Ees) determined LV contractility. Adjustments of pre‐ and afterload were done by constriction of the inferior caval vein and occlusion of the descending aorta. Mitral annulus area indexed to body surface area (MAAi), annular circularity index (ACI), and non‐planarity angle (NPA) were calculated by computational analysis. MAAi was more dynamic in response to loading interventions than ACI and NPA. However, MAAi maximal cyclical reduction (−Δr) and average deformational velocity (−v¯) did not change accordingly (p = 0.31 and p = 0.22). Reduced Ees was associated to attenuation in MAAi‐Δr and MAAi‐v¯ . In conclusion, increased cardiac load and reduced LV contractility may cause deterioration of mitral annular dynamics, likely impairing coaptation and increasing susceptibility to valvular incompetence.The purpose of this study was to investigate the effects of loading conditions and left ventricular (LV) contractility on mitral annular dynamics. In 10 anesthetized pigs, eight piezoelectric transducers were implanted equidistantly around the mitral annulus. High‐fidelity catheters measured left ventricular pressures and the slope of the end‐systolic pressure‐volume relationship ( In a large animal model applying a hybrid methodology with sonomicrometer array localization and computational analysis, we determine that mitral annular dynamics are load‐ and contractility‐dependent. These findings may provide explanations for pathological mechanisms in mitral regurgitation and premises for novel treatment strategies. In a large animal model applying a hybrid methodology with sonomicrometer array localization and computational analysis, we determine that mitral annular dynamics are load‐ and contractility‐dependent. These findings may provide explanations for pathological mechanisms in mitral regurgitation and premises for novel treatment strategies.1The mitral annulus (MA) is an integral part of the mitral valve apparatus. During the cardiac cycle, the MA undergoes a geometric deformation from circular to ellipsoid with subsequent reduction in mitral annular area, as well as three‐dimensional folding and flattening of the mitral annulus saddle shape. The alterations of annular geometry through the cardiac cycle are thought to reduce leaflet stress and sustain coaptation in ventricular systole, and facilitate ventricular filling in diastole  is commonly associated with abnormal annular geometry, and correcting for annular dilatation is a fundamental principle of mitral valve repair  of either sex (average weight 58 (SD 5) kg) were used. As previously described, the premedication and anesthetic protocol has been evaluated for safe use of neuromuscular blocking agents and with minor influence on cardiac and hemodynamic function , diazepam (10 mg), and atropine (1 mg) and mask‐ventilated with 3% isoflurane until induction of intravenous anesthesia. Two intravenous access lines were established on which the animal was administered a combination of fentanyl (0.02 mg kg−1), midazolam (0.3 mg kg−1), pentobarbital (15 mg kg−1), and pancoronium (0.063 mg kg−1). The animals were thereafter mechanically ventilated with a mixture of nitrous oxide (57%–58%) and oxygen  through a tracheotomy and monitored by regular blood gases, surface electrocardiogram (ECG), pulse oximetry, rectal temperature, and diuresis. Anesthesia was maintained with continuous intravenous infusion of fentanyl (0.02 mg kg−1 h−1), midazolam (0.3 mg kg−1 h−1), pancuronium (0.2 mg kg−1 h−1), and pentobarbital (4 mg kg−1 h−1). Fluid was substituted with Ringer's acetate at 15 mL kg−1 h−1 throughout the experiment, and bolus was given after weaning from cardiopulmonary bypass.The study was performed in compliance with the European Communities Council Directive of 2010 (63/EU) and approved by the Norwegian State Commission for Laboratory Animals (Project ID: 14687). Ten Norwegian landrace pigs (−1), pre‐calibrated micromanometer‐tipped pressure transducers  were placed in the left ventricle through the apex of the heart and in the left atrium through the left atrial appendage together with a fluid‐filled catheter for zero‐referencing. A second fluid‐filled catheter was placed in the descending aorta through the left carotid artery for monitoring purposes. Endovascular occlusive balloon catheters were implanted in the descending aorta through the femoral artery, and the inferior caval vein (IVC) was snared with a surgical snugger. Five two‐millimeter piezoelectric transducers (Sonometrics Corp.) were placed epicardially; one at the apex of the heart and four equidistantly at the ventricular equatorial plane. After full heparinization (500 IU kg−1), cardiopulmonary bypass was prepared with a 23‐Fr two‐stage venous cannula through the right atrium and 17‐Fr arterial cannula through the femoral artery. While on cardiopulmonary bypass the ascending aorta was cross‐clamped, and the heart arrested with antegrade cold crystalloid cardioplegia (St. Thomas' Solution No 2). The mitral valve was exposed through a left atriotomy, and eight piezoelectric transducers were sutured to the mitral annulus. The left atrium was closed, and the animal weaned from cardiopulmonary bypass. Mean cardiopulmonary bypass and aortic cross‐clamp times were 98 (SD 15) and 55 (SD 15) min, respectively.In dorsal recumbency, the heart was exposed through median sternotomy and suspended in a pericardial cradle. After partial heparinization . After weaning from cardiopulmonary bypass, sonomicrometer array localization was used to determine the transducer positions at 8.53 ms intervals, which gives accurate measurements within a 1% error margin and a theoretical spatial resolution of 0.024 mm  following aortic occlusion. To adjust for weight differences, volumes and area measurements were indexed to body surface area (BSA) calculated with the Kelley formula as BSA (m2) = 734⋅BWkg0.656  and immediately after plateau of peak systolic left ventricular pressures (LV‐SPV = π6D2⋅L) , and end‐systolic (ES) wall thickness in the three‐dimensional echocardiography recordings . ED was defined as the point at which there was a rise in the first derivative of left ventricular pressure (dP/dt), coinciding with the right lower corner of the pressure‐volume loop. Correspondingly, ES was set at the minimum LV volume coinciding with the left upper corner of the pressure‐volume loop. The load‐independent index of the left ventricular contractility was determined by the slope (Ees) of a linear regression line through the end‐systolic pressure‐volume relationship of 10 sequential heartbeats during ICC.Left ventricular volume was estimated through a two‐axis ellipsoid model  and imported into MATLAB  where the mitral annulus was reconstructed by performing a cubic spline interpolation through the coordinate points. The mitral annular area (MAA) was obtained by projecting the interpolated spline onto its corresponding least squares plane and calculating the 2D area. Principal component analysis (PCA) was then performed on the annular spline to make geometric calculations independent of transducer positions. The principal axes were designated to intersect the septolateral (SL) and commissural dimensions. The intercommissural width (ICW) was expressed as the longest distance between the commisures and was calculated by acquiring the annular points that intersected the first principal axis. Likewise, the SL distance was expressed as the distance separating the anterior and posterior horn of the annulus by defining the annular splines intersection of the second principal axis (Appendix v¯), an average of the first derivative of time was calculated from the descending segments of cyclical deformation. For the presentation of cyclical alterations of geometric variables, data were transformed with linear temporal interpolation and normalized for time. The fractional change of each annular metric was calculated as the percentual difference in relation to the end‐systolic geometric configuration of the previous heartbeat.To describe deformational kinematics to mitral annular geometry, maximum cyclical reduction (Δr) was determined as the absolute (ACI) or percentual (MAA and NPA) difference between the maximum and minimum measurement for each heartbeat. To determine the velocity of geometric deformation . After testing for normality (Shapiro–Wilk test) and equal variance (Brown‐Forsythe test) a One‐way Analysis of Variance for repeated measurements or Friedman Repeated Measures Analysis on Ranks was used whenever appropriate to compare baseline versus ICC and AO. If significant, post hoc multiple comparisons were done with Holm‐Sidak tests or Dunn's tests. For comparison of mitral annular deformational kinematics to left ventricular contractile index, simple linear regression analysis was performed with 95% confidence interval. All values are given as mean ± SE or median  unless otherwise noted. 