Original Research n Cardiac
Imaging
Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.
Diagnosis of Functionally Significant Coronary Stenosis with Exercise CT Myocardial Perfusion Imaging1 Michel Habis, MD Said Ghostine, MD Adela Rohnean, MD André Capderou, MD, PhD Jean-François Paul, MD
1
From the Department of Cardiology, Centre Medico Chirurgical Parly 2, Le Chesnay, France (M.H.); Departments of Cardiology (S.G.) and Radiology (A.R., J.F.P.), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; Department of Physiology, School of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre, France (A.C.); and INSERM UMR 999, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (A.C.). Received April 11, 2014; revision requested June 3; revision received July 20; accepted August 15; final version accepted August 26. Address correspondence to J.F.P., Department of Radiology, Institut Mutualiste Montsouris, 42 Bd Jourdan, 75014 Paris, France (e-mail: [email protected]).
Purpose:
To assess the feasibility of exercise perfusion computed tomography (CT) in patients suspected of having hemodynamically significant coronary stenosis.
Materials and Methods:
This study had institutional review board approval, and all patients gave informed consent. Thirty-two consecutive patients (26 men [mean age, 63 years] and six women [mean age, 71 years]) with 55 coronary stenoses of at least 50% underwent coronary CT angiography (one stenosis in 13 patients, two stenoses in 15 patients, and three stenoses in four patients). CT myocardial perfusion imaging was performed within 1 minute after patients performed supine exercise on an ergometer secured to the CT table. The pressure-rate product was computed to assess level of exercise. The myocardial enhancement ratio between stenotic and normally perfused territories was determined for each stenosis. Fractional flow reserve less than 0.8, as measured during invasive coronary angiography, was the reference for defining significant stenoses. Receiver operating characteristic curves were constructed to determine the myocardial enhancement ratio cutoff value.
Results:
In the per-patient analysis, a myocardial enhancement ratio cutoff of 0.8 performed best for identifying functionally significant stenosis: Sensitivity was 95% (21 of 22 patients), specificity was 90% (nine of 10 patients), positive predictive value was 95% (21 of 22 patients), negative predictive value was 90% (nine of 10 patients), and accuracy was 94% (30 of 32 patients). Corresponding values in the per-stenosis analysis were 97% (29 of 30 stenoses), 96% (23 of 24 stenoses), 97% (29 of 30 stenoses), 96% (23 of 24 stenoses), and 96% (52 of 54 stenoses), respectively.
Conclusion:
Exercise CT myocardial perfusion imaging is feasible and accurate for assessment of the functional significance of coronary stenosis. RSNA, 2014
q
RSNA, 2014
q
684
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
W
ith the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation, or COURAGE, trial, it was established that adding percutaneous coronary intervention to optimal medical therapy does not improve survival or cardiovascular outcomes in patients with stable angina (1). However, patients were included in the COURAGE trial on the basis of at least 70% ischemia provoking coronary artery stenosis at invasive coronary angiography (ICA). Fractional flow reserve (FFR) measurement during ICA has emerged as the reference standard for assessment of the functional significance of coronary artery stenosis, with a cutoff of 0.8. In patients with stable angina and an FFR of less than 0.8, percutaneous coronary intervention significantly decreased the need for urgent revascularization (2). In another study, the frequency of major adverse cardiac events after percutaneous coronary intervention was 28% lower when the intervention was guided with FFR rather than visual interpretation of ICA images (3). Coronary computed tomographic (CT) angiography is a sensitive, noninvasive method for ruling out coronary artery stenosis (4,5) but can lead to overestimation of stenosis severity. Discrepancy between the percentage of coronary arterial narrowing and its functional significance was demonstrated nearly 20 years ago (6) and was confirmed in studies on the comparison of different coronary artery stenosis imaging with FFR measurement (7,8). In the FFR versus Angiography for Multivessel Evaluation—or FAME—trial, FFR was more than 0.8 for 63% of visually estimated intermediate stenoses
(50%–70%) and 20% of severe (70%– 90%) stenoses (9). A noninvasive method that produces reliable information on both the anatomy and the functional significance of coronary artery stenosis would decrease the need for ICA. Adenosine CT myocardial perfusion imaging (MPI) has been proven to be reliable compared with FFR and adenosine cardiac magnetic resonance perfusion imaging (10). Other complex coronary CT angiography techniques without stress induction have been used to compare stenosis anatomy characteristics (11), transluminal attenuation gradient across a stenosis (12), or noninvasive FFR derived from computational fluid dynamics technology (13) to the reference FFR measured during ICA. We hypothesize that postexercise CT will show perfusion defects in territories supplied by coronary arteries with functionally significant stenoses. Our objective was to assess the feasibility of exercise perfusion CT in patients suspected of having hemodynamically significant coronary stenosis.
Materials and Methods In this prospective single-center study, we included consecutive patients suspected of having coronary artery disease in whom coronary CT angiography performed at our institution from July 2012 to July 2013 showed at least one coronary artery stenosis of at least 50% as assessed by means of visual inspection. CT MPI was performed after a supine exercise test on the CT table (Fig 1). Myocardial perfusion polar maps of territories supplied by
Implications for Patient Care Advances in Knowledge nn Exercise-stress myocardial perfusion CT can help determine whether coronary artery disease causes ischemia.
nn Exercise-stress myocardial perfusion CT is a feasible alternative to other methods for detection of ischemia in patients with coronary artery disease.
nn Perfusion defects defined by using a myocardial enhancement ratio threshold of 0.8 correlate strongly with fractional flow reserve.
nn Exercise-stress perfusion CT can be used to determine the functional significance of coronary artery stenoses detected with coronary CT angiography.
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
Habis et al
stenotic arteries were compared with FFR values measured across the same stenoses during ICA. Our institutional review board approved the study protocol, and all patients gave informed consent before study inclusion. Inclusion criteria were age of 35–85 years and suspicion of coronary artery disease on the basis of any of the following: chest pain, dyspnea, abnormal resting electrocardiography (ECG) findings, inconclusive stress test results, and multiple cardiovascular risk factors. Exclusion criteria were previous myocardial infarction or coronary revascularization (n = 45), acute coronary syndrome (n = 2), creatinine clearance lower than 30 mL/min (n = 4), allergy to iodinated contrast media (n = 2), inability to exercise in the supine position (peripheral arterial, orthopedic, rheumatic, or advanced respiratory disease) (n = 5), atrial fibrillation (n = 6), left ventricular dysfunction (ejection fraction , 30% at echocardiography) (n = 4), implanted pacemaker or defibrillator (n = 2), significant valvular heart disease (n = 2), significant left main coronary artery stenosis at coronary CT angiography (n = 3), and ventricular arrhythmias (n = 4). A positive exercise
Published online before print 10.1148/radiol.14140861 Content codes: Radiology 2015; 274:684–692 Abbreviations: CI = confidence interval ECG = electrocardiography FFR = fractional flow reserve ICA = invasive coronary angiography MER = myocardial enhancement ratio MPI = myocardial perfusion imaging ROC = receiver operating characteristic Author contributions: Guarantors of integrity of entire study, M.H., S.G., J.F.P.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, M.H., J.F.P.; clinical studies, M.H., S.G., A.R., J.F.P.; statistical analysis, A.C., J.F.P.; and manuscript editing, M.H., A.C., J.F.P. Conflicts of interest are listed at the end of this article.
685
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
Habis et al
Figure 1
Figure 1: Photograph shows how the ergometer was secured to the CT table. CT myocardial perfusion imaging was performed immediately after exercise on the ergometer.
stress test finding was not an exclusion criterion (n = 4).
