Thin Cap Fibroatheroma Defined as Lipid Core Abutting Lumen (LCAL) on Integrated Backscatter Intravascular Ultrasound　– Comparison With Optical Coherence Tomography and Correlation With Peri-Procedural Myocardial Infarction –

Abstract

Background: This study evaluated the ability of a newly developed integrated backscatter intravascular ultrasound (IB-IVUS) system (VISIWAVE, Terumo, Tokyo, Japan) to detect optical coherence tomography (OCT)-verified thin cap fibroatheroma (TCFA) and assessed the correlation with peri-procedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI).

Methods and Results: One hundred culprit lesions in 100 consecutive patients with ischemic heart disease who consented to repeated IVUS and OCT prior to PCI were studied. Of 100 lesions, 48 had OCT-verified TCFA with a cap thickness <65 µm. Such lesions had larger percentage lipid area and lipid angle >2 quadrants on IB-IVUS. A lipid core abutting lumen (LCAL) was defined as a lipid core pool in the plaque area, directly contacting with the lumen regardless of its circumferential extension. IB-IVUS-identified TCFA defined as a combination of percentage lipid area ≥53.6%, remodeling index ≥1.03, and the presence of LCAL was the best predictor of OCT-verified TCFA with sensitivity, specificity, positive and negative predictive values, and accuracy of 72.9%, 90.4%, 87.5%, 78.3%, and 82.0%, respectively. IB-IVUS-identified TCFA as well as OCT-verified TCFA were significant independent predictors of PMI, after adjusting for other predictors on multivariate analysis.

Conclusions: IB-IVUS can be used to identify plaques with a high prevalence of TCFA. Such techniques can therefore potentially be used to identify lesions with an elevated risk of PMI after PCI. (Circ J 2015; 79: 808–817)

The presence of thin cap fibroatheroma (TCFA) has been associated with peri-procedural myocardial infarction (PMI) after percutaneous coronary intervention (PCI).^1,2 Although intravascular ultrasound (IVUS) has been used to evaluate coronary plaque and guide coronary intervention in recent years, it is unable to visualize thin fibrous caps because of its limited axial resolution (100–150 µm). In contrast, intracoronary optical coherence tomography (OCT) has a higher resolution (10 µm) as compared with IVUS, and is therefore readily able to visualize thin fibrous cap and thereby identify TCFA.^3–5 Its low tissue penetration, however, limits its ability to quantitatively assess plaque morphology. Comprehensive plaque assessment therefore currently appears to require both techniques, limiting their application in clinical practice.

Editorial p 754

Integrated backscatter IVUS (IB-IVUS) utilizes time-domain information from the spectral analysis of radio frequency data from ultrasound backscatter to resolve differences in plaque characteristics.^6,7 It is not known whether a newly developed high resolution IB-IVUS system (VISIWAVE) is able to quantitatively detect the presence of OCT-verified TCFA or predict the risk of PMI. We therefore assessed whether OCT-verified TCFA can be detected using contemporary high-resolution IB-IVUS technology and whether IB-IVUS-identified TCFA is associated with PMI after elective PCI.

Methods

Subjects

Between October 2010 and July 2012, 100 consecutive patients with ischemic heart disease who consented to repeated IVUS and OCT prior to undergoing elective PCI were prospectively recruited to the study. All patients had OCT, IB-IVUS, and quantitative coronary angiography (QCA) performed, which was then used to guide subsequent coronary intervention.^8,9 Only native coronary lesions were included in the study. Patients were excluded if they had lesions located in totally occluded arteries, tortuous vessels, or had severe calcification hindering precise intracoronary imaging. For similar reasons, those with ostial or left main stem lesions were excluded. The study was approved by the local ethics committee of Fujita Health University and was carried out according to the guidelines of the Declaration of Helsinki. Written informed consent was obtained from all patients.

Image Acquisition

A 6-/7-Fr guiding catheter was introduced through the femoral or radial approach after intravenous heparin at 100 IU/kg. Selective coronary angiography was performed after intracoronary injection of nitrates.^9–11 Following the passage of a 0.014-inch guidewire across the lesion, the mechanical IVUS catheter (ViewIT, 40 MHz, 2.5 Fr; Terumo, Tokyo, Japan) was serially introduced over the wire and positioned distal to the lesion. The lesion was then imaged using motorized pullback (0.5 mm/s). The IB-IVUS system (IB-IVUS; YD, Nara, Japan) was connected to the IVUS imaging system (VISIWAVE; Terumo) together with radiofrequency (RF) signal trigger and video image outputs to obtain the RF signal during acquisition. Ultrasound backscattered signals were acquired, digitized, and subjected to spectral analysis and stored electronically with IVUS images for offline analysis.

