Circulation: Cardiovascular Imaging

ORIGINAL ARTICLE

Level of Vascular Inflammation Is Higher in Acute

Coronary Syndromes Compared with Chronic
Coronary Disease
Makoto Araki , MD, PhD; Tomoyo Sugiyama, MD, PhD; Akihiro Nakajima, MD; Taishi Yonetsu , MD, PhD;
Lena Marie Seegers, MD; Damini Dey , PhD; Hang Lee , PhD; Iris McNulty, RN; Yumi Yasui, MD; Yun Teng, MD;
Tatsuhiro Nagamine, MD; Tsunekazu Kakuta , MD, PhD; Ik-Kyung Jang , MD, PhD,

BACKGROUND: Vascular inflammation has been recognized as one of the key factors in the pathogenesis of acute coronary
syndromes (ACS). Pericoronary adipose tissue (PCAT) attenuation by computed tomography angiography has emerged as a
marker specific for coronary artery inflammation. We examined the relationship between clinical presentation and coronary
artery inflammation assessed by PCAT attenuation and coronary plaque characteristics.

METHODS: Patients with ACS or stable angina pectoris (SAP) who underwent preintervention coronary computed tomography
angiography and optical coherence tomography were enrolled. PCAT attenuation was measured around the culprit lesion and
in the proximal 40 mm of all coronary arteries. PCAT attenuation and optical coherence tomography findings were compared
between patients with ACS versus SAP.

RESULTS: Among 471 patients (ACS: 198, SAP: 273), PCAT attenuation was higher in ACS patients than in SAP patients
both at the culprit plaque level (−67.5±9.6 Hounsfield unit [HU] versus −71.5±11.0 HU, P<0.001) and at the culprit vessel
level (−68.3±7.7 HU versus −71.1±7.9 HU, P<0.001). The mean PCAT attenuation of all 3 coronary arteries was also
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significantly higher in ACS patients than in SAP patients (−68.8±6.3 HU versus −70.5±7.1 HU, P=0.007). After adjusting
patient characteristics, not only thin-cap fibroatheroma (OR: 3.41; 95% CI: 1.89–6.17) and macrophages (OR: 3.32; 95%
CI: 1.76–6.26) but also PCAT attenuation around the culprit plaque (OR: 1.03; 95% CI: 1.00–1.05) was associated with the
clinical presentation of ACS.

CONCLUSIONS: PCAT attenuation at culprit plaque, culprit vessel, and pan-coronary levels was higher in ACS patients than in
SAP patients. Vascular inflammation appears to play a crucial role in the development of ACS.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04523194

Key Words: acute coronary syndrome ◼ stable angina ◼ computed tomography angiography
◼ optical coherence tomography ◼ pericoronary adipose tissue attenuation

V
ascular inflammation has been recognized as one
of the key factors for the development of coronary
atherosclerosis and acute coronary syndromes
(ACS).1 It has been reported that modification of sys-
temic inflammation by cytokine inhibitors can reduce
the risk of cardiovascular events.2 Although it is gener-
ally accepted that ACS has a higher level of systemic
inflammation,3 the direct relationship between vascular
inflammation and clinical presentation has not been
fully studied in vivo. Better understanding of the level

Correspondence to: Ik-Kyung Jang, MD, PhD, Cardiology Division, Massachusetts General Hospital, Harvard Medical School, 55 Fruit Street, GRB 800, Boston, MA
02114. Email ijang@mgh.harvard.edu; Tsunekazu Kakuta, MD, PhD, Division of Cardiovascular Medicine, Tsuchiura Kyodo General Hospital, 4-1-1 Otsuno, Tsuchiura,
Ibaraki 300-0028, Japan. Email kaz@joy.email.ne.jp
This article was sent to Linda D. Gillam, MD, MPH, Senior Guest Editor, for review by expert referees, editorial decision, and final disposition.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCIMAGING.122.014191.
For Sources of Funding and Disclosures, see page 810.
© 2022 American Heart Association, Inc.
Circulation: Cardiovascular Imaging is available at www.ahajournals.org/journal/circimaging

Circ Cardiovasc Imaging. 2022;15:e014191. DOI: 10.1161/CIRCIMAGING.122.014191 November 2022 803

