased-array

systems operate at a centre-frequency of20 MHz. Higher ultra-

sound frequencies are associated with better image resolution; but

increasing the frequency beyond 45 MHz has been limited because

of decreased tissue penetration.6,7 Electronic systems have up to

64 transducer elements in an annular array that are activated

sequentially to generate the cross-sectional image. In general, elec-

tronic catheter designs are slightly easier to set up and use,

whereas mechanical probes offer superior image quality. Electronic

IVUS catheters have the ability to display blood flow in colour to

facilitate distinction between lumen and wall boundaries.

Combined intravascular imagingcathetersAnother imaging modality able to characterize coronary athero-

sclerosis (i.e. lipid core) invasively is NIR spectroscopy (NIRS).8

To this aim, the 3.2F FDA-approved near infrared spectroscopy

catheter is used. This catheter is compatible with a conventional

0.014 guidewire, contains a rotating (240 Hz) NIRS light source

at its tip, and is pulled back by a motor drive unit at 0.5 mm/s. 9

A newer catheter has been introduced. The 3.2F rapid exchange

Apollo catheter combines a 40 MHz real-time IVUS catheter

with a standard NIRS catheter (Figure5). In the SPECTACL (SPEC-

Troscopic Assessment of Coronary Lipid) trial, which was a paral-

lel first-in-human multicentre study designed to demonstrate the

Figure 1 This figure illustrates the nature of heterogeneity of the atherosclerosis disease and the lack of correlation of intravascular ultra-

sound findings (AD) and angiography appearance (E). Patient presented with stable angina due to a significant lesion in the right coronary

artery which was stented (not shown). A greyscale IVUS pullback in the left anterior descending was performed in order to better characterize

the mild lesion present in its mid segment. (A) Shows a large eccentric plaque in the ostium of the left anterior descending that angiographically

has minimum lumen compromise. (B) Depicts a soft concentric plaque. (C) Shows a mixed plaque. (D) Depicts an eccentric, soft lesion.

Imaging of coronary atherosclerosis 2457


3/17

applicability of the lipid core plaques detection algorithm in 106

living patients, it has been confirmed that the intravascular NIRS

system safely obtained spectral data in patients that were similar

to those from autopsy specimens.10 Currently, an observational

study of cholesterol in coronary arteries (COLOR registry,

NCT00831116) is aimed enrolling at 1000 patients in 14

centres in the USA. In Europe, this imaging modality is being

used in the IBIS 3 trial which is a study that will be able to

assess the effects of rosuvastatin on the content of necrotic core

(IVUS-VH) and lipid-containing regions (NIR spectroscopy) at 52

weeks.

Characterization ofatherosclerosis

Atheroma: pathological insightsA detailed description of atherosclerosis development and compo-

sition is beyond the scope of this review. Nevertheless, we high-

light here some important concepts that will support the use of

tissue characterization imaging modalities for plaque typification.

In brief, an atheroma is formed by an intricate sequence of

events, not necessarily in a linear chronologic order, that involves

Figure 2 Intravascular ultrasound signal is obtained from the vessel wall (A). Greyscale intravascular ultrasound imaging is formed by the

envelope (amplitude) (B) of the radiofrequency signal (C). By greyscale, atherosclerotic plaque can be classified into four categories: soft, fibro-

tic, calcified, and mixed plaques. (D) Shows a cross-sectional view of a greyscale image. The blue lines limit the actual atheroma. The frequency

and power of the signal commonly differ between tissues, regardless of similarities in the amplitude. From the backscatter radiofrequency data

different types of information can be retrieved: virtual histology (E), palpography (F), integrated backscattered (IB) intravascular ultrasound (G),

and iMAP (H ). Virtual histology is able to detect four tissue types: necrotic core, fibrous, fibrofatty, and dense calcium. Plaque deformability at

palpography is reported in strain values, which are subsequently categorized into four grades according to the ROtterdam Classification (ROC).

The tissues characterized by integrated backscattered (IB) intravascular ultrasound are lipidic, fibrous, and calcified; and iMAP detects fibrotic,

lipidic, necrotic, and calcified.

H.M. Garcia-Garcia et al.2458


4/17

extracellular lipid accumulation, endothelial dysfunction, leucocyte

recruitment, intracellular lipid accumulation (foam cells), smooth

muscle cell migration and proliferation, expansion of extracellularmatrix, neoangiogenesis, tissue necrosis, and mineralization at

later stages. The ultimate characteristic of an atherosclerotic

plaque at any given time depends on the relative contribution of

each of these features.11 Thus, in histological cross-sections, the

pathologic intimal thickening is rich in proteoglycans and lipid

pools, but no trace of necrotic core is seen. The earliest lesion

with a necrotic core is the fibroatheroma (FA), and this is the pre-

cursor lesion that may give rise to symptomatic heart disease.

Thin-capped fibroatheroma (TCFA) is a lesion characterized by a

large necrotic core containing numerous cholesterol clefts. The

overlying fibrous cap is thin and rich in inflammatory cells, macro-

phages, and T lymphocytes with a few smooth muscle cells.

Atheroma: linking pathology conceptsand intracoronary imagingFigure6 outlines the virtual histology plaque and lesion types that

are proposed based on the previous paragraph which describes

pathologic data.12

On the basis of tissue echogenicity (i.e. their appearance), not

necessarily histological composition, atheromas have been classi-

fied in four categories by greyscale IVUS: (i) soft plaque (lesion

echogenicity less than the surrounding adventitia), (ii) fibrous

plaque [intermediate echogenicity between soft (echolucent)

atheromas and highly echogenic calcified plaques], (iii) calcified

plaque (echogenicity higher than the adventitia with acoustic sha-

dowing), and (iv) mixed plaques (no single acoustical subtype rep-

resents .80% of the plaque)13 (Figure 1).

Description of the validation against pathology of the IVUS grey-

scale and the IVUS-based imaging modalities for plaque character-

ization is beyond the scope of this review. All available validation

reports are to be found in the list of references.35,1423

Detection of calcificationThe presence, depth and circumferential distribution of calcifica-

tion are important factors not only for selecting the type of inter-

ventional device and estimating the risk of vessel dissection and

perforation during PCI,24 but also in designing and conducting

studies on progression/regression of coronary atheroma. Plaques

with moderate to severe calcification showed no change or pro-gression of atheroma size.25 Thus, careful selection of coronary

segments to evaluate the effect of drugs on coronary atherosclero-

sis should be considered.

On IVUS, calcium appears as bright echoes that obstruct the

penetration of ultrasound (acoustic shadowing) (Figure1C). There-

fore, IVUS detects only the leading edge of calcium and cannot

determine its thickness. Using greyscale IVUS, a three-dimensional

and quantitative analysis of atherosclerotic plaque composition by

automated differential echogenicity has been developed to facili-

tate automatic detection of calcified areas.16

Virtual histology, in comparison with histology, has a predictive

accuracy of 96.7% for detection of dense calcium.26

Coronary remodellingCoronary remodelling refers to a continuous process involving

changes in vessel size measured by the external elastic membrane

(EEM) cross-sectional area (also called vessel cross-sectional

areaCSA). Positive remodelling occurs when there is an

outward increase in EEM. Negative remodelling occurs when

the EEM decreases in size (shrinkage of the vessel).13 The magni-

tude and direction of remodelling can be expressed by the follow-

ing index: EEM CSA at the plaque site divided by EEM CSA at the

reference non-diseased vessel. Positive remodelling will demon-

strate an index .

1.0, while negative remodelling has an index,1.0. Direct evidence of remodelling can only be demonstrated

in serial studies showing changes in the EEM CSA over time,

since remodelling may also be encountered at the normal-

appearing reference coronary segment.27

Pathological studies have also suggested a relationship between

positive vessel remodelling and plaque vulnerability. Vessel with

positive remodelling showed increased inflammatory marker con-

centrations, larger lipid cores, paucity of smooth muscle cells,

and medial thinning.2830 Several IVUS studies have linked positive

vessel remodelling with culprit31 and ruptured coronary

plaques.32,33 Positive remodelling has been observed more often

in patients with acute coronary syndromes than in those with

Figure 3 (A) Shows a greyscale image. (B) Depicts a VH image created using the Revolution 45-MHz IVUS catheter, which is currently under

development by Volcano. This plaque is classified as a fibroatheroma as it has a visible fibrous cap covering a more than 10% confluent necrotic

core. (C) Shows the corresponding histological section.



5/17

stable coronary artery disease (CAD),34,35 and has been identified

as an independent predictor of major adverse cardiac events in

patients with unstable angina.36 Plaques exhibiting positive remo-

delling also had more often thrombus and signs of rupture.37

The pattern of remodelling has also been correlated with plaque

composition; soft plaques are associated with positive remodelling

while fibrocalcific plaques more often have negative or constrictive

remodelling.38 Similar findings have been observed in studies

Figure 4 Intravascular ultrasound systems. The console of the Boston Scientific is iLabw ultrasound imaging system (A) and the iCrossTM is

the coronary imaging catheter (B). The Console of the Volcanos s5TM ultrasound imaging system and the Eagle EyeTM platinum coronary

imaging catheter are shown in (Cand D). (Eand F) The console of the Terumo Corporation Visiwave and the IVUS catheter ViewIT are shown.



