Small coronary calcifications are not detectable by 64-slice contrast enhanced computed tomography

We randomly selected 23 patients (18 male, mean age 54 ± 11 year) from the subpopulation that was imaged in our institute for PROSPECT trial. The patients were treated in our institution for acute myocardial infarction or unstable angina. They were only included in our study if an IVUS pullback was performed in one or more of their coronary arteries, if they underwent MSCT coronary angiography shortly before or after (on average 2.0 days after the IVUS acquisition) the interventional procedure, if they had a heart rate lower than 70 bpm during the MSCT acquisition and had no prior coronary bypass surgery. Exclusion criteria to perform the MSCT were renal failure, contrast allergy, irregular heart rate, contra-indication to β-blockade. More details regarding the patient selection criteria can be found elsewhere [19].

Based on a power calculations in a pilot study, we aimed for 100 calcifications on IVUS, which we reached by inclusion of 23 patients. Of these patients we only included arteries that were not stented. Patient demographics are given in Table 1. Our institutional review board approved the initial study protocol, and all patients gave informed consent.

Patients received ≥200 μg of intracoronary nitroglycerin before acquisition. One or more of the coronary arteries of these patients were imaged by IVUS with commercially available 40 MHz (Atlantis SR Pro, Boston Scientific, Boston, Massachusetts) ultrasound catheters. A motorized pullback was performed at 0.5 mm/s, starting >10 mm distal to the segment analyzed and ending at the aorta-ostial junction. Images were recorded on DVD and off-line analysis with an image-based ECG-gating method [20] was performed such that images shortly before systole were extracted from the complete pullback. This provides us with a stack of gated IVUS images with an axial spacing of approximately 0.5 mm (see Fig. 1a).

The patient preparation, scan protocol, and image reconstruction procedure have been previously described [21]. Briefly, MSCT was only performed in patients who had a sinus rhythm, who had no contra-indications to the administration of contrast agents and who were able to hold their breath for 15 s. Patients with heart rates above 70 beats per minute were administered a single oral dose of 100 mg metoprolol 45 min before scanning. Scanning was performed on a 64-slice MSCT scanner (Sensation64^®, Siemens, Germany). A non-contrast enhanced scan for calcium scoring with a z-spacing of 1.5 mm was followed by a contrast enhanced scan (Iomeron 400^®, Bracco, Italy) according to a standardized optimized contrast enhanced scanning protocol. No adaptation of the protocol was applied to adjust for body mass index or body surface area. A bolus tracking technique was used to synchronize the arrival of contrast in the coronary arteries with the initiation of the scan. Images were reconstructed with ECG-gating, initially during the mid- to end-diastolic phase (350 ms before the R-wave) with a temporal window of 165 ms. If image quality was poor, more reconstructions at different phases of the cardiac cycle were generated, sometimes combined with a different temporal window; the reconstruction with the best image quality was chosen for further processing. A medium-smooth reconstruction kernel was applied (B30f). The in-plane voxel size was approximately 0.3 mm and the slice thickness 0.4 mm.

Goal of the registration process was to reconstruct cross-sectional MSCT images of the coronary artery at the same axial position where the IVUS images were obtained. Details regarding the registration procedure, for which we used in-house developed software (based on MeVisLab, Mevis, Bremen, Germany), can be found elsewhere [18].

Briefly, the registration process was performed as follows: After ECG-gating the IVUS images had an axial distance of approximately 0.5 mm (Fig. 1a). In this IVUS stack we identified bifurcations, which were used as landmarks (Fig. 1b). To register the MSCT to the IVUS images a centerline of the vessel of interest was manually drawn in the MSCT dataset starting from the ostium. Perpendicular to the centerline, cross-sectional images of the vessel were equidistantly generated at every 0.2 mm (see Fig. 1d). In this MSCT image set we searched for the IVUS-derived landmarks (see Fig. 1c). Sampling the MSCT data set with a higher axial resolution compared to the IVUS images (0.2 mm axial distance versus 0.5 mm) enabled us to register the bifurcations in the two data sets more accurately. After manual registration of the side-branches, cross-sectional MSCT images perpendicular to the centerline were generated again, but now such that the number of MSCT images between the landmarks was equal to the number of IVUS images between the landmarks (Fig. 1e). As registration is only possible between landmarks, at least two bifurcations had to be identified on both imaging modalities. The result of this registration procedure is a corresponding MSCT image for each IVUS image between the most proximal and most distal landmark, thus enabling a one-to-one comparison between these images.

The IVUS images were inspected for the presence of calcium in the wall. Calcium was identified by its specific echogenic appearance, accompanied by an acoustic shadow [7]. Calcifications can extend over multiple IVUS images. Since it is not possible to reliably identify the trailing edge of calcifications, we only determined the length and the maximum circumferential angle of each calcification. The length of a calcification was calculated by multiplying the number of slices the calcium extends over by the mean distance between the images. The angle of a calcification was determined by drawing two vectors on each cross-section from the center of the vessel to the corners of the acoustic shadowing (see Fig. 2a). For each calcification the largest angle was determined. The IVUS images were analyzed blinded to the MSCT images.

The MSCT images were analysed with in-house developed software based on MeViLab (Mevis, Bremen, Germany), using a window setting between 500 and 700 HU with at a level between 150 and 250 HU. We identified calcifications in MSCT cross-sectional images as any structure with a density of 130 HU or more that could be visualized separately from the contrast enhanced coronary lumen (because its density was above the contrast enhanced lumen) and that could be assigned to the coronary artery wall. Structures with an intensity <130 HU, but clearly embedded in or adjacent to the surrounding non-calcified plaque with a lower intensity were also defined as calcifications.

Identification of the calcifications was supported by gradient images. Gradient images are derived from the normal images and they represent the local change in image intensity (Fig. 2b, c). The transition from high intensity lumen to the low intensity epicardial tissue is depicted as a white ring in the gradient image. The transition from the high intensity lumen to a calcified plaque results in a second ring adjacent to the ring of the lumen. All the MSCT cross-sections were checked for calcifications blinded from the IVUS images.

For each calcification detected in the IVUS images we determined whether it was also present in the corresponding MSCT image, and vice versa. Based upon these analyses we identified three groups: (1) calcifications identified on both modalities; (2) calcifications identified on IVUS only and (3) calcifications identified on MSCT only.

For the calcifications that were missed in the contrast enhanced scan, we checked if these calcifications could be identified on the non enhanced calcium score scan. To be able to compare the 3D voxel space from the two MSCT scans, the two data sets have to be registered. This procedure is difficult since anatomical landmarks, like bifurcating arteries, are not visible in the non contrast enhanced scan. These analyses were performed only for those MSCT scans for which a reliable matching could be performed.