 Araki et al
CLINICAL PERSPECTIVE
Although it is generally accepted that acute coro-
nary syndrome (ACS) has a higher level of systemic
inflammation, the direct relationship between vas-
cular inflammation and clinical presentation has not
been fully studied in vivo. Pericoronary adipose tissue
(PCAT) attenuation by computed tomography angiog-
raphy has emerged as a marker specific for coronary
artery inflammation. Recent studies demonstrated that
high PCAT attenuation was associated with increased
cardiac mortality. In the present study, PCAT attenu-
ation and plaque characteristics assessed by opti-
cal coherence tomography were compared between
patients with ACS versus SAP. Among 471 patients
(ACS: 198, SAP: 273), PCAT attenuation was higher
in ACS patients than in SAP patients both at the cul-
prit plaque level (−67.5±9.6 Hounsfield unit [HU]
versus −71.5±11.0 HU, P<0.001) and the culprit
vessel level (−68.3±7.7 HU versus −71.1±7.9 HU,
P<0.001). The mean PCAT attenuation of all 3 coro-
nary arteries was also higher in ACS patients than in
SAP patients (−68.8±6.3 HU versus −70.5±7.1 HU,
P=0.007). After adjusting patient characteristics, not
only thin-cap fibroatheroma and macrophages but
also PCAT attenuation around the culprit plaque was
associated with the clinical presentation of ACS. Cur-
rent results strongly suggest that not only plaque mor-
phology but also inflammation plays an important role
in the development of ACS. Anti-inflammatory therapy
may have additional value in those subjects with high
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PCAT attenuation for the prevention of ACS and car-
diac death.
Nonstandard Abbreviations and Acronyms
ACS acute coronary syndromes
CTA computed tomography angiography
HU Hounsfield unit
PCAT pericoronary adipose tissue
SAP stable angina pectoris
TCFA thin-cap fibroatheroma
of coronary vascular inflammation may lead to bet-
ter risk stratification and potentially targeted thera-
pies. Recently, a novel noninvasive marker of vascular
inflammation through measurement of pericoronary
adipose tissue (PCAT) attenuation using computed
tomography angiography (CTA) has emerged.4,5 A
previous study reported that high PCAT attenuation
(high vascular inflammation) of the proximal coronary
arteries is associated with increased cardiac mortal-
ity.6 Optical coherence tomography (OCT) enables
the assessment of coronary plaque characteristics in
detail. The current study examined the level of coro-
nary vascular inflammation and plaque characteristics
Circ Cardiovasc Imaging. 2022;15:e014191. DOI: 10.1161/CIRCIMAGING.122.014191
Acute Coronary Syndromes and Coronary Inflammation
in relation to clinical presentation, by comparing ACS
and stable angina pectoris (SAP) patients.
METHODS
The data that support the findings of this study are available
from the corresponding author upon reasonable request.
Study Population
Patients who presented with ACS (unstable angina pectoris or
nonST-segment elevation myocardial infarction) or SAP who
underwent both CTA and OCT imaging of the culprit lesion
before intervention between January 2011 and July 2020
were included (NCT04523194). The reason for choosing this
period was that CTA image acquisition was performed by using
a single CT system. ST-segment elevation myocardial infarc-
tion patients were not included in this study. All CTA and OCT
images were acquired at Tsuchiura Kyodo General Hospital
(Ibaraki, Japan) and submitted to Massachusetts General
Hospital (Massachusetts, USA) for analysis.
A diagnosis of unstable angina pectoris and nonST-seg-
ment elevation myocardial infarction was made according to the
American Heart Association/American College of Cardiology
guidelines.7 Unstable angina pectoris was defined as having
newly developed or accelerating chest symptoms on exer-
tion or rest angina within 2 weeks without biomarker release.
NonST-segment elevation myocardial infarction was defined as
ischemic symptoms in the absence of ST-segment elevation on
the electrocardiogram with elevated cardiac biomarkers. SAP
was defined as chest pain on exertion without changes in fre-
quency, intensity, and duration of symptoms in the previous 4
weeks and positive stress test. The culprit lesion was identi-
fied by the site investigators who performed the procedure, and
data were entered in the data collection form. Subsequently, the
data were reviewed and compared with coronary angiogram
by the investigators at the core laboratory at Massachusetts
General Hospital. The culprit lesion was defined as the tightest
lesion on coronary angiogram or as the site of percutaneous
coronary intervention (PCI), if PCI was performed. If a multives-
sel PCI was performed during the same procedure, the culprit
plaque was considered the one with the highest degree of ste-
nosis. Those cases with discordance between collected data
and the interpretation of the readers at the core laboratory, or
with uncertain culprit lesions were excluded from further analy-
sis. Demographic and clinical data were collected at Tsuchiura
Kyodo General Hospital and sent to Massachusetts General
Hospital. The glomerular filtration rate (eGFR) was calculated
by using Chronic Kidney Disease Epidemiology Collaboration
(CKD-EPI) equation,8 and renal insufficiency was defined as
eGFR <60 mL/min/1.73 m2.
Between January 2011 and July 2020, 221 patients
who presented with ACS (52 unstable angina pectoris and
169 nonST-segment elevation myocardial infarction) and
296 patients with SAP underwent both CTA and OCT imag-
ing prior to intervention. Among ACS patients, 10, 1, and 1
patients were excluded for an underlying mechanism of calci-
fied nodule, spontaneous coronary artery dissection, and coro-
nary spasm, respectively, 4 patients for poor image quality, 1
patient for ACS caused by in-stent restenosis, 5 patients for
culprit lesion located in the left main, and 1 patient for culprit
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 Araki et al Acute Coronary Syndromes and Coronary Inflammation

