Analysis of Segmental Strain for the Detection of Chronic Ischemic Scars in Non-Contrast Cardiac MRI Cine Images: A Feasibility Study

Aims Cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement (LGE) is considered the gold standard for scar detection after myocardial infarction. In times of increasing skepticism about gadolinium depositions in brain tissue and contraindications of gadolinium administration in some patient groups, tissue strain-based techniques for detecting ischemic scars should be further developed as part of clinical protocols. Therefore, the objective of the present work was to investigate the feasibility of scar detection in segmental strain calculations based on routinely acquired non-contrast cine images in patients with chronic infarcts. Methods Forty-six patients with chronic infarcts and scar tissue in LGE images (5 female, mean age 52 ± 19 years) and 24 gender- and age- matched healthy controls (2 female, mean age 47 ± 13 years) were included. Global (global peak circumferential [GPCS], global peak longitudinal [GPLS], global peak radial strain [GPRS]) and segmental (segmental peak circumferential [SPCS], segmental peak longitudinal [SPLS], segmental peak radial strain [SPRS]) strain parameters were calculated from standard balanced SSFP cine sequences using commercially available software (Segment CMR, Medviso, Sweden). Two independent blinded readers localized potentially infarcted segments in segmental circumferential strain calculations (endo-/epicardially contoured short axis cine and resulting polar plot strain map) and by visual wall motion assessment of cine images. Results Global strain values were reduced in patients compared to controls (GPCS p= 0.02; GPLS p= 0.04; GPRS p= 0.01). Patients with preserved ejection fraction showed also reduced GPCS compared to healthy individuals (p=0.04). In patients, mean SPCS was signicantly impaired in subendocardially (- 5,4% +/- 2) and in transmurally infarcted segments (- 1,2% ± 3) compared to remote myocardium (-12,9% +/- 3, p= 0.02 and 0.03, respectively). ROC analysis revealed an optimal cut- off value for SPCS for discriminating infarcted


Introduction
Myocardial infarction often results in irreversible scar formation of the myocardium. Cardiac magnetic resonance imaging (MRI) with late gadolinium enhancement (LGE) is considered the gold standard method for detection and visualization of scar tissue after myocardial infarction (MI) [1,2]. To this end, intravenous application of gadolinium-based contrast agents is required for visualizing scar tissue, as there are currently no alternatives in cardiac MRI for this task. LGE sequences are time consuming and typically use up more than 50% of the exam time due to the required 10-15 min time delay after contrast agent administration, which is important for contrast retention in scar tissue [3]. Moreover, the intravenous application of gadolinium-based contrast agents is restricted in patients with acute and chronic renal failure [4]. Additionally, intravenous contrast agent application may cause an allergic reaction in some circumstances, which can be life threatening [5]. Finally, recent studies suggest possible deposition of linear gadolinium chelates, e.g. in brain and bone [6,7], which is nurturing uncertainty among both patients and treating physicians. Therefore, alternative scar detection methods based on routinely acquired cine images increasingly gain attention [8][9][10].
During cardiac contraction, myocardial deformation can be described by vectors in the radial, circumferential and longitudinal directions. In healthy myocardium, negative strain values are measured for circumferential and longitudinal direction during systole, while radial strain yields positive values due to thickening in the radial direction during ventricular contraction [11]. Scar tissue leads to regionally altered strain behavior of the myocardium due to reduced contractility of myo broblasts, which replace myocytes after infarction [12].
Different techniques for measuring global and regional myocardial deformation have been developed in the past two decades, like myocardial tagging [13,14], tissue displacement encoding with stimulated echoes [15] and strain encoded imaging [16]. All these techniques -with myocardial tagging being the reference modality for evaluating myocardial strain -have in common, that sequences need to be acquired additionally to an already long clinical protocol. Myocardial feature tracking (FT) was introduced for myocardial strain quanti cation using routinely acquired steady-state free precession (SSFP) cine sequences as input [9,[17][18][19]. Based on optical ow methods [20] or non-rigid algorithm for image registration and segmentation [21,22], myocardial borders can be identi ed and displacement of myocardial segments can be tracked throughout the cardiac cycle.
Recent studies focused on the investigation of global strain parameters in patients with acute and chronic infarcts, revealing reduced global longitudinal and global circumferential strain in these patients [23,24]. Until now, only few studies examined segmental strain in patients with infarction [25,26], probably because reduced accuracy and reproducibility of segmental strain values was reported for optical ow-based FT methods [27]. FT software based on non-rigid algorithm for image registration and segmentation revealed higher accuracy and better reproducibility in segmental strain [21,22] and therefore can be potentially used for scar detection in cine images with su cient discrimination between remote and infarcted myocardium. The purpose of this study was to examine global and segmental strain values in patients with chronic infarcts and healthy controls and to investigate the feasibility of using segmental strain for scar detection in non-contrast cine images.

