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Imaging/Diagnostic Testing Contrast enhanced and functional magnetic resonance imaging for the detection of viable myocardium after infarction Paul Dendale, MD,a Philippe R. Franken, MD,b Pierre Block, MD,a Yiannis Pratikakis,c and Albert De Roos, MDd Brussels, Belgium, and Leiden, The Netherlands Purpose Viable myocardium after acute myocardial infarction may be characterized by magnetic resonance imaging (MRI) either by demonstration of recovery of wall motion under dobutamine stress or by perfusion patterns after contrast medium administration. This study examines the relation between the two techniques. Materials and Methods Gradient-echo MRI at rest and under low-dose dobutamine stress was performed in 28 patients within the first 2 weeks after acute myocardial infarction. In addition, spin-echo MRI was performed after gadolinium-DOTA administration. Wall motion at rest and under stress was scored to assess the contractile reserve of the infarct regions. Infarct enhancement patterns were classified as subendocardial, transmural, or as a doughnut pattern. Result Subendocardial or absent infarct enhancement was related to functional recovery under stress in 31 of 37 infarct segments. Transmural infarct enhancement was correlated with the absence of functional recovery in 10 of 17 infarct segments (p < 0.002), indicating nonviability. The doughnut pattern was exclusively associated with the absence of viability (five of five). Conclusion Contrast enhancement patterns are related to residual myocardial viability. (Am Heart J 1998:135:875-80.) In the era of widespread use of thrombolysis and direct coronary artery dilation, noninvasive techniques for detecting jeopardized but viable myocardium are becoming important for patient management. Two different approaches can be used that rely on the alterations that can be found after infarction. Metabolic disturbances with an increased reliance on glycolysis are known to occur frequently in ischemic myocardium. Metabolic imaging techniques such as positron emission tomography or thallium or fatty acid scintigraphy rely on these changes to differentiate viable tissue from infarction. Conversely, contractile reserve determination with low-dose dobutamine From the Departments of aCardiology, bNuclear Medicine, and cElectronics, Free University of Brussels (VUB); and the dDepartment of Radiology, University Hospital Leiden. This work was supported by a grant from the Belgische Cardiologische Liga and the Nationaal Fonds voor Wetenschappelijk Onderzoek. The Gadolinium contrast (Dotarem R) was provided by Guerbet. Submitted June 20, 1997; accepted Dec. 17, 1997. Reprint requests: Paul Dendale, MD, Heart Centre, Virga Jesse Hospital, Stadsomvaart 11, 3500 Hasselt, Belgium. Copyright © 1998 by Mosby, Inc. 0002-8703/98/$5.00 + 0 4/1/88881 echocardiography or magnetic resonance imaging (MRI) is based on the knowledge that the depressed contractile function of viable myocardium can be recruited by inotropic stimulation. MRI allows different approaches for viability detection, depending on the imaging technique used. Spin echo imaging is well suited to measure precisely the wall thickness of the infarct region.1 A minimal wall thickness of more than 6 mm suggests viable tissue in long-term situations.2 The use of contrast agents during spin echo or ultrafast perfusion imaging3-19 is useful in the more acute stages of the infarction. Functional imaging with wall thickening and the contractile response to dobutamine is the most recently described technique.20,21 In this study, the relation between contrast enhancement patterns and functional studies is analyzed. Methods Patient population Twenty-eight patients presenting with an acute myocardial infarction (creatine kinase peak >500 IU/L) and treated with thrombolysis or direct percutaneous transluminal coronary angioplasty (PTCA) were prospectively entered in the study. American Heart Journal May 1998 876 Dendale et al. Figure 1 Twenty-two male and six female patients with a mean age of 64 ± 12 years were scanned within the first 2 weeks after infarction. Eighteen patients presented with an inferior or lateral infarction and 10 patients with an anterior or septal infarction based on ECG. The presumed infarct region was determined on the basis of the ECG evolution and the results of the coronary angiogram. Twenty-five patients underwent coronary angiography in the first 2 weeks after the infarction. One patient showed normal coronary arteries, three had single-vessel, seven had two-vessel, and 14 had three-vessel disease. Seven of the 25 patients examined had occluded infarct-related arteries. The culprit artery was the left anterior descending in nine patients, left circumflex artery in 12, and right coronary artery in four. Exclusion criteria were hemodynamic instability, irregular heart rate, contraindications for MRI (pacemakers or ferromagnetic vascular clips), or contrast medium injection. The protocol was approved by the Ethical Committee of the Free