Comparison of Dobutamine Stress Magnetic Resonance, Adenosine Stress Magnetic Resonance, and Adenosine Stress Magnetic Resonance Perfusion
Background— Dobutamine stress MR (DSMR) is highly accurate for the detection of inducible wall motion abnormalities (IWMAs). Adenosine has a more favorable safety profile and is well established for the assessment of myocardial perfusion. We evaluated the diagnostic value of IWMAs during dobutamine and adenosine stress MR and adenosine MR perfusion compared with invasive coronary angiography.
Methods and Results— Seventy-nine consecutive patients (suspected or known coronary disease, no history of prior myocardial infarction) scheduled for cardiac catheterization underwent cardiac MR (1.5 T). After 4 minutes of adenosine infusion (140 μg · kg−1 · min−1 for 6 minutes), wall motion was assessed (steady-state free precession), and subsequently perfusion scans (3-slice turbo field echo-echo planar imaging; 0.05 mmol/kg Gd-BOPTA) were performed. After a 15-minute break, rest perfusion was imaged, followed by standard DSMR/atropine stress MR. Wall motion was classified as pathological if ≥1 segment showed IWMAs. The transmural extent of inducible perfusion deficits (<25%, 25% to 50%, 51% to 75%, and >75%) was used to grade segmental perfusion. Quantitative coronary angiography was performed with significant stenosis defined as >50% diameter stenosis. Fifty-three patients (67%) had coronary artery stenoses >50%; sensitivity and specificity for detection by dobutamine and adenosine stress and adenosine perfusion were 89% and 80%, 40% and 96%, and 91% and 62%, respectively. Adenosine IWMAs were seen only in segments with >75% transmural perfusion deficit.
Conclusions— DSMR is superior to adenosine stress for the induction of IWMAs in patients with significant coronary artery disease. Visual assessment of adenosine stress perfusion is sensitive with a low specificity, whereas adenosine stress MR wall motion is highly specific because it identifies only patients with high-grade perfusion deficits. Thus, DSMR is the method of choice for current state-of-the-art treatment regimens to detect ischemia in patients with suspected or known coronary artery disease but no history of prior myocardial infarction.
Received November 25, 2003; de novo received February 28, 2004; revision received April 15, 2004; accepted April 5, 2004.
In recent years, pharmacological stress testing has evolved as an alternative to physical exercise for the detection of inducible myocardial ischemia. The diagnostic performance of the stress tests may vary considerably, depending on the imaging modality (echocardiography, MRI, nuclear techniques) or stress agent used. Routinely used pharmacological stress agents are adenosine or dipyridamole and the synthetic β-adrenergic agent dobutamine. There is controversy regarding the “optimal” pharmacological stress agent; according to guidelines, adenosine should be used mainly for myocardial perfusion measurements, whereas dobutamine is advised for the detection of stress-inducible wall motion abnormalities (IWMAs). A large number of studies are available on the relative value of different stressors for different imaging modalities. However, the value of such studies may be reduced by performing the test on different days, which may significantly influence results, or by different physicians based in different departments. In addition, each modality has different advantages and disadvantages; thus, the resulting information describes the value of the modality rather than the stressor.1–4 To determine the diagnostic value of the stress agents, it seems reasonable to directly compare adenosine and dobutamine stress for wall motion analysis using the same imaging modality and, if possible, to concomitantly assess segmental myocardial perfusion under adenosine stress. Cardiac MR is favorable regarding both functional measurements: It allows assessment of even subtle wall motion disturbances resulting from the consistently high endocardial border definition, and the measurement of myocardial perfusion can be integrated into the same examination, with the high spatial resolution of the scans facilitating the determination of the transmural extent of a regional perfusion deficit.
Thus, the present study sought to determine the diagnostic performance of MRI for the assessment of IWMAs under dobutamine and adenosine stress and to determine the extent of concomitantly occurring adenosine-inducible perfusion abnormalities.
