Clinical Significance of the Presence or Absence of Lipid‐Rich Plaque Underneath Intact Fibrous Cap Plaque in Acute Coronary Syndrome

Introduction

In the past decade, the clinical outcomes of patients with acute coronary syndrome (ACS) have dramatically improved because of the development of pharmacological and interventional therapies. Nevertheless, ACS remains one of the main causes of death globally. Pathological studies have proposed 3 major mechanisms of coronary thrombosis causing ACS, including plaque rupture (PR), plaque erosion, and calcified nodule, of which PR is the most common phenotype.¹, ² Although culprit plaques without evident PR (those with erosion or calcified nodules) account for approximately one third of ACS,³, ⁴ their prevalence has been underestimated in clinical practice because of the limited ability of imaging modalities to identify these phenotypes, particularly in vivo. With the use of high‐resolution images from optical coherence tomography (OCT), previous studies proposed an OCT definition of plaque erosion that is characterized by thrombosis overlying a plaque with intact fibrous cap (IFC). It has been reported that ACS caused by plaques with PR and IFC showed different morphological characteristics at both the culprit plaque and nonculprit plaques⁵; these plaques also yielded different clinical courses.⁶, ⁷ A large lipid component, represented by a necrotic core, is one of the most important factors of vulnerable plaque, which is considered a precursor of coronary thrombosis.¹, ⁸, ⁹ The existence of a necrotic core is essential for the onset of PR, followed by coronary thrombosis per the pathological definition of PR. However, plaque erosion may occur on the surface of the plaques, irrespective of the presence of a necrotic core,⁶, ¹⁰ and little is known about the prevalence of the lipid component beneath plaque erosion and its impact on clinical outcomes. OCT enables the identification of plaque underlying coronary thrombosis, including lipid‐rich plaque (LRP), which corresponds to a necrotic core or lipid pooling in histological analysis.¹¹ The aim of this study was to investigate the prevalence and clinical significance of LRP in patients with IFC who underwent percutaneous coronary intervention (PCI) and OCT evaluation of the culprit plaque.

Methods

The data that support the findings of this study are available from the corresponding author on reasonable request.

Study Population

The institutional database of intravascular OCT examinations performed at Tsuchiura Kyodo General Hospital (Ibaraki, Japan), between November 2008 and May 2017 (n=3192), was retrospectively queried to identify patients of interest who met the following inclusion criteria: patients who underwent primary/urgent PCI for ACS and those with a consent for OCT examination of the culprit lesion during PCI and future data use and follow‐up for the analysis. The culprit lesion was identified on the basis of coronary angiogram, ECG, or echocardiogram. Exclusion criteria were as follows: lesions requiring balloon angioplasty before OCT imaging; in‐stent thrombosis, restenosis lesions, and bypass graft lesions; poor OCT image quality; patients with delayed presentation of >12 hours after onset; and patients in whom the culprit lesion could not be identified. Thus, the OCT images of 579 culprit lesions in 579 patients with ACS were analyzed in the present study (Figure 1).

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Institutional exclusion criteria for OCT imaging in patients with ACS were cardiogenic shock, congestive heart failure, significant left main coronary artery disease, and suboptimal results after thrombectomy with TIMI (Thrombolysis in Myocardial Infarction) 0 to 2 flow. ST‐segment–elevation myocardial infarction was defined as follows: continuous chest pain that lasted >30 minutes, arrival at the hospital within 12 hours from the onset of symptoms, ST‐segment elevation >0.1 mV in >2 contiguous leads or new left bundle‐branch block on a 12‐lead ECG, and elevated cardiac markers. Non–ST‐segment–elevation myocardial infarction was defined as ischemic symptoms in the absence of ST‐segment elevation on ECG with elevated cardiac markers. Unstable angina was defined as angina at rest or one episode lasting >20 minutes during the preceding 48 hours and normal levels of cardiac markers. The primary outcome measure was major adverse cardiac events (MACEs), which is defined as a composite of cardiac death, acute myocardial infarction, and ischemia‐driven remote revascularization (>3 months from the index PCI). Scheduled revascularization for nonculprit lesions that were identified in index coronary angiograms was not considered as a MACE. Device‐oriented composite end point was defined as a composite of cardiac death, target‐vessel myocardial infarction, and ischemia‐driven target lesion remote revascularization.

