1INSERM-U647/ESRF, Grenoble, France
2Department of Cardiology, Grenoble University Hospital, BP217 38043 Grenoble, France
3MRI Unit, Grenoble University Hospital, Grenoble, France
4ID17-ESRF, Grenoble, France
5Canadian Light Source, Saskatoon, Canada
Received 21 August 2004; revised 12 January 2005; accepted 13 January 2005; online publish-ahead-of-print 25 February 2005.
* Corresponding author. Tel: +33 476 765 507; fax: +33 476 765 623. E-mail address: bbertrand{at}chu-grenoble.fr
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Abstract |
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Methods and results We recruited 57 men, 46 months after successful PTCA. We visualized the right coronary artery (RCA) in 27 patients with 36 stented segments [12 segments with ISR>50% by quantitative coronary angiography (QCA)], and the left anterior descending artery (LAD) in 30 patients with 37 stented segments (10 ISR). SRA and QCA were performed within 2 days of each other. Two experienced observers unaware of QCA data evaluated the SRA results. Image quality was good or excellent in most patients. Global sensitivity was 64%, specificity was 95%, and positive and negative predictive values were 85%. Inter-observer kappa concordance coefficient was 0.86. False negatives involved short eccentric lesions and superimposed segments, most frequently of the LAD. False positives occurred in intermediate stenoses slightly overestimated by SRA.
Conclusion In men, this minimally invasive approach, using small radiation doses, detects significant ISR in the RCA, but the LAD poses difficulties because of superimposition with others structures.
Key Words: Angiography Coronary disease Restenosis Stents Synchrotron radiation
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Introduction |
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Magnetic resonance imaging (MRI) and multi-detector computed tomography (MDCT) can provide non-invasive visualization of coronary arteries, with still some limitations, but stented segments pose particular problems and these techniques have not, as yet, been clinically validated.5 The shortest acquisition times achievable with MDCT scanners (of a few hundred milliseconds) cannot prevent motion artefacts,6,7 which reduce the accuracy of stenosis assessments. Arterial wall calcifications are well detected by MDCT and MRI, but an accurate quantification of the arterial lumen in calcified segments is often not possible. Advantages of MRI include the lack of irradiation and the fact that circulatory flux produces spontaneous contrast; although better results are achieved when intravascular contrast agents are used.8 However, the need to acquire data during several heartbeats limits the accurate measurement of stenosis in small distal coronary arteries. Thus, in the proximal parts, or in segments with a diameter>2 mm9 of non-stented coronary arteries, MRI and MDCT can achieve sensitivities of >90%, and specificities >80%.5,10 Permeability control of arterial or venous grafts is also an important issue, which is now effective with these techniques.11,12
In stented segments, the visualization of the lumen is still challenging. Despite the recently improved spatial resolution, the metal artefacts in MDCT images arising from the stent struts exaggerate the actual size of the stent, and obscure in-stent abnormalities within the lumen.13 In MRI images, the metal artefacts produced by conventional stents are larger, and jeopardize the in-stent lumen assessment.14 Up to now, no data on ISR imaging with MRI or MDCT, compared with selective angiography, have been published.
Selective coronary angiography remains the reference method for imaging the coronary lumen and for precise quantification of stenoses, but it is not recommended as a first line test for detecting restenosis. Synchrotron radiation angiography (SRA) after bolus injection of an iodinated contrast agent in a central vein, is an imaging method using the different attenuations of two X-ray monochromatic beams when energies bracket the sharp rise of the iodine mass attenuation at 33.17 keV. After subtraction of images simultaneous acquired at two different energies, the background is suppressed and iodine-containing structures are enhanced. The previous studies with SRA, performed in Stanford (SSRL),15 Hamburg (HASYLAB),16 Brookhaven (NSLS),17 and Tsukuba (KEK),18 demonstrated satisfactory feasibility. The aim of the current study was to compare the diagnostic accuracy of SRA with conventional angiography for the detection of ISR.
