Protruding Aortic Plaque and Coronary Plaque Vulnerability

Abstract

Background

Protruding aortic plaque is known to be associated with an increased risk for future cardiac and cerebrovascular events. However, the relationship between protruding aortic plaque and coronary plaque characteristics has not been systematically investigated.

Methods and Results

A total of 615 patients who underwent computed tomography angiography, and preintervention optical coherence tomography imaging were included. Coronary plaque characteristics were compared to evaluate coronary plaque vulnerability in patients with protruding aortic plaque on computed tomography angiography. 615 patients, the 186 (30.2%) patients with protruding aortic plaque were older and had more comorbidities such as hypertension, chronic kidney disease, and a prior myocardial infarction than those without. They also had a higher prevalence of coronary plaques with vulnerable features such as thin‐cap fibroatheroma (85 [45.7%] versus 120 [28.0%], P<0.001), lipid‐rich plaque (165 [88.7%] versus 346 [80.7%], P=0.014), macrophages (147 [79.0%] versus 294 [68.5%], P=0.008), layered plaque (117 [62.9%] versus 213 [49.7%], P=0.002), and plaque rupture (96 [51.6%] versus 111 [25.9%], P<0.001). Patients with protruding aortic plaque experienced more major adverse cardiac and cerebrovascular events, including all‐cause mortality, nonfatal acute coronary syndromes, and stroke (27 [14.7%] versus 21 [4.9%], P<0.001; 8 [4.3%] versus 1 [0.2%], P<0.001; 5 [2.7%] versus 3 [0.7%], P=0.030; and 5 [2.7%] versus 2 [0.5%], P=0.013, respectively).

Conclusions

The current study demonstrates that patients with protruding aortic plaque have more features of coronary plaque vulnerability and are at increased risk of future adverse events.

Nonstandard Abbreviations and Acronyms

CCS

chronic coronary syndrome

CTA

computed tomography angiography

Clinical Perspective.

What Is New?

• The presence of a protruding aortic plaque, characterized by an irregular and spiculated appearance on computed tomography angiography, is associated with a higher incidence of cardiac and cerebrovascular events in the future.

• The current study demonstrated that patients with protruding aortic plaque had a higher prevalence of vulnerable features in the coronary arteries and higher levels of inflammatory markers.

What Are the Clinical Implications?

• Our study indicates that higher cardiac and cerebrovascular events in patients with protruding aortic plaque are related to higher levels of local vascular and systemic inflammation.

• Since previous studies demonstrated that anti‐inflammatory therapy offered the potential for risk reduction in patients with protruding aortic plaque, higher‐intensity management with anti‐inflammatory drugs might have additional value in patients with protruding aortic plaques.

• Future studies are warranted to investigate the optimal treatment for patients with high panvascular inflammation with protruding aortic plaque and vulnerable plaques in coronary arteries.

Atherosclerosis is a panvascular inflammatory process involving the aorta and coronary arteries. ¹ Disruption and embolization of atheromatous plaque are recognized as one of the major complications of advanced atherosclerosis, which can cause ischemia of organs, leading to acute coronary syndromes (ACS), strokes, or acute limb ischemia. ² , ³ , ⁴ Protruding aortic plaque represents extensive atheromatous disease with diffuse ulcers associated with soft, loosely held debris. ⁵ , ⁶ , ⁷ Previous studies reported that protruding aortic plaque on computed tomography angiography (CTA) showed combinations of vulnerable plaques and intimal/subintimal injuries evaluated by nonobstructive angioscopy. ⁸ , ⁹ Optical coherence tomography (OCT) enables the assessment of detailed coronary plaque characteristics. ¹⁰ However, the relationship between protruding aortic plaque and detailed coronary artery plaque morphology has not been investigated. The aim of the current study was to evaluate the relationship between protruding aortic plaque identified on CTA and detailed coronary plaque characteristics evaluated by OCT.