CT Protocols For all CT protocols, we used a dualsource 128-section CT scanner (Somatom Definition Flash; Siemens, Erlangen, Germany) with a temporal resolution of 75 msec per image, a gantry time of 300 msec, and dual-tube acquisition. Patients were asked to stop their beta-blocker treatment 48 hours before exercise CT MPI. Coronary CT angiography.—Contrast medium (1 mL per kilogram of body weight of iopromide 370 mg/mL; Bayer, Berlin, Germany) was injected. Retrospective acquisition with ECG dose modulation was used if the heart rate was at least 60 beats per minute, and high-pitch acquisition was used if the heart rate was less than 60 beats per minute. Tube voltage and current were adjusted to patient morphology (100 kVp and 280 mAs for patients lighter than 70 kg, 100 kVp and 370 mAs for patients between 70 and 80 kg, and 120 kVp and 400 mAs for patients heavier than 80 kg). No patient received beta-blocker therapy prior to coronary CT angiography. The images were assessed visually for coronary artery stenoses by an ex perienced observer (J.F.P., with 15 years 686
of experience with coronary CT angiography). Stenosis-related perfusion defects at rest were assessed by using a narrow window (center, 150 HU; window, 300 HU), which was adjusted manually if necessary. Patients with at least 50% stenosis as assessed visually and no related myocardial perfusion defect at rest were asked to undergo supine exercise CT MPI either on the same day or within the next 2 weeks. Exercise CT MPI.—An exercise device (Angio; Lode, Groningen, the Netherlands) was secured to the CT table for use by the patient in the supine position. Heart rate and ECG data were recorded by using the three-lead ECG device integrated in the CT scanner. Blood pressure was monitored during exercise. Exercise intensity was increased in 30-W steps every 2 minutes. Exercise was stopped when any of the following five criteria were met: chest pain, significant ST segment deviation, maximal systolic blood pressure above 250 mm Hg, heart rate at the maximal predicted value, and patient exhaustion. The peak workload was recorded in watts or metabolic equivalents at exercise discontinuation. The rate-pressure double product was computed as heart rate times systolic arterial pressure at peak stress. Within 1 minute after exercise discontinuation, the patient’s
feet were removed from the ergometer, and CT MPI was performed by using 1 mL per kilogram of body weight of iopromide 370 mg/mL, perfused at a rate of 8 mL/sec. An 18-gauge needle was inserted into a large antecubital fossa vein and connected to an extension line 2.5 mm in diameter. Helical acquisition was performed at 100 kVp and 120–200 mAs, depending on patient size (volume CT dose index, 24–29 mGy, without ECG dose modulation). The entire heart was covered by using a pitch of 0.17. Images were reconstructed at 10% R-R cycle intervals by using 3-mm section thickness. Mean radiation dose was estimated in millisieverts for each acquisition by computing the doselength product in milligray centimeters, by using a conversion factor of 0.014. Image postprocessing.—Perfusion polar maps were generated automatically by using dedicated software (Intuition; Terarecon, San Mateo, Calif). The best diastolic (60%–90%) and systolic (20%–50%) myocardial perfusion images were chosen on the basis of visual assessment. Delineations of the inner and outer myocardial layers were corrected manually when inadequate on the automatically generated maps. Two 17-segment bull’s-eye displays (systolic and diastolic phases) were produced, and the mean pixel density in each segment was determined (Fig 2, C). We calculated the standard deviation of myocardial segmental enhancement between the diastolic and systolic phases in normal patients. The standard deviation was 10%. We used 2 standard deviations (20%) as the threshold, indicating that areas of low myocardial attenuation were potential artifacts mimicking perfusion defects. True perfusion defects are more likely to persist across multiple phases (14). When the difference of segmental myocardial enhancement was at least 20% between the systolic and diastolic phases, the lowest value was considered an artifact and discarded (five of 32 patients). For each phase, the myocardial enhancement ratio (MER) was computed as the lowest segmental density value in the stenotic territory divided by the mean density
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
Habis et al
Figure 2
Figure 2: A, B, Exercise CT MPI images in a 49-year-old man. A, Rest coronary CT angiography image shows homogeneous enhancement of the myocardium. B, Postexercise CT image clearly shows a large perfusion defect in the septal and apical walls (arrows). C, Polar attenuation map shows a large perfusion defect in the left anterior descending artery territory (blue) (FFR = 0.56 and MER = 0.63) but no perfusion defect in the lateral territory (FFR = 0.81 and MER = 0.86). D, Coronary angiogram shows a 70% stenosis of the left anterior descending artery (blue arrow) and a 60% stenosis of the marginal artery (green arrow).
value in a nonstenotic related artery in the same patient. Measurements were read on 17-segment model polar maps. Each segment was matched to a coronary artery territory on the basis of coronary CT angiography anatomy. In patients with three-vessel coronary artery disease, the territory supplied by the arterial branch with the least severe stenosis was used as the denominator for MER computation. The distribution determined with coronary CT angiography was used when the
coronary artery corresponding to a perfusion defect was difficult to identify. The mean of the systolic and diastolic MER values was compared with the FFR value.
ICA and FFR Assessment ICA.—All patients underwent ICA within 7 days of coronary CT angiography to confirm the diagnosis of significant coronary artery stenosis. Selective coronary angiography was performed by using the standard technique, with
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
5-F or 6-F catheters. Intracoronary nitrate injection (1 mg of isosorbide dinitrate) was performed routinely after stenosis identification. An experienced operator (S.G., with 12 years of experience with conventional coronary angiography), who was blinded to the CT findings, assessed all stenoses visually on at least two orthogonal images. An intermediate or significant stenosis was defined as a mean diameter reduction of at least 50% on two orthogonal views. Patients were classified on the 687
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
basis of the number of at least 50% stenoses identified at ICA. FFR.—FFR was measured in all nonoccluded coronary arteries at least 2.5 mm in diameter with at least 50% diameter stenoses according to visual assessment of the ICA images. A 0.014-inch pressure guidewire (Aeris Pressure Wire; St Jude Medical, Uppsala, Sweden) was calibrated and electronically equalized with the aortic pressure, then advanced distal to the coronary artery stenosis through a 6-F guiding catheter. Hyperemia was induced by an intracoronary bolus of adenosine (180 mg). FFR was computed as the ratio of the mean hyperemic distal coronary artery pressure measured with the pressure wire over the mean aortic pressure measured with the guiding catheter. FFR value of less than 0.80 was considered the reference to indicate a functionally significant coronary artery stenosis. Occluded coronary arteries were assumed to generate ischemia. Angioplasty or coronary artery bypass grafting was performed as determined by the FFR values, without knowledge of the exercise CT MPI findings.
Statistical Analysis Categorical variables were described as number and percentage and continuous variables as mean 6 standard deviation or median (minimum, maximum), depending on the result of the Shapiro-Wilk test for normality. Correlations between non-normally distributed variables were assessed by using the nonparametric Spearman test. The best MER cutoff for separating significant and nonsignificant coronary artery stenoses was determined by plotting the receiver operating characteristic (ROC) curve. Cutoff performance was assessed at the patient and stenosis levels, on the basis of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Proportions were reported as percentages with 95% confidence intervals (CIs). All statistical tests were two tailed, and P values less than .05 were considered to indicate a significant difference. The statistical 688
Habis et al
Table 1 Baseline Patient Characteristics and Supine Exercise Data Characteristic
Value
No. of patients Patient sex No. of men No. of women No. of stenoses No. of occlusions Age (y)* No. of patients with hypercholesterolemia No. of patients with hypertension No. of patients with family history of coronary artery disease No. of smokers No. of patients with diabetes Body mass index (kg/m2) Previous inconclusive stress tests No. of patients with one-vessel disease No. of patients with two-vessel disease No. of patients with three-vessel disease Heart rate at peak stress (beats/min)† HR at acquisition (beats/min)† Rate-pressure double product Work load (W)‡
32 26 (81) 6 (19) 45 9 65 6 12 23/32 (72) 17/32 (53) 17/32 (53) 13/32 (41) 4/32 (12) 26 6 4 SPECT (three), exercise ECG (five), stress echo (one) 13/32 (41) 15/32 (47) 4/32 (12) 131 6 16 (84) 105 6 21 (68) 23 898 6 4761 134 6 44 (7.5 6 1.6)
Note.—Numbers in parentheses are percentages, unless indicated otherwise. * Data are means 6 standard deviations. †
Numbers in parentheses are percentage predicted values.
‡
Numbers in parentheses are metabolic equivalents.
analysis was performed by using R version 3.0.0 software (R Foundation, Vienna, Austria).
Results Baseline Patient Characteristics We included 32 patients—26 men (mean age, 63 years; range, 40–84 years) and six women (mean age, 71 years; range, 57–81 years). Mean age was not significantly different between men and women (Student t test). Fifty-five coronary artery stenoses were depicted, at the following locations: left anterior descending artery (n = 29; proximal, eight stenoses; middle, 17 stenoses; and distal, four stenoses), right coronary artery (n = 16; proximal, four stenoses; middle, 10 stenoses; and distal, two stenoses), and left circumflex artery (n = 10; proximal,
five stenoses; and distal, five stenoses). Table 1 depicts baseline patient characteristics. Seventeen of 32 patients (53%) had body mass index values higher than 25 kg/m2. Three patients were referred for coronary CT angiography because of persistent chest pain despite normal findings at single photon emission CT; their coronary CT angiography images showed significant stenosis in the left anterior descending (n = 2) or circumflex (n = 1) arteries. Six patients were evaluated after receiving inconclusive findings at exercise ECG (n = 5) or echocardiography (n = 1).
