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J Am Coll Cardiol, 2007; 49:2440-2449, doi:10.1016/j.jacc.2007.03.028
(Published online 7 June 2007). © 2007 by the American College of Cardiology Foundation |
,1,4,2,3
,2,*
* University of Oxford Centre for Clinical Magnetic Resonance Research, Oxford, United Kingdom
Department of Cardiovascular Medicine, University of Oxford, Oxford, United Kingdom
Department of Radiology, John Radcliffe Hospital, Oxford, United Kingdom
Department of Cardiology, John Radcliffe Hospital, Oxford, United Kingdom
|| Advanced Imaging Research Center, Oregon Health & Science University, Portland, Oregon.
Manuscript received September 21, 2006; revised manuscript received March 2, 2007, accepted March 6, 2007.
* Reprint requests and correspondence: Dr. Joseph B. Selvanayagam, University of Oxford, Cardiovascular Medicine, Headley Way, Headington, Oxford, United Kingdom. (Email: joseph.selvanayagam{at}cardiov.ox.ac.uk).
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Background: Myocardial perfusion imaging is considered one of the most compelling applications for CMR at 3-T. The 3-T systems provide increased signal-to-noise ratio and contrast enhancement (compared with 1.5-T), which can potentially improve spatial resolution and image quality.
Methods: Sixty-one patients (age 64 ± 8 years) referred for elective diagnostic coronary angiography (CA) for investigation of exertional chest pain were studied (before angiogram) with first-pass perfusion CMR at both 1.5- and 3-T and at stress (140 µg/kg/min intravenous adenosine, Adenoscan, Sanofi-Synthelabo, Guildford, United Kingdom) and rest. Four short-axis images were acquired during every heartbeat using a saturation recovery fast-gradient echo sequence and 0.04 mmol/kg Gd-DTPA bolus injection. Quantitative CA served as the reference standard. Perfusion deficits were interpreted visually by 2 blinded observers. We defined CAD angiographically as the presence of 
1 stenosis of 50% diameter in any of the main epicardial coronary arteries or their branches with a diameter of 2 mm.
Results: The prevalence of CAD was 66%. All perfusion images were found to be visually interpretable for diagnosis. We found that 3-T CMR perfusion imaging provided a higher diagnostic accuracy (90% vs. 82%), sensitivity (98% vs. 90%), specificity (76% vs. 67%), positive predictive value (89% vs. 84%), and negative predictive value (94% vs. 78%) for detection of significant coronary stenoses compared with 1.5-T. The diagnostic performance of 3-T perfusion imaging was significantly greater than that of 1.5-T in identifying both single-vessel disease (area under receiver-operator characteristic [ROC] curve: 0.89 ± 0.05 vs. 0.70 ± 0.08; p < 0.05) and multivessel disease (area under ROC curve: 0.95 ± 0.03 vs. 0.82 ± 0.06; p < 0.05). There was no difference between field strengths for the overall detection of coronary disease (area under ROC curve: 0.87 ± 0.05 vs. 0.78 ± 0.06; p = 0.23).
Conclusions: Our study showed that 3-T CMR perfusion imaging is superior to 1.5-T for prediction of significant single- and multi-vessel coronary disease, and 3-T may become the preferred CMR field strength for myocardial perfusion assessment in clinical practice.
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The most widely used techniques in the assessment of myocardial perfusion have significant limitations. Although single-photon emission computed tomography (SPECT) myocardial perfusion imaging is a useful tool for noninvasive diagnosis of myocardial ischemia, it is susceptible to attenuation artifacts (2). Positron emission tomography (PET) imaging corrects for attenuation but has limited availability and higher expense. Both SPECT and PET involve exposure to ionizing radiation. Cardiovascular magnetic resonance imaging (CMR) is emerging as an alternative noninvasive approach for the assessment of myocardial perfusion, because it offers superior spatial resolution (3) that potentially allows differentiation between subendocardial and subepicardial perfusion, does not involve ionizing radiation, and, like PET, has the potential to measure myocardial perfusion in absolute terms (4,5). Contrast agents can be tracked as they traverse the myocardium after intravenous (IV) injection, allowing assessment of myocardial perfusion at rest and during pharmacologic stress with vasodilators such as adenosine (6,7).
