Int J Cardiovasc Imaging (2015) 31:77–89 DOI 10.1007/s10554-015-0665-3
ORIGINAL PAPER
Integrated cardiac magnetic resonance imaging with coronary magnetic resonance angiography, stress-perfusion, and delayed-enhancement imaging for the detection of occult coronary artery disease in asymptomatic individuals Kyoung Doo Song1 • Sung Mok Kim1,2 • Yeon Hyeon Choe1,2 • Wooin Jung1 Sang-Chol Lee2,3 • Sung-A Chang2,3 • Yoon Ho Choi4 • Jidong Sung3,4
•
Received: 13 April 2015 / Accepted: 15 April 2015 / Published online: 28 April 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract To evaluate the feasibility of using coronary magnetic resonance angiography (CMRA) with stressperfusion and delayed-enhancement MRI as a screening tool for the detection of coronary artery disease (CAD) in asymptomatic subjects. Three hundred and forty-one selfreferred asymptomatic subjects were enrolled in this study. Cardiac MR imaging was performed using a 1.5-T scanner with a 32-channel cardiac coil. Coronary artery stenosis, regional wall motion abnormalities, myocardial perfusion abnormalities, and delayed myocardial enhancement were analyzed. The occurrence of new chest pain and cardiac events was assessed in 332 subjects (97.3 %) over an average 29 ± 6 months (range, 18–39 months) follow-up period. A total of 3296 (82.4 %) of 4000 coronary artery segments examined exhibited diagnostic image quality on combined whole-heart and volume-targeted CMRA. Combined MRI detected significant CADs in 13 (3.8 %) of 341 subjects. Among these, 11 subjects (84.6 %) had both
& Yeon Hyeon Choe [email protected] 1
Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
2
HVSI Imaging Center, Heart Vascular Stroke Institute; Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
3
Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
4
Center for Health Promotion; Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
coronary artery stenosis (C50 % by diameter) on CMRA and stress-perfusion defects in corresponding areas. Five of the 13 subjects showed evidence of old myocardial infarctions on delayed-enhancement MRI. Three subjects (0.9 %) underwent percutaneous coronary intervention after CAD was detected on cardiac MRI. There were no cardiac events during the follow-up period in subjects who complied with follow-up. Normal stress-perfusion and delayed-enhancement MRI lead to excellent outcomes when used to predict future cardiac events in asymptomatic subjects. Coronary MRA correlates well with stress-perfusion MRI for detecting significant CAD and helps exclude CAD in asymptomatic individuals. Keywords Coronary artery disease Asymptomatic diseases Myocardial perfusion Magnetic resonance imaging Magnetic resonance angiography Abbreviations CAD Coronary CCTA Coronary CMRA Coronary MRI Magnetic
artery disease CT angiography magnetic resonance angiography resonance imaging
Introduction Coronary artery disease (CAD) is the leading cause of death worldwide [1]. Risk prediction algorithms based on traditional risk factors, quantification of coronary artery calcium, and coronary computed tomographic angiography (CCTA) has been used to identify individuals at higher risk for CAD. However, traditional risk factor analysis has the
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potential limitation of underestimating risk in young individuals and in women [2, 3]. Many studies have demonstrated the prognostic value of coronary calcium scores (CCS) for predicting future cardiac events in asymptomatic individuals [4–8]. Although increasing levels of calcification correlate with higher specificities for obstructive CAD, they do not directly correlate with degree of stenosis [9, 10]. CCTA enables the detection of calcified and noncalcified plaques, and thus more definitively identifies obstructive CAD. The diagnostic accuracy of CCTA for the detection of CAD has been described in many previous studies [11–14]. However, high-density calcification can cause blooming artifacts that lead to overestimates of the degree of coronary stenosis. Additionally, the high radiation doses used in CCTA remain a challenge. While CCTA has already been used as a screening tool for the detection of CAD [15], appropriate indications for the use of this imaging modality have yet to be established. Coronary magnetic resonance angiography (CMRA) has been available for nearly 20 years [16]. Although CMRA has the major advantage of not using ionizing radiation, it is not widely used because of relatively low spatial resolution, long image acquisition time, and low success rates [16]. However, considerable advances have recently been made in magnetic resonance imaging (MRI) technology, and the diagnostic performance of CMRA for diagnosing CAD has improved as a result [16–20]. Some studies have reported that stress perfusion MRI with or without delayed-enhancement MRI exhibits good accuracy for the detection of CAD with significant coronary artery obstruction [21–27], although most of these were performed in high-risk patients. Recent reports indicate that the combined use of CMRA, delayed-enhancement MRI, and stress-perfusion improves diagnostic accuracy [28, 29]. To date, there have been no data published regarding the potential role of CMRA combined with perfusion and delayed-enhancement MRI for the detection of CAD in asymptomatic subjects. In this study, we intended to evaluate the feasibility of a comprehensive cardiac MRI protocol including coronary MRA, stress-perfusion, and delayed-enhancement MRI for the detection of CAD in asymptomatic subjects.
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promotion center, between May 2010 and February 2012. We excluded 23 patients who did not undergo CMRA (n = 5), or who had a history of myocardial infarction or angina (n = 11) and had previously undergone percutaneous coronary intervention (PCI) (n = 7). A total of 341 selfreferred asymptomatic subjects were enrolled in our study. Acquisition of MRI data All patients underwent cardiac MRI using a 1.5-T scanner (Magnetom Avanto, Syngo MR B17 version; Siemens Medical Solutions, Erlangen, Germany) with a 32-channel phased-array receiver coil during repeated breath-holds. Beta-blockers were not administered before CMRA. Nitroglycerin (0.4 mg, sublingual) was given to subjects 2 min before whole-heart CMRA (WHCMRA). After localization, cine images of the left ventricle (LV) were acquired using a steady-state free-precession sequence in 4-chamber and 2-chamber views. Then, stressperfusion MRI and short-axial views for obtaining 8–12 contiguous 30 short-axis slices with retrospective electrocardiography triggering were taken to include the entire LV, with a slice thickness of 6 and 4-mm gaps after stressperfusion MRI (Fig. 1). After cine imaging, adenosine was infused at a rate of 0.14 mg/kg/min under continuous electrocardiography and blood pressure monitoring. After 3 min of adenosine infusion, the perfusion stress sequence was triggered 5 s after the start of intravenous infusion of 0.1 mmol/kg gadobutrol (Gadovist; Bayer Healthcare, Berlin, Germany) at an injection rate of 3 ml/sec, followed by a 30-ml saline flush. The perfusion pulse sequences were performed using the following technical parameters: turboFLASH; repetition time (TR), 2.19 ms; echo time (TE), 1.07 ms; inversion time, 100 ms; acceleration factor (GRAPPA), 2; field of view, 340 9 293 mm; matrix, 160 9 98; pixel spacing, 2.125 mm 9 2.125 mm; number of slices, 4 [4 short axis (basal, mid-to-basal, mid, and apical)]; and slice thickness, 8 mm. Eighty dynamic MR images were acquired at each slice location depending on heart rate (HR), with a 1 min– 1 min 30 s total acquisition time. Combined Coronary MRA, Stress Perfusion, and Late Gd-Enhanced MRI
Materials and methods Study population This retrospective study was approved by our Institutional Review Board and the requirement for informed consent was waived. We retrospectively enrolled 364 consecutive individuals who underwent cardiac MRI during checkup at our health
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Cine MRI (2CV, 4CV)
Stress Perfusion
Cine MRI (SA, 3CV)
WH CMRA
Rest Perfusion
Late Gdenhanced MRI
Targeted CMRA
Fig. 1 The order of cardiac MR sequences for comprehensive examination. CMRA coronary MR angiography, CV chamber view, SA short-axial, WH whole-heart
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Navigator-gated electrocardiography (ECG)-triggered three-dimensional (3D) WHCMRA including 128 transverse slices was acquired using a fast imaging steady-state precession sequence (TrueFISP) (repetition time, 3.76 ms; echo time, 1.6 ms; flip angle, 90°; slice thickness, 1 mm; field-of-view, 320 9 290 9 128 mm; pixel spacing, 0.625 9 0.625 mm) with a T2 preparation (duration, 40 ms) and a fat suppression pre-pulse. Four-chamber cine MR images were used to determine the optimal trigger delay time and acquisition window for the WHCMRA. Either the diastolic-phase or systolic phase was chosen for the acquisition window by evaluating the movement of the right coronary artery (RCA). The data acquisition window ranged from 150 to 200 ms for diastolic-phase data acquisition and 50–100 ms for systolicphase data acquisition. The navigator-gating window was set at ±5 mm. In the current study, all coronary MRAs were performed using the generalized autocalibrating partially parallel acquisition technique (GRAPPA) with an acceleration factor of 2. Three-dimensional (3D) breath-hold volume-targeted CMRA (VTCMRA) scans were acquired along the orientation of the RCA, left circumflex artery (LCX), and left anterior descending branch (LAD). Oblique planes for RCA/LCX-targeted imaging were obtained from three points in the RCA and the LCX. The imaging slab of the left main (LM)/LAD-targeted scan was determined using three points in the LM and LAD coronary artery as a unit. The locations of the RCA and LAD were confirmed on 3D WHCMRA to rule out alterations due to patient movement. The basic pulse sequence was a TrueFISP. The imaging parameters were as follows: TR, 3.79 ms; TE, 1.6 ms; flip angle, 90°; slab thickness, 31.2 mm; field-of-view, 320 mm 9 290 mm; number of partitions, 12; imaging time, 12–24 s; slice thickness, 2.6 mm; pixel spacing, 0.625 9 0.625 mm; and acceleration factor (GRAPPA), 3. The left main coronary artery (LCA), LAD, and RCA were imaged in a double oblique orientation, which had previously been determined by WHCMRA. Image data acquisition was delayed until end-diastole. Standard delayed gadolinium-enhanced imaging was acquired using a phase-sensitive inversion recovery (PSIR) technique 15 min after another injection of 0.1 mmol/kg Gadovist for rest perfusion imaging using contiguous shortaxis image acquisition of 10–12 slices at 6 mm thickness and a 4-mm interslice gap. Inversion delay times were typically 280–360 ms. Analysis of MRI data All scans were analyzed by two experienced observers (each with 2 years of experience in cardiac MRI) who were blinded to all clinical information.
