Displacement Encoding With Stimulated Echoes Enables the Identification of Infarct Transmurality Early Postmyocardial Infarction

Segmental extent of infarction assessed by late gadolinium enhancement (LGE) imaging early post‐ST‐segment elevation myocardial infarction (STEMI) has utility in predicting left ventricular functional recovery.

Data Conclusion: Circumferential strain with DENSE is a functional measure of infarct severity and may remove the need for gadolinium contrast agents in some circumstances. Level of Evidence: 2 Technical Efficacy Stage: 5 J. MAGN. RESON. IMAGING 2020;52:1722-1731.
T HE TRANSMURAL EXTENT of myocardial infarction per myocardial segment, acquired using late gadolinium enhancement (LGE) imaging early post-ST-segment elevation myocardial infarction (STEMI), has prognostic importance for the recovery of myocardial contractile function and prediction of major adverse cardiac events in the longer term. 1,2 In the acute phase post-STEMI, segmental LGE extent overestimates infarction due to coexistent myocardial edema, inflammation, and hemorrhage. 3 In fact, a segmental cutoff of 75% has been proposed in patients imaged early post-STEMI to determine viability rather than the 50% threshold used in chronic coronary syndromes. 4 T 1 mapping and extracellular volume fraction (ECV) estimation enable an alternative and complementary assessment of infarct severity to LGE-derived segmental extent of infarction. Segmental T 1 values have been reported to be strongly correlated with the extent of infarction on LGE imaging, and ECV has been reported to be a superior marker than LGE to identify segmental myocardial functional improvement. 5,6 However, these conventional techniques require the use of gadolinium contrast agents and are contraindicated in patients with chronic kidney disease.
Myocardial strain has the potential to provide new insights into the pathophysiology of STEMI. [7][8][9][10][11] The advantages of quantitative methods beyond the left ventricular ejection fraction (LVEF) and wall-motion scoring include improved diagnostic sensitivity and specificity, less interobserver and intraobserver variability, and novel parameters of biomechanical function. 7 Displacement encoding with stimulated echoes (DENSE) has advantages over tagging, which is historically regarded as the gold standard technique for cardiac magnetic resonance imaging (MRI)-derived strain. [12][13][14][15][16][17][18] Specifically, the accuracy of DENSE strain is equivalent to that of tagging, and interobserver reproducibility of DENSE is better than that of tagging. 19,20 Furthermore, the time required to perform strain analysis of DENSE images is less than that for conventional tagging analysis. 19 Studies previously demonstrated that DENSE-derived global circumferential strain had incremental benefit over acute infarct size to predict major adverse cardiac events, and segmental circumferential strain with DENSE provided incremental utility over the segmental extent of infarction to predict myocardial functional recovery by wall-motion scoring. 10,11 Further work needs to be carried out to assess if DENSE can obviate the use of gadolinium contrast agents in patients postmyocardial infarction.
The aims of the study were to investigate if segmental strain with DENSE would be: 1) a stronger predictor of infarct transmurality than feature-tracking strain, and 2) noninferior to ECV in acute STEMI patients.
A modified Look-Locker inversion recovery prototype sequence (work-in-progress sequence 488, Siemens Healthcare) was used for T 1 mapping and performed in three short-axis slices at middiastole (basal, mid-LV, apical), before and 20 minutes postgadolinium contrast, in line with recommendations. 26 Typical parameters were: bandwidth~1090 Hz/pixel; flip angle 35 ; TE 1.1 msec; inversion time (TI) of first experiment 100 msec; TI increment 80 msec; matrix 192 × 124 pixels; spatial resolution 2.2 × 1.8 × 8.0 mm; slice thickness 8 mm; scan time 17 heartbeats. Each study participant had a blood sample acquired prior to the MR scan in order to obtain a hematocrit.