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 non–ST‐segment–elevation acute coronary syndromes (NSTE‐ACS) (non–ST‐segment–elevation myocardial infarction or unstable angina pectoris) or chronic coronary syndrome (CCS) who underwent both contrast‐enhanced CTA and OCT imaging of the culprit lesion before intervention were selected from the database, Massachusetts General Hospital (MGH) (Massachusetts, USA) and Tsuchiura Kyodo General Hospital (Ibaraki, Japan) Coronary Imaging Collaboration (NCT04523194). Diagnoses of non–ST‐segment–elevation myocardial infarction and unstable angina pectoris were made according to concurrent American Heart Association /American College of Cardiology guidelines. ¹¹ Non–ST‐segment–elevation myocardial infarction was defined as ischemic symptoms in the absence of ST‐segment–elevation on the electrocardiogram with elevated cardiac biomarkers. Unstable angina pectoris was defined as having newly developed or accelerating ischemic symptoms on exertion or rest angina within 2 weeks without biomarker release. CCS was defined as chest pain on exertion without change in frequency, intensity, and duration of symptoms in the previous 4 weeks or a positive stress test. When percutaneous coronary intervention (PCI) was performed, the tightest or most complex lesion on a coronary angiogram or the PCI site was taken as the culprit lesion. In the cases of multivessel PCI, the one with the highest degree of stenosis or with the most complex morphology was considered the culprit lesion.

A total of 291 patients presenting with NSTE‐ACS (230 with non–ST‐segment–elevation myocardial infarction, 61 with unstable angina pectoris) and 360 with CCS underwent both contrast‐enhanced CTA and OCT imaging before coronary intervention between January 2011 and October 2022 (Figure 1). Among patients with NSTE‐ACS, 2 patients were excluded for coronary spasm, 1 for myocardial infarction with nonobstructive coronary arteries, and 1 for spontaneous coronary artery dissection. In addition, 5 patients were excluded for culprit lesions located in the left main coronary artery, 2 for in‐stent restenosis, 3 for no OCT images before PCI, and 1 for poor image quality. Among patients with CCS, 2 patients were excluded for a culprit lesion located in the left main coronary artery, 9 for in‐stent restenosis, 8 for no OCT images before PCI, and 2 for poor image quality. Thus, 276 patients with NSTE‐ACS and 339 patients with CCS were included in the final analysis (Figure 1). The Massachusetts General Hospital and Tsuchiura Kyodo General Hospital Coronary Imaging Collaboration study was approved by the Institutional Review Boards at Massachusetts General Hospital and Tsuchiura Kyodo General Hospital. Written informed consent for enrollment in the Tsuchiura Kyodo General Hospital's institutional database for potential future investigations was provided by all participants. The study protocol conforms to the ethical guidelines of the Declaration of Helsinki.

Figure 1. Study flowchart.

Between January 2011 and October 2022, 291 patients presenting with NSTE‐ACS (230 with NSTEMI, 61 with UAP) and 360 with CCS underwent both CTA and OCT imaging before intervention. Among patients with NSTE‐ACS, 2 patients were excluded for coronary spasm, 1 for myocardial infarction with MINOCA, and 1 for spontaneous coronary artery dissection. In addition, 5 patients were excluded for culprit lesions located in the left main coronary artery, 2 for in‐stent restenosis, 3 for no OCT images before PCI, and 1 for poor image quality. Among patients with CCS, 2 patients were excluded for culprit lesion located in the left main coronary artery, 9 for in‐stent restenosis, 8 for no OCT images before PCI, and 2 for poor image quality. Thus, 276 NSTE‐ACS (91 patients with NSTE‐ACS with protruding aortic plaque and 185 patients with NSTE‐ACS without protruding aortic plaque) and 339 patients with CCS (95 patients with CCS with protruding aortic plaque and 244 patients with CCS without protruding aortic plaque) were included in the final analysis. CCS indicates chronic coronary syndrome; CTA, computed tomography angiography; HR, hazard ratio; LMCA, left main coronary artery; MINOCA, myocardial infarction with nonobstructive coronary arteries; NSTE‐ACS, non–ST‐segment–elevation acute coronary syndromes; NSTEMI, non–ST‐segment–elevation myocardial infarction; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; SCAD, spontaneous coronary artery dissection; and UAP, unstable angina pectoris.

