Int J Cardiovasc Imaging (2014) 30:949–957 DOI 10.1007/s10554-014-0415-y
ORIGINAL PAPER
Assessment of perfusion and wall-motion abnormalities and transient ischemic dilation in regadenoson stress cardiac magnetic resonance perfusion imaging Mohammad R. Hojjati • Raja Muthupillai • James M. Wilson • Ourania A. Preventza • Benjamin Y. C. Cheong
Received: 23 January 2014 / Accepted: 31 March 2014 / Published online: 5 April 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Vasodilator first-pass stress cardiac magnetic resonance perfusion imaging [stress cardiac magnetic resonance (CMR)] is a reliable, noninvasive method for evaluating myocardial ischemia; however, it does not routinely evaluate metrics such as wall-motion abnormality (WMA) and transient ischemic dilation (TID). Using the new selective A2A adenosine receptor agonist regadenoson, we tested a novel protocol for assessing perfusion defects, WMA, and TID in a single stress CMR session. We evaluated 29 consecutive patients who presented for clinically indicated regadenoson stress CMR. Immediately before and after the regadenoson stress perfusion sequence, we obtained baseline and
post-stress cine images in the short-axis orientation to detect worsening or newly developed WMAs. This approach also allowed evaluation of TID. Delayed-enhancement imaging was performed in the standard orientations. All patients tolerated the procedure well. Thirteen patients (45 %) had perfusion abnormalities, and four patients developed TID. Seven patients had WMAs, and three of them also had TID. Patients with TID ± WMAs had multivessel disease documented by coronary angiography. By using regadenoson to assess myocardial ischemia during stress CMR, perfusion defects, WMAs, and TID can be evaluated in a single imaging session. To our knowledge, we are the first to describe this novel approach in a vasodilator stress CMR study.
Electronic supplementary material The online version of this article (doi:10.1007/s10554-014-0415-y) contains supplementary material, which is available to authorized users.
Keywords Magnetic resonance imaging Myocardial perfusion imaging Coronary artery disease Wall-motion abnormalities Transient ischemic dilation Regadenoson Adenosine A2A receptor antagonists
M. R. Hojjati J. M. Wilson Department of Cardiology, Texas Heart Institute, Houston, TX, USA R. Muthupillai B. Y. C. Cheong Department of Diagnostic and Interventional Radiology, St. Luke’s Medical Center, Texas Heart Institute, Houston, TX, USA R. Muthupillai B. Y. C. Cheong (&) Department of Radiology, Baylor College of Medicine, 6720 Bertner Avenue, MC 2-270, Houston, TX 77030, USA e-mail: [email protected] J. M. Wilson B. Y. C. Cheong Department of Medicine, Baylor College of Medicine, Houston, TX, USA O. A. Preventza Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
Introduction Coronary artery disease (CAD) is the leading cause of death globally [1]. Currently, a number of noninvasive imaging modalities are routinely used to evaluate patients with suspected or proven CAD, thereby clarifying the presence, extent, and hemodynamic significance of the disease, as well as its prognosis. Compared to coronary angiography—the gold standard for CAD evaluation—and to other noninvasive modalities, such as single photon emission computed tomography (SPECT), vasodilator stress cardiac magnetic resonance (CMR) perfusion imaging (herein referred to as stress CMR) can accurately assess the severity of CAD [2–6]. A stress CMR that is negative for CAD indicates an excellent short- to medium-term prognosis [7–9].
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In contrast to stress echocardiography and SPECT, CMR evaluation of myocardial ischemia via stress perfusion does not routinely assess new or worsening wallmotion abnormality (WMA) or transient ischemic dilation (TID). Development of WMA during dobutamine stress echocardiography (DSE) and dobutamine CMR is the hallmark of myocardial ischemia [10, 11]. Even with normal SPECT results, the presence of TID is a significant prognosticator for future cardiac events [12]. The main reason that WMA and TID are not included in stress perfusion CMR evaluation of myocardial ischemia could be because of the choice of the vasodilator. Until recently, adenosine (AdenoscanÒ, Astellas Pharma US, Inc., Northbrook, IL, USA) has been the main vasodilatory stress agent used for stress CMR. However, the half-life of adenosine is extremely short (on the order of seconds), and this short half-life does not permit the evaluation of WMA or TID under stress conditions without prolonging the duration of the vasodilatory stress. Recently, regadenoson (LexiscanÒ, Astellas Pharma US, Inc., Northbrook, IL, USA), a novel selective A2A adenosine receptor agonist that specifically mediates coronary vasodilation, was approved for clinical use. When used as a pharmacologic stress agent, regadenoson has the advantages of being administered as a bolus and having a longer duration of action than adenosine [13]. The prolonged action of regadenoson might be particularly useful in the context of stress CMR. Therefore, we modified our clinical protocol to include an additional stack of short-axis cine images obtained immediately after stress perfusion to evaluate stress-induced WMAs and TID. In this report, we provide the results of a retrospective analysis of our patient data, which we performed to determine the feasibility and usefulness of this approach.
Methods Study design The study cohort comprised 29 consecutive patients who were referred to us for CMR stress perfusion studies. All CMR imaging was performed with a commercial 1.5 T magnetic resonance (MR) scanner (Achieva, Philips Healthcare, Best, The Netherlands). A dedicated, 32-channel radiofrequency (RF) receiver coil was used for signal reception. The imaging protocol consisted of five distinct phases, which are described in detail below. Informed consent was obtained from each patient before the clinical CMR perfusion study was begun, as per standard hospital policy. Due to the retrospective nature of this study, our local institutional review board waived the need to obtain informed consent for data analysis.
