ORIGINAL PAPER

Longitudinal heterogeneity of coronary artery distensibilityin plaques related to acute coronary syndrome

Osamu Sasaki • Toshihiko Nishioka • Yoshiro Inoue • Ami Isshiki • Takashi Akima •

Kentarou Toyama • Aki Koike • Toshiyuki Ando • Mikio Yuhara • Shun-ichi Sato •

Tetsuo Kamiyama • Masato Kirimura • Hiroyuki Ito • Yoshiaki Maruyama • Nobuo Yoshimoto

Received: 9 November 2010 / Accepted: 31 January 2012 / Published online: 10 February 2012

� Springer-Verlag 2012

Abstract

Background How coronary distensibility contributes to

stable or unstable clinical manifestations remains obscure.

We postulated that the heterogeneous plaque distensibility

is associated with unstable clinical presentations in patients

with acute coronary syndrome (ACS).

Methods and results Seventeen and 19 ACS-related and -

unrelated lesions, respectively, were visualized using

intravascular ultrasound imaging with simultaneous intra-

coronary pressure recording. Systolic and diastolic lumen

cross-sectional areas were measured at the lesion site and at

five evenly spaced sites between the proximal and distal

reference sites. The coronary distensibility index and

stiffness index b were calculated for each site and averaged

for each coronary segment. Maximal distensibility index,

standard deviation and the difference between maximal and

minimal distensibility indices within each segment were

significantly higher in the ACS-related than -unrelated

plaques (5.6 ± 2.3 vs. 3.7 ± 1.8, p \ 0.001, 2.1 ± 0.9 vs.

1.1 ± 0.6, p \ 0.001 and 5.3 ± 2.3 vs. 2.8 ± 1.5, p \0.001, respectively). Moreover, the difference in the dis-

tensibility index between the lesion site of ACS-related

plaques and the immediate proximal site was significantly

larger (2.88 ± 2.35 vs. 1.17 ± 1.44, p = 0.022) than that

in ACS-unrelated plaques.

Conclusions Coronary artery distensibility is longitudi-

nally more heterogeneous in ACS-related than-unrelated

plaques, especially between the lesion and the immediate

proximal site.

Keywords Intravascular ultrasound � Compliance �Stiffness index b � Thrombus

Introduction

The major mechanism of acute coronary syndrome (ACS),

including acute myocardial infarction (MI) and unstable

angina, is considered to be intracoronary thrombus for-

mation subsequent to atherosclerotic plaque rupture or

erosion. Rupture-prone vulnerable plaque is characterized

by a thin fibrous cap and a large necrotic core, and pla-

ques rupture when large mechanical stresses develop in

the most fragile portion of the fibrous cap (shoulder

region) [1–3]. Recent intravascular ultrasound (IVUS)

studies have indicated that culprit lesions in ACS are

characterized by large eccentric plaques with an echolu-

cent zone, ulceration, thrombus formation, spotty calcium

deposits and more positive remodeling compared with

culprit lesions in stable angina pectoris or non-culprit

lesions in ACS [4–13], and that culprit coronary artery

walls are more distensible in ACS than in stable angina

[14, 15]. Coronary artery distensibility has been studied

using IVUS imaging and it is reportedly determined by

age, diabetes mellitus, and the size or thickness, eccen-

tricity, composition and remodeling of the imaged plaque

[14–22]. However, how increased vessel distensibility in

the ACS-related coronary artery contributes to unstable

O. Sasaki � T. Nishioka (&) � Y. Inoue � A. Isshiki �K. Toyama � A. Koike � T. Ando � M. Yuhara � S. Sato �T. Kamiyama � M. Kirimura � H. Ito � Y. Maruyama �N. Yoshimoto