OCT imaging was performed with a Fourier-domain OCT system using a Dragonfly catheter (C7XR; LightLab Imaging, Westford, MA, USA) at a rotation speed of 100 frames/s with a non-occlusion technique.^12,13 OCT was undertaken during the injection of low-molecular-weight dextran, which was used to clear blood away from the field of view.¹⁴ Motorized pullback was started at a rate of 20 mm/s for a length of 54 mm. The images were saved in the OCT image system digitally for subsequent analysis. All the lesions were treated with stent implantation using standard techniques at the operator’s discretion. IVUS and OCT were used to ensure adequate stent expansion and were then repeated to ensure successful stent deployment.^15–17

Intracoronary Image Analysis

Intracoronary image analysis was carried out with the consensus of 3 experienced observers (Y.O., T.M., M. Ohota) blinded to clinical records or details during assessment. For OCT, fibrous cap thickness was assessed. Corresponding images from IVUS and OCT were identified using the distance from anatomical landmarks such as side branches or calcium deposits, as well as images from simultaneous fluoroscopy and angiography.^3,9,18

Grayscale IVUS Analysis

The grayscale and IB-IVUS analysis were performed with VISIATRAS^TM (Terumo).¹⁹ A cross-sectional luminal area was defined as the integrated area central to the intimal leading edge echo.^9,18,20,21 The total vessel cross-sectional area (vessel area) was defined as the area inside the interface between the plaque-media complex and adventitia (area inside the external elastic membrane).^9,18,20,21 Plaque area was defined as vessel area minus luminal area. Vessel volumes and lumen volumes were then calculated using Simpson’s technique. The plaque volume was calculated by subtracting lumen volume from vessel volume.

IB-IVUS Analysis

Integrated backscatter values for each tissue component were calculated as an average power using a fast Fourier transform of the frequency component of the backscattered signal, measured in decibels (dB), from a small volume of tissue.^6,7,11,22

The percentage fibrous volume (fibrous volume/plaque volume) and the percentage lipid volume (lipid volume/plaque volume) were automatically calculated by the IB-IVUS system. The percentage of high signal volume (calcification on the inner surface that could be measured with the formula IB-IVUS/plaque volume) was also automatically calculated by the IB-IVUS system as a high-signal volume.^6,7,11,22 In the current study, we defined lipid core abutting lumen (LCAL) as a lipid pool in direct contact with the lumen regardless of its circumferential extension (Figure 1).

Figure 1.

Representative examples of (A) angiographic, (B,C) optical coherence tomography, (D) integrated backscatter intravascular ultrasound, and (E) grayscale intravascular ultrasound of (Top) thin cap fibroatheroma and (Bottom) non-thin cap fibroatheroma lesions. LA, lumen area; LCAL, lipid core abutting lumen; PA, plaque area; SB, side branch; VA, vessel area.

Axial Resolution of the IVUS System

The axial resolution of conventional IVUS 20–40 MHz IVUS transducer systems is approximately 80 µm.²³ In this study, we measured 1,180 samples (ViewIT; Terumo), and determined that the axial resolution of the Terumo IVUS system was 69±6 µm (Appendix S1, Figure S1).

OCT Analysis

For OCT, calcification within plaque was identified by the presence of well-delineated and low back-scattering heterogeneous regions, and fibrous plaques identified by the presence of homogeneous high backscattering areas.^{3,4,16,24–26} Lipid necrotic pools were identified as areas less well delineated than calcifications (ie, diffusely bordered) and exhibiting lower signal density and more heterogeneous back-scattering than fibrous plaques.^{3,4,16,24–26} The latter are associated with overlying signal-rich bands, corresponding to the fibrous cap.