University of Brussels, and the patients gave informed consent before entering the study. MRI examination All patients were examined between 6 and 14 days after the infarction with a gradient echo and a spin echo MRI examination after discontinuation of β-blockers for at least 48 hours. All MRI images were acquired with a 1.0 Tesla Siemens Magnetom in double oblique orientation, resulting in short-axis representation. A spin echo series was obtained 15 minutes after injection of 0.1 mmol/kg gadolinium-DOTA (Dotarem, Guerbet, Aulnay-sous-Bois, France). The whole of the left ventricle was scanned with slices of 8 mm thickness and 2 mm gap. All MRIs were made with a field of view of 300 using the body coil and an acquisition matrix of 128 × 256 lines. Each series was made with two acquisitions, a repetition time (TR) equivalent to the RR interval and an echo time (TE) of 25 msec. A gradient echo series was made with two midventricular short-axis slices of 10 mm thickness and a gap of 20 mm. The TR was 50 msec; the TE was 6 msec, with a flip angle of 30 degrees. The number of phases was dictated by the RR interval (12 to 20 phases). After this series, a continuous infusion of dobutamine in a dose of 5 mg/kg/min was started and the gradient echo MRI was repeated with exactly the same parameters 5 minutes after the beginning of the perfusion. Image analysis Subendocardial anteroseptal infarct enhancement: spin echo image (top). Transmural lateral infarct enhancement pattern (middle). Transmural lateral infarct enhancement with central hypointense zone: “doughnut pattern” (bottom). All MRIs were stored on optical disk and transferred to a SUN spark station (Sun Microsystems) for image analysis. From the spin echo series, the two slices corresponding to the level of the gradient echo images were selected for analysis. The analysis of the wall thickening and the contrast American Heart Journal Volume 135, Number 5, Part 1 Dendale et al. 877 Table I. Relation between infarct enhancement on spin echo imaging and diagnosis of viability on dobutamine gradient echo MRI (p < 0.0003) Dobutamne negative Transmural Subendocardial Normal Total Dobutamine positive 10 4 2 16 enhancement patterns was done by one observer on separate days. The spin echo images were examined for a signal enhancement in the region of the infarction induced by the contrast agent by use of the method described by Bouchard et al.22 The window width was set to zero, and the window level was adjusted to completely null the signal of the myocardium opposite the area with increased signal intensity. The borders of the remaining zone of high intensity were then drawn and the window width and level were returned to baseline. The relation between the contour drawn and the endocardium and epicardium were analyzed. The signal enhancement pattern was classified as transmural, subendocardial, or absent. Subendocardial infarct enhancement (Fig. 1, top) was defined as an enhancement that in no place reached the epicardium. Transmural enhancement was defined as a signal increase extending to the epicardium (Fig. 1, middle). All regions with an increased signal intensity were examined for the presence of central zones of reduced signal intensity (Fig. 1, bottom). A signal enhancement surrounding a region without signal was defined as a “doughnut pattern.” The gradient echo images were analyzed separately from the spin echo images. The myocardium in the region of interest was classified as showing normal contractility, hypokinesis (diminished but not absent wall thickening in comparison to the other segments in the same slice), or akinesis (absent wall thickening). The dobutamine-stimulated images were classified as unchanged wall thickening or improved wall thickening (hypokinesis to normal; akinesis to hypokinesis or normokinesis). 3 11 2 16 Normal Total 4 7 11 22 17 22 15 54 segments. Of the 19 segments with transmural signal enhancement, five were found to have a central region of low-signal intensity, whereas none of the segments with a subendocardial pattern showed this feature. In the gradient echo study, 22 segments were akinetic, 12 were hypokinetic, and the remaining 22 were normokinetic. Fifty-four of the dobutamine-stimulated dynamic images were of sufficient quality to be analyzed: they showed improvement in wall motion in 16 of the 32 slices with abnormal wall motion at rest and unchanged wall motion in 16. Relation between infarct enhancement pattern and coronary anatomy In transmural infarct enhancement, 22% of the vessels were occluded compared with 30% in the subgroup with subendocardial enhancement and 25% in the subgroup with absence of infarct enhancement, a difference that was not significant. Relation between infarct enhancement pattern and basal wall thickening The chi-square test with Yates correction was used to analyze the significance of the difference between subgroups. In segments with transmural infarct enhancement, abnormal wall thickening was present in 15 of 19 (79%) segments, most of them being akinetic (12 of 15). Four of