Division of Cardiology, Saitama Medical Center,

Saitama Medical University, 1981 Kamoda,

Kawagoe, Saitama 350-8550, Japan

e-mail: nishioka@saitama-med.ac.jp

T. Akima

Division of Cardiology, Saitama City Hospital, Saitama, Japan

123

Clin Res Cardiol (2012) 101:545–551

DOI 10.1007/s00392-012-0424-6

clinical manifestations has not been elucidated. We pos-

tulated that as coronary atherosclerosis gradually advan-

ces, the coronary artery basically stiffens and becomes

rigid due to intimal thickening, fibrosis, calcification and

smooth muscle cell proliferation, and coronary distensi-

bility decreases. However, the development of lipid-rich

atheroma with thin fibrous cap would locally increase

coronary distensibility. Therefore, the difference in coro-

nary distensibility between adjacent sites, especially

between soft atheromatous tissue and relatively hard

sclerotic tissue would increase, and we defined this intra-

plaque difference in coronary distensibility as heteroge-

neity. Furthermore, such heterogeneity might concentrate

mechanical stress at the border between distensible plaque

and relatively stiff tissue, thus leading to the unstable

clinical presentations that arise in patients with ACS.

Therefore, we investigated the longitudinal difference in

coronary distensibility between ACS-related and -unre-

lated plaques using IVUS imaging.

Methods

Study population

We studied 31 patients (28 men and 3 women; mean age

61 years) with stable angina pectoris or ACS who under-

went diagnostic or interventional cardiac catheterization.

None had undergone previous intervention to treat the

target lesion. According to clinical status, ECG findings,

laboratory data and coronary angiographic findings, we

classified these patients into a group with stable angina

pectoris (n = 14) and a group with ACS (n = 17) includ-

ing two with unstable angina, five with ST elevation MI

and 10 with non-ST elevation MI. Culprit lesions of stable

angina were judged from stress myocardial perfusion

imaging and angiographic findings, and those of ACS were

identified from ECG, echocardiography and angiographic

findings. We imaged 17 ACS-related and 19 ACS-unre-

lated lesions using IVUS. The following lesions were

excluded from quantitative analysis: those in which IVUS

images were suboptimal for quantitative measurements

because of heavy intimal calcification (largest arc of cal-

cium, [60�), those in which the proximal reference site

could not be identified due to ostial location of the lesion

and those with a lumen of \1.5 mm2 or which were

occluded (wedged) by the imaging catheter. Our institu-

tional review board approved the study protocol and all

patients provided written informed consent to participate in

all associated procedures.

Standard risk factors as well as current medications were

identified from a review of the medical records of each

patient.

IVUS study protocol

Before coronary intervention, IVUS studies proceeded

using a 2.9/3.2-Fr 30-MHz long monorail imaging catheter

(UltraCross�) or a 2.9-Fr 40-MHz long monorail imaging

catheter (Atlantis�) and an imaging console (ClearView�;

all from Boston Scientific Corporation, Boston, MA).

Thirty-six de novo coronary artery lesions in 31 patients

were imaged by IVUS with simultaneous intracoronary

pressure recording. After angiography, the imaging cathe-

ter was introduced into the target artery through a 6–7-Fr

coronary guiding catheter over a 0.014-in. guidewire. To

prevent possible vasospasm and to maximize vasodilation,

nitroglycerin (100–200 lg) was directly administered into

the coronary artery immediately before IVUS imaging.

After advancing the imaging catheter across the lesion to

the distal portion of the vessel under fluoroscopic guidance,

IVUS imaging proceeded during slow retraction (0.5 mm/s)

of the imaging catheter and intracoronary pressure was

simultaneously recorded. The IVUS images were recorded

on 0.5-in. high-resolution super-VHS videotapes.

Qualitative and quantitative IVUS analysis

Ruptured plaques contained a cavity that communicated

with the lumen and an overlying residual fibrous cap

fragment. A fissure without a cavity communicating with a

true lumen was not included in the analysis [6, 7].