Study population
From September 2018 to June 2019 46 patients (5 female, mean age 52 ± 19 years) with chronic ischemic scars as detected in standard LGE images were used for this retrospective study. Patients with recent myocardial infarction (within the last 4 weeks), unstable angina or previously diagnosed primary cardiomyopathies were excluded. A control group of 24 healthy age-and gender matched individuals (2 female, mean age 47 ± 13 years) were also enrolled during the same time period. This study was conducted in accordance to the Declaration of Helsinki and its later amendments and the institutional review board approved this retrospective study (Cantonal ethics commission Zurich, BASEC-Nr. 2019-00808). All participants gave written informed consent. Data including image material were handled anonymously.
CMR data acquisition CMR was performed on a 1.5T MR system (Achieva, Philips Healthcare, Best, the Netherlands) using a dedicated 5-channel phased array coil. Cine balanced SSFP images in standard long-axis geometries , segmental peak radial strain [SPRS]) strain parameters were calculated from standard balanced SSFP cine sequences using commercially available software (Segment CMR, Medviso, Lund, Sweden) in accordance with the American Heart Association`s 16 segment model. After image registration by the software, endocardium and epicardium of short axis cine images were manually contoured in end-diastole and in end-systole and results were automatically calculated by the software. Contours could be manually corrected throughout the cardiac cycle, if necessery. All FT strain analysis were perfomed blinded to patient information and LGE images. Twentyfour cases were chosen for performing interobserver agreement.
Localization of potentially infarcted segments in circumferential strain calculations and in cine images -Two independent blinded readers were advised to localize potentially infarcted segments in segmental circumferential strain calculations (endo-/epicardially contoured short axis cine images and resulting polar plot strain map, Fig. 1) as well in the corresponding cine short axis images by visual wall motion assessment.

Statistical analyses
Statistical analyses were performed using commercially available software (SPSS, release 20.0; SPSS, Chicago, IL, USA). Quantitative data are expressed as means ± standard deviations and categoric data are expressed as numbers or percentages. The Kolmogorov-Smirnov Test was used to evaluate normal distribution. Depending on distribution of normality, two-tailed paired t-tests and 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. The Intraclass Correlation Coe cient (ICC) was used to determine interobserver agreement in strain calculations and to determine interobserver agreement in identi ed infarcted segments in circumferential strain calculations and in visual wall motion assessment. ICC = 0.60-0.74 was considered good and ICC > 0.74 was considered excellent agreement [28]. Receiver operating characteristics (ROC) curve analysis was performed to determine the cut-offs of segmental strain values and area under the curve (AUC) for circumferential and radial strain in order to differentiate infarcted from remote myocardium. ROC curve analysis was not performed for segmental longitudinal strain due to lacking signi cance between strain values in infarcted and remote myocardium. Statistical signi cance was assumed at a p-value below 0.05.
Segmental strain: From 736 segments 147 segments were diagnosed with scars on LGE images (20%), of which 102 were considered transmurally infarcted and 45 were subendocardially infarcted. The average amount of infarcted segments per patient was 3.4 (range: 2-7). The most frequently infarcted segments were segment 4, 7 and 10, in descending order.
Localization of infarcted segments in circumferential strain calculations and by visual wall motion assessment: Localization of potentially infarcted segments based on segmental circumferential strain calculations (endo-/epicardially contoured short axis cine images and resulting polar plot strain map, Fig. 1) revealed 118 infarcted segments from 147 infarcted segments (80,3%, 88 transmural, 30 subendocardial; Fig.5) with excellent interobserver agreement (ICC 0.904, 95%CI: 0.845-0.933). 29 infarcted segments were not detected (24 subendocardial and 5 transmural), among them one patient with only a small transmural scar in segment 15. All other patients diagnosed with scars in LGE images had at least one impaired segment in circumferential strain calculations and the missed infarcted segments were localized adjacent to already diagnosed infarcts.

