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J Am Coll Cardiol, 2007; 49:1059-1067, doi:10.1016/j.jacc.2006.10.069
(Published online 23 February 2007). © 2007 by the American College of Cardiology Foundation |
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,*
,1
* Department of Cardiology, Technion-Israel Institute of Technology, Haifa, Israel
Department of Nuclear Medicine, Technion-Israel Institute of Technology, Haifa, Israel
Department of Medical Imaging, Technion-Israel Institute of Technology, Haifa, Israel
Division of Invasive Cardiology, Rambam Health Care Campus and the B. Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
|| Functional Imaging, General Electric Healthcare Technologies, Tirat Hacarmel, Israel.
Manuscript received June 29, 2006; revised manuscript received August 31, 2006, accepted October 18, 2006.
* Reprint requests and correspondence: Dr. Shmuel Rispler, Department of Nuclear Medicine, Rambam Medical Center, Haifa 31096, Israel. (Email: s_rispler{at}rambam.health.gov.il).
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Abstract |
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Background: Myocardial perfusion imaging (MPI) with SPECT is of value for assessing the physiologic significance of coronary lesions. Computed tomography coronary angiography is a new technique to noninvasively detect coronary stenosis, with high sensitivity and negative predictive value (NPV) but lower specificity and positive predictive value (PPV). The experimental SPECT/CTCA hybrid imaging device (Infinia gamma camera and LightSpeed16 CT, General Electric, Milwaukee, Wisconsin) enables concurrent assessment of coronary anatomy and myocardial perfusion.
Methods: Fifty-six patients with angina pectoris underwent single-session SPECT-MPI and CTCA with the hybrid device and coronary angiography (CA) within 4 weeks. The ability of fused SPECT/CTCA images to diagnose physiologically significant lesions showing >50% stenosis and reversible perfusion defects in the same territory was determined and compared with CTCA stand-alone.
Results: Of a total of 224 coronary segments in 56 patients, 12 patients and 54 segments (23%) were excluded from further analysis of CTCA. Overall, 170 coronary segments were evaluated. The sensitivity, specificity, PPV, and NPV of CTCA were 96%, 63%, 31%, and 99%, respectively, as compared with 96%, 95%, 77%, and 99%, respectively, for SPECT/CTCA.
Conclusions: Hybrid SPECT/CTCA imaging results in improved specificity and PPV to detect hemodynamically significant coronary lesions in patients with chest pain. Single-photon emission computed tomography/CTCA might play a potentially important role in the noninvasive diagnosis of coronary artery disease and introduce an objective decision-making tool for assessing the need for interventions in each occluded vessel.
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Contrast enhanced multidetector computed tomography (CT) offers several advantages over angiography. As a noninvasive procedure requiring only intravenous access, the risk of arterial vascular trauma is eliminated. At present, however, CT is hampered by technical limitations, with suboptimal ability to precisely and consistently detect the presence and location of coronary lesions (4).
Myocardial perfusion scintigraphy is one of the principal diagnostic tools for the assessment of the extent and severity of myocardial ischemia (5). Stress-rest single-photon emission computed tomography (SPECT) is a well-established imaging method for evaluating the presence and extent of hemodynamically significant coronary artery disease (CAD), further improved by the introduction of gated studies (6,7). However, the diagnostic accuracy of myocardial perfusion imaging (MPI) might be adversely affected by attenuation, scatter, and blur. Hybrid imaging modalities with systems such as SPECT/CT and positron emission tomography/CT have been initially developed to overcome these technical limitations by photon attenuation correction, with the goal to further improve image quality, with subsequent enhancement of the diagnostic accuracy (4).
The integration of sequential, near-simultaneous anatomic and physiologic information from CT and MPI might be of potential value for the clinical assessment and effective treatment of CAD. The combined SPECT/CT device provides noninvasive CT-based evaluation of coronary anatomy in the same setting with the MPI-SPECT evaluation of its hemodynamic significance and might therefore offer higher clinical efficacy than the current clinical diagnostic methods.