The IVUS images were evaluated offline after the pro-

cedure using an image analysis system. Figure 1 shows that

a coronary segment of interest was defined between two

side branches with a diameter of [1 mm. Systolic and

diastolic external elastic membrane cross-sectional areas

(EEM CSA, mm2) and lumen cross-sectional areas (lumen

CSA, mm2) at the intimal leading edge within this coronary

Fig. 1 Schematic presentation of coronary segment analyzed by

intravascular ultrasound. Coronary segment is defined between two

side branches with diameter [1 mm. Within this coronary segment,

IVUS measurements were taken at lesion site with smallest lumen

area and at five evenly spaced sites. L lesion site, DM distal middle

site, DR distal reference site, M middle site, PM proximal middle site,

PR proximal reference site

546 Clin Res Cardiol (2012) 101:545–551

123

segment were measured at the lesion site with the smallest

lumen CSA and at five evenly spaced sites (proximal ref-

erence site with the largest lumen CSA in the segment

proximal to the lesion site, distal reference site with the

largest lumen CSA in the segment distal to the lesion site,

middle site at the mid portion between both reference sites

and proximal middle site at the mid portion between the

proximal reference and middle sites and distal middle site

at the mid portion between the distal reference and middle

sites). Plaque plus media CSA (mm2) was calculated as

EEM CSA–lumen CSA and plaque burden (%) as plaque

plus media CSA/EEM CSA 9100. Systolic and diastolic

lumen diameters (LD) were calculated assuming that the

cross section was circular.

Coronary artery distensibility

Individual variations in vascular tone were minimized by

administering 100–200 lg of nitroglycerin immediately

before the IVUS study. The largest lumen CSA assessed by

IVUS was determined by tracing the lumen-intima border

at peak systole and the smallest lumen CSA at peak dias-

tole within one cardiac cycle by synchronizing IVUS

images and intracoronary pressure tracing (Fig. 2). Chan-

ges in intracoronary pressure during one cardiac cycle were

measured at the tip of the guiding catheter. Coronary artery

distensibility was defined as the ‘‘distensibility index’’ and

‘‘stiffness index b’’ obtained from the following formulae

as described [13, 14, 17–23].

Distensibility index¼ lumen CSA change=ðfdiastolic lumen CSAÞ= SBP�DBPð Þg�103

Stiffness index b = [ln (SBP/DBP)]/(LD change/diastolic

LD), where SBP and DBP indicate systolic and diastolic

intracoronary pressure and ln is the natural logarithm.

These indices were calculated for each site, the maximal

and minimal values were identified, and then the average

value and standard deviation were calculated for each

coronary segment. Furthermore, differences in coronary

distensibility index and stiffness index b were calculated

between adjacent sites. We defined coronary artery dis-

tensibility as being longitudinally more heterogeneous

when the maximal-minimal value or standard deviation

of these two indices within each coronary segment, or

the difference in these two indices between adjacent sites

significantly differed. Since only patients with ischemic

heart diseases were imaged using IVUS, a normal range

of heterogeneity in coronary artery distensibility was not

accessible and heterogeneity was assessed not as absolute

values but as relative differences between the two

groups.

Statistical analyses

All data are expressed as mean ± standard deviation.

Continuous variables between two groups were compared

using an unpaired t test. Differences in distensibility index

and stiffness index b within the same plaque were com-

pared using the one-way analysis of variance and Fisher’s

PLSD as a post hoc test. Frequencies between two groups

were compared using Fisher’s exact test. Differences were

considered statistically significant at p \ 0.05.

Results

All IVUS studies were completed without vascular com-

plications. Table 1 shows that the baseline characteristics

did not significantly differ between the two study groups.

Fig. 2 Simultaneous recording of IVUS images and intracoronary

pressure tracing. IVUS images were synchronized with intracoronary

pressure at peak (end-systole) and bottom (end-diastole) of pressure

by electrocardiogram monitoring

Clin Res Cardiol (2012) 101:545–551 547

123

Rupture was evident only in four ACS-related plaques

(23.5%) and in one ACS-unrelated plaque (5.3%), and all

rupture sites were located immediately proximal to the

lesion (minimum lumen) sites.

Quantitative IVUS measurements other than coronary

artery distensibility

Table 2 shows the quantitative IVUS results. The ACS-

related and -unrelated plaques did not significantly differ

even in terms of EEM CSA.

Difference in coronary artery distensibility

Table 3 compares the coronary artery distensibility index

and stiffness index b between ACS-related and -unrelated

plaques. The distensibility index was significantly higher at

the lesion site than at other sites in both types of plaques.

