Segmental strain for scar detection in acute myocardial infarcts and in follow-up exams using non-contrast CMR cine sequences

Background The purpose of the study was to investigate feasibility of infarct detection in segmental strain derived from non-contrast cardiac magnetic resonance (CMR) cine sequences in patients with acute myocardial infarction (AMI) and in follow-up (FU) exams. Methods 57 patients with AMI (mean age 61 ± 12 years, CMR 2.8 ± 2 days after infarction) were retrospectively included, FU exams were available in 32 patients (35 ± 14 days after first CMR). 43 patients with normal CMR (54 ± 11 years) served as controls. Dedicated software (Segment CMR, Medviso) was used to calculate global and segmental strain derived from cine sequences. Cine short axis stacks and segmental circumferential strain calculations of every patient and control were presented to two blinded readers in random order, who were advised to identify potentially infarcted segments, blinded to LGE and clinical information. Results Impaired global strain was measured in AMI patients compared to controls (global peak circumferential strain [GPCS] p = 0.01; global peak longitudinal strain [GPLS] p = 0.04; global peak radial strain [GPRS] p = 0.01). In both imaging time points, mean segmental peak circumferential strain [SPCS] was impaired in infarcted tissue compared to remote segments (AMI: p = 0.03, FU: p = 0.02). SPCS values in infarcted segments were similar between AMI and FU (p = 0.8). In SPCS calculations, 141 from 189 acutely infarcted segments were accurately detected (74.6%), visual evaluation of correlating cine images detected 43.4% infarcts. In FU, 80% infarcted segments (91/114 segments) were detected in SPCS and 51.8% by visual evaluation of correlating short axis cine images (p = 0.01). Conclusion Segmental circumferential strain derived from routinely acquired native cine sequences detects nearly 75% of acute infarcts and 80% of infarcts in subacute follow-up CMR, significantly more than visual evaluation of correlating cine images alone. Acute infarcts may display only subtle impairment of wall motion and no obvious wall thinning, thus SPCS calculation might be helpful for scar detection in patients with acute infarcts, when LGE images are not available.


Background
Upon myocardial infarction, scar tissue is best visualized by cardiac magnetic resonance imaging (CMR) with late gadolinium enhancement (LGE) [1]. Intravenous application of gadolinium-based contrast agents is mandatory before acquiring LGE sequences. However, gadolinium Open Access *Correspondence: Malgorzata.Polacin@usz.ch should be used carefully in some patient groups, such as patients with severely reduced kidney function. Gadolinium-free options for the detection of ischemic myocardial scars are limited. One promising alternative is scar detection using regional myocardial deformation parameters [2,3]. Myocardial deformation during cardiac contraction can be quantified by myocardial feature tracking (FT) based on routinely acquired, non-contrast cine sequences [4,5]. Necrosis of myocytes after myocardial infarction with subsequent scar replacement disturbs mechanical properties of the myocardium with consecutively altered global and segmental strain [6]. Especially chronic myocardial scars with wall thinning and noticeable wall motion abnormality result in significant segmental strain impairment, which can be used to distinguish scar tissue from remote myocardium [2,3,7]. In contrast, acute infarcts might lack significant myocardial wall thinning and display less wall motion abnormalities in cine images. Therefore, the impact of acute and subacute infarcts on segmental strain needs to be further analyzed. In this study, global and segmental strain derived from non-contrast cine images was analyzed in patients with acute myocardial infarction (AMI) and in subacute follow-up (FU) exams and the practicability of using segmental strain for scar detection in both exams was investigated.

Study population
From July 2019 until December 2020 57 patients (15 female, mean age 61 ± 12 years) with AMI in CMR (imaging 2.8 ± 2 days [range 0-6 days] after reperfusion therapy) were retrospectively assessed. In those patients, CMR was performed to evaluate extent of infarction after revascularization [8]. Thirty-two out of 57 patients had a FU exam (35 ± 14 days, [range 20-86 days]). Patients with concomitant primary cardiomyopathies (n = 2) or nondiagnostic LGE images (n = 3) were not enrolled. Fourtythree individuals (13 female, mean age 54 ± 11 years) with normal CMR examinations during the same time period were also retrospectively included. CMR referrals in the control group were exclusion of structural heart disease (n = 16) and exclusion of coronary artery disease (n = 27). Demographic characteristics of patients and controls are shown in Table 1a, b, respectively.