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MR imaging protocol First, for each patient, a set of multiplanar survey images was acquired, and these survey images were used to plan conventional steady-state free-precession (SSFP) cine imaging of the heart in the standard orientations. The SSFP cine imaging sequence parameters were: repetition time (TR)/ echo time (TE), 3.4/1.7 ms; flip angle (FA), 55°; temporal resolution, 36–40 ms; in-plane resolution, 2 9 2 mm, with a slice thickness of 8 mm and a gap of 2 mm; and breath-hold duration, 6–8 heartbeats per slice. Standard orientations were acquired, including a complete left ventricular (LV) shortaxis cine before regadenoson administration. Second, regadenoson (400 mcg) was injected as a bolus into an antecubital vein, followed by a 30-cc saline flush. Approximately 60 s after the injection, 0.2 cc/kg of gadopentetate dimeglumine (MagnevistÒ; Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, USA) was administered at 4 cc/s through an antecubital vein, followed by 20 cc of normal saline at the same injection rate via a power injector (Spectris SolarisÒ; Medrad Inc., Indianola, PA, USA). Perfusion of the MR contrast bolus through the myocardium was studied by using a T1-weighted, saturationrecovery-prepared, spoiled gradient echo sequence, with three slices covering the basal, middle, and distal third of the left ventricle in the short-axis orientation. The LV apex was not imaged. The acquisition parameters for the stress CMR were as follows: TR, 2.8 ms; TE, 1.4 ms; saturation recovery preparation time, 125 ms; FA, 20°; acquired voxel size, 2.5 9 2.5 9 8 mm3; and parallel imaging acceleration factor, 2. Third, immediately after stress testing, another set of cine SSFP of the entire left ventricle in the short-axis orientation was acquired by using the same imaging parameters as before regadenoson administration. The only modification was adjustment to the heart rate, if necessary; the temporal resolution remained unchanged. During poststress cine imaging, the patients were monitored to ensure that they were in stable condition. They were also confirmed to have no significant clinical symptoms related to persistence of regadenoson in the circulatory system that would require immediate aminophylline administration. Fourth, immediately after the second set of functional studies was conducted, 50–100 mg of aminophylline, depending on the patient’s weight, was given intravenously to reverse the residual effect of the regadenoson. Approximately 15 min after the stress perfusion study, a rest perfusion study was performed by using the same imaging protocol, with the same injection rate and amount of contrast material. Finally, without administering further gadolinium, we performed delayed-enhancement (DE) imaging by using an inversion-recovery-prepared, T1-weighted, gradient-echo
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sequence, approximately 10 min after the last gadoinlium injection. We typically obtained a set of short-axis images in addition to the standard long-axis images, as detailed previously [14]. Image analysis The data were transferred to a commercially available workstation (ViewForumÒ; Philips Medical Systems) for analysis. An experienced observer manually drew endocardial and epicardial contours on each LV cine slice before and after stress perfusion in the short-axis orientation at end-diastole and end-systole to obtain quantitative LV functional values used to determine global end-diastolic volume (EDV) and end-systolic volume (ESV), as well as the LV ejection fraction. The stress and rest perfusion data were qualitatively analyzed side-by-side by an experienced observer using the standard American Heart Association 17-segment model (excluding the apex), without the knowledge of whether coronary angiography was available. A segment was classified as ischemic if it met all of the following criteria: (a) persistent myocardial hypo-enhancement for at least 3 heartbeats after maximal enhancement in a normal segment during stress perfusion; (b) lack of hypo-enhancement during rest perfusion; and (c) lack of enhancement in the corresponding segment during DE-MRI. The extent of ischemia was classified as subendocardial or transmural. Similarly, WMAs were analyzed qualitatively by comparing the baseline and immediate post-stress short-axis cine images simultaneously, using the MR workstation. An abnormal (ischemic) response was defined as worsening of LV segmental wall thickening and excursion between rest and stress [15]. A metric quantifying of the TID was computed by estimating the ratio of post-stress to baseline EDV and post-stress to baseline ESV. We chose a cutoff of 1.12, which was previously used by El-Mahalawy and colleagues [16]. The extent of DE within the myocardium was also quantified by using a visual scoring system [14]. Descriptive data are expressed as the mean value ± SD.
Results Twenty-nine patients (20 men and 9 women; mean age 62 ± 11 years) underwent stress CMR using the regadenoson imaging protocol defined above. All patients completed the entire stress CMR, and no significant adverse events occurred. Table 1 shows the patients’ demographic characteristics, including the indications for the stress perfusion study. Approximately 75 % of the patients were known to have CAD, and more than 50 % had diabetes
951 Table 1 Baseline characteristics of the study cohort (n = 29) Age (year)
62 ± 11
Male (%)
69
Diabetes mellitus (%)
52
Hypertension (%)
76
Known coronary artery disease (%)
72
Previous myocardial infarction (%)
34
Hyperlipidemia (%)
72
Previous revascularization (%)
41
Congestive cardiac failure (%)
17
Cerebrovascular accident (%)
14
Reason for testing (%) Chest pain
29
Abnormal stress test
24
Evaluation of underlying ischemia with known disease
38
Other
9 2
Body surface area (m , mean ± SD)
2.13 ± 0.28
Body mass index (kg/m2, mean ± SD)
32.7 ± 7.4
Table 2 Quantitative left ventricular functional data for the study cohort Variable
During stress
At rest
P value*
End-diastolic volume (ml)
190 ± 74
187 ± 72
0.28
End-systolic volume (ml)
98 ± 64
100 ± 60
0.04
Stroke volume (ml)
94 ± 21
86 ± 21
0.0001
Ejection fraction (%)
54 ± 14
50 ± 12
0.0001
Heart rate (beats/min)
85 ± 14
69 ± 13
0.0001
* As determined by a 2-sample t test
mellitus. The main indication for stress CMR was the evaluation of CAD. Table 2 shows the quantitative LV functional values for the study cohort. There was a significant increase in the heart rate and stroke volume after regadenoson administration. A total of 13 patients (45 %) had reversible perfusion abnormalities indicative of underlying ischemia. Their stress CMR and clinical findings are summarized in Table 3. All patients with abnormal perfusion CMR results had angiographic confirmation of CAD. Four patients (patients 2, 3, 7, and 11) developed TID with increased EDV, ESV, or both during stress, and 3 of these patients also had worsening WMAs (a total of seven patients in this study had worsening WMAs). All patients with TID and worsening WMAs had significant CAD, and two patients also had previous coronary artery bypass surgery. Patients with worsening WMAs alone also had significant CAD. Finally, all new or worsening WMAs coincided with stress
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EDV (ml) (S/R)a
1.03
1.17
1.12
1.07
1.11
0.96
1.16
0.99
0.99
0.96
Pt
1
123
2
3
4
5
6
7
8
9
10
0.90
1.04
0.96
1.09
0.75
0.88
1.03
1.24
1.10
0.61
ESV (ml) (S/R)a
4
2
2
2
8
-1
2
-6
4
5
D EF (%) (S–R)
Distal 2/3 of lateral wall became akinetic from severe hypokinesia
Distal 2/3 of inferior wall and distal 2/3 of lateral walls became akinetic from severe hypokinesia
Absent
Absent
Absent
Absent
Worsening of baseline WMAs, with hypokinesia in basal anterior wall and adjacent anteroseptum
Worsening of baseline WMAs, with severe hypokinesia in distal 2/3 of anterior wall and adjacent septum
Worsening of baseline WMAs from hypokinesia to akinesia in most of inferior wall and inferoseptum poststress
