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To describe progression of coronary atherosclerotic plaque over time by computed tomography (CT) angiography stratified by plaque composition and its association with cardiovascular risk profiles.
Data on the progression of atherosclerosis stratified by plaque composition using non-invasive assessment by CT are limited and hampered by high measurement variability.
This analysis included patients who presented with acute chest pain to the emergency room but had initially no evidence for acute coronary syndrome. All patients underwent contrast enhanced 64-slice CT at baseline and after 2-years using a similar protocol. CT datasets were co-registered and assessed for presence of calcified and non-calcified plaque at 1mm cross-sections of the proximal 40mm of each major coronary artery. Plaque progression over time and its association to risk factors were determined. Measurement reproducibility and correlation to plaque volume was performed in a subset of patients.
We included 69 patients (mean age 55±12years, 59% male) and compared 8,311 co-registered cross-sections at baseline and follow-up. At baseline, any plaque, calcified plaque, and non-calcified were detected in 12.5%, 10.1%, and 2.4% of cross-sections per patient. There was significant progression in the mean number of cross-sections containing any plaque (16.5±25.3 versus 18.6±25.5, p=0.01) and non-calcified plaque (3.1±5.8 versus 4.4±7.0, p=0.04), but not calcified plaque (13.3±23.1 versus 14.2±22.0, p=0.2). In longitudinal regression analysis, the presence of baseline plaque, number of cardiovascular risk factors and smoking were independently associated with plaque progression after adjustment for age, gender and follow-up time interval. The semi-quantitative score based on cross-sections correlated close with plaque volume progression (r=0.75, p<0.0001) and demonstrated an excellent intra- and inter-observer agreement (κ=0.95 and κ=0.93, retrospectively).
Coronary plaque burden of patients with acute chest pain significantly increases over two years. Progression over time is dependent on plaque composition and cardiovascular risk profile. Larger studies are needed to confirm these results and to determine the effect of medical treatment on progression.
Serial assessment of coronary plaque burden has contributed to the understanding of the natural history and pathophysiology of coronary artery disease (CAD) and as a surrogate end point for the evaluation of novel cardiovascular therapeutics (1–8). Invasive modalities such as intravascular ultrasound (IVUS) and serial selective coronary angiography are considered gold standard methods to measure progression of atherosclerotic plaque and stenoses over time (4). However, these modalities are limited by their invasive nature, and the specific characteristics they are able to measure. Non-invasively, repeated measurements of coronary artery calcium (CAC) by electron-beam or multi-detector computed tomography (CT) have been employed to assess changes in CAC burden. However, CAC represents only one component of atherosclerotic plaque and follow-up studies of CAC assessing the role of both medical therapies and cardiovascular risk factors have led to contradictory results (2,9–12). More recently, contrast-enhanced coronary multidetector CT has been established as a robust and reliable modality to non-invasively detect the presence, extent, and composition of coronary plaque (13,14). However, the few studies available suggest a high measurement variability of quantitative assessment of plaque area and volume data (15,16).
In the present study, we determined the intra- and inter-observer variability of a new semi-quantitative method to assess the presence, extent and composition of atherosclerotic plaque as detected by 64-slice coronary CT angiography. This method was employed to assess changes in atherosclerotic plaque burden over two years in a cohort of patients with acute chest pain. In addition, we evaluated measurement variability of our semi-quantitative score based on cross-sections and its correlation to plaque volume measurements. Finally we determined whether changes in atherosclerotic plaque burden were independently associated with traditional cardiovascular risk profiles and correlated this new score with change in plaque volume in a subset of patients.
Patients were prospectively enrolled from the ROMICAT trial, a prospective, observational cohort study of coronary CT angiography in patients with acute chest pain but inconclusive initial evaluation (negative cardiac enzymes, non-diagnostic ECG) in the emergency department (17).