Discussion
This study examined global and segmental myocardial deformation indices in patients with chronic ischemic scars and the feasibility of using segmental strain for scar detection in non-contrast cine images.
Main ndings of this study are: a) global strain values are markedly impaired in patients with infarcts, also in patients with preserved EF compared to controls b) both transmurally and subendocardially infarcted segments show signi cantly reduced segmental circumferential strain compared to remote myocardium in infarct patients c) 80% of infarcted segments could be correctly localized from segmental circumferential strain calculations based on non-contrast cine images, while only 54% of infarcted segments could be detected by visual wall motion assessment of cine images.
Scar tissue leads to altered strain behavior of the myocardium due to reduced contractility of myo broblasts, which replace myocytes after infarction. Recent studies focused on the investigation of global strain parameters in patients with acute and chronic infarcts, revealing reduced global longitudinal and global circumferential strain in these patients [23,24]. Until now, only few studies examined segmental strain in patients with infarction [25,26], possibly because reduced accuracy and reproducibility of segmental strain values was reported for optical ow-based FT methods in the past [27]. The FT software used in this study is based on a non-rigid algorithm for image registration and segmentation and showed higher reliability and interobserver agreement in segmental strain than software based on optical ow methods [21,22]. In line with current study results, GPLS, GPCS and GPRS was reduced in our patient cohort compared to healthy controls [30]. Strain parameters were able to detect subclinical impairment of cardiac function in infarct patients with normal ejection fraction, concluding that strain is a more sensitive parameter for cardiac function compared to LVEF [31]. Moreover, we discovered that remote myocardium in infarct patients has lower mean strain values compared to healthy controls, suggesting subclinical changes in strain behavior of remote myocardium of patients after ischemia and scar formation [32] [33].
Both transmural and subendocardial scars showed signi cantly impaired mean SPCS compared to remote myocardium as well as impeded mean SPRS in transmurally infarcted segments. There are no de nite cut-off values published for discriminating infarcts from remote myocardium. In our patient cohort the derived cut-off value was − 7,2% for segmental circumferential strain (below which segments are considered remote) and 16,6% for radial stain (above which segments are considered remote). Cut-off values for circumferential strain were comparable with those from other research groups [34] [26], but the cut-off value for radial strain was higher than in other studies, mostly due to already higher normal value for radial strain in our patient group. In our patient group, mean segmental longitudinal strain was not signi cantly impaired in scar tissue compared to remote myocardium.
Based on the observation of markedly impaired mean SPCS in scars, we examined infarct localization in segmental circumferential strain calculations (endo-/epicardially contoured short axis cine images and resulting polar plot strain map) in all 46 patients by two readers, blinded to LGE images. While visual wall motion assessment based on non-contrast cine short axis images detected about half of all infarcted segments (53,7%), 80% of infarcted segments could be localized correctly in circumferential strain calculations. One patient with a small transmural scar in the posterior wall was not detected in segmental circumferential strain calculation. Further analysis of the other 28 missed infarcted segments showed that those segments were localized adjacent to already as "infarcted" classi ed segments and were mostly subendocardial.
Our study shows that strain calculations are of substantial bene t for scar detection in non-contrast cine images compared to scar detection based on visual wall motion assessment. This method shows a promising alternative for scar detection in patients who cannot receive or refuse gadolinium. Since FT is already in clinical use, this method can be easily incorporated in the clinical routine in contrast to elaborate postprocessing methods like machine learning techniques, that are often time consuming. Combined use of strain calculations and T1 mapping could probably enhance the diagnostic accuracy of scar localization in non-contrast MRI protocols even more [35].

Limitations
Some study limitations must be acknowledged. This is a retrospective analysis of data from 46 patients and 24 age-and gender matched controls and most patients and controls are male. Equal amount of both genders should be investigated, since it has been shown, that global strain values differ between men and women [36,37]. Further studies with more patients are needed to establish reliable cut-off segmental strain values for remote and scarred myocardium. The bene t of segmental circumferential strain calculations over visual wall motion evaluation based on cine images should be investigated in a prospective setting. Finally, since strain parameters are based on myocardial deformation, akinetic but not infarcted myocardium ("stunned myocardium") may provide false positive results in strain calculations.

Conclusion
Global strain parameters are impaired in patients with chronic infarcts compared to healthy individuals.
80% of infarcted segments could be detected in segmental circumferential strain calculations based on non-contrast cine images, while visual wall motion assessment of cine images revealed only about 54% of all infarcted segments. Analysis of segmental circumferential strain shows a promising alternative for scar detection in patients who cannot receive or decline gadolinium. This technique may be a further step in reducing gadolinium in cardiac MRI protocols in the future.     ROC curves for distinguishing infarcted and remote myocardium based on strain parameters. In SPCS the optimal cut-off is -7,2% (sensitivity of 89,4 % and speci city of 85,7%) and in SPRS the optimal cut-off is 16,6% (sensitivity of 83,3% sensitivity and speci city of 76,5%). ROC= Receiver operating characteristic, SPCS= segmental peak circumferential strain, SPRS= segmental peak radial strain Localization of infarcted segments in segmental circumferential strain calculations (SPCS) showed signi cantly more infarcted segments (80,3 %) than visual assessment of wall motion abnormalities in cine images (53,7%); infarcted segments in LGE images served as gold standard. Brackets signalize signi cantly different strain values between groups. LGE = late gadolinium enhancement, SPCS = segmental peak circumferential strain, VWMA = visual wall motion assessment

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