Three-Dimensional Fibrous Cap Structure of Coronary Lipid Plaque　― ST-Elevation Myocardial Infarction vs. Stable Angina ―

Abstract

Background: Fibrous cap thickness (FCT) is one of the key features of coronary vulnerable plaque. FCT is measured at an arbitrary point, determined on visual assessment of 2-D cross-sectional imaging. This method has poor reproducibility. The aim of this study was to compare the 3-D structure of FC in non-culprit lipid plaques between patients with ST-elevation myocardial infarction (STEMI) and with stable angina (SA) on optical coherence tomography.

Methods and Results: A total of 54 non-culprit plaques from 23 STEMI and 23 SA patients were evaluated. Thin cap fibroatheroma (TCFA), defined as lipid plaque with FCT <80 µm, was identified using a novel algorithm. The number of TCFA, surface area of each TCFA, and the sum total area of TCFA in the target vessel were measured. Patients with STEMI had a greater median number of TCFA (9, IQR 1–17 vs. 2, IQR 0–5; P=0.002), the largest median single TCFA area (0.40, IQR 0.14–0.69 vs. 0.08, IQR 0.04–0.16 mm²; P<0.001) and median sum total area of TCFA (1.04, IQR 0.41–1.95 vs. 0.24, IQR 0.08–0.48 mm², P<0.004).

Conclusions: Patients with STEMI, as compared with those with SA, have greater vulnerability to non-culprit plaque.

Lipid plaque with thin fibrous cap (FC) in the coronary arteries is thought to be responsible for the majority of major adverse cardiac events (MACE).¹ In the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, thin cap fibroatheroma (TCFA) in non-culprit areas was one of the predictors of future MACE.² Moreover, an optical coherence tomography (OCT) study by Uemura et al showed that TCFA was one of the predictors of rapid plaque progression.³ A recent OCT study, however, has shown that TCFA predicted MACE in only 2.4% of patients at 4-year follow-up.⁴ One of the reasons for these contradictory findings could be the definition of TCFA. Currently, TCFA is measured at an arbitrary point determined by visual assessment on a qualitative level: in other words, even though 2 lesions may have TCFA with the same FC thickness (FCT), the distribution and total sum area of thin FC may be different. Moreover, this type of measurement is subject to greater intra- and inter-observer variability. Wang et al proposed a computer-aided method that allows 3-D volumetric analysis of FC, which may overcome this bias.⁵

Editorial p 1197

So far, there have been no reports comparing the distribution and total sum area of non-culprit TCFA between acute coronary syndrome (ACS) and stable angina (SA) patients. The aim of the present study was therefore to compare non-culprit TCFA patterns using the novel volumetric analysis algorithm between patients presenting with ST-elevation myocardial infarction (STEMI) and SA.

Methods

Subjects were selected from the Massachusetts General Hospital (MGH) OCT Registry. The MGH OCT Registry is an international multi-center registry of patients who have undergone OCT of the coronary arteries, and involves 20 sites across 6 countries (http://www.clinicaltrials.gov: NCT01110538). For the purpose of this study, we identified non-culprit plaques in the culprit vessel of patients with STEMI caused by plaque rupture. Non-culprit lesions were defined as plaque seen on angiogram that had not been treated. Plaques with >30% diameter stenosis as compared with the reference diameter on OCT were included in the present study. Next, we matched the STEMI patients to SA patients with non-culprit plaques in the culprit vessel. We did not choose the culprit plaques because we could not measure accurate FCT at the rupture site. In total, of 1,203 patients with ACS, 239 patients presenting with STEMI were enrolled. Of these, 76 patients had sufficient segment length (defined as length >30 mm) of the target vessel segment imaged, and 58 non-culprit plaques were detected in 37 patients. We further excluded 31 plaques due to suboptimal image quality. Finally, 27 plaques in 23 patients with STEMI were analyzed. We selected an additional 23 SA patients with 27 plaques, matched to STEMI patients by age and gender (Supplementary Figure).

A frequency-domain OCT system (C7, FD-OCT; St. Jude Medical, St. Paul, MN, USA) was used. The technique of intracoronary OCT has been previously described.⁶ All images were de-identified, digitally stored, and submitted to the MGH Cardiology Laboratory for Integrative Physiology and Imaging (Boston, MA, USA). All OCT images were analyzed at every 1-mm interval for qualitative assessment and in every frame for quantitative assessment.