6/17

utilizing virtual histology; positive remodelling was directly corre-

lated with the presence and the size of the necrotic core, and

inversely associated with fibrotic tissue39 (Figure7).

Vulnerable plaque and thrombiAcute coronary syndromes are often the first manifestation of cor-

onary atherosclerosis, making the identification of plaques at high

risk of complication an important component of strategies to

reduce casualties. Approximately 60% of clinically evident plaque

ruptures originate within an inflamed TCFA.40,41

The definition of a VH-TCFA is a lesion fulfilling the following

criteria in at least 3 frames: (i) plaque burden 40%; (ii) confluent

necrotic core 10% in direct contact with the lumen (i.e. no

visible overlying tissue).42 Using this definition of VH-TCFA, in

patients with ACS who underwent IVUS of all three epicardial cor-

onaries, on average, there were 2 VH-TCFA per patient with half

of them showing outward remodelling.42

Hong et al. reported the frequency and distribution of TCFA

identified by virtual histology intravascular ultrasound in acute cor-

onary syndrome (ACS 105 patients) and stable angina pectoris

(SAP 107 patients) in a 3-vessel IVUS-VH study.43 There were

Figure 5 Left anterior oblique view of the right coronary artery where the angiographic appearance of the Apollo catheter can be seen (A).

The proximal near infrared spectroscopy (NIRS) optical core and distal ultrasound transducer (IVUS) are both clearly visible ( B). A picture of

the Apollo catheter tip indicating the relative positions to each other of the NIRS light source and IVUS probe (C). The combined intravascular

ultrasound images and chemical information from a pullback through the right coronary artery obtained using the Apollo catheter. The chemo-

gram obtained from the Apollo catheter pullback, with the stented area as indicated ( D). The chemogram is a map of the measured probability

of the lipid core plaque (LCP) from each scanned arterial segment; the yellow regions represent those with the highest probability for the

presence of the LCP, while red regions represent those with the lowest. The chemogram displays the pullback position against the circumfer-

ential position of the measurement in degrees. The represents a region of the coronary artery where insufficient NIRS signals were obtainedto generate a chemogram. In this image the proximal end of the stent is located in an area with a high probability of the LCP (yellow). The block

chemogram provides a summary of the raw data from the chemogram and displays the probability that an LCP is present for all measurements

in a 2 mm block of coronary artery. The order of probability for the presence of the LCP from highest to lowest is yellow, light brown, brown,

and red (E). The longitudinal IVUS pullback, with NIRS overlay (F). The lilac and blue lines mark the anatomical position on the IVUS, and the

corresponding position on the chemogram during pullback, enabling simultaneous assessment of plaque structure and composition. ( G) Shows a

cross-sectional intravascular ultrasound image with the chemogram obtained from ( D), demonstrating well opposed clearly identifiable stent

struts (ss), highlighting the ability of the Apollo catheter to be used as a standalone IVUS catheter if required. The corresponding longitudinal

IVUS image and chemogram is indicated by the lilac line on ( D), (E), and (F). The chemogram indicates that there is a low probability of lipid

present in the stented plaque. (H) A cross-sectional IVUS image distal to the stent demonstrates the presence of echolucent plaque between 1

and 7 oclock. The chemogram displays a high probability of lipid in this plaque. The corresponding longitudinal IVUS image, and chemogram are

indicated by the blue lines on (D), (E), and (F).



7/17

2.5+1.5 in ACS and 1.7+1.1 in SAP VH-TCFAs per patient, P ,

0.001. Presentation of ACS was the only independent predictor

for multiple VH-TCFA (P 0.011). Eighty-three per cent of

VH-TCFAs were located within 40 mm of the coronary.

The potential value of these VH IVUS-derived plaque types in

the prediction of adverse coronary events was evaluated in an

international multicentre prospective study, the Providing Regional

Observations to Study Predictors of Events in the Coronary Tree

study (PROSPECT study), which has been completed but not yet

published.Although plaque characteristics (i.e. tissue characterization) do

not yet influence current therapeutic guidelines, the available

clinical imaging modalities, IVUS and IVUS-based tissue character-

ization techniques such as virtual histology, integrated basckscat-

tered IVUS, and iMAP, have the ability to identify some of the

pathological atheroma features described above and could help

us to advance further our understanding on atherosclerosis

Figure2 .

Plaque rupturesoccur at sites of significant plaque accumulation,

but are often not highly stenotic by coronary angiography due to

positive vascular remodelling.32,33,44 The transition to plaque

rupture has been characterized by the presence of active

inflammation (monocyte/ macrophage infiltration), thinning of the

fibrous cap (,65 mm), development of a large lipid necrotic

core, endothelial denudation with superficial platelet aggregation

and intraplaque haemorrhage.45

Ruptured plaques may have a variable appearance in IVUS; the

American College of Cardiology clinical expert consensus docu-

ment recommended use of the following definitions: (i) Plaque

ulceration: A recess in the plaque beginning at the luminal-intimal

border, typically without enlargement of the EEM compared with

the reference segment. (ii) Plaque rupture: plaque ulcerationwith a tear detected in a fibrous cap. Contrast injections may be

used to prove and define the communication point.46

The tear of the rupture (identified in 60%) occurs more often

at the shoulder of the plaque than in the centre.32,47,48 IVUS fea-

tures of ruptured plaques are as follows: large in volume, eccentric,

have mixed or soft composition and irregular surface, and are

associated with positive vessel remodelling.32,33,49,50 Ruptured

plaques have less calcium, especially superficial calcium, but a

larger number of small (,908 arc) calcium deposits, particularly

deep calcium deposits.51

Several IVUS studies have reported the frequency and distri-

bution of ruptured plaques in the coronary arteries (Table1).

Figure 6 Virtual histology plaque types. FF, fibrofatty; FT, fibrous tissue; NC, necrotic core and DC, dense calcium.



8/17

Intravascular ultrasound has also been used to assess the

natural evolution of ruptured plaques. Up to 50% of the ruptured

plaques detected in a first ACS event heal with medical therapy,

without significant change in plaque size.52 Another study

revealed complete healing of plaque rupture in 29% of the

patients treated with statins and incomplete healing in untreated

patients.53

Thrombus represents the ultimate pathological feature leading

to ACS. Thrombus is usually recognized as an echolucent intra-

luminal mass, often with a layered or pedunculated appearance

by IVUS.13 Fresh or acute thrombus may appear as an echodense

intraluminal tissue, which does not follow the circular appearanceof the vessel wall, while an older, more organized thrombus has a

darker ultrasound appearance. However, none of these IVUS fea-

tures are a hallmark for thrombus, and one should consider slow

flow (fresh thrombus), air, stagnant contrast or black hole, an

echolucent neointimal tissue observed after drug eluting stent

and radiation therapy, as differential diagnoses.13 In addition,

IVUS resolution is limited to precisely characterize thrombus. In

a study in patients with acute myocardial infarction (AMI), intra-

coronary thrombus was observed in all cases by optical coher-

ence tomography (OCT) and angioscopy but was identified in

only 33% by IVUS.54

Clinical applications: diagnostic

Determination of severity and extentof atherosclerosisDetermination of severity and extent of atherosclerosis remains

one of the main diagnostic clinical applications of intravascular

imaging, as angiography and non-invasive methods lack spatial or

temporal resolution for accurate coronary disease assessment.

Assessment of atheroma burdenQuantification of atheroma or plaque area in cross-sectional IVUS

images is performed by subtracting the lumen area from the EEM

area. Hence, an IVUS-defined atheroma area is a combination of

plaque plus media area. The atheroma area can be calculated in

each frame (cross-sectional image), and total atheroma volume

(TAV) can be calculated based on the pullback speed during

imaging acquisition. Atheroma volume can be reported as the

per cent of the volume of the EEM occupied by atheroma,

namely per cent atheroma volume (PAV). Parameters commonly

used to report the extent of the coronary atherosclerosis are

shown in Figure8 .

Figure 7 Relationship between vessel wall remodelling and plaque composition. At the top, six consecutive greyscale frames are shown. (A)

The size of the plaque is smaller when compared with the cross-section shown in (B). (B) The vessel wall is also clearly larger resulting in a

remodelling index of 1.1. Thus, the vessel needs to grow to accommodate the plaque without affecting lumen size (Glagov phenomenon).

The atheroma in (B) is also necrotic core rich. This suggests that positive remodelled plaques are commonly necrotic core rich. VCSA,

vessel cross-sectional area.



9/17
http://eurheartj.oxfordjournals.org/


10/17

Research applications

Intravascular imaging has played an important role in the under-

standing of atherosclerosis disease in humans and translation of

novel therapies to the clinical arena.