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Methods |
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The Grenoble 2 Research Ethical Committee approved the protocol as a study without direct benefit to the participants; for this reason, the total irradiation dose was strictly limited to 200 mSv skin dose per patient (2 mSv effective dose). All patients gave written consent to participate. Patients with severe myocardial dysfunction (left ventricular ejection fraction <35%), cardiac arrhythmia (atrial fibrillation or presence of extra ventricular beats), allergy to iodine, renal insufficiency (creatinemia >150 µmol/L), small superficial veins of the upper limbs, or obese patients (weight superior to 120 kg) were excluded. The sample size was determined by the accessibility to the European Synchrotron Radiation Facility (ESRF) with scheduled time periods. First, patients were imaged after right coronary artery (RCA) stenting (n=27), then after left anterior descending artery (LAD) stenting (n=30).
Synchrotron radiation technical set-up
High intensity X-rays with a broadband spectrum were delivered via the ESRF medical beamline that permits monochromatic beams to be generated at any energy. Image contrast can be enhanced by selecting the most effective energy level for each procedure. The K-edge subtraction technique uses the sharp rise in the photoelectric component of the attenuation coefficient of iodine at the binding energy of the K-electron (33.17 keV for iodine). Two images obtained with monochromatic X-rays are simultaneously acquired, just below (E) and just above (E+) the K-edge energy of the contrast agent. The resulting logarithmically subtracted image (or iodine image) allows quantification of the contrast agent concentration in the sample because other materials are subtracted.19 Using the same principle, a so-called tissue image can be generated, in which the iodine contribution is eliminated. The monochromator, a single bent-Laue silicon crystal, generates the E+ and E beams. The X-ray fan formed by the two beams crossing at the sample position is 0.8 mm high and 150 mm wide. The two beams diverge after the sample and are recorded independently with a dual-line detector (pixel size 0.350 mm).
The patient is translated up and down in order to construct a two dimensional image.
Imaging procedure
Two hours before synchrotron imaging, patients received 510 mg bisoprolol (or equivalent beta-blocker), 10 mg benzodiazepine, and 10 mg molsidomine. They also received 20 mg of hydrocortisone to prevent an allergic reaction. A 4F pigtail catheter was inserted into a brachial vein and advanced into the subclavian vein or the superior vena cava under fluoroscopy. In the imaging room, the patient was placed on the scanning device seat in an upright position, with arms raised to eliminate image overlap problems. Patients were asked to hold a deep breath: a single image was acquired at a low X-ray dose before injecting the contrast agent checked the orientation. The following sequences were acquired in similar breath holding conditions in order to image the same cardiac area. The transit time was then measured (time-to-peak procedure) between the injection of 10 mL contrast agent and the arrival of the bolus in the heart, using a series of five synchrotron images at low X-ray dose (5 mSv skin dose) (Figure 1). The mean transit time was 13 s (range 818). Once this contrast agent had disappeared, the imaging sequence took place: 3045 mL of iodine (Iomeron® 350 mg/mL) were injected using an auto injector (at the rate of 18 mL/s). The image sequence was started a few seconds after the injection of the contrast agent depending on the transit time, while the scanning device was moving up and down. The time delay between the two images was 1.3 s. The patients easily performed a breath holding no longer than 20 s. ECG triggering was possible for the first image: using this technique a scan could be taken in the end-systolic phase to avoid LAD superimposition on the left chambers, or in the end-diastolic phase to obtain the best filling of the coronary arteries. Each image line (0.35 mm thick) was acquired in 1.4 ms, and thus no motion artefact occurred. The complete image was obtained within 0.6 s. The dimension of the scan images was 15x15 cm, with a pixel size of 0.35x0.35 mm. The duration of the procedure was 1 h per session. Two incidences were foreseen for each artery in order to optimize the lesions image quality, except for clearly lesions visualizations obtained after the first scan. This occurred in case of suspected eccentricity, superimposition, or tortuous segment. The lesions were quantified in the best incidence. If a second session was required, we waited 40 min to permit the full evacuation of iodine. The left anterior oblique (LAO 3540°) projection was used to visualize the RCA (Figure 2). A second projection was used in 19 cases (18 LAO 8090°, 1 LAO 20°). The right anterior oblique (RAO 3050°) projection was used to visualize the LAD (Figure 3). A second projection was used in 14 cases, using a slightly different RAO position (10 patients) or a LAO (4 patients). The integrated equivalent radiation dose to the skin was <200 mSv for the complete procedure.