Absent
WMA
SE in entire lateral wall and in proximal 2/3 of anterior and distal inferior walls
SE defect in entire RCA and LCx territories and distal 2/3 of LAD territories
SE defect in distal 2/3 of inferior wall, and distal septal, anterior and lateral walls
SE defect in proximal 2/3 of anterior wall, basal anterolateral wall, and distal septum and inferior walls
Transmural defect in entire anterolateral and inferior walls; SE defect in entire inferoseptum and inferolateral wall
25 % scar in entire inferolateral wall and 75 % scar in distal anterior wall
25 % scar in RCA territory and distal 1/3 of left ventricle
50 % scar in basal inferoseptum and basal inferior and lateral walls
Fully viable
50–75 % in basal and mid inferolateral wall
Fully viable
25–50 % scar in lateral wall
SE defect in proximal 2/3 of anterior wall
SE defect in basal and mid anteroseptum
100 % scar in mid inferior wall and part of basal inferior wall
SE defect in entire anterior wall, adjacent anteroseptum, proximal and distal inferior wall
Severe disease in distal LAD. Severe disease in LCx and OM. Chronic occlusion of PDA
Severe 3-vessel disease
Chronic occlusion of distal LCx and RCA. Diffuse disease in distal LAD and 50 % stenosis in proximal RCA
80 % mid LAD lesion. Patent stent in D1. Distal RCA occluded with patent SVG
80–90 % mid RCA lesions
History of Behcet’s disease; PAD of proximal LAD detected
70 % stenosis at juncture of proximal and mid LAD; widely patent mid LCx stent
Distal LAD disease treated by PCI. Not able to cross LCx and OM lesions
Pt underwent CABG
Aggressive medical management
Mid LAD lesion treated with PCI
RCA lesion treated with PCI
Pt underwent left internal mammary bypass surgery
Stenosis treated with PCI
Patient declined further invasive examination
RCA lesion not amenable to PCI. Repeat PCI to LAD ISR
100 % RCA ISR of proximal LAD. Non-obstructive disease in LCx
25 % scar in mid anterior wall; 50 % scar in basal inferoseptum; 50 % scar in basal and mid inferior wall; 100 % scar in apex
Transmural defect in entire inferior wall; transmural defect in basal septum and SE defect in mid and distal septum; SE defect in mid anterior wall Angiography in 2011 reviewed previous SVG-to-RCA graft occlusion; LAD stent patent. Stent placed in OM due to severe stenosis
PCI of LAD lesion
Management
70 % mid LAD lesion
Coronary angiographic findings
Fully viable
DE-MRI
SE defect in distal inferior wall and distal septum
Reversible perfusion abnormalities
Table 3 Stress magnetic resonance imaging data from patients with abnormal perfusion study results
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CMR perfusion abnormalities. Figure 1 and Videos A–D are representative images from patient 2. The remaining 16 patients had normal myocardial perfusion and no evidence of stress-induced WMAs or TID. The mean stress:rest ratios for EDV and ESV were 0.99 and 0.87, respectively. In addition, the LV ejection fraction underwent an average increase of 5.2 % after regadenoson administration.
The stress:rest ratio of EDV or ESV was used to assess transient ischemic dilation
Discussion
a
Pt patient, EDV end-diastolic volume, S stress, R rest, ESV end-systolic volume, D change, EF ejection fraction, WMA wall-motion abnormality, DE-MRI delayed-enhancement magnetic resonance imaging, SE subendocardial, LAD left anterior descending artery, PCI percutaneous coronary intervention, RCA right coronary artery, ISR in-stent restenosis, LCx left circumflex artery, SVG saphenous vein graft, OM obtuse marginal artery; PAD pseudoaneurysmal dilation, D1 first diagonal artery, CABG coronary artery bypass surgery, PDA posterior descending artery
RCA lesion treated by PCI 90 % proximal RCA stenosis; 50 % stenosis in ramus intermedius Fully viable SE of proximal 2/3 of RCA territory and transmural defect in distal inferior wall 0.98 13
0.92
3
Hypokinesia of inferior wall became severely hypokinetic
Pt underwent CABG 80 % stenosis in LAD and 90 % stenosis in LCx and OM artery Fully viable SE in entire LAD territory. SE defect in entire lateral and inferior walls, sparing inferoseptum 0.96 12
0.94
2
Absent
Pt underwent CABG 90 % stenosis in proximal LAD; 90 % stenosis in obtuse marginal artery and 90 % stenosis in PDA 25 % scar in distal 2/3 territories supplied by LAD 1.14 11
1.19
-3
Severe hypokinesia of distal 2/3 of lateral wall became akinetic; hypokinetic distal anterior wall became severely hypokinetic
Transmural defect in distal 2/3 territories supplied by LAD. Most of lateral wall has SE defect
Management ESV (ml) (S/R)a EDV (ml) (S/R)a Pt
Table 3 continued
D EF (%) (S–R)
WMA
Reversible perfusion abnormalities
DE-MRI
Coronary angiographic findings
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To our knowledge, this report is the first to describe a CMR protocol in which perfusion abnormalities, WMAs, and TID can be assessed as a part of a single stress CMR-based ischemia workup using the novel A2A adenosine receptor agonist regadenoson. We demonstrated that this procedure is feasible without significantly prolonging examination time, indicating that this simple protocol can easily be implemented into existing stress CMR protocols. According to the ‘‘ischemic cascade’’ theory for significant coronary artery stenosis, perfusion abnormality precedes diastolic dysfunction and regional WMA [17]. Reversible perfusion abnormities on SPECT and stressinducible WMAs on DSE studies are the hallmarks of myocardial ischemia. For both stress-imaging modalities, TID has been used as a prognosticator and is a marker of extensive CAD and adverse outcomes [12, 18–21]. However, WMAs and TID are not typically assessed as part of the routine clinical protocol for stress CMR. In 1 study that compared adenosine stress echocardiography to dobutamine stress echocardiography, the sensitivity, specificity, and accuracy were 40, 93, and 62 versus 76, 60, and 70 %, respectively [22]. During exercise or dobutamine stress echocardiography, the primary effect is elevation of the heart rate and blood pressure, which increases myocardial blood flow and oxygen demand. The ischemic cascade model predicts that in areas with significant stenosis that cannot meet the oxygen requirement, perfusion abnormality will occur before the development of WMA [17]; however, patients may not necessarily develop WMA with vasodilatory adenosine stress. This may explain the relatively poor diagnostic performance of adenosine echocardiography compared to dobutamine stress echocardiography. Should a new or worsening WMA occur, it would suggest significant underlying coronary artery stenosis ([50 %), in a vessel supplying at least 5 % of the myocardium [23, 24]. In the context of stress CMR, our new protocol is particularly advantageous in many ways. In traditional stress CMR studies, adenosine must be administered as an infusion for the duration of 3–4 min to elicit a peak hyperemic response before stress CMR perfusion study can be initiated. Because adenosine has a short duration of action and a short half-life,
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Fig. 1 Cardiac magnetic resonance perfusion images from a 68-years-old man (patient 2). The patient had a past history of ischemic heart disease, with delayed presentation of a non-STsegment elevation myocardial infarction. He had a stent in his left anterior descending artery. A first-pass perfusion study showed reversible perfusion defects in the inferior wall, septum, and mid anterior wall [videos A (stress perfusion) and B (rest perfusion)]. After vasodilator administration, the basal and mid inferior walls and the adjacent inferoseptum had become moderately hypokinetic [videos C (rest functional cine) and D (immediate after-stress cine)]. See Table 3 for the results of delayed-enhancement magnetic resonance imaging
