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Cardiac Imaging |
1 From the Cardiovascular Center (O.G., T.S., I.V., P.K., F.R.E., T.F.L., P.A.K.) and Institute of Diagnostic Radiology (L.H., H.S., S.L., H.A.), University Hospital Zurich, Ramistrasse 100, NUK C 32, CH-8091 Zurich, Switzerland; and the Zurich Center for Integrative Human Physiology, University of Zurich, Switzerland (P.A.K.). Received July 24, 2007; revision requested September 10; revision received October 27; accepted December 14; final version accepted January 7, 2008. Supported by a grant from the Swiss National Science Foundation (professorship grant no. PP00A-68835) and by a grant of the National Center of Competence in Research, Computer Aided and Image Guided Medical Interventions of the Swiss National Science Foundation. Address correspondence to P.A.K. (e-mail: pak@usz.ch).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Materials and Methods: All patients gave written informed consent after the study details, including radiation exposure, were explained. The study protocol was approved by the local institutional review board. In patients referred for elective conventional coronary angiography, an additional 64-section CT angiography study and a myocardial perfusion imaging study (1-day adenosine stress-rest protocol) with technetium 99m–tetrofosmin SPECT were performed before conventional angiography. Coronary artery diameter narrowing of 50% or greater at CT angiography was defined as stenosis and was compared with the myocardial perfusion imaging findings. Quantitative coronary angiography served as a reference standard for CT angiography.
Results: A total of 1093 coronary segments in 310 coronary arteries in 78 patients (mean age, 65 years ± 9 [standard deviation]; 35 women) were analyzed. CT angiography revealed stenoses in 137 segments (13%) corresponding to 91 arteries (29%) in 46 patients (59%). SPECT revealed 14 reversible, 13 fixed, and six partially reversible defects in 31 patients (40%). Sensitivity, specificity, and negative and positive predictive values, respectively, of CT angiography in the detection of reversible myocardial perfusion imaging defects were 95%, 53%, 94%, and 58% on a per-patient basis and 95%, 75%, 96%, and 72% on a per-artery basis. Agreement between CT and conventional angiography was very good (96% and 
= 0.92 for patient-based analysis, 93% and = 0.84 for vessel-based analysis).
Conclusion: Sixty-four–section CT angiography can help rule out hemodynamically relevant CAD in patients with intermediate to high pretest likelihood, although an abnormal CT angiography study is a poor predictor of ischemia.
© RSNA, 2008
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Myocardial perfusion imaging with single photon emission computed tomography (SPECT) is a widely established method for noninvasively evaluating the hemodynamic significance of coronary artery stenoses (11). In addition to its diagnostic accuracy, SPECT provides important prognostic information that may be helpful for cardiac risk stratification and in guiding further therapeutic decisions (12–14). By contrast, the purely anatomic information depicted with invasive and noninvasive angiographic techniques offers limited hemodynamic and prognostic data on which clinical decision-making can be based (9), unless additional techniques such as fractional flow reserve measurements or intravascular ultrasonography are applied.
Recent reports of studies in small groups of patients (15–18) indicate that CT angiography is an accurate tool for ruling out hemodynamically relevant CAD but that it has only limited value for the detection of lesions that induce perfusion defects at myocardial perfusion imaging. However, these studies included relatively small numbers of patients, used 16-section CT, or did not include conventional angiography for the validation of CT angiography results. Thus, the purpose of our study was to prospectively determine the accuracy of 64-section CT angiography in the depiction of CAD that induces perfusion defects at myocardial perfusion imaging with SPECT, by using myocardial perfusion imaging as the reference standard.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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CT Angiogram Acquisition
All examinations were performed with a 64-section CT scanner (Somatom Sensation 64; Siemens Medical Solutions, Forchheim, Germany). Scanning parameters were as follows: detector collimation, 32 x 0.6 mm; section collimation, 64 x 0.6 mm by means of a z-flying focal spot; gantry rotation time, 330 msec; pitch, 0.2; tube voltage, 120 kV; and tube current–time product, 700 mAs. A bolus of 80 mL of iodixanol (Visipaque 320 [320 mg of iodine per milliliter]; GE Healthcare, Buckinghamshire, England) followed by 30 mL of saline solution was continuously injected into a right antecubital vein through an 18-gauge catheter at a flow rate of 5 mL/sec. Bolus tracking was performed with a region of interest (size range, one-quarter to one-third of the diameter of the ascending aorta) placed in the ascending aorta by an experienced radiographer (L.H., H.S., or S.L., each with at least 2 years of experience in cardiovascular imaging), and image acquisition was automatically started 5 seconds after the signal attenuation reached the predefined threshold of 140 HU.