Cardiac allograft diseaseMost clinical adverse events in transplant patients occur after

1 year. Cumulative incidence of cardiac events per patient year

was 0.9% within the first year, increasing to 1.9% by 5 years.

Cardiac events accounted for 3.8% of the deaths by the end of

the first year, rising to 18% of total mortality by 7 years afterheart transplantation. After the first year of transplantation, 36%

(20/55) of the patients died because of sequelae of CAD.55

Death is usually silent because heart is denervated. Therefore,

there is a need for screening in order to detect coronary athero-

sclerosis early. The presence of obstructive coronary disease in

angiography is a predictor of any cardiac event [odds ratio (OR)

3.44, P , 0.05], as well as a predictor of cardiac death (OR 4.6,

P , 0.05). However, a pathological study reported 10 patients

who died or underwent retransplantation within 2 months of cor-

onary angiography. One quarter of the patients had intermediate

lesions or atheromatous plaques. Fresh or organizing thrombus

was most often associated with discrete lesions and accountedfor all complete occlusions. Authors concluded that transplant

CAD has a heterogeneous histologic and angiographic appearance,

with angiographic underestimation of disease in some patients.

Accordingly, many active transplant centres incorporated IVUS

imaging into their post-transplant surveillance, but there is no con-

sensus on how frequent IVUS should be performed. The predictive

value of IVUS has been explored in a study that included 143

patients who underwent 3-vessel IVUS investigation at 1 and 12

months after transplantation. The change in intimal thickness was

calculated (0.5 mm was defined as rapidly progressive vasculopa-

thy). At 1 year, rapid progression was demonstrated in 37% of the

patients and in 47% of them a new lesion was found. At 5.9 years,

patients with rapid progression died more than their counterparts

(26 vs. 11%, P 0.03). The combined endpoint of death and MI

was also more frequently seen in patients with rapid progression

(51 vs. 16%, P , 0.0001).56

Intravascular ultrasound has been also used to assess novel

therapies in heart transplantation recipients. Eisen et al. random-

ized 634 patients to receive 1.5 mg of everolimus per day (209

patients), 3.0 mg of everolimus per day (211 patients), or 1.0

3.0 mg of azathioprine per kilogram of body weight per day (214

patients), in combination with cyclosporine, corticosteroids, and

statins. The primary efficacy endpoint was a composite of death,

graft loss or retransplantation, loss to follow-up, biopsy-provedacute rejection of grade 3A, or rejection with haemodynamic com-

promise. At 1 year, IVUS showed that the average increase in

maximal intimal thickness was significantly smaller in the two ever-

olimus groups than in the azathioprine group.57

Drug effects on atherosclerosisThe initial observations about a positive continuous relationship

between coronary heart disease risk and blood cholesterol levels

led to the conduction of a number of IVUS-based studies to evalu-

ate the effect of different lipid lowering drugs on atheroma size.

The efficacy of lowering low-density lipoprotein cholesterol(LDL-C) with inhibitors of hydroxymethylglutaryl-coenzyme A

reductase (statins) is unequivocal; however, the change in ather-

oma size by statins is not constant across all IVUS studies

(Table2). There are many potential explanations for these discre-

pancies in IVUS studies such as drug properties, dose, and duration

of treatment. In early studies like the GAIN study,58 atheroma

volume was not reduced by atorvastatin despite the reduction in

LDL-C (86 vs. 140 mg/dL) at 12 months. In contrast, the REVER-

SAL study59 showed that LDL-C levels were further lowered by

atorvastatin vs. pravastatin (110 vs. 79 mg/dL) which was associ-

ated with an increase of 2.7% of the atheroma volume in

pravastatin-treated patients and in a 0.4% reduction in the

Figure 8 Parameters commonly used to report the extent of the coronary atherosclerosis are the total atheroma volume (TAV) and the per

cent atheroma volume (PAV). EEM, external elastic membrane; CSA, cross-sectional area.



11/17

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Table 2 Intravascular ultrasound progression/regression studies

Study Design Year Treatment n FU Primary endpoint Res

Statin trials

GAIN58 RCT 2001 Atorvastatin 48 12 months Plaque volume

Control 51 1

ESTABLISH84 RCT 2004 Atorvastatin 24 6 months % Change in plaque volume 1

Control 24 REVERSAL59 RCT 2004 Atorvastatin 253 18 months % Change in plaque volume

Pravastatin 249

Jensenet al.85 Non-RCT 2004 Simvastatin 40 12 months % Change in plaque volume 6.3

Petronioet al.86 RCT 2005 Simvastatin 36 12 months Plaque volume 22

Control 35

Nishioka et al.87 Non-RCT 2004 Pravastatin, atorvastatin, simvastatin, and

fluvastatin

22 6 months Plaque Volume 3

Control 26 3

Taniet al.88 RCT 2005 Pravastatin 52 6 months % Change in plaque volume 214

Control 23

ASTEROID89 Non-RCT 2006 Rosuvastatin 349 24 months Change in PAV 20

Takashimaet al.90 Non-RCT 2007 Pitavastatin 41 6 months % Change in plaque volume 21

Control 41

COSMOS91 Non-RCT 2009 Rosuvastatin 126 18 months Change in PAV 2

JAPAN-ACS92 RCT 2009 Atorvastatin 127 8 12

months

% Change in plaque volume 21

Pitavastatin 125 21

Hirayama Non-RCT 2009 Atorvastatin 28 28 weeks % Change in plaque volume 29

80 weeks 21

ACAT (acyl-coenzyme A:cholesterol acyltransferase) inhibitor trials

A-PLUS93 RCT 2004 Avasimibe 50 mg 108 24 months Change in PAV

Avasimibe 250 mg 98

Avasimibe 750 mg 117

Placebo 109

ACTIVATE64 RCT 2006 pactimibe 206 18 months Change in PAV 0

Placebo 202 20

Increasing high-density lipoprotein therapies

ApoA-I Milano94 RCT 2003 ApoA-I Milano 15 mg/kg 21 5 weeks Change in PAV 21

ApoA-I Milano 45 mg/kg 15 20

Placebo 11 0

ERASE62 RCT 2007 CSL-111 (reconstituted HDL infusion) 89 4 weeks % change in plaque volume 23

Placebo 47 21

CART-295 RCT 2008 Succinobucol (AGI-1067) 183 12 months Absolute change in plaque volume 2

Placebo 49 20

Other therapies

byguestonOctober10,2012 http://eurheartj.oxfordjournals.org/ Downloadedfrom
http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/


12/17

CAMELOT65 RCT 2004 Amlodipine 91 24 months Change in PAV

Enalapril 88 0

Placebo 95

Waseda Non-RCT 2006 Losartan 41 7 months Change in plaque area 29

Non-ARB 23 7 months 29

ILLUSTRATE63 RCT 2007 Torcetrapib + atorvastatin 464 24 months Change in PAV 0Atorvastatin 446 0.

PERSPECTIVE66 RCT 2007 Perindopril 75 36 months Change in plaque area 20

Placebo 69 20

PERISCOPE68 RCT 2008 Pioglitazone 179 18 months Change in PAV 20.16

Glimepiride 181 0.73

STRADIVARIUS96 RCT 2008 Rimonabant 335 18 months Change in PAV 0.25

Placebo 341 0.51

ENCORE II97 RCT 2009 Nifedipine 97 18 24

months

% change in plaque volume 5

Placebo 96 3

APPROACH67 RCT 2010 rosiglitazone 233 18 months Change in PAV 20

Glipizide 229 0.

IVUS-based tissue characterization studies

Yokoyamaet al.98 RCT 2005 Atorvastatin 25 6 months Overall plaque size and tissue

characterization by IB IVUS

Ato

plaq

Control 25

Kawasakiet al.99 RCT 2005 Pravastatin 17 6 months Overall tissue characterization by IB IVUS Stat

Atorvastatin 18

Diet 17

IBIS 271 RCT 2008 Darapladib 175 12 months Necrotic core volume by IVUS VH Dar

Placebo 155

Nasu et al.69 Non-RCT 2009 Fluvas tati n 40 12 months Overall tissue characterizati on by IVUS VH Fluv

Control 40

Honget al.70 RCT 2009 Simvastatin 50 12 months Overall tissue characterization by IVUS VH Bot

fibro

Rosuvastatin 50

Toiet al.100 RCT 2009 Atorvastatin 80 2 3 weeks Overall tissue characteri zati on by IVUS VH Pita

Pivastatin 80

Miyagi et al.101 Non-RCT 2009 Statin (pravastatin, pitavastatin,

atorvastatin, fluvastatin, simvastatin)

44 6 months Overall tissue characterization by IB IVUS Stat

Non-statin 56

IVUS, intravascular ultrasound; IB, integrated backscatter; VH, virtual histology; FU, follow-up; SD, standard deviation; CI, confidence interval; RCT, randomized controlled trial; IB, inte

byguestonOctober10,2012 http://eurheartj.oxfordjournals.org/ Downloadedfrom
http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/http://eurheartj.oxfordjournals.org/


13/17

atheroma volume in atorvastatin-treated patients. The clinical sig-

nificance and the accuracy of IVUS for such measurements are

still debatable, but these results were statistically significant. The

PROVE-IT study,60 showed that the lower the LDL-C and

C-reactive protein values, the greater the reduction in clinical

events and atheroma progression.