Contrast‐Enhanced CTA Acquisition and Protruding Aortic Plaque 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. ¹² Contrast‐enhanced 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, and field matrix of 512×512, and scan slice thickness of 0.5 mm. Acquisition of CTA 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 units. Images were acquired after a bolus injection of 30 to 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 prospective ECG‐triggering or retrospective ECG‐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. Protruding aortic plaque analysis was performed with RadiAnt DICOM Viewer software (Version 2022.1.1, Medixant, Poland). Protruding aortic plaque on CTA was defined as previously reported: (1) protruding mobile atheroma or thrombi into the aorta and (2) uneven or spiculated thickening of the aortic wall ≥4 mm. ¹³ , ¹⁴ The aorta was divided into 4 anatomic segments: the ascending thoracic aorta, which extends from the sinotubular junction to the innominate artery; the aortic arch, which extends from the innominate to the left subclavian artery; the descending thoracic aorta, which extends from the left subclavian artery to the diaphragm; and the abdominal aorta, which extends from the diaphragm to the level of the aortic bifurcation. ⁷ The intraobserver and interobserver kappa coefficients for protruding aortic plaque were k=1.000 and 1.000, respectively.

OCT Analysis

OCT examination was performed using either a frequency‐domain (C7/C8, OCT Intravascular Imaging System, St. Jude 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 MGH OCT Core Laboratory for analysis and analyzed by independent investigators who were blinded to patients' data, using an offline review workstation (St. Jude Medical). Qualitative and quantitative analyses were defined using previously established criteria ¹⁰ by independent investigators blinded to the clinical, angiographic, and laboratory data.

Data Collection and Follow‐Up

In this study, suspected significant stenosis in nonculprit vessels on angiogram was assessed by fractional flow reserve during the first PCI procedure at the operator's discretion or by scintigram or myocardial perfusion magnetic resonance imaging later if necessary. Additional PCI, either during the same procedure or on a later date, was performed based on these evaluations and documented as a staged PCI. Patients were followed up annually after discharge for up to 5 years, during which all‐cause mortality, nonfatal ACS, stroke, and unplanned ischemia‐driven revascularization were recorded. Unplanned ischemia‐driven revascularization was defined as revascularization (including PCI and coronary artery bypass graft) for documented myocardial ischemia by physiological tests or symptoms during the follow‐up period. Unplanned ischemia‐driven revascularization was further classified into target lesion revascularization, target vessel revascularization, and nontarget vessel revascularization. Target vessel revascularization and nontarget vessel revascularization were defined as the revascularization of a de novo lesion in a culprit or nonculprit vessel, excluding the stent site and 5‐mm segments from its edges. Major adverse cardiovascular and cerebrovascular events (MACCE) were defined as composite end points of all‐cause mortality, nonfatal ACS, stroke, and unplanned ischemia‐driven revascularization.

Statistical Analysis

Statistical analysis was performed with SPSS 28.0 (version 28.0 for Windows; SPSS, Inc., Chicago, IL) and R version 4.0.2 (R Foundation for Statistical Computing). Categorical data are presented as counts and percentages and were compared using the χ² test or Fisher exact test, as appropriate. Continuous variables are shown as mean±SD or median (25th–75th percentiles), as appropriate, depending on the normality of distribution. Between‐group differences in continuous variables were compared using the Student t test or Mann–Whitney U test as appropriate. A P value <0.05 was considered statistically significant. The cumulative incidence rates for MACCE, all‐cause mortality, stroke, and unplanned ischemia‐driven revascularization were estimated using the Kaplan–Meier method and were compared using the log‐rank test. Hazard ratios (HRs) and associated 95% CIs were estimated with a Cox regression model. To verify the proportional hazards assumption, Schoenfeld's residual test was used. The multivariable Cox proportional hazards model was used to evaluate the association between the clinical and morphologic factors and 5‐year MACCE. Patient characteristics that had significant differences between patients with or without protruding aortic plaque were included in univariable analysis, and variables with P values <0.05 were included in multivariable analysis. P values <0.05 of 2‐tail tests were considered significant.