Synchronized to the ECG data, CT data sets were retrospectively reconstructed in 5% steps from 30% to 80% of the R-R interval. The "adaptive cardio volume" approach was used for image reconstruction. This approach switches to a two-segment reconstruction algorithm at heart rates greater than 65 beats per minute. ECG pulsing for radiation dose reduction was used in all patients. All patients were in stable sinus rhythm, and the mean heart rate during the CT examination was 62 beats per minute ± 9 (standard deviation). All patients received 1.25–2.5 mg of sublingual isosorbiddinitrate (Isoket Spray; Schwarz Pharma, Munchenstein, Switzerland) 2–3 minutes before CT angiography, and 10 patients were pretreated with 5–15 mg of intravenous metoprolol tartrate (Lopresor; Daiichi Sankyo, Thalwil, Switzerland). No serious adverse events secondary to nitroglycerin, metoprolol, or contrast agent administration were reported.
All data sets were reconstructed by using a medium soft-tissue convolution kernel (B30f) with an effective section thickness of 1 mm and increments of 0.8 mm (mean field of view, 155 mm ± 21; range, 120–175 mm; image matrix, 512 x 512 pixels). The data set that provided the best image quality was reconstructed with the same parameters by using a sharp tissue convolution kernel (B46f). All data were transferred to an external workstation (Leonardo; Siemens).
CT Angiogram Interpretation
CT angiogram interpretation was performed with axial source images, multiplanar and curved reformations, and thin-slab maximum intensity projections. First, image quality for each data set was rated by one reader (L.H., with 3 years of experience in cardiovascular imaging) by using a previously published five-point ranking scale (20): a score of 1 indicated no motion artifacts and clear delineation of the segment; a score of 2, minor artifacts and mild blurring of the segment; a score of 3, moderate artifacts and moderate blurring without structure discontinuity; a score of 4, severe artifacts and doubling or discontinuity in the course of the segment; and a score of 5, that the image was nonevaluable and vessel structures were not differentiable. Coronary arteries were subdivided according to a 15-segment model proposed by the American Heart Association (21).
Then, each segment was visually evaluated in two planes—one parallel and one perpendicular to the course of the vessel—with regard to coronary artery delineation. On these images, the degree of diameter stenosis was semiquantitatively graded on a decimal scale in 10% steps from 0% to 100% by two independent radiologists (L.H. and H.A., with 5 years of experience) who were both blinded to the clinical history and to the findings from myocardial perfusion imaging and conventional angiography. In cases of disagreement in stenosis grading of greater than 10%, a consensus reading between both readers was performed. When the difference between readers was 10%, the mean diameter stenosis was calculated. A significant stenosis was defined as narrowing of the coronary diameter of 50% or greater, and all vessels with a diameter of 1.5 mm or greater were included in the analysis.
Myocardial Perfusion Imaging Image Acquisition
SPECT imaging was performed by using a 1-day ECG-gated stress-rest protocol. Pharmacologic stress was induced by infusion of adenosine (0.33% solution in 0.9% saline, created by local university pharmacy division) at a standard rate of 140 µg per kilogram of body weight per minute (22), and a dose of 250–350 MBq of technetium 99m–tetrofosmin was injected 3 minutes into the state of pharmacologic stress. This was followed by an injection of three times the stress dose at rest according to a standard protocol (23). Patients were told to refrain from ingesting caffeine-containing beverages for at least 12 hours, nitrates and calcium channel blockers for 24 hours, and β-blockers for 48 hours before the myocardial perfusion imaging study. Gated SPECT studies were performed with a dual-head detector camera (Millenium VG & Hawkeye; GE Healthcare); a low-energy, high-resolution collimator; a 20% symmetric window at 140 keV; a 64 x 64 matrix; an elliptic orbit with step-and-shoot acquisition at 3° intervals over 180°; and a 20-second dwell time per stop. Acquisitions were gated at 16 frames per R-R cycle with a 50% window of acceptance.