33.1max, and LV‐ESP) as compared to baseline , with a subsequent reduction in indexed end‐diastolic volume and stroke volume (LV‐EDVi and LV‐SVi) (p < 0.001 for both). Following AO, heart rate decreased (p = 0.008), and left ventricular pressures significantly increased , also increasing indexed end‐systolic volume (LV‐ESVi) (p = 0.007).The hemodynamic responses to transient ICC and AO can be viewed in Table 3.2i) decreased significantly in response to ICC at ED and SPmax (p = 0.013 and p = 0.008), and increased following aortic occlusion at ED, SPmax, and ES . However, dynamic changes to MAAi expressed as cyclical reduction (MAAi‐Δr) and average velocity of deformation (MAAi‐v¯) did not change significantly with interventions to left ventricular load.The cyclical deformation and fractional change for each mitral annular geometric variable during baseline, ICC, and AO are illustrated in Figure max, and ES), and in terms of annular kinematics (ACI‐Δr and ACI‐v¯). The NPA was not altered significantly during ICC but was significantly increased at SPmax and ES after aortic occlusion (p = 0.021 and p = 0.029). In response to AO, the average velocity of deformation (NPA‐v¯) was significantly attenuated as compared to baseline (p = 0.011). However, the percentual cyclical reduction of NPA (NPA‐Δr) did not change significantly with interventions to LV load.ACI remained essentially unaffected by loading interventions both in absolute values at the designated cyclic intervals  and kinematics of annular deformation. MAAi‐Δr and MAAi‐v¯ was significantly correlated to Ees , with reduced contractility associated to attenuation in maximum percentual reduction and reduced velocity of deformation in MAAi. NPA‐Δr showed significant positive correlation to Ees , while no significant correlation was seen with NPA‐v¯ . ACI was not significantly correlated to Ees either in cyclical reduction or velocity of deformation .Figure 44.1The present study demonstrates that in an experimental large animal model, mitral annular dynamics are both load‐ and contractility‐dependent. More specifically, the mitral annular area appears more vulnerable to acute changes in load than annular circularity and saddle shape Table . FollowiFurthermore, we demonstrate an association between left ventricular contractility and annular deformation Figure . Most no4.2In a normal valve, the geometry of the mitral annulus facilitates the filling of the LV in diastole and enables peak tethering forces during ventricular systole to be naturally balanced by distributing stresses generated from increased ventricular pressures toward closure and effective leaflet coaptation. It is reasonable to assume that annular dilatation and diminished annular saddle shape will significantly increase leaflet stress during ventricular systole and diminish the efficacy of coaptation  following reduced LV contractility may delay mitral valve closure and result in an ineffective coaptation (Breithardt et al., The vulnerability to functional MR in patients in absence of ventricular enlargement and atrial fibrillation has not been offered a unifying explanation. One possible explanation, as observed in patients with ventricular functional MR treated with cardiac resynchronization therapy, is that an attenuated rise in LV pressure (Furthermore, functional MR has been shown to be dynamic and may substantially worsen in response to exercise and loading conditions (Bertrand et al., Also demonstrated herein, transient inferior caval constriction results in a uniform reduction of the mitral annular area with no change in circularity and saddle shape and a concomitant reduction in end‐diastolic LV volume Tables  and 2. CIrrespective of mitral valvular competency, mitral annular velocity measurements are a useful determinant of LV function, which is commonly used in clinical practice. This is based on the assumption that mitral annular longitudinal displacement corresponds to the shortening of longitudinal ventricular muscle fibers (Seo et al., 4.4Using sonomicrometry array localization with piezoelectric transducers allows for physiologic experiments to be performed with a high degree of temporal and spatial resolution (Gorman 3rd et al., Conventional analyses utilizing sonomicrometer transducers or radiopaque markers assume perfect anatomical placement. For instance, commissures can be difficult to identify in the arrested animal heart, and calculations of circularity require dimensions at exact orthogonal angles. Small deviations in marker or transducer positions will produce differing results and impair comparability. By applying a hybrid approach with computational analysis, previous methodological limitations can be overcome. In the present study, we have adopted a computational analysis using cubic spline interpolation and principal component analysis that allows precise measurements to be obtained unrestricted of marker or transducer positions. Also, in preference to area calculations by usual Delaunay triangulation in which marker positions are interconnected with straight lines, we advocate the use of a spline interpolation technique representative of a biologic structure. Furthermore, for comparison of data from different cardiac cycles, we encourage that data should be corrected for sampling frequency and heart rate. In the current study, this was performed with linear interpolation, which provides a reliable concatenation of data points considering the high sampling frequency of the sonomicrometric acquisition.4.5First, the experiments were conducted in an open‐chest animal model under general anesthesia, which influences both cardiac and hemodynamic function. Second, the experimental protocol did not include a controlled intervention to increase or reduce LV contractility. Instead, variations of LV contractility were achieved as a result of the cardiodepressant effects from cardiopulmonary bypass and anesthetic agents. Finally, the experiments were performed during acute conditions in a small sample of young animals without any known pathology, for which the translational significance to human physiology should be interpreted with caution.4.6In conclusion, the present study demonstrates that loading conditions and ventricular contractility influence aspects of mitral annular geometry and deformation, possibly explaining the susceptibility of certain patient populations to acute mitral incompetence.R.M.P. planned and executed all the experiments, acquired ethical consent, analyzed data and prepared figures, and wrote the manuscript. H.M.D.A. and V.E.P. performed computational analyses. K.G. and J.P.E.K. aided in the design and execution of experiments and provided guidance and advice in data analysis and writing of the manuscript. P‐R.S. and L.S. provided surgical assistance in animal experiments. B.S. and A.L. performed perfusion on cardiopulmonary bypass in animal experiments. R.H. provided advice in the design and study implementation, as well as in the writing of the manuscript. S.U. was the principal supervisor of the research project and was involved in all parts of the study.The work was supported by Western Norway Regional Health Authority and Simon Fougner Hartmann's Foundation.The authors declare no conflicts of interest relevant to this study.