lesion located in the diagonal branch. Among SAP patients, 2
patients were excluded for uncertain culprit lesion, 13 patients
for poor image quality, 6 patients for in-stent restenosis, and
2 patients for culprit lesion located in the left main. Calcified
nodule was excluded because it has distinct mechanism for the
development of ACS. Thus, 198 ACS and 273 SAP patients
were included in the final analysis (Figure 1). The study pro-
tocol was reviewed by each institutional ethics committee.
Written informed consent for enrollment in the Tsuchiura Kyodo
General Hospital’s institutional database for potential future
investigations was provided by all participants. Thus, a waiver
of consent for this project was granted by Tsuchiura Kyodo
General Hospital.
Coronary CTA Acquisition and PCAT Attenuation
Analysis
CT image acquisition was performed using a 320-slice CT
scanner (Aquilion ONE; Canon Medical Systems Corporation,
Otawara, Tochigi, Japan) in accordance with the Society of
Cardiovascular Computed Tomography guidelines.9 Oral and/
or intravenous beta blockers were administered if a patient’s
resting heart rate was >65 bpm. Sublingual nitroglycerin (0.3
or 0.6 mg) was administered immediately before CTA scanning.
Coronary CTA images were acquired with the following scan
protocol: tube voltage of 120 kVp, tube current of 50 to 750
mA, gantry rotation speed of 350 ms per rotation, field matrix of
512 × 512, and scan slice thickness of 0.5 mm. Acquisition of
CT data and the electrocardiography trace were automatically
started as soon as the signal density level in the ascending
aorta reached a predefined threshold of 150 Hounsfield unit
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60 mL of contrast media (iopamidol, 370 mg iodine/mL, Bayer
Yakuhin, Ltd., Osaka, Japan) at a rate of 3 to 6 mL/s, using pro-
spective electrocardiography-triggering or retrospective elec-
trocardiography-gating with automatic tube current modulation.
All scans were performed during a single breath-hold. Images
were reconstructed at a window centered at 75% of the R-R
interval to coincide with left ventricular diastasis.
PCAT attenuation analysis was performed using semiauto-
mated software (Autoplaque version 2.5; Cedar-Sinai Medical
Center, CA).10 Peri-coronary adipose tissue was defined as
all voxels with CT attenuation between −190 and −30 HU
located within a radial distance from the outer coronary wall
equal to the diameter of the vessel.5,10 PCAT attenuation was
defined as the average CT attenuation of adipose tissue within
the defined region of interest.10 To evaluate the level of inflam-
mation around the culprit plaque, the proximal and distal bor-
ders of the culprit plaque were manually defined, and average
PCAT attenuation was determined along the entire length of
the culprit plaque (Figure S1). To evaluate the level of inflam-
mation in each major coronary artery, PCAT attenuation was
measured in the proximal 40 mm segment of the left anterior
descending artery (LAD) and left circumflex artery (LCx) and
the proximal 10 to 50 mm segment of the right coronary artery
(RCA).6 To evaluate the level of pan-vascular inflammation, we
calculated the mean PCAT attenuation of the 3 major coronary
arteries in each patient. Representative images of PCAT atten-
uation analysis at the culprit plaque level is shown in Figure 2.
OCT Image Acquisition and Analysis
OCT examination was performed using either a frequency-

(HU). Images were acquired after a bolus injection of 30 to domain (C7/C8, OCT Intravascular Imaging System, St. Jude

Figure 1. Study flowchart.

Between January 2011 and July 2020, 221 patients who presented with ACS (52 UAP and 169 NSTEMI) and 296 patients with SAP
underwent both CTA and culprit lesion optical coherence tomography imaging prior to intervention. Among ACS patients, 10, 1, and 1 patients
were excluded for an underlying mechanism of calcified nodule, spontaneous coronary artery dissection, and coronary spasm, respectively,
4 patients for poor image quality, 1 patient for ACS caused by in-stent restenosis, 5 patients for culprit lesion located in the left main, and 1
patient for culprit lesion located in the diagonal branch. Among SAP patients, 2 patients were excluded for uncertain lesion, 13 patients for
poor image quality, 6 patients for in-stent restenosis, and 2 patients for culprit lesion located in the left main. Thus, 198 ACS and 273 SAP
patients were included in the final analysis. ACS indicates acute coronary syndromes; CTA, computed tomography angiography; NSTEMI, non-
ST-segment elevation myocardial infarction; SAP, stable angina pectoris; SCAD, spontaneous coronary artery dissection; and UAP, unstable
angina pectoris.

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 Araki et al Acute Coronary Syndromes and Coronary Inflammation

Figure 2. Pericoronary adipose tissue (PCAT) attenuation analysis around the culprit plaque in acute coronary syndromes (ACS)
and stable angina pectoris (SAP) patients.
Representative images of PCAT attenuation analysis around the culprit plaque in the mid-right coronary artery. A, An ACS (non-ST-segment
elevation myocardial infarction) patient (mean PCAT attenuation: −46.4 Hounsfield unit [HU]). B, An SAP patient (mean PCAT attenuation:
−103.8 HU). PCAT attenuation around the culprit plaque was higher in ACS patients than in SAP patients.

Medical, St. Paul, MN) or a time-domain (M2/M3 Cardiology
Imaging Systems, LightLab Imaging Inc., Westford, MA) OCT
system. All OCT images were submitted to the core laboratory
at Massachusetts General Hospital and analyzed by 2 indepen-
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variables were compared using the Student t test. Nonnormally
distributed variables were compared using the Mann-Whitney U
test. Categorical data were expressed as absolute frequencies and
percentages, and compared using the Chi-square test or Fisher