This study was approved by the local ethics committee and conformed to the Declaration of Helsinki statement on research involving human subjects. Informed consent for registration into the institutional OCT database and potential future analysis of data were provided by all participants after thorough explanation of the protocol and potential risks related to imaging before catheterization.

OCT Image Acquisition and Analysis

OCT images were acquired before PCI procedures for lesions showing TIMI 3 flow without suspected angiographic thrombi and evaluated (Data S1). PR was defined as a plaque showing disruption of the fibrous cap with or without cavity formation. IFC was defined as a plaque where the fibrous cap of the culprit lesion was intact. Lipid was characterized as a diffusely bordered, signal‐poor region underlying a signal‐rich band that corresponded to the fibrous cap. For plaques with lipid, lipid length and arc were measured on the longitudinal reconstructed view or cross‐sectional image by an independent investigator (E.U.). LRP was defined as a plaque with lipid having the maximal lipid arc (>90°) and lipid length (>1 mm). In addition, thrombus length, maximal arc of the thrombus, and thrombus volume were measured according to the previous studies.¹² In brief, for the measurements of thrombus, OCT images were analyzed at 0.2‐mm intervals. Thrombus area was traced by planimetry in frames with clear visualization of the vessel contours >270°; otherwise, thrombus area was calculated by subtracting residual lumen area from the vessel contour area extrapolated from the nearest visible frames. Thrombus length was calculated by the number of frames with OCT thrombus multiplied by frame interval (0.2 mm). Thrombus arc was measured from the center of the residual lumen, and the maximum value was obtained as the maximum thrombus arc. Lesions with massive thrombus or calcified nodules were excluded from further analysis because plaque morphological characteristics could not be identified in those with massive thrombus, and the pathological nature of calcified nodules is different from that of LRP. Thereafter, culprit lesions were divided into 3 categories, according to the OCT findings: lesions with PR (PR group), IFC with LRP (IFC‐LRP group), and IFC without LRP (IFC–non‐LRP group) (Figure 2).

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Angiography Analysis

Baseline coronary angiograms obtained before OCT image acquisition or interventional procedures were analyzed with offline software (QAngio XA 7.3; Medis, Leiden, the Netherlands). Angiographic lesion morphological characteristics were classified according to the American Heart Association/American College of Cardiology lesion classification.¹³

Statistical Analysis

Categorical values are presented as counts and proportions, and comparisons between groups were performed using the χ² test or Fisher's exact test, depending on the data. Continuous values, showing a normal distribution, are expressed as mean±SD; and Student t test was performed to compare the values among groups. Nonnormally distributed, continuous values are expressed as median (25th–75th percentile), and the Mann‐Whitney U test was used to compare between the groups. The Kruskal‐Wallis test was performed to compare continuous variables among the 3 groups; post hoc comparisons were performed using pairwise comparisons between groups. Intraobserver and interobserver variabilities for categorical OCT variables were estimated using the κ coefficient. Survival curves using the Kaplan‐Meier methods were produced for the presence of PR, LRP, or massive thrombus as the culprit lesion; and they were compared using the log‐rank test. The predictors of MACEs were determined using the Cox proportional hazards regression model. The covariates used in multivariate analysis were selected using the criterion of P<0.20 in the univariate analysis. The proportional hazards assumption was checked using statistical tests and graphical diagnostics based on the scaled Schoenfeld residuals. A collinearity index was used for checking linear combinations among covariates, and the Akaike information criterion was used for avoiding overfitting. All statistical analyses were performed with SPSS 18.0 (SPSS Inc, Chicago, IL) and R, version 3.0.2 (The R Foundation for Statistical Computing, Vienna, Austria). P<0.05 was considered statistically significant.

Results

Patient Characteristics and Angiographic and Procedural Findings

Of 579 culprit lesions of ACS analyzed in the present study, underlying plaque morphological characteristics could not be categorized via OCT in 69 lesions because of massive thrombus (n=45), calcified nodule (n=21), or spontaneous coronary dissection (n=3). After excluding these lesions, 510 culprit lesions of ACS were included in the final analysis. In the subsequent OCT analysis, 328 lesions (64.3%) were categorized into the PR group, 122 lesions (23.9%) were categorized into the IFC‐LRP group, and 60 lesions (11.8%) were categorized into the IFC–non‐LRP group (Figure 1). Clinical characteristics of the PR, IFC‐LRP, and IFC–non‐LRP groups are summarized in Table 1. Angiographic and procedural data are summarized in Table 2.