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Image quality of coronary MRA Image quality was assessed using a 4-point scale as follows: 1 = poor (coronary vessel blurred or noisy image), 2 = moderate (coronary vessel visible with low diagnostic confidence due to artifacts), 3 = good (coronary artery adequately visualized on diagnostic quality image with mild artifacts), and 4 = excellent (coronary artery clearly visible) [30]. Image quality was evaluated on a per segment basis according to the modified American Heart Association classification [31]. On WHCMRA, all segments of coronary arteries were evaluated. On VTCMRA, however, only nine segments [RCA (proximal, mid, distal), LM, LAD (proximal, mid, distal), LCX (proximal, distal)] were evaluated because the posterior descending coronary artery (PDA), obtuse marginal (OM) branches, and diagonal branches were not routinely included in the VTCMRA images. The image quality of WHCMRA versus VTCMRA was also evaluated. Grades 3 and 4 were considered to be of diagnostic quality. To assess interobserver variability for interpretation of CMRA, an additional observer (with 3 years of experience in cardiac MRI) independently evaluated the datasets in a randomly selected sample of 50 studies. In order to identify factors that affect CMRA image quality, the following variables were evaluated: age, sex, MRI operator, and mean HR for both whole-heart and targeted CMRA, with the addition of effective scan duration and navigator efficiency for WHCMRA only. Navigator efficiency was defined as the number of accepted navigator-gated acquisitions divided by the total number of acquisitions. Evaluation of coronary artery disease Only coronary artery segments with diagnostic image quality (image quality score C3) were assessed for the evaluation of coronary artery stenosis. If coronary artery stenosis was suspected, post-processing image reconstruction including a volume-rendered technique, curved multiplanar reformation, and cross-sectional analysis was performed with Aquarius iNtuition 4.4.6 software (TeraRecon, San Mateo, CA, USA). The luminal diameter at the site of maximal stenosis was compared with mean values at the proximal and distal reference sites (Fig. 2). The severity of stenosis was graded as normal-appearing (0–24 %), mild (25–49 %), moderate (50–74 %), and severe (C75 %) [32]. Perfusion abnormalities were defined as black or dark grey myocardium at the peak of the bolus, subendocardial signal reduction persisting for longer than the first pass of contrast material through the LV cavity and lasting for five or more consecutive dynamics (not visible on the remainder of the perfusion scan), signal reduction in several slices and
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Fig. 2 Assessment of right coronary artery stenosis on CMRA images. a whole-heart CMRA; b, volume-targeted CMRA
neighboring regions [33], and perfusion defects in any segment with C25 % transmurality [24]. Myocardial perfusion abnormalities were evaluated by visual comparisons of stress and rest perfusion studies with scores of 0 (normal), 1 (equivocal), 2 (subendocardial), or 3 (transmural). Regional wall motion abnormalities and myocardial thickness were evaluated on cine images. The presence or absence of previous myocardial infarction or fibrosis was evaluated on delayed-enhancement MR images. These results were correlated with data obtained from CMRA. Significant CAD was defined as greater than 50 % stenosis on diagnostic quality imaging or subendocardial or transmural hypoperfusion in the vascular territory regardless of CMRA results. Although the image quality of CMRA was non-diagnostic, we ruled out clinically significant CAD if no other abnormal findings were identified on other imaging sequences including stress-perfusion images, delayed enhancement images, and cine images. Clinical outcomes and additional diagnostic tests Follow-up data were obtained via review of medical records. Any occurrence of new chest pain or cardiac
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events (cardiac death, non-fatal myocardial infarction, and unstable angina) was noted. If additional diagnostic tests such as CCTA, stress echocardiography, or invasive coronary angiography (ICA) were performed within 90 days of cardiac MRI, those results were also recorded. If follow-up data were not available, patients were contacted via telephone to determine outcomes. Comparison of coronary MRA with coronary CTA If additional CCTA was performed within 90 days of cardiac MRI, the degree of coronary artery stenosis was compared with coronary MRA. Statistical analysis The image quality of WHCMRA, VTCMRA, and combined WHCMRA and VTCMRA were compared using paired t-tests, taking into account the Bonferroni correction for multiple comparisons. Kappa statistics were used to evaluate interobserver agreement for assessment of image quality. Multiple linear regression analysis was performed to identify factors that affect the image quality of MRA.
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All statistical analyses were conducted using commercially available software packages (PASW Statistics, version 18.0; SPSS, Chicago, IL, USA). P values \0.05 were considered to be statistically significant.
Results Clinical characteristics of the study population are summarized in Table 1. The whole examination took 34 min on average per patient (range, 29–40 min). The mean HR was 63 ± 9.8 beats/min (range, 40–103) during WHCMRA. The navigator efficiency was 60.6 ± 11.7 % for WHCMRA. WHCMRA took 6.4 min on average (range, 6.1–10.2 min). Adenosine stress perfusion MRI was performed safely and tolerated well in all subjects. Image quality of MRA Table 2 shows the mean image quality scores for WHCMRA, VTCMRA, and combined WHCMRA and VTCMRA (3.01 ± 0.93, 2.93 ± 0.98, and 3.35 ± 0.67, respectively). A total of 4000 coronary artery segments were evaluated. The number of coronary artery segments that exhibited diagnostic image quality increased from 2793 (69.8 %) on WHCMRA to 3296 (82.4 %) on combined
Table 1 Characteristics of the study group
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whole-heart and targeted MRA. The mean image quality of combined CMRA was better than those of both WHCMRA and VTCMRA (P \ 0.001). The mean image qualities of WHCMRA versus VTCMRA were not significantly different (P = 0.387). In 228 (66.9 %) of the 341 total subjects, all coronary artery segments met diagnostic image quality standards (Fig. 3). For patients in whom the proximal and mid portions of coronary arteries (LM, p-LAD, m-LAD, p-RCA, m-RCA, and p-LCX) were evaluated, 256 (75.1 %) of 341 subjects met diagnostic image quality standards for all segments. Diagnostic image quality was obtained in 306 (89.7 %) of LMs, 292 (85.6 %) of LADs, 286 (83.9 %) of RCAs, and 288 (85.7 %) of LCXs. Table 3 shows the results of multiple linear regression analysis used to assess factors that affect CMRA image quality. HR and navigator efficiency had significant effects on the image quality of WHCMRA. Age and HR had significant effects on the image quality of targeted CMRA. Coronary artery disease Twenty-four (10.5 %) of 228 subjects who had diagnostic imaging quality for all coronary artery segments on combined CMRA had coronary artery stenosis that was mild (n = 19), moderate (n = 8), or severe (n = 4) (Fig. 4). Twelve subjects (3.5 %) exhibited stress-perfusion defects
Total (n = 341)
Male (n = 227)
Female (n = 114) 54.1 ± 7.4
Age, years
55.3 ± 7.6
55.9 ± 7.7
BMI, kg/m2
24.2 ± 2.9
24.8 ± 2.8
23.1 ± 2.6
Systolic blood pressure, mm Hg
118.5 ± 15.9
119.5 ± 15.1
116.6 ± 17.2
Diastolic blood pressure, mm Hg
76.3 ± 10.6
78.6 ± 8.9
71.9 ± 12.1
HTN
113 (33.1)
83 (36.6)
20 (17.5)
DM
35 (10.2)
32 (14.1)
3 (2.6)
Cholesterol, mg/dl
192.0 ± 35.8
189.1 ± 3.9
197.7 ± 38.7
Triglyceride, mg/dl HDL cholesterol, mg/dl
137.8 ± 78.1 50.8 ± 13.1
149.7 ± 85.0 47.3 ± 11.1
114.1 ± 55.0 57.7 ± 14.0
LDL cholesterol, mg/dl
120.7 ± 32.6
119.9 ± 31.2
122.1 ± 35.3
Fasting blood glucose, mg/dl
106.3 ± 22.5
109.4 ± 24.3
100.1 ± 16.8
HbA1C, %
5.8 ± 0.9
5.9 ± 0.9
5.6 ± 0.6
BUN, mg/dl
13.6 ± 3.1
14.0 ± 3.1
12.9 ± 3.0
Serum creatinine, mg/dl
0.8 ± 0.2
0.9 ± 0.1
0.7 ± 0.1
History of stroke
8 (2.3)
7 (3.1)
1 (0.9)
Family history of premature CAD
39 (11.4)
23 (10.1)
16 (14.0)
Smoking
87 (25.5)
83 (36.6)
4 (3.5)
Ex-smoking
95 (27.9)
95 (41.9)
0 (0)
FRS
11.7 ± 4.3
12.6 ± 4.1
10 ± 4.0
Data are presented as n (%) and mean ± SD when appropriate BMI body mass index, BUN blood urea nitrogen, CAD coronary artery disease, DM diabetes mellitus, FRS Framingham risk score, HDL high-density lipoprotein, HTN hypertension, LDL low-density lipoprotein
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Table 2 Comparison of image quality of whole-heart, volume-targeted, and combined coronary MRA Total no.