dent investigators (M.A. and A.N.) who were blinded to patients’
data, using an offline review workstation (St. Jude Medical). Any
discordance was resolved by consensus with a third reviewer.
Lipid was defined as a signal-poor region with a diffuse bor-
der, and the degree of lipid arc and the overlying fibrous cap
thickness was measured in lipid plaques.11,12 Lipid length was
obtained on the longitudinal view, and lipid index was calculated
as the product of mean lipid arc and lipid length.13 Lipid-rich
plaque was defined as a plaque with a maximal lipid arc >90°.11
Thin-cap fibroatheroma (TCFA) was defined as a plaque with
maximal lipid arc >90° and thinnest fibrous cap thickness <65
µm.11,14 Macrophage accumulation was defined as the presence
of highly backscattering focal regions within the fibrous cap.15
Microvessel was defined as the presence of signal-poor struc-
tures with vesicular or tubular shapes.12,13 Cholesterol crystals
were identified as thin and linear regions of high signal intensity
with high backscattering within a plaque.12,13 Calcification was
defined as a signal-poor or heterogeneous region with a sharply
delineated border.12 Layered plaque was defined as a plaque
with one or more layers of different optical density and a clear
demarcation from underlying components.16–19 Calcified nodule
was defined as single or multiple regions of calcium that pro-
trude into the lumen with fibrous cap disruption.20 Percent area
stenosis was calculated using the formula: (reference lumen
area − minimum lumen area)/reference lumen area × 100.
exact test, as appropriate. A multivariable logistic model with multi-
ple predictor variables was used to determine significant predictors
for the clinical presentation of ACS. Variables with a P value <0.10
in the univariable model were entered into the multivariable model.
A 2-sided P value of <0.05 was considered statistically significant.
Statistical analyses were performed using R software version 3.6.2
(R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Baseline Patient Characteristics
Baseline characteristics are shown in Table 1. Patients
who presented with ACS were significantly younger (mean
age 64.0 years versus 67.0 years, P=0.004) and more fre-
quently current smokers (42.4% versus 22.1%, P<0.001).
Patients with ACS also had significantly higher levels of
total cholesterol (mean 194.2 mg/dL versus173.5 mg/
dL, P<0.001), LDL-cholesterol (mean 120.9 mg/dL ver-
sus 96.3 mg/dL, P<0.001), white blood cells count (mean
7828.8/µL versus 5869.0/µL, P<0.001), and high sensi-
tivity C-reactive protein (median 0.12 mg/L versus 0.07
mg/L, P<0.001) than patients who presented with SAP.

Statistical Analysis OCT Findings

Continuous variables with normal distribution were expressed as OCT findings are shown in Table 2. The prevalence of
mean±SD, while median (interquartile range) was used to sum- TCFA (43.4% versus 23.9%, P<0.001) and macrophage
marize nonnormally distributed variables. Normally distributed (80.3% versus 66.3%, P=0.001) was significantly higher,

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 Araki et al Acute Coronary Syndromes and Coronary Inflammation

Table 1. Baseline Patient Characteristics Table 2. Culprit Plaque Optical Coherence Tomography
Findings
ACS (n = 198) SAP (n = 273) P
Age, y 64.0±11.7 67.0±10.8 0.004 ACS (n = 198) SAP (n = 273) P

Men 162 (81.8) 219 (79.3) 0.558 Lipid-rich plaque 165 (83.3) 227 (82.2) 0.806

BMI, kg/m 2
24.75±3.45 24.69±3.25 0.855 Minimum fibrous cap 0.06 (0.05–0.11) 0.10 (0.06–0.16) <0.001
thickness, µm
Hypertension 130 (65.7) 205 (74.3) 0.052
Maximum lipid arc, ° 260.0 211.0 <0.001
Hyperlipidemia 95 (48.0) 179 (64.9) <0.001 (216.0–313.8) (161.9–266.9)
Diabetes 67 (33.8) 120 (43.5) 0.036 Mean lipid arc, ° 199.7±49.5 174.0±49.0 <0.001
Current smoking 84 (42.4) 61 (22.1) <0.001 Lipid length, mm 12.3±4.3 16.5±7.4 <0.001
Renal insufficiency 38 (19.2) 62 (22.5) 0.425 Lipid index, °mm 1739.0±927.5 1775.2±1287.9 0.757
Previous MI 10 (5.1) 59 (21.4) <0.001 TCFA 86 (43.4) 66 (23.9) <0.001
Previous PCI 13 (6.6) 81 (29.3) <0.001 Macrophage 159 (80.3) 183 (66.3) 0.001
Medication Microvessel 109 (55.1) 153 (55.4) 1.000
Statin 45 (22.7) 209 (75.7) <0.001 Cholesterol crystal 68 (34.3) 126 (45.7) 0.014
ACEi or ARB 128 (64.6) 168 (60.9) 0.442 Calcification 94 (47.5) 180 (65.2) <0.001
Laboratory data Layered plaque 113 (57.1) 149 (54.0) 0.514
Creatinine, mg/dL 0.90±0.87 0.85±0.35 0.329 Minimum lumen area, 1.14±0.77 1.34±0.76 0.006
 Total cholesterol, 194.2±41.8 173.5±38.0 <0.001 mm2
mg/dL Lesion length, mm 12.3±4.3 16.5±7.4 <0.001
LDL-C, mg/dL 120.9±36.3 96.3±31.4 <0.001 Area stenosis, % 81.8±9.5 79.6±9.6 0.010
HDL-C, mg/dL 48.8±13.5 49.3±13.2 0.677 Values shown are n (%) or mean±standard deviation. Normally distributed
 Triglycerides, mg/dL 113.0 126.0 0.300 continuous variables were compared using the Student t test. Nonnormally dis-
(79.0–179.0) (89.5–182.0) tributed continuous variables were compared using the Mann-Whitney U test.
Categorical data were compared using the Chi square test or Fisher exact test,
HbA1c, % 6.2±1.3 6.3±1.0 0.347
as appropriate. ACS indicates acute coronary syndromes; SAP, stable angina pec-
WBC, count/µL 7828.8±2713.2 5869.0±1692.3 <0.001 toris; and TCFA, thin-cap fibroatheroma.
 High sensitivity 0.12 (0.05–0.53) 0.07 (0.00–0.19) <0.001
C-reactive protein, P<0.001) (Figure 3A). This difference was most notable
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mg/L
Culprit vessel 0.105
RCA 50 (25.3) 65 (23.6)
LAD 110 (55.6) 176 (63.8)
LCx 38 (19.2) 35 (12.7)
Values shown are n (%), mean±standard deviation, or median (25th–75th per-
centile). Normally distributed continuous variables were compared using the Stu-
dent t test. Nonnormally distributed continuous variables were compared using the
Mann-Whitney U test. Categorical data were compared using the Chi square test.
ACEi indicates angiotensin-converting enzyme inhibitor; ACS, acute coronary
syndromes; ARB, angiotensin II receptor blocker; BMI, body mass index; HbA1c,
hemoglobin A1c; HDL, high-density lipoprotein; LAD, left anterior descending
artery; LCx, left circumflex artery; LDL, low-density lipoprotein; MI, myocardial
infarction; PCI, percutaneous coronary intervention; RCA, right coronary artery;
SAP, stable angina pectoris; and WBC, white blood cell.
minimum lumen area was smaller (1.14 mm2 versus 1.34
mm2, P=0.006), and lesion was shorter (12.3±4.3 mm
versus 16.5±7.4 mm, P<0.001) in ACS patients than SAP
patients. The prevalence of cholesterol crystal (34.3%
versus 45.7%, P=0.014) and calcification (47.5% versus
65.2%, P<0.001) was lower in ACS patients.
PCAT Attenuation at Culprit Plaque and Vessel
Levels
PCAT attenuation in the culprit plaque was significantly
higher (more inflammation) in ACS patients than in
SAP patients (−67.5±9.6 HU versus −71.5±11.0 HU,
when the left anterior descending artery was the culprit
vessel (Figure S2). At the culprit vessel level, PCAT attenu-
ation was also significantly higher in ACS patients than
in SAP patients (−68.3±7.7 HU versus −71.1±7.9 HU,
P<0.001) (Figure 3B). This difference was most prominent
when the left anterior descending artery was the culprit
vessel (Figure S3). The mean PCAT attenuation of all 3
coronary arteries was significantly higher in ACS patients
than in SAP patients (−68.8±6.3 HU versus −70.5±7.1
HU, P=0.007) (Figure 3C). PCAT attenuation in culprit
plaque and culprit vessel levels were significantly higher in
patients with lipid-rich plaque than those without lipid-rich
plaque (−69.3±7.9 HU versus −73.0±7.7 HU, P<0.001
and −69.4±6.6 HU versus −71.9±7.4 HU, p = 0.002,
respectively). PCAT attenuation in culprit plaque and
culprit vessel levels were significantly higher in patients
with macrophage than in those without macrophage
(−69.3±8.2 HU versus −71.6±7.1 HU, P=0.005 and
−69.1±6.8 HU versus −71.7±6.6 HU, P<0.001, respec-
tively). There was no significant association between other
OCT plaque characteristics and PCAT attenuation.12
Subgroup Analysis (Analysis Excluding Left
Circumflex Artery)
Since the left circumflex artery has wide anatomical varia-
tions and does not necessarily reflect background vascular