Results

Baseline Patient Characteristics

Baseline characteristics are shown in Table 1. Of 615 patients, 186 (30.2%) had protruding aortic plaque. The patients with protruding aortic plaque, compared with those without, were older (71.0 [64.0–76.0] versus 66.0 [57.0–73.0], P<0.001), had more hypertension (145 [78.0%] versus 290 [67.6%], P=0.012), more chronic kidney disease (66 [35.5%] versus 86 [20.0%], P<0.001), and more prior myocardial infarction (37 [19.9%] versus 53 [12.4%], P=0.015). Angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers, and β‐blockers were more commonly used in patients with protruding aortic plaque compared with those without (144 [77.4%] versus 276 [64.3%], P=0.002, and 120 [64.5%] versus 209 [48.7%], P<0.001, respectively). Patients with protruding aortic plaque had lower levels of estimated glomerular filtration rate (65.1 [56.0–74.9] versus 73.5 [63.3–84.5], P<0.001) and higher levels of high‐sensitivity C‐reactive protein and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) (0.14 mg/dL [0.05–0.41] versus 0.08 mg/dL [0.03–0.25], P=0.005, and 207 pg/mL [89–692] versus 155 pg/mL [67–450], P=0.004, respectively) than those without protruding aortic plaque.

Table 1.

Baseline Patient Characteristics in Patients With or Without Protruding Aortic Plaque

Variables	Overall patients (n=615)		P value
	Patients with protruding aortic plaque n=186 (30.2%)	Patients without protruding aortic plaque n=429 (69.8%)
Age, y	71.0 (64.0–76.0)	66.0 (57.0–73.0)	<0.001
Male	155 (83.3)	345 (80.4)	0.395
BMI, kg/m2	24.3 (22.2–26.7)	24.5 (22.2–26.4)	0.645
Current smoker	48 (25.8)	121 (28.2)	0.221
Hypertension	145 (78.0)	290 (67.6)	0.012
Dyslipidemia	101 (54.3)	248 (57.8)	0.371
Diabetes	87 (46.8)	167 (38.9)	0.079
Chronic kidney disease	66 (35.5)	86 (20.0)	<0.001
NSTE‐ACS
NSTEMI	71 (38.2)	146 (34.0)	0.324
UAP	20 (10.8)	39 (9.1)	0.520
CCS	95 (51.1)	244 (56.9)	0.184
Prior MI	37 (19.9)	53 (12.4)	0.015
Prior PCI	42 (22.6)	73 (17.0)	0.104
Medication
Aspirin	93 (50.0)	192 (44.8)	0.880
DAPT	76 (40.9)	164 (38.2)	0.755
ACE‐I/ARB	144 (77.4)	276 (64.3)	0.002
Statin	104 (55.9)	237 (55.2)	0.942
β‐Blocker	120 (64.5)	209 (48.7)	<0.001
Laboratory data
WBC, count/μL	6270 (5298–8083)	6070 (5040–7875)	0.260
Triglyceride, mg/dL	121 (82–192)	120 (87–179)	0.947
TC, mg/dL	176 (144–199)	177 (148–206)	0.085
LDL, mg/dL	100 (72–122)	99 (76–128)	0.222
HDL, mg/dL	46 (40–57)	49 (41–58)	0.173
HbA1c, %	6.2 (5.7–6.9)	6.0 (5.6–6.8)	0.216
eGFR, mL/min per 1.73 m2	65.1 (56.0–74.9)	73.5 (63.3–84.5)	<0.001
hs‐CRP, mg/dL	0.14 (0.05–0.41)	0.08 (0.03–0.25)	0.005
NT‐proBNP, pg/mL	207 (89–692)	155 (67–450)	0.004
Culprit plaque location			0.092
RCA	55 (29.6)	95 (22.1)
LAD	108 (58.1)	262 (61.1)
LCX	23 (12.4)	72 (16.8)