For all patients, the summed nongated SPECT image set was reconstructed at a dedicated workstation (eNTEGRA or Xeleris; GE Medical Systems, Milwaukee, Wis) by using an iterative reconstruction algorithm (ordered-subset expectation maximization with two iterations and 10 subsets) with x-ray based attenuation correction as previously described (24,25) into short-axis, vertical long-axis, and horizontal long-axis sections encompassing the entire left ventricle. In addition, polar maps of perfusion, wall motion, and wall thickening were produced by using a commercially available software package (Cedars QGS/QPS; Cedars-Sinai Medical Center, Los Angeles, Calif) (26). No serious adverse events following radionuclide injection or pharmacologic stress agent administration were reported. Image quality of myocardial perfusion images was amenable to visual interpretation in all patients.
Myocardial Perfusion Image Interpretation
SPECT image interpretation was visually performed in consensus by two nuclear cardiologists (O.G., with 3 years of experience in cardiac radionuclide imaging, and P.A.K., with 10 years of experience)—both of whom were blinded to the clinical history and to the findings from CT and conventional angiography—on short-axis, horizontal long-axis, and vertical long-axis sections and semiquantitative polar maps of perfusion as previously reported (27). Anterior and septal wall perfusion defects were allocated to the left anterior descending (LAD) coronary artery, lateral defects were allocated to the left circumflex (LCX) coronary artery, and inferior defects were allocated to the right coronary artery (RCA). In the watershed regions, allocation was determined according to the main extension of the defect onto the lateral, anterior, or inferior wall. Reversible perfusion defects were considered to represent myocardial ischemia. Fixed perfusion defects with concomitant regional wall motion abnormalities were considered to be myocardial scars (27). A partially reversible defect was defined as a fixed defect that increased in size during stress.
Quantitative Coronary Angiography
Conventional coronary angiography was performed according to standard techniques, and multiple views were digitally stored on a designated workstation. The angiograms were evaluated by an experienced observer (F.R.E., with 15 years of experience in invasive coronary angiography) who was blinded to the results from CT angiography and myocardial perfusion imaging. The coronary arteries were subdivided according to the same model used for the CT angiography images (21) and were quantitatively assessed with the use of an automated edge-detection system (Xcelera 1.2; Philips Medical Systems, Best, the Netherlands). Quantitative coronary angiography measurements were performed (for all lesions visually estimated to represent narrowing greater than 25%) in two image planes and included the diameter of the reference vessel (proximal and distal to the stenosis), the minimal luminal diameter, and the extent of stenosis (defined as the diameter of the reference vessel minus the minimal luminal diameter, divided by the reference diameter and multiplied by 100%). For biplane assessment, diameters obtained in both image planes were averaged. A significant stenosis was defined as a diameter reduction of 50% or greater.
Statistical Analysis and Reference Standards
To evaluate the diagnostic performance of CT angiography in the detection of coronary stenoses that induced perfusion defects at myocardial perfusion imaging (reference standard), we performed a patient-based and a vessel-based analysis. Sensitivity, specificity, and accuracy were calculated from 
2 tests of contingency, and 95% confidence intervals (CIs) were calculated from binomial expression. Accuracy was determined as the percentage of correct diagnoses in the entire sample (28). Nonevaluable segments were censored as positive findings in the vessel-based and patient-based analyses, reflecting the intention-to-diagnose nature of the study (29). We calculated negative predictive values (NPVs) and positive predictive values (PPVs) by incorporating disease prevalence on the basis of the Bayes formula and likelihood ratios for a positive or negative test result as previously reported (30). The CT angiography results were further compared with the findings from quantitative coronary angiography, the latter being the reference standard for the diagnosis of coronary artery stenoses.
Agreement between CT and conventional angiography was assessed with Cohen statistics. Univariate logistic regression analysis was used to compare the findings from CT angiography and conventional angiography with the myocardial perfusion imaging results. The regression results are presented as odds ratios and their respective 95% CIs. Receiver operating characteristic (ROC) analysis was applied to compare the diagnostic performance of CT angiography and conventional angiography (using the cutoff for significant coronary stenoses as the variable parameter) in the detection of reversible perfusion defects by comparing the respective areas under the ROC curve (AUCs) (28). The optimal cutoff point was determined by using the Youden index (J value) (calculated as the maximum of J = SN + SP – 1, where SN is sensitivity and SP is specificity, for each cutoff value) (31).