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 Araki et al
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Figure 3. Differences in pericoronary adipose tissue (PCAT)
attenuation between acute coronary syndromes (ACS) and
stable angina pectoris (SAP).
PCAT attenuation was compared between ACS patients and SAP
patients using the Student t test. PCAT attenuation in the culprit
plaque (A), the culprit vessel (B), and the mean value of all 3 major
coronary arteries (C) was significantly higher in ACS patients
compared with SAP patients.
Circ Cardiovasc Imaging. 2022;15:e014191. DOI: 10.1161/CIRCIMAGING.122.014191
Acute Coronary Syndromes and Coronary Inflammation
inflammation of the entire coronary tree,4,6 we performed
a subgroup analysis excluding the left circumflex artery.
Among 401 patients whose culprit vessel was right coro-
nary artery or left anterior descending artery, 160 patients
presented with ACS and 241 patients with SAP. Even
after the exclusion of the left circumflex artery from the
analysis, PCAT attenuation in the culprit plaque and culprit
vessel and the mean of right coronary artery and left ante-
rior descending artery were significantly higher in ACS
patients than in SAP patients, a finding consistent with the
main results of the whole study cohort (Figure S4).
Determinants of Clinical Presentation of ACS
In univariable analysis, absence of hypertension, hyper-
lipidemia, diabetes mellitus, history of MI, history of PCI,
statin use, cholesterol crystal, and calcification, age, cur-
rent smoking, TCFA, macrophage, minimum lumen area,
lesion length, and PCAT attenuation around the culprit
plaque were significantly associated with the clinical pre-
sentation of ACS. After adjusting patient characteristics,
presence of TCFA (OR: 3.41; 95% CI: 1.89–6.17) and
macrophage (OR: 3.32; 95% CI: 1.76–6.26), absence
of cholesterol crystal (OR: 0.55; 95% CI: 0.31–0.96),
minimum lumen area (OR: 0.67; 95% CI: 0.47–0.94),
lesion length (OR: 0.86; 95% CI: 0.82–0.91) and PCAT
attenuation around the culprit plaque (OR: 1.03; 95% CI:
1.00–1.05) were determinants of the ACS clinical pre-
sentation (Table S1).
DISCUSSION
The current study demonstrated that (1) patients who
presented with ACS, compared with those with SAP,
had a higher level of vascular inflammation measured
by PCAT attenuation at culprit plaque, culprit vessel, and
pan-coronary levels; (2) After adjusting patient charac-
teristics, not only TCFA (OR: 3.41; 95% CI: 1.89–6.17)
and macrophage (OR: 3.32; 95% CI: 1.76–6.26) but also
PCAT attenuation around the culprit plaque (OR: 1.03;
95% CI: 1.00–1.05) was significantly associated with
the clinical presentation of ACS.
Vascular inflammation has been recognized as one of
the key factors for atherosclerotic plaque formation and
the development of ACS.1 Inflammation stimulates a local
immune reaction and activates macrophages, mast cells,
and T cells to release cytokines that inhibit collagen synthe-
sis and proteases such as matrix metalloproteinase which
digest fibrous cap components.21 It is known that elevated
plasma inflammatory biomarkers such as high sensitivity
C-reactive protein and Interleukin-6 are associated with
cardiovascular events.22 Recent studies have demonstrated
that antiinflammatory therapy of interleukin-1β or interleu-
kin-6 inhibitors led to favorable cardiac outcomes.2,23 PCAT
attenuation is an emerging marker of vascular inflamma-
tion. PCAT modulates inflammation signaling pathways in
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 Araki et al Acute Coronary Syndromes and Coronary Inflammation

