Plaque Rupture, Compared With Plaque Erosion, Is Associated With a Higher Level of Pancoronary Inflammation

Abstract

OBJECTIVES

The aim of this study was to compare the level of coronary inflammation between plaque rupture and plaque erosion using pericoronary adipose tissue (PCAT) attenuation.

BACKGROUND

Vascular inflammation plays a key role in plaque rupture, while the role of inflammation in plaque erosion remains less well defined. PCAT attenuation determined using computed tomography has emerged as a marker specific for coronary artery inflammation.

METHODS

Patients with non-ST-segment elevation acute coronary syndromes who underwent preintervention coronary computed tomographic angiography and optical coherence tomographic culprit lesion imaging were enrolled. PCAT attenuation was measured around the culprit lesion and in the proximal 40 mm of all coronary arteries.

RESULTS

Among 198 patients, plaque rupture was the underlying mechanism in 107 (54.0%) and plaque erosion in 91 (46.0%). Plaque rupture had higher PCAT attenuation than plaque erosion both at the culprit plaque level (−65.8 ± 7.5 HU vs −69.5 ± 11.4 HU; P = 0.010) and at the culprit vessel level (−67.1 ± 7.1 HU vs −69.6 ± 8.2 HU; P = 0.024). The mean PCAT attenuation of all 3 coronary arteries was also significantly higher in patients with plaque rupture than in plaque erosion, indicating a higher level of inflammation (−67.9 ± 5.7 HU vs −69.9 ± 6.8 HU; P = 0.030). In multivariable analysis, plaque rupture was significantly associated with high PCAT attenuation.

CONCLUSIONS

PCAT attenuation in culprit plaque, culprit vessel, and all 3 coronary arteries was higher in plaque rupture than in plaque erosion. The results suggest that pancoronary inflammation plays a more significant role in plaque rupture than in plaque erosion. (Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration; NCT04523194) (J Am Coll Cardiol Img 2022;15:828–839) © 2022 by the American College of Cardiology Foundation.

Vascular inflammation has been recognized as one of the key factors for atherosclerotic plaque formation and the development of acute coronary syndromes (ACS) (1). Recent studies have revealed that modification of systemic inflammation by cytokine inhibitors can reduce the risk for cardiovascular events and increase myocardial salvage after myocardial infarction (2,3). Thus, detection of vascular inflammation not only helps estimate the level of vascular instability but may also guide targeted therapy. Recently, a novel noninvasive marker of vascular inflammation through measurement of pericoronary adipose tissue (PCAT) attenuation using computed tomographic angiography (CTA) has been developed (4,5). A previous large study reported that high PCAT attenuation (high vascular inflammation) of the proximal coronary arteries is associated with increased cardiac mortality (6). Another study reported that PCAT attenuation is associated with features of high-risk plaques on CTA (7). It is widely accepted that vascular inflammation plays a more important role in plaque rupture than in plaque erosion (8,9). However, a direct comparison of the level of vascular inflammation between plaque rupture and plaque erosion has not been reported. Optical coherence tomography (OCT) has made it possible to diagnose the underlying mechanism in patients with ACS (10–13). Using a combined approach of CTA and OCT, in the present study we examined the differences in the level of coronary inflammation between patients with ACS with plaque rupture and plaque erosion using both PCAT attenuation on the basis of CTA and culprit plaque phenotype identified by OCT.

METHODS

STUDY POPULATION.

Patients who presented with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and who underwent both CTA and OCT of the culprit lesion prior to intervention were selected from a newly established database, Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration (NCT04523194). All computed tomographic (CT) angiographic and optical coherence tomographic images were acquired at Tsuchiura Kyodo General Hospital and submitted to Massachusetts General Hospital for analysis. A diagnosis of NSTE-ACS was made according to the American Heart Association/American College of Cardiology guidelines (14). NSTE ACS included non-ST-segment elevation myocardial infarction (NSTEMI) and unstable angina pectoris. NSTEMI was defined as ischemic symptoms in the absence of ST-segment elevation on electrocardiography with elevated cardiac biomarkers. Unstable angina pectoris was defined as having newly developed or accelerating chest symptoms on exertion or rest angina within 2 weeks without biomarker release. Between January 2011 and July 2020, 221 patients who presented with NSTE-ACS underwent both CTA and culprit-lesion OCT prior to intervention. Among them, 12 patients with underlying mechanisms other than plaque rupture or plaque erosion, 5 patients with culprit lesions located in the left main coronary artery, 4 patients with insufficient imaging quality, 1 patient with ACS caused by in-stent restenosis, and 1 patient with a culprit lesion located in a diagonal branch were excluded (Supplemental Figure 1). Thus, 198 patients were included in the final analysis. The study protocol 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 ANGIOGRAPHIC ANALYSIS.