Thrombi were identified as masses protruding into the vessel lumen. Although red thrombi consisting mainly of red blood cells were observed as high back-scattering protrusions with signal-free shadowing on OCT, white thrombus containing mainly platelets and white blood cells was characterized by signal-rich and low back-scattering billowing projections protruding into the lumen.²⁶

OCT-verified TCFA was defined as areas where cap thickness was <65 µm with a lipid pool >2 quadrants.^{3,4,5,26–28} In the thinnest portion of fibrous cap thickness detected on OCT, the measurement of fibrous cap thickness was performed 3 times, and the average value was defined as OCT fibrous cap thickness.²⁷ When the precise fibrous cap thickness could not be obtained (eg, the absence of a well-defined lipid core or the presence of thrombus interfering with the assessment), measurements were performed in the nearest adjacent OCT slice. Of note, smallest sampling distance between frames was 0.20 mm according to the OCT image acquisition protocol in the present study.

IB-IVUS and OCT Fibrous Cap Thickness

As previously described, fibrous plaques with underlying lipid pool were divided into regions of interest (ROI) every 10° rotation from the center of the catheter and averaged, and the fibrous cap thickness every 2° within the ROI.²⁸ In 100 consecutive patients and 100 cross-sections, consisting of fibrous cap thickness measured on both OCT and IB-IVUS, we evaluated whether cap thickness measured on OCT was correlated with that on the newly developed IB-IVUS system.

QCA

QCA analysis was performed using the computer-based edge-detection Coronary Angiography Analysis System (CAAS II; Pie Medical, Maastricht, The Netherlands) as previously described.^8,9,29 In brief, interpolated reference vessel diameter, minimum lumen diameter (MLD), and percentage diameter stenosis were obtained using the guiding catheter as a scaling device from the QCA system.^8,9,29

Biochemical Analysis

Cardiac troponin I (cTnI) was measured before and 24 h after PCI. Serum cTnI was measured using enzyme immunoassay kit (Stratus CS TroponinI; TestPak, Tokyo, Japan). The upper reference limit is 0.07 ng/ml, with 99th percentile values as normal with a 10% coefficient of variation of 0.06 ng/ml. Recent ESC guidelines have defined MI associated with PCI as an elevation of cTnI >5-fold the 99th percentile upper reference limit.³⁰ Therefore, we defined cTnI >0.35 ng/ml as MI after PCI.

Statistical Analysis

All data were analyzed using SPSS for Windows V21.0 (IBM, Chicago, IL, USA). Continuous values are expressed as mean±SD for normally distributed variables or as median (interquartile range) for non-parametric data. Differences in categorical variables were assessed using the chi-square test or Fisher’s exact test. Differences between parametric continuous variables were assessed using unpaired or paired t-test as appropriate. Fibrous cap thickness measured on IB-IVUS and OCT was compared using Bland-Altman plot as well as by calculating concordance correlation coefficients.³¹ Receiver operating characteristic (ROC) analysis was performed to determine the cut-offs for each IVUS parameter for OCT-verified TCFA. The added discriminative value after adding LCAL and/or lipid volume and/or lipid angle to the established IVUS parameters for OCT-verified TCFA was estimated using the c-statistic. This was compared for a baseline model consisting of established IVUS parameters for OCT-verified TCFA, and an enriched model with LCAL and/or lipid volume and/or lipid angle using the DeLong method.³² Intra- and inter-observer reproducibility in identifying LCAL were assessed using κ value. To assess the relationship between IB-IVUS-identified TCFA and PMI after PCI, multiple logistic regression analysis was used. Two-tailed P<0.05 was considered significant.

Results

In total, 100 consecutive patients (100 lesions; 72% patients male; mean age, 66 years) were enrolled after excluding 10 patients due to difficulty in performing precise intracoronary imaging. Baseline clinical and lesion characteristics at the time of intervention for 100 patients are summarized in Table 1. Of the 100 patients, 40 had acute coronary syndrome (ACS): 10 presented with non-ST elevation myocardial infarction and 30 with unstable angina. The remaining 60 patients had stable angina.