Lipid index was calculated as mean lipid arc multiplied by lipid length.⁷ In addition, the presence or absence of TCFA, macrophage accumulation, cholesterol crystals, and microvessels were noted. FCT was measured at the thinnest part 3 times, and the average value was calculated. TCFA was defined as lipid plaque with FCT <80 µm. This threshold was chosen according to a previous report.⁸ Macrophage accumulation on the OCT images was identified by an increased signal intensity in a granular pattern within the plaque, accompanied by heterogeneous back shadows.⁹ Cholesterol crystals were characterized as a high-intensity thin linear structure beside a lipid core. Microvessels were defined as a small vesicular or tubular structure with a diameter 50–300 µm. Calcification was also recorded, when an area with low backscatter and a sharp border was identified inside a plaque.¹⁰ The computer-aided method that allows volumetric analysis of FC has been described and validated previously.⁵ In short, we segmented FC boundaries in each frame of the lipid plaque with the aid of the computerized method. Next, the FCT at every point of the cap boundary was determined, and the FCT area per plaque was measured and classified into 3 categories: FCT <80 µm (TCFA), 80–200 µm and >200 µm. The FCT map was projected to an en face view with respect to the centroid (arithmetic mean position of all the points of the defined shape) of the lumen for FC analysis. If FCT was <80 µm and occupied by ≥3 frames and occupied by ≥20°, it was defined as 1 area (Figures 1,2).

Figure 1.

Representative images of fibrous cap thickness (FCT) mapping in 2 patients with ST-elevation myocardial infarction (STEMI) and 2 patients with stable angina (SA). FCT was quantified at every point on the cap. The thickness map was projected to an en face view with respect to the centroid of the lumen. The centroid (arithmetic mean position of all the points of the defined shape) of the lumen was used as the reference because the FC area was quantified using this reference. Likewise, the optical coherence tomography (OCT) cross-sectional images were projected to an en face view with respect to the centroid of the lumen. The en face FCT map was color-coded according to a pre-defined color map (red, <80 µm; green: 80–200 µm; blue, >200 µm), and fused with the en face OCT image. As shown on the images, patients with STEMI, as compared to those with SA, have a greater number of thin cap fibroatheromas (TCFA; defined as lipid plaque with FCT <80 µm), the largest single TCFA area, and the greater total sum area of TCFA.

Figure 2.

Representative images of thin cap fibroatheroma (TCFA) area calculation. (A) En face view of a coronary artery. Beige, non-lipid-rich plaque. Red, green and blue, lipid-rich plaque with fibrous cap thickness (FCT) <80 µm; 80–200 µm; and >200 µm, respectively. If an area had FCT <80 µm and occupied by ≥3 frames and occupied by ≥20°, it was defined as 1 TCFA area. Circled areas, 3 TCFA with FCT <80 µm. Dashed line, segment of the vessel shown on cross-sectional view in B. (B) Cross-sectional view of coronary artery shown in (A). This case shows the complex morphology of lipid-rich plaque and FC, which may not be captured using the standard measurement criteria. Yellow, lipid inside the vessel wall.

Minimum lumen area (MLA) location was defined as MLA±1 mm. The proximal part of the lesion was defined as the segment between the proximal edge of the lesion and the MLA. Lesion was defined as a mass lesion within the artery wall, focal intimal thickening, or loss of the layered intima, media, adventitia architecture, according to the OCT consensus document.¹¹ The distal part of the lesion was defined as the segment between the MLA and the distal edge of the lesion.

Statistical Analysis

Categorical variables are presented as n (%). The normality of distribution of continuous variables was examined using the Kolmogorov-Smirnov test. Normally distributed data are presented as mean±SD, and non-normally distributed data, as median (IQR). Fisher’s exact test or chi-squared test was used for categorical variables, and Student’s t-test or Mann-Whitney U-test was used to compare continuous variables. The propensity score method was applied to identify SA patients matched with STEMI patients by age and gender. In multivariate analysis the following variables were included: age, sex, body mass index, statin therapy, β-blocker therapy, and non-STEMI. The cut-off point for TCFA area was defined as the median TCFA area of all patients in the study (0.6496 mm²). All tests were 2-sided, and P<0.05 represented statistical significance. All analyses were performed using SPSS version 23.0 (SPSS, Chicago, IL, USA).

Results

The baseline characteristics were similar between the groups except for the more frequent use of statins and β-blockers in the SA group (Table 1). The median location of the lesion as well as the median length of the segment imaged was similar between the 2 groups: 48 mm (IQR, 44–50 mm) in the STEMI group and 50 mm (IQR, 46–50 mm) in the SA group (P=0.300).

Table 1. Baseline Patient Characteristics

	STEMI (n=23)	Stable angina (n=23)	P-value
Age (years)	66 (54–74)	67 (54–72)	0.947
Gender, male	17 (74)	19 (83)	0.475
BMI (kg/m2)	24.0 (23.2–25.4)	25.7 (23.4–27.4)	0.253
Hypertension†	15 (65)	16 (70)	0.753
Hyperlipidemia‡	17 (74)	15 (65)	0.372
Diabetes mellitus	6 (26)	11 (49)	0.127
Smoker (current)	15 (65)	12 (52)	0.380
Statin	6 (26)	14 (61)	0.017
β-blocker	1 (4)	11 (48)	0.001
ACEI/ARB	5 (22)	11 (48)	0.063

Data given as median (IQR) or n (%). ^†Blood pressure >140/90 mmHg or the use of antihypertensive drugs. ^‡Low-density lipoprotein cholesterol >140 mg/dL or the use of statin. ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; BMI, body mass index; STEMI, ST-elevation myocardial infarction.