Total, LA/RAConduit, LA/RABooster). In cFD reduced myocardial strain  and nT1 values  were observed compared to controls. In vFD findings were comparable to controls. LV-GCS provided the closest Area under the curve (AUC) to nT1  for discrimination of cFD versus controls. Significantly lower LV-GLS/LV-GCS was found in male compared to female cFD . In six non-hypertrophied female cFD with normal nT1 LATotal -GLS was the only discriminating parameter with an accuracy of 86%. LV-GLS, LV-GCS and LATotal -GLS can detect impaired cardiac mechanics of cFD besides nT1. LATotal -GLS might identify non-hypertrophied female cFD. Variants p.D313Y/p.A143T did not reveal cardiac involvement by multiparametric CMR.Cardiac manifestation of classical Fabry disease (cFD) varies with sex and presence of left ventricular hypertrophy. p.D313Y/p.A143T variants (vFD) represent milder late-onset phenotypes, however, data on vFD are scarce. Patients with FD  and 14 healthy controls underwent 1.5 T CMR including Cine, LGE, native T1 mapping(nT1) and myocardial strain(CMR-FT). CMR-FT was assessed using ventricular longitudinal, circumferential, radial , and atrial longitudinal strain (LA/RA Progressive GLA substrate accumulation, especially the sphingolipid globotriaosylceramide (Gb3) in the heart2 causes left ventricular hypertrophy (LVH), myocardial fibrosis and arrhythmias2 up to lethal FD cardiomyopathy3.Fabry disease (FD) is a rare X-linked, lysosomal storage disease caused by mutations in the alpha galactosidase A gene (GLA) leading to a deficiency of its encoding lysosomal enzyme4. p.D313Y and the p.A143T variants are novel GLA mutations, caused by substitutions of tyrosine for aspartic acid at codon 313 and alanine for threonine at codon 143 of the GLA protein, respectively. Patients with these mutations (vFD) were more often oligosymptomatic compared to classical FD patients (cFD), however with apparent cardiac manifestations7. In contrast to cFD, where enzyme replacement (ERT) or chaperone therapy may reduce LVH and improve myocardial function8, a treatment in vFD is controversially discussed6.Besides the classical phenotype of FD, milder late-onset phenotypes and genetic variants of unknown significance have been described previously9 while native T1 reduction may visualize myocardial sphingolipid accumulation at earlier10 and pre-hypertrophic FD stages11. CMR feature tracking strain (CMR-FT) may assess early changes in myocardial mechanics more sensitive compared to echocardiography due to the excellent image quality across both ventricles12. However, the data on T1 mapping13 and CMR-FT analysis in FD is scarce and refer to cFD only15.CMR is crucial for an accurate, non-invasive assessment of cardiac manifestations of FD. Late gadolinium enhancement (LGE) is present at progressed FD stageThe purpose of the study was (i) to evaluate possible alterations of T1 mapping and CMR-FT in all four cardiac chambers in cFD and in patients carrying the p.D313Y or p.A143T variants (vFD) compared to controls and (ii) to compare the diagnostic yield of the multiparametric CMR parameters to identify Fabry patients.4, vFD = 145 , 16, no cardiac medication, age ≥ 18 years.The study investigated 51 patients with genetically proven FD . All patients and controls gave their written informed consent to use CMR information for research purposes.All Fabry patients were outpatients in stable health condition, referring to a clinically indicated CMR between 12/2014 and 12/2017. Exclusion criteria included standard contraindications to CMR. All participants underwent CMR, ECG and echocardiography during the same study visit. Blood samples of all participants were obtained routinely ± 3 days before/after CMR. Troponin T, NTproBNP, and lyso-Gb3 were quantified. Troponin T concentrations ≥ 14 pg/mL were considered abnormal, using the 99th percentile of the normal distribution3, TE 1.67 ms, TR 3.34 ms, FA 60°, parallel acquisition technique: SENSE. LGE images in short- and in long-axis were acquired using end-diastolic phase-sensitive inversion recovery (PSIR) sequence ten minutes after bolus injection of contrast media (0.1 mmol/kg Gd-DOTA (Dotarem®) with following parameters: voxel size 1.36 × 1.36 × 8 mm3, TE 2.40 ms, TR 5.50 ms, FA 15°. Native T1 mapping was performed using a 3(3)5-modified Look-Locker inversion recovery (MOLLI) sequence on end-diastolic LV short axes in the septal LV wall at basal and mid cavity level, avoiding the blood–myocardial boundary16. Normal T1 values were within the range of the mean ± 2 SD of the mean T1 time of the control group20.Clinically indicated CMR was performed on a 1.5-T scanner . Standard retrospectively gated SSFP cine was performed in short- and in long-axis to assess the LV volumes and function. Imaging parameters were: voxel size 1.36 × 1.36 × 6 mm20. LVH was defined as maximum wall thickness (MWT) > 12 mm or increased indexed rendleft ventricular mass (LVMi) on CMR according to age- and sex-matched normal reference ranges in adults16. For most accurate CMR-FT measurements, endocardial and epicardial contours drawn on cine images were transferred to QStrain, where the tissue tracking algorithm was applied including an automated detection of myocardial borders throughout the complete cardiac cycle. Long-axis cine images were used to compute global longitudinal strain (GLS) and short-axis images were used to compute global circumferential (GCS) strain. Both orientations were used to compute global radial (GRS) strain and are presented separately. Long-axis RV, LA and RA contours were tracked from endocardium in long-axis slices21. Global longitudinal atrial strain  was further divided into the three atrial phasic functions22: LA/RATotal strain , LA/RAConduit strain , and LA/RABooster strain . Global LA and LV longitudinal strain measurements were averaged in 2- and 4-chamber views. LA/RA maximum/minimum was defined at end-systole/end-diastole12. LGE was assessed semi-quantitatively20 on PSIR images using 5 standard deviations (SD) above the mean remote myocardium23 and presented in % of total LV mass.All CMR data analysis was performed by 2 trained observers blinded to all clinical information. All reported CMR values represent means of both observers. Cardiac volumes and functions were assessed using post-processing software . Fischer exact and χ2 tests were used for comparing proportions. Inter-observer agreement was assessed by intra-class correlation coefficients (ICC) and defined as poor (ICC < 0.4), good (ICC = 0.4–0.75), or excellent (ICC > 0.75) agreement24. Abnormally low native T1 values were defined as T1 < 996 ms, i.e., 2SDs below the mean of the controls of 1036 ± 20 ms. Diagnostic accuracy of correctly identified FD patients and FD patients with normal septal T1 times was calculated by Receiver-operating characteristic (ROC) analyses. Optimal cut-offs were obtained by the Youden index. Areas under the curves (AUCs) were compared by the DeLong method. Statistical significance was defined as a two-tailed value of p < 0.05.Normality of continuous data was tested using Shapiro–Wilk test. Categorical data are presented as counts/percentages and continuous variables as means/standard deviation. Mann–Whitney U test or Student’s t test was used for two patients’ group comparisons, where appropriate. Three patients’ group were compared by one-way analysis of variance (ANOVA) for normally distributed parameters or Kruskal–Wallis test otherwise with post hoc Tukey–Kramer test and Bonferroni correction for multiple comparisons . Only 20 cFD and none of the vFD received ERT at the timepoint of the CMR study  were found in cFD compared to controls . However, LV-GLS, LVMi, and the frequency and amount of LGE were significantly different in male compared to female cFD , whereas all left atrial strain parameters didn’t show any sex-specific difference , LAConduit-GLS (p = 0.81), LABooster-GLS (p = 0.72)).In male cFD native T1, LV-GLS, LV-GCS and LVMi were significantly altered with more pronounced difference compared to controls in contrast to female cFD Table . LV-GLS p < 0.05 for all, Table Total-GLS (26 ± 11 vs. 38 ± 5%) and LAConduit-GLS (13 ± 10 vs. 24 ± 4%) were observed in the cFD LVH + cohort compared to controls  were predominantly males (67%) and had significantly more Holter abnormalities like supraventricular/ventricular extrasystoles (SVES/VES), non-sustained ventricular tachycardia (nsVT), increased Lyso-Gb3 (21 ± 20 ng/ml vs. 9 ± 16 ng/ml), hs Troponin T (25 ± 24 ng/l vs. 5 ± 5 ng/l), NT-proBNP (526 ± 562 pg/ml vs. 80 ± 43 pg/ml) and higher prevalence of LGE (67% vs. 6%) compared to non-hypertrophied FD patients (cFD LVH-)  and controls  vs. 38 ± 5%(Controls), p = 0.04; 21 ± 5% (LAConduit-GLS) vs. 24 ± 4% (Controls), p = 0.05, Fig. p < 0.01, Fig. In hypertrophied cFD patients, LV-GCS was the only strain parameter, which was significantly reduced compared to controls independent of the presence of LGE (−18 ± 4% (cFD LVH + /LGE +) vs. −20 ± 3% (cFD LVH + /LGE-) vs. −26 ± 3% (Controls), 2 vs. 31 ± 6 ml/m2, p = 0.03, lower LV-GCS  and LATotal-GLS values were observed  had normal septal T1 values > 996 ms with minimally increased Lyso-Gb3 of 2.2 ± 1.1 (norm: < 0.9 ng/ml), normal other blood sample results , without left ventricular hypertrophy (LVH-), diastolic dysfunction (E/A > 2), atrial fibrillation or myocardial fibrosis (LGE-). However, compared with female controls, significantly larger left atrial volumes , cut-off: < 33%, Table The diagnostic yield of native T1 mapping and strain parameters to identify cFD was assessed by ROC analyses among the subgroup of 51 patients (37 cFD patients and 14 controls). Native T1 (cut-off: < 995 ms) had the highest AUC of 0.92 (95%CI: 0.81–0.98) for cFD discrimination, followed by LV-GCS (AUC: 0.84 (95%CI: 0.71–0.92), cut-off: > −21%) and LATotal-GLS and LV-GLS, 74% (95%CI: 60–84) for LAConduit-GLS and 72% (95%CI: 58–82) for LV-GCS without significant differences among the accuracies  had the highest AUC of 0.88 (95%CI: 59–90) and an accuracy of 86% (95%CI: 59–97) to identify cFD with normal T1 times among the subgroup of 13 females  for native T1 mapping, 77% (95%CI: 64–87) for LATotal-GLS ICC: 0.88 (95%CI 0.80–0.94), The inter-observer agreement for all strain measurements ranged from good (RA-GRS ICC: 0.55 (95% CI 0.43–0.78) to excellent (LV-GCS ICC: 0.85 (95%CI 0.72–0.92), LAThis study evaluated clinical and CMR-based parameters of cFD and vFD carrying the p.D313Y and p.A143T variants compared to controls and assessed the diagnostic yield of multiparametric CMR using native T1 mapping and CMR-FT strain in four cardiac chambers.Total-GLS, LAConduit-GLS) in cFD, which revealed non-inferior diagnostic