Coronary CT Angiography and Exercise CT MPI One patient did not perform the exercise because an inferior perfusion defect associated with a 90% right coronary artery stenosis was obvious at rest. The time from coronary CT
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
angiography to exercise CT MPI in the remaining 31 patients ranged from 30 minutes to 2 weeks. Heart rate at peak stress and during CT acquisition, maximal rate-pressure product, and highest workload are reported in Table 1. Exercise was discontinued in eight of 32 patients with rate-pressure products of less than 20 000 (three of whom had chest pain and/or an ST segment depression). Postexercise acquisition was performed within 1 minute after peak stress. In four patients, recovery from exercise was associated with a marked decrease in heart rate at acquisition (to ,50% maximal predicted value). Rate-pressure product was greater than 20 000 in 75% of patients (24 of 32 patients). No adverse events occurred during exercise CT MPI. Total contrast material volume injected was 148 mL 6 29 (two infusions of 1 mL per kilogram of body weight each). Radiation dose was 4.6 mSv 6 2.5 during coronary CT angiography and 5.6 mSv 6 2.8 during exercise CT MPI. Median MER for all coronary artery stenoses was 0.77 (range, 0.48–0.96).
ICA and FFR Measurement No patients experienced cardiovascular events during the interval between coronary CT angiography and ICA. The percentages of patients with one-, two-, and three-vessel disease were 41% (13 of 32), 47% (15 of 32), and 12% (four of 32), respectively. The left anterior descending artery, circumflex artery, and right coronary artery were stenotic in 97% (31 of 32), 34% (11 of 32), and 41% (13 of 32) of patients, respectively. FFR was measured for 45 stenoses (one omitted); the remaining nine stenoses (left anterior descending artery in two cases, circumflex artery in one case, and right coronary artery in six cases) resulted in complete occlusion and were therefore assumed to be associated with FFR values less than 0.8. Median measured FFR value was 0.83 (range, 0.26–0.98) and, of 45 stenoses with FFR measurements, 47% (21 of 45) had FFR values less than 0.8. Thus, 30 stenoses in all were classified
as being associated with FFR values less than 0.8.
Comparison of MER after Exercise CT MPI and FFR The ROC curve analysis showed that the best MER cutoff for identifying significant stenoses, defined as having FFR values less than 0.8, was 0.8 (area under the ROC curve, 0.98 6 0.02) (Fig 3). Exercise CT MPI was therefore considered to indicate ischemia when MER was less than 0.8. The performance of this MER cutoff in the diagnosis of significant stenosis was assessed per patient and per stenosis, for all 54 stenoses and for the 45 stenoses without arterial occlusion (Table 2). At the patient level, MER less than 0.8 had a sensitivity of 95% (21 of 22 patients; 95% CI: 77, 100), a specificity of 90% (nine of 10 patients; 95% CI: 55, 100), a positive predictive value of 95% (21 of 22 patients; 95% CI: 77, 100), a negative predictive value of 90% (nine of 10 patients; 95% CI: 55, 100), and an accuracy of 94% (30 of 32 patients; 95% CI: 79, 99) for diagnosis of functionally significant stenosis, defined as FFR less than 0.8. At the stenosis level, when all 54 stenoses were considered, sensitivity was 97% (29 of 30 stenoses; 95% CI: 83, 100), specificity was 96% (23 of 24 stenoses; 95% CI: 79, 100), positive predictive value was 97% (29 of 30 stenoses; 95% CI: 83, 100), negative predictive value was 96% (23 of 24 stenoses; 95% CI: 79, 100), and accuracy was 96% (52 of 54 stenoses; 95% CI: 87, 100); when only the 45 nonoccluded stenoses were considered, sensitivity was 95% (20 of 21 stenoses; 95% CI: 76, 100), specificity was 96% (23 of 24 stenoses; 95% CI: 79, 100), positive predictive value was 95% (20 of 21 stenoses; 95% CI: 76, 100), negative predictive value was 96% (23 of 24 stenoses; 95% CI: 79, 100), and accuracy was 96% (43 of 45 stenoses; 95% CI: 86, 99). In the patient-level analysis, only two patients were misclassified: One had a false-negative result, and the other had a false-positive result. All the stenoses in our four patients with threevessel disease were correctly diagnosed by using exercise CT MPI. Although the
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
Habis et al
Figure 3
Figure 3: Graph demonstrates the ROC curve for the 45 stenoses with FFR measurements. The best MER cutoff is 0.8 (area under the ROC curve, 0.98 6 0.02).
occluded vessels were expected to have MER values less than 0.8, one such vessel had a MER value of 0.89. For the 45 nonoccluded stenotic coronary arteries, MER showed a significant (r2 = 0.58) but nonlinear correlation with the corresponding FFR value (Fig 4).
Discussion This study provides evidence that, in patients with stable coronary artery disease, supine exercise on a CT table is feasible for assessing myocardial perfusion during conditions of physiologic stress, providing stenosis-related functional information. A quantitative measure, the myocardial enhancement ratio obtained directly after exercise, may reliably be used to predict significant coronary artery stenosis as compared with FFR as the reference standard. In a previous study, visual assessment of stenosis severity on coronary CT angiography images showed high sensitivity (94%) but low specificity (40%) for the identification of functionally significant stenoses on the basis of FFR values (7). In the present study, exercise CT MPI improved both sensitivity and specificity for the identification of functionally significant stenosis, 689
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
Habis et al
Table 2 Comparison of Exercise and Adenosine
Analysis Type Per-patient analysis Per-vessel analysis with occlusions Per-vessel analysis without occlusions
No. of Patients or Stenotic Vessels Sensitivity (%)
Specificity (%)
Positive Predictive Value (%)
Negative Predictive Value (%)
Accuracy (%)
32 54
95 (21/22) [77, 100] 97 (29/30) [83, 100]
90 (9/10) [55, 100] 96 (23/24) [79, 100]
Exercise* 95 (21/22) [77, 100] 97 (29/30) [83, 100]
90 (9/10) [55, 100] 96 (23/24) [79, 100]
94 (30/32) [79, 99] 96 (52/54) [87, 100]
45
95 (20/21) [76, 100]
96 (23/24) [79, 100]
95 (20/21) [76, 100]
96 (23/24) [79, 100]
96 (43/45) [86, 99]
Adenosine Visual analysis Per-patient analysis Per-vessel analysis Transmural perfusion ratio Per-patient analysis Per-vessel analysis
39 118
95 (19/20) [73, 100] 87 (34/39) [72, 95]
95 (18/19) [72, 100] 95 (75/79) [87, 98]
95 (19/20) [73, 100] 89 (34/38) [74, 97]
95 (18/19) [72, 100] 94 (75/80) [85, 98]
95 (37/39) 92 (109/118)
38 116
95 (18/19) [72, 100] 71 (27/38) [64, 84]
89 (17/19 [66, 98] 95 (74/78) [87, 98]
90 (18/20) [67, 98] 87 (27/31) [69, 96]
94 (17/18) [71, 100] 87 (74/85) [78, 93]
92 (35/38) 87 (101/116)
Note.—Numbers in parentheses are the data used to calculate percentages. Numbers in brackets are 95% CIs. Comparison of exercise CT MPI and adenosine CT MPI accuracies to detect significant stenosis were compared with FFR with the corresponding methods used for quantifying myocardial perfusion hypoenhancement. Adenosine results according to visual analysis or transmural perfusion ratio are from reference 15. * All exercise data were acquired by using the myocardial enhancement ratio.
Figure 4
Figure 4: Plot depicts the correlation between MER and FFR for the 45 stenoses with FFR measurements. R 2 = 0.58. An MER cutoff of 0.8 was used to correctly classify 43 of 45 stenoses. The dashed line is the identity line.