A total of 54 non-culprit lipid plaques, consisting of 27 in the STEMI group and 27 in the SA group were analyzed. Both lesion length as well as lipid length were similar between the 2 groups (Table 2). Overall lipid burden (mean and maximum lipid arc, and lipid index) was significantly greater in the patients with STEMI. By conventional measurements, lipid burden was greater, FCT was thinner, and TCFA was more frequent in the STEMI group.

Table 2. Non-Culprit Lipid Plaques: Conventional OCT Findings

	STEMI (n=27)	Stable angina (n=27)	P-value
Lesion length (mm)	13.0 (10.0–15.0)	11.0 (8.0–15.0)	0.129
Lipid length (mm)	7.0 (6.0–9.0)	6.0 (4.75–8.25)	0.162
Mean lipid arc (°)	156 (146–174)	134 (116–152)	0.001
Max lipid arc (°)	200 (179–240)	161 (150–199)	0.008
Lipid index	1,064 (894–1,670)	862 (602–1,241)	0.023
FCT (μm)	70 (60–80)	80 (80–120)	0.007
TCFA	23 (85)	14 (52)	0.008
Macrophage accumulation	20 (74)	16 (59)	0.328
Calcification	14 (52)	11 (41)	0.487
Cholesterol crystals	6 (22)	5 (18)	0.788
Microchannel	13 (48)	8 (30)	0.196
Reference area (mm2)	7.7 (5.7–10.1)	8.9 (6.2–10.7)	0.194
MLA (mm2)	4.7 (3.0–5.9)	4.6 (2.4–6.1)	0.702
Diameter stenosis (%)	55.3 (41.3–68.9)	51.3 (41.8–64.3)	0.328

Data given as median (IQR) or n (%). FCT, fibrous cap thickness; MLA, minimum lumen area; OCT, optical coherence tomography; TCFA, thin cap fibroatheroma. Other abbreviations as in Table 1.

On 3-D volumetric FCT analysis, patients with STEMI had a greater median number of TCFA with FCT <80 µm (Table 3). Also, the largest single median TCFA area with FCT <80 µm as well as total median sum of TCFA area with FCT <80 µm were greater in the STEMI group. In contrast, patients with SA had greater median area with FCT >200 µm.

Table 3. Three-Dimensional Volumetric Fibrous Cap Analysis

	STEMI	Stable angina	P-value
Plaques with FCT <80 μm	n=23	n=14
No. TCFA	9 (1–17)	2 (0–5)	0.002
Largest single TCFA area (mm2)	0.40 (0.14–0.69)	0.08 (0.04–0.16)	<0.001
Total sum of TCFA area (mm2)	1.04 (0.41–1.95)	0.24 (0.08–0.48)	<0.004
Plaques with FCT >200 μm	n=27	n=27
Total sum area (mm2)	3.77 (1.23–6.48)	5.97 (2.28–10.35)	0.022

Data given as median (IQR). Other Abbreviations as in Tables 1,2.

On multivariate analysis, STEMI was the only independent predictor of greater TCFA area (OR, 8.8; 95% CI: 1.255–61.870; P=0.029). When the distribution of areas with FCT <80 µm was analyzed in all patients with the data refers to all patients, the proximal part of the lesion had the largest mean TCFA area (Table 4).

Table 4. FCT vs. Lesion Section in Total Group of the Patients

	Proximal part (n=28)	MLA (n=24)	Distal part (n=32)	P-value (overall)	P-value†	P-value‡	P-value§
Area of FCT <80 μm (mm2)	0.43 (0.09–1.37)	0.14 (0.05–0.28)	0.17 (0.03–0.45)	0.019	0.017	0.022	0.932

^†Proximal part of the lesion vs. MLA; ^‡proximal vs. distal part of the lesion; ^§MLA vs. distal part of the lesion. Abbreviations as in Table 2.

Discussion

TCFA are believed to represent the coronary plaques at the highest risk of an acute coronary event. On histology, TCFA are defined as a large necrotic core with a thin overlying FC.¹ The spatial resolution of OCT allows for the detailed analysis of TCFA in vivo, not possible with any other intravascular modality.¹² To our knowledge, this is the first report to show differences in the pattern of non-culprit TCFA between patients with SA and those with STEMI. In the present study we have shown that patients with STEMI have (1) greater median number of TCFA; (2) greater largest single median TCFA area; (3) greater total sum median TCFA area; and, moreover, in STEMI patients (4) the proximal part of the plaque has the largest median area of TCFA.