Image quality Whole heart CMRA
Targeted CMRA
Combined CMRA
No. of diagnostic quality images on combined CMRA (percentage)
No. of diagnostic quality images with C2 mm (percentage)
p-RCA
341
3.06 ± 1.02
3.11 ± 0.99
3.48 ± 0.79
296 (86.8)
296 (86.8)
m-RCA
340
3.02 ± 1.04
3.05 ± 1.00
3.44 ± 0.83
291 (85.6)
291 (85.6)
d-RCA
329
3.01 ± 1.04
2.90 ± 1.01
3.35 ± 0.86
274 (83.3)
270 (82.1)
PDA
330
3.04 ± 1.02
3.04 ± 1.02
236 (71.5)
178 (53.9)
LM
341
3.13 ± 0.82
2.99 ± 1.00
3.44 ± 0.70
306 (89.7)
306 (89.7)
p-LAD
341
3.08 ± 0.84
2.96 ± 1.00
3.42 ± 0.71
305 (89.4)
305 (89.4)
m-LAD
340
2.96 ± 0.89
2.92 ± 0.98
3.36 ± 0.75
293 (86.2)
293 (86.2)
d-LAD
316
2.88 ± 0.90
2.92 ± 1.00
3.30 ± 0.79
268 (84.8)
264 (83.5)
Diagonal
339
2.95 ± 0.89
2.95 ± 0.89
234 (69.0)
114 (33.6)
p-LCX d-LCX
336 313
3.00 ± 0.90 2.95 ± 0.92
3.30 ± 0.76 3.25 ± 0.80
288 (85.7) 262 (83.7)
288 (85.7) 257 (82.1)
Marginal
334
2.99 ± 0.89
243 (72.8)
231 (69.2)
Mean
2.83 ± 0.94 2.78 ± 0.97
2.99 ± 0.89 3.01 ± 0.93
2.93 ± 0.98
3.35 ± 0.67
CMRA coronary magnetic resonance angiography, LAD left anterior descending branch, LCX left circumflex artery, LM left main, MRA magnetic resonance angiography, PDA posterior descending coronary artery, RCA right coronary artery
that were subendocardial (n = 9) or transmural (n = 3) (Fig. 5). Among them, 11 subjects had moderate or severe coronary artery stenosis on CMRA and stress-perfusion defects in corresponding areas. As a result, 13 subjects (3.8 %) were considered to have significant CAD. Among the 12 subjects who had stress-perfusion defects, five patients (1.5 %) also had regional wall motion abnormalities, delayed myocardial enhancement, and mild thinning of the myocardium in the corresponding area, and were thus diagnosed as having previous myocardial infarction. These five patients did not show clinical or laboratory findings (such as electrocardiography) of previous myocardial infarction before cardiac MRI. Clinical outcomes and additional diagnostic tests Clinical follow-up data were available for 97.3 % (332/341) of the study subjects (Fig. 6). The mean follow-up period was 29 ± 6 months (range 18–39 months). One patient complained of new onset chest pain 2 weeks after undergoing cardiac MRI, which was normal. No coronary artery stenosis was identified on follow-up CCTA in this patient, and subsequent stress echocardiography was also negative. Three patients who did not have any abnormal findings on CMRA complained of chest pain during the follow-up period, but they did not undergo any additional diagnostic tests. There were no cardiac events reported during the follow-up period. Three subjects (0.9 %) underwent PCI due to abnormal findings on cardiac MRI. One patient had severe stenosis in LAD and RCA and stress-perfusion defects in the
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corresponding territories. Another patient had moderate stenosis in LM and severe stenosis in proximal LAD and stress-perfusion defects. Additional CCTA showed severe stenosis in the corresponding segments (Fig. 5). The other patient exhibited perfusion defects in RCA territory and CMRA showed moderate stenosis in RCA. Therefore, additional CCTA was performed, and severe stenosis of the RCA was detected. Six subjects underwent additional CCTA after cardiac MRI because of new onset chest pain (n = 1), moderate or severe stenosis (n = 5) on CMRA or a perfusion defect (with non-diagnostic image quality on CMRA [n = 1], moderate stenosis on CMRA [n = 3], or severe stenosis on CMRA [n = 2]) (Fig. 7). Five of these patients had diagnostic image quality CMRA. Four of five patients (80 %) with moderate to severe stenosis (C50 %) on CMRA showed moderate to severe stenosis on CCTA. CCTA revealed moderate to severe coronary artery stenosis in five (83.3 %) of six patients with perfusion defects on stress myocardial perfusion MRI. Clinical characteristics of subjects with significant CAD on cardiac MRI are summarized in Table 4.
Discussion We evaluated the feasibility of using CMRA in combination with adenosine-stress perfusion and delayed enhancement MRI as a screening tool for the detection of occult CAD. As part of this study, the image quality of CMRA was also evaluated. Diagnostic image quality was
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Fig. 3 Whole-heart coronary MR angiography in subjects without significant coronary artery disease. The volume-rendered image shows three coronary artery vessels without stenosis (a). The curved planar image shows three patent vessels in a different subject (b)
Table 3 Results of multiple linear regression analysis examining factors that affect Coronary MRA image quality Variable
Whole-heart MRA
Volume-Targeted MRA
Regression coefficient (b)
SD
P value
Regression coefficient (b)
SD
P value
Age
-0.008
0.006
0.176
-0.021
0.006
\0.001
Sex
0.118
0.110
0.283
0.126
0.091
0.163
MRI operator
–
–
0.457
–
–
0.084
Operator 1a
–
–
–
–
–
–
Operator 2
-0.388
0.282
0.171
-0.002
0.179
0.990
Operator 3
-0.088
0.210
0.678
0.311
0.200
0.121
Operator 4
-0.009
0.167
0.956
0.240
0.153
0.118
Heart rate
-0.022
0.005
\0.001
-0.013
0.004
0.002
Effective scan duration
-0.113
0.087
0.157
–
–
–
Navigator efficiency
0.016
0.005
\0.001
–
–
–
MRA magnetic resonance angiography, SD standard deviation a
Reference for test of between-subjects effects
obtained in 82.4 % of coronary artery segments when WHCMRA was combined with VTCMRA. In addition, our data show that HR, navigator efficiency, and age affect the
image quality of CMRA. While CMRA may not be sufficient as the sole screening tool for detection of occult CAD, our results indicate that lowering HR and
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Fig. 4 A 71-year-old male with severe coronary artery stenosis and old myocardial infarction. The patient had no past medical history of coronary artery disease and denied cardiovascular symptoms. The curved planar reformatted image of volume-targeted coronary MR angiography shows severe stenosis (arrow) in the middle segment of the left anterior descending branch (a). The curved planar reformatted image of volume-targeted coronary MR angiography shows focal
severe stenosis (arrow) in the distal segment of the right coronary artery (b). Delayed contrast-enhanced MRI shows severe apical wall thinning and hyperenhancement (arrow) suggesting old myocardial infarction (c). Invasive angiography shows severe segmental stenosis (arrow in d) of middle segment of left anterior descending branch and focal severe stenosis (arrow in e) in the distal segment of the right coronary artery
maintaining regular respiration cycles can improve image quality. Based on the combined interpretation of CMRA, stressperfusion MRI, and delayed enhancement MRI, three subjects (0.9 %) underwent PCI. In one case, the image
quality of CMRA was non-diagnostic, though there was a perfusion defect on stress-perfusion MRI and no abnormal findings on delayed enhancement MRI. Thus, significant CAD was not missed in this patient, indicating that the possibility of missing such findings may be decreased by
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Fig. 5 A 69-year-old asymptomatic male with severe coronary artery stenosis. Stressperfusion MRI shows subendocardial perfusion defects (arrowheads) in mid ventricle segments (a). Coronary CT angiography shows significant stenosis in the left main coronary artery and three vessels (b). Invasive coronary angiography confirms moderate stenosis (arrow) in the left main coronary artery and severe stenosis in the ostium of the left anterior descending branch with an abnormality in fractional flow reserve with adenosine (0.63) (c). Percutaneous coronary intervention was performed in the left main and proximal left anterior descending branch
combining stress-perfusion and delayed enhancement MRI with CMRA. In addition, no cardiac events occurred during a mean follow-up period of 29 months when the results of the combined interpretation were normal. Collectively, these findings suggest that CMRA combined with stressperfusion and delayed enhancement MRI may be used as a screening tool for significant CAD. There were perfusion defects in most patients (92.3 %, 12/13) with significant CAD who were diagnosed with cardiac MRI. However, the role of CMRA might be to exclude CADs by demonstrating normal coronary arteries despite dark-rim artifacts on stress myocardial perfusion MRI. The sensitivity and specificity of stress-perfusion cardiac MRI were 67 and 61 %, respectively, in the MR-IMPACT II study of 533 patients [27]. These results seem to reflect real-world clinical practice. Bettencourt et al. [28] demonstrated that