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Statistical analysis
Sensibility, specificity, and kappa concordance coefficient were assessed with 95% confidence intervals.
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Results |
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Conventional angiography findings
The RCA was visualized in 27 patients with 36 stent implantations: 6 on the first horizontal segment, 26 on the second descending, and 4 on the third up to the crux.
During the study period, ISR occurred in 10 patients and in 12 segments: four patients had angina, six were symptom-free, but four had ischaemia documented either with thallium or a stress test. Arteries analysis by QCA showed for the RCA, a mean reference diameter of the analysed segments equal to 3.30±0.59 mm (2.144.46) and a mean minimal lumen diameter (MLD) equal to 2.0±0.9 mm (0.243.76). ISR looked focal in eight segments, diffuse in three, and proliferative in one. The ISR rate for the RCA as determined by QCA was 33% (12/36).
The LAD was examined in 30 patients with 37 stents implanted on the proximal (n=15), mid (n=17), and distal (n=2) segments of the LAD, or on a diagonal artery (n=3). During the study period, nine patients had restenosis on QCA in 10 restenotic segments, two had angina, seven were symptom-free, but four had documented ischaemia. Arteries analysis by QCA showed for the LAD, a mean reference diameter of the analysed segments equal to 2.52 ± 0.46 mm (1.623.42) and a mean MLD equal to 1.59±0.79 mm (0.03.14). ISR looked focal in six cases and diffuse in four. The ISR rate on the LAD as determined by QCA was 27% (10/37).
SRA findings
The SRA image quality was excellent in 31 patients (54%), good in 23 (40%), and fair or less in 3 (5%). However, one patient stented in the proximal LAD without restenosis on QCA was excluded because of the poor SRA image quality.
Patients with more than one stented-segment were imaged (1.3 stent/patient), which leads to potential biases due to a patient effect, as the independence assumption is not strictly obeyed. However, these biases sound acceptable since the ability of the method to detect intra stent stenosis depends much more on the stent location and lesion anatomy rather than on the patient himself.
With the two-category classification (less or more than 50% stenosis), five divergences between the SRA observers occurred, giving an inter-observer reproducibility of 93%. The inter-observer kappa was excellent: 0.86 (0.780.94). The divergences occurred in two short eccentric lesions, in two superimposed lesions of the LAD on the diagonal, and one unexplained.
With the two-category classification at the 70% threshold, the inter-observer kappa was 0.70 (0.371.03).
The four-category classification (thresholds: 30, 50, and 70%) led to a moderate overall unweighted kappa value: 0.52 (0.350.68) and 70% reproducibility.
Diagnostic accuracy
SRA successfully detected the presence of ISR (using the greater or less than 50% criteria) with a sensitivity of 64±20% for both observers, specificity 94±7% and 96±5%, PPV 82 and 88%, negative predictive value (NPV) 85 and 86% (Table 1).
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For LAD, when stenosis on QCA was 30%, SRA ruled out restenosis with an NPV of 87 and 84% and a specificity of 91 and 87% for the two observers. At the 70% threshold, discrepancies between observers increased: sensitivity 66 and 33%, specificity 100%, PPV 100 and 50%. On the LAD, half of the lesions were underestimated or missed; however, this may not be significant because of the small number of patients with severe restenosis. On the other hand, the SRA diagnosis of no severe restenosis (70% threshold) was reliable (NPV: 94 and 88%).
Safety and tolerability
Patient tolerance of SRA was excellent and no major complications occurred. In one case, positioning of the pigtail catheter in the superior vena cava for synchrotron imaging was difficult because of a small and tortuous brachial vein. This difficulty was overcome by using a hydrophilic guide wire. The patient experienced periphlebitis, which resolved after a few days.