the five segments with a central hypointense region were akinetic. Among the 22 segments with subendocardial enhancement, 15 (68%) showed abnormal wall thickening, with a slight predominance of hypokinesis (9 of 15). Segments without infarct enhancement were most often normokinetic (11 of 15). Results Relation between infarct enhancement pattern and contractile response to low-dose dobutamine On the spin echo images, an increased signal intensity was observed in 41 (73%) of the 56 infarct segments: a transmural enhancement was found in 19 segments, and a nontransmural in the remaining 22 Table I shows a significant relation between contrast MRI and the response to low-dose dobutamine stimulation (p = 0.0003). Transmural infarct enhancement corresponded with dobutamine-negative myocardium Statistical analysis 878 Dendale et al. in 10 of 17 (59%) cases, whereas subendocardial infarct enhancement was related to normal or dobutamine-positive myocardium in 18 of 22 (82%) cases. The five segments with a doughnut pattern were all dobutamine negative (nonviable). Only two of 15 segments without infarct enhancement were shown as nonviable by dobutamine MRI. Combination of the different imaging techniques The combination of transmural infarct pattern with akinesis was related to an absence of contractile reserve in 9 of 10 (90%) segments, whereas nontransmural or absent infarct enhancement in combination with hypokinesis predicted a positive response to dobutamine in 7 of 9 (78%) (p < 0.001). In all cases, a doughnut pattern was predictive of nonviability, independently of the wall motion. Discussion In this study, two major infarct enhancement patterns were detected after contrast spin echo MRI: subendocardial and transmural. In the transmural group, a homogeneous pattern and a pattern with a central hypointense zone (doughnut pattern) were found. A significant association was found between contrast pattern, wall thickening, and contractile reserve. Transmural infarct enhancement was found predominantly in akinetic segments, whereas subendocardial or absent infarct enhancement was found more in hypokinetic segments. Almost half of the homogeneous transmural patterns showed improved wall thickening during dobutamine stimulation, suggesting viability, whereas the doughnut pattern was specific for necrotic myocardium. Subendocardial or absent contrast patterns showed contractile reserve in more than 80%. The combination of the information of contrast and wall motion analysis resulted in the distinction of subgroups with very high (>75%) and very low (<15%) probability of viability. Infarct enhancement in myocardial infarction In our study, 25 of the 28 patients (89%) showed an infarct enhancement on spin echo imaging. The published literature confirms the accuracy of contrast enhanced MRI in the detection and quantification of a recent infarction. In a study by Van Dijkman et al.,16,17 a clear increase in signal intensity was seen after gadolinium contrast in the acute phase of myocardial infarction. This change remained present for at least 6 weeks after the infarction. American Heart Journal May 1998 The absence of enhancement in three of our patients can be explained by the size23 and localization of the infarction (apical images are more difficult to analyze), or by the presence of ischemic or stunned, but not necrotic, tissue. Also, the variability in signal intensity in normal myocardium reduces the contrast between infarction and normal tissue, and this might decrease the sensitivity for the detection of infarction. The slice selection was done without knowledge of the localization of the infarction; therefore we cannot exclude the possibility that a study using more slices to image the heart would have found zones with signal enhancement. The data in the literature are not conclusive in determining the exact nature of infarct enhancement in spin echo imaging: the presence of edema in the infarct region does not explain the time course of the signal increase. Although at 6 weeks edema in the infarct region has certainly disappeared, some studies16,17 still show a clear increase in signal intensity in the infarct region. The influence of uptake and washout kinetics of the contrast product might play an important role. As studies with contrast enhanced CT scanning24 and MRI25,26 have already shown, the signal intensity increases first in the normal myocardium, and the infarct is visualized only several minutes later, probably due in part to the slower blood flow in the infarct region. Infarct enhancement patterns and viability In our study, two main infarct enhancement patterns were identified: transmural and subendocardial. Most segments with a transmural infarct enhancement pattern were found to be akinetic (12 of 19), with 41% (7 of 17) showing viability (defined as the presence of contractile reserve during dobutamine). Of the five segments with a doughnut pattern, four were akinetic, and none showed signs of contractile reserve. In contrast, subendocardial enhancement was related to hypokinesis or