compared with coronary CT angiography alone. Our ROC curve analysis demonstra ted that 0.8 was the optimal MER cutoff for identifying functionally significant stenoses on the basis of FFR values less 690
than 0.8. FFR has been reported to be 93% accurate in identifying stenoses responsible for ischemia (16). FFR is not always reliable for estimating absolute myocardial perfusion: In case of diffuse coronary artery disease, the coronary flow reserve may be significantly decreased in the absence of significant segmental stenosis. Inversely, preserved microvascular function or arterial remodeling may prevent ischemia in a myocardial territory fed by a significant stenosis (FFR , 0.8) (17,18). The diagnostic performance of exercise CT MPI in our study compares favorably with that of adenosine CT MPI (15,19). In a previous study, investigators assessed the incremental value of adenosine CT MPI for stenoses of at least 50% on coronary CT angiography images compared with the same FFR reference standard (19). Eleven of 116 vessels (9%) were negative for hemodynamically significant stenosis according to transmural perfusion ratio (the ratio of subendocardial to subepicardial contrast-enhanced attenuation) measurement. We used exercise, a more physiological stressor than adenosine. Another assessment
of perfusion defects according to semiquantitative estimation of myocardial blood flow (20) allowed an increase in specificity, positive predictive value, and diagnostic accuracy over coronary CT angiography. However, it required a 30-second breath hold during image acquisition, which limits its applicability to patients in good clinical condition. Exercise CT MPI requires additional contrast material and radiation exposure when compared with methods based on computational fluid dynamics, but that approach requires 5 hours of off-site analysis (13), which limits its practical utility for routine application Another approach for estimating the functional significance of a stenosis is the use of the transluminal attenuation gradient (linear regression coefficient between luminal attenuation and axial distance) across the stenosis. This gradient has been reported to be useful in the prediction of significantly abnormal FFR values (12). However, neither of these methods can be used to evaluate myocardial perfusion or the collateral blood supply directly. The high temporal resolution (75 msec) and contrast material infusion
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
rate (8 mL/sec) in our study allowed us to obtain sufficient image quality, despite exercise-related tachycardia. No adverse events were recorded during exercise CT MPI. Exercising in a supine position on the CT table minimized the time from peak stress to acquisition. Studies of exercise echocardiography have shown a 7%–30% decrease in sensitivity when looking for akinesia after exercising on a treadmill instead of during supine bicycle exercising (21,22). Hypoperfusion precedes akinesia, as is known from the sequence of events in the ischemic cascade (23). Whether the myocardial perfusion defect detected with CT disappears less quickly after exercise than akinesia is questionable. However, wall motion analysis was not evaluated in the current study. Exercise in the supine position increases venous return, thereby increasing cardiac output and left ventricle stroke work, which could increase the accuracy of stress to detect ischemia. In a comparison of imaging after exercising on a treadmill or in the supine position, the rate-pressure double products were similar, but myocardial ischemia was more extensive after supine exercise (21). Our two patients who were misclassified did not perform an invalid exercise (6 and 9 metabolic equivalents, respectively, with a double product of more than 20 000 for both). A noticeable heart rate decrease occurred in four patients during recovery from exercise but did not affect the diagnostic performance of MER determination. The rationale for performing coronary CT angiography before functional testing is discussed in a recent report (24) that outlines the limited predictive value of various stress tests (exercise test, stress echocardiography, and SPECT imaging). In previous studies, investigators have established that coronary CT angiography has a high negative predictive value of 90%–97% for functionally significant stenoses of less than 50% (7,15,19). Therefore, starting with a coronary CT angiography assessment of coronary anatomy can save time and decrease costs and radiation exposure compared with SPECT, and absence
of potentially significant stenoses obviates the need for subsequent functional testing. Our findings are relevant only to patients with stable coronary artery disease, in sinus rhythm, and without previous revascularization, myocardial infarction, or myocardial dysfunction. In addition, we excluded patients with stenoses of less than 50% according to coronary CT angiography images, since performing ICA in such patients would have been unethical. The high incidence of functionally significant coronary artery disease in this patient group may have affected the diagnostic performance of CT MPI in our study. For patients with three-vessel disease, we used enhancement in the territory supplied by the least severe coronary artery branch stenosis as the denominator for computing the MER. Motion artifacts are probably more common with exercise, but the multiphase acquisition and high temporal resolution of our technique seem to effectively circumvent this drawback (14). To limit bias, we used an image postprocessing workstation to automatically determine the contrast-enhanced attenuation values. The same reader performed the coronary CT angiography and exercise CT MPI evaluations, which seems preferable over having two different readers (14). Finally, coronary flow reserve assessed with positron emission tomography would probably be a better comparator for exercise CT MPI. Exercise CT MPI is a physiological method that performs well for the assessment of the functional significance of coronary stenosis. Studies in larger numbers of patients are warranted before using the combination of coronary CT angiography and exercise CT MPI as a gatekeeper to defer ICA.
Habis et al
References 1. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356(15):1503–1516. 2. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve–guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367(11):991–1001. 3. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360(3):213–224. 4. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64–multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52(21):1724–1732. 5. Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52(25):2135–2144. 6. Folland ED, Vogel RA, Hartigan P, et al. Relation between coronary artery stenosis assessed by visual, caliper, and computer methods and exercise capacity in patients with single-vessel coronary artery disease. The Veterans Affairs ACME Investigators. Circulation 1994;89(5):2005–2014. 7. Meijboom WB, Van Mieghem CA, van Pelt N, et al. Comprehensive assessment of coronary artery stenoses: computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina. J Am Coll Cardiol 2008;52(8): 636–643. 8. Waksman R, Legutko J, Singh J, et al. FIRST: Fractional Flow Reserve and Intravascular Ultrasound Relationship Study. J Am Coll Cardiol 2013;61(9):917–923.
Acknowledgment: The authors thank Antoinette Wolfe, MD, for her assistance in the preparation of this manuscript.
9. Tonino PA, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55(25):2816–2821.
Disclosures of Conflicts of Interest: M.H. disclosed no relevant relationships. S.G. disclosed no relevant relationships. A.R. disclosed no relevant relationships. A.C. disclosed no relevant relationships. J.F.P. disclosed no relevant relationships.
10. Bettencourt N, Chiribiri A, Schuster A, et al. Direct comparison of cardiac magnetic resonance and multidetector computed tomography stress-rest perfusion imaging for detection of coronary artery disease. J Am Coll Cardiol 2013;61(10):1099–1107.
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
691
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
11. Nakazato R, Shalev A, Doh JH, et al. Aggregate plaque volume by coronary computed tomography angiography is superior and incremental to luminal narrowing for diagnosis of ischemic lesions of intermediate stenosis severity. J Am Coll Cardiol 2013;62(5): 460–467. 12. Wong DT, Ko BS, Cameron JD, et al. Transluminal attenuation gradient in coronary computed tomography angiography is a novel noninvasive approach to the identification of functionally significant coronary artery stenosis: a comparison with fractional flow reserve. J Am Coll Cardiol 2013;61(12): 1271–1279. 13. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011;58(19):1989–1997. 14. Mehra VC, Valdiviezo C, Arbab-Zadeh A, et al. A stepwise approach to the visual interpretation of CT-based myocardial perfusion. J Cardiovasc Comput Tomogr 2011;5(6): 357–369.
692
Habis et al
15. Ko BS, Cameron JD, Meredith IT, et al. Computed tomography stress myocardial perfusion imaging in patients considered for revascularization: a comparison with fractional flow reserve. Eur Heart J 2012;33(1):67–77.
20. Greif M, von Ziegler F, Bamberg F, et al. CT stress perfusion imaging for detection of haemodynamically relevant coronary stenosis as defined by FFR. Heart 2013;99(14): 1004–1011.
16. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334(26):1703– 1708.
21. Badruddin SM, Ahmad A, Mickelson J, et al. Supine bicycle versus post-treadmill exercise echocardiography in the detection of myocardial ischemia: a randomized single-blind crossover trial. J Am Coll Cardiol 1999;33(6):1485–1490.
17. Johnson NP, Kirkeeide RL, Gould KL. Is discordance of coronary flow reserve and fractional flow reserve due to methodology or clinically relevant coronary pathophysiology? JACC Cardiovasc Imaging 2012;5(2): 193–202. 18. Johnson NP, Gould KL. Physiological basis for angina and ST-segment change PET-verified thresholds of quantitative stress myocardial perfusion and coronary flow reserve. JACC Cardiovasc Imaging 2011;4(9):990–998. 19. Ko BS, Cameron JD, Leung M, et al. Combined CT coronary angiography and stress myocardial perfusion imaging for hemodynamically significant stenoses in patients with suspected coronary artery disease: a comparison with fractional flow reserve. JACC Cardiovasc Imaging 2012;5(11):1097–1111.
22. Presti CF, Armstrong WF, Feigenbaum H. Comparison of echocardiography at peak exercise and after bicycle exercise in evaluation of patients with known or suspected coronary artery disease. J Am Soc Echocardiogr 1988;1(2):119–126. 23. Nesto RW, Kowalchuk GJ. The ischemic cascade: temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987;59(7):23C–30C. 24. Chinnaiyan KM, Raff GL, Goraya T, et al. Coronary computed tomography angiography after stress testing: results from a multicenter, statewide registry, ACIC (Advanced Cardiovascular Imaging Consortium). J Am Coll Cardiol 2012;59(7):688–695.
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
Imaging
Note: This copy is for your personal non-commercial use only. To order presentation-ready copies for distribution to your colleagues or clients, contact us at www.rsna.org/rsnarights.
Diagnosis of Functionally Significant Coronary Stenosis with Exercise CT Myocardial Perfusion Imaging1 Michel Habis, MD Said Ghostine, MD Adela Rohnean, MD André Capderou, MD, PhD Jean-François Paul, MD
1
From the Department of Cardiology, Centre Medico Chirurgical Parly 2, Le Chesnay, France (M.H.); Departments of Cardiology (S.G.) and Radiology (A.R., J.F.P.), Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; Department of Physiology, School of Medicine, Université Paris-Sud, Le Kremlin-Bicêtre, France (A.C.); and INSERM UMR 999, Centre Chirurgical Marie Lannelongue, Le Plessis-Robinson, France (A.C.). Received April 11, 2014; revision requested June 3; revision received July 20; accepted August 15; final version accepted August 26. Address correspondence to J.F.P., Department of Radiology, Institut Mutualiste Montsouris, 42 Bd Jourdan, 75014 Paris, France (e-mail: [email protected]).
Purpose:
To assess the feasibility of exercise perfusion computed tomography (CT) in patients suspected of having hemodynamically significant coronary stenosis.