the effect of the drug ceases almost instantaneously when the medication is discontinued. Although this is a desirable attribute, it does not permit the evaluation of WMA or TID. In contrast, regadenoson is given via a fast bolus injection and allows one to acquire CMR perfusion data during the peak hyperemic response almost immediately, simplifying the stress CMR procedure [25, 26]. Regadenoson has a key pharmacokinetic attribute of eliciting a peak hyperemic response marked by a 2.5-fold increase in coronary blood flow for approximately 2.4 min immediately after the peak onset of action (estimated to be 33 s after bolus injection); it also maintains at least a twofold increase in blood flow for about 6 min after injection [13]. In addition, because of regadenoson’s enhanced receptor selectivity, it has a more favorable side-effect profile than does adenosine. By taking advantage of regadenoson’s pharmacologic properties and obtaining baseline and immediate post-stress cine images while the hemodynamic effect of regadenoson persists, physicians could potentially evaluate the onset of any new WMA as part of the stress CMR protocol. In most modern MR scanners, cine SSFP images can be acquired very rapidly (5–6 s per slice), and functional
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imaging of the entire left ventricle in the short-axis orientation can be readily completed within a couple of minutes while the effects of regadenoson still persist. Acquiring a stack of short-axis cine images permits the reliable computation of LV volumes before and after regadenoson is administered, making it possible to estimate TID. To our knowledge, Bodi and colleagues [27] are the only other authors to describe the use of stress CMR for assessing WMAs. In their study, dipyridamole was used as the stress agent, and the immediate post-stress images for WMA assessment were confined to 2-chamber, 4-chamber, and short-axis (basal, mid, and apical) cine views. The images were also obtained at a relatively low spatial resolution. In our protocol, the same spatial resolution was used throughout the examination, and the entire left ventricle was imaged both at rest and under stress, providing for comprehensive analysis of WMAs that could easily be analyzed side-byside. Whole-heart coverage in the pre- and post-contrast SSFP cine images also allowed us to assess TID, which would not have been possible with Bodi’s method. The additional acquisition of cine MR data after regadenoson administration has the potential to improve the
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sensitivity of ischemia assessment. Stress CMR is sometimes fraught with technical issues such as the well-known dark-rim artifact (a result of lower spatial resolution and contrast agent concentration) and missed data acquisition due to arrhythmias or the patient’s inability to perform a breath-hold over the course of the first-pass perfusion [28]. Therefore, the ability to acquire another set of cine MR imaging data under stress conditions may be clinically useful, providing WMA and TID data complimentary to the perfusion images. The computation of TID from the pre- and post-stress LV quantitative values is straightforward at the cost of a couple of minutes of additional postprocessing time. In the DSE study by El-Mahalawy et al. [16], a TID cutoff of 1.12 (either EDV or ESV ratio) achieved the best sensitivity (90 %) and specificity (94 %) for detecting 3-vessel CAD. Yao and colleagues reported that a cutoff of 1.17 (EDV ratio) for detecting extensive and severe CAD had 100 % sensitivity but only 54 % specificity [15]. In healthy volunteers, end-diastolic and end-systolic diameters were shown to be reduced in low-dose and peak-dose DSE [29]. In our current study, due to the limited number of patients and the lack of reports concerning stress CMR TID data, we chose a cutoff of 1.12 as previously used by El-Mahalawy et al. [16]. The proposed etiology of the development of TID has been attributed to many factors, such as subendocardial hypoperfusion [19], LV systolic dysfunction due to failure of reduction in LV systolic cavity size [20], and an increase in epicardial area in severe CAD leading to LV end-diastolic enlargement during stress [15]. The subendocardial region is more susceptible to ischemia than is the subepicardial region. In patients who have significant CAD with stress-induced ischemia, the subendocardial region will have a marked reduction in radiotracer uptake during SPECT that may not be well visualized, resulting in thinner walls and an apparent increase in LV size [19]. On the other hand, subendocardial ischemia during stress CMR could lead to decreased wall thickening and excursion and, therefore, TID. Unlike SPECT, which has relatively poor spatial resolution, CMR can define the subendocardial myocardial border accurately for volumetric analysis even when hypoperfusion is present. With high spatial and contrast resolution, CMR has been shown to be reproducible and accurate and is considered the gold standard for assessing cardiac function [30]. Therefore, any potential change in EDV and ESV can be detected during stress CMR without any geometric assumptions about the shape of the heart. Although this report is intended only to describe the new stress CMR protocol that was recently introduced at our hospital, the findings from this limited study raise some intriguing questions. A significant majority (75 %) of our
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patients with TID and WMA were found to have extensive CAD as determined by angiography. Previous studies have also reported that the detection of new WMAs in conjunction with TID estimation may reflect significant underlying CAD [15, 16, 18, 19, 21]. Furthermore, TID has been shown to be an important prognosticator in CAD patients. Therefore, the presence of TID and WMA may suggest a relatively large ischemic burden, and this knowledge may affect patient management and clinical outcome. However, these questions need to be answered in a prospective, large clinical trial that directly evaluates the additive clinical value of this modified protocol. The acquisition of an extra set of short-axis cine images adds only a few extra minutes of imaging time, and the analysis and estimation of TID is fairly straightforward and can be easily incorporated into routine clinical practice. The ability to perform all these assessments simultaneously may increase the sensitivity and accuracy of CMR perfusion for evaluating ischemic CAD.
Limitations The small number of subjects in our cohort was a limiting factor in assessing the diagnostic and prognostic potential of this new protocol. In addition, our study population had a relatively high prevalence of CAD. The presence of TID has been reported to represent significant 3-vessel disease [16], but our current study had too few patients for us to determine the accuracy of TID in the detection of 3-vessel disease. We extrapolated DSE TID data for use in this study, though the mechanism for inducing ischemia in stress CMR is different than that in DSE. However, even in low-dose DSE in healthy volunteers, the LV dimensions were shown to be reduced [29]. In addition, the limited number of subjects did not allow us to determine the optimal cut-off for TID assessment. Finally, no long-term follow-up data were available to confirm whether TID identified by stress CMR indicated a poor cardiovascular outcome.
Conclusions Using our new stress CMR protocol, we have demonstrated the feasibility of assessing perfusion, WMA, and TID in a single setting by using the new adenosine A2A receptor antagonist regadenoson. This protocol is straight-forward and can easily be incorporated into the existing stress protocol without significantly increasing examination time or patient discomfort. Acknowledgments We are grateful to Virginia C. Fairchild and Nicole Stancel, Ph.D., ELS, of the Section of Scientific Publications
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at the Texas Heart Institute, Houston, Texas, for providing editorial assistance. Conflict of interest
None.