the vascular wall through paracrine and vasocrine man-
ners.24 Conversely, inflammation inhibits adipocyte differ-
entiation and intracellular accumulation, resulting in the
compositional change in PCAT.4,5 Recent studies demon-
strated that high PCAT attenuation was associated with
increased cardiac mortality6 and progression of nonculprit
plaque.25 A previous study with a small number of patients
(35 patients) reported that PCAT attenuation around the
culprit plaque was higher in ACS patients than in stable
coronary artery disease patients.10 In the present study with
a larger number of patients (471 patients), PCAT attenua-
tion was associated with the clinical presentation of ACS.
In addition, we analyzed not only PCAT attenuation but also
OCT plaque characteristics. The impact of PCAT attenua-
tion was incremental when it was added to conventional
plaque characteristics that represent vascular inflamma-
tion (ie, TCFA and macrophage). Current results strongly
suggest that not only plaque morphology but also inflam-
mation plays an important role in the development of ACS
(Figure 4). Antiinflammatory therapy may have additional
value in those subjects with high PCAT attenuation for the
prevention of ACS and cardiac death.
Detection of vulnerable plaque may help to identify
patients who could benefit from aggressive prevention
treatments such as PCSK9 inhibitors or antiinflammatory
therapies. A prospective virtual histology intravascular
ultrasound study reported that patients with TCFA, mini-
mum lumen area <4.0 mm2, and plaque burden ≥70%
Downloaded from http://ahajournals.org by on December 16, 2022
were at higher risk for major adverse cardiac events in
3 years.26 However, most of the major adverse cardiac
events were driven by unstable or progressive angina
rather than cardiac death or MI. A retrospective 4-year
follow-up OCT study also reported that the presence of
lipid-rich plaque in nonculprit regions was a risk factor for
future major adverse cardiac events.27 However, only 2
(1.1%) of 174 TCFAs caused acute MI during the 2-year
follow-up.28 These results raise a question on the defini-
tion of “vulnerable plaque.” In the present study, we dem-
onstrated that not only high-risk plaque morphology but
also high PCAT attenuation was associated with ACS.
This indicates that the assessment of coronary inflam-
mation may be used for risk stratification.
Limitations
First, this was a retrospective study that included patients
who underwent both CTA and OCT. Because patients
underwent CTA first, patients without significant ste-
nosis on CTA might have been excluded from invasive
procedures such as coronary angiography or OCT. Thus,
significant selection bias cannot be excluded. Second,
the number of patients was small. However, it should be
noted that this was a mechanistic study and not an out-
comes trial. Third, histological analysis of adipocytes was
not available in the present study for the evaluation of
the level of vascular inflammation. Fourth, OCT findings

Figure 4. Vascular inflammation and development of acute coronary syndromes (ACS).

Patients who presented with ACS had a higher level of vascular inflammation measured by pericoronary adipose tissue (PCAT) attenuation
at culprit plaque, culprit vessel, and pan-coronary levels. After adjusting patient characteristics, not only thin-cap fibroatheroma (TCFA) and
macrophage but also PCAT attenuation around the culprit plaque was associated with the clinical presentation of ACS. Current results
strongly suggest that vascular inflammation plays a crucial role in the development of ACS. Red arrows indicate TCFA. Yellow arrows indicate
macrophages. SAP indicates stable angina pectoris.

Circ Cardiovasc Imaging. 2022;15:e014191. DOI: 10.1161/CIRCIMAGING.122.014191 November 2022 809

