Highlights
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Layered plaque, an optical coherence tomography equivalent of healed plaque, has been gaining attention.
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Burden of plaque layer in relation to layered plaque characteristics was evaluated.
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Layer index was used to assess layer burden.
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Some characteristics are significantly associated with large layer burden.
Recently, layered plaque, an optical coherence tomography equivalent of healed plaque, has been gaining attention. However, detailed layered plaque characteristics including the burden of plaque layer have not been investigated. Patients with acute coronary syndromes who underwent preintervention optical coherence tomography imaging of culprit lesion were included. Layer index, a product of the mean layer arc and layer length, was correlated with the pattern of layer and culprit pathology. In addition, layer index was compared between culprit and nonculprit plaques. Finally, predictors for greater layer index were identified using general linear modeling. In 349 patients, 99 culprit plaques had layered phenotype (28.4%), whereas among 465 nonculprit plaques, 165 had layered pattern (35.5%). Layer index was greater in multilayer pattern versus single-layer pattern (1,688.5 vs 996.6, p <0.001), interrupted layer phenotype versus intact layer phenotype (1,276.5 vs 646.8, p <0.001), rupture versus erosion at culprit lesion (1,191.0 vs 861.8, p <0.001), and culprit versus nonculprit plaque (1,475.6 vs 983.4, p <0.001). The general linear modeling revealed that multilayer pattern (regression coefficient b [B] 7.332, p <0.001), interrupted layer phenotype (B 4.624, p <0.001), culprit lesion (B 2.792, p = 0.001), lipid-rich plaque (B 1.953, p = 0.032), and culprit plaque rupture (B: 1.943, p = 0.008) were the significant predictors for greater layer index. In conclusion, layer index (burden of layered plaque) was greater in multilayer pattern, interrupted layer phenotype, at culprit plaque, lipid-rich plaque, and in cases with culprit plaque rupture.
Layered plaque, a signature of previous plaque destabilization and healing, has become a focus of intense research during the past several years as its biologic implication differs depending on clinical presentations. Layered plaque has features of vulnerability both at culprit and nonculprit sites. , The prevalence of layered plaque differs depending on clinical presentation: higher prevalence of layered plaques in patients with stable angina compared with those with acute coronary syndromes (ACSs). These findings indicate that layered plaque formation depends on the balance between local and systemic thrombogenicity and endogenous antithrombotic mechanisms. However, detailed characteristics of layered plaques including burden of plaque layer has not been fully investigated. The present study was conducted to evaluate the morphologic details of layered plaques and to identify the predictors for greater burden of layered plaque using optical coherence tomography (OCT).
Methods
Patients were selected from the Massachusetts General Hospital OCT Registry (NCT01110538) and the EROSION (effective antithrombotic therapy without stenting: intravascular OCT-based management in plaque erosion) study databases (NCT02041650). A total of 349 patients with ACS who had preintervention OCT imaging and complete data including analyzable OCT were included ( Supplementary Figure 1 ). , The definition of clinical presentation and other methods are described in Supplementary Materials . The method for coronary angiographic analysis is described in the Supplementary Materials .
OCT imaging was performed using a frequency-domain (C7/C8, OCT Intravascular Imaging System, St. Jude Medical, St. Paul, Minnesota) OCT system. Aspiration thrombectomy was allowed before OCT imaging in patients with thrombolysis in myocardial infarction flow grade <2 and/or occlusive thrombus. Predilation with a balloon was not allowed. All OCT images were submitted to the Massachusetts General Hospital OCT Core Laboratory for offline analysis. OCT image analysis was performed using an offline review workstation (Ilumien Optis, St. Jude Medical) by independent investigators who were blinded to the clinical, angiographic, and laboratory data. Layered plaques were identified as plaques presenting ≥1 layers of different optical densities and a clear demarcation from underlying components in ≥3 consecutive frames. , , Given the lack of established criteria for the quantification of plaque layer, the angular extension and length of plaque layer were measured to obtain a “layer arc” and a “layer length” to determine the extent of plaque layer. Layer arc was measured at 1-mm intervals. The layer index was defined as mean layer arc × layer length ( Figure 1 ). Layered plaques were classified into 3 groups based on the maximum layer arc: focal type (maximum layer arc less than 180°), intermediate type (maximum layer arc >180° and <360°), and circumferential type (maximum layer arc of 360°) ( Figure 2 ). In addition, according to the number of identifiable layers, layered plaques were classified as single- or multilayered pattern ( Figure 2 ). Furthermore, layered plaques were classified into 2 types based on the shape of layer demarcation: interrupted layer pattern, when a borderline of layer was blurred or broken on ≥1 cross-sectional OCT images; intact layer pattern, when entire demarcation was clearly visible in all cross-sectional OCT images with layer ( Figure 2 ). In the culprit lesion, underlying mechanism of current ACS event was categorized into plaque rupture or plaque erosion using previously established OCT criteria. Additional plaque analysis was performed according to the previously established criteria as described in the Supplementary Materials . Good intraobserver and interobserver agreement was noted in the classification of layer circumferential extension type (focal pattern, intermediate type, or circumferential type) (κ 0.91 and 0.82, respectively), single- or multilayer pattern (κ 0.86 and 0.81), and layer pattern (intact or interrupted) (κ 0.89 and 0.82).