A TCFA is thought to be the precursor of plaque rupture, leading to ACS in the majority of cases.^2,3,13 Our group previously reported that FCT in patients with plaque rupture measured 60±17µm.¹⁴ Moreover, patients with culprit plaque ruptures have a 4-fold higher prevalence of TCFA in non-culprit regions.¹⁵ As observed in the PROSPECT study, however, plaques with TCFA do not necessarily lead to plaque rupture and MACE, and are instead indicators of increased risk of future cardiac events. In fact, not all of the studies found an association between TCFA and increased risk of cardiovascular events. Xing et al in a recent OCT study showed that although lipid-rich plaque was a predictor of MACE at 4-year follow-up, FCT did not predict cardiac events.⁴

There are several plausible explanations for plaque growth and plaque vulnerability, but the question of why only a small number of TCFA lead to ACS remains unanswered.¹⁶ First, FCT may undergo dynamic changes over time due to physical or biological factors.^17–19 Second, FC is a 3-D structure, and measuring FCT at a single point may not be representative of its complexity. The generalization may introduce bias on how TCFA is diagnosed and how results of studies are interpreted.

In the current study, we compared FCT patterns of the non-culprit plaques in patients with STEMI and SA. We showed that TCFA is dispersed through the whole plaque, creating multiple weak areas. This pattern was especially notable in STEMI patients who had almost 3-fold more TCFA, as well as a 3-fold larger surface area in individual TCFA as compared with SA patients. Importantly, patients with STEMI had a larger area of FCT <200 µm and a smaller area of FCT >200 µm, as compared with SA patients. Moreover, we showed that even in patients with STEMI, there is a great diversity in both the number of TCFA as well as the size of the largest single TCFA (Table 3). Interestingly, not all patients with SA had less pronounced features of plaque vulnerability, as expressed in TCFA area. Based on the present results, it is conceivable that plaque vulnerability may not depend on the single point thickness of FC (as it is measured in current practice), but rather on the largest area of thin FC or even a sum of several TCFA located in close proximity to each other. This hypothesis could explain the variability in FCT of ruptured plaque between different studies. In theory, STEMI and SA patients with the largest area of thin FC could have increased risk of plaque rupture. Future research with follow-up is needed to confirm the present findings. Moreover, based on the present data, it may be plausible that the changes of the whole FC pattern, rather than FCT measured at 1 location, may be a better indicator of the response to treatment and the risk for future events.

Recently our group showed that low endothelial shear stress was associated with both baseline high-risk plaque phenotype, as well as progression to higher risk phenotype at 6-month follow-up.^17,20 Low endothelial shear stress may be found most frequently in the proximal and distal part of the vessel, whereas it is rarely observed in the MLA region.²¹ In the present study, the proximal part of the non-culprit lesion had the largest total sum area of FCT <80 µm. Intriguingly, it was followed by the distal part of the lesion and then the MLA region, but we did not find any differences in the area between the latter 2. This is in line with a previous study in which plaque rupture in ACS patients was most frequently found in the proximal part of the lesion.²² Ino et al, in an OCT study, showed that almost half of the plaque ruptures in STEMI patients were localized in the proximal part of the lesion.²² Likewise, in a more recent intravascular ultrasound study, plaque rupture was more frequently localized in the upstream part of the lesion.²³

Study Limitations

Several limitations should be noted. First, this study was a retrospective analysis, although data were collected prospectively. OCT was performed at the operator’s discretion and therefore subject to potential selection bias. Second, because the computerized algorithm requires high-quality OCT with no severe artefacts or residual blood, the sample size was relatively small. Third, the relatively small number of patients might have introduced a selection bias. Last, previous pathology and in vivo studies showed that STEMI patients have more features of plaque vulnerability as compared with SA patients. So far, however, a detailed description of TCFA pattern has not been reported. We believe that this is the first study to demonstrate distinct differences in FC pattern between STEMI and SA patients using a novel algorithm.

Conclusions

Patients with STEMI, as compared with those with SA, have a greater overall median number of TCFA, larger median surface area of TCFA, as well as a greater median total sum area of TCFA. Moreover, TCFA are dispersed through the whole plaque, rather than creating 1 weak area. These results may increase the knowledge of the mechanisms of plaque rupture and may redefine the concept of plaque vulnerability.

Acknowledgments

The authors thank all the investigators and all supporting staff. Dr. Jang’s research was supported by Mr. and Mrs. Michael and Kathryn Park, and by Mrs. and Mr. Gill and Allan Gray.

Disclosures

I.-K.J. has received educational grant from Abbott Vascular. The other authors declare no conflicts of interest.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-19-0007

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