Although studies have shown that visual and semiquantitative assessment of perfusion CMR at 1.5-Tesla (T) has moderate accuracy for detection of CAD (8–11), it remains principally limited by low differences in contrast enhancement between normal and underperfused myocardium. Compared to perfusion CMR at 1.5-T, 3-T systems provide increased signal-to-noise ratio (12) and contrast enhancement (12,13), which can be used to improve spatial resolution and image quality. The aim of this study was to assess the clinical utility of CMR perfusion at 3-T in a population of patients with suspected CAD.
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CMR protocol. Patients were asked to avoid agents that could potentiate (dipyridamole) or antagonize (e.g., caffeine, methylxanthines) the effects of adenosine for at least 24 h before CMR. Each patient underwent CMR at both 1.5-T (Sonata, Siemens Medical Solutions, Erlangen, Germany) and 3-T (Trio, Siemens Medical Solutions) on the same day. The scanners had gradient systems with the same specifications, with optimal and identical settings for echo and repetition time in each instance, so that for a segmented gradient echo sequence, the differences in intrinsic signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) between the 2 field strengths were accurately reflected. Perfusion imaging on each system was performed at least an hour apart and in randomized order. Images were acquired with the patient supine, using coils optimized for body imaging by Siemens: anterior phased-array surface coils and either posterior phased-array surface coils (at 3-T) or 2 elements of the integrated spine coil (at 1.5-T). An active Siemens electrocardiogram lead set was used, with the 3 leads positioned over the anterior chest wall.
Cine CMR. Cine CMR was performed at 1.5-T. From standard pilot images, short-axis cine images covering the entire left ventricle (LV) were acquired using an electrocardiogram-gated steady-state free precession sequence (echo time 1.5 ms, repetition time 3 ms, flip angle 60°).
Perfusion CMR. Throughout each CMR scan, patients were monitored by electrocardiography, noninvasive sphygmomanometry, and pulse oximetry. After 4 min of IV adenosine infusion (140 µg/kg/min; Adenoscan, Sanofi-Synthelabo, Guildford, United Kingdom), or earlier if angina was provoked, a gadolinium-based contrast agent (Gadodiamide, Omniscan, GE Healthcare, Amersham, United Kingdom) was administered at a dose of 0.04 mmol/kg body weight (IV injection rate 6 ml/s), followed by a 15-ml saline flush at the same rate. The contrast dose was chosen to allow repeat measurement after a delay of at least 1 h and to be within the dose range used previously for semiquantitative analysis of perfusion (9). Perfusion images were acquired every cardiac cycle during the first pass of contrast, using a T1-weighted fast-gradient echo (turbo fast low-angle shot) sequence (echo time 1.04 ms, repetition time 2 ms, saturation recovery time 100 ms, voxel size 2.1 x 2.6 x 8 mm; flip angle 18° at 1.5-T and 17° at 3-T) while patients held their breath for as long as possible in end-inspiration. The last 38 patients underwent parallel imaging with 2-fold acceleration at both field strengths. Four short-axis slices, positioned from the base to the apex of the LV, were obtained. The same imaging sequence was repeated 15 min later without adenosine to obtain perfusion images at rest.
Coronary angiography. Less than 2 weeks after the CMR examination, all patients underwent coronary angiography using standard techniques. Images of the coronary arteries were obtained in multiple projections, and, as much as possible, overlap of side branches and foreshortening of relevant coronary stenoses was avoided.
CMR analysis. For each patient, using Argus software (version VA60C, Siemens AG), left ventricular end-diastolic and -systolic volumes, ejection fraction, and mass were calculated in the standard way by manually tracing the endocardial and epicardial contours in end-diastolic and -systolic images obtained at 1.5-T.
Perfusion CMR scans were interpreted in random order by 2 observers acting in consensus, blinded to all data, including clinical information, field strength, and angiographic and cine CMR findings. For visual grading of perfusion deficits, stress and rest perfusion scans were magnified and displayed simultaneously. The presence of a perfusion deficit was defined by the following criteria: 1) the regional hypoenhancement persisted for more than 3 phases after maximal enhancement of segments that appeared most normal, 2) the area of hypoenhancement corresponded with a coronary artery territory (left anterior descending artery: anterior or septal segments; left circumflex artery: lateral segments; right coronary artery: inferior segments), and 3) regional signal intensity or contrast enhancement was reduced or delayed compared to other myocardial segments in the same slice. Within this definition, perfusion deficits could be either fixed (present at stress and rest) or inducible (present at stress only). Perfusion analysis of each myocardial segment (except the apex) was performed using the 17-segment model recommended by the American Heart Association (14). Each myocardial segment was graded as 0 (normal), 1 (possible perfusion deficit), or 2 (definite perfusion deficit). A third observer interpreted all segments that were graded as "possible perfusion deficits" and the majority decision of all 3 observers was used to determine the presence or absence of a perfusion deficit. The presence of artifacts was graded according to type (respiratory, dark rim, reconstruction, and so forth) and severity.