We hypothesize that the single-session assessment of CAD with the combination of SPECT and computed tomography coronary angiography (CTCA) will noninvasively provide comprehensive information that will improve the diagnostic ability relative to anatomical methods and might therefore represent a physiology-based decision-making tool for determining the need for revascularization.
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Imaging equipment. The studies were performed on a hybrid SPECT/CT research system (Infinia gamma camera and LightSpeed16 CT, GE Healthcare Technologies, Milwaukee, Wisconsin) that comprises a dual head variable angle gamma camera and a 16-slice CT scanner. These components share a common table and are spatially aligned to enable sequential acquisition of the SPECT and CT studies. Processing of SPECT (emission) data was performed on a Xeleris workstation, and processing of the CTCA data was performed on an Advantage Windows 4.2P workstation (both from GE Healthcare Technologies).
MPI-SPECT imaging. The MPI studies were performed with a same-day rest/stress dual-isotope protocol in all patients. The gamma camera component is equipped with low-energy, high-resolution parallel-hole collimators, with the detectors at 90° to each other. Sixty projections were acquired over a 180° orbit into a 64 x 64 matrix, with a pixel size of 6.8 mm and a time/projection of 20 s. For the rest study, 111 MBq (3 mCi) of thallium-201 (Tl-201) were administered, with imaging starting within 15 min after the intravenous injection. Energy window width setting of 30% and 20% for the peaks 70 keV and 167 keV, respectively, were used. The scan resulted in SPECT images containing all the photons within the energy window. The total average effective radiation dose received during MPI-SPECT was 25 mSv.
The stress test was performed immediately after the rest scan. Of the 56 patients, 14 were exercise stress tested, whereas 42 underwent pharmacologic stress testing. Stress electrocardiography-gated MPI was performed with 700 MBq (19 mCi) of 99mTc-methoxyisobutylisonitrile (Tc-MIBI), injected at peak ergometric or pharmacologic stress. For Tc-MIBI acquisition the energy window width setting was of 20%. After the stress test, in preparation for the CTCA, 9 (20%) patients with heart rate over 80 beats/min received Metoprolol orally. Immediately before CTCA, 2 patients (4%) with heart rate over 80 beats/min required intravenous administration of metoprolol. Nitroglycerin was not administered in any of the patients.
Both the rest and stress SPECT studies were followed by a low-dose (30 mA, 140 keV) CT scan (CT-AC) further used for correcting the emission data for photon attenuation. The CT-AC scan was performed only over the area of the heart, as defined by the technologist. The patient was instructed not to move during study progression to obtain good co-registration between the emission and the transmission scans.
CTCA imaging. In immediate sequence with the MPI stress study and without moving the patient from the table of the scanner, CTCA was performed, with the 16 detectors helical electrocardiography-gated scanner. The acquisition parameters included a rotation time of 0.5 s, tube voltage of 120 kV, and current of 420 mA, acquired for 0.625-mm or 1.25-mm slice thickness, depending on the axial scan range (e.g., larger for post-coronary artery bypass graft patients) and breath hold duration capability. The scanner automatically sets the helical pitch in the range 0.275:1 to 0.325:1, as a function of heart rate. Contrast material was delivered intravenously by a dual automatic injector, with 85 cc of Ultravist 370, at 4 ml/s. followed by 50 ml of saline flush at 3 ml/s. A semi-automated bolus-tracking technique (SmartPrep, GE Healthcare Technologies) was used for determining the contrast-enhanced scanning delay. This technique obtains real-time low-radiation-dose serial scans after the start of contrast material injection. The threshold that triggered the CTCA scan was set at a 50-Hounsfield unit increase relative to the previous scan, measured into a region of interest in the ascending aorta. The duration of the CTCA scan was approximately 22 s. A single- or multi-segment reconstruction method was applied, depending on the patient’s heart rate, resulting in slices of 0.625-mm or 1.25-mm thickness. Immediately with the completion of the scan a late diastole phase (75% of R-R time) was automatically reconstructed. After the release of the patient, off-line retrospective reconstruction was applied to obtain the phases from 0% to 90% of R-R interval, by steps of 10% as well as 45% and 75%. The matrix size of the CT slices was 512 x 512. The total average effective radiation dose received during CTCA, CT for calcium scoring, and CT for attenuation correction was calculated from the scan parameters with conversion factors taken from Prokop et al. (8). The values were 14 mSv for male and 19 mSv for female patients. The total average radiation exposure from the combine SPECT-MPI and CTCA was 41.5 mSv.