Values are n (%) or median (25th–75th percentile). ACE‐I indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; CCS, chronic coronary syndrome; DAPT, dual anti‐platelet therapy; eGFR, estimated glomerular filtration rate; HbA1c, hemoglobin A1c; HDL, high‐density lipoprotein; hs‐CRP, high‐sensitivity C‐reactive protein; LAD, left anterior descending artery; LCX, left circumflex artery; LDL, low‐density lipoprotein; MI, myocardial infarction; NSTE‐ACS, non–ST‐segment–elevation acute coronary syndromes; NSTEMI, non–ST‐segment–elevation myocardial infarction; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; PCI, percutaneous coronary intervention; RCA, right coronary artery; TC, total cholesterol; UAP, unstable angina pectoris; and WBC, white blood cell.

OCT Analysis

OCT characteristics are shown in Table 2. Thin‐cap fibroatheroma, defined as a lipid plaque with a minimum fibrous cap thickness <65 μm and a lipid arc >90°, was significantly more frequent in patients with protruding aortic plaque than in those without (85 [45.7%] versus 120 [28.0%], P<0.001) (Table 2 and Figure 2). Lipid‐rich plaque (165 [88.7%] versus 346 [80.7%], P=0.014), macrophage (147 [79.0%] versus 294 [68.5%], P=0.008), layered plaque (117 [62.9%] versus 213 [49.7%], P=0.002), and plaque rupture (96 [51.6%] versus 111 [25.9%], P<0.001) were more frequent in patients with protruding aortic plaque than in those without (Table 2 and Figure 2). As for lipid plaque analysis, patients with protruding aortic plaque had significantly higher mean lipid arc (196±65° versus 185±65°, P=0.040), maximum lipid arc (270° [212–360] versus 240° [173–315], P=0.006), lipid length (10.3 [7.0–15.8] mm versus 8.1 [5.7–12.4] mm, P<0.001), and lipid index (2100 [1197–3108] versus 1517 [951–2552], P<0.001) compared with patients without protruding aortic plaque (Table 2). Tables S1 and S2 include the prevalence of each feature of coronary plaque vulnerability in patients presenting with NSTE‐ACS or CCS, respectively.

Table 2.

OCT Findings in Culprit Plaque in Patients With or Without Protruding Aortic Plaque

Variables	Overall patients (n=615)		P value
	Patients with protruding aortic plaque (n=186, 30.2%)	Patients without protruding aortic plaque (n=429, 69.8%)
TCFA	85 (45.7)	120 (28.0)	<0.001
Lipid‐rich plaque	165 (88.7)	346 (80.7)	0.014
Mean lipid arc, °	196±65	185±65	0.040
Maximum lipid arc, °	270 (212–360)	240 (173–315)	0.006
Lipid length, mm	10.3 (7.0–15.8)	8.1 (5.7–12.4)	<0.001
Lipid index	2100 (1197–3108)	1517 (951–2552)	<0.001
Macrophage	147 (79.0)	294 (68.5)	0.008
Layered plaque	117 (62.9)	213 (49.7)	0.002
Plaque rupture	96 (51.6)	111 (25.9)	<0.001
Microvessels	80 (43.0)	209 (48.7)	0.193
Cholesterol crystal	54 (29.0)	135 (31.5)	0.548
Minimal lumen area, mm2	1.04 (0.86–1.54)	1.04 (0.77–1.36)	0.443

Values are mean±SD, n (%), or median (25th–75th percentile). OCT indicates optical coherence tomography; and TCFA, thin‐cap fibroatheroma.

Figure 2. Prevalence of OCT features of plaque vulnerability in patients with or without protruding aortic plaque.