CMR data analysis Strain analysis
Dedicated software (Segment v3.0 R7946, Medviso, Lund, Sweden) was used to calculate global and segmental strain derived from native cine sequences as previously described [3]. Duration of data loading, image registration, contouring of myocardial borders and strain calculation was 9 min 58 s ± 35 s (range 9 min 4 s-11 min 31 s) per patient or control, respectively. Blinded to patient information (patient or control) and to LGE images, all strain analyses were performed by one reader (reader A: 5 years of experience in cardiac imaging). Interobserver agreement was performed on 28 random cases by a second reader due to the semi-automatic nature of strain analyses (reader B: 2 years of experience in cardiac imaging, blinded to the results of reader A).

Infarct detection in circumferential strain calculations and in cine images
Reader A and B were advised to identify possibly infarcted segments in segmental circumferential strain calculations (right column of Fig. 1a, b) as well as in the corresponding short axis cine images, recognizing visual wall motion abnormalities (VWMA) as previously described [3]. Datasets of all patients (AMI and FU exams) and controls were mixed and presented in random order to both readers. Both readers were blinded to each other, to LGE/edema images (Fig. 1a, b, left column) and to clinical information.

Assessment of affected segments in LGE images and T2w
In a separate session, both readers had to define affected segments (short axis LGE, black-blood T2-weighted images with fat saturation), including classification of affected segments in LGE images in viable (below 50% infarcted wall thickness) or non-viable segments (more than 50% infarcted wall). Readers were blinded to clinical information and each other. Reference standard was the

Statistical analyses
Statistics were performed using commercially available software (IBM SPSS Statistics, release 25.0; SPSS, Armonk, NY). Categoric data are expressed as numbers or percentages and quantitative data are expressed as means ± standard deviations. Normal distribution was tested by the Kolmogorov-Smirnov test. Two-tailed paired t tests or Wilcoxon signed rank were used to compare global and segmental strain values as well as to compare infarcted segments found in LGE, circumferential strain calculations and by visual wall motion assessment. Interobserver agreement was investigated using the intraclass correlation coefficient (ICC). ICC = 0.50-0.75 was considered moderate, ICC = 0.75-0.9 was considered good and ICC > 0.9 was considered excellent agreement [10]. Receiver operating characteristics (ROC) were calculated to determine the cut-offs of segmental strain values and area under the curve (AUC) for segmental strain (SPCS, SPRS and SPLS) in order to differentiate infarcted from remote myocardium. Statistical significance was supposed at a p value below 0.05.
In the subgroup of patients with follow-up exams 118 out of 512 segments showed LGE (23%). Mean scar burden at acute imaging timepoint was 25.1% ± 5 per patient (range 12-56%) with mostly non-viable scars (117/118), further 10 segments had myocardial edema without concomitant LGE. Scar burden decreased in follow-up exams (20.7 ± 4, range 5-48%) and 15 segments were reclassified from non-viable in AMI exams to viable in FU (Table 1b). No LGE was found in the control group.