The present study was performed in consecutive subjects who agreed to participate in a two-year follow-up. These patients were contacted by phone and the return visit included a structured clinical interview. Subjects with a creatinine clearance of less than 50 mL/min or atrial fibrillation were excluded. All other subjects underwent repeated contrast-enhanced coronary CT scanning (n=69). The study was approved by the institutional review board of the Massachusetts General Hospital, and all subjects provided written informed consent.
Baseline and follow-up cardiac CT scans were performed using 64-slice scanner technology (Sensation 64, Siemens Medical Solutions, Forchheim, Germany) and identical acquisition protocols as detailed previously (17). Axial CT images were reconstructed with a slice thickness of 0.75 mm and increments of 0.4 mm with retrospective ECG gating.
Coronary reconstructions blinded to patient name and study date were transferred to an offline workstation and curved multi-planar reformations generated (Circulation, Leonardo, Siemens Medical Solutions, Germany). The extent of atherosclerotic plaque burden at both baseline and follow-up was assessed for the entire left main (LM), and the proximal 40 mm of the left anterior descending (LAD), left circumflex (LCX), and right (RCA) coronary artery on 1 mm thick cross-sections reconstructed in 1 mm increments without gaps or overlaps (figure 1). The proximal coronary tree was selected for analysis as these segments contain the culprit lesions in the majority of ACS presentations, and typically have higher image quality on contrast enhanced CT than distal segments (18,19).
For the LCX, the larger of the true circumflex and the obtuse marginal artery was analyzed. To ensure correct co-registration, the first cross-section analyzed in any vessel was immediately distal to either the aorta (in the case of the LM and RCA) or the bifurcation of the left anterior descending artery and the left circumflex (for LAD and LCX). The centerline of the artery was used to advance in 1 mm increments distally to obtain the second and all subsequent cross-sections.
Reconstructed arteries and cross-sections were first analyzed for image quality by two experienced observers and graded as evaluable or non-evaluable. An artery or cross-section was determined non-evaluable when either motion or poor contrast-to-noise ratio rendered the detection of plaque in the artery impossible. Any cross-section deemed unevaluable either at baseline or follow-up was excluded from analysis.
An experienced reader, blinded to time of scanning (baseline/ follow-up) determined the presence of calcified or non-calcified plaque in all evaluable cross-sections. Calcified plaque was defined by any structure distinct from the vessel lumen within the artery wall with a CT attenuation of greater than 130 HU. The presence of any calcification within the corresponding cross-section rendered the cross-section as calcified. Non-calcified plaque was defined by a structure assigned to the coronary artery wall with CT attenuation above the surrounding tissue, but below that of the contrast enhanced lumen without any calcified plaque being present (20).
Inter- and intra-observer variability for plaque detection were assessed in 15 randomly selected subjects at baseline and follow-up by two independent observers blinded to the patient identity and scan date and with a lag period of 2 weeks between the intra-observer readings.
In order to compare volumetric plaque progression with the semi-quantitative score, only patients who had plaque at baseline were eligible (n=38). In addition, we limited analysis to arteries with excellent image quality because measurements of plaque volume are more likely to be affected by decreased image quality than the newly defined score, as prior studies demonstrated significantly increased inter-observer variability for quantification of coronary plaque in cases with poor image quality (21). As a result, we measured plaque volume (in mm3) at baseline and follow-up in 34 vessels (18 LAD, 10 LCX, 6 RCA in 24 patients) using automated software on an offline work-station (SUREPlaque, Vitrea 2, Vital Images, Plymouth, MN, USA). The outer vessel boundary and inner luminal boundary of the proximal 40 mm of the selected coronary artery were initially automatically traced and subsequently manually adjusted in a cross-sectional view. Pixels with attenuation between +1300 and −100 HU within the area between outer vessel boundary and inner luminal boundary were defined as plaque.