TCFA, lipid‐rich plaque, macrophages, layered plaque, and plaque rupture were more frequently observed in patients with protruding aortic plaque than in those without protruding aortic plaque. OCT indicates optical coherence tomography; and TCFA, thin‐cap fibroatheroma.

Clinical Outcomes

Clinical follow‐up was obtained in 610 patients (99.2%). During 716 (389–1592) days of the median follow‐up period, 48 patients (7.9%) developed MACCE (all‐cause mortality [5 patients: 0.8%], nonfatal ACS [8 patients: 1.3%], stroke [7 patients: 1.1%], and unplanned ischemia‐driven revascularization [28 patients: 4.6%]) (Table 3). The 5‐year cumulative incidence rate for MACCE was higher in patients with protruding aortic plaque than in those without (HR, 3.29 [95% CI, 1.86–5.83]; P<0.001) (Figure 3A). The Schoenfeld's residual test demonstrated that there was no significant trend (P=0.301). Furthermore, the 5‐year cumulative incidence rates for all‐cause mortality, nonfatal ACS, and stroke were also higher in patients with protruding aortic plaque than those without (HR, 20.07 [95% CI, 2.51–160.53], P<0.001), HR, 4.29 [95% CI, 1.02–17.95], P=0.030), and HR, 6.19 [95% CI, 1.20–31.93, P=0.013], respectively) (Figure 3B through 3D, and Table S3). In patients with protruding aortic plaque, 2 patients developed a stroke and subsequently died, and 1 patient experienced nonfatal ACS and subsequently died. In patients without protruding aortic plaque, 1 patient underwent target vessel revascularization and subsequently died. Therefore, in these patients, the first event was counted for MACCE (Table 3). In addition, the relationship between the location of protruding aortic plaques and clinical outcomes was investigated; there were no significant relationships between the location of protruding aortic plaques and 5‐year MACCE (Table S4). Comparing the relationship between differences in aortic assessment range on CT and clinical outcomes, there were no significant differences between aortic assessment ranges on 5‐year MACCE (Table S5). The univariable and multivariable analyses of patient characteristics and 5‐year MACCE are shown in Table S6. In multivariable analyses, protruding aortic plaque and NSTE‐ACS were significantly associated with 5‐year MACCE (P<0.001 and P=0.003, respectively). The highest HR was influenced by protruding aortic plaque (HR, 3.110 [1.733–5.581]), followed by NSTE‐ACS (2.157 [1.174–3.964]). The results when each event was counted as a separate event are shown in Table S3. The 5‐year cumulative incidence rates for unplanned ischemia‐driven revascularization did not have a significant difference in 2 groups but tended to be higher in patients with protruding aortic plaque compared with those without (HR, 1.86 [95% CI, 0.88–3.93], P=0.099) (Figure 3E and Table S3). Details of unplanned ischemia‐driven revascularization are shown in the Table S7.

Table 3.

MACCE in Patients With or Without Protruding Aortic Plaque

Events	MACCE in patients with protruding aortic plaque (n=184)	MACCE in patients without protruding aortic plaque (n=426)	Patients with protruding aortic plaque versus those without protruding aortic plaque
			HR (95% CI)	P value
MACCE	27 (14.7)	21 (4.9)	3.29 (1.86–5.83)	<0.001
Details of MACCE
All‐cause mortality	5 (2.7)	0 (0.0)
Nonfatal ACS	5 (2.7)	3 (0.7)
Stroke	5 (2.7)	2 (0.5)
Unplanned ischemia‐driven revascularization	12 (6.5)	16 (3.8)

Values are n (%) and HR (95% CI). HR is obtained from univariable Cox proportional hazards regression. ACS indicates acute coronary syndromes; HR, hazard ratio; and MACCE, major adverse cardiovascular and cerebrovascular events.

Figure 3. Five‐year cumulative incidence for MACCE, all‐cause mortality, nonfatal ACS, stroke, or unplanned ischemia‐driven revascularization in patients with or without protruding aortic plaque.

