Our study was approved by the institutional ethics committee, and the written informed consent was obtained from each patient. The study design was retrospective. Patients were recruited from an existing prospective study database consisting of consecutive patients suspected of CAD presenting with acute or stable chest pain to our hospital between March 2017 and November 2019. Patients who underwent cardiac dual-energy CT scan, resting 13N-ammonia positron emission tomography (PET) and invasive coronary angiography (ICA) within one week time interval between examinations were enrolled. Patients were excluded if they had history of myocardial infarction, cardiomyopathy, myocarditis, contraindication to iodinated contrast agent, atrial fibrillation or renal dysfunction (estimated glomerular filtration rate < 60 ml/min/1.73 m2).
PET data acquisition and image analyses
PET examinations were performed at rest on ECAT EXACT (CTI-Siemens, Knoxville, Tennessee, USA), which provide 47 tomographic slices. Patients abstained from food at least 6 h before the PET examination. Resting PET myocardial blood flow imaging was acquired 15 min after 13N-ammonia (555 MBq) was injected. Tomographic images were reconstructed by the filtered back projection method. Typical horizontal long axis, vertical long axis, and short axis tomographic views of the left ventricle were obtained by an image processing workstation for image analysis.
PET images were visually analyzed by 2 experienced readers who were blinded to the patient information. Horizontal long axis, vertical long axis, and short axis images were assessed on a per-segment and -territory basis using American Heart Association 17-segment model [10]. The disagreement of diagnosis between 2 readers was settled by a consensus reading. The disagreement of diagnosis between 2 readers was settled by a consensus reading.
Invasive coronary angiography
ICA was performed by standard catheterization in accordance with the American College of Cardiology Guidelines for Coronary Angiography [11]. ICA was evaluated by quantitative coronary angiography (QCA; QuantCor QCA, Siemens AG Healthcare) by 2 cardiologists in consensus who were blinded to the dual-energy CT and PET results. All coronary artery stenosis was graded at least 2 orthogonal views and measurement was performed in the projection that showed the highest degree of stenosis. A mismatch between PET and ICA was defined as a positive PET scan with a negative ICA for significant coronary stenoses or a negative PET scan with a positive ICA for significant coronary stenoses.
Dual-energy CT scan protocol
All CT examinations were performed at rest state using dual-energy mode of a 128-slice dual-source CT (DSCT; SOMATOM Definition Flash, Siemens Healthcare, Forchheim, Germany). Before the examination, the heart rate of each patient was measured. If the resting heart rate was higher than 65 beats per minute (bpm) and no contraindication to the use of β-blockers, metoprolol tartrate (Beloc, AstraZeneca, Wedel, Germany) was administered intravenously in fractions of 5–25 mg before the examination. Scanning parameters were as follows: 2 × 64 × 0.6 mm acquisition collimation with z-flying focal spot technique, and heart rate adaptive pitch of 0.17–0.35. Automated tube current modulation (Care Dose 4D, Siemens Healthcare) was used. One tube of DSCT system was operated with 165 reference mAs per rotation at 100 kV, and the second tube was automatically operated with 140 reference mAs per rotation at 140 kV. All scans were performed in cranio-caudal direction of supine position during a mid-inspiratory breath-hold.
The scanning range started from above the origin of the coronary arteries to below the dome of the diaphragm. Contrast agent was injected by a dual-syringe injector (Stellant D, Medrad, Indianola, USA) using an 18-gauge intravenous needle placed in the right antecubital vein. A triphasic injection protocol was used [12]. First, 50 mL of pure contrast media (Iopromide, Ultravist 370, 370 mg/mL, Bayer-Schering Pharma, Berlin, Germany) was administered. Thereafter, 30 mL of 70%/30% saline/contrast medium mixture was administered. Finally, 30 mL of saline was administered. The injection rate for all phases was 5 mL/s. Contrast agent application was controlled by a bolus tracking technique. A region of interest was placed in the aortic root, and image acquisition automatically started 7 s after the signal attenuation reached the predefined threshold of 100 Hounsfield units (HU).
Dual-energy CT post-processing
CCTA and resting myocardial DE-CTP were reconstructed from data of single arterial phase dual-energy CT scanning. The CCTA images were reconstructed with 0.75 mm slice thickness, 0.5 mm increment, 75 ms temporal resolution, and B26f kernel. All images were reconstructed by the same person to reduce bias. Then the reconstructed CCTA images were transferred to multi-modality work-place (MMWP, Siemens Healthcare, Forchheim, Germany) and loaded into the Circulation application for further analysis.
The DE-CTP images were reconstructed with 1.5 mm slice thickness, 1.0 mm increment, 280 ms temporal resolution, and a dedicated dual-energy convolution kernel (D30f). By default, raw data were automatically reconstructed into low-kilovoltage (100 kV) images and high-kilovoltage (140 kV) images. Then the 100 kV and 140 kV images were transferred to MMWP and loaded into dual-energy Heart PBV (Siemens Healthcare) to calculate the iodine distribution maps, with color-coded of “Hot Body 8 bit”. A normal myocardial area was chosen to normalize the iodine distribution maps [13].
Dual-energy CT image analyses
All dual-energy CT images were assessed on MMWP and patient information was removed. Images were assessed independently by two cardiac radiologists who were blinded to the patient information and disagreements were resolved by consensus. We performed separate readings of resting DE-CTP and CCTA. Readings were spaced at 2-week intervals to minimize recall bias.
The DE-CTP images were visually analyzed on a per-segment -territory and -patient basis according to the American Heart Association 17-segment model [10]. In color-coded iodine distribution maps, light orange indicated the highest iodine content and gray indicated the absence of iodine. For DE-CTP, the normal myocardium was defined as homogeneous light orange without any gray area; myocardial perfusion defect was defined as distinct grey area compared with normal surrounding myocardium. Diagnostic accuracy of resting myocardial DE-CTP in detecting myocardial perfusion defects was assessed using resting 13N-ammonia PET as the gold standard.
CCTA images were analyzed for coronary obstructive stenosis ≥ 50% for each vessel (left anterior descending coronary artery, right coronary artery, and left circumflex coronary artery) based on axial source images, cross-sectional views, multiplanar reformations, curved planar reformations and thin-slab maximum intensity projection images. The association between coronary artery distribution and myocardial segments was analyzed on the basis of the AHA recommendations [10]. In view of the possibility of the mismatch between vessels and segments based on the AHA model, curved planar reconstruction or three-dimensional CT renderings was used to establish one to one relationship between each myocardial segment and the coronary artery that supplies it, providing accurate registration between them (Fig. 1D). Diagnostic accuracy of cardiac dual-energy CT in detecting flow-limiting stenoses was assessed by CCTA combined with resting myocardial DE-CTP, using ICA plus resting 13N-ammonia PET as the gold standard.
Statistical analysis
Statistical analysis was performed using SAS version 9.1 (SAS Institute Inc., Cary, North Carolina), and the threshold of significance was P value < 0.05. Quantitative variables were expressed as mean value ± standard deviation. The diagnostic performance was calculated, including sensitivity, specificity, positive predictive value, negative predictive value, and accuracy with 95% confidence intervals. Additionally, the receiver operating characteristic (ROC) curve analysis was performed. The area under the ROC curves (AUCs) were compared by the DeLong method. Kappa tests were used to assess intra- and interobserver agreement in CCTA and resting myocardial DE-CTP analysis in 10 randomly selected patients. The Kappa value was interpreted as follows: 0–0.20 poor agreement, 0.21–0.40 fair agreement, 0.41–0.60 moderate agreement, 0.61–0.8 good agreement, and > 0.81 excellent agreement.