the integration of CMRA into a stress-perfusion and delayed enhancement MRI study improved per-patient diagnostic performance for the detection of significant CADs (C90 % stenosis/occlusion or fractional flow reserve B0.80). In their study of 43 symptomatic patients, adding CMRA to the stress-perfusion and delayed enhancement protocol improved sensitivity (79 vs. 96 %) and negative predictive value (78 vs. 94 %) with a global diagnostic accuracy of 93 %. Therefore, the diagnostic performance of stress-perfusion cardiac MRI may be improved by adding anatomical information from CMRA. Patients with myocardial ischemia or old myocardial infarction can be asymptomatic [34]. Detection of significant CAD in patients with silent ischemia or in subjects at high risk of CAD, especially diabetics, may prevent future adverse cardiac events [35–37]. However, coronary
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Fig. 6 Clinical outcomes of all enrolled subjects. F/U followup, PCI percutaneous coronary intervention
Total Subjects n = 341
No significant coronary artery disease on cardiac MRI n = 328 (96.2%)
Subjects with available follow-up data n = 332 (97.3%)
Significant coronary artery disease on cardiac MRI n = 13 (3.8%)
PCI n = 3 (0.9%)
F/U
F/U
No coronary events n = 321 (94.1%)
No coronary events n = 10 (2.9%)
Significant Coronary Artery Disease (n = 13)
CMRA
Moderate
Moderate
Severe
Non-diagnostic
Stress-perfusion
Negative
Positive
Positive
Positive
(n = 1)
(n = 7)
(n = 4)
(n = 1)
Additional CCTA
Mild
Severe
Moderate
Severe
Moderate
(n = 6)
(n = 1)
(n = 2)
(n = 1)
(n = 1)
(n = 1)
Results
Follow up
Follow up
PCI
Follow up
PCI
Follow up
(n = 1)
(n = 5)
(n = 2)
(n = 3)
(n = 1)
(n = 1)
Fig. 7 Flow chart of 13 patients with significant coronary artery disease on combined coronary MR angiography and adenosine-stress perfusion MRI. CCTA coronary CT angiography, CMRA coronary MR angiography, PCI percutaneous coronary intervention
CT angiography, cardiac single photon emission tomography, and positron emission tomography involve radiation exposure to patients if they are used to screen patients for the detection of silent CAD. Cardiac MRI with stress perfusion and CMRA may be the best radiation-free modality for screening. The use of coronary CT angiography or stress cardiac MRI in asymptomatic subjects has not been justified by previous research [38–40]. The costeffectiveness of applying imaging examinations in asymptomatic subjects cannot be generalized to the general population. However, the prevalence of significant CAD (C50 % diameter stenosis) in 5 % and of severe stenosis (C75 % diameter stenosis) in 2 % of 1000 middle-aged asymptomatic subjects found by Choi et al. [15] is not
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negligible, and 16 subjects (1.6 %) in their sample of 1000 were confirmed to have severe stenosis (C75 % diameter stenosis) on the basis of ICA. Their study population consisted of mostly low-risk (55.7 %) or moderate-risk subjects (34.1 %) as defined by the revised National Cholesterol Education Program (NCEP) guidelines, and the average Framingham Risk Score (FRS) was 5.2 ± 5.0. Although the average FRS (11.7 ± 4.3) in our study was slightly higher, the rate of revascularization (0.9 %) in our study was similar to that (1.4 %) observed by Choi et al. [15]. According to Kwong et al. [36], silent myocardial infarctions were found in 28 % of 107 diabetic patients without previous histories of myocardial infarction on
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Table 4 Characteristics of subjects with significant coronary artery disease on cardiac MRI Total (n = 13) Age, years
63 ± 8.9
Male
10 (76)
BMI, kg/m2
24.8 ± 2.9
Systolic blood pressure, mmHg
124.8 ± 2.8
Diastolic blood pressure, mmHg
75.3 ± 12.1
HTN
7 (53.8)
DM Cholesterol, mg/dl
4 (30.7) 197.7 ± 43.8
Triglyceride, mg/dl
159.0 ± 63.1
HDL cholesterol, mg/dl
42.1 ± 10.1
LDL cholesterol, mg/dl
131.8 ± 39.9
Fasting blood glucose, mg/dl
120.9 ± 38.3
HbA1C, %
6.7 ± 2.0
BUN, mg/dl
13.2 ± 4.6
Serum creatinine, mg/dl
0.8 ± 0.2
History of stroke
0 (0)
Family history of premature CAD
1 (7.6)
Smoking
4 (30.7)
Ex-smoking
7 (53.8)
FRS
14.0 ± 6.6
Data are n (%) and mean ± SD when appropriate BMI body mass index, BUN blood urea nitrogen, CAD coronary artery disease, DM diabetes mellitus, FRS Framingham risk score, HDL high-density lipoprotein, HTN hypertension, LDL low-density lipoprotein
delayed gadolinium-enhanced MRI, a finding associated with poorer prognosis [35, 36]. Therefore, high risk subjects may benefit from the opportunity to undergo noninvasive studies that reliably enable the assessment of silent myocardial ischemia and infarction. The percentage (10.2 %) of diabetics in our study was slightly higher than that (7.3 %) in the sample examined by Choi et al. [15], while the rate (3.8 %) of significant coronary artery stenosis in our study was slightly lower. A previous study reported that WHCMRA was successfully obtained in 92 % of patients [30]. The image quality score of WHCMRA in that study ranged from 2.4 to 3.8, while scores for the proximal segments of the coronary arteries ranged from 3.4 to 3.8. Image quality was only assessed in successfully-obtained WHCMRA images, and the image quality score scale was slightly different from that used in the present study. However, the image quality of WHCMRA in the previous study was slightly better than that achieved in our study, even when these factors were considered. This discrepancy may be due to differences in image acquisition methods. One of the causes of suboptimal image quality in WHCMRA is complex breathing
motion patterns. To overcome this problem, an abdominal belt was used in the previous study. In addition, another report demonstrated that using an abdominal belt increased WHCMRA scan efficiency in both British and Japanese patients [41]. Therefore, modifications of image acquisition methods may improve WHCMRA image quality and increase the feasibility of using CMRA as a screening tool for CAD. Signal intensity of CMRA in the lumen of the coronary arteries may not be sufficient for 3D image reconstruction for the detection and calculation of coronary artery stenosis. Therefore, VTCMRA with breath-hold or respiratorygating performed in the longitudinal direction of three coronary arteries can be beneficial for depicting the proximal to middle segments of LAD and LCX and the proximal to distal segments of RCA with improved vessel sharpness [17]. Free-breathing WHCMRA is a time-consuming examination that requires 6–10 min using a 32-channel cardiac coil, while breath-hold VTCMRA required only 12–24 s in our study. Therefore, VTCMRA may replace WHCMRA because it is more efficient. As in our study, VTCMRA may be sufficient to screen for CAD in the proximal to middle segments of coronary arteries in subjects without cardiac symptoms. WHCMRA can be adopted in symptomatic patients along with stress-perfusion and delayed enhancement MRI. Our study has a few limitations. First, we did not have long-term follow-up data evaluating clinical outcomes. Additionally, we did not evaluate the diagnostic performance of CMRA or combined CMRA and stress-perfusion or delayed enhancement MRI. Our study was also performed using subjects who underwent cardiac MRI at a health promotion center, suggesting potential selection bias. Finally, we did not evaluate the cost-effectiveness of CMRA with perfusion and delayed enhancement MRI as a screening tool for detection of CAD. We found that CMRA has insufficient image quality for use as a screening tool for the detection of CAD. However, technical advances such as high-field strength MRI, multichannel cardiac coils, and faster imaging sequences may improve image quality and reduce imaging time.
Conclusion Coronary MRA combined with stress myocardial perfusion MRI and delayed contrast-enhanced MRI may help rule out significant CAD in asymptomatic subjects. The combination of WHCMRA and VTCMRA improves CMRA quality compared to WHCMRA or VTCMRA alone. Conflict of interest of interest.