Methods for coronary angiographic analysis are described in the Supplemental Methods.

CORONARY CTA AND PCAT ATTENUATION ANALYSIS.

CT image acquisition was performed using a 320-slice CT scanner (Aquilion ONE, Canon Medical Systems) in accordance with Society of Cardiovascular Computed Tomography guidelines (15). Oral and/or intravenous beta-blockers were administered if a patient’s resting heart rate was >65 beats/min. Sublingual nitroglycerin (0.3 or 0.6 mg) was administered immediately before CTA. Coronary CT angiographic images were acquired with the following scan protocol: tube voltage 120 kVp, tube current 50 to 750 mA, gantry rotation speed 350 ms per rotation, field matrix 512 × 512, and scan slice thickness 0.5 mm. Acquisition of CT data and the electrocardiographic trace were automatically started as soon as the signal density level in the ascending aorta reached a predefined threshold of 150 HU. Images were acquired after a bolus injection of 30 to 60 mL of contrast media (iopamidol, 370 mg iodine/mL, Bayer Yakuhin) at a rate of 3 to 6 mL/s, using prospective electrocardiographic triggering or retrospective electrocardiographic 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 semiautomated software (Autoplaque version 2.5, Cedar-Sinai Medical Center) (7). PCAT 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). PCAT attenuation was defined as the average CT attenuation of adipose tissue within the defined region of interest (7). To evaluate the level of inflammation in culprit plaques, the proximal and distal border of the culprit plaque were manually defined, and PCAT attenuation was measured in 2 different ways (Figure 1): average PCAT attenuation was determined along the entire length of the culprit plaque (“culprit plaque PCAT attenuation”). In addition, average PCAT attenuation along a 4-mm segment centered on the point of maximum luminal stenosis severity was also measured to evaluate PCAT attenuation of culprit lesions irrespective of plaque length (“culprit lesion PCAT attenuation”). A length of 4 mm was chosen on the basis of previous near-infrared spectroscopy intravascular ultrasound studies (16,17). To evaluate the level of inflammation in each major coronary artery, PCAT attenuation was measured in the proximal 40-mm segment of the left anterior descending coronary artery (LAD) and left circumflex coronary artery (LCx) and the proximal 10- to 50-mm segment of the right coronary artery (6). To evaluate the level of panvascular inflammation, we calculated the mean PCAT attenuation of the 3 major coronary arteries in each patient.

FIGURE 1. Analysis of PCAT Attenuation in Culprit Plaque.

Representative images of curved (A) and straightened (B) multiplanar reconstruction view and pericoronary adipose tissue (PCAT) attenuation measurement (C) of culprit plaque. PCAT attenuation was measured at the culprit plaque and within the defined 4-mm culprit segment.

OCT IMAGE ACQUISITION AND ANALYSIS.

OCT was performed using a frequency-domain (C7/C8, OCT Intravascular Imaging System, St. Jude Medical) or time-domain (M2/M3 Cardiology Imaging Systems, Light Lab Imaging) system. Aspiration thrombectomy was allowed before OCT in patients with TIMI (Thrombolysis In Myocardial Infarction) flow grade <2 and/or occlusive thrombus. All optical coherence tomographic images were submitted to the Massachusetts General Hospital core laboratory for off-line analysis. Optical coherence tomographic image analysis was performed using an off-line review workstation (Ilumien Optis, St. Jude Medical) by independent investigators who were blinded to the clinical, angiographic, and laboratory data. Plaque rupture was identified by the presence of fibrous cap discontinuity with a communication between the lumen and the inner core of plaque or with a cavity formation within the plaque (18,19). Plaque erosion was identified by the presence of attached thrombus overlying an intact plaque or luminal surface irregularity at the culprit lesion (20). Additional plaque analysis performed is described in the Supplemental Methods (13). Good intraobserver and interobserver agreement was noted in the classification of culprit mechanism (plaque rupture or plaque erosion) (κ = 0.91 and κ = 0.84, respectively). The median interval between CTA and invasive angiography (OCT) was 4.0 hours (IQR: 2.0–27.0 hours).

SUBGROUP ANALYSIS.

