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Clinical Investigation |
1 Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands; 2 Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; 3 Interuniversity Institute of The Netherlands, Utrecht, The Netherlands; 4 Cardiovascular Center, Aalst, Belgium; and 5 Department of Nuclear Medicine, Leiden University Medical Center, Leiden, The Netherlands
Correspondence: For correspondence or reprints contact: Jeroen J. Bax, MD, PhD, Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands. E-mail: jbax{at}knoware.nl
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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90% luminal narrowing). Gated SPECT findings were classified as normal or abnormal (reversible or fixed defects) and were allocated to the territory of one of the various coronary arteries. Results: In coronary arteries with a calcium score of 10 or less, the corresponding myocardial perfusion was normal in 87% (n = 194/224). In coronary arteries with extensive calcifications (score > 400), the percentage of vascular territories with normal myocardial perfusion was lower, 54% (n = 13/24). Similarly, in most of the normal coronary arteries on multislice CT angiography, the corresponding myocardial perfusion was normal on SPECT (156/175, or 89%). In contrast, the percentage of normal SPECT findings was significantly lower in coronary arteries with obstructive lesions (59%) or with total or subtotal occlusions (8%) (P < 0.01). Nonetheless, only 48% of vascular territories with normal perfusion corresponded to normal coronary arteries on multislice CT angiography, whereas insignificant and significant stenoses were present in, respectively, 40% and 12% of corresponding coronary arteries. Conclusion: Although a relationship exists between the severity of CAD on multislice CT and myocardial perfusion abnormalities on SPECT, analysis on a regional basis showed only moderate agreement between observed atherosclerosis and abnormal perfusion. Accordingly, multislice CT and gated SPECT provide complementary rather than overlapping information, and further studies should address how these 2 modalities can be integrated to optimize patient management.
Key Words: coronary artery disease • computed tomography • ischemia
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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This paradigm has been challenged with the emergence of noninvasive coronary angiography using multislice CT. Because information on coronary anatomy can now be obtained noninvasively, multislice CT coronary angiography is being performed increasingly often at earlier stages of the disease, in the absence of a functional evaluation (1). Preliminary data comparing multislice CT with SPECT show that, in fact, a large discrepancy exists between the anatomic extent of CAD and ischemia and that many stenoses do not result in abnormal perfusion (1,2). Thus, it remains undetermined in which sequence the tests should be performed and, ultimately, who will benefit from the performance of noninvasive coronary angiography. To design proper evaluation strategies, one must understand how anatomic and functional findings relate to each other on a regional basis, per vessel distribution territory.
Therefore, we have further explored, in an unselected patient population, the relationship between the severity of anatomic CAD based on coronary calcium and multislice CT angiography and the severity of perfusion abnormalities based on SPECT.
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MATERIALS AND METHODS |
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Multislice CT Coronary Angiography
First, a prospective coronary calcium scan was obtained before multislice CT angiography. The collimation was 4 x 3.0 mm; gantry rotation time, 500 ms; tube voltage, 120 kV; and tube current, 200 mA. The temporal window was set at 75% after the R wave for electrocardiographically triggered prospective reconstruction. The coronary calcium score was derived using dedicated software (Vitrea2; Vital Images). Coronary calcium was identified as a dense area in the coronary artery exceeding the threshold of 130 HU. The Agatston score, both global and per coronary artery, was recorded for each patient. Coronary calcium scores were classified into 4 categories (
10, 11–100, 101–400, and >400).
For the contrast-enhanced helical scan, data were acquired with a collimation of either 16 x 0.5 or 64 x 0.5 mm and a tube rotation time of 400, 450, or 500 ms (depending on the heart rate). The tube current was 300 mA, at a voltage of 120 kV. In 31 patients, 16-slice CT (Aquilion 16; Toshiba Medical Systems) was used (3), and in 109 patients, 64-slice CT (Aquilion 64; Toshiba Medical Systems) was used. Nonionic contrast material (iomeprol [Iomeron 400]; Bracco) was administered in the antecubital vein at a volume of 120–140 mL for 16-slice CT and of 80–110 mL for 64-slice CT, depending on the total scanning time, and at a rate of 5 mL/s, followed by a saline flush. Subsequently, datasets were reconstructed and transferred to a remote workstation as previously described (3).