The first study showing regression of plaque size was the

ASTEROID trial.61

At 24 months treatment with rosuvastatin40 mg daily resulted in lowering of LDL-C to 60.8 mg/dL and

elevation of high-density lipoprotein cholesterol (HDL-C) by

14.7%. These lipid effects were associated with statistically signifi-

cant, albeit small reductions in PAV (0.79%) and the TAV (6.8%).

Intravascular ultrasound studies have also demonstrated coronary

plaque modification in HDL-treated patients. The infusion of syn-

thetic HDL-C particles containing the variant apolipoprotein,

apoA-I Milano, complexed with phospholipids (ETC-216) reduced

the PAV by 21.06% (3.17% P 0.02 compared with the baseline)

in the combined ETC-216 group at 5 weeks. On the contrary, in

the placebo group, the PAV increased by 0.14% (3.09%; P 0.97

compared with the baseline). In the ERASE study,62 60 patients

were randomly assigned to receive 4 weekly infusions of placebo

(saline), 111 to receive 40 mg/kg of reconstituted HDL (CSL-111),

and 12 to receive 80 mg/kg of CSL-111. The latter was discontinued

due to liver function test abnormalities. Within the treated group,

the percentage change in the atheroma volume was 23.4% with

CSL-111 (P , 0.001 vs. baseline), while for the placebo group it

was 21.6% (P 0.48 between groups). It is still unclear what the

future holds for these therapeutical agents.

Patients with human deficiency of cholesterylester transfer

protein (CETP) have elevated circulating levels of HDL-C. This

has led to investigation on CETP inhibition as a novel and poten-

tially effective approach to elevate HDL-C. In the ILLUSTRATE

trial, the PAV (the primary efficacy measure) increase was similarlylow in patients receiving atorvastatin monotherapy vs. in those

receiving the combined torcetrapibatorvastatin therapy after 24

months (0.19 vs. 0.12%, respectively).63

The enzyme acyl-coenzyme A:cholesterol acyltransferase

(ACAT) esterifies cholesterol in a variety of cells and tissues. Inhi-

bition of ACAT1, by blocking the esterification of cholesterol,

could prevent the transformation of macrophages into foam cells

and slow the progression of atherosclerosis, while inhibition of

ACAT2 would be expected to decrease serum lipid levels. In the

ACTIVATE study, the change in the PAV was similar in the pacti-

mibe (100 mg daily) and placebo groups (0.69 and 0.59%, respect-

ively; P

0.77).

64

Systolic blood pressure has been shown to be an independent

predictor of plaque progression by IVUS.65 A randomized study

of patients with CAD and a diastolic blood pressure

,100 mmHg treated with placebo or antihypertensive therapy

using either amlodipine 10 mg daily or enalapril 20 mg daily

showed that patients treated with amlodipine had a reduction in

plaque size and also a reduction in cardiovascular events when

compared with placebo at 24 months.65 The PERSPECTIVE

study,66 a substudy of the EUROPA trial, evaluated the effect of

perindopril on coronary plaque progression in 244 patients.

There were no differences in changes in IVUS plaque measure-

ments detected between the perindopril and placebo groups.

Thiazolidinediones increase insulin sensitivity in peripheral

tissues, thereby lowering glucose, and also lower blood pressure

and inflammatory markers, and improve lipid profile, endothelial

function, and carotid IMT. Thiazolidinediones (i.e. rosiglitazone

and pioglitazone) may therefore reduce progression of coronary

atherosclerosis compared with other antidiabetic drugs. Two

studies have addressed this question. The APPROACH (Rosiglita-

zone study)67

and the PERISCOPE (Pioglitazone study) trials.68

Achange in PAV in the APPROACH study was not different in

patients allocated to glipizide or rosiglitazone [20.64%, 95% con-

fidence interval (CI) 21.46, 0.17; P 0.12], while in the PERI-

SCOPE study pioglitazone vs. glimepiride was associated with

favourable effects on the change of PAV ( 0.16+0.21 vs.

0.73+0.20%, P 0.002). Rosiglitazone significantly reduced the

normalized TAV by 5.1 mm3 (95% CI 210.0, 20.3; P 0.04)

when compared with glipizide, whereas pioglitazone just failed to

achieve a statistically significant change in the TAV ( 5.5+1.6

vs. 1.5+1.5 mm3, P 0.06) when compared with glimepiride.

Pioglitazone resulted in comparable plaque size reduction (i.e.

TAV) as rosiglitazone, but this reduction was associated with an

almost double reduction in vessel size. The formula of change in

the PAV has as a numerator change in atheroma volume and as

denominator change in vessel volume; this may mask the specific

directional changes in its numerator and denominator when used

as primary endpoint to compare two pharmacological agents.

There are several recent reports showing serial changes of

plaque composition in patients treated with various statin treat-

ments. In one of them, patients with stable angina pectoris (n

80) treated with fluvastatin for 1 year had significant regression

of the plaque volume, and changes in the atherosclerotic plaque

composition with a significant reduction of the fibrofatty volume

(P , 0.0001). This change in the fibrofatty volume had a significant

correlation with change in the LDL-cholesterol level (r 0.703,P , 0.0001) and change in the hsCRP level (r 0.357, P

0.006).69 Of note, the necrotic core did not change significantly.

In a second study, Hong et al. randomized 100 patients with

stable angina and ACS to either rosuvastatin 10 mg or simvastatin

20 mg for 1 year. The overall necrotic core volume significantly

decreased (P 0.010) and the fibrofatty plaque volume increased

(P 0.006) after statin treatments. Particularly, there was a signifi-

cant decrease in the necrotic core volume (P 0.015) in the

rosuvastatin-treated subgroup. By multiple stepwise logistic

regression analysis, they showed that the only independent

clinical predictor of decrease in the necrotic core volume was

the baseline HDL-cholesterol level (P

0.040, OR: 1.044, 95%CI 1.002 1.089).70

The IBIS 2 study compared the effects of 12 months of treat-

ment with darapladib (oral Lp-PLA2 inhibitor, 160 mg daily) or

placebo in 330 patients.71 This study failed to demonstrate the

treatment effect of darapladib on the two co-primary endpoints

(i.e. density of high strain values by palpography and change in

hsCRP). Other endpoints included changes in the necrotic core

size (IVUS-VH) and atheroma size (IVUS-greyscale). Background

therapy was comparable between groups, with no difference in

the LDL-cholesterol at 12 months. In the placebo-treated group,

however, the necrotic core volume increased significantly,

whereas darapladib halted this increase, resulting in a significant



14/17

treatment difference of25.2 mm3 (P 0.012). These intraplaque

compositional changes occurred without a significant treatment

difference in the TAV.

Nevertheless, there is no a single report describing a clear direct

association between reduction in the plaque size and/or the plaque

composition with reduction in clinical events. This is in part due to

the fact that clinical outcome studies are expensive since they have

to include a large population (that should be imaged at least at two

different time points) that has to be followed up for a long period

of time to collect the number of events (which are becoming

scarce due to improvement in the standard of care) needed to

assess the treatment effect.

Future directions

In the future, integration of multiple image technologies in a single

catheter is likely to provide a more comprehensive assessment ofthe coronary vasculature.

IVUS-VH has a limited axial resolution (100 200 mm) not

allowing a precise measurement of the fibrous thin cap; on the

contrary OCT is a high-resolution imaging technique (10

20 mm) that can be used in the assessment of microstructure,

but only using OCT in plaque-type characterization can be a

source of misclassification. The OCT signal has in fact a low pen-

etration, limited to 12 mm, and could not detect lipid pools or

calcium behind thick fibrous caps, thus producing inaccurate

detection of signal-poor areas.72 The combined use of IVUS-VH

analysis and OCT seems to improve the accuracy for TCFA

detection.73,74

Intravascular ultrasound guidance during the treatment of

chronic total occlusions, in which the most exacting parts of the

procedure are to enter into the proximal part of the occlusion

and to keep the guidewire within the limits of the vessel to

avoid coronary perforations, with a forward-looking intravascular

ultrasound (FL-IVUS) holds promise because it is able to visualize

the vessel, plaque morphology, and true and false lumens in front

of the imaging catheter. The Preview catheter is currently under-

going preclinical and early clinical evaluation. It is a single-use,

over-the-wire imaging catheter, and the distal imaging tip is

shown in Figure9 .

Conflict of interest: M.A.C. is a consulting speaker (,10 000

USD threshold) and received research grants (through the

University and/or core lab) from Boston Scientific and Lightlab,

and is a consulting speaker for the drug companies: Sanofi and

Eli Lilly (,10 000 USD per year).

References1. Roberts WC, Jones AA. Quantitation of coronary arterial narrowing at necropsy

in sudden coronary death: analysis of 31 patients and comparison with 25

control subjects. Am J Cardiol 1979;44:3945.