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ORIGINAL PAPER
Assessment of perfusion and wall-motion abnormalities and transient ischemic dilation in regadenoson stress cardiac magnetic resonance perfusion imaging Mohammad R. Hojjati • Raja Muthupillai • James M. Wilson • Ourania A. Preventza • Benjamin Y. C. Cheong
Received: 23 January 2014 / Accepted: 31 March 2014 / Published online: 5 April 2014 Ó Springer Science+Business Media Dordrecht 2014
Abstract Vasodilator first-pass stress cardiac magnetic resonance perfusion imaging [stress cardiac magnetic resonance (CMR)] is a reliable, noninvasive method for evaluating myocardial ischemia; however, it does not routinely evaluate metrics such as wall-motion abnormality (WMA) and transient ischemic dilation (TID). Using the new selective A2A adenosine receptor agonist regadenoson, we tested a novel protocol for assessing perfusion defects, WMA, and TID in a single stress CMR session. We evaluated 29 consecutive patients who presented for clinically indicated regadenoson stress CMR. Immediately before and after the regadenoson stress perfusion sequence, we obtained baseline and
post-stress cine images in the short-axis orientation to detect worsening or newly developed WMAs. This approach also allowed evaluation of TID. Delayed-enhancement imaging was performed in the standard orientations. All patients tolerated the procedure well. Thirteen patients (45 %) had perfusion abnormalities, and four patients developed TID. Seven patients had WMAs, and three of them also had TID. Patients with TID ± WMAs had multivessel disease documented by coronary angiography. By using regadenoson to assess myocardial ischemia during stress CMR, perfusion defects, WMAs, and TID can be evaluated in a single imaging session. To our knowledge, we are the first to describe this novel approach in a vasodilator stress CMR study.
Electronic supplementary material The online version of this article (doi:10.1007/s10554-014-0415-y) contains supplementary material, which is available to authorized users.
Keywords Magnetic resonance imaging Myocardial perfusion imaging Coronary artery disease Wall-motion abnormalities Transient ischemic dilation Regadenoson Adenosine A2A receptor antagonists
M. R. Hojjati J. M. Wilson Department of Cardiology, Texas Heart Institute, Houston, TX, USA R. Muthupillai B. Y. C. Cheong Department of Diagnostic and Interventional Radiology, St. Luke’s Medical Center, Texas Heart Institute, Houston, TX, USA R. Muthupillai B. Y. C. Cheong (&) Department of Radiology, Baylor College of Medicine, 6720 Bertner Avenue, MC 2-270, Houston, TX 77030, USA e-mail: [email protected] J. M. Wilson B. Y. C. Cheong Department of Medicine, Baylor College of Medicine, Houston, TX, USA O. A. Preventza Division of Cardiothoracic Surgery, Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA
Introduction Coronary artery disease (CAD) is the leading cause of death globally [1]. Currently, a number of noninvasive imaging modalities are routinely used to evaluate patients with suspected or proven CAD, thereby clarifying the presence, extent, and hemodynamic significance of the disease, as well as its prognosis. Compared to coronary angiography—the gold standard for CAD evaluation—and to other noninvasive modalities, such as single photon emission computed tomography (SPECT), vasodilator stress cardiac magnetic resonance (CMR) perfusion imaging (herein referred to as stress CMR) can accurately assess the severity of CAD [2–6]. A stress CMR that is negative for CAD indicates an excellent short- to medium-term prognosis [7–9].
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In contrast to stress echocardiography and SPECT, CMR evaluation of myocardial ischemia via stress perfusion does not routinely assess new or worsening wallmotion abnormality (WMA) or transient ischemic dilation (TID). Development of WMA during dobutamine stress echocardiography (DSE) and dobutamine CMR is the hallmark of myocardial ischemia [10, 11]. Even with normal SPECT results, the presence of TID is a significant prognosticator for future cardiac events [12]. The main reason that WMA and TID are not included in stress perfusion CMR evaluation of myocardial ischemia could be because of the choice of the vasodilator. Until recently, adenosine (AdenoscanÒ, Astellas Pharma US, Inc., Northbrook, IL, USA) has been the main vasodilatory stress agent used for stress CMR. However, the half-life of adenosine is extremely short (on the order of seconds), and this short half-life does not permit the evaluation of WMA or TID under stress conditions without prolonging the duration of the vasodilatory stress. Recently, regadenoson (LexiscanÒ, Astellas Pharma US, Inc., Northbrook, IL, USA), a novel selective A2A adenosine receptor agonist that specifically mediates coronary vasodilation, was approved for clinical use. When used as a pharmacologic stress agent, regadenoson has the advantages of being administered as a bolus and having a longer duration of action than adenosine [13]. The prolonged action of regadenoson might be particularly useful in the context of stress CMR. Therefore, we modified our clinical protocol to include an additional stack of short-axis cine images obtained immediately after stress perfusion to evaluate stress-induced WMAs and TID. In this report, we provide the results of a retrospective analysis of our patient data, which we performed to determine the feasibility and usefulness of this approach.
Methods Study design The study cohort comprised 29 consecutive patients who were referred to us for CMR stress perfusion studies. All CMR imaging was performed with a commercial 1.5 T magnetic resonance (MR) scanner (Achieva, Philips Healthcare, Best, The Netherlands). A dedicated, 32-channel radiofrequency (RF) receiver coil was used for signal reception. The imaging protocol consisted of five distinct phases, which are described in detail below. Informed consent was obtained from each patient before the clinical CMR perfusion study was begun, as per standard hospital policy. Due to the retrospective nature of this study, our local institutional review board waived the need to obtain informed consent for data analysis.