OCT Findings

OCT findings were compared among the 3 groups (Table 3). Compared with IFC‐LRP, lesions with PR had significantly thinner fibrous caps, more frequent thin‐cap fibroatheroma, longer lipid length, and greater maximum lipid arc at the culprit lesion. Culprit lesions with PR had significantly greater volume of OCT‐defined thrombus than those with IFC‐LRP or IFC–non‐LRP. The intraobserver and interobserver κ values for the qualitative assessments of PR were 0.89 and 0.87, respectively; for LRP assessment, they were 0.88 and 0.85, respectively.

Follow‐Up Data

During a median follow‐up duration of 621 days (range, 415–1589 days), 85 patients (16.7%) experienced MACEs. The numbers of adverse events are summarized in Table 4, and the comparison of patient characteristics between those with and without MACEs is summarized in Table S1. Second‐generation, drug‐eluting stents were used less frequently in patients with MACEs than in those without. American Heart Association/American College of Cardiology type B2/C lesions, LRP via OCT, and thin‐cap fibroatheroma via OCT were more frequently observed in patients with MACEs than in those without MACEs. Kaplan‐Meier analysis revealed that MACE‐free survival rate was significantly higher in the IFC group, which combined the IFC‐LRP and IFC–non‐LRP groups, than in the PR group (P=0.005) (Figure 3A). When we stratified patients according to the existence of LRP in the OCT image of the culprit lesion, MACE‐free survival rate was significantly worse in patients with LRP than in those without LRP (P=0.005) (Figure 3B). Moreover, in patients with a culprit lesion with IFC, a significantly higher MACE‐free survival rate was observed in the IFC–non‐LRP group compared with the IFC‐LRP group (P=0.037) (Figure 4A), and a significantly lower device‐oriented composite end point rate was observed in the IFC–non‐LRP group compared with the IFC‐LRP group (P=0.047) (Figure 4B). The incidence of MACEs was significantly higher in association with the increase in the quadrant of maximal lipid arc in patients with IFC (Figure 5).

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The multivariate Cox proportional hazard analysis demonstrated that culprit lesion morphological characteristics of IFC–non‐LRP on OCT, use of second‐generation drug‐eluting stents, estimated glomerular filtration rate, and culprit lesion with American Heart Association/American College of Cardiology type B2/C were independent predictors of MACEs (Table 5). In this model, no violation of proportional hazard over time was detected. MACE‐free survival rate was significantly preferable in patients with IFC‐LRP than in those with IFC‐LRP and IFC–non‐LRP (Figure 6A). Moreover, patients with massive thrombus were associated with poor prognosis, similarly to the patients with PR (Figure 6B).

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Discussion

To the best of our knowledge, this is the first study demonstrating the prognostic significance of LRP in culprit lesions with IFC defined via OCT. Major findings of the present study were as follows: (1) the vast majority of culprit lesions with PR exhibited LRP using OCT, whereas approximately one third of the lesions with IFC did not show LRP; (2) MACE‐free survival rate was significantly worse in patients with PR than in those with IFC; (3) MACE‐free survival rate was significantly worse in patients with LRP in culprit lesions compared with those without LRP; and (4) MACE‐free survival was significantly preferable in patients with IFC showing no LRP than in those with IFC with LRP.

Differing Clinical Courses Based on Different Morphological Plaque Characteristics