Materials and Methods:
This study had institutional review board approval, and all patients gave informed consent. Thirty-two consecutive patients (26 men [mean age, 63 years] and six women [mean age, 71 years]) with 55 coronary stenoses of at least 50% underwent coronary CT angiography (one stenosis in 13 patients, two stenoses in 15 patients, and three stenoses in four patients). CT myocardial perfusion imaging was performed within 1 minute after patients performed supine exercise on an ergometer secured to the CT table. The pressure-rate product was computed to assess level of exercise. The myocardial enhancement ratio between stenotic and normally perfused territories was determined for each stenosis. Fractional flow reserve less than 0.8, as measured during invasive coronary angiography, was the reference for defining significant stenoses. Receiver operating characteristic curves were constructed to determine the myocardial enhancement ratio cutoff value.
Results:
In the per-patient analysis, a myocardial enhancement ratio cutoff of 0.8 performed best for identifying functionally significant stenosis: Sensitivity was 95% (21 of 22 patients), specificity was 90% (nine of 10 patients), positive predictive value was 95% (21 of 22 patients), negative predictive value was 90% (nine of 10 patients), and accuracy was 94% (30 of 32 patients). Corresponding values in the per-stenosis analysis were 97% (29 of 30 stenoses), 96% (23 of 24 stenoses), 97% (29 of 30 stenoses), 96% (23 of 24 stenoses), and 96% (52 of 54 stenoses), respectively.
Conclusion:
Exercise CT myocardial perfusion imaging is feasible and accurate for assessment of the functional significance of coronary stenosis. RSNA, 2014
q
RSNA, 2014
q
684
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
W
ith the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation, or COURAGE, trial, it was established that adding percutaneous coronary intervention to optimal medical therapy does not improve survival or cardiovascular outcomes in patients with stable angina (1). However, patients were included in the COURAGE trial on the basis of at least 70% ischemia provoking coronary artery stenosis at invasive coronary angiography (ICA). Fractional flow reserve (FFR) measurement during ICA has emerged as the reference standard for assessment of the functional significance of coronary artery stenosis, with a cutoff of 0.8. In patients with stable angina and an FFR of less than 0.8, percutaneous coronary intervention significantly decreased the need for urgent revascularization (2). In another study, the frequency of major adverse cardiac events after percutaneous coronary intervention was 28% lower when the intervention was guided with FFR rather than visual interpretation of ICA images (3). Coronary computed tomographic (CT) angiography is a sensitive, noninvasive method for ruling out coronary artery stenosis (4,5) but can lead to overestimation of stenosis severity. Discrepancy between the percentage of coronary arterial narrowing and its functional significance was demonstrated nearly 20 years ago (6) and was confirmed in studies on the comparison of different coronary artery stenosis imaging with FFR measurement (7,8). In the FFR versus Angiography for Multivessel Evaluation—or FAME—trial, FFR was more than 0.8 for 63% of visually estimated intermediate stenoses
(50%–70%) and 20% of severe (70%– 90%) stenoses (9). A noninvasive method that produces reliable information on both the anatomy and the functional significance of coronary artery stenosis would decrease the need for ICA. Adenosine CT myocardial perfusion imaging (MPI) has been proven to be reliable compared with FFR and adenosine cardiac magnetic resonance perfusion imaging (10). Other complex coronary CT angiography techniques without stress induction have been used to compare stenosis anatomy characteristics (11), transluminal attenuation gradient across a stenosis (12), or noninvasive FFR derived from computational fluid dynamics technology (13) to the reference FFR measured during ICA. We hypothesize that postexercise CT will show perfusion defects in territories supplied by coronary arteries with functionally significant stenoses. Our objective was to assess the feasibility of exercise perfusion CT in patients suspected of having hemodynamically significant coronary stenosis.
Materials and Methods In this prospective single-center study, we included consecutive patients suspected of having coronary artery disease in whom coronary CT angiography performed at our institution from July 2012 to July 2013 showed at least one coronary artery stenosis of at least 50% as assessed by means of visual inspection. CT MPI was performed after a supine exercise test on the CT table (Fig 1). Myocardial perfusion polar maps of territories supplied by
Implications for Patient Care Advances in Knowledge nn Exercise-stress myocardial perfusion CT can help determine whether coronary artery disease causes ischemia.
nn Exercise-stress myocardial perfusion CT is a feasible alternative to other methods for detection of ischemia in patients with coronary artery disease.
nn Perfusion defects defined by using a myocardial enhancement ratio threshold of 0.8 correlate strongly with fractional flow reserve.
nn Exercise-stress perfusion CT can be used to determine the functional significance of coronary artery stenoses detected with coronary CT angiography.
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
Habis et al
stenotic arteries were compared with FFR values measured across the same stenoses during ICA. Our institutional review board approved the study protocol, and all patients gave informed consent before study inclusion. Inclusion criteria were age of 35–85 years and suspicion of coronary artery disease on the basis of any of the following: chest pain, dyspnea, abnormal resting electrocardiography (ECG) findings, inconclusive stress test results, and multiple cardiovascular risk factors. Exclusion criteria were previous myocardial infarction or coronary revascularization (n = 45), acute coronary syndrome (n = 2), creatinine clearance lower than 30 mL/min (n = 4), allergy to iodinated contrast media (n = 2), inability to exercise in the supine position (peripheral arterial, orthopedic, rheumatic, or advanced respiratory disease) (n = 5), atrial fibrillation (n = 6), left ventricular dysfunction (ejection fraction , 30% at echocardiography) (n = 4), implanted pacemaker or defibrillator (n = 2), significant valvular heart disease (n = 2), significant left main coronary artery stenosis at coronary CT angiography (n = 3), and ventricular arrhythmias (n = 4). A positive exercise
Published online before print 10.1148/radiol.14140861 Content codes: Radiology 2015; 274:684–692 Abbreviations: CI = confidence interval ECG = electrocardiography FFR = fractional flow reserve ICA = invasive coronary angiography MER = myocardial enhancement ratio MPI = myocardial perfusion imaging ROC = receiver operating characteristic Author contributions: Guarantors of integrity of entire study, M.H., S.G., J.F.P.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, M.H., J.F.P.; clinical studies, M.H., S.G., A.R., J.F.P.; statistical analysis, A.C., J.F.P.; and manuscript editing, M.H., A.C., J.F.P. Conflicts of interest are listed at the end of this article.
685
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
Habis et al
Figure 1
Figure 1: Photograph shows how the ergometer was secured to the CT table. CT myocardial perfusion imaging was performed immediately after exercise on the ergometer.
stress test finding was not an exclusion criterion (n = 4).