2. Escaned J, Baptista J, Di Mario C, Haase J, Ozaki Y, Linker DT, de Feyter PJ,

Roelandt JR, Serruys PW. Significance of automated stenosis detection during

quantitative angiography. Insights gained from intracoronary ultrasound

imaging.Circulation 1996;94:966972.

3. Sathyanarayana S, Carlier S, Li W, Thomas L. Characterisation of atherosclerotic

plaque by spectral similarity of radiofrequency intravascular ultrasound signals.

EuroIntervention 2009;5:133139.

4. Kawasaki M, Bouma BE, Bressner J, Houser SL, Nadkarni SK, MacNeill BD,

Jang IK, Fujiwara H, Tearney G J. Diagnostic accuracy of optical coherence tom-

ography and integrated backscatter intravascular ultrasound images for tissue

characterization of human coronary plaques. J Am Coll Cardiol 2006;48:8188.

Figure 9 Forward-looking intravascular ultrasound (Volcano Corporation) is a 45 MHz transducer oriented at a 458 angle at the tip of the

catheter, which rotates providing a forward-looking cone of visualization (A). A 0.014-inch chronic total occlusion dedicated guidewire can be

advanced through the catheter. Thus, a true lumen position can be maintained under forward-looking intravascular ultrasound guidance while

treating chronic total occlusion via antegrade. An forward-looking intravascular ultrasound view of the proximal end of the chronic total occlu-

sion phantom model (B), and directed in real time to maintain a true lumen position.



15/17

5. Schaar JA, De Korte CL, Mastik F, Strijder C, Pasterkamp G, Boersma E,

Serruys PW, Van Der Steen AF. Characterizing vulnerable plaque features

with intravascular elastography. Circulation 2003;108:26362641.

6. Lockwood GR, Ryan LK, Hunt JW, Foster FS. Measurement of the ultrasonic

properties of vascular tissues and blood from 35 65 MHz. Ultrasound Med

Biol 1991;17:653666.

7. Bridal SL, Fornes P, Bruneval P, Berger G. Parametric (integrated backscatter

attenuation) images constructed using backscattered radio frequency signals

(2556 MHz) from human aortae in vitro. Ultrasound Med Biol 1997;23:

215229.

8. Gardner CM, Tan H, Hull EL, Lisauskas JB, Sum ST, Meese TM, Jiang C,

Madden SP, Caplan JD, Burke AP, Virmani R, Goldstein J, Muller JE. Detection

of lipid core coronary plaques in autopsy specimens with a novel catheter

based near-infrared spectroscopy system. Am Coll Cardiol Img2008;1:638648.

9. Gardner CM, Tan H, Hull EL, Lisauskas JB, Sum ST, Meese TM, Jiang C,

Madden SP, Caplan JD, Burke AP, Virmani R, Goldstein J, Muller JE. Detection

of lipid core coronary plaques in autopsy specimens with a novel catheter-based

near-infrared spectroscopy system. JACC Cardiovasc Imaging2008;1:638648.

10. Waxman S, Dixon SR, LAllier P, Moses JW, Petersen JL, Cutlip D, Tardif JC,

Nesto RW, Muller JE, Hendricks MJ, Sum ST, Gardner CM, Goldstein JA,

Stone GW, Krucoff MW. In vivo validation of a catheter-based near-infrared

spectroscopy system for detection of lipid core coronary plaques: initial

results of the SPECTACL study. JACC Cardiovasc Imaging2009;2:858868.

11. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden

coronary death: a comprehensive morphological classification scheme for ather-

osclerotic lesions. Arterioscler Thromb Vasc Biol2000;20:12621275.

12. Garca-Garca HMMG, Lerman A, Vince DG, Margolis MP, van Es GA,Morel MA, Nair A, Virmani R, Burke AP, Stone GW, Serruys PW. Tissue charac-

terisation using intravascular radiofrequency data analysis: recommendations for

acquisition, analysis, interpretation and reporting. Eurointervention 2009;5:177.

13. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ,

Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG. American College of Cardiology

Clinical Expert Consensus Document on Standards for Acquisition, Measure-

ment and Reporting of Intravascular Ultrasound Studies (IVUS). A report of

the American College of Cardiology Task Force on Clinical Expert Consensus

Documents. J Am Coll Cardiol 2001;37:14781492.

14. Di Mario C, The SH, Madretsma S, van Suylen RJ, Wilson RA, Bom N,

Serruys PW, Gussenhoven EJ, Roelandt JR. Detection and characterization of

vascular lesions by intravascular ultrasound: an in vitro study correlated with his-

tology. J Am Soc Echocardiogr1992;5:135146.

15. Prati F, Arbustini E, Labellarte A, Dal Bello B, Sommariva L, Mallus MT, Pagano A,

Boccanelli A. Correlation between high frequency intravascular ultrasound and

histomorphology in human coronary arteries. Heart2001;85:567570.16. Bruining N, Verheye S, Knaapen M, Somers P, Roelandt JR, Regar E, Heller I, de

Winter S, Ligthart J, Van Langenhove G, de Feijter PJ, Serruys PW, Hamers R.

Three-dimensional and quantitative analysis of atherosclerotic plaque compo-

sition by automated differential echogenicity. Catheter Cardiovasc Interv 2007;

70:968978.

17. Nair A, Kuban BD, Tuzcu EM, Schoenhagen P, Nissen SE, Vince DG. Coronary

plaque classification with intravascular ultrasound radiofrequency data analysis.

Circulation 2002;106:22002206.

18. Nair A, Margolis MP, Kuban BD, Vince DG. Automated coronary plaque charac-

terisation with intravascular ultrasound backscatter: ex vivo validation.EuroInter-

vention 2007;3:113120.

19. Nasu K, Tsuchikane E, Katoh O, Vince DG, Virmani R, Surmely J-Fi, Murata A,

Takeda Y, Ito T, Ehara M, Matsubara T, Terashima M, Suzuki T. Accuracy of in

vivo coronary plaque morphology assessment: a validation study of in vivo

virtual histology compared with in vitro histopathology. J Am Coll Cardiol 2006;

47:24052412.

20. Nasu K, Tsuchikane E, Katoh O, Vince DG, Margolis PM, Virmani R, Surmely JF,

Ehara M, Kinoshita Y, Fujita H, Kimura M, Asakura K, Asakura Y, Matsubara T,

Terashima M, Suzuki T. Impact of intramural thrombus in coronary arteries on

the accuracy of tissue characterization by in vivo intravascular ultrasound radio-

frequency data analysis. Am J Cardiol 2008;101:10791083.

21. Granada JF, Wallace-Bradley D, Win HK, Alviar CL, Builes A, Lev EI, Barrios R,

Schulz DG, Raizner AE, Kaluza GL. In vivo plaque characterization using intravas-

cular ultrasound-virtual histology in a porcine model of complex coronary

lesions. Arterioscler Thromb Vasc Biol 2007;27:387393.

22. Van Herck J, De Meyer G, Ennekens G, Van Herck P, Herman A, Vrints C. Vali-

dation of in vivo plaque characterisation by virtual histology in a rabbit model of

atherosclerosis.EuroIntervention 2009;5:149156.

23. Thim T, Hagensen MK, Wallace-Bradley D, Granada JF, Kaluza GL, Drouet L,

Paaske WP, Botker HE, Falk E. Unreliable assessment of necrotic core by

VHTM IVUS in porcine coronary artery disease. Circ Cardiovasc Imaging2010;

3:384391.

24. Silber S, Albertsson P, Aviles FF, Camici PG, Colombo A, Hamm C, Jorgensen E,

Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W. Guidelines

for percutaneous coronary interventions. The task force for percutaneous cor-

onary interventions of the European society of cardiology.Eur Heart J 2005;26:

804847.

25. Bruining N, de Winter S, Roelandt JR, Rodriguez-Granillo GA, Heller I, van

Domburg RT, Hamers R, de Feijter PJ. Coronary calcium significantly affects

quantitative analysis of coronary ultrasound: importance for atherosclerosis

progression/regression studies. Coron Artery Dis 2009;20:409414.

26. Nair AMP, Kuban BD, Vince DG. Automated coronary plaque characterization

with intravascular ultrasound backscatter: ex vivo validation. Eurointervention

2007;3:113130.

27. Nissen SE, Gurley JC, Grines CL, Booth DC, McClure R, Berk M, Fischer C,

DeMaria AN. Intravascular ultrasound assessment of lumen size and wall mor-

phology in normal subjects and patients with coronary artery disease. Circulation

1991;84:10871099.

28. Pasterkamp G, Schoneveld AH, van der Wal AC, Haudenschild CC, Clarijs RJ,

Becker AE, Hillen B, Borst C. Relation of arterial geometry to luminal narrowing

and histologic markers for plaque vulnerability: the remodeling paradox. J Am

Coll Cardiol 1998;32:655662.

29. Varnava AM, Mills PG, Davies MJ. Relationship between coronary artery remo-

deling and plaque vulnerability. Circulation 2002;105:939943.