Discussion
This study analyzed the feasibility of using segmental strain for scar detection in patients with acute and subacute myocardial infarcts. Segmental circumferential strain calculations based on native cine images detected all patients with AMI and 80% of infarcted segments in subacute follow-up exams.
In the clinical setting, established alternatives for scar detection in native CMR sequences are limited. With native T1 mapping, scar and remote myocardium can be differentiated due to different tissue relaxation times [11,12]. However, additional mapping sequences need to be acquired and in order to achieve accurate measurements standardized parameters for healthy myocardium need to be defined separately for every scanner. Moreover, while acute infarcts can be reliably detected in native T1 maps, T1 values of infarcted areas normalize after acute infarction with resulting lower specificity for chronic infarcts [13]. Some artificial intelligencebased techniques successfully detected scar tissue in  non-contrast cine CMR sequences [14,15], but these methods are mostly still in a proof-of-concept stage and are not yet practicable in clinical use. Myocardial feature tracking (FT) was introduced as a novel technique for myocardial strain quantification based on routinely acquired cine sequences. Infarcted tissue leads to altered global and segmental myocardial strain due to reduced contractility of fibroblasts, that gradually replace necrotic myocardium after myocardial infarction [6]. Impairment of global strain in patients with acute and chronic infarcts has been reported by various studies [16,17]. Accordingly, GPLS, GPRS and especially GPCS was impeded in our patient cohort compared to healthy controls. Studies analyzing segmental strain in patients with infarcts in the last decade revealed heterogenous results, in particular problems with accuracy and reproducibility of segmental strain values have been reported [18]. Newer algorithms for strain quantification based on non-rigid algorithm for image registration and segmentation with tracking of the whole image content-instead of tracking myocardial borders only-seem to accurately identify scarred myocardium in segmental circumferential strain [19,20].
Chronic scars with wall motion abnormalities and myocardial wall thinning lead to severe impairment of regional deformation parameters in contrast to healthy tissue, allowing distinction of remote and infarcted segments in regional strain measurements [2,7].
However, the impact of acute infarcts on segmental strain in native cine images has not yet been sufficiently investigated. In contrast to chronic infarcts, which may be visible with the bare eye in cine images due to wall thinning or dyskinesia and are characterized by replacement fibrosis, acutely infarcted myocardium with its various pathophysiologic processes including necrosis and edema mostly lacks wall thinning and has often only subtle wall motion abnormality [21,22]. Therefore, possible strain impairment in acute infarcts is apparently based on different mechanisms compared to strain impairment in chronic scars. Nevertheless, similar to chronic infarcts, regional mechanical impairment of acutely infarcted myocardium was best reflected in circumferential strain calculations [23]. In our patient cohort, mean SPCS in infarcted tissue was significantly impaired compared to SPCS of remote myocardium and this was observed in both acute imaging as well as in subacute follow-up CMRs. Comparing both exams, infarcted tissue showed similar mean SPCS values, remote myocardium on the other hand showed slightly more impairment in the acute imaging timepoint. Further analyses revealed that edematous segments adjacent to infarcts caused strain impairment, suggesting influence of myocardial edema on segmental circumferential strain. Accordingly, Fig. 4 Localization of infarcted segments showed in segmental circumferential strain calculations. Segmental strain calculations showed significantly more infarcted segments than visual assessment of wall motion abnormalities in cine images and this was significant in both imaging time points. In follow-up exams more infarcted segments were found in visual assessment of wall motion compared to acute infarcts (52% vs. 44.4%).
LGE late gadolinium enhancement, SPCS segmental peak circumferential strain, VWMA visual wall motion assessment false positive classification of edematous segments as "infarcted" by both readers was observed in the acute timepoint. After edema subsided in follow-up exams, no false positive results were noticed.
Similar to chronic infarcts, infarcted segments could be distinguished from healthy myocardium with high sensitivity and specificity below a calculated threshold in SPCS calculations, while sensitivity and specificity was markedly lower for corresponding thresholds in SPRS and SPLS.
Direct comparison of wall motion and segmental circumferential strain calculations of every patient in a blinded dataset revealed markedly more infarcted segments in SPCS calculations than by analyzing cine images only and this was true for the acute timepoint (74.6% vs. 43.4%) as well as in follow-up exams (80% vs. 52%). The higher amount of infarcted segments detected by VWMA in follow-up exams could be explained with the incremental myocardial thinning weeks after infarction.
Perfect sensitivity for the detection of patients with AMI was observed in SPCS calculations, where missed infarcted segments belonged to patients already classified as "patient with infarction" by the readers. In follow-up exams, when LGE burden subsided, some scarred segments were reclassified from non-viable to viable scars. Viable scars showed lesser SPCS impairment than nonviable infarcts and in fact one patient with a small viable scar was classified as "patient with no infarction" in SPCS calculations by both readers. SPCS impairment mainly correlates with damage of circumferentially orientated myocardial fibers, that lay below the superficial subendocardial fibers of the LV myocardium [24,25]. In viable scars, deeper lying circumferential fibers are probably not enough affected to cause significant SPCS impairment. This is a relevant limitation of this study, since most infarcts in our patient cohort were non-viable. Furthermore, regional deformation parameters detected by segmental strain are influenced by various factors and are not specific for ischemic tissue damage. Further studies are needed to analyse segmental strain in patients with infarcts and concomitant cardiac diseases that are known to influence global strain like cardiomyopathies or storage disease [26,27]. Moreover, temporary cardiac conditions like myocardial hibernation or stunning or even benign anatomical variants like a left ventricular diverticulum with potential impact on segmental strain needs to be examined, preferably in a prospective setting with a larger patient cohort. In this retrospective study with initially 57 patients, follow-up exams were available in only 32 individuals. The mean interval of 5 weeks between initial imaging and follow-up CMR is presumably not long enough to measure remodelling, because of still ongoing pathophysiologic processes and distant time points should be investigated for that matter in further studies. In addition, segmental circumferential strain calculations use the 16-segment model and apical infarction (segment 17) cannot be detected in SPCS calculations.
Ultimately, strain measurements were performed with only one software. Recent studies show, that strain values are not interchangeable between different vendors, thus vendor-specific threshold values need to be defined for infarcted and remote myocardium [20].

Conclusion
Segmental circumferential strain derived from routinely acquired non-contrast cine sequences detects nearly 75% of acute infarcts and 80% of infarcts in subacute followup CMR, significantly more than visual evaluation of cine images alone. Especially in acute infarcts, where wall motion abnormalities may be subtle and wall thinning is not yet present, this technique may aid infarct detection in patients with ischemic heart disease, who cannot receive or reject gadolinium application or when LGE images are non-diagnostic. However, since strain impairment is not specific for ischemic tissue damage, further studies