CT Protocols For all CT protocols, we used a dualsource 128-section CT scanner (Somatom Definition Flash; Siemens, Erlangen, Germany) with a temporal resolution of 75 msec per image, a gantry time of 300 msec, and dual-tube acquisition. Patients were asked to stop their beta-blocker treatment 48 hours before exercise CT MPI. Coronary CT angiography.—Contrast medium (1 mL per kilogram of body weight of iopromide 370 mg/mL; Bayer, Berlin, Germany) was injected. Retrospective acquisition with ECG dose modulation was used if the heart rate was at least 60 beats per minute, and high-pitch acquisition was used if the heart rate was less than 60 beats per minute. Tube voltage and current were adjusted to patient morphology (100 kVp and 280 mAs for patients lighter than 70 kg, 100 kVp and 370 mAs for patients between 70 and 80 kg, and 120 kVp and 400 mAs for patients heavier than 80 kg). No patient received beta-blocker therapy prior to coronary CT angiography. The images were assessed visually for coronary artery stenoses by an ex perienced observer (J.F.P., with 15 years 686
of experience with coronary CT angiography). Stenosis-related perfusion defects at rest were assessed by using a narrow window (center, 150 HU; window, 300 HU), which was adjusted manually if necessary. Patients with at least 50% stenosis as assessed visually and no related myocardial perfusion defect at rest were asked to undergo supine exercise CT MPI either on the same day or within the next 2 weeks. Exercise CT MPI.—An exercise device (Angio; Lode, Groningen, the Netherlands) was secured to the CT table for use by the patient in the supine position. Heart rate and ECG data were recorded by using the three-lead ECG device integrated in the CT scanner. Blood pressure was monitored during exercise. Exercise intensity was increased in 30-W steps every 2 minutes. Exercise was stopped when any of the following five criteria were met: chest pain, significant ST segment deviation, maximal systolic blood pressure above 250 mm Hg, heart rate at the maximal predicted value, and patient exhaustion. The peak workload was recorded in watts or metabolic equivalents at exercise discontinuation. The rate-pressure double product was computed as heart rate times systolic arterial pressure at peak stress. Within 1 minute after exercise discontinuation, the patient’s
feet were removed from the ergometer, and CT MPI was performed by using 1 mL per kilogram of body weight of iopromide 370 mg/mL, perfused at a rate of 8 mL/sec. An 18-gauge needle was inserted into a large antecubital fossa vein and connected to an extension line 2.5 mm in diameter. Helical acquisition was performed at 100 kVp and 120–200 mAs, depending on patient size (volume CT dose index, 24–29 mGy, without ECG dose modulation). The entire heart was covered by using a pitch of 0.17. Images were reconstructed at 10% R-R cycle intervals by using 3-mm section thickness. Mean radiation dose was estimated in millisieverts for each acquisition by computing the doselength product in milligray centimeters, by using a conversion factor of 0.014. Image postprocessing.—Perfusion polar maps were generated automatically by using dedicated software (Intuition; Terarecon, San Mateo, Calif). The best diastolic (60%–90%) and systolic (20%–50%) myocardial perfusion images were chosen on the basis of visual assessment. Delineations of the inner and outer myocardial layers were corrected manually when inadequate on the automatically generated maps. Two 17-segment bull’s-eye displays (systolic and diastolic phases) were produced, and the mean pixel density in each segment was determined (Fig 2, C). We calculated the standard deviation of myocardial segmental enhancement between the diastolic and systolic phases in normal patients. The standard deviation was 10%. We used 2 standard deviations (20%) as the threshold, indicating that areas of low myocardial attenuation were potential artifacts mimicking perfusion defects. True perfusion defects are more likely to persist across multiple phases (14). When the difference of segmental myocardial enhancement was at least 20% between the systolic and diastolic phases, the lowest value was considered an artifact and discarded (five of 32 patients). For each phase, the myocardial enhancement ratio (MER) was computed as the lowest segmental density value in the stenotic territory divided by the mean density
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
Habis et al
Figure 2
Figure 2: A, B, Exercise CT MPI images in a 49-year-old man. A, Rest coronary CT angiography image shows homogeneous enhancement of the myocardium. B, Postexercise CT image clearly shows a large perfusion defect in the septal and apical walls (arrows). C, Polar attenuation map shows a large perfusion defect in the left anterior descending artery territory (blue) (FFR = 0.56 and MER = 0.63) but no perfusion defect in the lateral territory (FFR = 0.81 and MER = 0.86). D, Coronary angiogram shows a 70% stenosis of the left anterior descending artery (blue arrow) and a 60% stenosis of the marginal artery (green arrow).
value in a nonstenotic related artery in the same patient. Measurements were read on 17-segment model polar maps. Each segment was matched to a coronary artery territory on the basis of coronary CT angiography anatomy. In patients with three-vessel coronary artery disease, the territory supplied by the arterial branch with the least severe stenosis was used as the denominator for MER computation. The distribution determined with coronary CT angiography was used when the
coronary artery corresponding to a perfusion defect was difficult to identify. The mean of the systolic and diastolic MER values was compared with the FFR value.
ICA and FFR Assessment ICA.—All patients underwent ICA within 7 days of coronary CT angiography to confirm the diagnosis of significant coronary artery stenosis. Selective coronary angiography was performed by using the standard technique, with
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
5-F or 6-F catheters. Intracoronary nitrate injection (1 mg of isosorbide dinitrate) was performed routinely after stenosis identification. An experienced operator (S.G., with 12 years of experience with conventional coronary angiography), who was blinded to the CT findings, assessed all stenoses visually on at least two orthogonal images. An intermediate or significant stenosis was defined as a mean diameter reduction of at least 50% on two orthogonal views. Patients were classified on the 687
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
basis of the number of at least 50% stenoses identified at ICA. FFR.—FFR was measured in all nonoccluded coronary arteries at least 2.5 mm in diameter with at least 50% diameter stenoses according to visual assessment of the ICA images. A 0.014-inch pressure guidewire (Aeris Pressure Wire; St Jude Medical, Uppsala, Sweden) was calibrated and electronically equalized with the aortic pressure, then advanced distal to the coronary artery stenosis through a 6-F guiding catheter. Hyperemia was induced by an intracoronary bolus of adenosine (180 mg). FFR was computed as the ratio of the mean hyperemic distal coronary artery pressure measured with the pressure wire over the mean aortic pressure measured with the guiding catheter. FFR value of less than 0.80 was considered the reference to indicate a functionally significant coronary artery stenosis. Occluded coronary arteries were assumed to generate ischemia. Angioplasty or coronary artery bypass grafting was performed as determined by the FFR values, without knowledge of the exercise CT MPI findings.
Statistical Analysis Categorical variables were described as number and percentage and continuous variables as mean 6 standard deviation or median (minimum, maximum), depending on the result of the Shapiro-Wilk test for normality. Correlations between non-normally distributed variables were assessed by using the nonparametric Spearman test. The best MER cutoff for separating significant and nonsignificant coronary artery stenoses was determined by plotting the receiver operating characteristic (ROC) curve. Cutoff performance was assessed at the patient and stenosis levels, on the basis of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy. Proportions were reported as percentages with 95% confidence intervals (CIs). All statistical tests were two tailed, and P values less than .05 were considered to indicate a significant difference. The statistical 688
Habis et al
Table 1 Baseline Patient Characteristics and Supine Exercise Data Characteristic
Value
No. of patients Patient sex No. of men No. of women No. of stenoses No. of occlusions Age (y)* No. of patients with hypercholesterolemia No. of patients with hypertension No. of patients with family history of coronary artery disease No. of smokers No. of patients with diabetes Body mass index (kg/m2) Previous inconclusive stress tests No. of patients with one-vessel disease No. of patients with two-vessel disease No. of patients with three-vessel disease Heart rate at peak stress (beats/min)† HR at acquisition (beats/min)† Rate-pressure double product Work load (W)‡
32 26 (81) 6 (19) 45 9 65 6 12 23/32 (72) 17/32 (53) 17/32 (53) 13/32 (41) 4/32 (12) 26 6 4 SPECT (three), exercise ECG (five), stress echo (one) 13/32 (41) 15/32 (47) 4/32 (12) 131 6 16 (84) 105 6 21 (68) 23 898 6 4761 134 6 44 (7.5 6 1.6)
Note.—Numbers in parentheses are percentages, unless indicated otherwise. * Data are means 6 standard deviations. †
Numbers in parentheses are percentage predicted values.
‡
Numbers in parentheses are metabolic equivalents.
analysis was performed by using R version 3.0.0 software (R Foundation, Vienna, Austria).
Results Baseline Patient Characteristics We included 32 patients—26 men (mean age, 63 years; range, 40–84 years) and six women (mean age, 71 years; range, 57–81 years). Mean age was not significantly different between men and women (Student t test). Fifty-five coronary artery stenoses were depicted, at the following locations: left anterior descending artery (n = 29; proximal, eight stenoses; middle, 17 stenoses; and distal, four stenoses), right coronary artery (n = 16; proximal, four stenoses; middle, 10 stenoses; and distal, two stenoses), and left circumflex artery (n = 10; proximal,
five stenoses; and distal, five stenoses). Table 1 depicts baseline patient characteristics. Seventeen of 32 patients (53%) had body mass index values higher than 25 kg/m2. Three patients were referred for coronary CT angiography because of persistent chest pain despite normal findings at single photon emission CT; their coronary CT angiography images showed significant stenosis in the left anterior descending (n = 2) or circumflex (n = 1) arteries. Six patients were evaluated after receiving inconclusive findings at exercise ECG (n = 5) or echocardiography (n = 1).
Coronary CT Angiography and Exercise CT MPI One patient did not perform the exercise because an inferior perfusion defect associated with a 90% right coronary artery stenosis was obvious at rest. The time from coronary CT
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
angiography to exercise CT MPI in the remaining 31 patients ranged from 30 minutes to 2 weeks. Heart rate at peak stress and during CT acquisition, maximal rate-pressure product, and highest workload are reported in Table 1. Exercise was discontinued in eight of 32 patients with rate-pressure products of less than 20 000 (three of whom had chest pain and/or an ST segment depression). Postexercise acquisition was performed within 1 minute after peak stress. In four patients, recovery from exercise was associated with a marked decrease in heart rate at acquisition (to ,50% maximal predicted value). Rate-pressure product was greater than 20 000 in 75% of patients (24 of 32 patients). No adverse events occurred during exercise CT MPI. Total contrast material volume injected was 148 mL 6 29 (two infusions of 1 mL per kilogram of body weight each). Radiation dose was 4.6 mSv 6 2.5 during coronary CT angiography and 5.6 mSv 6 2.8 during exercise CT MPI. Median MER for all coronary artery stenoses was 0.77 (range, 0.48–0.96).