In 30 patients, the mid-ventricular slice of the rest scan was selected by an observer blinded to patient information and field strength. For all phases in each selected slice, using Argus software, the observer measured the mean signal intensity (SI) in a region of interest (ROI) at least 12 pixels in size, placed in the anteroseptal myocardial segment, as well as the standard deviation of the noise in a circular region outside the body and anterior to the chest wall. Care was taken to avoid epicardial fat and ventricular cavity blood pool. Image SNR was calculated as (peak SI in the ROI)/(SD of noise), and CNR of the SI traces was calculated as (peak SI in the ROI – mean before-contrast SI in the ROI)/(SD of before-contrast SI in the ROI).
Angiographic analysis.
The diagnostic X-ray angiogram served as the reference standard in defining the degree of coronary stenosis. Each myocardial segment was ascribed a coronary artery territory according to standard criteria (14). Any lesion with a diameter stenosis of >40% by handheld caliper was subsequently analyzed by computerized quantitative methods using the Siemens Quantcor Coronary Analysis software. The contrast-filled catheter was used for image magnification calibration. Significant CAD was defined angiographically as the presence of at least 1 stenosis of 50% diameter in any of the main epicardial coronary arteries or their branches with a diameter of 2 mm.
Statistical analysis. Data analysis was performed using SPSS 14.0 for Windows (SPSS Inc., Chicago, Illinois). Continuous data were compared using t tests, which were paired where appropriate (e.g., adenosine infusion time, pulse rate, systolic and diastolic blood pressure, rate pressure product, SNR, CNR). Chi-square tests were used to compare discrete data. The Fisher exact test was used when the assumptions of the chi-square test were not met. Using computer software (Medcalc 9.1.0.1 [EC] , Mariakerke, Belgium), receiver-operating characteristic (ROC) curve analyses were performed to compare the diagnostic performance of perfusion CMR at each field strength (15,16). Statistical tests were 2-tailed, and p < 0.05 was considered to be significant.
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Table 1 outlines the baseline characteristics of the study cohort. Seventy-five percent of the cohort were men with a mean age of 64 years, reflecting the referral pattern for diagnostic angiography in our hospital. Although women represented only one-quarter of the study group, they accounted for more than one-half of the normal studies in our cohort. X-ray coronary angiography demonstrated significant coronary artery stenoses in 66% of patients (40 of 61). There was an even distribution of patients with no significant CAD (n = 21) and single-vessel (n = 19) or multivessel (n = 21) disease. In terms of the anatomic location of the coronary stenoses, 30 patients (49%) had significant left anterior descending (LAD) coronary artery stenosis, 20 (33%) had significant left circumflex coronary artery stenosis, and 25 (41%) had significant right coronary artery (RCA) stenosis. Although the prevalence of CAD was high, and more than one-half of patients with significant coronary disease had more than 1 affected vessel, mean LV ejection fraction was well preserved at 68 ± 9%. There was a trend (p = 0.08) to increased mass index in those patients with CAD, possibly related to the predominance of men in this group.
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demonstrate patient examples at both field strengths.
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Image analysis and artifacts. All images acquired were of sufficient quality for analysis, and no images were excluded. There was no significant difference in the number of scans classified as having a "possible perfusion deficit" that required interpretation by a third reviewer: 7 of 61 (11.5%) scans at 3-T and 4 of 61 (6.6%) scans at 1.5-T (p = 0.30). Dark-rim artifacts (17) (hypoenhanced zone in the subendocardial layer before contrast material arrival) were observed more commonly at 1.5-T compared with 3-T (23% patients at 1.5-T vs. 8% of patients at 3-T, p < 0.01). Reconstruction artifacts attributable to parallel imaging in the region of the heart occurred in 4 patients (6%) at 3-T and 2 patients (3%) at 1.5-T (p = 0.4).