We performed 2 subgroup analyses (subgroup analysis excluding LCx and subgroup analysis in different clinical presentations). The LCx has various anatomical variations and does not necessarily reflect background vascular inflammation of the entire coronary tree (4,6). Thus, in the subgroup analysis excluding the LCx, we excluded patients whose culprit vessel was the LCx, and we also excluded PCAT attenuation of the LCx from the non–culprit vessel analysis. In the subgroup analysis in different clinical presentation, we evaluated the differences in PCAT attenuation between plaque rupture and plaque erosion in patients who presented with NSTEMI and in those with unstable angina pectoris.

CLINICAL OUTCOME ASSESSMENT.

Patients were followed up at 1 year after catheterization. Clinical events (composite of all-cause death, myocardial infarction, and target lesion revascularization [TLR]) were recorded. Myocardial infarction was defined as ST-segment elevation myocardial infarction or NSTEMI (14). TLR was defined as any revascularization procedure of the target lesion. We compared the differences of PCAT attenuation in culprit plaque and culprit vessel and the mean PCAT attenuation of all 3 coronary arteries between patients with and those without clinical events.

STATISTICAL ANALYSIS.

Categorical data are presented as counts and percentages and were compared using the chi-square test or Fisher exact test as appropriate. Continuous data are presented as mean ± SD or median (IQR) as appropriate, depending on the normality of distribution. Between-group differences in continuous variables were compared using Student’s t-test or the Mann-Whitney U test as appropriate. The normality of distribution was evaluated using the Kolmogorov-Smirnov test. A general linear model with multiple predictor variables was used to determine significant predictors for PCAT attenuation. Variables with P values <0.10 in the univariate test were entered into the multivariable modeling. We confirmed that the variance inflation factors of all variables ranged from 1.00 to 1.05 in all 3 multivariable models (Supplemental Table 1). We also confirmed that distributions of residual were normally distributed in all 3 multivariable models using the Kolmogorov-Smirnov test (Supplemental Table 2). All analyses were performed using SPSS version 25 for Windows (SPSS).

RESULTS

BASELINE CHARACTERISTICS AND ANGIOGRAPHIC FINDINGS.

Baseline characteristics are shown in Table 1. Among 198 patients, 107 (54.0%) had plaque rupture and 91 (46.0%) had plaque erosion at the culprit lesion. Plaque rupture presented more frequently with NSTEMI than plaque erosion. The level of high sensitivity C-reactive protein (hsCRP) was not significantly different between plaque rupture and plaque erosion. Angiographic findings are shown in Supplemental Table 3. Patients with plaque rupture had more severe diameter stenosis and longer lesion length than those with plaque erosion.

TABLE 1. Baseline Characteristics.

	Patients With Culprit Rupture (n = 107)	Patients With Culprit Erosion (n = 91)	P Value
Age, y	64.6 ± 11.3	63.3 ± 12.2	0.356
Male	88 (82.2)	74 (81.3)	0.867
Clinical presentation			0.005
NSTEMI	91 (85.0)	62 (68.1)
Unstable angina pectoris	16 (15.0)	29 (31.9)
HTN	72 (67.3)	58 (63.7)	0.600
DL	48 (44.9)	47 (51.6)	0.341
DM	41 (38.3)	25 (27.5)	0.107
CKD (eGFR <60 mL/min/1.73 m2)	24 (22.4)	14 (15.4)	0.210
Current smoking	43 (40.2)	41 (45.1)	0.525
Laboratory data
Creatinine clearance, mL/min/1.73 m2	0.90 ± 0.82	0.92 ± 0.99	0.983
Low-density lipoprotein cholesterol, mg/dL	118.2 ± 37.7	124.3 ± 34.8	0.279
High-density lipoprotein cholesterol, mg/dL	46.8 ± 11.6	50.2 ± 14.0	0.052
Triglyceride, mg/dL	157.1 ± 122.8	137.8 ± 83.7	0.322
HbA1c, %	6.3 ± 1.2	6.1 ± 1.3	0.196
WBC, count/μL	7,909 ± 2,568	7,808 ± 2,928	0.603
hsCRP, mg/L	1.85 (0.80–6.13)	1.10 (0.50–6.20)	0.230
Ejection fraction, %	60.1 ± 9.0	62.1 ± 8.3	0.015
ASA use at admission	26 (24.3)	20 (22.0)	0.700
Statin use at admission	27 (25.2)	18 (19.8)	0.361
Total amount of contrast used, mL	278.3 ± 60.6	275.8 ± 61.5	0.812
Culprit vessel			0.070
LAD	53 (49.5)	56 (61.5)
LCx	20 (18.7)	19 (20.9)
RCA	34 (31.8)	16 (17.6)

Values are mean ± SD, n (%), or median (IQR).