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MR imaging protocol First, for each patient, a set of multiplanar survey images was acquired, and these survey images were used to plan conventional steady-state free-precession (SSFP) cine imaging of the heart in the standard orientations. The SSFP cine imaging sequence parameters were: repetition time (TR)/ echo time (TE), 3.4/1.7 ms; flip angle (FA), 55°; temporal resolution, 36–40 ms; in-plane resolution, 2 9 2 mm, with a slice thickness of 8 mm and a gap of 2 mm; and breath-hold duration, 6–8 heartbeats per slice. Standard orientations were acquired, including a complete left ventricular (LV) shortaxis cine before regadenoson administration. Second, regadenoson (400 mcg) was injected as a bolus into an antecubital vein, followed by a 30-cc saline flush. Approximately 60 s after the injection, 0.2 cc/kg of gadopentetate dimeglumine (MagnevistÒ; Bayer HealthCare Pharmaceuticals Inc., Wayne, NJ, USA) was administered at 4 cc/s through an antecubital vein, followed by 20 cc of normal saline at the same injection rate via a power injector (Spectris SolarisÒ; Medrad Inc., Indianola, PA, USA). Perfusion of the MR contrast bolus through the myocardium was studied by using a T1-weighted, saturationrecovery-prepared, spoiled gradient echo sequence, with three slices covering the basal, middle, and distal third of the left ventricle in the short-axis orientation. The LV apex was not imaged. The acquisition parameters for the stress CMR were as follows: TR, 2.8 ms; TE, 1.4 ms; saturation recovery preparation time, 125 ms; FA, 20°; acquired voxel size, 2.5 9 2.5 9 8 mm3; and parallel imaging acceleration factor, 2. Third, immediately after stress testing, another set of cine SSFP of the entire left ventricle in the short-axis orientation was acquired by using the same imaging parameters as before regadenoson administration. The only modification was adjustment to the heart rate, if necessary; the temporal resolution remained unchanged. During poststress cine imaging, the patients were monitored to ensure that they were in stable condition. They were also confirmed to have no significant clinical symptoms related to persistence of regadenoson in the circulatory system that would require immediate aminophylline administration. Fourth, immediately after the second set of functional studies was conducted, 50–100 mg of aminophylline, depending on the patient’s weight, was given intravenously to reverse the residual effect of the regadenoson. Approximately 15 min after the stress perfusion study, a rest perfusion study was performed by using the same imaging protocol, with the same injection rate and amount of contrast material. Finally, without administering further gadolinium, we performed delayed-enhancement (DE) imaging by using an inversion-recovery-prepared, T1-weighted, gradient-echo
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sequence, approximately 10 min after the last gadoinlium injection. We typically obtained a set of short-axis images in addition to the standard long-axis images, as detailed previously [14]. Image analysis The data were transferred to a commercially available workstation (ViewForumÒ; Philips Medical Systems) for analysis. An experienced observer manually drew endocardial and epicardial contours on each LV cine slice before and after stress perfusion in the short-axis orientation at end-diastole and end-systole to obtain quantitative LV functional values used to determine global end-diastolic volume (EDV) and end-systolic volume (ESV), as well as the LV ejection fraction. The stress and rest perfusion data were qualitatively analyzed side-by-side by an experienced observer using the standard American Heart Association 17-segment model (excluding the apex), without the knowledge of whether coronary angiography was available. A segment was classified as ischemic if it met all of the following criteria: (a) persistent myocardial hypo-enhancement for at least 3 heartbeats after maximal enhancement in a normal segment during stress perfusion; (b) lack of hypo-enhancement during rest perfusion; and (c) lack of enhancement in the corresponding segment during DE-MRI. The extent of ischemia was classified as subendocardial or transmural. Similarly, WMAs were analyzed qualitatively by comparing the baseline and immediate post-stress short-axis cine images simultaneously, using the MR workstation. An abnormal (ischemic) response was defined as worsening of LV segmental wall thickening and excursion between rest and stress [15]. A metric quantifying of the TID was computed by estimating the ratio of post-stress to baseline EDV and post-stress to baseline ESV. We chose a cutoff of 1.12, which was previously used by El-Mahalawy and colleagues [16]. The extent of DE within the myocardium was also quantified by using a visual scoring system [14]. Descriptive data are expressed as the mean value ± SD.
Results Twenty-nine patients (20 men and 9 women; mean age 62 ± 11 years) underwent stress CMR using the regadenoson imaging protocol defined above. All patients completed the entire stress CMR, and no significant adverse events occurred. Table 1 shows the patients’ demographic characteristics, including the indications for the stress perfusion study. Approximately 75 % of the patients were known to have CAD, and more than 50 % had diabetes
951 Table 1 Baseline characteristics of the study cohort (n = 29) Age (year)
62 ± 11
Male (%)
69
Diabetes mellitus (%)
52
Hypertension (%)
76
Known coronary artery disease (%)
72
Previous myocardial infarction (%)
34
Hyperlipidemia (%)
72
Previous revascularization (%)
41
Congestive cardiac failure (%)
17
Cerebrovascular accident (%)
14
Reason for testing (%) Chest pain
29
Abnormal stress test
24
Evaluation of underlying ischemia with known disease
38
Other
9 2
Body surface area (m , mean ± SD)
2.13 ± 0.28
Body mass index (kg/m2, mean ± SD)
32.7 ± 7.4
Table 2 Quantitative left ventricular functional data for the study cohort Variable
During stress
At rest
P value*
End-diastolic volume (ml)
190 ± 74
187 ± 72
0.28
End-systolic volume (ml)
98 ± 64
100 ± 60
0.04
Stroke volume (ml)
94 ± 21
86 ± 21
0.0001
Ejection fraction (%)
54 ± 14
50 ± 12
0.0001
Heart rate (beats/min)
85 ± 14
69 ± 13
0.0001
* As determined by a 2-sample t test
mellitus. The main indication for stress CMR was the evaluation of CAD. Table 2 shows the quantitative LV functional values for the study cohort. There was a significant increase in the heart rate and stroke volume after regadenoson administration. A total of 13 patients (45 %) had reversible perfusion abnormalities indicative of underlying ischemia. Their stress CMR and clinical findings are summarized in Table 3. All patients with abnormal perfusion CMR results had angiographic confirmation of CAD. Four patients (patients 2, 3, 7, and 11) developed TID with increased EDV, ESV, or both during stress, and 3 of these patients also had worsening WMAs (a total of seven patients in this study had worsening WMAs). All patients with TID and worsening WMAs had significant CAD, and two patients also had previous coronary artery bypass surgery. Patients with worsening WMAs alone also had significant CAD. Finally, all new or worsening WMAs coincided with stress
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EDV (ml) (S/R)a
1.03
1.17
1.12
1.07
1.11
0.96
1.16
0.99
0.99
0.96
Pt
1
123
2
3
4
5
6
7
8
9
10
0.90
1.04
0.96
1.09
0.75
0.88
1.03
1.24
1.10
0.61
ESV (ml) (S/R)a
4
2
2
2
8
-1
2
-6
4
5
D EF (%) (S–R)
Distal 2/3 of lateral wall became akinetic from severe hypokinesia
Distal 2/3 of inferior wall and distal 2/3 of lateral walls became akinetic from severe hypokinesia
Absent
Absent
Absent
Absent
Worsening of baseline WMAs, with hypokinesia in basal anterior wall and adjacent anteroseptum
Worsening of baseline WMAs, with severe hypokinesia in distal 2/3 of anterior wall and adjacent septum
Worsening of baseline WMAs from hypokinesia to akinesia in most of inferior wall and inferoseptum poststress