The authors declare that they have no conflict
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ORIGINAL PAPER
Integrated cardiac magnetic resonance imaging with coronary magnetic resonance angiography, stress-perfusion, and delayed-enhancement imaging for the detection of occult coronary artery disease in asymptomatic individuals Kyoung Doo Song1 • Sung Mok Kim1,2 • Yeon Hyeon Choe1,2 • Wooin Jung1 Sang-Chol Lee2,3 • Sung-A Chang2,3 • Yoon Ho Choi4 • Jidong Sung3,4
•
Received: 13 April 2015 / Accepted: 15 April 2015 / Published online: 28 April 2015 Ó Springer Science+Business Media Dordrecht 2015
Abstract To evaluate the feasibility of using coronary magnetic resonance angiography (CMRA) with stressperfusion and delayed-enhancement MRI as a screening tool for the detection of coronary artery disease (CAD) in asymptomatic subjects. Three hundred and forty-one selfreferred asymptomatic subjects were enrolled in this study. Cardiac MR imaging was performed using a 1.5-T scanner with a 32-channel cardiac coil. Coronary artery stenosis, regional wall motion abnormalities, myocardial perfusion abnormalities, and delayed myocardial enhancement were analyzed. The occurrence of new chest pain and cardiac events was assessed in 332 subjects (97.3 %) over an average 29 ± 6 months (range, 18–39 months) follow-up period. A total of 3296 (82.4 %) of 4000 coronary artery segments examined exhibited diagnostic image quality on combined whole-heart and volume-targeted CMRA. Combined MRI detected significant CADs in 13 (3.8 %) of 341 subjects. Among these, 11 subjects (84.6 %) had both
& Yeon Hyeon Choe [email protected] 1
Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
2
HVSI Imaging Center, Heart Vascular Stroke Institute; Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
3
Division of Cardiology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
4
Center for Health Promotion; Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Ilwon-Ro, Gangnam-Gu, Seoul 135-710, Republic of Korea
coronary artery stenosis (C50 % by diameter) on CMRA and stress-perfusion defects in corresponding areas. Five of the 13 subjects showed evidence of old myocardial infarctions on delayed-enhancement MRI. Three subjects (0.9 %) underwent percutaneous coronary intervention after CAD was detected on cardiac MRI. There were no cardiac events during the follow-up period in subjects who complied with follow-up. Normal stress-perfusion and delayed-enhancement MRI lead to excellent outcomes when used to predict future cardiac events in asymptomatic subjects. Coronary MRA correlates well with stress-perfusion MRI for detecting significant CAD and helps exclude CAD in asymptomatic individuals. Keywords Coronary artery disease Asymptomatic diseases Myocardial perfusion Magnetic resonance imaging Magnetic resonance angiography Abbreviations CAD Coronary CCTA Coronary CMRA Coronary MRI Magnetic
artery disease CT angiography magnetic resonance angiography resonance imaging
Introduction Coronary artery disease (CAD) is the leading cause of death worldwide [1]. Risk prediction algorithms based on traditional risk factors, quantification of coronary artery calcium, and coronary computed tomographic angiography (CCTA) has been used to identify individuals at higher risk for CAD. However, traditional risk factor analysis has the
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potential limitation of underestimating risk in young individuals and in women [2, 3]. Many studies have demonstrated the prognostic value of coronary calcium scores (CCS) for predicting future cardiac events in asymptomatic individuals [4–8]. Although increasing levels of calcification correlate with higher specificities for obstructive CAD, they do not directly correlate with degree of stenosis [9, 10]. CCTA enables the detection of calcified and noncalcified plaques, and thus more definitively identifies obstructive CAD. The diagnostic accuracy of CCTA for the detection of CAD has been described in many previous studies [11–14]. However, high-density calcification can cause blooming artifacts that lead to overestimates of the degree of coronary stenosis. Additionally, the high radiation doses used in CCTA remain a challenge. While CCTA has already been used as a screening tool for the detection of CAD [15], appropriate indications for the use of this imaging modality have yet to be established. Coronary magnetic resonance angiography (CMRA) has been available for nearly 20 years [16]. Although CMRA has the major advantage of not using ionizing radiation, it is not widely used because of relatively low spatial resolution, long image acquisition time, and low success rates [16]. However, considerable advances have recently been made in magnetic resonance imaging (MRI) technology, and the diagnostic performance of CMRA for diagnosing CAD has improved as a result [16–20]. Some studies have reported that stress perfusion MRI with or without delayed-enhancement MRI exhibits good accuracy for the detection of CAD with significant coronary artery obstruction [21–27], although most of these were performed in high-risk patients. Recent reports indicate that the combined use of CMRA, delayed-enhancement MRI, and stress-perfusion improves diagnostic accuracy [28, 29]. To date, there have been no data published regarding the potential role of CMRA combined with perfusion and delayed-enhancement MRI for the detection of CAD in asymptomatic subjects. In this study, we intended to evaluate the feasibility of a comprehensive cardiac MRI protocol including coronary MRA, stress-perfusion, and delayed-enhancement MRI for the detection of CAD in asymptomatic subjects.
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promotion center, between May 2010 and February 2012. We excluded 23 patients who did not undergo CMRA (n = 5), or who had a history of myocardial infarction or angina (n = 11) and had previously undergone percutaneous coronary intervention (PCI) (n = 7). A total of 341 selfreferred asymptomatic subjects were enrolled in our study. Acquisition of MRI data All patients underwent cardiac MRI using a 1.5-T scanner (Magnetom Avanto, Syngo MR B17 version; Siemens Medical Solutions, Erlangen, Germany) with a 32-channel phased-array receiver coil during repeated breath-holds. Beta-blockers were not administered before CMRA. Nitroglycerin (0.4 mg, sublingual) was given to subjects 2 min before whole-heart CMRA (WHCMRA). After localization, cine images of the left ventricle (LV) were acquired using a steady-state free-precession sequence in 4-chamber and 2-chamber views. Then, stressperfusion MRI and short-axial views for obtaining 8–12 contiguous 30 short-axis slices with retrospective electrocardiography triggering were taken to include the entire LV, with a slice thickness of 6 and 4-mm gaps after stressperfusion MRI (Fig. 1). After cine imaging, adenosine was infused at a rate of 0.14 mg/kg/min under continuous electrocardiography and blood pressure monitoring. After 3 min of adenosine infusion, the perfusion stress sequence was triggered 5 s after the start of intravenous infusion of 0.1 mmol/kg gadobutrol (Gadovist; Bayer Healthcare, Berlin, Germany) at an injection rate of 3 ml/sec, followed by a 30-ml saline flush. The perfusion pulse sequences were performed using the following technical parameters: turboFLASH; repetition time (TR), 2.19 ms; echo time (TE), 1.07 ms; inversion time, 100 ms; acceleration factor (GRAPPA), 2; field of view, 340 9 293 mm; matrix, 160 9 98; pixel spacing, 2.125 mm 9 2.125 mm; number of slices, 4 [4 short axis (basal, mid-to-basal, mid, and apical)]; and slice thickness, 8 mm. Eighty dynamic MR images were acquired at each slice location depending on heart rate (HR), with a 1 min– 1 min 30 s total acquisition time. Combined Coronary MRA, Stress Perfusion, and Late Gd-Enhanced MRI
Materials and methods Study population This retrospective study was approved by our Institutional Review Board and the requirement for informed consent was waived. We retrospectively enrolled 364 consecutive individuals who underwent cardiac MRI during checkup at our health
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Cine MRI (2CV, 4CV)
Stress Perfusion
Cine MRI (SA, 3CV)
WH CMRA
Rest Perfusion
Late Gdenhanced MRI
Targeted CMRA
Fig. 1 The order of cardiac MR sequences for comprehensive examination. CMRA coronary MR angiography, CV chamber view, SA short-axial, WH whole-heart
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Navigator-gated electrocardiography (ECG)-triggered three-dimensional (3D) WHCMRA including 128 transverse slices was acquired using a fast imaging steady-state precession sequence (TrueFISP) (repetition time, 3.76 ms; echo time, 1.6 ms; flip angle, 90°; slice thickness, 1 mm; field-of-view, 320 9 290 9 128 mm; pixel spacing, 0.625 9 0.625 mm) with a T2 preparation (duration, 40 ms) and a fat suppression pre-pulse. Four-chamber cine MR images were used to determine the optimal trigger delay time and acquisition window for the WHCMRA. Either the diastolic-phase or systolic phase was chosen for the acquisition window by evaluating the movement of the right coronary artery (RCA). The data acquisition window ranged from 150 to 200 ms for diastolic-phase data acquisition and 50–100 ms for systolicphase data acquisition. The navigator-gating window was set at ±5 mm. In the current study, all coronary MRAs were performed using the generalized autocalibrating partially parallel acquisition technique (GRAPPA) with an acceleration factor of 2. Three-dimensional (3D) breath-hold volume-targeted CMRA (VTCMRA) scans were acquired along the orientation of the RCA, left circumflex artery (LCX), and left anterior descending branch (LAD). Oblique planes for RCA/LCX-targeted imaging were obtained from three points in the RCA and the LCX. The imaging slab of the left main (LM)/LAD-targeted scan was determined using three points in the LM and LAD coronary artery as a unit. The locations of the RCA and LAD were confirmed on 3D WHCMRA to rule out alterations due to patient movement. The basic pulse sequence was a TrueFISP. The imaging parameters were as follows: TR, 3.79 ms; TE, 1.6 ms; flip angle, 90°; slab thickness, 31.2 mm; field-of-view, 320 mm 9 290 mm; number of partitions, 12; imaging time, 12–24 s; slice thickness, 2.6 mm; pixel spacing, 0.625 9 0.625 mm; and acceleration factor (GRAPPA), 3. The left main coronary artery (LCA), LAD, and RCA were imaged in a double oblique orientation, which had previously been determined by WHCMRA. Image data acquisition was delayed until end-diastole. Standard delayed gadolinium-enhanced imaging was acquired using a phase-sensitive inversion recovery (PSIR) technique 15 min after another injection of 0.1 mmol/kg Gadovist for rest perfusion imaging using contiguous shortaxis image acquisition of 10–12 slices at 6 mm thickness and a 4-mm interslice gap. Inversion delay times were typically 280–360 ms. Analysis of MRI data All scans were analyzed by two experienced observers (each with 2 years of experience in cardiac MRI) who were blinded to all clinical information.