ASA = aspirin; CKD = chronic kidney disease; DL = dyslipidemia; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; HbA_1c = glycated hemoglobin; hsCRP = high-sensitivity C-reactive protein; HTN = hypertension; LAD = left anterior descending coronary artery; LCx = left circumflex coronary artery; NSTEMI = non-ST-segment elevation myocardial infarction; RCA = right coronary artery; WBC = white blood cell.

OCT FINDINGS.

The results of optical coherence tomographic analysis are shown in Table 2. The prevalence of lipid-rich plaque, thin-cap fibroatheroma, macrophages, cholesterol crystal, and calcification were higher in plaque rupture compared with plaque erosion. Patients with plaque rupture had thinner fibrous caps and greater lipid burden than those with plaque erosion.

TABLE 2. Culprit-Plaque Optical Coherence Tomographic Findings.

	Culprit Plaque Rupture (n = 107)	Culprit Plaque Erosion (n = 91)	P Value
Lipid-rich plaque	107 (100.0)	58 (63.7)	<0.001
Thinnest FCT, μm	60 (50–70)	110 (82–152)	<0.001
Max lipid arc, ◦	273 (225–337)	231 (173–279)	0.001
Mean lipid arc, ◦	209 ± 47	186 ± 44	0.002
Lipid length, mm	9.3 ± 3.5	7.0 ± 3.0	<0.001
Lipid index	1,979.9 ± 946.1	1,322.8 ± 690.8	<0.001
TCFA	76 (71.0)	10 (11.0)	<0.001
Macrophages	98 (91.6)	61 (67.0)	<0.001
Microvessels	57 (53.3)	52 (57.1)	0.585
Cholesterol crystal	47 (43.9)	21 (23.1)	0.002
Calcification	58 (54.2)	36 (39.6)	0.040
Layered plaque	55 (51.4)	59 (64.8)	0.057
Minimal flow area, mm2	1.14 ± 0.68	1.13 ± 0.86	0.931
Area stenosis, %	82.6 ± 8.6	81.1 ± 10.0	0.260

Values are n (%), median (IQR), or mean ± SD.

FCT = fibrous cap thickness; TCFA = thin-cap fibroatheroma.

PCAT ATTENUATION AT THE CULPRIT PLAQUE LEVEL AND VESSEL LEVEL.

PCAT attenuation in the culprit plaque was significantly higher (more inflammation) in patients with plaque rupture than in those with plaque erosion (Figure 2A). This difference was most pronounced when the LAD was the culprit vessel (Supplemental Figure 2). PCAT attenuation in the culprit lesion (4 mm) was also significantly higher in patients with plaque rupture than in those with plaque erosion (Figure 2B).

FIGURE 2. Differences on PCAT Attenuation Between Plaque Rupture and Plaque Erosion.

Pericoronary adipose tissue (PCAT) attenuation in culprit plaque was significantly higher in patients with plaque rupture than in those with plaque erosion (A). PCAT attenuation at culprit lesion (4 mm) was significantly higher in patients with plaque rupture than those with plaque erosion (B). PCAT attenuation in the culprit vessel was significantly higher in patients with plaque rupture than in those with plaque erosion (C). The mean PCAT attenuation value of all 3 major coronary arteries was higher in patients with plaque rupture than in those with plaque erosion (D). Student’s t-test was applied to obtain P values.

At the culprit vessel level, PCAT attenuation was significantly higher in patients with plaque rupture than in those with plaque erosion (Figure 2C). This difference was also most pronounced when the LAD was the culprit vessel (Supplemental Figure 3). The mean PCAT attenuation of all 3 coronary arteries was also significantly higher in patients with plaque rupture than in those with plaque erosion (Figure 2D).

OCT FEATURES AND PCAT ATTENUATION AT THE CULPRIT PLAQUE.

Features of plaque vulnerability by OCT were compared with PCAT attenuation (Figure 3). Culprit plaques with a lipid-rich phenotype and macrophages had significantly higher PCAT attenuation than those without. Other features of plaque vulnerability, including thin-cap fibroatheroma, microvessels, and a layered phenotype, showed numerically higher but not statistically significant PCAT attenuation values

FIGURE 3. Optical Coherence Tomographic Features and PCAT Attenuation in Culprit Plaque.