yield to native T1 mapping in discriminating cFD from controls  and left atrium 27. This discrepancy of study results might be explained by several effects.Significantly reduced LV-GLS, LV-GCS, LAFD Table . HoweverFD Table . Our obs15 and 57%27, alike in the present study with 54%, which might have affected the total group results. Regional LS differences between the LV base and apex might have caused global LS changes after averaging all regional LS values to one peak GLS, as observed in our and in other studies27. This requires further comparison of regional and global longitudinal strain in the future.The percentage of female cFD predominated in these two studies with 63%p = 0.03 for both LV-GLS and LV-GCS). This finding was accompanied by significantly reduced native T1 times in male compared to female cFD patients . We suppose that the sex-specific differences of left ventricular strain parameters  in this study are most probably caused by three major factors:28. This increased myocardial sphingolipid storage caused a mechanical dysfunction that impaired left ventricular strain, as shown by Vijapurau et al.14.The X-linked mode of inheritance and the consequent significant reduction in alpha-galactosidase A activity lead to higher intracellular sphingolipid accumulation in the myocardium in male cFD patients, indicated by significantly reduced native T1 times compared to female cFD patients, as previously described14.Significantly increased LVMi was found in our male cFD patients compared to female cFD patients, which was shown to be an independent predictor of impaired myocardial deformation on multivariate linear regression analysis by the same scientific group2.Higher LGE frequency and amount in our male cFD patients resulted in a stiffer left ventricle with impaired myocardial contractilityOur data reveal a sex-specific variance in LV-GLS and LV-GCS with significantly reduced values in male compared to female cFD patients  with significantly increased LV-GCS compared to male cFD LVH-, might have caused comparable results to controls.In cFD LVH + patients only LV-GCS was significantly reduced irrespective of LGE compared to controls Fig. . This isTotal-GLS and LAConduit-GLS showed a tendency towards significant difference between non-hypertrophied cFD patients without LGE (LVH-/LGE-) and controls. Moreover, a subgroup of six female non-hypertrophied cFD patients with normal native septal T1 times and without atrial fibrillation had significantly reduced LATotal-GLS and LV-GCS values and significantly enlarged left atrial volumes compared to female controls  to further improve its prognosisFinally, all aforementioned strain parameters as well as their prognostic values require further investigation by larger, prospective studies in future.14, the p.D313Y and p.A143T variants were not associated with any subclinical/manifest cardiac involvement by LGE, T1 mapping or CMR-FT in our study. The LGE of the single p.D313Y FD variant was in apical inferolateral location, atypical for cFD, which probably resulted from the patient’s arterial hypertension and/or diabetes mellitus, rather than from the p.D313Y variant. This is in line with a recently published systematic review of 35 studies on p.D313Y, which found a low frequency of clinical features specific for cFD and no intracellular Gb3 accumulation in heart biopsies in p.D313Y carriers37. Instead, most studies revealed an involvement of the central and peripheral nervous system caused by p.D313Y37 and p.A143T38 FD variants.Unlike cFD15. Second, CMR imaging was performed at 1.5 T using a single post-processing vendor for volumetry, T1 mapping, and CMR-FT, so our results may not be applicable to another software analysis due to variety of feature tracking strain results among different vendors39. Third, strain rates and regional strain parameters weren’t assessed as they are instantaneous measures with unavoidable estimation errors and consecutively less accurate12 compared to strain values, which are time-integral parameters.Our study had several limitations. First, due to the rarity of FD and the retrospective study design we included a small number of selected Fabry patients and controls, so that the diagnostic performance of the provided CMR-derived parameters should be interpreted with caution. Moreover, an assessment of T2 mapping and adjustments for the duration of ERT or underlying disease severity was not possible, as previously describedTotal-GLS) CMR-FT can detect impaired cardiac mechanics of cFD besides native T1 mapping with LV-GCS providing the closest diagnostic yield to native T1 mapping. A sex-specific variability existed for LV-GLS/LV-GCS with significantly lower strain values in male cFD. LATotal-GLS might accurately distinguish between oligosymptomatic female cFD patients and female controls. The FD-associated variants p.D313Y and p.A143T did not reveal any cardiac involvement by LGE, T1 mapping or CMR-FT.Left ventricular (LV-GLS/LV-GCS) and left atrial (LASupplementary Information.


Left ventricular assist devices (LVAD) can be utilized for heart failure patients as a bridge to transplant, bridge to destination, or bridge to recovery. Given the lack of a universally accepted consensus for assessing myocardial recovery, techniques and strategies in LVAD explantation also vary. In addition, the incidence of LVAD explantation remains relatively low, and surgical techniques of explantation continue to be areas of interest. Our approach using a felt-plug Dacron technique is an effective way to preserve left ventricular geometry and cardiac function. We describe a technically reproducible approach for ventriculotomy closure during HeartMate3  left ventricular assist device (LVAD) explantation. A 35-year-old Hispanic male with a past medical history of polysubstance abuse , presented with cardiogenic shock SCAI stage D, INTERMACS 1 profile. He was not responding to dual inotropic therapy with escalating requirements of milrinone and dobutamine. The decision was made to implant an HM3 LVAD. At the time of HM3 implant, pathology of the left ventricular apical core specimen showed a marked increase in subepicardial adipose tissue and focal contraction-band necrosis most consistent with idiopathic dilated cardiomyopathy. His postoperative course was unremarkable.After initiation of guideline-directed medical therapy and abstinence from further drug use, he presented to the emergency room 9 months later with asymptomatic low flow alarms of < 1 L/min at 5500 rotations per minute (RPM). Transthoracic echocardiogram (TTE) showed a well-seated HM3 device and inflow cannula, a left ventricular ejection fraction (LVEF) of 40% to 45%, a 4.6-cm LV end-diastolic diameter, and notable opening of the aortic valve with each beat. There were no suction events, arrythmias, nor evidence of hemolysis or pump thrombosis (lactate dehydrogenase 213 U/L). There was no evidence of end-organ damage with normal creatinine (0.78 mg/dL) and liver function tests ; international normalized ratio was therapeutic (2.8), and the patient had New York Heart Association class 1 complaints. A ramp study was performed, slowly decreasing the speed from 5500 RPM to 4000 RPM, with peak exercise to 8.6 metabolic equivalents being achieved . LV recoA left anterolateral thoracotomy at the sixth interspace was performed. LV function was assessed without cardiopulmonary bypass and the LVAD off, and the patient continued to be appropriate for explantation. Peripheral cannulation was done and cardiopulmonary bypass commenced. A plug was made using a rolled polytetrafluoroethylene (PTFE) felt, which was sewn into a 20-mm collagen-impregnated Hemashield Platinum woven double velour polyester graft . Next, a 20-mm pericardial patch was sewn to one end of the tubular graft using 4-0 prolene. A 20-mm circular opening was made within a PTFE felt ring, approximately 15 mm in width, and sewn into the tubular graft 1 cm away from the pericardial patch end . A seconA postoperative computed tomography (CT) scan demonstrated the residual LVAD fixation ring with the hemostatic synthetic plug present and without any notable LV thrombus . The patLVAD explantation following successful myocardial recovery is a rare entity, with literature citing 1% to 2% occurrence.145An additional factor to consider is the high perioperative morbidity and mortality risk for patients undergoing LVAD explantation due to prior adhesions, bleeding, and infection risks. It is prudent to keep operative and cardiopulmonary bypass times short, and therefore minimally invasive approaches are also being attempted to minimize operative times and reduce the aforementioned risks. Several approaches such as ligation of the outflow tract, device and sewing ring removal with subsequent ventriculoplasty, or occlusion of the sewing ring have been described in literature.4789101112Surgical approaches described for LVAD explant include redo-sternotomies, left anterior thoracotomies, and left subcostal incisions with options to (1) simply ligate the outflow graft, leaving the LVAD in situ; (2) explant the LVAD followed by plication of the left ventriculotomy; or (3) fixate plugs onto the ring. As Baldwin et al. described following a HeartMate2 (HM2) explant, leaving the driveline in place after its transection may pose an infection risk postoperatively.13147910The ease and practical nature of using a felt-plug Dacron technique is an effective way to preserve LV geometry and cardiac function without the need for increased cardiopulmonary bypass and operative times. We do not have experience with another explant technique specific to the HM3; rather, our approach is based on an HM2 explantation technique previously published by Cohn et al.Our case highlights areas of knowledge and research that warrant further investigation. Firstly, we identified that there is a small percentage of patients who will have LV recovery that requires LVAD explantation, and a need for a standardized approach and criteria is necessary. As such, given the low incidence, any surgical intervention, such as the one described using the felt-plug Dacron technique, may be difficult to study in a randomized fashion when compared with other techniques described in literature. Lastly, a majority of the patients described in literature in whom a plug was used were anticoagulated post-explant for different periods of time due to the potential nidus of thrombus formation as the blood contacts the artificial surface.7910The ease and practical nature of using a felt-plug Dacron technique is an effective way to preserve LV geometry and cardiac function without the need for increased cardiopulmonary bypass and operative times.