ICA and FFR Measurement No patients experienced cardiovascular events during the interval between coronary CT angiography and ICA. The percentages of patients with one-, two-, and three-vessel disease were 41% (13 of 32), 47% (15 of 32), and 12% (four of 32), respectively. The left anterior descending artery, circumflex artery, and right coronary artery were stenotic in 97% (31 of 32), 34% (11 of 32), and 41% (13 of 32) of patients, respectively. FFR was measured for 45 stenoses (one omitted); the remaining nine stenoses (left anterior descending artery in two cases, circumflex artery in one case, and right coronary artery in six cases) resulted in complete occlusion and were therefore assumed to be associated with FFR values less than 0.8. Median measured FFR value was 0.83 (range, 0.26–0.98) and, of 45 stenoses with FFR measurements, 47% (21 of 45) had FFR values less than 0.8. Thus, 30 stenoses in all were classified
as being associated with FFR values less than 0.8.
Comparison of MER after Exercise CT MPI and FFR The ROC curve analysis showed that the best MER cutoff for identifying significant stenoses, defined as having FFR values less than 0.8, was 0.8 (area under the ROC curve, 0.98 6 0.02) (Fig 3). Exercise CT MPI was therefore considered to indicate ischemia when MER was less than 0.8. The performance of this MER cutoff in the diagnosis of significant stenosis was assessed per patient and per stenosis, for all 54 stenoses and for the 45 stenoses without arterial occlusion (Table 2). At the patient level, MER less than 0.8 had a sensitivity of 95% (21 of 22 patients; 95% CI: 77, 100), a specificity of 90% (nine of 10 patients; 95% CI: 55, 100), a positive predictive value of 95% (21 of 22 patients; 95% CI: 77, 100), a negative predictive value of 90% (nine of 10 patients; 95% CI: 55, 100), and an accuracy of 94% (30 of 32 patients; 95% CI: 79, 99) for diagnosis of functionally significant stenosis, defined as FFR less than 0.8. At the stenosis level, when all 54 stenoses were considered, sensitivity was 97% (29 of 30 stenoses; 95% CI: 83, 100), specificity was 96% (23 of 24 stenoses; 95% CI: 79, 100), positive predictive value was 97% (29 of 30 stenoses; 95% CI: 83, 100), negative predictive value was 96% (23 of 24 stenoses; 95% CI: 79, 100), and accuracy was 96% (52 of 54 stenoses; 95% CI: 87, 100); when only the 45 nonoccluded stenoses were considered, sensitivity was 95% (20 of 21 stenoses; 95% CI: 76, 100), specificity was 96% (23 of 24 stenoses; 95% CI: 79, 100), positive predictive value was 95% (20 of 21 stenoses; 95% CI: 76, 100), negative predictive value was 96% (23 of 24 stenoses; 95% CI: 79, 100), and accuracy was 96% (43 of 45 stenoses; 95% CI: 86, 99). In the patient-level analysis, only two patients were misclassified: One had a false-negative result, and the other had a false-positive result. All the stenoses in our four patients with threevessel disease were correctly diagnosed by using exercise CT MPI. Although the
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
Habis et al
Figure 3
Figure 3: Graph demonstrates the ROC curve for the 45 stenoses with FFR measurements. The best MER cutoff is 0.8 (area under the ROC curve, 0.98 6 0.02).
occluded vessels were expected to have MER values less than 0.8, one such vessel had a MER value of 0.89. For the 45 nonoccluded stenotic coronary arteries, MER showed a significant (r2 = 0.58) but nonlinear correlation with the corresponding FFR value (Fig 4).
Discussion This study provides evidence that, in patients with stable coronary artery disease, supine exercise on a CT table is feasible for assessing myocardial perfusion during conditions of physiologic stress, providing stenosis-related functional information. A quantitative measure, the myocardial enhancement ratio obtained directly after exercise, may reliably be used to predict significant coronary artery stenosis as compared with FFR as the reference standard. In a previous study, visual assessment of stenosis severity on coronary CT angiography images showed high sensitivity (94%) but low specificity (40%) for the identification of functionally significant stenoses on the basis of FFR values (7). In the present study, exercise CT MPI improved both sensitivity and specificity for the identification of functionally significant stenosis, 689
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
Habis et al
Table 2 Comparison of Exercise and Adenosine
Analysis Type Per-patient analysis Per-vessel analysis with occlusions Per-vessel analysis without occlusions
No. of Patients or Stenotic Vessels Sensitivity (%)
Specificity (%)
Positive Predictive Value (%)
Negative Predictive Value (%)
Accuracy (%)
32 54
95 (21/22) [77, 100] 97 (29/30) [83, 100]
90 (9/10) [55, 100] 96 (23/24) [79, 100]
Exercise* 95 (21/22) [77, 100] 97 (29/30) [83, 100]
90 (9/10) [55, 100] 96 (23/24) [79, 100]
94 (30/32) [79, 99] 96 (52/54) [87, 100]
45
95 (20/21) [76, 100]
96 (23/24) [79, 100]
95 (20/21) [76, 100]
96 (23/24) [79, 100]
96 (43/45) [86, 99]
Adenosine Visual analysis Per-patient analysis Per-vessel analysis Transmural perfusion ratio Per-patient analysis Per-vessel analysis
39 118
95 (19/20) [73, 100] 87 (34/39) [72, 95]
95 (18/19) [72, 100] 95 (75/79) [87, 98]
95 (19/20) [73, 100] 89 (34/38) [74, 97]
95 (18/19) [72, 100] 94 (75/80) [85, 98]
95 (37/39) 92 (109/118)
38 116
95 (18/19) [72, 100] 71 (27/38) [64, 84]
89 (17/19 [66, 98] 95 (74/78) [87, 98]
90 (18/20) [67, 98] 87 (27/31) [69, 96]
94 (17/18) [71, 100] 87 (74/85) [78, 93]
92 (35/38) 87 (101/116)
Note.—Numbers in parentheses are the data used to calculate percentages. Numbers in brackets are 95% CIs. Comparison of exercise CT MPI and adenosine CT MPI accuracies to detect significant stenosis were compared with FFR with the corresponding methods used for quantifying myocardial perfusion hypoenhancement. Adenosine results according to visual analysis or transmural perfusion ratio are from reference 15. * All exercise data were acquired by using the myocardial enhancement ratio.
Figure 4
Figure 4: Plot depicts the correlation between MER and FFR for the 45 stenoses with FFR measurements. R 2 = 0.58. An MER cutoff of 0.8 was used to correctly classify 43 of 45 stenoses. The dashed line is the identity line.
compared with coronary CT angiography alone. Our ROC curve analysis demonstra ted that 0.8 was the optimal MER cutoff for identifying functionally significant stenoses on the basis of FFR values less 690
than 0.8. FFR has been reported to be 93% accurate in identifying stenoses responsible for ischemia (16). FFR is not always reliable for estimating absolute myocardial perfusion: In case of diffuse coronary artery disease, the coronary flow reserve may be significantly decreased in the absence of significant segmental stenosis. Inversely, preserved microvascular function or arterial remodeling may prevent ischemia in a myocardial territory fed by a significant stenosis (FFR , 0.8) (17,18). The diagnostic performance of exercise CT MPI in our study compares favorably with that of adenosine CT MPI (15,19). In a previous study, investigators assessed the incremental value of adenosine CT MPI for stenoses of at least 50% on coronary CT angiography images compared with the same FFR reference standard (19). Eleven of 116 vessels (9%) were negative for hemodynamically significant stenosis according to transmural perfusion ratio (the ratio of subendocardial to subepicardial contrast-enhanced attenuation) measurement. We used exercise, a more physiological stressor than adenosine. Another assessment
of perfusion defects according to semiquantitative estimation of myocardial blood flow (20) allowed an increase in specificity, positive predictive value, and diagnostic accuracy over coronary CT angiography. However, it required a 30-second breath hold during image acquisition, which limits its applicability to patients in good clinical condition. Exercise CT MPI requires additional contrast material and radiation exposure when compared with methods based on computational fluid dynamics, but that approach requires 5 hours of off-site analysis (13), which limits its practical utility for routine application Another approach for estimating the functional significance of a stenosis is the use of the transluminal attenuation gradient (linear regression coefficient between luminal attenuation and axial distance) across the stenosis. This gradient has been reported to be useful in the prediction of significantly abnormal FFR values (12). However, neither of these methods can be used to evaluate myocardial perfusion or the collateral blood supply directly. The high temporal resolution (75 msec) and contrast material infusion
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
rate (8 mL/sec) in our study allowed us to obtain sufficient image quality, despite exercise-related tachycardia. No adverse events were recorded during exercise CT MPI. Exercising in a supine position on the CT table minimized the time from peak stress to acquisition. Studies of exercise echocardiography have shown a 7%–30% decrease in sensitivity when looking for akinesia after exercising on a treadmill instead of during supine bicycle exercising (21,22). Hypoperfusion precedes akinesia, as is known from the sequence of events in the ischemic cascade (23). Whether the myocardial perfusion defect detected with CT disappears less quickly after exercise than akinesia is questionable. However, wall motion analysis was not evaluated in the current study. Exercise in the supine position increases venous return, thereby increasing cardiac output and left ventricle stroke work, which could increase the accuracy of stress to detect ischemia. In a comparison of imaging after exercising on a treadmill or in the supine position, the rate-pressure double products were similar, but myocardial ischemia was more extensive after supine exercise (21). Our two patients who were misclassified did not perform an invalid exercise (6 and 9 metabolic equivalents, respectively, with a double product of more than 20 000 for both). A noticeable heart rate decrease occurred in four patients during recovery from exercise but did not affect the diagnostic performance of MER determination. The rationale for performing coronary CT angiography before functional testing is discussed in a recent report (24) that outlines the limited predictive value of various stress tests (exercise test, stress echocardiography, and SPECT imaging). In previous studies, investigators have established that coronary CT angiography has a high negative predictive value of 90%–97% for functionally significant stenoses of less than 50% (7,15,19). Therefore, starting with a coronary CT angiography assessment of coronary anatomy can save time and decrease costs and radiation exposure compared with SPECT, and absence
of potentially significant stenoses obviates the need for subsequent functional testing. Our findings are relevant only to patients with stable coronary artery disease, in sinus rhythm, and without previous revascularization, myocardial infarction, or myocardial dysfunction. In addition, we excluded patients with stenoses of less than 50% according to coronary CT angiography images, since performing ICA in such patients would have been unethical. The high incidence of functionally significant coronary artery disease in this patient group may have affected the diagnostic performance of CT MPI in our study. For patients with three-vessel disease, we used enhancement in the territory supplied by the least severe coronary artery branch stenosis as the denominator for computing the MER. Motion artifacts are probably more common with exercise, but the multiphase acquisition and high temporal resolution of our technique seem to effectively circumvent this drawback (14). To limit bias, we used an image postprocessing workstation to automatically determine the contrast-enhanced attenuation values. The same reader performed the coronary CT angiography and exercise CT MPI evaluations, which seems preferable over having two different readers (14). Finally, coronary flow reserve assessed with positron emission tomography would probably be a better comparator for exercise CT MPI. Exercise CT MPI is a physiological method that performs well for the assessment of the functional significance of coronary stenosis. Studies in larger numbers of patients are warranted before using the combination of coronary CT angiography and exercise CT MPI as a gatekeeper to defer ICA.