Culprit plaques with lipid-rich plaque and macrophages had higher pericoronary adipose tissue (PCAT) attenuation than those without these plaque characteristics. Culprit plaques with thin-cap fibroatheroma (TCFA), microvessels, and layered phenotype also had numerically higher PCAT attenuation than those without these plaque characteristics, although these differences were not statistically significant. Student’s t-test was applied to obtain P values.

UNIVARIABLE AND MULTIVARIABLE ANALYSIS OF PCAT ATTENUATION AND CLINICAL CHARACTERISTICS.

Table 3 shows the univariable and multivariable analyses of PCAT attenuation and clinical characteristics. In all multivariable analyses of PCAT attenuation at the culprit plaque, culprit vessel, and all 3 coronary artery levels, plaque rupture and male sex were associated with high PCAT attenuation values.

TABLE 3. Univariable and Multivariable Analysis of PCAT Attenuation.

	Univariable		Multivariable
	Regression Coefficient b (95% CI)	P Value	Regression Coefficient b (95% CI)	P Value
Culprit plaque PCAT attenuation
Plaque rupture (vs plaque erosion)	3.647 (0.917 to 6.376)	0.009	2.902 (0.319 to 5.484)	0.028
Age	−0.003 (−0.126 to 0.120)	0.961
Male (vs female)	5.960 (1.629 to 10.291)	0.007	5.968 (1.999 to 9.937)	0.003
NSTEMI (vs unstable angina)	4.051 (0.504 to 7.598)	0.025	3.710 (0.548 to 6.871)	0.021
HTN	2.548 (−0.329 to 5.425)	0.083	1.848 (−0.789 to 4.485)	0.170
DL	−1.242 (−3.930 to 1.446)	0.365
DM	0.860 (−1.881 to 3.601)	0.538
CKD	0.507 (−3.072 to 4.091)	0.781
Current smoking	1.480 (−1.193 to 4.153)	0.278
ASA	0.419 (−2.736 to 3.573)	0.795
Statin	−2.048 (−5.116 to 1.019)	0.191
Culprit vessel PCAT attenuation
Plaque rupture (vs plaque erosion)	2.475 (0.327 to 4.623)	0.024	2.429 (0.389 to 4.470)	0.020
Age	−0.011 (−0.095 to 0.074)	0.806
Male (vs female)	6.039 (3.012 to 9.066)	<0.001	6.009 (3.071 to 8.946)	<0.001
NSTEMI (vs unstable angina)	2.078 (−0.631 to 4.788)	0.133
HTN	1.600 (−0.708 to 3.907)	0.174
DL	−1.489 (−3.626 to 0.649)	0.172
DM	1.148 (−1.097 to 3.393)	0.316
CKD	0.187 (−2.838 to 3.211)	0.904
Current smoking	1.338 (−0.811 to 3.488)	0.222
ASA	−0.408 (−3.125 to 2.309)	0.768
Statin	−0.995 (−3.458 to 1.467)	0.428
3-vessel PCAT attenuation
Plaque rupture (vs plaque erosion)	1.978 (0.211 to 3.745)	0.028	1.730 (0.136 to 3.325)	0.033
Age	0.002 (−0.071 to 0.075)	0.953
Male (vs female)	5.742 (3.235 to 8.249)	<0.001	5.531 (3.271 to 7.791)	<0.001
NSTEMI (vs unstable angina)	0.842 (−1.337 to 3.022)	0.449
HTN	2.122 (0.215 to 4.009)	0.029	1.527 (−0.153 to 3.208)	0.075
DL	−1.175 (−2.924 to 0.574)	0.188
DM	1.609 (−0.138 to 3.357)	0.071	1.386 (−0.287 to 3.059)	0.104
CKD	0.221 (−2.239 to 2.681)	0.860
Current smoking	1.031 (−0.728 to 2.790)	0.251
ASA	−0.357 (−2.574 to 1.861)	0.753
Statin	−0.110 (−2.104 to 1.884)	0.914

Abbreviations as in Table 1.

SUBGROUP ANALYSIS (ANALYSIS EXCLUDING THE LCx).