30. Burke AP, Kolodgie FD, Farb A, Weber D, Virmani R. Morphological predictors

of arterial remodeling in coronary atherosclerosis. Circulation 2002;105:

297303.

31. Kotani J, Mintz GS, Castagna MT, Pinnow E, Berzingi CO, Bui AB, Pichard AD,

Satler LF, Suddath WO, Waksman R, Laird JR Jr, Kent KM, Weissman NJ. Intra-vascular ultrasound analysis of infarct-related and non-infarct-related arteries in

patients who presented with an acute myocardial infarction. Circulation 2003;

107:28892893.

32. Maehara A, Mintz GS, Bui AB, Walter OR, Castagna MT, Canos D, Pichard AD,

Satler LF, Waksman R, Suddath WO, Laird JR Jr, Kent KM, Weissman NJ. Mor-

phologic and angiographic features of coronary plaque rupture detected by

intravascular ultrasound. J Am Coll Cardiol 2002;40:904910.

33. von Birgelen C, Klinkhart W, Mintz GS, Papatheodorou A, Herrmann J,

Baumgart D, Haude M, Wieneke H, Ge J, Erbel R. Plaque distribution and vas-

cular remodeling of ruptured and nonruptured coronary plaques in the same

vessel: an intravascular ultrasound study in vivo. J Am Coll Cardiol 2001;37:

18641870.

34. Jeremias A, Spies C, Herity NA, Pomerantsev E, Yock PG, Fitzgerald PJ,

Yeung AC. Coronary artery compliance and adaptive vessel remodelling in

patients with stable and unstable coronary artery disease. Heart 2000;84:

314319.35. Nakamura M, Nishikawa H, Mukai S, Setsuda M, Nakajima K, Tamada H,

Suzuki H, Ohnishi T, Kakuta Y, Nakano T, Yeung AC. Impact of coronary

artery remodeling on clinical presentation of coronary artery disease: an intra-

vascular ultrasound study. J Am Coll Cardiol 2001;37:6369.

36. Gyongyosi M, Yang P, Hassan A, Domanovits H, Laggner A, Weidinger F,

Glogar D. Intravascular ultrasound predictors of major adverse cardiac events

in patients with unstable angina. Clin Cardiol 2000;23:507515.

37. Gyongyosi M, Yang P, Hassan A, Weidinger F, Domanovits H, Laggner A,

Glogar D. Arterial remodelling of native human coronary arteries in patients

with unstable angina pectoris: a prospective intravascular ultrasound study.

Heart1999;82:6874.

38. Tauth J, Pinnow E, Sullebarger JT, Basta L, Gursoy S, Lindsay J Jr, Matar F. Pre-

dictors of coronary arterial remodeling patterns in patients with myocardial

ischemia. Am J Cardiol 1997;80:13521355.

39. Rodriguez-Granillo GA, Serruys PW, Garcia-Garcia HM, Aoki J, Valgimigli M, van

Mieghem CA, McFadden E, de Jaegere PP, de Feyter P. Coronary artery remo-

delling is related to plaque composition.Heart2006;92:388391.

40. Virmani R, Burke AP, Farb A, Kolodgie FD. Pathology of the vulnerable plaque.

J Am Coll Cardiol 2006;47(Suppl. 8):C13 C18.

41. Schaar JA, Muller JE, Falk E, Virmani R, Fuster V, Serruys PW, Colombo A,

Stefanadis C, Ward Casscells S, Moreno PR, Maseri A, van der Steen AF. Termi-

nology for high-risk and vulnerable coronary artery plaques. Report of a meeting

on the vulnerable plaque, June 17 and 18, 2003, Santorini, Greece. Eur Heart J

2004;25:10771082.

42. Garcia-Garcia HM, Goedhart D, Schuurbiers JC, Kukreja N, Tanimoto S,

Daemen J, Morel MA, Bressers M, van Es GA, Wentzel J, Gijsen F, van der

Steen AF, Serruys PW. Virtual histology and remodeling index allow in vivo

identification of allegedly high risk coronary plaques in patients with acute cor-

onary syndromes: a three vessel intravascular ultrasound radiofrequency data

analysis.Eurointervention 2006;2:338344.

43. Hong MK, Mintz GS, Lee CW, Lee JW, Park JH, Park DW, Lee SW, Kim YH,

Cheong SS, Kim JJ, Park SW, Park SJ. A three-vessel virtual histology intravascular

H.M. Garcia-Garcia et al.2469a


16/17

ultrasound analysis of frequency and distribution of thin-cap fibroatheromas in

patients with acute coronary syndrome or stable angina pectoris. Am J Cardiol

2008;101:568572.

44. Fujii K, Mintz GS, Carlier SG, Costa JR Jr, Kimura M, Sano K, Tanaka K, Costa RA,

Lui J, Stone GW, Moses JW, Leon MB. Intravascular ultrasound profile analysis of

ruptured coronary plaques. Am J Cardiol 2006;98:429435.

45. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, Farb A,

Guerrero LJ, Hayase M, Kutys R, Narula J, Finn AV, Virmani R. Intraplaque

hemorrhage and progression of coronary atheroma. N Engl J Med 2003;349:

23162325.

46. Mintz GS, Nissen SE, Anderson WD, Bailey SR, Erbel R, Fitzgerald PJ, Pinto FJ,

Rosenfield K, Siegel RJ, Tuzcu EM, Yock PG, ORourke RA, Abrams J,

Bates ER, Brodie BR, Douglas PS, Gregoratos G, Hlatky MA, Hochman JS,

Kaul S, Tracy CM, Waters DD, Winters WL. American College of Cardiology

Clinical Expert Consensus Document on Standards For Acquisition, Measure-

ment and Reporting of Intravascular Ultrasound Studies (IVUS): a report of

the American College of Cardiology Task Force on Clinical Expert Consensus

Documents developed in collaboration with the European Society of Cardiology

endorsed by the society of cardiac angiography and interventions. J Am Coll

Cardiol 2001;37:14781492.

47. Jensen LO, Mintz GS, Carlier SG, Fujii K, Moussa I, Dangas G, Mehran R,

Stone GW, Leon MB, Moses JW. Intravascular ultrasound assessment of

fibrous cap remnants after coronary plaque rupture. Am Heart J 2006;152:

327332.

48. Ge J, Chirillo F, Schwedtmann J, Gorge G, Haude M, Baumgart D, Shah V, von

Birgelen C, Sack S, Boudoulas H, Erbel R. Screening of ruptured plaques in

patients with coronary artery disease by intravascular ultrasound. Heart1999;81:621627.

49. von Birgelen C, Klinkhart W, Mintz GS, Wieneke H, Baumgart D, Haude M,

Bartel T, Sack S, Ge J, Erbel R. Size of emptied plaque cavity following spon-

taneous rupture is related to coronary dimensions not to the degree of

lumen narrowing. A study with intravascular ultrasound in vivo. Heart 2000;

84:483488.

50. Fujii K, Kobayashi Y, Mintz GS, Takebayashi H, Dangas G, Moussa I, Mehran R,

Lansky AJ, Kreps E, Collins M, Colombo A, Stone GW, Leon MB, Moses JW.

Intravascular ultrasound assessment of ulcerated ruptured plaques: a compari-

son of culprit and nonculprit lesions of patients with acute coronary syndromes

and lesions in patients without acute coronary syndromes. Circulation2003;108:

24732478.

51. Fujii K, Carlier SG, Mintz GS, Takebayashi H, Yasuda T, Costa RA, Moussa I,

Dangas G, Mehran R, Lansky AJ, Kreps EM, Collins M, Stone GW, Moses JW,

Leon MB. Intravascular ultrasound study of patterns of calcium in ruptured cor-

onary plaques. Am J Cardiol 2005;96:352357.52. Rioufol G, Gilard M, Finet G, Ginon I, Boschat J, Andre-Fouet X. Evolution of

spontaneous atherosclerotic plaque rupture with medical therapy: long-term

follow-up with intravascular ultrasound. Circulation 2004;110:28752880.

53. Hong MK, Mintz GS, Lee CW, Suh IW, Hwang ES, Jeong YH, Park DW, Kim YH,

Han KH, Cheong SS, Kim JJ, Park SW, Park SJ. Serial intravascular ultrasound evi-

dence of both plaque stabilization and lesion progression in patients with rup-

tured coronary plaques: effects of statin therapy on ruptured coronary

plaque. Atherosclerosis 2007;191:107114.

54. Kubo T, Imanishi T, Takarada S, Kuroi A, Ueno S, Yamano T, Tanimoto T,

Matsuo Y, Masho T, Kitabata H, Tsuda K, Tomobuchi Y, Akasaka T. Assessment

of culprit lesion morphology in acute myocardial infarction: ability of optical

coherence tomography compared with intravascular ultrasound and coronary

angioscopy. J Am Coll Cardiol 2007;50:933939.