An interventional cardiologist who was unaware of the SPECT data evaluated the multislice CT angiograms to determine whether atherosclerosis was absent, present but not significantly stenotic (50% luminal narrowing), present and significantly stenotic (50% luminal narrowing), or present and totally or subtotally occlusive (90% luminal narrowing). In the analysis, the left main coronary artery was considered part of the left anterior descending coronary artery. In patients who had undergone previous coronary bypass grafting, the graft and its distal runoff were evaluated. In the case of an occluded or stenosed graft, the native coronary artery proximal to the anastomosis also was included in the analysis.
Stress–Rest Gated SPECT
In all patients, stress–rest gated SPECT (2 x 500 MBq of 99mTc-tetrofosmin) was performed using symptom-limited exercise or pharmacologic (adenosine or dobutamine) stress as previously described (4). After acquisition with a triple-head SPECT camera (GCA 9300/HG; Toshiba Corp.), data were reconstructed in long- and short-axis projections perpendicular to the heart axis. The short-axis data were displayed in polar map format, with the maps divided into 17 segments (5) and normalized to peak myocardial activity (100%). The 17 segments were allocated to the territories of the different coronary arteries as previously described (5). Perfusion defects were identified on the stress images (tracer activity < 75% of maximum) and classified as ischemia (reversible defects, with a 10% increase in tracer uptake on the resting images) or scar tissue (fixed defects, without a 10% increase in tracer uptake on the resting images). Accordingly, the findings were classified as either normal or abnormal, with the latter being further classified as either reversible or irreversible defects. The gated images were used to assess regional wall motion to improve differentiation between perfusion abnormalities and attenuation artifacts. For irreversible defects, whether the defects were located in a region with a documented previous myocardial infarction was recorded. Left ventricular ejection fraction was derived from the gated SPECT data using previously validated automated software (quantitative gated SPECT [QGS]; Cedars-Sinai Medical Center); gating was performed only at rest.
Statistical Analysis
Continuous variables were expressed as mean ± SD. Patient groups were compared using 1-way ANOVA for continuous variables and the 
2 test with Yates correction for categoric variables. A P value of less than 0.05 was considered statistically significant.
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RESULTS |
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On SPECT, 420 vascular territories were available, of which 327 (78%) showed normal myocardial perfusion. Abnormal perfusion was observed in the remaining 93 territories (22%). In 20 territories, fixed defects corresponding to territories with a known previous myocardial infarction were observed. Of the remaining 73 vascular territories, 41 showed ischemia and 27 showed fixed defects, whereas 5 territories showed both. Figure 2C displays the distribution of perfusion findings among the territories of the different coronary arteries.
Stenoses on Multislice CT Angiography Versus Coronary Artery Calcium Score.
The average coronary artery calcium score was 1.4 ± 6.0 for normal coronary arteries and increased to 111.6 ± 212.9 and 313.3 ± 600.4 for coronary arteries with insignificant and significant stenoses, respectively (P < 0.001, Kruskal–Wallis). When only total or subtotal occlusion was considered, the extent of coronary calcifications was even higher, 656.5 ± 280.9 (P < 0.001). In most coronary arteries with a coronary calcium score below 100 (n = 284, or 90%), no significant stenoses were demonstrated. Of the 33 of 60 coronary arteries with a calcium score between 100 and 400, significant stenoses were present in 45%. This percentage further increased to 60% in the 25 coronary arteries with a calcium score above 400.
Perfusion on SPECT Versus Coronary Artery Calcium Score.
The average calcium score in coronary arteries with normal myocardial perfusion on SPECT was 69 ± 167, whereas a significantly higher calcium score of 272 ± 646 was noted for coronary arteries with abnormal myocardial perfusion on SPECT (P < 0.001, Mann–Whitney).
Figure 3 shows the distribution of normal and abnormal myocardial perfusion (with exclusion of 19 vascular territories with previous myocardial infarction) according to the different calcium scores. In most of the coronary arteries with no or minimal calcium (score 10) (n = 194, or 87%), the SPECT findings were normal. The percentage showing normal perfusion was only slightly lower (85%) in coronary arteries with a calcium score between 11 and 100 (P = not statistically significant [NS]). In coronary arteries with more extensive calcifications, the percentage showing normal myocardial perfusion on SPECT was significantly lower: 75% for coronary arteries with calcium scores between 100 and 400 and 54% for coronary arteries with calcium scores above 400 (P = 0.008).
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10) for normal perfusion was 87% (Fig. 4A), but the value of significant calcium (score > 400) for prediction of abnormal perfusion was only 46% (Fig. 4B).
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Normal on SPECT but Abnormal on Multislice CT Angiography.