At baseline, we collected information on cardiovascular risk profile for all study participants. History of CAD was defined by previous symptomatic coronary artery disease treated by medication or coronary revascularization (stent placement or coronary bypass grafting). Measurement of blood pressure, serum lipids, and fasting blood glucose were obtained during index presentation. Hypertension was defined by a systolic blood pressure of ≥140 mmHg or diastolic of ≥90 mmHg or current anti-hypertensive treatment. Hyperlipidemia was defined by a total cholesterol ≥200 mg/dL or treatment with lipid lowering medication and diabetes by fasting blood glucose ≥126 mg/dL or treatment with hypoglycemic medication. Smoking was defined by current or previous daily cigarette use. Family history of CAD was defined as the occurrence of myocardial infarction in a first degree relative <55 years of age for males and <65 years of age for females. Statin medication was defined as ongoing statin treatment at baseline. The Framingham Risk Score was calculated for each patient using the established regression model (22).
Continuous measures were summarized by mean ± standard deviation and categorical by percentage (counts) unless otherwise specified. Accordingly, Wilcoxon signed rank test, paired t-test and Fishers exact test were used to assess for differences within continuous and categorical variables. Evaluation of inter- and intra-observer agreement was performed by Kappa statistic.
Linear regression was used to determine the amount of plaque volume contained in a single cross-section including the 95% confidence intervals (95%-CI). Absolute and relative change in plaque burden using the semi-quantitative score and the volumetric approach were determined using a Pearson correlation coefficient (r).
In order to estimate the mean plaque rate change over two-year follow-up interval after adjusting for the known cardiovascular risk factors (CVRF), longitudinal linear regression models were employed, which handled the correlated outcomes within persons measured on the baseline and follow-up by the Generalized Estimating Equations (GEE) approach with identity link function. Further, the top quartile of plaque progression was used to identify subjects who progressed rapidly and were compared to demographics, statin use, and return visits to the ED with the remaining cohort.
In order to balance specificity and sensitivity to detect progression, we prospectively determined that the number of cross-sections containing plaque per patient had to increase at least by 2 in order to represent progression. To maintain sensitivity, we performed measurements in 1 mm increments. To maintain specificity, an increase of at least 2 was required.
All performed tests were two-sided and a p-value <0.05 was considered as statistically significant. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Baseline demographics for the 69 patients are presented in table 1. The mean age of patients returning was 55±12, 59% male, and 10 had a history of prior CAD (15%). The median Framingham Risk Score in the cohort was 9 (interquartile range: 4.5–11.4).
Heart rate during the scan was not different between baseline and follow-up (63.0±7.3 vs. 62.7±7.5 beats per minute, p=0.63 respectively). There were 11/276 (4.0%) arteries and 640/9199 (7.0%) cross-sections that were not evaluable at baseline and of these, 10/11 (90.9%) arteries and 513/640 (80.2%) cross-sections were also not evaluable at follow-up. There were an additional 2/276 (0.7%) arteries and 248/9199 (2.7%) cross-sections not evaluable at follow-up. Hence, among all patients a total of 13/276 (4.7%) arteries, and 888/9199 (9.7%) cross-section were excluded from analysis due to image quality (motion or poor contrast-to-noise ratio).
In a subset of 15 randomly selected patients at baseline and follow-up (n=4057 cross-sections) the intra- and inter-observer agreement for the detection of any plaque per cross-section was excellent (κ=0.95, 95%-CI: 0.94–0.97, and κ=0.93, 95%-CI: 0.92–0.95; respectively). Plaque type specific analysis, intra- and-inter observer agreement was excellent for the detection of calcified (κ=0.96, 95%-CI: 0.95–0.97 and κ=0.97, 95%-CI: 0.96–0.98, respectively) and very good for the detection of non-calcified plaque (κ=0.76, 95%-CI: 0.68–0.83; and κ=0.73, 95%-CI: 0.65–0.81, respectively).
At baseline, on average 16.5±25.3 (12.5%) cross-sections contained any atherosclerotic plaque per patient (table 2). Calcified was 5 times more frequently detected than non-calcified plaque (13.3±23.1 (10.1%) and 3.1±5.8 (2.4%); respectively).