The study was conducted in accordance with the standards of the Charité and Virchow-Klinikum Ethics Committee. Seventy-nine consecutive patients referred to our hospital for cardiac catheterization who were complaining of chest pain were prospectively enrolled after written informed consent was obtained. Patients were eligible if they had suspected or known coronary artery disease (CAD; with or without prior percutaneous revascularization) but no prior history of myocardial infarction, no significant Q waves in the admittance ECG, and no prior coronary surgery. Patients were excluded if they had typical contraindications for MRI or administration of dobutamine and adenosine. All patients were instructed to refrain from cigarettes, tea, coffee, β-blockers, and antianginal medication for at least 24 hours before the MR study.
MR was performed with the patient in the supine position with a 1.5-T MR scanner (Philips Intera CV) equipped with a PowerTrak6000 gradient system (23 mT/m; 219-μs rise time) and software package release 9. Cardiac synchronization was performed with 4 electrodes placed on the left anterior hemithorax (Vector-ECG).
Figure 1 shows the course of the examination. After acquisition of rest cine scans in the standard views (apical, mid, and basal short-axis views; 4-, 2-, and 3-chamber views), the adenosine infusion (140 μg · kg−1 · min−1; total duration, 6 minutes) was started, and the standard cine scans were repeated after 4 minutes of adenosine infusion. Within the last minute of the infusion, the adenosine stress MR perfusion scan was performed to visualize the identical 3 short-axis geometries using 60 dynamic acquisitions during the administration of a gadolinium-BOPTA intravenous bolus (dosage, 0.05 mmol/kg; infusion rate, 4 mL/s) and applying a previously described breathhold scheme.5
A 15-minute waiting period allowed equilibration of the contrast agent within the myocardium while the patient remained in position. After the break, the examination was continued, repeating the identical MR perfusion scan at rest.
Directly afterward, a DSMR examination was carried out following a standard high-dose regimen (up to 40 μg · kg−1 · min−1) plus atropine (up to 2 mg) if needed to reach target heart rate defined as age-predicted submaximal heart rate [(220−age)×0.85]. Termination criteria were as previously published.6
For cine imaging, a steady-state free precession sequence with retrospective gating [25 phases per cardiac cycle; repetition time (TR), 2.7 ms; echo time (TE), 1.4 ms; flip angle, 60°] during an end-expiratory breathhold of 4 to 6 seconds was used. Typical in-plane spatial resolution was 1.8×1.8 mm with a slice thickness of 8 mm.
For perfusion imaging, a 3-slice turbo field echo-echo planar imaging sequence (TR, 9.3 ms; TE, 3.3 ms; flip angle, 30°) was used with 1 saturation prepulse per slice before data readout (prepulse delay, 130 ms; typical spatial resolution, 2.4×2.4×8 mm).
Segmental analysis of the cine scans was performed by the consensus of 2 observers (I.P., C.J.) blinded to the perfusion scans and invasive coronary angiography using a synchronized quad-screen image display and applying the standard scoring system (1=normokinesis, 2=hypokinesis, 3=akinesis, 4=dyskinesis).7,8 To adequately compare segmental wall motion with the short-axis perfusion scan, the apical segment (number 17) was not considered. For dobutamine scans, ischemia was defined as ≥1 segments showing IWMAs (ie, an increase in the segmental wall motion score of ≥1); a biphasic response was considered to indicate ischemia. Adenosine stress MR scans were analyzed twice: once using identical criteria as for dobutamine (analysis A, see above) and once using the additional criterion of segmental absence of a hyperkinetic response as an indicator of IWMAs (analysis B).2,9,10 In patients with WMAs at rest, all segments with resting akinesis were not considered for further analysis.
