MedicaMundi

G. Korosoglou - University of Heidelberg, Department of Cardiology, Heidelberg, Germany.

T.B. Ivanc - CT Clinical Science, Philips Healthcare, Highland Heights, OH, USA.

D.K. Mueller - CT Clinical Science, Philips GmbH Healthcare Division, Hamburg, Germany.

H.A. Katus - University of Heidelberg, Department of Cardiology, Heidelberg, Germany

Heidelberg University Hospital

Heidelberg University Hospital (Figure 1a), founded in 1386, is one of the largest and most renowned medical centers in Europe. It is closely linked to Heidelberg University Medical School, founded in 1388, which is the oldest within Germany.

The university hospital is actually made up of 12 hospitals, most of them being situated on the New Campus (University of Heidelberg), about 10 driving minutes away from the old town (Figure 1b). Heidelberg University Hospital is constantly developing new methods of diagnosis and treatment at the forefront of biomedical science for the benefit of all patients.

This article summarizes the advances of plaque analysis with computed tomography (CT) and describes the principles of the plaque delineation. It also presents new interdisciplinary research, where CT plaque analysis representing non-invasive diagnostic imaging is compared with results from biochemical marker analysis in laboratory diagnostics. Finally, we provide an outlook to the future of plaque assessment using cardiac CT and spectral CT. 

Despite advances in the treatment of coronary artery disease (CAD), atherosclerosis remains the leading cause of death in Western societies and the predominant underlying cause of sudden cardiac death [1, 2]. In this regard the role of inflammation in all stages of atherosclerosis is now widely appreciated [3]. Conventional X-ray coronary angiography has been the modality of choice for diagnosing the presence and extent of CAD. However, this technique is invasive, only visualizes the vessel lumen, and provides limited information on the composition of atherosclerotic plaque [4]. 

Recent developments in coronary computed tomography angiography (CCTA) and the dedicated post-processing tools of the Philips Extended Brilliance Workspace (EBW) constituted a major step towards the non-invasive detection of CAD, including the characterization of atherosclerotic plaques [5-10]. Moreover, in patients with acute coronary syndromes (ACS) the rupture of unstable (also called vulnerable) coronary atherosclerotic plaques with initiation of thrombus formation and embolization of atherosclerotic debris can lead to myocardial cell necrosis, due to the occlusion of the coronary vessel. In such patients leakage of the biochemical marker troponin leads to detectable levels of troponin in blood, aiding their diagnostic classification and risk stratification [11-13]. Minor elevations of troponin, however are also detectable in stabilized patients after ACS [14] and in patients with stable CAD [15].

CT plaque analysis software 

Threshold techniques in the gray value domain of CT have been sufficiently accurate to differentiate between soft and bony tissue, because of the pronounced difference in their X-ray attenuation. Soft tissue (muscle, organs) exhibits typical values of 20 - 70 Hounsfield Units (HU), whereas cortical bone resides at 400 - 1000 HU. However, delineation of healthy tissue components possessing similar attenuation profiles, and those mixed with multiple forms of pathological tissue in a narrow HU bandwidth, is challenging or even impossible for threshold-based approaches. As in numerous natural phenomena, the inherent variation in the histogram of measurement events around a mean HU can be described with a Gaussian (bell) curve. 

The degree of overlap of different tissue compartments (or even mixed tissue) and the associated Gaussian distributions can be substantial. The Gaussian mixture model was sought as a promising remedy to this complex problem where a given superposition of several Gaussian curves can be separated into its individual components. As Ayers et al. showed [16] in tumor staging, different tumor compartments representing both viable and necrotic tissue can be successfully separated by utilizing the Gaussian mixture model. They even demonstrated the capability of extracting volume information on tumor lesions. In this example the histogram of all HU values was assumed to comprise three compartments, enabling the monitoring of cancer therapy. 

This phenomenon can be extended to coronary plaque and was adopted in the design of Philips CT Plaque Analysis, part of Comprehensive Cardiac Analysis (CCA) on the EBW workstation, where different pathological tissues exhibit varying behavior in X-ray attenuation. To the best of our knowledge, Philips CT Plaque Analysis is the industry’s only application which utilizes this novel Gaussian mixture model technique. 

The clinical manifestation of calcified (“hard”) and non-calcified (“soft”) plaque is associated with distinctive therapeutic regimes. Mixed plaques residing in the intermediary realm of HU attenuation lead to a substantial overlap of the associated histograms. The risk of the patient suffering a life-threatening plaque rupture and subsequent release of a thrombus is more pronounced in the case of soft plaque. It is therefore imperative to characterize the plaque composition. An example of pronounced non-calcified contributions is shown in Figure 2, where there is a mixture of four Gaussian components.