The total acquisition time for the rest MPI, including CT for attenuation correction, was 15 min. The average duration of the second study phase, including the stress MPI with attenuation correction, CT for calcium score measurements, and planning and acquisition of CTCA, was approximately 23 min.
SPECT data processing. Perfusion data were reconstructed with ordered subsets expectation maximization (OSEM) iterative reconstruction, with and without attenuation correction. The attenuation maps were computed from the dedicated low-dose CT-AC scans acquired and registered with the emission data. As an initial step, the operator performed a visual analysis to ensure that the reconstructed emission volume (without attenuation correction) was properly aligned with the CT-AC volume. Subsequently, the Xeleris application performing this computation proceeded according to the following steps: 1) Reformat the CT slices into a volume having the same voxel and matrix size as the SPECT projections. 2) Convert the Hounsfield unit of the reformatted CT slices into linear attenuation coefficient corresponding to the energy of the emission isotope and depending on the effective energy spectrum of the CT device. For CT values <0, materials are assumed to have energy dependence similar to water. CT values larger than 0 are treated as being a mixture of bone and water. 3) Apply a Gaussian filter to finally obtain attenuation maps with a resolution similar to that of SPECT data.
The OSEM iterative reconstruction uses 2 iterations and 10 subsets, with a post- reconstruction low-pass Butterworth 3-dimensional (3D) filter. For the rest study a critical frequency of 0.35 Nyquist with an order of 10.0 was used, whereas for the stress part the critical frequency is 0.4 Nyquist and the order is 10.0. The same filtering scheme was applied for data reconstructed with and without attenuation correction. No scatter or depth-dependent resolution corrections were applied. One-pixel-thick oblique tomographic slices were generated and displayed in a standard format as short-axis, vertical, and horizontal long-axis slices.
CTCA data processing. The CardIQ application of the AW workstation (GE Healthcare Technologies) was used to obtain the following items from the multi-phase CTCA image: 1) 3D rendering of the myocardial walls, coronaries, and possibly bypass grafts; and 2) tracking and segmental analysis of coronary arterial tree and bypass grafts.
SPECT/CTCA. Three-dimensional fusion display of the coronary tree and myocardial perfusion was further obtained. Fusion of the coronary arteries segmented on the AW workstation and of a 3D rendering of the MPI-SPECT mapped on the left ventricle (LV) surface, obtained on the Xeleris workstation, was performed with the HeartFusion application (Emory University, Atlanta, Georgia). Because the SPECT/CTCA study had been performed without moving the patient, the coronary arteries and the LV surface were in close alignment. The HeartFusion program automatically performs an improvement of the alignment to compensate for respiratory or cardiac motion, or potential patient movement (9). In addition, minor manual realignment was performed in 9 patients (21%).
CA. Invasive CA was performed by expert interventional cardiologists, through the femoral approach, with standard Seldinger techniques with 6-F catheters. Images were acquired in at least 2 orthogonal optimal projection angles at 25 frames/s and digitally recorded on a Coroskop Top system (Siemens Medical Systems, Erlangen, Germany).
Image interpretation and analysis. Qualitative evaluations of imaging were performed by 3 separated, experienced groups of physicians initially blinded about the condition of the patients and unaware of the CA findings.