Table 1. Clinical, Angiographic, and Lesion Characteristics

	OCT-TCFA (−) (n=52)	OCT-TCFA (+) (n=48)	P-value
Age (years)	66±10	66±11	0.984
Male	34 (79)	31 (66)	0.169
Coronary risk factors
Diabetes mellitus	20 (38)	20 (42)	0.747
Hypertension	29 (67)	34 (72)	0.841
Hyperlipidemia	38 (73)	38 (79)	0.481
Smoking	27 (46)	27 (46)	0.206
Family history	5 (10)	11 (23)	0.070
SAP	44 (85)	16 (33)	<0.001
UAP	4 (8)	26 (54)	<0.001
NSTEMI	4 (8)	6 (13)	0.428
Prior CABG	0 (0)	1 (2)	0.339
Region of interest
LAD/LCX/RCA	26 (52)/10 (19)/16 (29)	22 (46)/4 (8)/22 (46)	0.157
ACC/AHA lesion type
A or B1	40 (77)	29 (60)	0.076
B2 or C	12 (23)	19 (40)	0.076
QCA
MLD (mm)	1.03±0.46	0.85±0.50	0.055
%DS (%)	61.6±12.0	61.8±12.8	0.947
RVD (mm)	2.65±0.43	2.98±2.04	0.123
Lesion length	17.4±5.0	18.1±4.6	0.491
Procedural data
Stent length (mm)	21.9±5.7	22.1±6.2	0.862
Stent diameter (mm)	3.0±0.4	3.0±0.3	0.874
Direct stent	18 (35)	18 (38)	0.767
Post dilatation (atm)	16.7±3.8	16.7±7.0	0.988
Post-inflation time (s)	44.8±15.0	42.7±14.3	0.490

Data given as mean±SD or n (%). %DS, %diameter stenosis; ACC/AHA, American College of Cardiology/American Heart Association; BMI, body mass index; CABG, coronary artery bypass graft; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; MI, myocardial infarction; MLD, minimum luminal diameter; NSTEMI, non-ST elevation MI; OCT, optical coherence tomography; QCA, quantitative coronary angiography; RCA, right coronary artery; RVD, reference vessel diameter; SA, stable angina; TCFA, thin cap fibroatheroma; UA, unstable angina.

Clinical characteristics were compared in 100 patients, consisting of 48 with OCT-TCFA and 52 without OCT-TCFA (Table 1). No significant differences were observed between the 2 groups with respect to age, sex and coronary risk factors. The prevalence of stable angina was higher in patients without OCT-TCFA than those with OCT-TCFA. Conversely, the prevalence of unstable angina was higher in patients with OCT-TCFA than in those without it. Cardiac TnI elevation after intervention was higher in patients with OCT-TCFA than in those without. No significant differences were found between the 2 groups for either qualitative or quantitative angiographic features (Table 1).

Grayscale IVUS Parameters and Presence of OCT-TCFA

No significant differences were found between the 2 groups with respect to vessel, lumen and plaque area (Table 2). Vessel and lumen volume were similar between the 2 groups, while the plaque volume was significantly greater in lesions with OCT-TCFA than in those without it (Table 2).

Table 2. Imaging Parameters vs. Presence of OCT-TFA

	OCT-TCFA (−) (n=52)	OCT-TCFA (+) (n=48)	P-value
Grayscale IVUS
Average vessel area (mm2)	13.6±5.8	14.3±4.9	0.514
Minimum lumen area (mm2)	3.5±2.1	3.4±2.5	0.770
Average plaque area (mm2)	9.2±4.3	10.5±4.2	0.159
Reference vessel area (mm2)	14.0±5.7	14.1±5.7	0.933
Lesion vessel area (mm2)	13.0±5.7	14.4±4.9	0.171
Remodeling index	0.95±0.21	1.11±0.16	<0.001
Plaque burden at MLD (%)	70.3±16.3	75.2±12.1	0.096
Vessel volume (mm3)	205.8±51.3	260.7±49.7	0.069
Lumen volume (mm3)	76.4±46.2	67.4±51.3	0.354
Plaque volume (mm3)	131.9±95.5	177.2±85.8	0.003
Plaque volume (%)	63.1±10.9	69.8±23.8	0.069
Lesion length (mm)	17.1±8.0	21.4±7.0	0.005
IB-IVUS
Lipid area (%)	47.8±10.9	55.2±3.4	<0.001
Fibrous area (%)	41.3±13.3	36.4±7.9	0.028
Dense fibrous area (%)	3.7±3.2	2.8±2.4	0.127
Calcification area (%)	1.0±1.3	1.0±1.5	0.729
Lipid angle >2 quads	21 (40)	40 (83)	<0.001
LCAL	23 (44)	46 (96)	<0.001
OCT
Cap thickness (μm)	132.7±87.3	54.8±14.4	<0.001
Lipid angle >2 quadrants	26 (50)	48 (100)	<0.001
Thrombus	6 (12)	9 (19)	0.318
Rupture	1 (2)	13 (27)	<0.001

Data given as mean±SD or n (%). IB-IVUS, integrated backscatter intravascular ultrasound; IVUS, intravascular ultrasound; LCAL, lipid core abutting lumen. Other abbreviations as in Table 1.