Among 159 patients whose culprit vessel was the LAD or right coronary artery, plaque rupture was observed at the culprit lesion in 87 patients (54.7%) and plaque erosion in 72 patients (45.3%). The results of this subgroup analysis are shown in Supplemental Figure 4. The results were consistent with the results from the overall cohort. Patients with plaque rupture, compared with erosion, had significantly higher PCAT attenuation at the culprit plaque and culprit lesion (4-mm) levels (Supplemental Figures 4A and 4B). PCAT attenuation in the culprit vessel was also significantly higher in patients with plaque rupture than in those with plaque erosion (Supplemental Figure 4C). PCAT attenuation of the nonculprit vessel was not different between plaque rupture and plaque erosion (Supplemental Figure 4D).

SUBGROUP ANALYSIS (DIFFERENCES IN PCAT ATTENUATION BETWEEN PLAQUE RUPTURE AND PLAQUE EROSION IN PATIENTS WHO PRESENTED WITH NSTEMI AND IN PATIENTS WITH UNSTABLE ANGINA PECTORIS).

In patients who presented with NSTEMI, those with plaque rupture showed numerically higher but not statistically significant PCAT attenuation values than those with plaque erosion (culprit plaque level: −65.9 ± 7.8 HU vs −67.5 ± 10.4 HU [P = 0.303]; culprit lesion [4-mm] level: −64.5 ± 8.2 HU vs −66.9 ± 11.5 HU [P = 0.161]; culprit vessel level: −67.4 ± 7.3 HU vs −68.5 ± 7.7 HU [P = 0.371]; mean of 3 coronary arteries: −68.1 ± 5.8 HU vs −69.4 ± 6.7 HU [P = 0.232]). Among patients who presented with unstable angina pectoris, those with plaque rupture showed significantly higher PCAT attenuation values than those with plaque erosion (culprit plaque level: −65.3 ± 6.1 HU vs −73.6 ± 12.4 HU [P = 0.004]; culprit lesion [4-mm] level: −64.7 7.2 HU vs −72.1 ± 14.0 HU [P = 0.023]; culprit vessel level: −65.9 ± 6.3 HU vs −72.1 ± 8.7 HU [P = 0.018]; mean of 3 coronary arteries: −66.7 ± 5.4 HU vs −71.0 ± 7.0 HU [P = 0.041]) (Supplemental Figures 6 and 7).

CLINICAL OUTCOMES.

In this analysis, 166 patients (83.8% of study population) who had 1-year follow-up data were included. During 1-year follow-up, 9 patients had clinical events (3 died, 1 had myocardial infarction, and 6 had TLR [1 patient had TLR after myocardial infarction]). PCAT attenuation in culprit plaque and culprit vessel and the mean PCAT attenuation of all 3 major coronary arteries were not significantly different between patients with and those without clinical events (Supplemental Table 4). The results of other additional analysis are shown in Supplemental Figures 5, 8, and 9.

DISCUSSION

The present study demonstrated that: 1) plaque rupture had a higher level of vascular inflammation measured by PCAT attenuation at the culprit plaque, culprit vessel, and pancoronary levels; and 2) optical coherence tomographic features of plaque vulnerability (lipid-rich plaque and macrophages) were associated with higher PCAT attenuation at the culprit plaque. To the best of our knowledge, this is the first study to compare the underlying mechanism of ACS (plaque rupture and plaque erosion) directly with the level of vascular inflammation using PCAT attenuation (Central Illustration).

CENTRAL ILLUSTRATION. Vascular Inflammation (Plaque Rupture vs Plaque Erosion).

Pericoronary adipose tissue attenuation in culprit plaque, culprit vessel, and all 3 major coronary vessels was significantly higher in patients with plaque rupture than those with plaque erosion. Plaque rupture is more strongly associated with panvascular inflammation, compared with plaque erosion.

VASCULAR INFLAMMATION AND ACS.

Vascular inflammation has been recognized as one of the key factors for atherosclerotic plaque formation and the development of ACS (1). In an early stage of atherosclerosis, apoptotic cells are cleaned by efferocytosis. However, in an advanced stage, efferocytosis becomes defective, which leads to cell necrosis and proinflammatory reactions. Inflammation stimulates a local immune reaction and activates macrophages, mast cells, and T cells to release cytokines, which inhibit collagen synthesis and proteases (such as matrix metalloproteinase), which digest fibrous cap components (21). Previous studies reported the significant association between plasma inflammatory biomarkers (such as hsCRP and interleukin-6) and coronary artery disease burden and cardiovascular events (22–24). In addition, recent studies have revealed that the blockade of inflammatory signals using interleukin-1β inhibitor or interleukin-6 inhibitor led to favorable outcomes (2,3). These studies indicate that vascular inflammation plays a key role in atherogenesis as well as the development of ACS. However, no study has demonstrated a direct link between the level of vascular inflammation and acute plaque destabilization.