Infarct Definition And Size
Infarction was defined by the occurrence of myocardial LGE revealed in orthogonal planes including phase swap acquisitions as appropriate by the scanning radiographers or fellow to rule out artifact. Microvascular obstruction was defined as a dark zone within an area of LGE. 29,30 The extent of late gadolinium enhancement (% LV mass) was assessed utilizing the full-width half-maximum thresholding method. 31 Transmural extent of infarction and the presence/absence of microvascular obstruction (MVO) were also analyzed on a segmental basis at basal, mid-LV, and apical short-axis slices. The transmural extent of infarct was then binarized into LGE >50% (yes/no) and in view of recent data, LGE >75% (yes/no). 4  Angiography revealed an occluded proximal left anterior descending artery, which was treated by percutaneous coronary angioplasty. Cardiac MR carried out 1-day postadmission revealed an extensive anteroseptal wall motion abnormality (a, mid left ventricular cine image at end-diastole, (b), corresponding image at mid-systole). The hypokinetic region had raised T 1 relaxation times on T 1 mapping (c, black arrows) and on late gadolinium enhancement imaging there was transmural infarction (d, black arrows) with microvascular obstruction (yellow arrow). (e) Peak systolic radial (left) and circumferential (right) strain maps with corresponding regions of reduced strain magnitude corresponding to the infarcted region (arrows).

Segmental T 1 and Extracellular Volume Fraction Quantification
Color-coded T 1 and extracellular volume (ECV) maps were generated based on inline-generated, motion-corrected raw images using QMap software V2.1 (Medis). Endocardial and epicardial contours were manually drawn and the LV was segmented according to the American Heart Association 16-segment model with respect to the anterior right ventricular insertion point. Segmental regions of interest comprising the middle 80% of the myocardial thickness with 10% myocardium omitted on the endo-and epicardial sides were constructed to avoid partial volume effects from neighboring tissue and blood pool.

Strain Analyses
The 2D DENSE images were analyzed off-line using DENSE analysis. Segmentation of the LV myocardium was performed semiautomatically after endo-and epicardial contours were drawn by K.M., using the anterior right ventricular insertion point as a reference. Spatiotemporal phase unwrapping was then carried out on the LV myocardium pixels, and displacement vectors were calculated. 28,32 Lagrangian strain was computed from these displacements and then projected into radial, circumferential (or longitudinal in long-axis acquisitions) directions relative to the LV center of mass. Diogenes feature-tracking software (TomTec Imaging Systems) was used to quantify strain from short-axis cine b-SSFP images. The same operator derived strain following a standard protocol taught by the software manufacturer. 33 The relevant Digital Imaging and Communications in Medicine (DICOM) folders were loaded into the program. The endocardial border was contoured on the end-diastolic image. Strain was generated based on border displacement.
Strain analysis was carried out by K.M. with C.M. (10 years MRI experience) carrying out interobserver variability assessment.

Statistical Analysis
Statistical analysis was performed using SPSS (IBM, Armonk, NY) or R v. 2.15 (Vienna, Austria) or higher. Normality was tested using the Shapiro-Wilk test. Continuous variables were expressed as mean AE standard deviation (SD) or median (Q1, Q3), depending on distribution. Skewed distributions were analyzed utilizing Mann-Whitney or Kruskal-Wallis tests; normal distributed data was analyzed using independent t-tests, as required. No correction was made for multiple comparisons. Correlation analyses were either Pearson or Spearman tests, depending on the distribution of variables. P < 0.05 was considered statistically significant. Diagnostic cutoff values were identified from the "OptimalCutpoints" package 34 using the Youden index. 35 The difference in area under the curve (AUC) was compared using the z-statistic using DENSE as the reference standard. Noninferiority was defined as a z-statistic P > 0.05 when compared with DENSE circumferential strain. AUCs were classified as 0.9-1 = excellent; 0.80-0.90 = good; 0.7-0.8 = fair; 0.6--0.7 = poor; 0.5-0.6 = fail. 36 Ten randomly identified datasets were deidentified. They were analyzed by K.M. for intraobserver repeatability and by C.M. for interobserver repeatability.

Sample Size Calculation
2D strain information was calculated and described in terms of segmental strain and correlated with the transmural extent of MI. The AUC for 2D strain for identification of MI on a per-segment basis was assessed. For a Type 1 error (α) of 0.05, power of 80% and 90%, and AUC of 0.85 and 0.90 with 2D strain, respectively, then 351 and 478 data points would be needed, respectively. 37

Results
Out of 62 patients who underwent MR, DENSE was not acquired in three of them, was unsuitable for analysis in two of them, and seven patients did not have T 1 maps acquired or the maps were unsuitable for analysis (Fig. 1). The analysis dataset included 50 patients, including 10 (20%) women and 40 (80%) men. The mean age was 59 AE 9 years. Demographics and a typical case are presented in Table 1 and Fig. 2, respectively. The MR scans were carried out, on average, 1 AE 0.5 days post-MI.