Cumulative incidence of MACCE (A) was defined as a composite end point of all‐cause mortality (B), nonfatal ACS (C), stroke (D), and unplanned ischemia‐driven revascularization (E). ACS indicates acute coronary syndromes; and MACCE, major adverse cardiovascular and cerebrovascular events.

Discussion

The current study demonstrated that patients with protruding aortic plaque, compared with those without, had (1) more frequent comorbid conditions; (2) a higher prevalence of plaques with vulnerable features in the coronary arteries; and (3) higher cumulative incidence of cardiac and cerebrovascular events.

Previous studies have shown that severely protruding atherosclerotic aortic plaque with an irregular and spiculated appearance on CTA, commonly called shaggy aorta, was considered one of the significant risk factors for both spontaneous (0.79%–4.5%) and procedural embolization. ¹⁵ , ¹⁶ Protruding aortic plaque is most often seen in the elderly ¹⁷ and in patients with hypertension, ¹⁸ in addition to those with chronic kidney disease, which might be related to chronic renal infarction. ¹⁹ Several studies have shown that up to 90% of patients with transcatheter aortic valve implantation have ischemic brain lesions on diffusion‐weighted magnetic resonance imaging. ²⁰ , ²¹ Recent angioscopy studies reported various combinations of vulnerable features and intimal/subintimal injuries at protruding aortic plaques. ⁸ , ²² Although vulnerability inside of the protruding aortic plaque had been reported using fluorine 19 (¹⁹F) magnetic resonance imaging and ¹⁸F‐fluoromisonidazole positron emission tomography, ²³ , ²⁴ to the best of our knowledge, this is the first detailed report that evaluated the relationship between protruding aortic plaque and coronary plaque vulnerability. OCT images from a representative case with protruding aortic plaque and vulnerable coronary plaque features such as thin‐cap fibroatheroma, lipid‐rich plaque, layered plaque, and plaque rupture are shown in Figure 4.

Figure 4. Representative case of patient with protruding aortic plaque.

A, Curved reformatted CTA image of the aorta. It shows protruding aortic plaques (B and C) and a flap detected at the level of the diaphragm (D). B, Axial CTA image with protruding plaque as low‐density at the level of the aortic arch. C, Axial CTA image with eccentric plaques at the level of the descending aorta. D, Axial CTA image with eccentric plaques with flaps at the level of the thoracoabdominal aorta. E, OCT image of plaque rupture. Plaque rupture is characterized by the presence of fibrous cap discontinuity with a cavity formation (asterisk) within the plaque. F, OCT image of TCFA. TCFA is a lipid‐rich plaque in which the minimum thickness of the fibrous cap (arrows) is <65 μm, and the lipid occupies >90° in circumference. G, OCT image of layered plaque. The double‐headed arrow indicates a layer of different optical densities. CTA indicates computed tomography angiography; OCT, optical coherence tomography; and TCFA, thin‐cap fibroatheroma.

Protruding aortic plaque is 1 aspect of the myriad complex metabolic, anatomic, and clinical abnormalities found in patients with atherosclerosis. It is frequently associated with carotid, renal, coronary, and peripheral vascular disease, as well as with abdominal aortic aneurysms. ²⁵ Several studies reported that inflammation plays a major role in aortic wall remodeling, protruding aortic plaque, and aortic dilatation. ²⁶ Protruding aortic plaque is related to reduced differentiation of adipocytes, increased inflammatory cytokine production, and downregulated anti‐inflammatory adipokines ²³ and is associated with higher levels of local and systemic inflammation. ²⁷