Functional mitral regurgitation (FMR) and tricuspid regurgitation (FTR) occur due to cardiac remodeling in the presence of structurally normal valve apparatus. Two main mechanisms are involved, distinguishing an atrial functional form (when annulus dilatation is predominant) and a ventricular form (when ventricular remodeling and dysfunction predominate). Both affect the prognosis of patients with heart failure (HF) across the entire spectrum of left ventricle ejection fraction (LVEF), including preserved (HFpEF), mildly reduced (HFmrEF), or reduced (HFrEF). Currently, data on the management of functional valve regurgitation in the various HF phenotypes are limited. This review summarizes the epidemiology, pathophysiology, and treatment of FMR and FTR within the different patterns of HF, as defined by LVEF. Functional (secondary) mitral (FMR) and tricuspid (FTR) valve regurgitation are shared across the entire spectrum of heart failure (HF) and negatively affect symptoms and prognosis ,2. They p < 0.001)   8]. In . In p < p = 0.164)   8,18]. ,18. p = In the entire spectrum of HF, FMR and FTR often coexist. Moderate or severe bivalvular functional regurgitation has been observed in about 35% of patients suffering from HFrEF ,18. In tTwo main mechanisms are responsible for functional mitral and tricuspid regurgitation: (1) the annular dilation and/or loss of annular contraction, through a condition of atrial remodeling ; (2) restricted leaflets motion due to ventricular remodeling, which implies papillary muscle displacement, causing chordal tethering . These geometrical alterations and functional impairments occur in the presence of a structurally normal valve apparatus.Ventricular FMR typically occurs in HFrEF due to ischemic or non-ischemic ventricular disease. According to the general classification, the presence of coronary artery disease affecting LV geometry and function allows for differentiation between ischemic and non-ischemic FMR. Dilated cardiomyopathy (DCM), regardless of its etiology, often leads to secondary MR, due to the changes in LV shape (increase in LV sphericity and enlargement in LV diameters). DCM recognizes genetic, but also acquired causes. Monogenic diseases, syndromic forms, and neuromuscular diseases are described among genetic forms. Drugs, toxins, and nutritional deficiencies can lead to acquired forms of DCM with FMR.p = 0.009] [p = 0.0012) [p = 0.001] [2 when compared with degenerative MR [The mechanism of FMR is valve tenting  . Specifi= 0.009] , HFmrEF  0.0012)  and HFrEative MR .Atrial FMR is common in AFib but also occurs in sinus rhythm. HFpEF can generate atrial FMR by causing an increase in left atrium (LA) pressure and, eventually, LA remodeling without needing AFib to develop  6,7,19,,19,24,25Previously published data showed that not all patients with significant aFMR had known atrial arrhythmias. Dziadzko V. et al. found that 46% of patients with aFMR do not have atrial arrhythmias . More reIn a Dziadzko V et al. study, patients with aFMR were significantly older than those with vFMR (80 ± 10 vs. 73 ± 14 years), translating into a different distribution of causes by age group . The aFMEven if current guidelines do not emphasize the need to discriminate the atrial from the ventricular mechanism in FMR, an early distinction is crucial to establish prognostic and therapeutic decisions . The proSimilar to the left side of the heart, right ventricular remodeling, causing leaflet tethering and systolic restricted motion, is typical of vFTR. This can occur in case of left heart diseases  resulting in pulmonary hypertension, primary pulmonary hypertension, secondary pulmonary hypertension and right ventricular dysfunction from any cause . Atrial FTR develops due to tricuspid annular dilatation following right atrium (RA) remodeling, with the concomitant valve leaflets, right ventricle (RV), pulmonary circulation, and left side of the heart being macroscopically normal  35,36,3,38. In HA remarkable past medical history for AFib is widespread in atrial FTR. Atrial and ventricular FTR can coexist in simultaneous RA and RV remodeling. The same happens in FTR due to cardiovascular implantable electronic devices .A stand-alone diagnosis of atrial FTR should make us search for HFpEF . The higp = 0.014) [p < 0.001) [p < 0.0001) [Distinguishing between the atrial and ventricular FTR has prognostic and therapeutic implications ,45,46. T= 0.014)  and HFpE< 0.001) . To our  0.0001) ,49. Atri 0.0001) ,50. Addi 0.0001) ,50,51,52A multidisciplinary approach is a cornerstone for adequately managing HF complicated by FMR or FTR. The team should include HF specialists, imaging experts, cardiac surgeons, interventional cardiologists, and electrophysiologists. Proper management of comorbidities, such as hypertension, diabetes, renal dysfunction, and depression, is also essential and improves outcomes ,54,55,56The first therapeutic approach includes guideline-directed drug therapy (GDMT), followed by surgical valve correction when indicated. Transcatheter repair and replacement for FMR and FTR are emerging as complementary and promising therapeutic options across all HF phenotypes. These techniques can significantly reduce the harmful effects of regurgitant volume overload and interrupt the vicious circle of valvular-driven HF progression.2, and in the absence of a scar at lead insertion [GDMT is the first mandatory therapeutic step in FMR complicating HFrEF (and likely HFmrEF and HFpEF). Treatment with beta-blockers, renin–angiotensin–aldosterone system antagonists, angiotensin receptor neprilysin inhibitors, and most recently, sodium-glucose co-transporter inhibitors, which may result in LV unloading and reverse remodeling and pleiotropic drug effects, secondarily reducing FMR ,38,57. Fnsertion . In addinsertion ,59,60. Hnsertion ,53. Reesnsertion . Gertz ensertion . Taken tnsertion .Surgical or transcatheter treatment is an option in patients with persistent FMR despite GDMT and, when applicable, CRT ,57. NowaEuropean guidelines recommend transcatheter edge-to-edge repair (TEER) in high-risk symptomatic MR not eligible for surgery and satisfying a set of anatomic criteria. This recommendation applies both to functional  and degenerative  etiology . AmericaThe Cardiovascular Outcomes Assessment of the MitraClip Percutaneous Therapy for Heart Failure Patients with Functional Mitral Regurgitation (COAPT) and Percutaneous Repair with the MitraClip Device for Severe Functional/Secondary Mitral Regurgitation (MITRA-FR) trials compared the TEER with the MitraClip device vs. GDMT in patients with FMR ,67. In tA recent study by Gertz ZM et al. analyzed patients in the COAPT trial with a history of AFib, assuming they were most likely to have a mixed atrial and ventricular FMR . PatientTranscatheter approaches mimicking surgical annuloplasty could also be helpful, particularly in atrial FMR ,76,77.Although preliminary data from multiple transcatheter techniques are encouraging, further studies are warranted to determine the most appropriate strategy for the different phenotypes of FMR across the entire LVEF spectrum.FTR in HFrEF, by increasing the risk of overt right-sided HF and end-organ dysfunction, negatively impacts symptoms and prognosis. Although consistent data on the direct effect of GDMT on the reduction of TR are missing, diuretics, sodium, and water restriction by acting on volume overload remain the cornerstone of medical treatment .Scientific guidelines recommend surgery for severe FTR only in the presence of associated left-sided lesions deserving simultaneous treatment. In these patients, surgery for FTR is also an option when the degree is not severe but the annulus is dilated ,57..Depending on the predominant etiology, surgical corrective measures should restore valve competence by addressing the underlying specific mechanisms. When annular dilatation is the primary mechanism of FTR , surgical annuloplasty is the preferred approach to reduce annular dimensions, remodel annular shape, and improve leaflets coaptation ,57. On tThe TriValve Registry showed a procedural success rate of 73%, periprocedural mortality of 0%, and a 30-days adverse event rate of 11% . A sub-op = 0.02). At 30 days, 87.0% of the TriClip patients and 4.8% of medical therapy patients had TR of no greater than moderate severity (p < 0.001). In addition, the quality-of-life score changed by a mean (±SD) of 12.3 ± 1.8 points in the TriClip group, as compared with 0.6 ± 1.8 points in the control group (p < 0.001) [Recent data from the randomized TRILUMIATE trial showed that TEER with the TriClip system  was safe for patients with severe TR, reducing the grade of regurgitation, and improving the quality of life . Into de< 0.001) . As regaAlthough surgery can effectively address atrial FTR, most patients with HFmrEF and HFpEF remain untreated because they are considered higher-risk surgical candidates. However, data from relatively small experiences and registries suggest that a transcatheter approach is valuable even for these patients ,86,87,88Prospective randomized studies addressing these unmet clinical needs across all HF stages must confirm these hypotheses generated from exploratory studies.Functional MR and TR are common findings in HFrEF, HFmrEF, and HFpEF. The proper and simultaneous recognition of the specific mechanism of regurgitation on the one hand and the phenotype of HF on the other is crucial for defining prognosis and therapy. GMDT is the first-line treatment for functional regurgitation across all HF phenotypes, followed by CRT in appropriately selected patients. Behind GDMT and CRT, surgical or transcatheter valve therapy is a valuable option for patients remaining symptomatic. Pharmacological and non-pharmacological treatments are complementary and can interrupt valvular-driven HF progression in appropriately selected patients.


