Author + information
- Received February 14, 2011
- Accepted April 19, 2011
- Published online July 1, 2011.
- Roberto Diletti, MD⁎,†,
- Hector M. Garcia-Garcia, MD, PhD⁎,
- Josep Gomez-Lara, MD⁎,
- Salvatore Brugaletta, MD⁎,
- Joanna J. Wykrzykowska, MD⁎,
- Nienke van Ditzhuijzen, MSc⁎,
- Robert Jan van Geuns, MD, PhD⁎,
- Evelyn Regar, MD, PhD⁎,
- Giuseppe Ambrosio, MD, PhD† and
- Patrick W. Serruys, MD, PhD⁎,⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Patrick W. Serruys, Erasmus Medical Center, 's-Gravendijkwal 230, 3015 CE Rotterdam, the Netherlands
Objectives The aim of this study was to evaluate the progression of atherosclerotic coronary plaques at bifurcations, using combined intravascular ultrasound–virtual histology (IVUS-VH) and optical coherence tomography (OCT).
Background Pathological findings reveal that atherosclerotic plaques characterized by the presence of large necrotic cores (NCs) with fibrous cap thicknesses < 65 μm are more prone to rupture. Accuracy in the detection of high-risk plaques could be improved by the combined use of IVUS-VH and OCT.
Methods IVUS-VH and OCT are 2 imaging modalities with different lateral resolutions and different depths of penetration. To provide a precise matching of the images, bifurcations were used as landmarks. IVUS-VH and OCT were performed in 56 bifurcations from 24 patients at baseline and at 6-month follow-up. All patients were treated with standard medical therapy. Bifurcations were studied at the proximal, in-bifurcation, and distal regions. Plaques were classified according to their composition as assessed by IVUS-VH and fibrous cap thickness as quantified by OCT.
Results At baseline, 27 NC-rich plaques were found. At 6-month follow-up, 22 (81%) did not show any significant change. Four new NC-rich lesions developed. At both time points, percent NC was higher and the fibrous cap was thinner at the proximal bifurcation rim compared with the distal. There were no significant changes in percent NC and fibrous cap thickness in the 3 bifurcation regions between baseline and follow-up examinations. No major cardiovascular events due to bifurcation lesion progression were observed.
Conclusions The combined use of IVUS-VH and OCT is a reliable tool to serially assess plaque progression and regression, and in the present study it was demonstrated to be safe and feasible. At 6-month follow-up, in this post–percutaneous coronary intervention patient population, most high-risk plaques remained unchanged, retaining their imaging classifications, nevertheless appearing to have remained clinically silent.
Plaque rupture and subsequent activation of the clotting cascade resulting in sudden intraluminal thrombosis are thought to be the most frequent cause of acute coronary syndromes (1,2). In pathology, precursor lesions, known as thin-cap fibroatheromas (TCFA), are characterized by a large pool of necrotic core (NC) covered by a thin fibrous cap <65 μm (3). The resolution of current intravascular ultrasound (IVUS) systems (100 to 200 μm) constitutes an important limitation of this technique for the measurement of fibrous cap thickness (4). Optical coherence tomography (OCT), in contrast, has higher resolution (10 to 20 μm) but low signal penetration. This can be a source of inaccurate assessment of NC size, especially in plaques with large plaque burden and positive remodeling, which is a characteristic of TCFA lesions (5). Therefore, combining the 2 imaging techniques might provide a more accurate method to investigate TCFAs (6,7).
There are only a few published reports of the combined use of IVUS and OCT in vivo (6,7) and none describing the longitudinal assessment of plaque progression and regression at bifurcations. The aim of the present study was therefore to evaluate serial changes in plaque type and composition at bifurcations of the main coronary arteries using combined IVUS–virtual histology (VH) and OCT.
Fifty-six bifurcations were selected from 24 patients presenting with stable angina, unstable angina, or silent ischemia. All patients were treated at the Thoraxcenter, Erasmus Medical Center (Rotterdam, the Netherlands), and enrolled in 2 different stent studies (ABSORB cohort B and SECRITT). Both studies used IVUS-VH and OCT as part of their protocols.
The bifurcations selected for this study were more than 5 mm away from the stented region and had side branch orifice diameters >1.5 mm as measured by OCT. Only bifurcations imaged with both modalities and for which imaging was of high quality were considered. All bifurcations fitting this inclusion criteria were included. All patients received standard medical therapy, including aspirin, clopidogrel, and statins, for at least 6 months.