Previous studies with CT Plaque Analysis

Philips’ advanced cardiac CT application, CCA, provides automatic, model-based, whole heart segmentation [17, 18] and zero-click coronary artery segmentation, enabling automatic extraction and visualization of the entire coronary tree. A quick measurement of the luminal percent diameter and percent area stenosis is available using Coronary Analysis where the vessel and lumen contours are displayed. 

CT Plaque Analysis, part of CCA on EBW v4.0.2, v4.5 and also available on IntelliSpace Portal from early 2011, provides an additional interactive tool to quantify and characterize coronary plaque composition from contrast cardiac CT exams. The semiautomatic application provides detection of plaque findings along the vessel wall using a simplified workflow via a single-click algorithm. Measurements comply with the standard intravascular ultrasound (IVUS) measurements and, additionally, provide a remodeling index for each plaque finding. 

The significance of CAD and several prominent case studies of CT Plaque Analysis were described by Dalager et al. in a previous article of Medicamundi [19]. Prior to invasive coronary angiography (CAG) and virtual histology IVUS (VH-IVUS), patients underwent a contrast-enhanced cardiac CT as part of a research project on the Philips Brilliance 64-channel scanner. CT findings correlated well with those of CAG. CT exams were evaluated with CT Plaque Analysis and CT findings showed agreement with those provided by VH-IVUS. This indicated that additional data on the entire disease state of the patient may guide further prevention and treatment options. 

In another study of 35 patients [20] scanned with Philips 256-slice Brilliance iCT scanner, the interobserver variability of non-calcified plaque lesion volume was lower than that of mixed and calcified lesions. It also revealed that the relative composition of non-calcified lesions is very reproducible indicating that there may be a role for MDCT in serial plaque assessment in non-calcified lesions. This study was limited to patients with a single lesion in the proximal left anterior descending (LAD) artery to allow the study to focus on the reproducibility of CT Plaque Analysis using the Gaussian mixture model avoiding confounding parameters related to vessel size or geometry. 

In our first study conducted in the University of Heidelberg [21], we evaluated the composition of atherosclerotic plaques with CT Plaque Analysis in 27 patients with high pre-test probability for CAD who underwent 256-slice non-contrast calcium scoring and contrast-enhanced cardiac CT angiography (CTA) with the Brilliance iCT followed by CAG and Quantitative Coronary Angiography (QCA) using commercially available software (Centricity QCA, GE Medical Systems). Using the CCA package, the grade of diameter stenosis was determined for each lesion and compared to the CAG findings with QCA as the gold standard. Using the Gaussian mixture model in CT Plaque Analysis calcified and non-calcified components of both low and intermediate attenuation (0 – 150 HU) were differentiated in atherosclerotic lesions. 

Our study showed a high correlation between stenosis severity by QCA and CTA. Using QCA as the clinical gold standard, CTA yielded high sensitivity, specificity and accuracy for the detection of both ≥ 50% and ≥ 75% diameter lesions. Assessment of plaque volume with CT Plaque Analysis yielded highly reproducible results and high agreement between observers for the differentiation between non-calcified, mixed and calcified plaques. Furthermore, prospective ECG-gated imaging with the 256-slice CT could be performed in most patients with suspected CAD limiting radiation exposure to ~3 mSv effective dose. Building upon our initial study, the University Clinic Heidelberg evaluated the ability of the Philips 256-slice Brilliance iCT in conjunction with the EBW CT Plaque Analysis software to assess the association of plaque size and composition with cardiac troponin T [22]. 

Most recently Lee et al. [23] assessed the intra- and inter-observer reproducibility in evaluating volume and characteristics of 42 non-calcified plaques from 39 asymptomatic patients using the Philips 256-slice Brilliance iCT scanner. Two experienced observers independently evaluated the lesions to determine interobserver variability and one of the observers repeated the evaluation of the entire dataset after an interval of at least 4 weeks to determine intraobserver variability. This study found reliable reproducibility for plaque volume, mean CT attenuation and remodeling index of non-calcified plaques indicating that CT Plaque Analysis of cardiac CTA exams might be helpful for risk stratification and serial assessment. 

Correlation of plaque content with Biomarker Troponin T 

Methods

Patients undergoing clinically indicated CCTA for suspected CAD were scanned on the Philips Brilliance iCT with 8 cm of longitudinal coverage, a tube voltage of 120 kVp and a gantry rotation time of 0.27 s (resulting in a nominal temporal resolution of 135 ms for prospective ECG-triggered axial scans). The detector collimation was 2 × 128 × 0.625 mm, creating 256 overlapping slices via a dynamic z-flying focal spot. Patients with non-sinus rhythm, elevated serum creatinine, previous bypass surgery or stenting, unstable angina, or a contraindication for the administration of contrast agent were excluded. Traditional risk factors for CAD were recorded at the time of the CT. 