The MPI-SPECT at stress and rest were visually assessed in consensus by 2 nuclear medicine physicians, unaware of the CTCA or conventional CA results. Raw data, cine display, and SPECT slices were analyzed. Perfusion defects were allocated to territories of coronary arteries. Defects in the anterior wall and the septum were allocated to the left anterior descending coronary artery (LAD); in the lateral wall to the left circumflex coronary artery (CRX); and in the inferior wall to the right coronary artery (RCA). Defects in the apex were allocated to the LAD, unless the defect extended to the lateral (CRX) or inferior (RCA) wall. Defects affecting both the LAD region and the CRX region were rated as left main artery (LM) disease. The SPECT imaging defined the presence of myocardial perfusion for each territory as showing 1 of the following patterns: 1) normal pattern showing homogeneous uptake of the radiotracer at rest and stress; 2) ischemic pattern showing a localized area of decreased perfusion at stress that is no longer seen or demonstrates partial improvement on the rest images; or 3) fixed pattern showing a localized perfusion defect that is unchanged between the rest and stress images.
Two radiologists interpreted CTCA images in consensus and visually categorized the major epicardial arteries and/or the bypass grafts as: 1) occlusion; 2) significant stenosis (over 50% diameter); 3) normal patency (no occlusion or stenosis); or 4) technically inadequate for further evaluation. Segments with a diameter of 2 mm and more of the LM, the LAD, the CRX, and the RCA were analyzed.
The CA interpretation was performed in consensus by 2 cardiologists. Visual assessment of vessel narrowing of 50% and more was defined as significant stenosis. To reflect daily clinical routine at our institution, quantitative CA was not performed.
Fused images were analyzed in joined reading sessions by nuclear medicine physicians, radiologists, and cardiologists, un-blinded to patients’ clinical data and CA results.
Three cardiologists were responsible for collecting and summarizing all the available clinical and imaging information and for organizing the joint reading sessions with the participation of all teams. These meetings were scheduled after each team summarized its own conclusions. A consensus report was sent to the referring physician.
The performance indexes of CTCA as a stand-alone diagnostic procedure were recorded. The ability of the CTCA and fused SPECT/CTCA study to detect hemodynamically significant lesions was analyzed and compared with the combined criteria from CA and SPECT as a reference standard. This standard defines a hemodynamically significant lesion as >50% vessel stenosis on CA with an associated reversible perfusion defect on MPI in the same territory.
Statistical analysis. A true positive (TP) CTCA or SPECT/CTCA segment was defined as >50% stenosis on CTCA or >50% stenosis with corresponding reversible perfusion defect on SPECT/CTCA confirmed by the reference standard as a hemodynamically significant lesion. True negative (TN), false positive (FP), and false negative (FN) results were defined with the same parameters. The value of the fused SPECT/CTCA images for correlating the stenotic coronary artery with corresponding perfusion defects was assessed, and performance indexes, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated with the known equations. The CTCA and SPECT/CTCA performance indexes were compared by means of the paired chi-square test for dependent samples proportion (McNemar test). The results of MPI-SPECT as a stand-alone procedure between the group of patients with SPECT/CTCA and those who had a technically unsatisfactory CTCA study were also compared with the chi-square test. This analysis was performed to assess whether the exclusion of some of the patients and/or coronary segments from the calculation of the performance of the fused imaging modality might have introduced some bias into the final study results.
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Coronary artery disease was documented by CA in 32 patients (73%) in 58 segments. Myocardial perfusion imaging detected ischemia in 24 patients in 41 segments and irreversible perfusion defects in 9 patients in 11 segments. The MPI-SPECT stand-alone data were successfully evaluated in all 12 patients and 54 coronary segments that were excluded from the final analysis of the SPECT/CTCA data. Ischemia was documented in 7 segments (13%), and fixed perfusion defects were present in 4 segments (7%). There was no statistically significant difference in the proportion of segments showing perfusion abnormalities on SPECT-MPI between the group that was excluded from the study as compared with the final 170 evaluated segments (13% vs. 24% segments with ischemia, p = NS; and 7% vs. 6% with fixed perfusion defects, p = NS).