However, indices at the lesion site and at five evenly

spaced sites, and the means of these indices in each coro-

nary segment between the proximal and distal reference

sites, did not significantly differ between the groups. The

maximal value, the difference between the maximal and

minimal values and the standard deviation of the distensi-

bility index within each coronary segment were signifi-

cantly higher (5.58 ± 2.37 vs. 3.67 ± 1.78, p = 0.01,

5.26 ± 2.27 vs. 2.76 ± 1.45, p \ 0.001 and 2.13 ± 0.89

vs. 1.13 ± 0.55, p \ 0.001, respectively) and the minimum

stiffness index b was significantly lower (5.1 ± 2.2 vs.

7.1 ± 2.6, p = 0.02) in ACS-related than -unrelated

plaques.

Moreover, the difference in the distensibility index

between the lesion site of ACS-related plaques and the

immediate proximal site was significantly larger

(2.88 ± 2.35 vs. 1.17 ± 1.44, p = 0.022) than that in

ACS-unrelated plaques. The difference in the distensibility

index between the lesion sites of ACS-related plaques and

immediately distal sites did not statistically differ

(p = 0.086) from that in ACS-unrelated plaques. The dif-

ference in the stiffness index b between adjacent sites did

not significantly differ.

Discussion

We showed here that although mean coronary distensibility

did not statistically differ, it was longitudinally more het-

erogeneous in ACS-related than -unrelated plaques, espe-

cially between the lesion and the immediate proximal site.

Table 1 Baseline characteristics of study population

Stable AP

(n = 14)

ACS

(n = 17)

p value

Age* 61.3 ± 9.1 56.5 ± 8.0 ns

Gender (male/female) 13/1 15/2 ns

Coronary risk factors

Hypertension 11 (78.6) 13 (76.4) ns

Diabetes mellitus 5 (35.7) 6 (35.3) ns

Hyperlipidemia 10 (71.4) 10 (58.8) ns

Smoking 6 (31.5) 10 (58.8) ns

Imaged vessel

LAD 11 13 ns

LCx 1 1 ns

RCA 2 3 ns

Medication

Statin 9 (47.4) 7 (41.1) ns

b-Blocker 9 (47.4) 7 (41.1) ns

CCB 7 (36.8) 7 (41.1) ns

Nitrates 13 (68.4) 15 (88.2) ns

ACE inhibitor 3 (15.8) 5 (29.4) ns

ARB 7 (36.8) 7 (41.1) ns

Type of ACS N/A UA 2

NSTEMI 10

STEMI 5

Data are expressed as numbers (%) of patients

ACE angiotensin converting enzyme, ACS acute coronary syndrome,

AP angina pectoris, ARB angiotensin receptor blocker, CCB calcium

channel blocker, LAD left anterior descending coronary artery, LCxleft circumflex coronary artery, NSTEMI non-ST elevation myocar-

dial infarction, RCA right coronary artery, STEMI ST elevation

myocardial infarction, UA unstable angina

* Mean ± standard deviation

Table 2 Quantitative intravascular ultrasound results

ACS-unrelated

plaque (n = 19)

ACS-related

plaque (n = 17)

p value

Proximal reference

Lumen CSA (mm2) 7.5 ± 2.3 7.0 ± 3.4 ns

EEM CSA (mm2) 12.9 ± 3.6 12.4 ± 4.9 ns

P ? M CSA (mm2) 5.4 ± 2.4 5.4 ± 2.7 ns

Plaque burden (%) 40.9 ± 11.3 43.2 ± 12.9 ns

Lesion

Lumen CSA (mm2) 3.7 ± 0.6 3.3 ± 1.0 ns

EEM CSA (mm2) 13.1 ± 3.8 11.3 ± 4.4 ns

P ? M CSA (mm2) 9.4 ± 3.6 8.0 ± 4.3 ns

Plaque burden (%) 69.9 ± 8.9 67.4 ± 14.8 ns

Distal reference

Lumen CSA (mm2) 8.0 ± 3.4 7.3 ± 3.6 ns

EEM CSA (mm2) 13.8 ± 4.9 11.6 ± 4.4 ns

P ? M CSA (mm2) 5.8 ± 2.9 4.3 ± 1.9 ns

Plaque burden (%) 41.2 ± 12.9 37.9 ± 12.1 ns

Data are expressed as mean ± standard deviation

ACS acute coronary syndrome, CSA cross sectional area, EEMexternal elastic membrane, P ? M plaque plus media