Similarly, perfusion scans were interpreted by 2 different observers (R.G., M.N.) who were blinded to the findings of wall motion analysis and coronary angiography. For visual grading of perfusion deficits, adenosine stress and rest perfusion scans were magnified 2-fold and displayed simultaneously. The transmural extent of an inducible perfusion deficit was determined from the single dynamic image showing the maximum extent of regional hypoenhancement (identical 16 myocardial segments). Hypoenhancement (perfusion deficit) was graded visually with regard to its transmural extent: 0=no regional hypoenhancement, 1=transmural extent <25%, 2=transmural extent 25% to 50%, 3=transmural extent 51% to 75%, and 4=transmural extent >75%. A regional hypoenhancement ≥25% in any segment was considered to be pathological (inducible perfusion deficit). As a global measure for the transmural perfusion deficit of the myocardium per patient, a transmural perfusion deficit index (TPDI) was calculated as the sum of all segmental transmurality scores divided by 16.
Quantitative Coronary Angiography
Quantitative coronary angiography (Philips Inturis Suite software) was performed with the observer unaware of the results of MRI. A significant coronary stenosis was defined as >50% stenosis (percent luminal diameter narrowing). Significant left main coronary stenosis was considered double-vessel disease.
For all continuous parameters, mean±SD is given. The paired Student’s t test or repeated-measures ANOVA was used to assess statistical significance of continuous variables. Group differences for categorical variables were tested with the χ2- or Fisher’s exact test. All tests were 2 tailed; P<0.05 was considered significant.
Sensitivity, specificity, accuracy, and predictive values (positive and negative) were calculated according to standard definitions and compared between groups (χ2 or Fisher’s exact test).
To determine the relationship of IWMAs with the degree of coronary stenosis and the TPDI, receiver-operating curve (ROC) analysis was performed, and the area under the curves was calculated.11
All data analysis was performed with SPSS for Windows 11.0.1 (SPSS Inc).
Patient Characteristics and Hemodynamic Data
Tables 1 and 2⇓ summarize the clinical and hemodynamic data. The average dosages of dobutamine and atropine leading to development of IWMAs was 36.2±5.6 μg · kg−1 · min−1 and 0.3±0.4 mg, respectively.
All segments showing resting akinesis (23 of 1264 segments) were excluded from further analysis. The remaining 1241 segments (1204 with normokinesis, 37 with hypokinesis) were used to assess the diagnostic value of each of the stress tests.
Table 3 shows the diagnostic value of each stress test for the detection of epicardial coronary stenoses using analysis B for adenosine stress MR. Using analysis A for adenosine stress MR, 7 additional patients showed no IWMAs (6 patients with false-negative and 1 patient with true-negative result), yielding a sensitivity of 30%, specificity of 100%, and diagnostic accuracy of 52%. One imaging example is shown in Figure 2; 2 additional examples can be downloaded at http://www.circulationaha.org (Figure 2A and Figure 2B).
Distribution of Perfusion Deficits in Segments With or Without IWMAs
Myocardial segments with dobutamine IWMAs showed perfusion abnormalities with varying transmurality (Figure 3A), whereas adenosine IWMAs occurred in the presence of perfusion deficits with >75% transmural extent only. Interestingly, in 57 of 257 segments (22.2%) with dobutamine IWMAs, no perfusion deficit could be detected. On a per-patient basis, 26 of 53 patients (49%) who were “test-positive” for dobutamine IWMAs showed ≥1 segment without adenosine-inducible perfusion deficit (segmental mismatch) but were correctly classified as test-positive by the adenosine perfusion because they all showed ≥1 segment(s) with an inducible perfusion deficit in another segment.
Myocardial segments without IWMAs showed a large variability of transmurality of perfusion deficits for both stress agents (Figure 3B): 19% of segments without dobutamine IWMAs and 23% of segments without adenosine IWMAs showed perfusion deficits ≥25%. For segments without dobutamine IWMAs, 3.7% had perfusion abnormalities with >50% transmurality (1.7% with >75% transmurality). A similar distribution was found for segments without adenosine IWMAs (5.0% with >50% and 1.7% with >75% transmurality).