No significant differences were found between the 2 groups with respect to reference vessel area and lesion vessel area. The remodeling index in lesions with OCT-TCFA was significantly greater than that for those without OCT-TCFA. Lesion length was significantly longer in lesions with OCT-TCFA than that in those without OCT-TCFA.

IB-IVUS Parameters and Presence of OCT-TCFA

Although the percentage dense fibrous area and percentage calcification area were similar between the 2 groups, the percentage lipid area was significantly greater in lesions with OCT-TCFA than in those without OCT-TCFA (Table 2). The percentage fibrous area was smaller in the OCT-verified TCFA group than the OCT-TCFA (–) group. The prevalence of lipid pool >2 quadrants in OCT-verified TCFA was higher than in the OCT-TCFA (–) group (Table 2). Lipid volume was significantly greater in the OCT-verified TCFA than OCT-TCFA (–) group and fibrous volume tended to be smaller. Dense fibrous volume and calcification volume were similar in the 2 groups.

OCT and Presence of OCT-TCFA

The prevalence of lipid pool >2 quadrants was significantly higher in lesions with OCT-TCFA than in those without OCT-TCFA (Table 2). Thrombus tended to be observed more frequently in lesions with OCT-TCFA than in those without OCT-TCFA, but this trend did not reach statistical significance. Plaque rupture was observed significantly more often in lesions with OCT-TCFA than in those without OCT-TCFA.

OCT and IB-IVUS Fibrous Cap Thickness

There was strong agreement between fibrous cap thickness measured by OCT and IB-IVUS (y=0.93x+15.1, r=0.91, P<0.0001; Figure 2). The mean difference in the fibrous cap thickness measured by OCT and IB-IVUS (OCT minus IB-IVUS) was –4.4 µm with 95% limits of agreement of ±98.7 µm.

Figure 2.

(A) Correlation between the cap thickness measured on VISIWAVE integrated backscatter intravascular ultrasound (IB-IVUS) and optical coherence tomography (OCT). (B) Bland-Altman plot.

Predictors of OCT-Verified TCFA

ROC curves were constructed to determine the model discrimination and optimum cut-off points of each IVUS parameter for predicting OCT-verified TCFA (Figure 3). The optimum cut-offs for remodeling index, plaque volume, and lesion length were 1.03, 130.8 mm³, and 17.5 mm, respectively (area under the curve [AUC]: 0.753, 0.718, and 0.710, respectively). The optimum cut-offs for percentage lipid area, percentage lipid angle, and percentage lipid volume were 53.6%, 180° and 66.0 mm³, respectively (AUC: 0.799, 0.724, and 0.839, respectively).

Figure 3.

Receiver operating characteristic analysis of intravascular ultrasound parameters used to predict optical coherence tomography-verified thin cap fibroatheroma. AUC, area under curve.

Table 3 summarizes sensitivities, specificities, positive predictive values, negative predictive values, and diagnostic accuracy for predicting OCT-verified TCFA.

Table 3. Grayscale IVUS Diagnosis of OCT-Verified TCFA

	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Accuracy (%)
Grayscale IVUS
Remodeling index (cut-off >1.03)	70.8	69.2	70.8	72.0	70.0
Plaque volume (mm3) (cut-off >130.8)	61.7	60.5	63.0	59.1	61.1
Lesion length (mm) (cut-off >17.5)	66.0	60.5	64.6	61.9	63.3
IB-IVUS
%Lipid area (cut-off >53.6%)	75.0	75.0	75.0	76.9	76.0
Lipid angle (cut-off >180°)	85.1	60.5	69.6	76.5	72.2
Cap thickness (cut-off <75 μm; LCAL)	93.6	81.4	84.6	92.1	87.8
IB-IVUS-identified TCFA†	72.9	90.4	87.5	78.3	82.0

^†Percentage lipid area >53.6%, remodeling index >1.03, LCAL. NPV, negative predictive value; PPV, positive predictive value. Other abbreviations as in Tables 1,2.