548 Clin Res Cardiol (2012) 101:545–551

123

Previous IVUS studies have indicated that coronary

vessels are more distensible in patients with ACS than with

stable angina [14, 15]. Jeremias et al. [14] explained the

association between increased coronary distensibility and

unstable clinical presentation as follows. Greater distensi-

bility might augment positive remodeling by pulsatile

stretch, leading to heightened metalloproteinase activity.

The difference in distensibility might also be related to

matrix changes such as the ratio of collagen to elastin and the

formation of a lipid pool. Differences in endothelial function

between stable and unstable plaques might be reflected in

differences in both remodeling and distensibility. However,

they did not refer to mechanical stress or strain on plaques

that could be the final trigger of plaque rupture. Takano et al.

[15] found that coronary distensibility at the proximal site

near the culprit lesion was greater in angioscopically defined

yellow, than white plaques. They considered that this was

partially due a difference in plaque composition and in

coronary remodeling. They also stated that the border of

normal intima and plaque, namely the ‘‘shoulder region,’’

must be exposed to mechanical stress caused by a difference

in regional distensibility. However, a longitudinal difference

in coronary distensibility within the same coronary plaque

was not described in either of these studies.

The relationship between ‘‘circumferential’’ mechanical

stress and plaque rupture has been extensively investigated

[1–3, 24, 25] and high stresses concentrated in the fibrous

cap, particularly at the junction with relatively normal

tissue (the ‘‘shoulder region’’) causes vulnerability to rup-

ture. Examinations of coronary plaque using intravascular

elastography or palpography have shown very high local

strain values (rate of deformation caused by stress) at the

shoulder regions of plaques [26, 27].

Plaques tend to rupture more frequently in the proximal

or upstream portions than in the distal or downstream por-

tions in the ‘‘longitudinal’’ direction [6, 28–30]. Li et al. [31,

32] found high stress concentrations within the fibrous cap

of a model of longitudinal blood flow and plaque interac-

tion, especially at the shoulder regions at the proximal part

of the plaque. Imoto et al. [33] assessed the distribution of

longitudinal stress within plaques using color mapping

based on computational structural analysis. They found a

concentration of equivalent stress at the tops of hills and

shoulders of homogeneous fibrous plaques and at a local-

ized surface immediately above a lipid core when present.

Gijsen et al. [34] measured local radial strain in vessel walls

using intravascular palpography and found that strain values

were significantly lower at the downstream region of the

plaque than at the upstream, shoulder and throat regions.

Although the regions of concentrated stresses or strains vary

among these studies, they nevertheless reveal significant

longitudinal heterogeneity in mechanical stresses or strains

over coronary plaque. As the ratio of the radial strain to

circumferential tensile stress is equal to the distensibility of

the tissue, this stress–strain relationship implies that an

increase in circumferential stress will cause radial strain to

increase [27, 35]. Although we assessed coronary distensi-

bility without regard to a difference in mechanical stresses

over the plaque, we consider that our findings are consistent

with these previous reports.

Table 3 Comparison of distensibility and stiffness indexes b between ACS-related and unrelated plaques