SNR and CNR. As expected, 3-T perfusion imaging provided a significant increase in both SNR (17 ± 6 at 3-T vs. 11 ± 2 at 1.5-T; p < 0.01) and CNR (17 ± 10 at 3-T vs. 11 ± 4 at 1.5-T; p < 0.01) compared with 1.5-T (Fig. 4). Although the order of the scans was randomized in a balanced manner, a further analysis was performed to elucidate whether the order of the scans influenced SNR or CNR. We found that SNR was significantly higher at 3-T compared with 1.5-T in those who had their first scan performed at 1.5-T (15.9 ± 6.25 vs. 10.6 ± 4.68, respectively, p < 0.01) and also in those who had their first scan performed at 3-T (17.8 ± 6.34 vs. 12.1 ± 2.51, respectively, p < 0.01). Similarly, CNR was higher at 3-T compared with 1.5-T in those who had their first scan performed at 1.5-T (16.3 ± 10.3 vs. 10.6 ± 4.68, respectively, p = 0.08) and also in those who had their first scan performed at 3-T (17.7 ± 9.97 vs. 11.8 ± 3.72, respectively, p < 0.05).
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To the best of our knowledge, this is the first study to assess systematically the utility of 3-T CMR perfusion imaging in diagnosing CAD in contemporary clinical practice. Prior studies at 1.5-T have shown that semiquantitative assessment of perfusion has good accuracy for detection of CAD, with a sensitivity of 91% and a specificity of 94% for detecting CAD as defined by PET (8) and a sensitivity of 87% to 88% and specificity of 85% to 90% compared to quantitative coronary angiography (8,9). However, visual assessment of perfusion CMR at 1.5-T has usually performed less well compared to semiquantitative assessment, with a sensitivity of 82% to 91% and specificity of 62% to 63% (11,18). Direct comparison between these studies is confounded by variation in pulse sequence, contrast dose, and angiographic definition of significant CAD. Paetsch et al. (18), in a study of 79 patients, of whom 67% had significant coronary disease using the same >50% coronary stenosis definition as we did, found that 1.5-T CMR perfusion imaging had a sensitivity of 91%, a specificity of 62%, and diagnostic accuracy of 81%, findings similar to the 1.5-T arm of our study.
Our significant increases in SNR and CNR for perfusion CMR at 3-T, compared with 1.5-T, are consistent with earlier work (12,13). The significantly higher diagnostic accuracy of 3-T perfusion found in our study is attributed to a combination of increased SNR, allowing detection of reductions in endocardial perfusion (the most sensitive parameter for a reduction of overall coronary blood flow [19]) and reduced occurrence of dark-rim artifact at 3-T. The latter can often be confused as a real perfusion deficit and probably explains the lower specificity seen at 1.5-T.
We used visual analysis in our cohort, as this is the most commonly used method in clinical practice and we wanted to compare the clinical utility of each field strength in the same population. Absolute and semiquantitative measurements of perfusion CMR have an important role in assessing myocardial blood flow in a research setting (5,20), but require time and labor-intensive afterprocessing and are not performed routinely in clinical practice.
Recently, Klem et al. (11) proposed that a combined CMR approach of stress-rest perfusion imaging followed by delayed enhancement imaging (DE-CMR) at 1.5-T is superior to perfusion imaging alone for depicting clinically significant coronary artery stenosis. Their study population differs from ours in that the prevalence of CAD is lower (40% vs. 66%), and they excluded patients with previous revascularization and MI. Notwithstanding these important differences, the performance of perfusion analysis alone in their study is lower than the performance of 1.5-T in our study, while using the interpretative algorithm incorporating DE-CMR in addition to perfusion markedly increases specificity in their cohort. Although DE-CMR was not performed in the current study, we have recently shown, in a separate population of patients with confirmed MI, that there was strong agreement between 1.5- and 3-T in the mass and transmural extent of hyperenhancing myocardium when using the same pulse sequence (21). Hence, the addition of DE-CMR to the imaging protocol at 3-T is clinically robust and might increase the specificity of 3-T perfusion imaging alone in this clinical setting.
As expected, we found greatly reduced specificity for detecting stenoses 70% at both field strengths, whereas sensitivity was increased at 3-T. This mirrors the findings of Klem et al. (11), who found similar changes in diagnostic performance dependent on the severity of coronary stenosis (detection of coronary stenosis 70%, as opposed to 50%, resulted in a reduction in specificity from 63% to 58% and an increase in sensitivity from 82% to 84%). It is salient to note that all 8 patients in our study who had lesions that were quantified between 50% and 69% had corresponding perfusion deficits; of these, 6 proceeded to coronary revascularization, and 2 were treated medically. Hence, despite being unaware of the CMR findings, the treating interventional cardiologist or cardiac surgeon considered these lesions to be clinically significant.