Relationship Between IWMAs and Severity of Coronary Stenosis
Figure 4A and 4B shows the results of the ROC analysis performed to determine the degree of coronary stenosis being related to a dobutamine or adenosine IWMA. For dobutamine IWMAs, the highest accuracy values were found for coronary stenoses >50% (cutoff, 47%), whereas for adenosine IWMAs, the highest accuracy values were found for coronary stenoses >75% (cutoff, 77%). The area under the curve was nearly identical for both stress agents.
Relationship Between IWMAs and Perfusion Deficit
Figure 5A and 5B shows the results of the ROC analysis carried out to determine the cutoff value for the TPDI to predict the occurrence of an IWMA under dobutamine or adenosine. The TPDI cutoff of 1.35 resulted in a high sensitivity and specificity for its ability to predict an adenosine IWMA. For dobutamine, a TPDI cutoff of 0.6 showed the highest sensitivity and specificity. The area under the curve for the prediction of an IWMA from the TPDI was greater for adenosine.
The main findings of our study are as follows. First, DSMR is superior to adenosine stress MR for the detection of IWMAs in the presence of significant epicardial coronary stenoses defined as >50% luminal narrowing. Second, coronary stenoses >50% are highly predictive of a dobutamine IWMA, whereas high-grade coronary stenoses >75% are associated with adenosine IWMAs. Third, visual assessment of adenosine stress–inducible perfusion deficits is sensitive with a low specificity. Fourth, adenosine IWMAs rather than dobutamine IWMAs are related to more extensive transmural perfusion deficits (TPDI cutoff, 1.35 versus 0.6; respectively). Fifth, myocardial segments with dobutamine IWMAs show varying degrees of perfusion deficits, whereas IWMAs under adenosine stress are found exclusively in the presence of concomitant high-grade segmental perfusion deficits (>75% transmurality). Finally, myocardial segments without dobutamine or adenosine IWMAs show varying degrees of perfusion deficits, which may have >50% transmurality in some cases.
The diagnostic accuracy reached for all 3 tests is within the range of previously published data on DSMR,6,12 adenosine stress echo,2 and adenosine stress MR perfusion using visual criteria.13 The higher sensitivity for DSMR found in the present study compared with previously published literature6 is probably related to the recent technical improvements in MR cine imaging; steady-state free precession sequences further improved endocardial border definition14 and, combined with parallel imaging techniques (SENSE) and retrospective ECG gating, allowed consistent acquisition of 25 phases per cardiac cycle during short breathholds. The lower specificity of DSMR is most likely due to the high proportion of patients with known CAD (52%) and prior percutaneous revascularization (48%).
To the best of our knowledge, no data on adenosine stress MR have been reported so far. Even though adenosine stress MR had a higher specificity compared with DSMR, the low sensitivity led to a significantly lower diagnostic accuracy. This may be due to 2 major reasons: (1) Adenosine IWMAs are inducible only in the fraction of patients with high-grade stenosis (>75%), or (2) adenosine is an insufficient stressor for the induction of “true” ischemia (relative ischemia resulting from an imbalance of myocardial oxygen demand and supply), which is a prerequisite for the development of IWMAs.
ROC analysis was done to determine the relationship between dobutamine and adenosine IWMAs and degree of coronary stenosis, demonstrating that the presence of a coronary stenosis >50% yielded high accuracy values for dobutamine IWMAs, whereas >75% diameter stenosis was required for adenosine IWMAs.
Examining the relationship of IWMAs with the transmurality of perfusion deficits, ROC analysis again showed a lower cutoff value for dobutamine versus adenosine IWMAs (TPDI of 0.6 versus 1.35, respectively), thus indicating that dobutamine IWMAs occur at lesser degrees of a global perfusion deficit. The higher cutoff and greater area under the curve for adenosine IWMAs underline the close relationship with the presence of extensive perfusion deficits. Additionally, adenosine IWMAs occurred exclusively in segments with >75% transmural perfusion deficit.