normal wall thickening in most segments, with a very high probability of viability (82%). However, in our study, a few important discrepancies were found between the results of the contrast study and the wall thickening studies: in four segments with transmural infarct enhancement, the wall thickening was completely normal, and four other segments without enhancement were akinetic, showing a positive response to dobutamine in two cases. For the former four segments, the timing of the contrast study could be an explanation: recovery of func- American Heart Journal Volume 135, Number 5, Part 1 tion (of stunned myocardium) might precede the disappearance of infarct enhancement. The lack of specificity of gadolinium contrast for necrosis is clearly demonstrated by these extreme cases. The absence of infarct enhancement in akinetic segments might be related to the presence of hibernating myocardium. Wall motion abnormalities are known to exist even in the absence of necrosis, and only a part will show recovery of function during stimulation with dobutamine. The four segments with akinesis and absence of infarct enhancement in our study were all dependent on severely stenosed (≥90%) or occluded vessels. Obviously, technical reasons such as imperfect matching of the segments might also explain part of the discrepancies observed, even though the side-to-side matching of the segments guaranteed the best possible concordance. Several other studies analyzed the relation between infarct enhancement and viability. In one study,5 a subendocardial signal increase was 100% predictive for wall motion improvement in the very short term (2 weeks). Transmural or nonhomogeneous infarct segments showed no improvement in wall motion. In an animal study using gadolinium,9 a good relation was found between signal increase and nonreversible jeopardized myocardium at 6 and 48 hours of reperfusion. In our study, several clear cases were found of patients with transmural infarct enhancement who showed viable myocardium on stimulation. As in our study, Judd et al.26 showed that hypoenhanced regions with a hyperenhanced rim were very sensitive for necrotic myocardium. The higher sensitivity in the latter study might be explained by the dynamic nature of their imaging sequence. The spin echo sequence in our study was done 15 minutes after injection of contrast, whereas Judd et al.26 followed the contrast evolution in the first 15 minutes using ultrafast imaging. In patients with low blood flow to the infarcted region, more time might be needed to allow accumulation of the contrast agent, resulting in different patterns depending on the time after infusion. This is supported by the time intensity curves of the study by Judd et al.,26 showing overlapping of the hyperenhanced and hypoenhanced curves at 14 minutes after the contrast injection. Clinical implications Contrast patterns might eventually preclude the necessity for low-dose dobutamine stimulation. As shown in our study, a negative contrast MRI or a subendocardial infarct enhancement would have a Dendale et al. 879 high positive predictive value for viability. In this subgroup of patients, viability studies by low-dose dobutamine would not be needed. In the subgroup of transmural infarct enhancement, the differentiation should be based on the presence or absence of hypointense zones and on wall motion analysis at rest and during stimulation. This way a rapid and accurate prediction of viability could be obtained. A larger trial, however, is needed to confirm these data before the technique is used in clinical practice. Limitations of the study No follow-up of wall motion was available, so the diagnosis of viability was made only by low-dose dobutamine MRI. However, a large body of literature exists showing the accuracy of low-dose dobutamine echocardiography to predict residual myocardial viability early after myocardial infarction, and recent studies have shown a comparable accuracy of MRI.20,21 Only two slices were analyzed in each patient, which could result in an underdiagnosis of myocardial infarction in our patients. However, most of the patients (46 of 56 slices, or 26 of 28 patients) showed an abnormality on at least one of the two slices. Also, because we directly compared the same slice on the different imaging techniques, the conclusions regarding the relation between contrast enhancement patterns and viability remain valid. Inasmuch as one investigator analyzed all images, no data about reproducibility of the analysis are available from this study. However, reproducibility was shown to be very good in an earlier publication.20 Conclusion Subendocardial and transmural signal intensity increase during contrast-enhanced spin echo MRI is often seen in the infarct region. These patterns can be of use in the determination of viability after infarction. The subendocardial infarct enhancement is accurate in predicting viability, whereas the transmural pattern can be seen in viable and in nonviable infarct regions. 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