Absent
WMA
SE in entire lateral wall and in proximal 2/3 of anterior and distal inferior walls
SE defect in entire RCA and LCx territories and distal 2/3 of LAD territories
SE defect in distal 2/3 of inferior wall, and distal septal, anterior and lateral walls
SE defect in proximal 2/3 of anterior wall, basal anterolateral wall, and distal septum and inferior walls
Transmural defect in entire anterolateral and inferior walls; SE defect in entire inferoseptum and inferolateral wall
25 % scar in entire inferolateral wall and 75 % scar in distal anterior wall
25 % scar in RCA territory and distal 1/3 of left ventricle
50 % scar in basal inferoseptum and basal inferior and lateral walls
Fully viable
50–75 % in basal and mid inferolateral wall
Fully viable
25–50 % scar in lateral wall
SE defect in proximal 2/3 of anterior wall
SE defect in basal and mid anteroseptum
100 % scar in mid inferior wall and part of basal inferior wall
SE defect in entire anterior wall, adjacent anteroseptum, proximal and distal inferior wall
Severe disease in distal LAD. Severe disease in LCx and OM. Chronic occlusion of PDA
Severe 3-vessel disease
Chronic occlusion of distal LCx and RCA. Diffuse disease in distal LAD and 50 % stenosis in proximal RCA
80 % mid LAD lesion. Patent stent in D1. Distal RCA occluded with patent SVG
80–90 % mid RCA lesions
History of Behcet’s disease; PAD of proximal LAD detected
70 % stenosis at juncture of proximal and mid LAD; widely patent mid LCx stent
Distal LAD disease treated by PCI. Not able to cross LCx and OM lesions
Pt underwent CABG
Aggressive medical management
Mid LAD lesion treated with PCI
RCA lesion treated with PCI
Pt underwent left internal mammary bypass surgery
Stenosis treated with PCI
Patient declined further invasive examination
RCA lesion not amenable to PCI. Repeat PCI to LAD ISR
100 % RCA ISR of proximal LAD. Non-obstructive disease in LCx
25 % scar in mid anterior wall; 50 % scar in basal inferoseptum; 50 % scar in basal and mid inferior wall; 100 % scar in apex
Transmural defect in entire inferior wall; transmural defect in basal septum and SE defect in mid and distal septum; SE defect in mid anterior wall Angiography in 2011 reviewed previous SVG-to-RCA graft occlusion; LAD stent patent. Stent placed in OM due to severe stenosis
PCI of LAD lesion
Management
70 % mid LAD lesion
Coronary angiographic findings
Fully viable
DE-MRI
SE defect in distal inferior wall and distal septum
Reversible perfusion abnormalities
Table 3 Stress magnetic resonance imaging data from patients with abnormal perfusion study results
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953
CMR perfusion abnormalities. Figure 1 and Videos A–D are representative images from patient 2. The remaining 16 patients had normal myocardial perfusion and no evidence of stress-induced WMAs or TID. The mean stress:rest ratios for EDV and ESV were 0.99 and 0.87, respectively. In addition, the LV ejection fraction underwent an average increase of 5.2 % after regadenoson administration.
The stress:rest ratio of EDV or ESV was used to assess transient ischemic dilation
Discussion
a
Pt patient, EDV end-diastolic volume, S stress, R rest, ESV end-systolic volume, D change, EF ejection fraction, WMA wall-motion abnormality, DE-MRI delayed-enhancement magnetic resonance imaging, SE subendocardial, LAD left anterior descending artery, PCI percutaneous coronary intervention, RCA right coronary artery, ISR in-stent restenosis, LCx left circumflex artery, SVG saphenous vein graft, OM obtuse marginal artery; PAD pseudoaneurysmal dilation, D1 first diagonal artery, CABG coronary artery bypass surgery, PDA posterior descending artery
RCA lesion treated by PCI 90 % proximal RCA stenosis; 50 % stenosis in ramus intermedius Fully viable SE of proximal 2/3 of RCA territory and transmural defect in distal inferior wall 0.98 13
0.92
3
Hypokinesia of inferior wall became severely hypokinetic
Pt underwent CABG 80 % stenosis in LAD and 90 % stenosis in LCx and OM artery Fully viable SE in entire LAD territory. SE defect in entire lateral and inferior walls, sparing inferoseptum 0.96 12
0.94
2
Absent
Pt underwent CABG 90 % stenosis in proximal LAD; 90 % stenosis in obtuse marginal artery and 90 % stenosis in PDA 25 % scar in distal 2/3 territories supplied by LAD 1.14 11
1.19
-3
Severe hypokinesia of distal 2/3 of lateral wall became akinetic; hypokinetic distal anterior wall became severely hypokinetic
Transmural defect in distal 2/3 territories supplied by LAD. Most of lateral wall has SE defect
Management ESV (ml) (S/R)a EDV (ml) (S/R)a Pt
Table 3 continued
D EF (%) (S–R)
WMA
Reversible perfusion abnormalities
DE-MRI
Coronary angiographic findings
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To our knowledge, this report is the first to describe a CMR protocol in which perfusion abnormalities, WMAs, and TID can be assessed as a part of a single stress CMR-based ischemia workup using the novel A2A adenosine receptor agonist regadenoson. We demonstrated that this procedure is feasible without significantly prolonging examination time, indicating that this simple protocol can easily be implemented into existing stress CMR protocols. According to the ‘‘ischemic cascade’’ theory for significant coronary artery stenosis, perfusion abnormality precedes diastolic dysfunction and regional WMA [17]. Reversible perfusion abnormities on SPECT and stressinducible WMAs on DSE studies are the hallmarks of myocardial ischemia. For both stress-imaging modalities, TID has been used as a prognosticator and is a marker of extensive CAD and adverse outcomes [12, 18–21]. However, WMAs and TID are not typically assessed as part of the routine clinical protocol for stress CMR. In 1 study that compared adenosine stress echocardiography to dobutamine stress echocardiography, the sensitivity, specificity, and accuracy were 40, 93, and 62 versus 76, 60, and 70 %, respectively [22]. During exercise or dobutamine stress echocardiography, the primary effect is elevation of the heart rate and blood pressure, which increases myocardial blood flow and oxygen demand. The ischemic cascade model predicts that in areas with significant stenosis that cannot meet the oxygen requirement, perfusion abnormality will occur before the development of WMA [17]; however, patients may not necessarily develop WMA with vasodilatory adenosine stress. This may explain the relatively poor diagnostic performance of adenosine echocardiography compared to dobutamine stress echocardiography. Should a new or worsening WMA occur, it would suggest significant underlying coronary artery stenosis ([50 %), in a vessel supplying at least 5 % of the myocardium [23, 24]. In the context of stress CMR, our new protocol is particularly advantageous in many ways. In traditional stress CMR studies, adenosine must be administered as an infusion for the duration of 3–4 min to elicit a peak hyperemic response before stress CMR perfusion study can be initiated. Because adenosine has a short duration of action and a short half-life,
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Fig. 1 Cardiac magnetic resonance perfusion images from a 68-years-old man (patient 2). The patient had a past history of ischemic heart disease, with delayed presentation of a non-STsegment elevation myocardial infarction. He had a stent in his left anterior descending artery. A first-pass perfusion study showed reversible perfusion defects in the inferior wall, septum, and mid anterior wall [videos A (stress perfusion) and B (rest perfusion)]. After vasodilator administration, the basal and mid inferior walls and the adjacent inferoseptum had become moderately hypokinetic [videos C (rest functional cine) and D (immediate after-stress cine)]. See Table 3 for the results of delayed-enhancement magnetic resonance imaging