Categoric data are presented as counts and percentages and are compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous data are presented as mean ± SD or median (25th to 75th percentile), as appropriate, depending on the normality of distribution. Between-group differences in continuous variables were compared using the t test or Mann–Whitney U test, as appropriate. A general linear model with multiple predictor variables was used to determine significant predictors for layer index. The generalized estimating equations approach was applied to account for within-subject correlation among the multiple plaques per single patient. All analyses were performed with SPSS (version 25 for Windows; SPSS, Inc., Chicago, Illinois). Other methods are described in Supplementary methods .
Results
Baseline characteristics are shown in Table 1 . Among 349 patients with ACS with an average age of 57 years, 266 (76.2%) were men and 242 presented with ST-segment elevation myocardial infarction (69.3%). This is the same cohort as the one that was previously reported in another study. OCT analysis identified 99 plaques with layered phenotype (28.4%) among 349 culprit plaques and 165 plaques with layered pattern (35.5%) among 465 nonculprit plaques. Baseline angiographic characteristics of layered plaques at culprit and nonculprit plaques are shown in Supplementary Table 1 .
| Variable | (n = 349) |
|---|---|
| Age (years) | 57.4 ± 11.3 |
| Men | 266 (76%) |
| BMI (kg/m 2 ) | 25.4 ± 3.2 |
| Clinical presentation | |
| STEMI | 242 (69%) |
| NSTE-ACS | 107 (31%) |
| Prior MI | 27 (8%) |
| Prior PCI | 37 (11%) |
| Hypertension | 177 (51%) |
| Dyslipidemia | 120 (34%) |
| Diabetes mellitus | 94 (27%) |
| Smoker | 197 (56%) |
| Laboratory data | |
| Creatinine clearance (mL/min/1.73m 2 ) | 81.7 (66.3 – 97.6) |
| Low-density lipoprotein cholesterol (mg/dl) | 116.0 (88.9 – 142.5) |
| High-density lipoprotein cholesterol (mg/dl) | 41.0 (38.6 – 50.3) |
| Triglyceride (mg/dl) | 138 (88 – 192) |
| HbA1c (%) | 6.0 (5.5 – 6.9) |
| LVEF (%) | 60.0 (54.0 – 62.0) |
Among 99 patients with layered pattern at culprit lesion, plaque rupture was the underlying pathology in 64 patients (64.6%), whereas plaque erosion was found in 35 subjects (35.4%). Culprit plaque characteristics between the rupture and the erosion groups are compared in Table 2 . Culprit layered plaques with acute rupture had greater layer index and more frequent interrupted layer pattern than those with acute erosion. In addition, vulnerable plaque features (higher prevalence of lipid-rich plaque, thin-cap fibroatheroma, and macrophage and thinner fibrous cap thickness) were more prevalent in acute rupture than in acute erosion.
| Variable | Culprit plaque rupture (n = 64) | Culprit plaque erosion (n = 35) | p Value |
|---|---|---|---|
| Lipid-rich plaque | 62 (97%) | 22 (63%) | < 0.001 |
| Thinnest FCT (μm) | 60 (42 – 63) | 80 (62 – 118) | < 0.001 |
| Mean lipid arc (degree) | 282 (229 – 360) | 218 (169 – 346) | 0.010 |
| Lipid length (mm) | 12.7 ± 5.6 | 10.9 ± 4.1 | 0.189 |
| Lipid index | 3731 ± 2057 | 2657 ± 1503 | 0.031 |
| TCFA | 51 (80%) | 7 (20%) | < 0.001 |
| Macrophage | 55 (86%) | 24 (69%) | 0.040 |
| Microvessels | 31 (48%) | 11 (31%) | 0.102 |
| Calcification | 22 (34%) | 12 (34%) | 0.993 |
| Minimal lumen area (mm 2 ) | 1.26 (0.95 – 1.88) | 1.10 (0.76 – 1.64) | 0.127 |
| Area stenosis (%) | 81.5 (73.2 – 85.7) | 80.1 (72.8 – 85.0) | 0.634 |
| Layer characteristics | |||
| Max layer arc (degree) | 256 (195 – 356) | 220 (148 – 267) | 0.020 |
| Mean layer arc (degree) | 178 ± 44 | 159 ± 45 | 0.041 |
| Layer length (mm) | 8.9 (6.7 – 12.6) | 5.6 (4.0 – 9.4) | 0.001 |
| Layer index | 1572.6 (1176.5 – 2279.5) | 1086.8 (589.0 – 1626.3) | 0.001 |
| Layer demarcation pattern | < 0.001 | ||
| Intact pattern | 5 (8%) | 13 (37%) | |
| Interrupted pattern | 59 (92%) | 22 (63%) | |
| Multi-layer pattern | 18 (28%) | 11 (31%) | 0.730 |
| Layer circumferential extension | 0.098 | ||
| Focal pattern | 10 (16%) | 10 (29%) | |
| Intermediate pattern | 39 (61%) | 22 (63%) | |
| Circumferential pattern | 15 (23%) | 3 (9%) |
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