Editorial on the Research TopicEmerging concepts and evidence in novel approaches for spasticity managementMany neurological diseases commonly cause spasticity. Spasticity may be associated with several important related symptoms, including; muscle tone, weakness, sleep disturbance, neurogenic bladder caused by detrusor spasticity, and pain. Optimization of spasticity treatment must balance the reduction of muscle spasticity and the related symptoms, as well as the recovery of motor function when possible. Facilitation and modulation of neural plasticity through rehabilitative treatment as early interventions with repetitive goal-oriented intensive therapy, non-invasive brain stimulation, and pharmacological agents are the keys to promoting motor recovery . ApproprThis research topic sheds light on recent advances in emerging theories and management of adult and pediatric spasticity. The examples are the hyaluronan hypothesis, dry needling, the hydro-dissection effect on spasticity, technology as non-invasive brain stimulation, peripheral magnetic or electrical stimulation, clinical and instrumental evaluations in spasticity, the precisions of injection, ergonomics during injection, dosage and dilution of botulinum toxin, phenol and alcohol, hyaluronidase, cryoneurolysis, surgical interventions, orthoses, and assistive devices, and even practical guidance for outpatient spasticity management during the coronavirus (covid-19) pandemic.Numerous breakthroughs and novel theories have emerged in the field of spasticity management; nevertheless, the absence of robust empirical data persists. Hence, the objective of this research topic is to present a comprehensive analysis of recent advancements and offer insights into the existing body of evidence relating to these advancements.Hashemi et al.): The presence of spasticity in individuals with upper motor neuron problems often leads to severe joint abnormalities, which often require neuro-orthopedic surgical interventions. This study addresses a significant gap in the literature by doing a comprehensive evaluation of the effectiveness of therapies for spasticity in adult patients. A comprehensive search yielded a total of 80 pertinent researches, while 40 trial articles were thoroughly analyzed to identify intervention areas. A lack of randomized controlled trials was observed. Although the absence of standardized evaluation procedures poses a significant difficulty, this review effectively illustrates the indisputable beneficial effects of meticulously chosen surgical interventions on the quality of life for individuals suffering with upper limb spasticity. The necessity for unified methodologies and established protocols becomes crucial to promote evidence-based decision-making in surgical selections and patient referrals.A review : A thorough examination of a cohort of 68 individuals who were referred for inpatient rehabilitation within a six-month period following their initial occurrence of stroke. According to the findings of the study, the patients, on average, underwent their initial phenol neurolysis for roughly 16.3 weeks, with the earliest being 19 days, and more than half of the patients for within 12 weeks of the occurrence of the stroke. The nerves most frequently targeted were the motor branches of the tibial and sciatic nerves. The early phenol neurolysis resulted in a significant reduction in the total amount of botulinum toxin (BoNT) required for the treatment of spasticity without any observed adverse effects.Original research : An illustration of the utilization of cryoneurotomy for controlling shoulder issues associated with spasticity in a 15-year-old male diagnosed with quadriplegic cerebral palsy, classified as Gross Motor Function Classification System 5 (GMFCS 5) is reported. The patient's lower limb spasticity was managed with botulinum toxin A (BoNT-A) injections. However, the decision was made to exclude the shoulder region from treatment due to concerns regarding the potential spread of the toxin and the risk of aspiration. After performing diagnostic nerve blocks, the patient underwent bilateral cryoneurotomies of the right and left lateral pectoral nerves (LPNs), with a duration of 3.5 min for each lesion. The intervention yielded a substantial enhancement in the range of motion (ROM) of the shoulder, as evidenced by the measurements increasing from 86° to 133° on the right side and from 90° to 139° on the left side. The beneficial effects were maintained during the 9-month follow-up period. Furthermore, the caregiver documented significant improvements in the patient's daily functioning, encompassing tasks such as dressing, bathing, transferring, and the ability to maintain a seated position for extended periods of time.A case report : The study had 16 individuals diagnosed with chronic motor incomplete tetraplegia who participated in a 24-week intervention. The intervention consisted of 60-minute sessions conducted three times per week. Participants were randomly assigned to one of two groups: the robotic locomotor training (RLT) group, which utilized the Ekso GT exoskeleton, or the activity-based therapy (ABT) group, which engaged in a combination of resistance, aerobic, and weight-bearing exercises. Remarkably, both interventions failed to produce a meaningful reduction in spasticity. The level of pain intensity showed an increase in both groups; however, it is worth noting that participants in both therapies saw a significant improvement in their subjective quality of life. The observed incongruity between heightened pain levels and enhanced quality of life underscores the necessity for more investigation via more extensive randomized controlled trials.Original research  AIS C and D. Participants previous physical activity is not specified. Despite the results, dosage and timing of exercise interventions should be considered to analyze the effects in spasticity. Given the significance of incorporating different forms of physical activity or exercises into rehabilitation protocols, it is imperative to promote the advancement of future research in order to enhance the quality of evidence. This entails prioritizing rigorous methodologies and optimizing the intensity, frequency, and duration of each exercise to effectively showcase their respective benefits. Furthermore, it is imperative that individuals with chronic incomplete tetraplegia acquire the necessary capabilities to engage in active exercise regimens. Episodes of pain, spasticity, and various forms of discomfort provide significant barriers to engaging in active exercise. All of these problems have to be effectively managed, prevented, or reduced.Massey et al.): The efficacy of non-invasive electrical stimulation (ES) in reducing spasticity in patients with spinal cord injury (SCI) was evaluated. A total of twenty-nine studies were examined, utilizing various assessment tools, including the Ashworth scale, modified Ashworth scale, pendulum test, and Penn spasm frequency scale. Several methods of non-invasive electrostimulation (ES) techniques were analysed,, such as transcutaneous electrical nerve stimulation (TENS), transcutaneous spinal cord stimulation (TSCS), and functional electrical stimulation (FES). The findings from meta-analyses demonstrate a statistically significant decrease in spasticity as measured by the Modified Ashworth Scale (MAS) in randomized controlled trials (RCTs). Analysis of non-RCT studies show an improvement with intervention at short term. The results of the pendulum test did not reveal any statistically significant differences. The neurophysiological outcomes exhibited a deficiency, underscoring the significance of their inclusion in forthcoming investigations. The effectiveness of non-invasive electrical stimulation (ES) relies heavily on the activation of afferent fibers.Systematic review and meta-analysis  scores, it has been observed that non-invasive electrical stimulation (ES) techniques exhibit efficacy in enhancing spasticity outcomes subsequent to Spinal Cord Injury (SCI), as compared to a control group. There is no observed correlation between neurophysiologic outcomes and clinical outcomes. The inclusion of papers in this analysis raises concerns about the quality of research, particularly with regards to blinding and a notable proportion of non-randomized trials. Moreover, there is considerable variation in the ES methods employed across various research.Suputtitada): Spasticity, which frequently arises as a result of stroke and upper motor neuron disease, exhibits intricate origins that encompass many sensitization mechanisms. Novel therapeutic approaches, including Extracorporeal Shockwave Therapy (ESWT), repetitive peripheral magnetic stimulation (rPMS), and needling procedures, have been developed to specifically address sensitization mechanisms, thereby presenting promising possibilities for the management of spasticity. ESWT has been suggested to potentially exert its effects via inducing nitric oxide synthesis, altering rheological properties, and