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Discussion |
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The procedure
For this study, patients (only men) were inpatients; the SRA procedure was easy, and it could be performed on an outpatient basis. Measuring the bolus transit time (mean time 13 s with 510 mL iodine infusion) allowed precise timing for image acquisition and patient positioning with an appropriate incidence for a given known segment. The lumen was clearly seen without artefacts due to calcification, stents, or cardiac motion. When heart rhythm was regular, synchronization with the cardiac cycle could be achieved for at least one image regardless of the heart rate. However, such synchronization was not necessary as no motion artefacts were observed: atrial fibrillation would therefore not prevent the use of SRA.
Image interpretation
The acquisition of two images at different monochromatic X-ray energies leads, with a simple mathematical procedure, to the iodine and tissue images. The pixel-to-pixel correspondence of these two images permits easy localization of the stent, even if it has a low radio-opacity (Figure 2A). A post-processing technique was used to enhance stent visualization. Of the five images acquired during the bolus transit, at least one was always optimal for lumen visualization without artefact.
In most cases, images of the RCA from the ostium to the crux were excellent in the first procedure using LAO 40°, with no superimposition on collaterals or the ventricular cavity. In the case of a tortuous segment, eccentric lesion, or occasional superimposition on a right pulmonary vein, a second session using LAO 80° was needed. Vessels with lumen diameters of <1.0 mm were clearly seen. False positives were due to a difficult analysis, in one case due to superimposition on the pulmonary vein. A divergence with QCA for one stenosis close to 50% (Figure 4) and two false negatives in very short lesions were due to the low signal-to-noise ratio. In this study, the radiation dose was limited; two false negatives occurred in overweight patients (94 and 98 kg) imaged with a low SNR and one patient (92 kg) was excluded because of the poor image quality. This might have been overcome by using higher X-ray doses (increased signal-to-noise ratio).
When compared with the conventional angiograms, satisfactory results were obtained with SRA for RCA images. The specificity and low false positive rate allowed a clear diagnosis of absence of restenosis.
Imaging of the left coronary artery was more difficult. The left main was not studied here because of the unsolved problem of superimposition on the aorta and because of the circumflex artery being superimposed on the full left ventricular cavity. For the LAD, the most useful approach is the RAO 40°, despite the problems of superimpositions on the left ventricle, the appendage or the aorta which must be carefully managed (Figure 5). The use of another orientation (mostly RAO 60°) provided only limited improvements. Proximal, mid, and distal segments were most often visualized. In our study, we noticed one superimposition of the proximal LAD on the left appendage, and two of the mid-LAD on the diagonal (Figure 6) or the LIMA. The distal LAD without superimposition was always clearly seen. One false negative occurred due to a highly eccentric mid-LAD lesion (Figure 7), which was classified as mild in RAO on QCA and synchrotron, but appeared as a severe stenosis only in the LAOcranial view of the conventional angiogram. The major limitations of the SRA techniques were mainly because of projective images and a limited number of incidences. On the LAD, some restenoses were not detected and the sensitivity (observer 1: 40% and observer 2: 50%) was lower than for the RCA (observer 1: 75% and observer 2: 83%), (P=0.03 Fisher exact test).
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The technique of subtracting images acquired at two energies closely bracketing the iodine K-edge permits the effective subtraction of all other structures, whether calcified or metallic;15 this is an important benefit of SRA. The iodine image allows quantification: even stenoses which do not appear as diameter reductions in the projection plane can be detected as the iodine thickness is reduced.
Limitations of the technique are related to the projective mode and the superimposition of other vascular structures. Some arterial segments, notably the left main and the circumflex, remain hard to distinguish. The knowledge of the segment one wants to image is therefore required. With regards to sensitivities and specificities, and assuming that our results are confirmed on larger studies, this SRA technique on stented segments can be favourably compared to CT and MRI techniques.
Clinical implications
SRA is accurate for the analysis of stented segments where other non-invasive techniques are less effective. It has the advantages of being unaffected by artefacts due to the stents, calcifications, or cardiac motion. Stenosis in any part of the RCA can be accurately visualized, but visualization of the LAD may cause problems due to superimposition of other vascular structures. Such a minimally invasive procedure could be repeated to follow-up patients at high risk of ISR, and can identify most of patients without restenosis.
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Acknowledgements |
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References |
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