Reproducibility of LCAL Identification

In the present study, the intra- and inter-observer reproducibility of LCAL identification was assessed in 51 randomly selected cases, and was found to be acceptable (κ, 0.82 and 0.75, respectively).

Discrimination of Predictive Models for OCT-Verified TCFA

When we added lipid volume alone, lipid angle alone, or LCAL alone to the baseline model with IVUS parameters consisting of percentage lipid area and remodeling index, the c-statistic became significantly greater only in the model with LCAL compared with the baseline model (0.972 vs. 0.840, P=0.002; Table 4). Based on these data, the following 3 criteria are required for IB-IVUS-identified TCFA: percentage lipid area, remodeling index, and LCAL.

Table 4. Discrimination of Predictive Models for OCT-Verified TCFA

Predictors for OCT-derived TCFA	C-statistic (95% CI)	P-value
Baseline (%lipid area+remodeling index)	0.840 (0.755–0.926)	–
Baseline + LCAL	0.972 (0.946–0.999)	0.002

Abbreviations as in Tables 1,2.

Predictors of PMI

IB-IVUS-identified TCFA was correlated with PMI after elective PCI on univariate analysis and after adjusting for other potential confounders (Table 5).

Table 5. Predictors of Peri-Procedural MI

	Univariate			Multivariate
	OR	95% CI	P-value	OR	95% CI	P-value
IB-IVUS
Pre-MLD (QCA, mm)	0.34	0.13–0.89	0.027	0.43	0.14–1.36	0.087
Plaque burden (%)	1.05	1.01–1.09	0.020	1.04	1.00–1.08	0.087
IB-IVUS-identified TCFA	10.7	3.85–29.5	<0.001	9.79	3.41–28.1	<0.001
OCT
Pre-MLD (QCA, mm)	0.36	0.13–0.89	0.027	0.31	0.08–1.13	0.087
Plaque burden (%)	1.05	1.01–1.09	0.020	1.04	0.99–1.09	0.132
OCT-verified TCFA	10.7	3.85–29.5	<0.001	29.8	7.41–119.8	<0.001

CI, confidence interval; OR, odds ratio. Other abbreviations as in Tables 1,2.

Discussion

We found that OCT-verified TCFA tended to have a larger plaque volume, higher remodeling index, and longer lesion length on grayscale IVUS; and more lipid plaque, lipid angle >2 quadrants, and less fibrous plaque on IB-IVUS. In addition, percentage lipid area >53.6%, remodeling index >1.03, and LCAL were statistically the best predictors of OCT-verified TCFA. Based on these data, it should be emphasized that IB-IVUS is most likely to identify the lesion with TCFA for this combination of 3 factors. On multivariate analysis, we found that IB-IVUS-identified TCFA as well as OCT-verified TCFA were independent predictors of PMI after elective PCI.

Previous histopathologic studies have reported that ACS are caused by the disruption of TCFA. Virmani et al reported that TCFA is characterized by necrotic core with an overlying fibrous cap measuring <65 µm, containing rare smooth muscle cells, but numerous macrophages.³³ In contrast, Narula et al reported that, in most cases, fibrous cap thickness in TCFA measured 75 µm on average.³⁴ The high resolution of OCT (approximately 10 µm) enables it to readily visualize the thin fibrous cap and thereby identify TCFA. Yabushita et al reported that the fibrous cap was consistent with a signal-rich layer overlying a signal-poor lipid pool on OCT.³⁵ Jang et al defined OCT-verified TCFA as areas where cap thickness was <65 µm and the signal-poor lipid pool was >2 quadrants.⁵ The availability of OCT, however, is limited and the requirement for a blood-free field can make imaging cumbersome. There has therefore been considerable interest in using contemporary IVUS techniques to identify TCFA.