Only 48% of vascular territories with normal perfusion on SPECT corresponded to normal coronary arteries. In most abnormal coronary arteries with normal perfusion (131, or 77%), lesions were insignificant and did not result in ischemia. In 40 vascular territories (10%), myocardial perfusion was completely normal despite significant lesions in the corresponding coronary artery on multislice CT. In these cases, coronary lesions may not have been hemodynamically relevant. Importantly, in 2 patients with a discrepancy between multislice CT and SPECT on a vessel basis, stenosis of both the right coronary artery and the left main coronary artery was present, but only the lesion in the right coronary artery was detected by abnormal perfusion. Finally, in 2 patients with completely normal perfusion on SPECT, 3-vessel disease was demonstrated on multislice CT.
Analysis on a Patient Basis
Multislice CT and SPECT Findings.
The average coronary calcium score per patient was 310 ± 775 (range, 0–6,264). Multislice CT coronary angiography showed normal findings in 43 patients (31%), whereas nonobstructive and obstructive CAD was noted in, respectively, 51 patients (36%) and 46 patients (33%). Normal perfusion on SPECT was noted in 77 patients (55%), whereas abnormal perfusion was noted in 63 patients (45%), corresponding to previous myocardial infarction in 15 patients (11%).
Stenoses on Multislice CT Angiography Versus Coronary Artery Calcium Score.
The average coronary artery calcium score was 3.8 ± 11 for patients with normal coronary arteries and increased to 207 ± 271 and 726 ± 1,239 for patients with insignificant and significant stenoses, respectively (P < 0.001, Kruskal–Wallis). In most patients (n = 45, or 88%) with a coronary calcium score of 10 or less, no significant stenoses were demonstrated. In 20 (35%) of the 57 patients with a calcium score between 11 and 400, significant stenoses were present. This percentage further increased to 65% in patients with a calcium score above 400.
Perfusion on SPECT Versus Coronary Artery Calcium Score.
The average calcium score for patients with normal myocardial perfusion on SPECT was 162 ± 332, whereas a significantly higher calcium score of 580 ± 1,232 was noted for patients with abnormal perfusion on SPECT (P < 0.05, Mann–Whitney).
In most patients without extensive calcium (score 100) (n = 49, or 78%), perfusion on SPECT was normal. The percentage with normal perfusion was slightly lower (60%) in patients with a calcium score between 101 and 400 (P = NS). Of coronary arteries with calcium scores above 400, the percentage showing normal myocardial perfusion on SPECT was even lower (41%, P = NS).
Perfusion on SPECT Versus Stenoses on Multislice CT Angiography.
In most patients with normal arteries on multislice CT angiography, perfusion on the corresponding SPECT study was normal as well (37/43, or 86%). Of the patients with insignificant stenoses on multislice CT angiography (n = 38, with the exclusion of 13 patients with abnormal perfusion corresponding to previous myocardial infarction), myocardial perfusion on SPECT was normal in 24 (63%). The percentage of SPECT studies showing normal perfusion further decreased to 36% in patients with at least 1 significant stenosis (P < 0.05). Thus, a normal artery on multislice CT angiography had a high predictive value for normal myocardial perfusion on SPECT (86%). However, similar to the vessel-based analysis, normal perfusion on SPECT did not exclude abnormalities on multislice CT angiography, because a normal artery on multislice CT angiography was found in only 37 (48%) of 77 patients with normal perfusion on SPECT.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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These observations highlight the fact that normal perfusion on SPECT does not exclude atherosclerosis. Accordingly, multislice CT and gated SPECT provide complementary rather than redundant information, because the techniques reflect distinct functional and anatomic pathophysiologic processes.
An Abnormal Artery on Multislice CT Does Not Necessarily Imply Ischemia
Most lesions (76%) on multislice CT did not result in perfusion abnormalities or ischemia on SPECT. In particular, 89% of nonobstructive lesions on multislice CT were not associated with perfusion abnormalities on SPECT. This observation underscores the ability of multislice CT to detect CAD at an earlier stage than can SPECT: Atherosclerosis is detected while perfusion is not yet compromised. Similar results were reported recently for 16-slice CT by Hacker et al., who demonstrated in 25 patients that only 8 (47%) of 17 significant stenoses on multislice CT resulted in abnormal perfusion on SPECT (2). Yet, in the present study, a stepwise increase in the incidence of perfusion abnormalities on SPECT was observed in relation to an increasing severity of atherosclerotic abnormalities on multislice CT (Fig. 5). In particular, total or subtotal occlusions were in 92% of cases associated with abnormal myocardial perfusion on SPECT. Also, less severe but still significant lesions resulted in abnormal perfusion in 41% of vascular territories. These findings illustrate the relationship between the severity of stenosis on multislice CT and the hemodynamic consequences as assessed by SPECT, but the results simultaneously highlight the discrepancy between atherosclerotic plaque burden and ischemia. As a result of variations in stenosis length, composition, angle, and location, as well as the presence or absence of collateral vessels, a stenosis may be incapable of producing symptoms in one patient whereas an apparently identical stenosis causes severe ischemia in another. Indeed, several studies comparing invasive coronary angiography findings with functional testing findings revealed at best a fair agreement, with approximately half the significant lesions showing abnormal myocardial perfusion (2,6). This, by virtue of its relative nature, detects severe reductions in coronary flow reserve while modest reductions in flow reserve may not result in detectable defects (7). Thus, abnormal findings on multislice CT do not necessarily result in abnormal perfusion on SPECT but may more frequently represent nonobstructive atherosclerosis. In patients with abnormal findings on multislice CT, functional testing is therefore mandatory to determine the hemodynamic consequences of those abnormalities.