Statistical analysis was performed by using software (SPSS, version 12.0.1 for Windows; SPSS, Chicago, Ill). Quantitative data are expressed as means ± standard deviations, and categoric data are given as percentages. A two-tailed P value of less than .05 was considered to indicate a statistically significant difference for all tests.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Myocardial Perfusion Imaging
Visual image analysis revealed 14 reversible, 13 fixed, and six partially reversible perfusion defects in 31 (40%) of 78 patients. The distribution of the perfusion defects among the different coronary artery territories was as follows: Reversible perfusion defects were found in the LAD artery (n = 8), LCX artery (n = 2), and RCA (n = 4), and fixed perfusion defects were found in the LAD artery (n = 4), LCX artery (n = 3), and RCA (n = 6), while partially reversible perfusion defects were found in the LAD artery (n = 1), LCX artery (n = 1), and RCA (n = 4).
Comparison of 64-Section CT Angiography with Conventional Coronary Angiography
Overall CAD prevalence at conventional angiography (defined by the presence of at least one stenosed coronary segment per patient) was 63% (49 of 78). Of the 92 coronary arteries with stenoses at conventional angiography, 81 were correctly identified with CT angiography (Figs 2, 3), whereas 11 were underestimated and therefore misclassified with CT angiography. Conversely, of the 218 nonstenotic coronary arteries, 208 were correctly identified at CT angiography, while 10 were erroneously classified as stenotic (Fig 4). Sensitivity, specificity, NPV, PPV, and accuracy, respectively, of CT angiography in the detection of coronary stenoses seen at conventional angiography (assuming a disease prevalence of 63% at conventional angiography) were 94% (46 of 49; 95% CI: 83%, 99%), 100% (29 of 29; 95% CI: 88%, 100%), 91%, 100%, and 96% (75 of 78; 95% CI: 89%, 99%) at patient-based analysis and 88% (81 of 92; 95% CI: 80%, 94%), 95% (208 of 218; 95% CI: 92%, 98%), 82%, 97%, and 93% (289 of 310; 95% CI: 90%, 96%) at vessel-based analysis. Overall agreement between CT angiography and conventional angiography for the detection of coronary stenoses was 96% (75 of 78; 95% CI: 89%, 99%; = 0.92) at patient-based analysis and 93% (289 of 310; 95% CI: 90%, 96%; = 0.84) at vessel-based analysis.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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Our results are in line with those of previous studies with 16-section and 64-section CT angiography (15–18). Hacker et al (15,16) reported a high NPV in ruling out hemodynamically relevant CAD with both scanner types and a low PPV with the 16-section CT scanner (29%) and the 64-section device (53%) (15,16). These results were confirmed by Schuijf and colleagues (17), who showed that only 59% of coronary stenoses 50% or greater at CT angiography were associated with a perfusion defect at SPECT. Predictive values were similar (NPV, 99%; PPV, 50%) in a previously published study by Gaemperli et al (18). However, several features of the latter studies need to be mentioned: First, the number of study participants was limited, rendering particularly a patient-based analysis difficult. Second, conventional coronary angiography results were not available in all patients. Third, no attenuation correction was performed for the SPECT images. And finally, a relatively large number of study participants were excluded because of insufficient image quality (15,16). Our study was designed to overcome these shortcomings by including a higher number of subjects, by ensuring that conventional coronary angiography was performed in all patients, by enhancing the diagnostic accuracy of SPECT by using x-ray–based attenuation correction, and, finally, by performing data interpretation on an intention-to-diagnose basis by censoring nonevaluable coronary arteries or patients as positive findings.
There are several explanations for the modest performance of 64-section CT angiography in the prediction of hemodynamically relevant CAD. For example, CT angiography results tend to overestimate coronary stenoses, particularly if calcifications are present, as compared with conventional coronary angiography (3–7). Furthermore, a false-negative CT angiography finding may result from a SPECT finding that is erroneously interpreted as a perfusion defect (ie, attenuation artifact) or from small-vessel disease. Finally and most importantly, the incongruence of CT angiography and myocardial perfusion imaging is inherent to the duality of morphologic versus functional testing (9,10). The technologic refinements implemented in the 64-section CT scanner generation have reduced the number of nonevaluable coronary segments (15,16), and further improvements may be expected with dual-source CT technology (8). However, the results of the present study and previous studies (15–17) support the notion that no matter how accurate CT angiography will possibly get with future technical advances, the two pieces of information obtained with myocardial perfusion imaging and morphology are difficult to compare. For example, our ROC analysis for the detection of perfusion defects showed similar AUCs for the reference standard, conventional angiography, and CT angiography, documenting a comparable performance of both techniques. Hence, many factors that are beyond the simple quantification of diameter narrowing and that therefore cannot be fully assessed with luminology will eventually determine whether or not a given lesion produces stress-induced ischemia. The calculated lesion severity cutoff value for predicting ischemia lies well within 50%–75%, which is generally perceived as the range of intermediate severity. A slightly lower cutoff value may be applied for patients with lower prevalence than that in our study population, as the high NPV of CT angiography renders this test most appropriate for ruling out CAD (15,16,18).