disrupting neuromuscular transmission. The administration of rPMS has been found to augment sensory input, activate the cortical regions of the brain, and induce softening of the underlying tissues. The primary objective of needling, particularly when employing sterile water injection, is to mitigate peripheral sensitivity and decrease pain associated with spasticity. Although showing potential, the heterogeneous characteristics of spasticity and variations in research methodologies underscore the necessity for additional investigation of these therapies, with the potential to enhance the quality of life for persons who experience spasticity following a stroke or other neurological disorders.Perspective  or carefully planned observational studies is essential. Nevertheless, within the context of the current interim phase, we recommend the implementation of these innovative techniques in accordance with the relevant clinical practice guidelines, even in the absence of definitive randomized controlled trials. It is imperative to gather comprehensive data on various aspects such as efficacy, side effects, cost effectiveness, and other pertinent factors through cohort studies. Furthermore, the decision to discontinue these procedures if there is little clinical efficacy or unacceptable side effects, and further for the alternating high-evidence treatment, holds significant importance in the context of clinical practice.An increasing amount of evidence suggests the effectiveness of various new interventions in the management of spasticity. The treatments encompass extracorporeal shockwave therapy (ESWT), repetitive peripheral magnetic stimulation (rPMS), needling, as well as the potential utilization of mechanical needling and sterile water injection, cryoneurolysis, non-invasive electrical stimulation (ES), robotic locomotor training, and innovative applications of established interventions such as surgical procedures, phenol neurolysis, and physical activity or exercises. This highlights the importance of doing a comprehensive examination of the pathophysiology of spasticity. The identification of these novel findings will contribute to the progress of alternative methodologies for the management of spasticity. The promotion of future evidence quality should give priority to randomized trials that have minimal limitations and well-executed observational studies that demonstrate substantial effects or demonstrate other qualifying factors. This approach ensures that the likelihood of future research significantly altering our level of confidence in the estimated effect is minimal.


Left ventricular non-compaction cardiomyopathy, often known as LVNC, is a form of congenital cardiomyopathy that is extremely uncommon. It is a condition that may be identified by an elevated number of endomyocardial trabeculations as well as an increase in their prominence. Alcoholic cardiomyopathy, also known as ACM, is a non-ischemic form of dilated cardiomyopathy that is characterized by contractile failure and an enlargement of the heart ventricles. It is not entirely known whether or not there is a clinically significant overlap in phenotypic characteristics between the two illnesses. We report a patient who had previously been diagnosed with ACM and who had cardiac MRI results that fit the criteria for both LVNC and ACM. A relatively uncommon and intriguing heart condition known as left ventricular non-compaction cardiomyopathy (LVNC) is characterized by an abundance of trabeculations and deep recesses in the left ventricular myocardium. Due to the condition's diverse clinical presentation and similarities to other cardiomyopathies, diagnosing it can be difficult. From childhood to maturity, LVNC can affect anyone and present with a variety of symptoms, from minor fatigue to potentially fatal heart failure and arrhythmias ,2. AlcohIn this case report, we provide a thorough examination of a patient identified as having left ventricular non-compaction cardiomyopathy and the effect of alcohol on the heart. We hope that this study will give readers a thorough grasp of the clinical characteristics, diagnostic process, management techniques, and results related to this complex cardiomyopathy. We aim to contribute by looking into the complexities of this case.This article was previously posted to the Authorea preprint server on August 24, 2023.In this case, a 49-year-old man with a longstanding history of chronic alcohol consumption presented at the outpatient clinic with a constellation of symptoms including dyspnea, chest pain, and palpitations. A physical examination revealed bilateral lung crackles and lower extremity edema, prompting further investigation. The first 2D echocardiogram showed signs of ACM, like global hypokinesia and a reduced left ventricular ejection fraction (LVEF) of 35%. His echocardiogram incidentally revealed prominent left ventricular trabeculations, raising suspicions of left ventricular noncompaction cardiomyopathy Figure . SubsequA comprehensive treatment strategy was initiated, encompassing aspirin, sacubitril-valsartan, furosemide, metoprolol, atorvastatin, and spironolactone, supplemented by strong counseling for alcohol abstinence. Encouragingly, the patient responded positively to treatment, marked by a regression of symptoms and improved exercise capacity. Scheduled follow-ups with the cardiologist are planned for ongoing arrhythmia screening and monitoring of left ventricular function.LVNC is a newly recognized congenital heart condition characterized by a "spongy" appearance of the myocardium, primarily at the left ventricular apex; hence, it is also named spongy myocardium, spongiform cardiomyopathy, hypertrabeculation, and persisting myocardial sinusoids. It can be associated with complex congenital heart defects or skeletal myopathy. It represents a halt in the normal maturation of the myocardium. This disease can present throughout life with progressive left ventricular systolic dysfunction . It resuA review of 59 studies in patients aged 12 and older found that the prevalence of LVNC differed depending on the diagnostic method used. Echocardiography showed a prevalence of 1.28%, while cardiac magnetic resonance imaging indicated a higher prevalence of 14.79%. Athletes had higher rates (3.16% by echocardiography and 27.92% by cardiac MRI). These variations highlight the challenges in assessing LVNC prevalence due to differing diagnostic criteria and population differences . Our patThe preferred diagnostic procedure is two-dimensional echocardiography. It can identify a two-layer myocardium with trabeculations and deep intertrabecular recesses that is composed of a thick non-compacted layer and a thin compacted layer at the mid-ventricular and apical levels. For the diagnosis of LVNC, there are three sets of echocardiographic criteria. The most commonly acknowledged verified echocardiographic criteria are the Jenni criteria, also known as Zurich criteria, for LVNC. They are evaluated at the base, mid, and apical levels in the parasternal short-axis view . As an aCardiac MRI (CMRI) imaging aids in more accurate LVNC identification. Assessment of the non-compacted to compacted ratio is one of the CMR criteria by Peterson with a sensitivity of 86% and specificity of 99%, which must be greater than 2.3 during diastole in any long-axis LV image to make a diagnosis of LVNC . A highlThe objectives of treatment include symptom management and lowering the risk of complications. Digoxin, diuretics, ACE inhibitors, beta-blockers, and afterload reduction medications are used to treat symptomatic patients. Anticoagulation and primary prevention of sudden cardiac death (SCD) are two management concerns that are specific to LVNC patients. If a left ventricular clot has been seen on imaging or if the patient has been diagnosed with atrial fibrillation, oral anticoagulation should be taken. CHADS2/CHADS2-Vasc scores should be used as guidance for risk assessment for patients who do not fit into either of these groups. Ejection fraction (EF) and degree of symptoms can help define goals of management in terms of the placement of an implantable cardioverter-defibrillator (ICD). It makes sense to move on with this technique if the patient satisfies the ICD criteria based on reduced EF. It has been documented that with normal EF, patients still have an increased chance of developing SCD . When a Left ventricular non-compaction is a rare congenital cardiomyopathy. Patients diagnosed with diabetes often have a poor prognosis, predisposing them to cardiac failure, sepsis, and cerebrovascular events. Due to the disorder's rarity and varied presentation, the best way to address it is with a team of professionals.This case report underscores the diagnostic challenges posed by concurrent LVNC and ACM. The patient's chronic alcohol use led to ACM with ventricular dilation, while LVNC indicators like elevated trabeculations were also present. Echocardiography and cardiac MRI confirmed both diagnoses. The case emphasizes the need for accurate diagnostic techniques and a comprehensive approach to differentiate overlapping cardiomyopathies. Successful management involved diverse interventions and counseling. The positive treatment response highlights the significance of early diagnosis. This report showcases the intricate interplay of symptoms, imaging, and diagnostic criteria in understanding complex cardiomyopathies for improved patient care.