The contrast agent protocol included the intravenous administration of incremental doses of 2.5 mg of metoprolol (range 2.5 - 25.0 mg), (Lopresor^®, Novartis, Pharma GmbH) 20 - 30 min before the CT in patients with heart rates ≥ 65 beats/min. If the heart rate remained ≥ 65 beats/min despite the administration of metoprolol, a helical CT with retrospective ECG-gating was performed. If the heart rate decreased to < 65 beats/min, a low-dose prospective ECG-triggered axial scan (Step & Shoot Cardiac) was performed. Time-current settings of 800 - 1050 mAs (depending on patient habitus) and 200 mAs were used for helical and axial acquisitions, respectively. Furthermore, sublingual glyceryl nitrate was administered immediately before the CT for coronary vasodilatation. Prior to CCTA, calcium scoring (HeartBeat-CS) was performed to exclude patients with calcium score above 800 Agatston Units from this study. 

For CCTA a bolus of 80 ml of contrast agent (Ultravist 370, Bayer Healthcare) was injected intravenously at a rate of 6 ml/s. Bolus tracking was deployed with simultaneous ECG recording. With helical acquisitions, reconstructions were routinely performed at 40%, 70%, 75% and 80% of the cardiac cycle. In axial mode the ECG-triggering was targeted at the 75% cardiac cycle. 

Analysis of coronary plaque volume and composition 

The composition of atherosclerotic plaque was assessed with the EBW using the CT Plaque Analysis option (ver. 4.0.2). The aim was to differentiate between calcified and non-calcified components on CT images according to regional attenuation values [7, 24-25]. According to the calcium content, plaques were classified into:

• soft (calcium content < 20%)
• mixed (calcium content between 20% - 80%)
• calcified (calcium content > 80%).

Soft and mixed plaques (with non-calcified content ≥ 20%) are expected to contain substantial amount of lipid cores or fibrotic tissues [24, 26] apart from calcified tissue, and were addressed as “non-calcified” plaques. For each coronary artery, the vessel lumen and wall were automatically registered, and after the identification of each lesion the boundaries were manually edited if necessary. Subsequently, the identified plaques were marked, and the validity of the proposed lesion areas was evaluated in adjacent cross-sectional multi-planar reconstructed images of the coronaries. Care was taken to correctly discriminate between iodinated blood (300 - 600 HU) and calcified plaque, and the Gaussian algorithm mode was used to distinguish between non-calcified components of low to intermediate attenuation (0 to 150 HU) and calcified plaque components with higher attenuation values, and for plaque content calculation. 

For each lesion the following parameters were assessed:

• non-calcified plaque volume for each individual lesion and per patient
• plaque composition
• vascular remodeling, defined as a change in the vessel diameter at the plaque site in comparison to the reference segment proximal to the lesion (reference diameter) of ≥ 10% [27]. 

Measurement of high sensitive troponin T (hsTnT)

At the University Clinic Heidelberg a highly sensitive troponin T assay (hsTnT) has recently been developed and validated. This allows the detection of TnT at the 99th percentile of a healthy reference cohort with < 10% variability, further enhancing the accuracy of 4^th generation assays [28]. Blood samples were collected from all patients within two hours before the CTA scans, centrifuged and stored at -80°C until analysis. An ELECSYS 2010 automated analyzer was used (Roche Diagnostics, Mannheim, Germany) for hsTnT quantification. 

Statistical analysis

The relation between Agatston score and total non-calcified plaque volume with hsTnT was assessed using linear regression analysis. Differences in hsTnT levels by stenosis severity and by plaque composition with or without vascular remodeling were assessed. Intra- and interobserver variability for quantification of plaque volume, plaque subtype categorization and vascular remodeling were calculated by repeated analysis of 40 randomly selected cases. The readings were separated by 8 weeks to minimize recall bias. Differences were considered statistically significant at p < 0.05. 

Results 

Clinical and demographic data of our patients are illustrated in Table 1. All CT scans were performed without adverse events, and diagnostic image quality was achieved in 1830 of 1848 available coronary segments (99.0%). 

Data presented as number of patients or as mean ± standard deviation.
* p < 0.001 for radiation exposure between prospective and retrospective scans.

Table 1. Demographic and CCTA data. 