Reproducibility Analyses
DENSE had statistically less intra-and interobserver variability as assessed by bias, limits of agreements, intraclass correlation coefficient, and correlation, when compared with feature-tracking (Supplementary Tables 2 and 3).

Per Patient Analysis
The mean LVEF was 52 AE 10%, and median infarct size was 13 (9, 21) % LV mass (Table 2). Global circumferential strain with both DENSE and feature-tracking had moderate negative correlations with LVEF; global radial strain (with feature-tracking) had a moderate correlation with LVEF. Global circumferential strain with both DENSE and featuretracking had moderate correlations with acute infarct size (Table 3).

Discussion
The main findings of the study were: 1) For the detection of segmental infarction, circumferential strain with DENSE was noninferior to ECV and superior to feature-tracking; 2) For the detection of MVO, circumferential strain with DENSE was superior to ECV and to feature-tracking; 3) Segmental radial strain with both techniques was a poor predictor of infarct characteristics.
Observer Repeatability Analysis DENSE had superior intraobserver and interobserver variabilities when compared with feature-tracking. This has important implications in studies investigating regional contractility post-STEMI, 1,2 as smaller sample sizes would be required to identify an improvement in myocardial functional recovery postintervention.

Segmental Strain and Infarct Characteristics
Segmental circumferential strain with DENSE was the strongest predictor of infarct transmurality >50%. We also investigated the utility of strain to identify segmental extent of infarction >75%, as recently identified by Bulluck et al, 4 as a possible threshold for identifying infarcted segments post-MI with less potential for functional recovery.  In this study, segmental circumferential strain with DENSE (AUC = 0.9) and feature-tracking (AUC = 0.7) were strong predictors for identifying segments with >75% infarct transmurality. This compared well with other studies utilizing strain-encoded MRI (n = 38 patients, AUC = 0.96) or with feature-tracking (74 patients, AUC = 0.91). 8,9 A possible explanation for the lower AUC in our study is that one of these previous studies included non-ST-segment elevation MI besides STEMI participants, and both studies excluded patients with previous MI or adverse characteristics.
In this study, circumferential strain with DENSE >-10% indicates severe infarct pathology but does not distinguish between subtypes of infarct severity. As the cardiac MRI was carried out 1 AE 0.5 days post-MI, this could be due to myocardial stunning postreperfusion., Given recent safety concerns of using gadolinium-based contrast agents (GBCAs) in patients with impaired renal function, DENSE has potential to remove the use of gadolinium-based imaging in post-MI patients. Up to 1 in 3 patients presented with STEMI have renal dysfunction 38 ; thus, contrast-free techniques enable a comprehensive MRI assessment in all patients. Furthermore, techniques such as DENSE can be used for serial cardiac imaging in view of reports of gadolinium accumulation in the brain. 39 Segmental radial strain with both DENSE and featuretracking was a poor predictor of infarct characteristics. It also had poor interobserver reproducibility when compared with circumferential strain. This could explain why there is a lack of information on the clinical utility of radial strain in detecting infarcted segments in patients with acute STEMI. 7 Extracellular Volume Fraction and Infarct Characteristics Segmental T 1 was a poor predictor of the segmental extent of infarction or the presence of MVO. Remote zone ECV has   been reported to be associated with adverse LV remodeling and segmental ECV expansion was associated with a reduction in segmental LV wall thickening, 40,41 and can predict segmental myocardial contractile recovery independent of segmental infarct size. 6 In our study, ECV performed as well as circumferential strain with DENSE to detect >50% and > 75% LGE in myocardial segments.

Limitations
The MRI scan was carried out hyperacutely, 1 AE 0.5 days post-MI due to clinical service pressures, with potential infarct size overestimation due to edema in the infarct zone territory. 5 Only three short-axis slices were acquired with DENSE and T 1 mapping, and tagging imaging was not acquired due to time constraints. Only STEMI patients with TIMI flow grade 0 or 1 at presentation were included in this study. This was a single-center study with small patient numbers (N = 50).

Conclusion
Segmental circumferential strain by DENSE has the potential to detect segmental acute severity of infarction without the need of GBCAs. This was a single-center observational study and further work is warranted.