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Image quality of coronary MRA Image quality was assessed using a 4-point scale as follows: 1 = poor (coronary vessel blurred or noisy image), 2 = moderate (coronary vessel visible with low diagnostic confidence due to artifacts), 3 = good (coronary artery adequately visualized on diagnostic quality image with mild artifacts), and 4 = excellent (coronary artery clearly visible) [30]. Image quality was evaluated on a per segment basis according to the modified American Heart Association classification [31]. On WHCMRA, all segments of coronary arteries were evaluated. On VTCMRA, however, only nine segments [RCA (proximal, mid, distal), LM, LAD (proximal, mid, distal), LCX (proximal, distal)] were evaluated because the posterior descending coronary artery (PDA), obtuse marginal (OM) branches, and diagonal branches were not routinely included in the VTCMRA images. The image quality of WHCMRA versus VTCMRA was also evaluated. Grades 3 and 4 were considered to be of diagnostic quality. To assess interobserver variability for interpretation of CMRA, an additional observer (with 3 years of experience in cardiac MRI) independently evaluated the datasets in a randomly selected sample of 50 studies. In order to identify factors that affect CMRA image quality, the following variables were evaluated: age, sex, MRI operator, and mean HR for both whole-heart and targeted CMRA, with the addition of effective scan duration and navigator efficiency for WHCMRA only. Navigator efficiency was defined as the number of accepted navigator-gated acquisitions divided by the total number of acquisitions. Evaluation of coronary artery disease Only coronary artery segments with diagnostic image quality (image quality score C3) were assessed for the evaluation of coronary artery stenosis. If coronary artery stenosis was suspected, post-processing image reconstruction including a volume-rendered technique, curved multiplanar reformation, and cross-sectional analysis was performed with Aquarius iNtuition 4.4.6 software (TeraRecon, San Mateo, CA, USA). The luminal diameter at the site of maximal stenosis was compared with mean values at the proximal and distal reference sites (Fig. 2). The severity of stenosis was graded as normal-appearing (0–24 %), mild (25–49 %), moderate (50–74 %), and severe (C75 %) [32]. Perfusion abnormalities were defined as black or dark grey myocardium at the peak of the bolus, subendocardial signal reduction persisting for longer than the first pass of contrast material through the LV cavity and lasting for five or more consecutive dynamics (not visible on the remainder of the perfusion scan), signal reduction in several slices and
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Fig. 2 Assessment of right coronary artery stenosis on CMRA images. a whole-heart CMRA; b, volume-targeted CMRA
neighboring regions [33], and perfusion defects in any segment with C25 % transmurality [24]. Myocardial perfusion abnormalities were evaluated by visual comparisons of stress and rest perfusion studies with scores of 0 (normal), 1 (equivocal), 2 (subendocardial), or 3 (transmural). Regional wall motion abnormalities and myocardial thickness were evaluated on cine images. The presence or absence of previous myocardial infarction or fibrosis was evaluated on delayed-enhancement MR images. These results were correlated with data obtained from CMRA. Significant CAD was defined as greater than 50 % stenosis on diagnostic quality imaging or subendocardial or transmural hypoperfusion in the vascular territory regardless of CMRA results. Although the image quality of CMRA was non-diagnostic, we ruled out clinically significant CAD if no other abnormal findings were identified on other imaging sequences including stress-perfusion images, delayed enhancement images, and cine images. Clinical outcomes and additional diagnostic tests Follow-up data were obtained via review of medical records. Any occurrence of new chest pain or cardiac
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events (cardiac death, non-fatal myocardial infarction, and unstable angina) was noted. If additional diagnostic tests such as CCTA, stress echocardiography, or invasive coronary angiography (ICA) were performed within 90 days of cardiac MRI, those results were also recorded. If follow-up data were not available, patients were contacted via telephone to determine outcomes. Comparison of coronary MRA with coronary CTA If additional CCTA was performed within 90 days of cardiac MRI, the degree of coronary artery stenosis was compared with coronary MRA. Statistical analysis The image quality of WHCMRA, VTCMRA, and combined WHCMRA and VTCMRA were compared using paired t-tests, taking into account the Bonferroni correction for multiple comparisons. Kappa statistics were used to evaluate interobserver agreement for assessment of image quality. Multiple linear regression analysis was performed to identify factors that affect the image quality of MRA.
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All statistical analyses were conducted using commercially available software packages (PASW Statistics, version 18.0; SPSS, Chicago, IL, USA). P values \0.05 were considered to be statistically significant.
Results Clinical characteristics of the study population are summarized in Table 1. The whole examination took 34 min on average per patient (range, 29–40 min). The mean HR was 63 ± 9.8 beats/min (range, 40–103) during WHCMRA. The navigator efficiency was 60.6 ± 11.7 % for WHCMRA. WHCMRA took 6.4 min on average (range, 6.1–10.2 min). Adenosine stress perfusion MRI was performed safely and tolerated well in all subjects. Image quality of MRA Table 2 shows the mean image quality scores for WHCMRA, VTCMRA, and combined WHCMRA and VTCMRA (3.01 ± 0.93, 2.93 ± 0.98, and 3.35 ± 0.67, respectively). A total of 4000 coronary artery segments were evaluated. The number of coronary artery segments that exhibited diagnostic image quality increased from 2793 (69.8 %) on WHCMRA to 3296 (82.4 %) on combined
Table 1 Characteristics of the study group
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whole-heart and targeted MRA. The mean image quality of combined CMRA was better than those of both WHCMRA and VTCMRA (P \ 0.001). The mean image qualities of WHCMRA versus VTCMRA were not significantly different (P = 0.387). In 228 (66.9 %) of the 341 total subjects, all coronary artery segments met diagnostic image quality standards (Fig. 3). For patients in whom the proximal and mid portions of coronary arteries (LM, p-LAD, m-LAD, p-RCA, m-RCA, and p-LCX) were evaluated, 256 (75.1 %) of 341 subjects met diagnostic image quality standards for all segments. Diagnostic image quality was obtained in 306 (89.7 %) of LMs, 292 (85.6 %) of LADs, 286 (83.9 %) of RCAs, and 288 (85.7 %) of LCXs. Table 3 shows the results of multiple linear regression analysis used to assess factors that affect CMRA image quality. HR and navigator efficiency had significant effects on the image quality of WHCMRA. Age and HR had significant effects on the image quality of targeted CMRA. Coronary artery disease Twenty-four (10.5 %) of 228 subjects who had diagnostic imaging quality for all coronary artery segments on combined CMRA had coronary artery stenosis that was mild (n = 19), moderate (n = 8), or severe (n = 4) (Fig. 4). Twelve subjects (3.5 %) exhibited stress-perfusion defects
Total (n = 341)
Male (n = 227)
Female (n = 114) 54.1 ± 7.4
Age, years
55.3 ± 7.6
55.9 ± 7.7
BMI, kg/m2
24.2 ± 2.9
24.8 ± 2.8
23.1 ± 2.6
Systolic blood pressure, mm Hg
118.5 ± 15.9
119.5 ± 15.1
116.6 ± 17.2
Diastolic blood pressure, mm Hg
76.3 ± 10.6
78.6 ± 8.9
71.9 ± 12.1
HTN
113 (33.1)
83 (36.6)
20 (17.5)
DM
35 (10.2)
32 (14.1)
3 (2.6)
Cholesterol, mg/dl
192.0 ± 35.8
189.1 ± 3.9
197.7 ± 38.7
Triglyceride, mg/dl HDL cholesterol, mg/dl
137.8 ± 78.1 50.8 ± 13.1
149.7 ± 85.0 47.3 ± 11.1
114.1 ± 55.0 57.7 ± 14.0
LDL cholesterol, mg/dl
120.7 ± 32.6
119.9 ± 31.2
122.1 ± 35.3
Fasting blood glucose, mg/dl
106.3 ± 22.5
109.4 ± 24.3
100.1 ± 16.8
HbA1C, %
5.8 ± 0.9
5.9 ± 0.9
5.6 ± 0.6
BUN, mg/dl
13.6 ± 3.1
14.0 ± 3.1
12.9 ± 3.0
Serum creatinine, mg/dl
0.8 ± 0.2
0.9 ± 0.1
0.7 ± 0.1
History of stroke
8 (2.3)
7 (3.1)
1 (0.9)
Family history of premature CAD
39 (11.4)
23 (10.1)
16 (14.0)
Smoking
87 (25.5)
83 (36.6)
4 (3.5)
Ex-smoking
95 (27.9)
95 (41.9)
0 (0)
FRS
11.7 ± 4.3
12.6 ± 4.1
10 ± 4.0
Data are presented as n (%) and mean ± SD when appropriate BMI body mass index, BUN blood urea nitrogen, CAD coronary artery disease, DM diabetes mellitus, FRS Framingham risk score, HDL high-density lipoprotein, HTN hypertension, LDL low-density lipoprotein
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Table 2 Comparison of image quality of whole-heart, volume-targeted, and combined coronary MRA Total no.