We attempted to avoid before-test referral bias by recruiting only those patients referred for diagnostic coronary angiography and not "healthy" volunteers, and after-test referral bias by performing X-ray coronary angiography after and independent of CMR findings. Our data at 3-T compare favorably with the published work on SPECT imaging under similar clinical circumstances. After adjusting for selection bias, Cecil et al. (22) found a corrected sensitivity and specificity of 82% and 59%, respectively, and Miller et al. (23) found a corrected sensitivity and specificity of 65% and 67%, respectively, for the detection of CAD by SPECT imaging. Compared with these results, the accuracy of visual assessment of perfusion CMR at 3-T indicates clinical utility, particularly taking into account its additional advantages of safety, tolerability, lack of ionizing radiation, and short examination time.
We found that perfusion imaging at either field strength had lower sensitivity for detection of significant coronary disease in the circumflex coronary artery compared to the LAD and RCA. Almost all (19 of 20) stenosed circumflex coronary arteries in our cohort were in the context of multi-vessel disease, and it is more difficult to detect hypoperfused myocardium in the case of "balanced" disease, especially by nonquantitative means. This difficulty might have been most acute in the circumflex territory because it is farthest from the radiofrequency coil and because visual, unlike semiquantitative, assessment of perfusion imaging cannot correct signal intensity for distance from the coil. We expect that semiquantitative assessment of images obtained by perfusion CMR at 3-T will provide even greater diagnostic accuracy for detection of significant coronary stenosis, most improved in the circumflex territory (9).
Residual contrast at the time of acquisition of the second set of perfusion images in each particular patient may have influenced the diagnostic accuracy or the SNR or CNR measured. However, in healthy human volunteers, Weinmann et al. (24) demonstrated that plasma concentration of gadolinium declines according to a bi-exponential function with a distribution phase with a mean half-life of 12 ± 7.8 min and concluded that its efficiency to enhance signal intensity will last only up to about 1 h after intravenous injection of 0.1 mmol/kg body mass. Accordingly, in our CMR protocol, the time interval between the sets of images acquired on each system was at least 1 h for each patient, and randomization of the order of the scans was balanced to avoid bias. Furthermore, our data indicate that the order of the scans did not influence diagnostic accuracy, SNR, or CNR at either field strength.
Study limitations. Although we found a significant superiority of 3-T over 1.5-T for the diagnosis of single-vessel and multivessel disease, we did not find a statistically significant difference between the 2 field strengths in the overall results. This is likely to be due to the small number of patients in this study, with consequent lower statistical power. Furthermore, ROC analysis indicated higher area under the curve values for 3-T in the overall analysis, as well as individual artery territories. We did not compare perfusion CMR with other myocardial perfusion techniques, such as SPECT and PET. The X-ray coronary angiogram is an imperfect reference standard but remains the established technique for making decisions regarding revascularization in clinical practice. Unlike perfusion CMR, X-ray coronary angiogram does not provide evaluation of hemodynamic severity of a stenosis and, consequently, the sensitivity and specificity of perfusion CMR might be reduced in certain predictable situations. The presence of a coronary stenosis of at least 50% supplying an area of myocardium that is well collateralized might fail to produce a perfusion deficit, even at stress, leading to a false-negative result. Similarly, perfusion CMR may yield false-positive results in microvascular disease and where a coronary artery supplying an area of MI has opened spontaneously or after therapeutic intervention. This was highlighted by the increase in specificity when patients with a history of prior MI were excluded from the analysis.
The true apex was not visualized in the perfusion images using our approach. However, a study by Elkington et al. (25) showed that long-axis views did not provide helpful information over short-axis slices alone and did not visualize inducible perfusion deficits in the true apex that had been demonstrated with SPECT studies. We therefore decided to maximize the number of short-axis slices, within the limits of the scanning sequence, to achieve maximum coverage of the left ventricle.
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1 Dr. Cheng is funded by a grant from the Oxfordshire Health Services Research Committee. 
2 Drs. Pegg, Karamitsos, and Selvanayagam are funded by the British Heart Foundation.
3 Dr. Karamitsos is also funded by a scholarship from Hellenic Cardiological Society.
4 Drs. Cheng and Pegg have contributed equally to this work.
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