the effect of the drug ceases almost instantaneously when the medication is discontinued. Although this is a desirable attribute, it does not permit the evaluation of WMA or TID. In contrast, regadenoson is given via a fast bolus injection and allows one to acquire CMR perfusion data during the peak hyperemic response almost immediately, simplifying the stress CMR procedure [25, 26]. Regadenoson has a key pharmacokinetic attribute of eliciting a peak hyperemic response marked by a 2.5-fold increase in coronary blood flow for approximately 2.4 min immediately after the peak onset of action (estimated to be 33 s after bolus injection); it also maintains at least a twofold increase in blood flow for about 6 min after injection [13]. In addition, because of regadenoson’s enhanced receptor selectivity, it has a more favorable side-effect profile than does adenosine. By taking advantage of regadenoson’s pharmacologic properties and obtaining baseline and immediate post-stress cine images while the hemodynamic effect of regadenoson persists, physicians could potentially evaluate the onset of any new WMA as part of the stress CMR protocol. In most modern MR scanners, cine SSFP images can be acquired very rapidly (5–6 s per slice), and functional
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imaging of the entire left ventricle in the short-axis orientation can be readily completed within a couple of minutes while the effects of regadenoson still persist. Acquiring a stack of short-axis cine images permits the reliable computation of LV volumes before and after regadenoson is administered, making it possible to estimate TID. To our knowledge, Bodi and colleagues [27] are the only other authors to describe the use of stress CMR for assessing WMAs. In their study, dipyridamole was used as the stress agent, and the immediate post-stress images for WMA assessment were confined to 2-chamber, 4-chamber, and short-axis (basal, mid, and apical) cine views. The images were also obtained at a relatively low spatial resolution. In our protocol, the same spatial resolution was used throughout the examination, and the entire left ventricle was imaged both at rest and under stress, providing for comprehensive analysis of WMAs that could easily be analyzed side-byside. Whole-heart coverage in the pre- and post-contrast SSFP cine images also allowed us to assess TID, which would not have been possible with Bodi’s method. The additional acquisition of cine MR data after regadenoson administration has the potential to improve the
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sensitivity of ischemia assessment. Stress CMR is sometimes fraught with technical issues such as the well-known dark-rim artifact (a result of lower spatial resolution and contrast agent concentration) and missed data acquisition due to arrhythmias or the patient’s inability to perform a breath-hold over the course of the first-pass perfusion [28]. Therefore, the ability to acquire another set of cine MR imaging data under stress conditions may be clinically useful, providing WMA and TID data complimentary to the perfusion images. The computation of TID from the pre- and post-stress LV quantitative values is straightforward at the cost of a couple of minutes of additional postprocessing time. In the DSE study by El-Mahalawy et al. [16], a TID cutoff of 1.12 (either EDV or ESV ratio) achieved the best sensitivity (90 %) and specificity (94 %) for detecting 3-vessel CAD. Yao and colleagues reported that a cutoff of 1.17 (EDV ratio) for detecting extensive and severe CAD had 100 % sensitivity but only 54 % specificity [15]. In healthy volunteers, end-diastolic and end-systolic diameters were shown to be reduced in low-dose and peak-dose DSE [29]. In our current study, due to the limited number of patients and the lack of reports concerning stress CMR TID data, we chose a cutoff of 1.12 as previously used by El-Mahalawy et al. [16]. The proposed etiology of the development of TID has been attributed to many factors, such as subendocardial hypoperfusion [19], LV systolic dysfunction due to failure of reduction in LV systolic cavity size [20], and an increase in epicardial area in severe CAD leading to LV end-diastolic enlargement during stress [15]. The subendocardial region is more susceptible to ischemia than is the subepicardial region. In patients who have significant CAD with stress-induced ischemia, the subendocardial region will have a marked reduction in radiotracer uptake during SPECT that may not be well visualized, resulting in thinner walls and an apparent increase in LV size [19]. On the other hand, subendocardial ischemia during stress CMR could lead to decreased wall thickening and excursion and, therefore, TID. Unlike SPECT, which has relatively poor spatial resolution, CMR can define the subendocardial myocardial border accurately for volumetric analysis even when hypoperfusion is present. With high spatial and contrast resolution, CMR has been shown to be reproducible and accurate and is considered the gold standard for assessing cardiac function [30]. Therefore, any potential change in EDV and ESV can be detected during stress CMR without any geometric assumptions about the shape of the heart. Although this report is intended only to describe the new stress CMR protocol that was recently introduced at our hospital, the findings from this limited study raise some intriguing questions. A significant majority (75 %) of our
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patients with TID and WMA were found to have extensive CAD as determined by angiography. Previous studies have also reported that the detection of new WMAs in conjunction with TID estimation may reflect significant underlying CAD [15, 16, 18, 19, 21]. Furthermore, TID has been shown to be an important prognosticator in CAD patients. Therefore, the presence of TID and WMA may suggest a relatively large ischemic burden, and this knowledge may affect patient management and clinical outcome. However, these questions need to be answered in a prospective, large clinical trial that directly evaluates the additive clinical value of this modified protocol. The acquisition of an extra set of short-axis cine images adds only a few extra minutes of imaging time, and the analysis and estimation of TID is fairly straightforward and can be easily incorporated into routine clinical practice. The ability to perform all these assessments simultaneously may increase the sensitivity and accuracy of CMR perfusion for evaluating ischemic CAD.
Limitations The small number of subjects in our cohort was a limiting factor in assessing the diagnostic and prognostic potential of this new protocol. In addition, our study population had a relatively high prevalence of CAD. The presence of TID has been reported to represent significant 3-vessel disease [16], but our current study had too few patients for us to determine the accuracy of TID in the detection of 3-vessel disease. We extrapolated DSE TID data for use in this study, though the mechanism for inducing ischemia in stress CMR is different than that in DSE. However, even in low-dose DSE in healthy volunteers, the LV dimensions were shown to be reduced [29]. In addition, the limited number of subjects did not allow us to determine the optimal cut-off for TID assessment. Finally, no long-term follow-up data were available to confirm whether TID identified by stress CMR indicated a poor cardiovascular outcome.
Conclusions Using our new stress CMR protocol, we have demonstrated the feasibility of assessing perfusion, WMA, and TID in a single setting by using the new adenosine A2A receptor antagonist regadenoson. This protocol is straight-forward and can easily be incorporated into the existing stress protocol without significantly increasing examination time or patient discomfort. Acknowledgments We are grateful to Virginia C. Fairchild and Nicole Stancel, Ph.D., ELS, of the Section of Scientific Publications
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at the Texas Heart Institute, Houston, Texas, for providing editorial assistance. Conflict of interest
None.
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