 Araki et al
of high-risk plaques and plaque burden on CT were not
assessed. Fifth, tube voltage can be reduced to lower
radiation exposure without compromising image quality
in slim patients. However, a tube voltage of 120 kVp was
part of the CTA imaging protocol at the institution where
patients were enrolled. Sixth, it is possible that vessel-
level PCAT analysis is affected by the PCAT attenua-
tion around the culprit plaque. The location of the culprit
plaque was analyzed in 362 patients with OCT images of
the coronary ostium. The location of the minimum lumen
area was considered the location of the culprit plaque.
Culprit plaques showed clustering in the proximal seg-
ment of 3 coronary arteries. Since vessel-level PCAT
analysis was performed in the proximal 40 mm segment
of coronary arteries, the location of most culprit plaques
(326/362, 90.1%) was overlapping with the location
of vessel-level PCAT analysis. Finally, all patients were
enrolled in Japan. Thus, current results may not apply to
other populations.
Conclusions
PCAT attenuation at culprit plaque, culprit vessel, and
pan-coronary levels was higher in ACS patients than in
SAP patients. Vascular inflammation may play a crucial
role in the development of ACS.
ARTICLE INFORMATION
Downloaded from http://ahajournals.org by on December 16, 2022
Received March 8, 2022; accepted October 7, 2022.
Affiliations
Cardiology Division, Massachusetts General Hospital, Harvard Medical School,
Boston, MA (M.A., A.N., L.M.S., I.M., I.-K.J.). Department of Cardiology, Tsuchiura
Kyodo General Hospital, Tsuchiura, Ibaraki, Japan (T.S., Y.Y., Y.T., T.N., T.K.). Depart-
ment of Interventional Cardiology, Tokyo Medical and Dental University, Tokyo,
Japan (T.Y.). Biomedical Imaging Research Institute, Cedars-Sinai Medical Center,
Los Angeles, CA (D.D.). Biostatistics Center, Massachusetts General Hospital,
Harvard Medical School, Boston, MA (H.L.). Division of Cardiology, Kyung Hee
University Hospital, Seoul, South Korea (I.-K.J.).
Sources of Funding
Dr. Jang’s research has been supported by Mrs. Gillian Gray through the Al-
lan Gray Fellowship Fund in Cardiology, and Mr. and Mrs. Michael and Kathryn
Park. Dr. Dey is supported by National Heart, Lung, and Blood Institute grants
(1R01HL148787-01A1 and 1R01HL151266). They had no role in the design
or conduct of this research.
Disclosures
Dr. Jang has received educational grant support from Abbott Vascular and a con-
sulting fee from Svelte Medical Systems and Mitobridge Inc. Outside the current
study, Dr. Dey has received software royalties from Cedars-Sinai Medical Center
and has a patent. All other authors have no relationships relevant to the contents
of this article to disclose.
Supplemental Material
Table S1
Figures S1−S4
REFERENCES
1. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med.
1999;340:115–126. doi: 10.1056/NEJM199901143400207
Circ Cardiovasc Imaging. 2022;15:e014191. DOI: 10.1161/CIRCIMAGING.122.014191
Acute Coronary Syndromes and Coronary Inflammation
2. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH,
Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. Antiinflam-
matory therapy with canakinumab for atherosclerotic disease. N Engl J Med.
2017;377:1119–1131. doi: 10.1056/NEJMoa1707914
3. Mulvihill NT, Foley JB. Inflammation in acute coronary syndromes. Heart.
2002;87:201–204. doi: 10.1136/heart.87.3.201
4. Antoniades C, Antonopoulos AS, Deanfield J. Imaging residual inflam-
matory cardiovascular risk. Eur Heart J. 2020;41:748–758. doi:
10.1093/eurheartj/ehz474
5. Antonopoulos AS, Sanna F, Sabharwal N, Thomas S, Oikonomou EK,
Herdman L, Margaritis M, Shirodaria C, Kampoli AM, Akoumianakis I, et al.
Detecting human coronary inflammation by imaging perivascular fat. Sci
Transl Med. 2017;9:eaal2658. doi: 10.1126/scitranslmed.aal2658
6. Oikonomou EK, Marwan M, Desai MY, Mancio J, Alashi A, Hutt
Centeno E, Thomas S, Herdman L, Kotanidis CP, Thomas KE, et al. Non-
invasive detection of coronary inflammation using computed tomography
and prediction of residual cardiovascular risk (the CRISP CT study): a post-
hoc analysis of prospective outcome data. Lancet. 2018;392:929–939. doi:
10.1016/S0140-6736(18)31114-0
7. Amsterdam EA, Wenger NK, Brindis RG, Casey DE Jr, Ganiats TG,
Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, et al. 2014 AHA/
ACC guideline for the management of patients with non-ST-elevation acute
coronary syndromes: a report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Circulation.
2014;130:e344–e426. doi: 10.1161/CIR.0000000000000134
8. Inker LA, Astor BC, Fox CH, Isakova T, Lash JP, Peralta CA, Kurella Tamura
M, Feldman HI. KDOQI US commentary on the 2012 KDIGO clinical prac-
tice guideline for the evaluation and management of CKD. Am J Kidney Dis.
2014;63:713–735. doi: 10.1053/j.ajkd.2014.01.416
9. Abbara S, Blanke P, Maroules CD, Cheezum M, Choi AD, Han BK,
Marwan M, Naoum C, Norgaard BL, Rubinshtein R, et al. SCCT guidelines
for the performance and acquisition of coronary computed tomographic
angiography: a report of the Society of Cardiovascular Computed Tomog-
raphy Guidelines Committee: endorsed by the North American Soci-
ety for Cardiovascular Imaging (NASCI). J Cardiovasc Comput Tomogr.
2016;10:435–449. doi: 10.1016/j.jcct.2016.10.002