Image quality Whole heart CMRA
Targeted CMRA
Combined CMRA
No. of diagnostic quality images on combined CMRA (percentage)
No. of diagnostic quality images with C2 mm (percentage)
p-RCA
341
3.06 ± 1.02
3.11 ± 0.99
3.48 ± 0.79
296 (86.8)
296 (86.8)
m-RCA
340
3.02 ± 1.04
3.05 ± 1.00
3.44 ± 0.83
291 (85.6)
291 (85.6)
d-RCA
329
3.01 ± 1.04
2.90 ± 1.01
3.35 ± 0.86
274 (83.3)
270 (82.1)
PDA
330
3.04 ± 1.02
3.04 ± 1.02
236 (71.5)
178 (53.9)
LM
341
3.13 ± 0.82
2.99 ± 1.00
3.44 ± 0.70
306 (89.7)
306 (89.7)
p-LAD
341
3.08 ± 0.84
2.96 ± 1.00
3.42 ± 0.71
305 (89.4)
305 (89.4)
m-LAD
340
2.96 ± 0.89
2.92 ± 0.98
3.36 ± 0.75
293 (86.2)
293 (86.2)
d-LAD
316
2.88 ± 0.90
2.92 ± 1.00
3.30 ± 0.79
268 (84.8)
264 (83.5)
Diagonal
339
2.95 ± 0.89
2.95 ± 0.89
234 (69.0)
114 (33.6)
p-LCX d-LCX
336 313
3.00 ± 0.90 2.95 ± 0.92
3.30 ± 0.76 3.25 ± 0.80
288 (85.7) 262 (83.7)
288 (85.7) 257 (82.1)
Marginal
334
2.99 ± 0.89
243 (72.8)
231 (69.2)
Mean
2.83 ± 0.94 2.78 ± 0.97
2.99 ± 0.89 3.01 ± 0.93
2.93 ± 0.98
3.35 ± 0.67
CMRA coronary magnetic resonance angiography, LAD left anterior descending branch, LCX left circumflex artery, LM left main, MRA magnetic resonance angiography, PDA posterior descending coronary artery, RCA right coronary artery
that were subendocardial (n = 9) or transmural (n = 3) (Fig. 5). Among them, 11 subjects had moderate or severe coronary artery stenosis on CMRA and stress-perfusion defects in corresponding areas. As a result, 13 subjects (3.8 %) were considered to have significant CAD. Among the 12 subjects who had stress-perfusion defects, five patients (1.5 %) also had regional wall motion abnormalities, delayed myocardial enhancement, and mild thinning of the myocardium in the corresponding area, and were thus diagnosed as having previous myocardial infarction. These five patients did not show clinical or laboratory findings (such as electrocardiography) of previous myocardial infarction before cardiac MRI. Clinical outcomes and additional diagnostic tests Clinical follow-up data were available for 97.3 % (332/341) of the study subjects (Fig. 6). The mean follow-up period was 29 ± 6 months (range 18–39 months). One patient complained of new onset chest pain 2 weeks after undergoing cardiac MRI, which was normal. No coronary artery stenosis was identified on follow-up CCTA in this patient, and subsequent stress echocardiography was also negative. Three patients who did not have any abnormal findings on CMRA complained of chest pain during the follow-up period, but they did not undergo any additional diagnostic tests. There were no cardiac events reported during the follow-up period. Three subjects (0.9 %) underwent PCI due to abnormal findings on cardiac MRI. One patient had severe stenosis in LAD and RCA and stress-perfusion defects in the
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corresponding territories. Another patient had moderate stenosis in LM and severe stenosis in proximal LAD and stress-perfusion defects. Additional CCTA showed severe stenosis in the corresponding segments (Fig. 5). The other patient exhibited perfusion defects in RCA territory and CMRA showed moderate stenosis in RCA. Therefore, additional CCTA was performed, and severe stenosis of the RCA was detected. Six subjects underwent additional CCTA after cardiac MRI because of new onset chest pain (n = 1), moderate or severe stenosis (n = 5) on CMRA or a perfusion defect (with non-diagnostic image quality on CMRA [n = 1], moderate stenosis on CMRA [n = 3], or severe stenosis on CMRA [n = 2]) (Fig. 7). Five of these patients had diagnostic image quality CMRA. Four of five patients (80 %) with moderate to severe stenosis (C50 %) on CMRA showed moderate to severe stenosis on CCTA. CCTA revealed moderate to severe coronary artery stenosis in five (83.3 %) of six patients with perfusion defects on stress myocardial perfusion MRI. Clinical characteristics of subjects with significant CAD on cardiac MRI are summarized in Table 4.
Discussion We evaluated the feasibility of using CMRA in combination with adenosine-stress perfusion and delayed enhancement MRI as a screening tool for the detection of occult CAD. As part of this study, the image quality of CMRA was also evaluated. Diagnostic image quality was
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Fig. 3 Whole-heart coronary MR angiography in subjects without significant coronary artery disease. The volume-rendered image shows three coronary artery vessels without stenosis (a). The curved planar image shows three patent vessels in a different subject (b)
Table 3 Results of multiple linear regression analysis examining factors that affect Coronary MRA image quality Variable
Whole-heart MRA
Volume-Targeted MRA
Regression coefficient (b)
SD
P value
Regression coefficient (b)
SD
P value
Age
-0.008
0.006
0.176
-0.021
0.006
\0.001
Sex
0.118
0.110
0.283
0.126
0.091
0.163
MRI operator
–
–
0.457
–
–
0.084
Operator 1a
–
–
–
–
–
–
Operator 2
-0.388
0.282
0.171
-0.002
0.179
0.990
Operator 3
-0.088
0.210
0.678
0.311
0.200
0.121
Operator 4
-0.009
0.167
0.956
0.240
0.153
0.118
Heart rate
-0.022
0.005
\0.001
-0.013
0.004
0.002
Effective scan duration
-0.113
0.087
0.157
–
–
–
Navigator efficiency
0.016
0.005
\0.001
–
–
–
MRA magnetic resonance angiography, SD standard deviation a
Reference for test of between-subjects effects
obtained in 82.4 % of coronary artery segments when WHCMRA was combined with VTCMRA. In addition, our data show that HR, navigator efficiency, and age affect the
image quality of CMRA. While CMRA may not be sufficient as the sole screening tool for detection of occult CAD, our results indicate that lowering HR and
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Fig. 4 A 71-year-old male with severe coronary artery stenosis and old myocardial infarction. The patient had no past medical history of coronary artery disease and denied cardiovascular symptoms. The curved planar reformatted image of volume-targeted coronary MR angiography shows severe stenosis (arrow) in the middle segment of the left anterior descending branch (a). The curved planar reformatted image of volume-targeted coronary MR angiography shows focal
severe stenosis (arrow) in the distal segment of the right coronary artery (b). Delayed contrast-enhanced MRI shows severe apical wall thinning and hyperenhancement (arrow) suggesting old myocardial infarction (c). Invasive angiography shows severe segmental stenosis (arrow in d) of middle segment of left anterior descending branch and focal severe stenosis (arrow in e) in the distal segment of the right coronary artery
maintaining regular respiration cycles can improve image quality. Based on the combined interpretation of CMRA, stressperfusion MRI, and delayed enhancement MRI, three subjects (0.9 %) underwent PCI. In one case, the image
quality of CMRA was non-diagnostic, though there was a perfusion defect on stress-perfusion MRI and no abnormal findings on delayed enhancement MRI. Thus, significant CAD was not missed in this patient, indicating that the possibility of missing such findings may be decreased by
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Fig. 5 A 69-year-old asymptomatic male with severe coronary artery stenosis. Stressperfusion MRI shows subendocardial perfusion defects (arrowheads) in mid ventricle segments (a). Coronary CT angiography shows significant stenosis in the left main coronary artery and three vessels (b). Invasive coronary angiography confirms moderate stenosis (arrow) in the left main coronary artery and severe stenosis in the ostium of the left anterior descending branch with an abnormality in fractional flow reserve with adenosine (0.63) (c). Percutaneous coronary intervention was performed in the left main and proximal left anterior descending branch
combining stress-perfusion and delayed enhancement MRI with CMRA. In addition, no cardiac events occurred during a mean follow-up period of 29 months when the results of the combined interpretation were normal. Collectively, these findings suggest that CMRA combined with stressperfusion and delayed enhancement MRI may be used as a screening tool for significant CAD. There were perfusion defects in most patients (92.3 %, 12/13) with significant CAD who were diagnosed with cardiac MRI. However, the role of CMRA might be to exclude CADs by demonstrating normal coronary arteries despite dark-rim artifacts on stress myocardial perfusion MRI. The sensitivity and specificity of stress-perfusion cardiac MRI were 67 and 61 %, respectively, in the MR-IMPACT II study of 533 patients [27]. These results seem to reflect real-world clinical practice. Bettencourt et al. [28] demonstrated that