We observed a significant 12.7% increase in the mean number of cross-sections containing any plaque (16.5±25.3 versus 18.6±25.5, p=0.01) (table 2, figure 2). When stratified by plaque composition there was a significant 41.9% increase in non-calcified plaque (3.1±5.8 versus 4.4±7.0, p=0.04) but no significant increase in mean number of cross-sections containing calcified plaque (13.3±23.1 versus 14.2±22.0, p=0.2).
Overall, plaque progression (defined as ≥2 cross-sections containing plaque) occurred in 26/69 (37.7%) subjects, no change was observed in 43/69 (62.3%) subjects, and none of the subjects 0/69 (0%) demonstrated plaque regression. Among patients in whom plaque was detected on the baseline scan, plaque progression occurred in 20/38 (52.6%) while no change was observed in the remaining 18/38 (47.4%) patients.
In a subset of 34 vessels on average 9±7 cross-sections plaque with a plaque volume of 100±77 mm3 at baseline and on average 11±8 cross-sections plaque with a plaque volume of 125±91 mm3 at follow-up were detected. One cross-section contained an average plaque volume of 7.6 mm3 (95%-CI: 5.8–9.5 mm3). Absolute and relative change in the semi-quantitative score were strongly correlated with absolute and relative change in plaque volume (r=0.75, p<0.0001 and r=0.79, p<0.0001; retrospectively, figure 3).
In univariate longitudinal regression models age, male gender, hypertension, hyperlipidemia, history of CAD, number of cardiovascular risk factors (CVRF), Framingham risk score (FRS), presence of baseline plaque, and baseline stain medication were significantly associated with progression of any atherosclerotic plaque (figure 4). In models adjusted for age, gender and the follow-up time interval, the presence of baseline plaque, number of cardiovascular risk factors (CVRF), smoking, and baseline stain medication were associated with increase in plaque over the follow-up period (figure 5).
Subjects who were in the highest quartile of plaque progression (n=17) did not differ with respect to age, gender, and statin medication (p=0.63, p=0.39, and p=0.38; respectively) from the remaining cohort. In contrast, subjects with rapid progression were more likely to return to the ED with recurrent chest pain as compared with the remaining cohort (29.4% vs. 7.7%, p=0.03).
In this study, we demonstrate a significant increase in coronary plaque burden over a two year period (12.7%, p=0.01) among patients with acute chest pain but without ACS using a highly reproducible semi-quantitative assessment of coronary plaque burden (kappa of 0.95 and 0.93 for intra- and inter-observer agreement, respectively). Our results further indicate that there are differences in progression rate according to plaque composition as we found no significant progression for calcified plaque while non-calcified plaque progressed significantly over time (41.9%, p=0.04). Progression of plaque was significantly associated with presence of baseline plaque, smoking, stain use, and number of cardiovascular risk factors in adjusted analysis. Furthermore, in a subset of vessels we demonstrate a robust correlation of the absolute and relative change of the semi-quantitative score to progression of actual plaque volume (r≥0.75, p<0.0001 for both).
Although feasibility of quantitative measurement of coronary plaque volume by 16- and 64-slice CT using methodology similar to IVUS has been previously described in selected patients with exceptional image quality, these studies found substantial inter-observer variability for the assessment of plaque volume between 16 and 37% (15,16). The lack of agreement has been related to low contrast resolution of CT and the resulting difficulty to correctly delineate the boundaries of smaller non-calcified plaques and further indicates the limited utility of this method for progression studies. As a result, many investigators have returned to using a qualitative description of plaque burden most often stratified by coronary segments (23–25).
In this study, we introduce a semi-quantitative technique with excellent observer reliability for both calcified and non-calcified plaque, based on the detection of plaque presence in consecutive cross-sections. This technique rendered a low inter-observer variability of 0.2%, which is a prerequisite to assess changes in plaque burden over time. Furthermore, we found a good correlation between absolute and relative change of the new semi-quantitative score with volumetric plaque progression (9±7 to 11±8 cross-sections plaque compared to 100±77 mm3 to 125±91 mm3 at baseline and follow-up; respectively, r≥0.75, p<0.0001 for both). The high concordance indicates that the semi-quantitative approach provides a good estimate of volumetric progression and that the differences as a result of cross sectional plaque progression (e.g. positive remodeling) may be limited. Although these initial results are encouraging, they warrant further confirmation in larger studies, optimally with IVUS and a detailed quantitative assessment of remodeling index.