10. Goeller M, Achenbach S, Cadet S, Kwan AC, Commandeur F,
Slomka PJ, Gransar H, Albrecht MH, Tamarappoo BK, Berman DS, et al.
Pericoronary adipose tissue computed tomography attenuation and high-
risk plaque characteristics in acute coronary syndrome compared with sta-
ble coronary artery disease. JAMA Cardiol. 2018;3:858–863. doi: 10.1001/
jamacardio.2018.1997
11. Kato K, Yonetsu T, Kim SJ, Xing L, Lee H, McNulty I, Yeh RW, Sakhuja R,
Zhang S, Uemura S, et al. Nonculprit plaques in patients with acute coro-
nary syndromes have more vulnerable features compared with those
with non-acute coronary syndromes: a 3-vessel optical coherence
tomography study. Circ Cardiovasc Imaging. 2012;5:433–440. doi:
10.1161/CIRCIMAGING.112.973701
12. Araki M, Park SJ, Dauerman HL, Uemura S, Kim JS, Di Mario C, Johnson TW,
Guagliumi G, Kastrati A, Joner M, et al. Optical coherence tomography in
coronary atherosclerosis assessment and intervention. Nat Rev Cardiol.
2022:684–703. doi: 10.1038/s41569-022-00687-9
13. Vergallo R, Uemura S, Soeda T, Minami Y, Cho JM, Ong DS, Aguirre AD,
Gao L, Biasucci LM, Crea F, et al. Prevalence and predictors of multiple
coronary plaque ruptures: in vivo 3-vessel optical coherence tomography
imaging study. Arterioscler Thromb Vasc Biol. 2016;36:2229–2238. doi:
10.1161/ATVBAHA.116.307891
14. Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from
sudden coronary death: a comprehensive morphological classification
scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000;20:
1262–1275. doi: 10.1161/01.atv.20.5.1262
15. Tearney GJ, Yabushita H, Houser SL, Aretz HT, Jang IK, Schlendorf KH,
Kauffman CR, Shishkov M, Halpern EF, Bouma BE. Quantification of macro-
phage content in atherosclerotic plaques by optical coherence tomography.
Circulation. 2003;107:113–119. doi: 10.1161/01.cir.0000044384.41037.43
16. Shimokado A, Matsuo Y, Kubo T, Nishiguchi T, Taruya A, Teraguchi I, Shiono Y,
Orii M, Tanimoto T, Yamano T, et al. In vivo optical coherence tomography
imaging and histopathology of healed coronary plaques. Atherosclerosis.
2018;275:35–42. doi: 10.1016/j.atherosclerosis.2018.05.025
17. Otsuka F, Joner M, Prati F, Virmani R, Narula J. Clinical classification of
plaque morphology in coronary disease. Nat Rev Cardiol. 2014;11:379–
389. doi: 10.1038/nrcardio.2014.62
18. Yamamoto MH, Yamashita K, Matsumura M, Fujino A, Ishida M, Ebara S,
Okabe T, Saito S, Hoshimoto K, Amemiya K, et al. Serial 3-vessel optical
November 2022 810
 Araki et al
coherence tomography and intravascular ultrasound analysis of chang-
ing morphologies associated with lesion progression in patients with
stable angina pectoris. Circ Cardiovasc Imaging. 2017;10:e006347. doi:
10.1161/CIRCIMAGING.117.006347
19. Fracassi F, Crea F, Sugiyama T, Yamamoto E, Uemura S, Vergallo R, Porto I,
Lee H, Fujimoto J, Fuster V, et al. Healed culprit plaques in patients with
acute coronary syndromes. J Am Coll Cardiol. 2019;73:2253–2263. doi:
10.1016/j.jacc.2018.10.093
20. Saita T, Fujii K, Hao H, Imanaka T, Shibuya M, Fukunaga M, Miki K,
Tamaru H, Horimatsu T, Nishimura M, et al. Histopathological validation
of optical frequency domain imaging to quantify various types of coronary
calcifications. Eur Heart J Cardiovasc Imaging. 2017;18:342–349. doi:
10.1093/ehjci/jew054
21. Hansson GK, Libby P, Tabas I. Inflammation and plaque vulnerability. J Intern
Med. 2015;278:483–493. doi: 10.1111/joim.12406
22. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and
other markers of inflammation in the prediction of cardiovascular dis-
ease in women. N Engl J Med. 2000;342:836–843. doi: 10.1056/
NEJM200003233421202
23. Broch K, Anstensrud AK, Woxholt S, Sharma K, Tøllefsen IM, Bendz B,
Aakhus S, Ueland T, Amundsen BH, Damås JK, et al. Randomized trial of
Downloaded from http://ahajournals.org by on December 16, 2022
Circ Cardiovasc Imaging. 2022;15:e014191. DOI: 10.1161/CIRCIMAGING.122.014191
Acute Coronary Syndromes and Coronary Inflammation
interleukin-6 receptor inhibition in patients with acute ST-segment eleva-
tion myocardial infarction. J Am Coll Cardiol. 2021;77:1845–1855. doi:
10.1016/j.jacc.2021.02.049
24. Mancio J, Oikonomou EK, Antoniades C. Perivascular adipose tis-
sue and coronary atherosclerosis. Heart. 2018;104:1654–1662. doi:
10.1136/heartjnl-2017-312324
25. Goeller M, Tamarappoo BK, Kwan AC, Cadet S, Commandeur F, Razipour A,
Slomka PJ, Gransar H, Chen X, Otaki Y, et al. Relationship between changes
in pericoronary adipose tissue attenuation and coronary plaque burden
quantified from coronary computed tomography angiography. Eur Heart J
Cardiovasc Imaging. 2019;20:636–643. doi: 10.1093/ehjci/jez013
26. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS,
Mehran R, McPherson J, Farhat N, Marso SP, et al. A prospective natural-
history study of coronary atherosclerosis. N Engl J Med. 2011;364:226–
235. doi: 10.1056/NEJMoa1002358
27. Xing L, Higuma T, Wang Z, Aguirre AD, Mizuno K, Takano M, Dauerman HL,
Park SJ, Jang Y, Kim CJ, et al. Clinical significance of lipid-rich plaque
detected by optical coherence tomography: a 4-year follow-up study. J Am
Coll Cardiol. 2017;69:2502–2513. doi: 10.1016/j.jacc.2017.03.556
28. Jang IK. Pursuit for the detection of vulnerable plaque. Eur Heart J.
2020;41:392–393. doi: 10.1093/eurheartj/ehz678
November 2022 811