Habis et al
References 1. Boden WE, O’Rourke RA, Teo KK, et al. Optimal medical therapy with or without PCI for stable coronary disease. N Engl J Med 2007;356(15):1503–1516. 2. De Bruyne B, Pijls NH, Kalesan B, et al. Fractional flow reserve–guided PCI versus medical therapy in stable coronary disease. N Engl J Med 2012;367(11):991–1001. 3. Tonino PA, De Bruyne B, Pijls NH, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360(3):213–224. 4. Budoff MJ, Dowe D, Jollis JG, et al. Diagnostic performance of 64–multidetector row coronary computed tomographic angiography for evaluation of coronary artery stenosis in individuals without known coronary artery disease: results from the prospective multicenter ACCURACY (Assessment by Coronary Computed Tomographic Angiography of Individuals Undergoing Invasive Coronary Angiography) trial. J Am Coll Cardiol 2008;52(21):1724–1732. 5. Meijboom WB, Meijs MF, Schuijf JD, et al. Diagnostic accuracy of 64-slice computed tomography coronary angiography: a prospective, multicenter, multivendor study. J Am Coll Cardiol 2008;52(25):2135–2144. 6. Folland ED, Vogel RA, Hartigan P, et al. Relation between coronary artery stenosis assessed by visual, caliper, and computer methods and exercise capacity in patients with single-vessel coronary artery disease. The Veterans Affairs ACME Investigators. Circulation 1994;89(5):2005–2014. 7. Meijboom WB, Van Mieghem CA, van Pelt N, et al. Comprehensive assessment of coronary artery stenoses: computed tomography coronary angiography versus conventional coronary angiography and correlation with fractional flow reserve in patients with stable angina. J Am Coll Cardiol 2008;52(8): 636–643. 8. Waksman R, Legutko J, Singh J, et al. FIRST: Fractional Flow Reserve and Intravascular Ultrasound Relationship Study. J Am Coll Cardiol 2013;61(9):917–923.
Acknowledgment: The authors thank Antoinette Wolfe, MD, for her assistance in the preparation of this manuscript.
9. Tonino PA, Fearon WF, De Bruyne B, et al. Angiographic versus functional severity of coronary artery stenoses in the FAME study fractional flow reserve versus angiography in multivessel evaluation. J Am Coll Cardiol 2010;55(25):2816–2821.
Disclosures of Conflicts of Interest: M.H. disclosed no relevant relationships. S.G. disclosed no relevant relationships. A.R. disclosed no relevant relationships. A.C. disclosed no relevant relationships. J.F.P. disclosed no relevant relationships.
10. Bettencourt N, Chiribiri A, Schuster A, et al. Direct comparison of cardiac magnetic resonance and multidetector computed tomography stress-rest perfusion imaging for detection of coronary artery disease. J Am Coll Cardiol 2013;61(10):1099–1107.
Radiology: Volume 274: Number 3—March 2015 n radiology.rsna.org
691
CARDIAC IMAGING: Significant Coronary Stenosis at Exercise CT Myocardial Perfusion Imaging
11. Nakazato R, Shalev A, Doh JH, et al. Aggregate plaque volume by coronary computed tomography angiography is superior and incremental to luminal narrowing for diagnosis of ischemic lesions of intermediate stenosis severity. J Am Coll Cardiol 2013;62(5): 460–467. 12. Wong DT, Ko BS, Cameron JD, et al. Transluminal attenuation gradient in coronary computed tomography angiography is a novel noninvasive approach to the identification of functionally significant coronary artery stenosis: a comparison with fractional flow reserve. J Am Coll Cardiol 2013;61(12): 1271–1279. 13. Koo BK, Erglis A, Doh JH, et al. Diagnosis of ischemia-causing coronary stenoses by noninvasive fractional flow reserve computed from coronary computed tomographic angiograms. Results from the prospective multicenter DISCOVER-FLOW (Diagnosis of Ischemia-Causing Stenoses Obtained Via Noninvasive Fractional Flow Reserve) study. J Am Coll Cardiol 2011;58(19):1989–1997. 14. Mehra VC, Valdiviezo C, Arbab-Zadeh A, et al. A stepwise approach to the visual interpretation of CT-based myocardial perfusion. J Cardiovasc Comput Tomogr 2011;5(6): 357–369.
692
Habis et al
15. Ko BS, Cameron JD, Meredith IT, et al. Computed tomography stress myocardial perfusion imaging in patients considered for revascularization: a comparison with fractional flow reserve. Eur Heart J 2012;33(1):67–77.
20. Greif M, von Ziegler F, Bamberg F, et al. CT stress perfusion imaging for detection of haemodynamically relevant coronary stenosis as defined by FFR. Heart 2013;99(14): 1004–1011.
16. Pijls NH, De Bruyne B, Peels K, et al. Measurement of fractional flow reserve to assess the functional severity of coronary-artery stenoses. N Engl J Med 1996;334(26):1703– 1708.
21. Badruddin SM, Ahmad A, Mickelson J, et al. Supine bicycle versus post-treadmill exercise echocardiography in the detection of myocardial ischemia: a randomized single-blind crossover trial. J Am Coll Cardiol 1999;33(6):1485–1490.
17. Johnson NP, Kirkeeide RL, Gould KL. Is discordance of coronary flow reserve and fractional flow reserve due to methodology or clinically relevant coronary pathophysiology? JACC Cardiovasc Imaging 2012;5(2): 193–202. 18. Johnson NP, Gould KL. Physiological basis for angina and ST-segment change PET-verified thresholds of quantitative stress myocardial perfusion and coronary flow reserve. JACC Cardiovasc Imaging 2011;4(9):990–998. 19. Ko BS, Cameron JD, Leung M, et al. Combined CT coronary angiography and stress myocardial perfusion imaging for hemodynamically significant stenoses in patients with suspected coronary artery disease: a comparison with fractional flow reserve. JACC Cardiovasc Imaging 2012;5(11):1097–1111.
22. Presti CF, Armstrong WF, Feigenbaum H. Comparison of echocardiography at peak exercise and after bicycle exercise in evaluation of patients with known or suspected coronary artery disease. J Am Soc Echocardiogr 1988;1(2):119–126. 23. Nesto RW, Kowalchuk GJ. The ischemic cascade: temporal sequence of hemodynamic, electrocardiographic and symptomatic expressions of ischemia. Am J Cardiol 1987;59(7):23C–30C. 24. Chinnaiyan KM, Raff GL, Goraya T, et al. Coronary computed tomography angiography after stress testing: results from a multicenter, statewide registry, ACIC (Advanced Cardiovascular Imaging Consortium). J Am Coll Cardiol 2012;59(7):688–695.
radiology.rsna.org n Radiology: Volume 274: Number 3—March 2015