Computed tomography coronary angiography detected CAD in 36 patients (82%) in 77 segments. At the time of the CTCA investigation, the mean heart rate was 68 beats/min (range 48 to 107 beats/min). The CTCA as a stand-alone diagnostic procedure had a sensitivity of 84%, specificity 74%, PPV 61%, and NPV 90% for detecting stenotic lesions in the coronary arteries as compared with the gold standard of CA. The performance of CTCA to detect hemodynamically significant lesion (defined by combined results of MPI-SPECT and CA) showed sensitivity, specificity, PPV, and NPV of 96%, 63%, 31%, and 99%, respectively.
Single-photon emission computed tomography/CTCA showed a sensitivity of 96%, specificity of 95%, PPV of 77%, and NPV of 99% for detecting hemodynamically significant lesions. There was a statistically significant increase in the specificity and PPV of SPECT/CTCA as compared with CTCA stand-alone for detecting hemodynamically significant coronary lesions (p < 0.001 for both) (Table 2).
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present the case of a 72-year-old woman with angina pectoris after recent anterior myocardial infarction. The patient underwent diagnostic CA that revealed significant stenoses in the LAD and CRX. The fusion of anatomic and physiologic information from CTCA and MPI showed that interventional therapy should be directed to the lesion in the LAD.
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The obstacles for routine use of CTCA as a sole test are multifactorial. Significant movement of the coronary arteries might occur during the cardiac cycle. The temporal resolution of multi-detector CT technology that involves rapid rotation of heavy collimated detectors is limited. The 16-slice CT device used in the present study was found to have only moderate diagnostic performance for the detection of significant coronary artery stenosis in a population with a high prevalence of CAD, similar to previous published results (11). Fifty-four of a total of 224 coronary segments (23%) could not be evaluated by CTCA because of respiratory or cardiac motion, patient movement, high heart rate, or heavy coronary calcifications.
The use of new devices with improved temporal and spatial resolution has led to a decrease in the number of coronary artery segments of suboptimal image quality. The 64-slice spiral CT scanners permit higher X-ray output and faster tube rotation. These improvements result in high-quality, nearly motion-free, isotropic image quality (12). It has been reported, however, that even with the use of 64-slice CT scanners for the evaluation of patients with chest pain, the PPV of CTCA is relatively low (12,13). Multi-detector CT has a relatively poor temporal resolution (approximately 165 to 210 ms) compared with that of other noninvasive methods of coronary imaging, such as electron-beam CT (approximately 50 ms) and magnetic resonance imaging (approximately 78 ms) (14). Therefore, CTCA remains sensitive to cardiac motion-induced artifacts, a major cause of image degradation (15,16). The right coronary artery seems particularly vulnerable (17).
Computed tomography coronary angiography also requires a slow and regular heart rate during the bolus first-pass acquisition. An inverse relationship between heart rate and image quality has been previously reported (14,15). Sixty-five beats/min was defined as the upper heart rate threshold that makes motion-free image quality possible (14). Hoffmann et al. (14,18) showed that a slightly higher threshold of 80 beats/min can be safely applied when using a 16-detector row scanner.
Calcifications or stents represent major causes for overestimation of luminal narrowing. Motion, noise, and contrast-related image deterioration is the main reason for false-negative CTCA findings (11). Although the extent of coronary artery calcifications provides unique anatomical information regarding the coronary atherosclerotic burden (19,20), calcium deposits cause strong X-ray attenuation and are the most frequent cause of high density artifacts. Studies comparing CTCA and conventional CA report that extensive coronary calcifications prevented assessment of a substantial number of segments (21–23). The PPV of CTCA is at present suboptimal. At present, the main clinical advantage of CTCA seems to be related to its high NPV, which allows for the exclusion of obstructive CAD (4,24).
Computed tomography coronary angiography detects the presence of multiple coronary lesions, but the hemodynamic consequences of these abnormalities, which are important for adequate therapeutic decisions, might be equivocal. For example, CTCA can detect stent patency but cannot accurately assess in-stent restenosis (25). In patients with multiple lesions, identification of the culprit lesion is not possible. This might lead to potential consequences of clinical significance, including the fact that the number of patients referred for cardiac catheterization will increase instead of decrease, and luminology might determine patient management with the so-called "oculostenotic reflex," resulting in a large number of therapeutic interventions.