PCAT ATTENUATION AND CORONARY ARTERY DISEASE.

Recent studies have demonstrated that PCAT attenuation on CTA is a novel marker of coronary vascular inflammation. Communication between the coronary vascular wall and PCAT is bidirectional. PCAT not only directly modulates signaling pathway in the vascular wall through paracrine and vasocrine action but is also affected by mediators from the diseased vessel (25). The structure of PCAT is changed by inflammatory stimulation from the underlying vessel: inflammation inhibits adipocyte differentiation and intracellular accumulation, resulting in a gradient in adipocyte size and the lipid to aqueous phase (4,5). PCAT attenuation reflects these structural changes in PCAT and can be used to estimate the level of inflammation in the coronary arteries. A recent large study revealed that high vascular inflammation measured by PCAT attenuation was associated with increased cardiac mortality (6). Another study reported that culprit plaques in patients with ACS had higher PCAT attenuation than those in patients with stable angina (7). An association between PCAT attenuation and the progression of nonculprit plaque was also reported (26). Taken together, these studies support a relationship between coronary inflammation measured by PCAT attenuation and coronary artery disease, and PCAT attenuation is being recognized as a promising marker for vascular inflammation and the future risk for cardiovascular events.

DIFFERENCES IN VASCULAR INFLAMMATION BETWEEN PLAQUE RUPTURE AND PLAQUE EROSION.

The present study revealed that ruptured culprit plaque had significantly higher PCAT attenuation than eroded culprit plaque. In addition, the presence of vulnerable plaque features such as a lipid-rich phenotype and macrophages were associated with higher PCAT attenuation in culprit plaque. These results are consistent with previous optical coherence tomographic and pathology studies that demonstrated that ruptured culprit plaques display more inflammatory and vulnerable plaque characteristics (large lipid burden and more macrophage infiltration) compared with eroded plaques (11,18,27,28). Inflammation causes lipid accumulation in the vessel wall, necrotic core formation, and a decrease in fibrous cap thickness. Eventually, a superficial fissure is formed by the mechanical force of blood pressure in the plaque, leading to occlusive thrombus formation (21,29). These data indicate that inflammation plays a crucial role in the pathogenesis of ACS caused by plaque rupture. In contrast, plaque erosion occurs over lesions rich in proteoglycans and smooth muscle cells with a local absence of endothelial cells (8). Although some inflammatory immune reactions are associated with this endothelial denudation process, the level of inflammation may be lower in plaque erosion cases, and inflammatory cell types and mechanisms are different between plaque erosion and plaque rupture (higher concentration of polymorphonuclear granulocytes are observed in eroded plaques, whereas macrophages and monocytes dominate in ruptured plaques) (8,30,31).

In the present study, PCAT attenuation was higher both at the culprit plaque level and the culprit vessel level in patients with plaque rupture than in those with plaque erosion. The likelihood of plaque rupture increases proportionally as PCAT attenuation of the culprit vessel increases (Figure 4). In addition, the mean PCAT attenuation of all 3 coronary arteries was significantly higher in patients with plaque rupture than in those with plaque erosion in the present study. These results indicate that plaque rupture is more strongly associated with panvascular inflammation than plaque erosion. This finding is consistent with a previous 3-vessel optical coherence tomographic study that showed that plaque rupture, compared with erosion, had a higher prevalence of vulnerable plaque features (macrophage accumulation and microvessels) even in nonculprit plaques (32). Interestingly, plasma hsCRP level was not significantly different between plaque rupture and plaque erosion in the present study. This result may imply that PCAT attenuation is more sensitive and specific for detecting coronary vascular inflammation than a systemic inflammatory biomarker.

FIGURE 4. Culprit-Vessel PCAT Attenuation Level and Probability of Plaque Rupture.

Patients were divided into 4 groups on the basis of culprit vessel pericoronary adipose tissue (PCAT) attenuation (−77.9 ± 4.2 HU in the low quartile, −70.8 ± 1.4 HU in the mid-low quartile, −65.8 ± 1.5 HU in the mid-high quartile, and −58.5 ± 4.0 HU in the high quartile). The probability of plaque rupture increased as PCAT attenuation in the culprit vessel increased.