Our results suggest that the rate of progression in patients presenting to the emergency department with acute chest pain over two years is 12.7% for any plaque. While we observed a large relative and significant increase in non-calcified plaque at 2-year follow-up (3.1±5.8 baseline versus 4.4±7.0 follow-up, p=0.04), the absolute change was similar between calcified and non-calcified plaque. This observation is in contrast to previous CT studies on the progression of CAC who reported progression as high as 40% per year even in asymptomatic subjects (3,9–12). However, it is consistent with IVUS studies which have suggested that the plaques may undergo only minimal changes over time (<1% per year atheroma volume measured by IVUS) (20). The discrepancy may be explained by the fact that most of CAC progression studies have relied on CT imaging acquisition techniques which have been shown to have significant measurement variability (22,26).
In out study, the negative association between plaque progression and diabetes is likely a reflection of the small number of diabetic patients within the cohort (n=4). Similarly, the finding that current statin treatment was associated with plaque progression can be attributed to confounding by history of CAD. However, our results suggest that subjects who had the highest rates of plaque progression (top quartile) were re-evaluated for recurrent chest pain more frequently during follow-up as compared to subjects in the bottom quartile of progression.
The baseline and follow-up CT scans were performed on the same scanner adhering to a standard protocol. A further strength is the standardized assessment of plaque, including assessment of intra- and inter-observer variability for both calcified and non-calcified plaque. Furthermore, the study uses a longitudinal regression model that enabled an assessment of progression accounting for baseline plaque burden and uses prospectively collected information on cardiovascular risk factors.
Our assessment is limited to the LM and the first 40 mm of the main coronary arteries. However, capturing proximal plaque may be most relevant as the majority of clinical events arise from these plaques (18). Also we used dedicated coronary evaluation software, which permit automated reconstruction of cross sectional images, the evaluation of each cross-section remains time consuming (15–20 minutes per patient). Further improvements in cross registration and documentation of assessments are necessary to enhance practicality.
In addition, our assessment does not capture cross-sectional plaque extension such as area growth or remodeling, which are important aspects of the progression of individual plaques. However, we found a robust correlation between volumetric progression and longitudinal semi-quantitative assessment (Pearson’s correlation coefficient 0.75; p<0.0001 for both absolute and relative change).
Finally, the present study describes the progression of atherosclerotic plaque stratified as calcified and non-calcified plaque. We omitted the category of mixed plaque because plaques seen as calcified in CT usually contain also non-calcified (fibrous or lipid rich) components, which are not visualized in CT due to the blooming effect of calcification (27). Moreover, in the current analysis we determine plaque progression on a cross-section rather than on a plaque basis.
A reliable non-invasive method to serially evaluate both calcified and non-calcified plaque provides a unique opportunity to validate plaque progression as a surrogate marker for the assessment of cardiovascular risk and most importantly for the effect of medical therapies for cardiovascular disease. The ability to detect progression of non-calcified plaque warrants further assessment and validation especially as a potential surrogate marker for the effects of medical therapy.
Coronary plaque burden of patients with acute chest pain significantly increases over two years but rate of progression is dependent on plaque composition and may be higher for non-calcified when compared to calcified plaque. Progression is further associated to cardiovascular risk profile at baseline. Larger studies are needed to confirm these results and to determine effect of medical treatment on progression.
This work was supported by the NIH (RO1 HL080053), and in part supported by Siemens Medical Solutions and General Electrics Healthcare. Dr. Shturman was supported by the National Institutes of Health grant T32HL076136. Dr. Lehman was supported by grants from the National Heart Foundation of Australia and the Royal Australian and New Zealand College of Physicians and Mr. Schlett in part by grants from the German Federal Ministry of Education and Research and the Foundation of German Business, Berlin.
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