Virtual histology IVUS (VH-IVUS) has gained widespread acceptance as a means of assessing plaque composition in-vivo. Rodriguez-Granillo et al reported that VH-identified TCFA (VH-TCFA) was defined as a necrotic core >10% without evident overlying fibrous tissue and a percent atheroma volume >40%.³⁶ The PROSPECT study found that the presence of VH-TCFA independently predicted the risk of subsequent non-culprit lesion-related major adverse cardiovascular events.¹ Thus, the detection of TCFA may be of utility in predicting the occurrence of ACS and guiding aggressive medical therapy. The axial resolution of VH-IVUS, however, is in the range 100–150 µm because the frequency of the VH-IVUS catheter is approximately 20 MHz. Therefore, it has been assumed that the absence of visible fibrous tissue overlying a necrotic core in VH-IVUS suggested a cap thickness <100–150 µm. The IB-IVUS system in the present study used a 40-MHz transducer and therefore was able to offer an axial resolution of at least 75 µm (Appendix S1, Figure S1). Although this resolution limit is of the same order of magnitude as fibrous cap thickness, we were able to infer the presence of a thin fibrous cap by identifying LCAL on IB-IVUS.

Using IB-IVUS, Miyamoto et al identified that percentage lipid area >55% and remodeling index >1.00 were independent predictors of OCT-verified TCFA,³⁷ but they did not include LCAL or similar surrogate markers of thin fibrous cap in their definition of TCFA. The present data suggest that LCAL is an independent predictor of OCT-verified TCFA, in addition to percentage lipid area and remodeling index. Indeed, the addition of LCAL to a baseline model consisting of percentage lipid area and remodeling index significantly improved model discrimination characteristics (c-statistic, 0.840 vs. 0.972, P=0.002).

In contrast to the previous reports, we used a newly developed high-resolution IB-IVUS system for assessing plaque morphology of OCT-verified TCFA. We found that the axial resolution of Terumo IVUS system was 69±6 µm (Appendix S1, Figure S1). Therefore, we assumed that LCAL suggested a fibrous cap thickness of ≤75 µm. Recently, Narula et al reported that most TCFA were in the range 54–84 µm, which is consistent with the present data,³⁴ and suggests that the definitions of “thin” derived from earlier studies may have been too stringent. Contemporary high-resolution IB-IVUS systems are therefore potentially able to identify all 3 features of TCFA traditionally determined using an OCT-based approach.

Importantly, using a more liberal approach, we found that high-resolution IB-IVUS-identified TCFA was able to predict the incidence of PMI after elective PCI. Uetani et al assessed plaque characteristics associated with MI after elective PCI on IB-IVUS,³⁸ and found that lipid volume for IB-IVUS was an independent predictor of PMI after elective PCI.³⁸ Moreover, they showed that the best discriminative value of lipid volume was 45.6 mm³ (sensitivity, 100%; specificity, 67.3%).³⁸ It remained unclear, however, whether TCFA identified on IB-IVUS was associated with PMI after elective PCI. The present study found that IB-IVUS-identified TCFA as well as OCT-verified TCFA independently predicted PMI after elective PCI, confirming the utility of this approach.

Clinical Implications

We were able to identify OCT-verified TCFA using IB-IVUS with reasonable sensitivity and specificity. The present data also suggest that IB-IVUS-identified TCFA is an independent predictor of PMI after elective PCI, as well as OCT-verified TCFA. These findings may be of use in guiding optimal medical therapy and possibly also procedural techniques. The possible benefit of using distal protection devices during PCI for selected lesions with TCFA as a means of reducing the risk of PMI merits further consideration.

Study Limitations

The present study has a number of limitations. First, the number of patients was small, reflecting the cost and challenges of performing comprehensive invasive plaque assessment. Second, this was not a randomized study, incurring the possibility of selection bias. Third, although IB-IVUS-identified TCFA was compared with the gold standard of OCT-verified TCFA, because all studies were performed in-vivo in a clinical setting, we have no histological data to further corroborate the findings. Finally, we excluded patients who had lesions located in totally occluded, severely calcified, and tortuous vessels due to the difficulty in performing precise intracoronary imaging. This may have introduced further selection bias and limited the generalizability of the findings.

Conclusions

Percentage lipid area >53.6%, remodeling index >1.03, and LCAL were the best independent predictors of IB-IVUS-identified TCFA. Moreover, IB-IVUS-identified TCFA was an independent predictor of PMI after elective PCI. The potential utility of detecting TCFA using IB-IVUS and using this to guide PCI strategies and medical therapy to optimize patient outcome requires further study.

Disclosures

None of the authors report any relevant disclosures or conflicts of interest.

Funding

This study was supported by an unrestricted grant from Fujita Health University, Toyoake, Japan.

Supplementary Files

Supplementary File 1

Appendix S1

Figure S1. Received reflected signal and ∆t_–6.

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-0758

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