In addition, the difference in PCAT attenuation between plaque rupture and plaque erosion was more obvious in patients with unstable angina pectoris than in those with NSTEMI. This difference in PCAT attenuation between plaque rupture and plaque erosion in patients with unstable angina pectoris could be caused by the low PCAT attenuation value in patients with plaque erosion who presented with unstable angina pectoris. When PCAT attenuation in plaque erosion cases was compared between NSTEMI and unstable angina pectoris, patients with NSTEMI had significantly higher PCAT attenuation values than those with unstable angina at the culprit plaque level (−67.5 HU ± 10.4 vs −73.6 ± 12.4 HU; P = 0.017) and culprit vessel level (−68.5 ± 7.7 HU vs −72.1 ± 8.7 HU; P = 0.049), while PCAT attenuation was not significantly different between patients with NSTEMI and those with unstable angina among patients with plaque rupture (culprit plaque level: −65.9 ± 7.8 HU vs −65.3 ± 6.1 HU [P = 0.748]; culprit vessel level: −67.4 ± 7.3 HU vs −65.9 ± 6.3 HU [P = 0.457]) (Supplemental Figures 10 and 11). These results may imply that in plaque erosion, the level of vascular inflammation might be a contributing factor to myocardial necrosis. Further studies are needed to test this hypothesis.

CLINICAL IMPLICATIONS.

The present study demonstrated that plaque rupture is more strongly associated with culprit plaque and vascular inflammation than plaque erosion. Thus, attention should be paid not only to treat the culprit lesion but also to prevent future events from the nonculprit plaques. Anti-inflammatory therapy may have a particular value in secondary prevention in patients with plaque rupture.

In the present study, the rates of statin and aspirin use were low despite significant risk factors (31.8% and 24.2% in patients with diabetes mellitus, 37.9% and 27.4% in patients with dyslipidemia, 26.2% and 24.6% in patients with hypertension, 21.6% and 24.1% in male patients, respectively). The low rates of statin and aspirin use reflect the practice pattern in Japan. Many Japanese patients are hesitant to take medications for primary prevention, preferring to make changes in diet and exercise. This cultural difference may explain the lower rate of statin use.

STUDY LIMITATIONS.

First, this was a retrospective study that included patients who underwent both CTA and OCT. In the present study, patients underwent CTA first. Thus, it is possible that those patients without significant stenosis on CTA (eg, those with MI with nonobstructive coronary arteries) were not brought to the cardiac catheterization laboratory for coronary angiography and OCT. Therefore, selection bias cannot be excluded.

Second, patients with ST-segment elevation myocardial infarction were not included in this study (33,34). Third, the number of patients included in this analysis was modest. However, it should be noted that this was a mechanistic study and not an outcomes trial.

Finally, all patients were enrolled in Japan. Thus, it is possible that present results may not be generalizable to other populations.

CONCLUSIONS

PCAT attenuation in culprit plaque, culprit vessel, and all 3 major coronary arteries was higher in patients with plaque rupture than in those with plaque. This result indicates that plaque rupture is more strongly associated with pancoronary inflammation compared with plaque erosion.

PERSPECTIVES.

COMPETENCY IN MEDICAL KNOWLEDGE:

Plaque rupture is thought to be related to vascular inflammation, while inflammation appears to play a less significant role in plaque erosion. However, direct comparison between plaque rupture and plaque erosion for the level of vascular inflammation has not been reported. In this study, we investigated the level of coronary vascular inflammation between plaque rupture and plaque erosion using PCAT attenuation on CTA and culprit-lesion OCT. PCAT attenuation in culprit plaque, culprit vessel, and all 3 major coronary arteries was higher in patients with plaque rupture than in those with plaque erosion, indicating that plaque rupture is more strongly associated with pancoronary inflammation compared with plaque erosion.

TRANSLATIONAL OUTLOOK:

A larger study with long-term follow-up is required to evaluate the clinical significance of these findings. Whether anti-inflammatory therapy is particularly effective in patients with high PCAT attenuation needs to be tested in randomized controlled trials.

ABBREVIATIONS AND ACRONYMS

ACS

acute coronary syndrome(s)

CT

computed tomographic

CTA

computed tomographic angiography

hsCRP

high sensitivity C-reactive protein

LAD

left anterior descending coronary artery

LCx

left circumflex coronary artery

NSTE-ACS

non-ST-segment elevation acute coronary syndrome(s)

NSTEMI

non-ST-segment elevation myocardial infarction

OCT

optical coherence tomography

PCAT

pericoronary adipose tissue

TLR

target lesion revascularization