Normal Perfusion on SPECT Does Not Exclude CAD
In the present study, atherosclerosis was present in 52% of coronary arteries with normal perfusion on SPECT. Moreover, advanced CAD with at least 1 significant, obstructive lesion was noted in 12% of territories with normal perfusion, underlining the fact that normal SPECT findings do not invariably exclude the presence of CAD. Indeed, studies correlating atherosclerosis assessment (based on coronary artery calcium scoring) to SPECT revealed similar observations, namely that extensive coronary calcifications are frequently observed in patients with normal perfusion on SPECT (8,9). These observations may initially appear to be in conflict with the extremely low annual event rate associated with normal SPECT findings—approximately 0.6% for patients without known CAD (10). Nonetheless, among patients with normal SPECT findings, certain subgroups, including patients referred for pharmacologic testing or with substantial comorbidity, have been identified that may actually be at an elevated risk (1.2%–2.0%) (11). In addition, patients with subclinical CAD, as demonstrated by multislice CT, may constitute another category that may have an elevated long-term risk of experiencing coronary events despite normal perfusion on SPECT; this hypothesis needs to be addressed by further outcome-based studies. However, knowledge of the presence and extent of subclinical CAD is still relevant and will help to identify patients who show normal perfusion on SPECT yet have atherosclerosis, thus requiring optimized medical therapy and aggressive lifestyle modification, in contrast to patients who show normal perfusion on SPECT and have no atherosclerosis, who may be reassured without the need for further routine visits to outpatient clinics.
Regional Analysis
Concerning the different coronary arteries and corresponding vascular territories, a relatively larger plaque burden, as reflected by a higher coronary calcium score, was observed in the left anterior descending coronary artery than in the right and left circumflex coronary artery. Also, slightly more abnormalities were encountered in the left anterior descending coronary artery and corresponding vascular territory during coronary angiography and perfusion imaging, respectively. Nonetheless, in the present study, significant stenoses in the right coronary artery tended to result most frequently in abnormal myocardial perfusion on SPECT, as may be attributable to the higher frequency of severe, total or subtotal occlusions in this coronary artery than in the left anterior and left circumflex coronary arteries.
Limitations
Some limitations need to be defined. First, this study related myocardial perfusion on SPECT to atherosclerosis in coronary arteries on multislice CT, and perfect alignment between these methods is difficult because variations in coronary anatomy hamper the precise definition of vascular territories. Also, a threshold of 50% luminal narrowing on multislice CT was applied, whereas a threshold of 70% might have resulted in increased agreement between the 2 techniques. Second, the study population consisted of patients with various clinical presentations, including both suspected and known CAD. Studies performed on more homogeneous populations may provide more uniform results, yet those results may not be generalizable to a "real-life" population referred for evaluation of CAD, such as the one included in the present study. Similarly, the applied stress protocols for gated SPECT were not identical, because they were performed as part of standard clinical routine.
Other limitations included the lack of attenuation correction for SPECT, which may partially explain the (albeit infrequent) abnormal SPECT findings in the presence of completely normal multislice CT findings. Also, no comparison to conventional coronary angiography was available. In addition, data were acquired with 2 different generations of multislice CT scanners, whereas ideally all patients would have been evaluated with 64-slice CT. Finally, several limitations of multislice CT in general need to be acknowledged. The technique involves radiation, and further technical developments are needed to lower the radiation burden. Also, motion artifacts and severe coronary calcifications have been shown to reduce diagnostic accuracy (12,13).
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CONCLUSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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References |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONReferences |
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