55. Uretsky BF, Kormos RL, Zerbe TR, Lee A, Tokarczyk TR, Murali S, Reddy PS,

Denys BG, Griffith BP, Hardesty RL et al. Cardiac events after heart transplan-

tation: incidence and predictive value of coronary arteriography. J Heart Lung

Transplant1992;11:S45S51.

56. Tuzcu EM, Kapadia SR, Sachar R, Ziada KM, Crowe TD, Feng J, Magyar WA,

Hobbs RE, Starling RC, Young JB, McCarthy P, Nissen SE. Intravascular ultra-

sound evidence of angiographically silent progression in coronary atherosclero-

sis predicts long-term morbidity and mortality after cardiac transplantation. J Am

Coll Cardiol 2005;45:15381542.

57. Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von

K aeppler H A, Star ling R C, S or en sen K , Hu mm el M , L in d JM,

Abeywickrama KH, Bernhardt P. Everolimus for the prevention of allograft rejec-

tion and vasculopathy in cardiac-transplant recipients. N Engl J Med2003;349:

847858.

58. Schartl M, Bocksch W, Koschyk DH, Voelker W, Karsch KR, Kreuzer J,

Hausmann D, Beckmann S, Gross M. Use of intravascular ultrasound to

compare effects of different strategies of lipid-lowering therapy on plaque

volume and composition in patients with coronary artery disease. Circulation

2001;104:387392.

59. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P, Vogel RA, Crowe T,

Howard G, Cooper CJ, Brodie B, Grines CL, DeMaria AN. Effect of intensive

compared with moderate lipid-lowering therapy on progression of coronary

atherosclerosis: a randomized controlled trial. J Am Med Assoc 2004;291:

10711080.

60. Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, Joyal SV,

Hill KA, Pfeffer MA, Skene AM. Intensive versus moderate lipid lowering with

statins after acute coronary syndromes. N Engl J Med2004;350:14951504.

61. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J,

Erbel R, Fruchart JC, Tardif JC, Schoenhagen P, Crowe T, Cain V, Wolski K,Goormastic M, Tuzcu EM. Effect of very high-intensity statin therapy on

regression of coronary atherosclerosis: the ASTEROID trial. J Am Med Assoc

2006;295:15561565.

62. Tardif JC, Gregoire J, LAllier PL, Ibrahim R, Lesperance J, Heinonen TM, Kouz S,

Berry C, Basser R, Lavoie MA, Guertin MC, Rodes-Cabau J. Effects of reconsti-

tuted high-density lipoprot ein infusions on coronary atherosclerosis: a random-

ized controlled trial. J Am Med Assoc2007;297:16751682.

63. Nissen SE, Tardif JC, Nicholls SJ, Revkin JH, Shear CL, Duggan WT, Ruzyllo W,

Bachinsky WB, Lasala GP, Tuzcu EM. Effect of torcetrapib on the progression of

coronary atherosclerosis. N Engl J Med2007;356:13041316.

64. Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ, Ganz P, Schoenhagen P,

Waters DD, Pepine CJ, Crowe TD, Davidson MH, Deanfield JE, Wisniewski LM,

Hanyok JJ, Kassalow LM. Effect of ACAT inhibition on the progression of coron-

ary atherosclerosis. N Engl J Med2006;354:12531263.

65. Nissen SE, Tuzcu EM, Libby P, Thompson PD, Ghali M, Garza D, Berman L,

Shi H, Buebendorf E, Topol EJ. Effect of antihypertensive agents on cardiovascu-

lar events in patients with coronary disease and normal blood pressure: the

CAMELOT study: a randomized controlled trial. J Am Med Assoc 2004;292:

22172225.

66. Rodriguez-Granillo GA, Vos J, Bruining N, Garcia-Garcia HM, de Winter S,

Ligthart JM, Deckers JW, Bertrand M, Simoons ML, Ferrari R, Fox KM,

Remme W, De Feyter PJ. Long-term effect of perindopril on coronary athero-

sclerosis progression (from the perindoprils prospective effect on coronary

atherosclerosis by angiography and intravascular ultrasound evaluation [PER-

SPECTIVE] study). Am J Cardiol 2007;100:159163.

67. Gerstein HC, Ratner RE, Cannon CP, Serruys PW, Garcia-Garcia HM,

van Es GA, Kolatkar NS, Kravitz BG, Miller DM, Huang C, Fitzgerald PJ,

Nesto RW. Effect of rosiglitazone on progression of coronary atherosclerosis

in patients with type 2 diabetes mellitus and coronary artery disease: the assess-

ment on the prevention of progression by rosiglitazone on atherosclerosis in

diabetes patients with cardiovascular history trial. Circulation 2010;121:

11761187.

68. Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De

Larochelliere R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM,

Tuzcu EM. Comparison of pioglitazone vs glimepiride on progression of coron-

ary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized

controlled trial. J Am Med Assoc2008;299:15611573.

69. Nasu K, Tsuchikane E, Katoh O, Tanaka N, Kimura M, Ehara M, Kinoshita Y,

Matsubara T, Matsuo H, Asakura K, Asakura Y, Terashima M, Takayama T,

Honye J, Hirayama A, Saito S, Suzuki T. Effect of fluvastatin on progression of

coronary atherosclerotic plaque evaluated by virtual histology intravascular

ultrasound. JACC Cardiovasc Interv2009;2:689696.

70. Hong MK, Park DW, Lee CW, Lee SW, Kim YH, Kang DH, Song JK, Kim JJ,

Park SW, Park SJ. Effects of statin treatments on coronary plaques assessed

by volumetric virtual histology intravascular ultrasound analysis. JACC Cardiovasc

Interv2009;2:679688.

71. Serruys PW, Garcia-Garcia HM, Buszman P, Erne P, Verheye S, Aschermann M,

Duckers H, Bleie O, Dudek D, Botker HE, von Birgelen C, DAmico D,

Hutchinson T, Zambanini A, Mastik F, van Es GA, van der Steen AF,

Vince DG, Ganz P, Hamm CW, Wijns W, Zalewski A. Effects of the direct

lipoprotein-associated phospholipase A(2) inhibitor darapladib on human coron-

ary atherosclerotic plaque. Circulation 2008;118:11721182.

72. Manfrini O, Mont E, Leone O, Arbustini E, Eusebi V, Virmani R, Bugiardini R.

Sources of error and interpretation of plaque morphology by optical coherence

tomography. Am J Cardiol 2006;98:156159.

73. Sawada T, Shite J, Garcia-Garcia HM, Shinke T, Watanabe S, Otake H,

Matsumoto D, Tanino Y, Ogasawara D, Kawamori H, Kato H, Miyoshi N,

Yokoyama M, Serruys PW, Hirata K. Feasibility of combined use of intravascular

ultrasound radiofrequency data analysis and optical coherence tomography for

detecting thin-cap fibroatheroma. Eur Heart J 2008;29:11361146.

74. Gonzalo N, Garcia-Garcia HM, Regar E, Barlis P, Wentzel J, Onuma Y, Ligthart J,

Serruys PW. In vivo assessment of high-risk coronary plaques at bifurcations

with combined intravascular ultrasound and optical coherence tomography.

JACC Cardi ovasc Imaging2009;2:473482.

Imaging of coronary atherosclerosis 2469b


17/17

75. Rioufol G, Finet G, Ginon I, Andre-Fouet X, Rossi R, Vialle E, Desjoyaux E,

Convert G, Huret JF, Tabib A. Multiple atherosclerotic plaque rupture in

acute coronary syndrome: a three-vessel intravascular ultrasound study. Circula-

tion 2002;106:804808. doi:10.1161/01.CIR.0000025609.13806.31

76. Hong MK, Mintz GS, Lee CW, Kim YH, Lee SW, Song JM, Han KH, Kang DH,

Song JK, Kim JJ, Park SW, Park SJ. Comparison of coronary plaque rupture

between stable angina and acute myocardial infarction: a three-vessel intravascu-

lar ultrasound study in 235 patients. Circulation 2004;110:928933.

77. Tanaka A, Shimada K, Sano T, Namba M, Sakamoto T, Nishida Y,

Kawarabayashi T, Fukuda D, Yoshikawa J. Multiple plaque rupture and C-reactive

protein in acute myocardial infarction. J Am Coll Cardiol 2005;45:15941599.

78. Hong MK, Mintz GS, Lee CW, Lee BK, Yang TH, Kim YH, Song JM, Han KH,

Kang DH, Cheong SS, Song JK, Kim JJ, Park SW, Park SJ. The site of plaque

rupture in native coronary arteries: a three-vessel intravascular ultrasound analy-

sis. J Am Coll Cardiol 2005;46:261265.

79. Tyczynski P, Pregowski J, Mintz GS, Witkowski A, Kim SW, Waksman R, Satler L,

Pichard A, Kalinczuk L, Maehara A, Weissman NJ. Intravascular ultrasound

assessment of ruptured atherosclerotic plaques in left main coronary arteries.

Am J Cardiol 2005;96:794798.