Previous OCT studies demonstrated that the patients with ACS exhibiting IFC in the culprit lesions showed preferable clinical outcomes after PCI compared with those with PR.⁶, ⁷ Niccoli et al investigated 139 patients with ACS, in whom the culprit lesions were categorized into PR (n=82) and IFC (n=57).⁶ The researchers reported that MACE was significantly more frequent in patients with PR, which is consistent with the present study. In our previous OCT study comprising 318 patients with ACS (141 patients with PR and 131 patients with IFC), we showed a lower rate of clinical cardiac events in patients with IFC than in those with PR.⁷ In both previous studies,⁶, ⁷ each adverse event besides target vessel revascularization showed a nonsignificant trend toward a higher incidence in patients with PR, which potentially indicates greater atheromatous burden not only in the culprit vessels, but also in nonculprit vessels of patients with PR compared with those with IFC. In fact, previous OCT and computed tomography studies showed that patients with ACS with concurrent PR in the culprit lesion exhibited vulnerable plaque morphological characteristics in nonculprit lesions or nonculprit vessels.¹⁴, ¹⁵, ¹⁶ In the present study, macrophage infiltration was significantly less in the IFC group without lipid than in the other 2 groups. Macrophage degradation of fibrous cap is an important contributor to atherosclerotic plaque instability. Previous reports showed a significantly higher macrophage density at the rupture site and LRP site.¹⁷ Moreover, macrophage was associated with arterial wall lipid deposition contributing to inflammatory processes.¹⁸ Previous reports also showed more macrophage volume suggested the extent of initial coronary plaque inflammation and had a possible role for the recurrence of angina after PCI.¹⁹, ²⁰ Therefore, our finding that macrophage infiltration was significantly less in the IFC–non‐LRP group than in the other 2 groups in patients with ACS might be linked with better prognosis after PCI.

Clinical Implications of LRP

Vulnerable plaque, which is generally defined as a plaque prone to rupture, is associated with a large necrotic core and thin fibrous cap, modified by inflammatory activities within the plaque.¹, ²¹ Therefore, plaque with a large lipid component is considered a precursor of cardiac events, which was elucidated in recent studies using intracoronary imaging modalities.⁸, ⁹, ²², ²³ The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study,²² in which patients presenting with ACS underwent 3‐vessel virtual histological intravascular ultrasound after successful PCI, demonstrated that thin‐cap fibroatheroma in nonculprit lesions, indicated via virtual histological intravascular ultrasound, was associated with future cardiac events. On the other hand, a subgroup analysis from the PROSPECT study showed that lesions without fibroatheroma were clinically stable and were rarely associated with clinical events during 3 years of follow‐up.²⁴ Conversely, Xing et al showed that in patients with LRP, identified via OCT at the nonculprit region of the coronary artery, LRP was associated with a higher MACE rate in comparison to those without LRP.⁸ In the present study, patients exhibiting LRP using OCT in the culprit lesion showed worse clinical outcomes compared with those without LRP (Figure 3B), which might be plausible considering the impact of LRP on future coronary events and the association between culprit lesion morphological characteristics and nonculprit lesion morphological characteristics.⁸, ¹⁴, ¹⁵ Moreover, in the present study, even if we selected the patients with plaques with IFC in the culprit lesions, the presence of LRP in the culprit lesion was associated with worse clinical outcomes in terms of composite adverse events (Figure 4A), which is primarily driven by revascularization for recurrent ischemia (Figure 4B).

Study Limitations

First, this study was a retrospective, observational study at a single center; therefore, selection bias may have influenced the results and the results may not be generalizable. Second, because of the wide range of the study period, adherence to optimal medical therapy was not excellent in the early period of the study. Third, the final decision to perform OCT examination was at the operator's discretion. Furthermore, as shown in the Methods section, OCT was not performed in patients with cardiogenic shock, congestive heart failure, significant left main disease, and TIMI 0 to 2 flow after thrombectomy because of safety concerns, which may have led to selection bias. Fourth, ACS with calcified nodules was excluded from the analysis to avoid confusion about the definition of IFC. Fifth, the presence of thrombus overlying the culprit lesion might have reduced the accuracy to assess the underlying plaque characteristics by OCT. Finally, because the identification of small PR in the thrombotic event is often difficult, PR might have been misdiagnosed as IFC in certain cases. This is an important limitation of OCT‐derived plaque categorization.

Conclusions

In patients with culprit lesions with IFC, the presence of LRP via OCT was significantly associated with an increased risk for future MACEs compared with those with IFC without LRP, which is primarily driven by revascularization for recurrent ischemia. Classification of culprit plaque morphological characteristics via OCT for both the presence or absence of PR and the underlying presence of LRP underneath IFC may be useful to stratify the risk for subsequent adverse events.

Disclosures

None.

Footnotes