These findings further corroborate the concept of relative versus absolute ischemia.10 Adenosine is known to cause absolute reductions in myocardial blood flow, which, according to our results, have to comprise >75% of the transmural extent of the respective segment to cause a WMA. Adenosine-inducible WMAs, together with such extensive blood flow maldistribution, were related to the presence of high-grade epicardial stenosis. Thus, adenosine has to be considered an insufficient stressor for detection of IWMAs resulting from coronary stenoses <75%.
Adenosine mainly induces myocardial blood flow inhomogeneities by vasodilatation and steal effects that do not necessarily result in WMAs. Previous studies found a clear disparity between scintigraphically detected perfusion abnormalities and IWMAs under adenosine stress.1,15 In the present study, MR perfusion imaging with its higher spatial resolution allowed us to identify the degree of transmurality of the perfusion deficit as a strong predictor of adenosine IWMAs. This observation fully supports the view that the alteration of blood flow induced by adenosine is insufficient to induce WMAs in less severe CAD (stenoses <75%).
Our study showed that with dobutamine stress there is also a disparity between the perfusion status and the induction of WMAs in a substantial number of segments: 59% of the segments without a dobutamine IWMA did not have a perfusion deficit, yet 19% had perfusion deficits with ≥25% transmurality, and 1.7% showed even >75% transmurality.
Additionally, we found adenosine IWMAs only in segments with a >75% transmural perfusion deficit, demonstrating that these patients suffer from extensive myocardial perfusion abnormalities. Consequently, our results emphasize that adenosine/dipyridamole IWMAs are useful only for identifying patients with high-grade perfusion deficits who are at high risk for future cardiac events.16,17
Yet, it should be stressed that assessment of patient prognosis alone does not sufficiently aid the cardiologist in clinical decision making. When aiming to follow the guidelines and apply current state-of-the-art treatment regimens of CAD,18 it is important to evaluate the hemodynamic impact of coronary lesions with 50% to 75% diameter reduction. Regarding this, DSMR represents the more powerful noninvasive diagnostic tool.
Approximately 20% of those segments developing dobutamine IWMAs did not show a visually assessable perfusion deficit. In our experience, such a segmental mismatch of dobutamine IWMAs and adenosine inducible perfusion deficits is quite frequent. However, all patients with a segmental mismatch were correctly classified as test-positive by the adenosine perfusion because they all showed ≥1 segment(s) with an inducible perfusion deficit in a different segment. The reasons may be as follows. First, “tethering effects” concomitantly occurring with dobutamine IWMAs might represent a possible explanation for visually more extensive segmental wall motion disturbances. Second, dobutamine may represent the stronger ischemic stimulus, ie, more extensive impairment of contractile function resulting from pronounced relative ischemia compared with the redistribution of myocardial blood flow as seen with adenosine.
The perfusion sequence, contrast agent (gadolinium-BOPTA), and its dosage were optimized for visual evaluation of MR perfusion. Previous publications reporting on semiquantitative analysis mainly used lower doses of gadolinium-DTPA for the quantitative approach5,19,20 because quantification but not visual assessment suffers from nonlinearity between contrast agent concentration and signal intensity. Thus, the present data do not allow for semiquantification, and we do not know whether it would produce the same results. Yet, for practical reasons, we deem the assessment of the transmurality of a perfusion deficit to be a clinically applicable and relevant approach.
DSMR proved highly accurate for the detection of IWMAs in patients with suspected or known CAD but no history of prior myocardial infarction. IWMAs during adenosine stress MR are strictly linked to high-grade perfusion deficits, thereby corroborating the role of vasodilator-inducible WMAs as a prognostic tool to identify patients at high risk for future cardiac events. Yet, adenosine stress MR cannot be recommended for the detection of IWMAs related to epicardial coronary stenoses.
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