the integration of CMRA into a stress-perfusion and delayed enhancement MRI study improved per-patient diagnostic performance for the detection of significant CADs (C90 % stenosis/occlusion or fractional flow reserve B0.80). In their study of 43 symptomatic patients, adding CMRA to the stress-perfusion and delayed enhancement protocol improved sensitivity (79 vs. 96 %) and negative predictive value (78 vs. 94 %) with a global diagnostic accuracy of 93 %. Therefore, the diagnostic performance of stress-perfusion cardiac MRI may be improved by adding anatomical information from CMRA. Patients with myocardial ischemia or old myocardial infarction can be asymptomatic [34]. Detection of significant CAD in patients with silent ischemia or in subjects at high risk of CAD, especially diabetics, may prevent future adverse cardiac events [35–37]. However, coronary
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Fig. 6 Clinical outcomes of all enrolled subjects. F/U followup, PCI percutaneous coronary intervention
Total Subjects n = 341
No significant coronary artery disease on cardiac MRI n = 328 (96.2%)
Subjects with available follow-up data n = 332 (97.3%)
Significant coronary artery disease on cardiac MRI n = 13 (3.8%)
PCI n = 3 (0.9%)
F/U
F/U
No coronary events n = 321 (94.1%)
No coronary events n = 10 (2.9%)
Significant Coronary Artery Disease (n = 13)
CMRA
Moderate
Moderate
Severe
Non-diagnostic
Stress-perfusion
Negative
Positive
Positive
Positive
(n = 1)
(n = 7)
(n = 4)
(n = 1)
Additional CCTA
Mild
Severe
Moderate
Severe
Moderate
(n = 6)
(n = 1)
(n = 2)
(n = 1)
(n = 1)
(n = 1)
Results
Follow up
Follow up
PCI
Follow up
PCI
Follow up
(n = 1)
(n = 5)
(n = 2)
(n = 3)
(n = 1)
(n = 1)
Fig. 7 Flow chart of 13 patients with significant coronary artery disease on combined coronary MR angiography and adenosine-stress perfusion MRI. CCTA coronary CT angiography, CMRA coronary MR angiography, PCI percutaneous coronary intervention
CT angiography, cardiac single photon emission tomography, and positron emission tomography involve radiation exposure to patients if they are used to screen patients for the detection of silent CAD. Cardiac MRI with stress perfusion and CMRA may be the best radiation-free modality for screening. The use of coronary CT angiography or stress cardiac MRI in asymptomatic subjects has not been justified by previous research [38–40]. The costeffectiveness of applying imaging examinations in asymptomatic subjects cannot be generalized to the general population. However, the prevalence of significant CAD (C50 % diameter stenosis) in 5 % and of severe stenosis (C75 % diameter stenosis) in 2 % of 1000 middle-aged asymptomatic subjects found by Choi et al. [15] is not
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negligible, and 16 subjects (1.6 %) in their sample of 1000 were confirmed to have severe stenosis (C75 % diameter stenosis) on the basis of ICA. Their study population consisted of mostly low-risk (55.7 %) or moderate-risk subjects (34.1 %) as defined by the revised National Cholesterol Education Program (NCEP) guidelines, and the average Framingham Risk Score (FRS) was 5.2 ± 5.0. Although the average FRS (11.7 ± 4.3) in our study was slightly higher, the rate of revascularization (0.9 %) in our study was similar to that (1.4 %) observed by Choi et al. [15]. According to Kwong et al. [36], silent myocardial infarctions were found in 28 % of 107 diabetic patients without previous histories of myocardial infarction on
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Table 4 Characteristics of subjects with significant coronary artery disease on cardiac MRI Total (n = 13) Age, years
63 ± 8.9
Male
10 (76)
BMI, kg/m2
24.8 ± 2.9
Systolic blood pressure, mmHg
124.8 ± 2.8
Diastolic blood pressure, mmHg
75.3 ± 12.1
HTN
7 (53.8)
DM Cholesterol, mg/dl
4 (30.7) 197.7 ± 43.8
Triglyceride, mg/dl
159.0 ± 63.1
HDL cholesterol, mg/dl
42.1 ± 10.1
LDL cholesterol, mg/dl
131.8 ± 39.9
Fasting blood glucose, mg/dl
120.9 ± 38.3
HbA1C, %
6.7 ± 2.0
BUN, mg/dl
13.2 ± 4.6
Serum creatinine, mg/dl
0.8 ± 0.2
History of stroke
0 (0)
Family history of premature CAD
1 (7.6)
Smoking
4 (30.7)
Ex-smoking
7 (53.8)
FRS
14.0 ± 6.6
Data are n (%) and mean ± SD when appropriate BMI body mass index, BUN blood urea nitrogen, CAD coronary artery disease, DM diabetes mellitus, FRS Framingham risk score, HDL high-density lipoprotein, HTN hypertension, LDL low-density lipoprotein
delayed gadolinium-enhanced MRI, a finding associated with poorer prognosis [35, 36]. Therefore, high risk subjects may benefit from the opportunity to undergo noninvasive studies that reliably enable the assessment of silent myocardial ischemia and infarction. The percentage (10.2 %) of diabetics in our study was slightly higher than that (7.3 %) in the sample examined by Choi et al. [15], while the rate (3.8 %) of significant coronary artery stenosis in our study was slightly lower. A previous study reported that WHCMRA was successfully obtained in 92 % of patients [30]. The image quality score of WHCMRA in that study ranged from 2.4 to 3.8, while scores for the proximal segments of the coronary arteries ranged from 3.4 to 3.8. Image quality was only assessed in successfully-obtained WHCMRA images, and the image quality score scale was slightly different from that used in the present study. However, the image quality of WHCMRA in the previous study was slightly better than that achieved in our study, even when these factors were considered. This discrepancy may be due to differences in image acquisition methods. One of the causes of suboptimal image quality in WHCMRA is complex breathing
motion patterns. To overcome this problem, an abdominal belt was used in the previous study. In addition, another report demonstrated that using an abdominal belt increased WHCMRA scan efficiency in both British and Japanese patients [41]. Therefore, modifications of image acquisition methods may improve WHCMRA image quality and increase the feasibility of using CMRA as a screening tool for CAD. Signal intensity of CMRA in the lumen of the coronary arteries may not be sufficient for 3D image reconstruction for the detection and calculation of coronary artery stenosis. Therefore, VTCMRA with breath-hold or respiratorygating performed in the longitudinal direction of three coronary arteries can be beneficial for depicting the proximal to middle segments of LAD and LCX and the proximal to distal segments of RCA with improved vessel sharpness [17]. Free-breathing WHCMRA is a time-consuming examination that requires 6–10 min using a 32-channel cardiac coil, while breath-hold VTCMRA required only 12–24 s in our study. Therefore, VTCMRA may replace WHCMRA because it is more efficient. As in our study, VTCMRA may be sufficient to screen for CAD in the proximal to middle segments of coronary arteries in subjects without cardiac symptoms. WHCMRA can be adopted in symptomatic patients along with stress-perfusion and delayed enhancement MRI. Our study has a few limitations. First, we did not have long-term follow-up data evaluating clinical outcomes. Additionally, we did not evaluate the diagnostic performance of CMRA or combined CMRA and stress-perfusion or delayed enhancement MRI. Our study was also performed using subjects who underwent cardiac MRI at a health promotion center, suggesting potential selection bias. Finally, we did not evaluate the cost-effectiveness of CMRA with perfusion and delayed enhancement MRI as a screening tool for detection of CAD. We found that CMRA has insufficient image quality for use as a screening tool for the detection of CAD. However, technical advances such as high-field strength MRI, multichannel cardiac coils, and faster imaging sequences may improve image quality and reduce imaging time.
Conclusion Coronary MRA combined with stress myocardial perfusion MRI and delayed contrast-enhanced MRI may help rule out significant CAD in asymptomatic subjects. The combination of WHCMRA and VTCMRA improves CMRA quality compared to WHCMRA or VTCMRA alone. Conflict of interest of interest.
The authors declare that they have no conflict
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