IVUS-VH acquisition and analysis
IVUS acquisitions were performed using an Eagle Eye catheter (Volcano Corporation, Rancho Cordova, California) with automatic continuous pullback at a speed of 0.5 mm/s. IVUS grayscale and IVUS-VH analyses were performed offline using dedicated software (8).
The OCT M3 (Time Domain-OCT) and C7 (Fourier Domain-OCT) systems were used in this study (LightLab Imaging, Inc., Westford, Massachusetts). For each patient, the same system was used for baseline and follow-up examinations. Measurements were performed offline by 2 independent observers using LightLab imaging software.
Fibrous cap thickness measurement was performed in each bifurcation frame at the thinnest part of the fibrous cap overlying the pool of NC. The reproducibility of this variable has been previously reported by our group (9).
Bifurcation matching analysis
IVUS-VH and OCT are 2 imaging modalities with different lateral resolutions and different depths of penetration. To provide a precise matching of the images, a strict selection of frames was followed using a method previously described (7). Only the main branches were analyzed, and for each bifurcation the following frames were considered: 1) the proximal rim of the side branch ostium; 2) the in-bifurcation site (the frame with the largest ostial diameter of the side branch); and 3) the distal rim of the side branch ostium (Fig. 1).
Plaque type classification
Plaques were classified according to the following previously described (7) hierarchical classification: 1) those with high percents of fibrotic tissue (adaptive intimal thickening, pathological intimal thickening, fibrotic plaque, and fibrocalcific plaque); and 2) NC-rich plaques (those with more than 10% confluent NC) (fibroatheroma and calcified fibroatheroma); if covered by fibrous caps thinner than 65 μm, they constitute TCFA and calcified TCFA.
These plaque types are reported per location within the bifurcation (at the distal, in-bifurcation, and proximal frames) and per bifurcation, defined as the worst plaque type within the bifurcation detected among the 3 frames considered.
In addition, we introduce an IVUS-VH and OCT–derived plaque risk index, defined as the ratio between the sum of NC-rich plaques and the sum of non-NC-rich plaques in a given bifurcation region. This index was calculated for each bifurcation region at both baseline and follow-up.
Categorical variables are presented as frequencies and percents. Continuous variables are presented as medians and interquartile ranges and were compared using the Wilcoxon signed rank test. A p value <0.05 was considered statistically significant. The bifurcation was the unit of analysis, without correction for correlated observations in the same subjects. Statistical analyses were performed using SPSS version 16.0 for Windows (SPSS, Inc., Chicago, Illinois).
Patients' baseline clinical characteristics are reported in Table 1. The median age was 67 years, and most patients were men (79%). At follow-up, all patients were treated with statins: 6 received rosuvastatin (4 received 10 mg and 2 received 20 mg), 9 patients received simvastatin (7 received 20 mg and 2 received 40 mg), and 9 patients received atorvastatin (6 received 40 mg, 2 received 20 mg, and 1 received 10 mg).
Results from the geometrical and compositional analysis at the distal rim, in-bifurcation, and proximal rim of the side branch ostium are reported in Table 2.
At follow-up, the median vessel cross-sectional area remained unchanged at the distal, in-bifurcation, and proximal frames, while median luminal cross-sectional area decreased slightly, resulting in an increase in plaque burden (Table 2).
Fibrous and fibrofatty tissue did not change between baseline and follow-up. Median NC cross-sectional area and percent NC nonsignificantly increased in each region. Dense calcium cross-sectional area significantly increased at the distal, in-bifurcation, and proximal segment (Table 2).
In NC-rich plaques (NC > 10% [fibroatheroma, calcified fibroatheroma, TCFA, and calcified TCFA]), the percent of NC nonsignificantly decreased over time at the distal rim (21.65% vs. 18.54%, p = 0.193), in-bifurcation (22.38% vs. 20.25%, p = 0.573), and proximal rim (23.15% vs. 18.06%, p = 0.317).
Distribution of IVUS-VH and OCT–derived plaque types at the 3 bifurcation regions
The distribution of NC-rich and NC-poor plaques is presented in Table 3. There was a gradient of disease from the proximal to the distal rim. NC-rich plaques were more frequently located at the proximal rim. Non–NC-rich plaques showed an inverse gradient. In addition, the highest value of the IVUS-VH and OCT–derived plaque risk index was found in the proximal rim of the bifurcations at both baseline and follow-up. From baseline to follow-up, the index increased in each region, implying that the number of NC regions relative to non-NC regions also increased (Table 3).