80. Pregowski J, Tyczynski P, Mintz GS, Kim SW, Witkowski A, Waksman R,

Pichard A, Satler L, Kent K, Kruk M, Bieganski S, Ohlmann P, Weissman NJ. Inci-

dence and clinical correlates of ruptured plaques in saphenous vein grafts: an

intravascular ultrasound study. J Am Coll Cardiol 2005;45:19741979.

81. Pregowski J, Tyczynski P, Mintz GS, Kim SW, Witkowski A, Satler L, Kruk M,

Waksman R, Maehara A , Weissman NJ. Intravascular ultrasound assessment of

the spatial distribution of ruptured coronary plaques in the left anterior des-

cending coronary artery. Am Heart J 2006;151:898901.82. Rodriguez-Granillo GA, Garcia-Garcia HM, Valgimigli M, Vaina S, van

Mieghem C, van Geuns RJ, van der Ent M, Regar E, de Jaegere P, van der

Giessen W, de Feyter P, Serruys PW. Global characterization of coronary

plaque rupture phenotype using three-vessel intravascular ultrasound radiofre-

quency data analysis. Eur Heart J 2006;27:19211927.

83. Hong YJ, Jeong MH, Choi YH, Ma EH, Ko JS, Lee MG, Park KH, Sim DS,

Yoon NS, Youn HJ, Kim KH, Park HW, Kim JH, Ahn Y, Cho JG, Park JC,

Kang JC. Differences in intravascular ultrasound findings in culprit lesions in

infarct-related arteries between ST segment elevation myocardial infarction

and non-ST segment elevation myocardial infarction. J Cardiol 2010;56:1522.

84. Okazaki S, Yokoyama T, Miyauchi K, Shimada K, Kurata T, Sato H, Daida H. Early

statin treatment in patients with acute coronary syndrome: demonstration of the

beneficial effect on atherosclerotic lesions by serial volumetric intravascular

ultrasound analysis during half a year after coronary event: the ESTABLISH

Study. Circulation 2004;110:10611068.

85. Jensen LO, Thayssen P, Pedersen KE, Stender S, Haghfelt T. Regression of cor-

onary atherosclerosis by simvastatin: a serial intravascular ultrasound study. Cir-

culation 2004;110:265270.

86. Petronio AS, Amoroso G, Limbruno U, Papini B, De Carlo M, Micheli A,

Ciabatti N, Mariani M. Simvastatin does not inhibit intimal hyperplasia and rest-

enosis but promotes plaque regression in normocholesterolemic patients

undergoing coronary stenting: a randomized study with intravascular ultrasound.

Am Heart J 2005;149:520526.

87. Nishioka H, Shimada K, Kataoka T, Hirose M, Asawa K, Hasegawa T,

Yamashita H, Ehara S, Kamimori K, Sakamoto T, Kobayashi Y, Yoshimura T,

Yoshiyama M, Takeuchi K, Yoshikawa J. Impact of HMG-CoA reductase inhibi-

tors for non-treated coronary segments. Osaka City Med J 2004;50:6168.

88. Tani S, Watanabe I, Anazawa T, Kawamata H, Tachibana E, Furukawa K, Sato Y,

Nagao K, Kanmatsuse K, Kushiro T. Effect of pravastatin on malondialdehyde-

modified low-density lipoprotein levels and coronary plaque regression as

determined by three-dimensional intravascular ultrasound. Am J Cardiol 2005;

96:10891094.

89. Nissen SE, Nicholls SJ, Sipahi I, Libby P, Raichlen JS, Ballantyne CM, Davignon J,Erbel R, Fruchart JC, Tardif J-C, Schoenhagen P, Crowe T, Cain V, Wolski K,

Goormastic M, Tuzcu EM, for the ASTEROID Investigators. Effect of very high-

intensity statin therapy on regression of coronary atherosclerosis: the ASTER-

OID trial. J Am Med Assoc2006;295:15561565.

90. Takashima H, Ozaki Y, Yasukawa T, Waseda K, Asai K, Wakita Y, Kuroda Y,

Kosaka T, Kuhara Y, Ito T. Impact of lipid-lowering therapy with pitavastatin, a

new HMG-CoA reductase inhibitor, on regression of coronary atherosclerotic

plaque. Circ J 2007;71:16781684.

91. Takayama T, Hiro T, Yamagishi M, Daida H, Hirayama A, Saito S, Yamaguchi T,

Matsuzaki M. Effect of rosuvastatin on coronary atheroma in stable coronary

artery disease: multicenter coronary atherosclerosis study measuring effects of

rosuvastatin using intravascular ultrasound in Japanese subjects (COSMOS).

Circ J 2009;73:21102117.

92. Hiro T, Kimura T, Morimoto T, Miyauchi K, Nakagawa Y, Yamagishi M, Ozaki Y,Kimura K, Saito S, Yamaguchi T, Daida H, Matsuzaki M. Effect of intensive statin

therapy on regression of coronary atherosclerosis in patients with acute coron-

ary syndrome: a multicenter randomized trial evaluated by volumetric intravas-

cular ultrasound using pitavastatin versus atorvastatin (JAPAN-ACS [Japan

assessment of pitavastatin and atorvastatin in acute coronary syndrome]

study). J Am Coll Cardiol 2009;54:293302.

93. Tardif JC, Gregoire J, LAllier PL, Anderson TJ, Bertrand O, Reeves F, Title LM,

Alfonso F, Schampaert E, Hassan A, McLain R, Pressler ML, Ibrahim R,

Lesperance J, Blue J, Heinonen T, Rodes-Cabau J. Effects of the acyl coenzyme

A:cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic

lesions. Circulation 2004;110:33723377.

94. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M,

Eaton GM, Lauer MA, Sheldon WS, Grines CL, Halpern S, Crowe T,

Blankenship JC, Kerensky R. Effect of recombinant ApoA-I Milano on coronary

atherosclerosis in patients with acute coronary syndromes: a randomized con-

trolled trial. J Am Med Assoc2003;290:22922300.95. Tardif JC, Gregoire J, LAllier PL, Ibrahim R, Anderson TJ, Reeves F, Title LM,

Schampaert E, LeMay M, Lesperance J, Scott R, Guertin MC, Brennan ML,

Hazen SL, Bertrand OF. Effects of the antioxidant succinobucol (AGI-1067)

on human atherosclerosis in a randomized clinical trial. Atherosclerosis 2008;

197:480486.

96. Nissen SE, Nicholls SJ, Wolski K, Rodes-Cabau J, Cannon CP, Deanfield JE,

Despres JP, Kastelein JJ, Steinhubl SR, Kapadia S, Yasin M, Ruzyllo W,

Gaudin C, Job B, Hu B, Bhatt DL, Lincoff AM, Tuzcu EM. Effect of rimonabant

on progression of atherosclerosis in patients with abdominal obesity and coron-

ary artery disease: the STRADIVARIUS randomized controlled trial. J Am Med

Assoc2008;299:15471560.

97. Luscher TF, Pieper M, Tendera M, Vrolix M, Rutsch W, van den Branden F, Gil R,

Bischoff KO, Haude M, Fischer D, Meinertz T, Munzel T. A randomized placebo-

controlled study on the effect of nifedipine on coronary endothelial function and

plaque formation in patients with coronary artery disease: the ENCORE II study.

Eur Heart J 2009;30:15901597.98. Yokoyama M, Komiyama N, Courtney BK, Nakayama T, Namikawa S,

Kuriyama N, Koizumi T, Nameki M, Fitzgerald PJ, Komuro I. Plasma low-density

lipoprotein reduction and structural effects on coronary atherosclerotic plaques

by atorvastatin as clinically assessed with intravascular ultrasound radio-

frequency signal analysis: a randomized prospective study. Am Heart J 2005;

150:287.

99. Kawasaki M, Sano K, Okubo M, Yokoyama H, Ito Y, Murata I, Tsuchiya K,

Minatoguchi S, Zhou X, Fujita H, Fujiwara H. Volumetric quantitative analysis

of tissue characteristics of coronary plaques after statin therapy using three-

dimensional integrated backscatter intravascular ultrasound. J Am Coll Cardiol

2005;45:19461953.

100. Toi T, Taguchi I, Yoneda S, Kageyama M, Kikuchi A, Tokura M, Kanaya T, Abe S,

Matsuda R, Kaneko N. Early effect of lipid-lowering therapy with pitavastatin on

regression of coronary atherosclerotic plaque. Comparison with atorvastatin.

Circ J 2009;73:14661472.

101. Miyagi M, Ishii H, Murakami R, Isobe S, Hayashi M, Amano T, Arai K, Ohashi T,Uetani T, Matsubara T, Murohara T. Impact of long-term statin treatment on

coronary plaque composition at angiographically severe lesions: a nonrando-

mized study of the history of long-term statin treatment before coronary angio-

plasty. Clin Ther2009;31:6473.

H.M. Garcia-Garcia et al.2469c
http://dx.doi.org/doi:10.1161/01.CIR.0000025609.13806.31http://dx.doi.org/doi:10.1161/01.CIR.0000025609.13806.31