Composition of atherosclerotic plaques

Examples of a soft and a mixed atherosclerotic lesion along with their corresponding Gaussian curves representing different plaque components are shown in Figure 3. 

Association of hsTnT with calcified and non-calcified plaque

Weak, albeit significant correlations were observed between the number of segments containing calcified plaque and total calcium scoring with hsTnT, see Figure 4a and b, respectively. Closer correlations were observed between the number of coronary segments containing non-calcified plaque and, particularly, with total non-calcified plaque volume, in Figure 3c and d, respectively.

Patients with normal coronaries exhibited significantly lower hsTnT levels compared to those with CAD. However, no differences were observed by stenosis severity (i.e. between patients with < 50% versus ≥ 50% stenosis), see Figure 5a. Conversely, strong differences were observed by plaque composition and vascular remodeling. Thus, patients with non-calcified plaque showed higher hsTnT levels compared to those with normal vessels or to those with only calcified plaque, and those with remodeled non-calcified plaque, showed markedly higher hsTnT levels than all other groups, see Figure 5b. 

The inter- and intraobserver variability for the assessment of total plaque burden, differentiation between soft, mixed and calcified plaque and for the assessment of vascular remodeling revealed good agreement between observers. 

Discussion and conclusion 

Our study demonstrates the ability of the EBW CT Plaque Analysis software to objectively assess the composition of plaque with high reproducibility and to quantify plaque volume on images of coronary vessels acquired using 256-slice CT. For the first time an association was established between plaque composition, analyzed from CT scans, and hsTnT, a widely accepted biomarker of increased cardiovascular risk. Patients with non-calcified coronary plaque, and especially those with remodeled lesions, exhibited increased hsTnT levels in blood compared to patients with normal vessels and to those with purely calcified lesions. 

Few studies have investigated the value of multi-slice CT for the characterization of atherosclerotic plaque composition so far, as conventional coronary angiography is regarded as the gold standard, and IVUS or histology as other reference standards. Atherosclerotic lesions prone to rupture (vulnerable plaques) are characterized by macrophage infiltration, high lipid content and overlying thin fibrous cap [29, 30]. Recently, the composition of plaques on CT was elegantly shown to be predictive for outcome [24]. Thus, patients with low-attenuation plaque and large plaque volumes exhibited a high likelihood of plaque rupture, associated with an increased rate of subsequent acute coronary syndromes. 

As the prognostic impact of cardiac CTA becomes clear, methods and tools that allow the objective and quantitative assessment of plaque volume and composition become crucial. Our data form an important foundation for the development of prospective imaging-based prevention studies to monitor the effectiveness of pharmacological interventions in regard to plaque burden. To facilitate the application of cardiac CT for screening and follow-up purposes however, a number of steps will be necessary towards the development and implementation of low-radiation dose protocols with prospective ECG-gating combined with lower tube voltages and iterative reconstruction algorithms. The first experiments of this kind are underway.

According to the acquired results, chronic, clinically silent coronary plaque rupture and micro-embolization may represent a potential pathophysiologic source of chronic troponin leakage in patients with stable CAD. Such micro-embolization may occur in the absence of flow-limiting stenosis, so that the dissociation between troponin leakage and stenosis severity, as observed in our study, is not surprising. On the other hand, increased cardiovascular risk in patients and in apparently healthy subjects with elevations of cardiac troponins [27, 31, 32] suggests that clinically silent plaque rupture causing repetitive microembolization may precede the clinical manifestation of myocardial infarction or sudden cardiac death [33]. This is in agreement with recent clinical findings that increased hsTnT concentrations are independently associated with the incidence of cardiovascular mortality in patients with stable CAD [15]. 

Further studies are now warranted to investigate the prognostic significance of our findings and to test the value of pharmacologic or interventional therapeutic strategies in larger patient cohorts.

Future outlook 

The delineation of plaque tissue awaits advances in CT to relieve the medical community from the limitations posed by the 40-year-old Hounsfield measurement principle. The first published phantom tests [34] with spectral CT – currently under development by the Philips Research Laboratories in Hamburg, Germany, and still in an early prototype phase – provide evidence that blood pool and plaque can be visualized selectively. Going one step further, combining dedicated contrast agents targeted tofibrin or macrophages and labeled with K-edge (causing dramatic changes in X-ray attenuation) with spectral CT could perhaps eventually allow the localization and quantification of even small amounts of soft plaque [35] through direct physical and chemical interactions.

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Figures

Figure 1a. The University Hospital of Medicine (Head of the Department:
Professor Hugo A. Katus).

Figure 1b. Old city of Heidelberg, Germany, with the traditional castle in the
background.