In the current study, patients with protruding aortic plaque, compared with those without, were older and more frequently had hypertension, chronic kidney disease, and prior myocardial infarction, which is in line with previous reports. ¹⁷ , ¹⁸ , ¹⁹ , ²⁸ Furthermore, patients with protruding aortic plaque had higher levels of high‐sensitivity C‐reactive protein and NT‐proBNP, more coronary plaque vulnerability, and experienced more major adverse cardiac and cerebrovascular events. A previous study reported that BNP was strongly associated with pan‐vascular inflammation and atherosclerosis, even in the absence of heart failure. ²⁹ Higher levels of high‐sensitivity C‐reactive protein and NT‐proBNP in patients with protruding aortic plaque are probably related to a high level of systemic inflammation. Our study demonstrated that patients with protruding aortic plaque, compared with those without, also had a higher level of coronary plaque vulnerability. ³⁰ A combination of elevated systemic and local plaque inflammation was probably related to a higher incidence of major cardiac and cerebrovascular events. The presence of aortic atheroma has been significantly associated with all‐cause mortality and stroke. ³¹ In our study, patients with protruding aortic plaque had higher MACCE (P<0.001), all‐cause mortality (P<0.001), and stroke (P=0.013), as well as nonfatal ACS (P=0.030), compared with those without. These findings indicate that patients with protruding aortic plaque had higher levels of vulnerability both in the coronary and cerebral arteries.

Currently, CTA, combined with myocardial perfusion or fractional flow reserve CT, allows the identification of hemodynamically significant coronary artery disease. ³² However, the significance of plaque morphology evaluated by CTA has not been systematically investigated. The results of this study indicate that protruding aortic plaques identified by CTA, which can be performed simultaneously with coronary CTA, can help to identify patients with high levels of pan‐vascular inflammation and hence, at higher risk for cardiac and cerebrovascular events in the future. Furthermore, previous studies demonstrated that anti‐inflammatory agents, such as statins, offered the potential for risk reduction in patients with protruding aortic plaque. ³¹ , ³³ In addition, colchicine has recently been demonstrated to reduce acute myocardial infarction, ischemic stroke, coronary revascularization, and cardiac death by reducing residual inflammatory risk. ³⁴ Thus, anti‐inflammatory agents, such as canakinumab and colchicine, in addition to statins, might have additional value in patients with protruding aortic plaques, in which there is a high level of pan‐vascular inflammation.

Limitations

Several limitations should be acknowledged. First, this was a retrospective analysis of patients who underwent both CTA and OCT. Therefore, selection bias cannot be excluded, because patients without significant coronary artery disease on CTA might have been excluded from invasive procedures, including intracoronary OCT. Second, this study did not include patients with ST‐segment elevation myocardial infarction. Third, laboratory data on inflammatory markers other than high‐sensitivity C‐reactive protein and NT‐proBNP were not available. Fourth, in the current study, patients primarily underwent CTA of the thoracic to the abdominal aorta, and the entire aorta was not visualized. Since previous studies have reported that spontaneous ruptured aortic plaques are often distributed in infrarenal and suprarenal abdominal aortas, the possibility cannot be excluded that protruding aortic plaque was potentially underdetected in the current study. Fifth, since CTA was the imaging modality to identify protruding aortic plaque in the current study, it was not possible to assess the detailed characteristics of those plaques, such as plaque rupture, erosion, and vulnerabilities. Sixth, in several cases, we could not analyze coronary CTA images due to their poor image quality. Finally, all enrolled patients were from Japan. Thus, these results might not apply to populations with different ethnic backgrounds.

Conclusions

The current study demonstrated that patients with protruding aortic plaque had more frequent comorbid conditions, had more vulnerable features in the coronary arteries, and experienced more major adverse cardiac and cerebrovascular events than those without protruding aortic plaque. These results suggest that patients with protruding aortic plaque have a higher level of pan‐vascular inflammation and are at higher risk for cardiovascular events in the future.

Sources of Funding

Dr Jang's research has been supported by Mrs Gillian Gray through the Allan Gray Fellowship Fund in Cardiology and by Mukesh and Priti Chatter through the Chatter Foundation.

Disclosures

Dr Jang has received educational grant support from Abbott Vascular. The remaining authors have no disclosures to report.

Supporting information

Tables S1–S7