Our study results confirm good agreement between 64-section CT angiography and conventional coronary angiography for the diagnosis of coronary artery stenoses. Nonetheless, motion artifacts and extensive calcifications of the coronary arteries remain a major limitation for a reliable luminal interpretation, despite the above-mentioned technical developments, and conventional coronary angiography is often needed to verify the findings at CT angiography. On the other hand, CT angiography provides additional information on plaque morphology (eg, lipid-laden plaques, ulcerations) (32) that may be useful in guiding therapeutic decisions and affect long-term prognosis. It appears reasonable to hypothesize that patients with normal perfusion at presentation despite subclinical atherosclerosis might be at low short-term risk but high long-term risk for cardiac events (33). However, the potential clinical value of such information remains to be elucidated and was beyond the scope of the present study.
Our study had limitations. There are shortcomings to using SPECT as the reference standard for functional relevant coronary stenoses. SPECT has a high sensitivity in the detection of significant coronary stenoses, but its specificity is somewhat lower, as SPECT is susceptible to a variety of artifacts (photon attenuation, respiratory motion, spillover from gut or liver activity) (11). In addition, the tetrofosmin myocardial uptake curve plateaus at lower levels of hyperemia than thallium. Therefore, the use of vasodilator stress has been questioned by some authors (34), although no difference was found between the technetium-labeled tracers and thallium in a large randomized multicenter trial (35). Considering the large experience accumulated over 2 decades, including the prognostic information of SPECT myocardial perfusion imaging, this technique can be regarded as being the best-evaluated and -established noninvasive imaging tool for the hemodynamic assessment of CAD. Moreover, the use of x-ray–based attenuation correction and information from gated SPECT—as in our patients—is known to improve the specificity of SPECT myocardial perfusion imaging studies without affecting their sensitivity (11). Regarding CT angiography, to reduce radiation exposure in our study, prospective tube current modulation was used in all patients. This technique allows a reduction in radiation exposure of up to 50% but may preclude the use of early systolic to midsystolic phases for coronary reconstruction at higher heart rates or in cases of arrhythmia.
In summary, 64-section CT angiography is a reliable tool for identifying patients without hemodynamically relevant CAD in an intermediate-to-high–risk population. Its implementation in clinical practice may help avoid the expense and high resource utilization incumbent with catheterization laboratory studies. Our results suggest that a multicenter trial, required to confirm these data, is justified. On the other hand, an abnormal CT angiography study—like an abnormal conventional angiography study—is a poor predictor of ischemia. Conversely, a normal myocardial perfusion imaging study does not exclude the presence of subclinical CAD as assessed with CT and conventional angiography for which aggressive cardiovascular risk modification may be warranted. This underlines the potential value of a comprehensive noninvasive CAD assessment including both morphologic and hemodynamic information.
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ADVANCES IN KNOWLEDGE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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IMPLICATION FOR PATIENT CARE |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Abbreviations: AUC = area under the ROC curve • CAD = coronary artery disease • CI = confidence interval • ECG = electrocardiography • LAD = left anterior descending • LCX = left circumflex • NPV = negative predictive value • PPV = positive predictive value • RCA = right coronary artery • ROC = receiver operating characteristic
Author contributions: Guarantors of integrity of entire study, O.G., P.A.K.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, O.G., T.S., I.V., P.K., L.H., H.S., S.L., H.A., P.A.K.; clinical studies, O.G., T.S., I.V., P.K., H.S., S.L., F.R.E., T.F.L., H.A., P.A.K.; statistical analysis, O.G., L.H., H.A., P.A.K.; and manuscript editing, all authors
Authors stated no financial relationship to disclose.
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONADVANCES IN KNOWLEDGEIMPLICATION FOR PATIENT CAREReferences |
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