Distensibility index Stiffness index b

ACS- unrelated ACS-related p value ACS-unrelated ACS- related p value

Proximal reference 2.23 ± 1.35 2.43 ± 2.73 ns 31.3 ± 57.4 7.0 ± 66.6 ns

Proximal middle 1.79 ± 2.25 1.98 ± 2.04 ns 50.8 ± 84.7 19.3 ± 27.1 ns

Middle 1.42 ± 0.80 1.36 ± 1.74 ns 22.1 ± 15.4 37.2 ± 46.6 ns

Distal middle 1.66 ± 1.31 1.08 ± 1.07 ns 30.6 ± 41.8 67.3 ± 82.1 ns

Distal reference 1.50 ± 1.66 1.33 ± 1.12 ns 45.1 ± 121.0 41.6 ± 68.8 ns

Lesion 3.01 ± 2.30* 3.93 ± 2.84* ns 16.9 ± 23.7 12.5 ± 13.1 ns

Mean 2.20 ± 1.74 2.40 ± 0.93 ns 33.4 ± 29.4 34.4 ± 20.5 ns

Maximum 3.67 ± 1.78 5.58 ± 2.37 0.010 101.2 ± 124.7 109.3 ± 92 ns

Minimum 0.91 ± 1.93 0.32 ± 0.23 ns 7.1 ± 2.6 5.1 ± 2.2 0.020

Maximum-minimum 2.76 ± 1.45 5.26 ± 2.27 \0.001 94.1 ± 125.1 104.2 ± 91.5 ns

Standard deviation 1.13 ± 0.55 2.13 ± 0.89 \0.001 39.0 ± 50 243.0 ± 39.8 ns

Lesion–just Proximal 1.17 ± 1.44 2.88 ± 2.35 0.022 48.8 ± 85.0 45.2 ± 72.8 ns

Lesion–just Distal 1.88 ± 1.59 3.42 ± 2.71 0.086 25.4 ± 25.1 53.1 ± 73.8 ns

Data are expressed as mean ± standard deviation

ACS acute coronary syndrome; mean, maximum, minimum and standard deviation are mean, maximal and minimal values and standard

deviation, respectively, of six imaged sites

* p \ 0.05 versus proximal reference, proximal middle, middle, distal middle and distal reference values

Clin Res Cardiol (2012) 101:545–551 549

123

We found here that coronary distensibility was more

longitudinally heterogeneous in ACS-related than -unre-

lated plaques, especially between the lesion and the

immediately proximal region. This heterogeneity might be

due to longitudinal differences in plaque composition as

well as in the types of mechanical stresses affecting the

plaque. Furthermore, such differential heterogeneity in

distensibility could increase mechanical stress at the

shoulder region between the plaque and relatively normal

tissue.

Study limitations

We examined longitudinal differences in coronary disten-

sibility. However, we could not measure circumferential

differences. Intravascular ultrasound elastography or pal-

pography might be more suitable for this purpose [26, 27,

34]. Coronary lesions with a lumen of \1.5 mm2 or those

that were occluded (wedged) by the imaging catheter were

excluded from this study. However, the IVUS catheter

itself might have altered coronary blood flow and trans-

mitted energy. Reflected pulse wave energy might increase

when complex acute longitudinal lesions are present. This

phenomenon might have affected our results. Other factors

such as pressure-characteristics (dp/dt) values, absolute

systolic and diastolic pressure values, flow dynamics,

vessel diameter, segmental vessel pathology (additional

lesions in the same vessel) and myocardial wall stress that

are associated with characteristics of the microcirculation

and myocardial function might also have affected calcu-

lations of the distensibility index and of the stiffness index

b. We analyzed 36 de novo human coronary lesions and

excluded heavily calcified, severely stenotic, restenotic,

post-intervention, ostial and chronic totally occlusive

lesions. Therefore, our findings might not be applicable to

these types of lesions.

Residual thrombus in patients with ACS might have

affected calculations of the distensibility index and stiff-

ness index b. Even thrombectomy does not guarantee

complete removal of a thrombus. All ACS-related lesions

were imaged after the onset of ACS, so the findings might

have been different had we examined vulnerable plaques

beforehand. Most previous studies have the same limita-

tions, except for that of Yamagishi et al. [11] who found

that large eccentric plaques containing an echolucent zone

that can be revealed by IVUS before ACS onset could be at

increased risk for instability.

Conclusions

This study using IVUS demonstrated that coronary dis-

tensibility was longitudinally more heterogeneous in ACS-

related than -unrelated plaques, especially between the

lesion site and the immediate proximal site.

Acknowledgments This study was supported in part by a research

grant from the Japan Foundation of Cardiovascular Research.

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