Bifurcation plaque types
At baseline, 27 NC-rich plaques were found, of which 6 were classified as thin-cap lesions (TCFA and calcified TCFA). Two fibroatheroma plaques became fibrotic and fibrocalcific (regressed), and 1 TCFA became a fibroatheroma (regressed). Two fibroatheromas became TCFAs (progressed), and 22 (81%) did not change. Four new NC-rich lesions developed from fibrotic and fibrocalcific plaques. Most (83%) thin-cap lesions did not change at 6-month follow-up (Fig. 2).
Fibrous cap thickness, distribution, and changes over time
Fibrous cap thickness significantly decreased from the distal to the proximal region at both baseline and follow-up (Fig. 3). However, no changes in cap thickness were observed from baseline to follow-up within each of the 3 regions (Table 4,Fig. 4). The same held for frames with thin-cap lesions, for which no changes in cap thickness were observed over time (Table 4).
The main findings of our study are as follows: 1) dual-modality acquisition and analysis at 2 different time points for the evaluation of coronary atherosclerosis is feasible, addressing the complementary limitations of the 2 imaging modalities. 2) In a post–percutaneous coronary intervention patient population treated with standard medical therapy, most NC-rich plaques remained unchanged in their composition as measured by IVUS-VH at 6-month follow-up, and most thin-cap lesions remained thin capped (<65 μm) as measured by OCT. 3) Although the study population was small, the serial imaging findings of plaque morphology were in line with the clinical outcomes.
Moreover, we observed that the proximal rim of the side branch ostium is more likely to contain a larger amount of NC and the thinnest fibrous cap within the bifurcation.
The plaque index, defined as the ratio of NC-rich to non-NC-rich frames, increased, implying a progression of the disease at 6 months. This finding is supported by the observation that in this small series, 4 new NC-rich plaques developed and 2 additional plaques became TCFAs. This progression was due mostly to an increase of NC in non–NC-rich plaques (development of new NC-rich areas).
To our knowledge, this is the first in vivo study evaluating longitudinal changes in plaque type and composition using combined plaque assessment with IVUS-VH and OCT.
Sawada et al. (6) recently reported in a small series that 54% of IVUS-VH–derived TCFAs were non-thin-cap lesions by OCT, and 6.3% of OCT-derived TCFAs were not definitively TCFAs. This study strongly supports the combined use of these 2 imaging modalities, which appears to be necessary for the correct detection of high-risk plaques. In addition, Manfrini et al. (5) reported that if used alone, OCT can lead to misinterpretations due to its low signal penetration, which does not allow an accurate detection of signal-poor areas with heterogeneous compositions.
Previously, Kubo et al. (10) reported in a serial population that 75% of TCFAs detected on VH healed at 1-year follow-up. Takarada et al. (11) reported that therapy with statins significantly increased fibrous cap thickness detected with OCT in a population with untreated hypercholesterolemia. However, potentially all single-modality imaging studies could have obtained different results by combining the 2 modalities, virtually increasing accuracy for TCFA detection.
Therefore, further investigations are needed to better understand the evolution of high-risk plaques in patients with optimal medical treatment, and the combined use of IVUS-VH and OCT could be a key tool to characterize the coronary model of future events (12).
This study might have been underpowered to detect differences in plaque composition, and the length of follow-up was short, so the study should be considered exploratory and hypothesis generating, without formal statistical hypotheses.
Local endothelial shear stress was not measured. We cannot exclude that different plaque progression and regression might be also associated in the present series to different shear stress conditions. Because the BVS (Abbott Laboratories, Abbott Park, Illinois) is a drug-eluting device, in bifurcations located distally to the scaffold, the drug might have a considerable impact on the progression or regression of atherosclerosis.
The combined use of IVUS-VH and OCT is a reliable tool to serially assess plaque progression and regression, and in the present study, it was demonstrated to be safe and feasible. At 6-month follow-up, in this post–percutaneous coronary intervention patient population, most high-risk plaques remained unchanged, retaining their imaging classification, nevertheless appearing to have remained clinically silent.
All authors have reported that they have no relationships to disclose. Drs. Diletti and Garcia-Garcia contributed equally to this work.
- Abbreviations and Acronyms
- intravascular ultrasound
- necrotic core
- optical coherence tomography
- thin-cap fibroatheroma
- virtual histology
- Received February 14, 2011.
- Accepted April 19, 2011.
- American College of Cardiology Foundation
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