To avoid these potential clinical limitations, integration of the anatomic information provided by CTCA with hemodynamic information provided by MPI-SPECT is needed and seems to be of value (4). In the present study we have demonstrated the feasibility and accuracy of combined SPECT/CTCA for visualization of coronary anatomy and of simultaneous assessment of the functional significance of lesion severity. Although angiography is the accepted standard for morphologic assessment of CAD, it is not a gold standard for myocardial perfusion (26,27). Large trials have shown that angiography cannot predict the recurrence of ischemia or re-occlusion in patients after thrombolysis (27–29). In patients with uncomplicated acute myocardial infarction, pre-discharge exercise MPI was superior to sub-maximal exercise treadmill testing and CA in predicting future cardiac events (30).
Single-photon emission computed tomography/CTCA seems to be a more accurate method for evaluation of specific subgroups of patients when questionable abnormalities are observed by CTCA. This might include patients with significant calcification in their coronary arteries or patients with complicated anatomy after bypass surgery or multiple stent implants. The concurrent availability of scintigraphic data allows for more clinical information to be derived from CTCA by the provision of simultaneous complementary functional assessment of the myocardial perfusion. If the present results are confirmed by further studies, with technically optimized devices with 64-slice CT, cardiac SPECT/CTCA might become, in future, the clinical standard in the evaluation of patients with complicated clinical scenarios that require noninvasive proof of ischemia before considering revascularization procedures.
The present study has several limitations. The experimental design included mostly patients with known stable CAD as defined by prior myocardial infarction or coronary artery bypass graft surgery. Although in this group of patients with an intermediate or high likelihood of ischemia the role of CTCA for risk stratification is not yet clearly defined, MPI has a well-established prognostic value. The extrapolation of the diagnostic accuracy data from a population with CAD to a population with previously unknown CAD is problematic. Further investigations will have to clarify how SPECT/CTCA will affect both risk stratification and therapy planning in patients with suspected CAD. The fact that only 5 women were included in the study weakens the results about the diagnostic accuracy of SPECT/CTCA for assessing hemodynamically significant coronary artery lesions in women. Twelve patients (21%) had non-diagnostic CTCA related to high heart rate and calcium score, motion artifacts, and other technical problems. Similar results have been reported by Hacker et al. (10) in a study showing that the vessel diameter could not be evaluated in 30% of coronary segments evaluated by 16-slice multidetector CT angiography. The CA interpretation was performed with visual analysis by 2 cardiologists in consensus, without the use of quantitative CA. Combined SPECT/CTCA images of the coronary anatomy and myocardial perfusion were evaluated with the non-corrected SPECT data, owing to current fusion software limitation. Assessment of attenuation-corrected SPECT/CTCA images might lead, in future, to better image quality and further improve the diagnostic accuracy of the hybrid modality. The results of the current study were based on a per-vessel (segment) analysis only. It is likely that the low PPV for CTCA was influenced by the known limitations of perfusion imaging to identify "multivessel ischemia" as opposed to per-patient diagnosis of CAD. Finally, using SPECT-MPI as one of the criteria to define the diagnostic performance of SPECT/CTCA, although somewhat problematic, is the accepted reference standard and has been previously used for assessment of the diagnostic value of other integrated imaging devices in patients with known or suspected CAD (31). An additional issue that has to be considered is the total radiation exposure from the combine SPECT-MPI and CTCA study, estimated at 41.5 mSv. It is expected that the radiation exposure to patients performing SPECT/CTCA will decrease significantly in the future after the implementation of a modified protocol including a single isotope rest/stress SPECT acquisition, performing a single CT scan for calcium scoring and attenuation correction, and also applying electrocardiography-modulated CTCA. These modifications are planned to be implemented in the next generation SPECT/CT research device.
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1 Dr. Israel has served as consultant for GE Healthcare Technologies. 
2 Adrian Soil has been an employee of Functional Imaging, GE Healthcare Technologies.
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