Given provider, patient, and health plan administrative burden, there is consensus that the medication prior authorization (PA) process needs to be streamlined and standardized. This includes broader adoption of electronic PA (ePA) solutions, including real-time clinical benefit determination. Insight into provider experiences with ePA will help health plans and pharmacy benefit managers (PBMs) prioritize efforts and investments in PA process improvement.To identify provider experiences with PA by their use of ePA technology in a national sample of providers from the United States.An online, nationwide survey was sent to licensed providers in 2020. The survey obtained information on provider experiences with PA, including PA workload, time to the communication of a PA decision, and other PA-related interactions with plans/PBMs. Provider characteristics and survey responses by provider use of ePA were compared using analysis of variance tests for items based on ordinal scales and a chi-square test statistic for nominal variables. Multivariable regression analyses identified associations between ePA use and PA experience variables, controlling for provider characteristics.P < 0.001) and spent more time on PA submissions (P = 0.003) than providers not using ePA software, but the duration of time from start to finish for a PA submission did not differ (P = 0.211). Providers who use ePA reported more difficulty identifying step therapy requirements (P = 0.005) and more frequently needing to submit additional documentation (P = 0.022). PA-related communication failures did not differ. Those using ePA reported a shorter time to PA decision (P = 0.004) than those not using ePA. Univariate descriptive findings were supported by multivariable analyses.Of 1,147 providers submitting usable surveys, 58% reported personally using ePA for at least some of their PA submissions, 88% submit at least 1 PA in a typical week, and most (82%) spend up to 5 hours a week on PA submissions. A majority (58.5%) reported that manual PA is often required. Those using ePA submitted a higher volume of PAs (This large, nationwide survey identified that a provider’s use of ePA was not associated with less provider time or fewer challenges in preparing and submitting PA requests. However, the use of ePA was associated with a reported shorter PA decision time. Efforts to standardize PA requirements, support of real-time benefits check functionality, and better integration of ePA processes into provider workflows may help reduce PA burden and treatment delays. Health plans must approve the use of some drugs before they will cover those drugs. This study surveyed doctors and other prescribing health care providers on this approval process. It found that providers who use software to ask for approval generally do not find the process quicker or easier, but health plans may take less time to reach a decision. Improvements are needed in the process and software to reduce the time doctors spend on requests. Implications for managed care pharmacyProviders who use electronic prior authorization (ePA) report a quicker time to approval but no improvement in the time spent on prior authorization (PA) or communication with health plans. Partial adoption of ePA plus the lack of a real-time exchange of PA requirements, clinical information, and decisions are possible reasons why provider burden is not lessened. The adoption of a real-time benefits check and better integration of ePA processes into provider workflows should reduce PA burden and reduce PA-related treatment delays.3 However, PA is also associated with administrative burden to providers.6 Noted challenges providers face include difficulty determining if a medication requires PA and, if so, payer-specific requirements for review and approval. PA is also associated with inefficiencies due to the provider and staff needing to navigate various communications channels . Finally, the time to payers’ PA decisions is unpredictable and often lengthy.9Managed care organizations use prior authorization (PA) as a utilization management strategy to promote the safe and appropriate use of medications. PA can help health plans manage costs of care by maximizing the therapeutic value of drug treatment.4 PA delays may start from the time of prescribing, with 60% of medical practices reporting that they do not initiate PA requests until made aware of the need for PA by the dispensing pharmacy.10 Once submitted, 16% of providers wait a few hours or less for a health plan’s response, whereas more than half (64%) report waiting 1 business day or longer.10 Unfortunately, delays can lead to nonadherence, with estimates of PA-related prescription abandonment rates ranging from 37% to 78%.11 Regardless of cause, nonadherence is a concern because of its adverse impact on health outcomes.A documented consequence of the PA process is treatment delay.12 Recommendations include judicious application of PA to medications, improvement in PA processes, and standardization of PA criteria. These same entities also support the adoption of electronic PA (ePA) solutions, which allow for digital preparation and submission of some or all aspects of PA requests. ePA tools may be incorporated into an electronic health record (EHR) system or may function outside of the EHR. ePA can facilitate aspects of the PA process, such as allowing providers to submit PA requests and supporting documentation and receive PA determinations from health plans.13Given these issues, numerous medical and pharmacy organizations endorse changes in the PA approach to ease the burden on providers and patients.15 However, studies also highlight barriers to ePA use, including no access and incomplete or inaccurate information on PA requirements at the time of prescribing.14 Furthermore, ePA solutions vary in functionality in terms of integration with the provider’s EHR, and access to benefit information varies by ePA tool and health plan/pharmacy benefit manager (PBM). Given the current limitations, providers using ePA may engage multiple PA processes, including the occasional use of manual processes. These factors can increase cognitive load, increase administrative costs, and create delays in PA submissions.14Research has shown that ePA can decrease processing and turnaround time for PA decisions.However, the literature evaluating how ePA affects provider burden and PA-related communications between providers and plans/PBMs is limited. This gap in the literature is relevant, as plans/PBMs seek to improve PA processes through ePA. Therefore, this study’s objective is to describe provider experiences with PA by their use of ePA technology in a national sample of providers in the United States.16 Psychiatry providers were oversampled, as they are the current focus of the digital “software-as-a-solution” platform under development by the study investigators.This survey study, conducted in late 2020, was conducted as part of an effort to design a digital solution for medication PA funded in part by a National Institute of Mental Health Small Business Technology Transfer Grant. The study sampled providers in specialties most likely to prescribe PA medications.Supplementary Survey 1 (available in online article).Investigators developed the survey content based on focus groups and stakeholder interviews. Select survey items were designed to identify provider experiences with PA, including PA volume and time spent on PA processes; time to payer communication of a PA decision; and interactions with plans/PBMs, including PA requirements and communication issues. Survey items included in this article are provided in Invitation emails with an embedded hyperlink were sent in October and November of 2020 to 100,000 licensed MD/DO, nurse practitioner (APRN), and physician assistant providers identified from a curated mailing list. Data were collected anonymously, and all participants provided electronic consent prior to taking the survey .Descriptive statistics were used to report provider characteristics and survey responses by the provider self-reported use of ePA. The number and percentage of responders are provided for each response option. Some item categories were collapsed to facilitate results interpretation. Analysis of variance tests were used to compare results by ePA use for survey items based on ordinal scales, and a chi-square test statistic was used for nominal variables. Multivariable ordered logistic regression analyses were performed to identify associations between ePA use and measures of provider PA experience, controlling for provider age, sex, specialty, patient volume, and the provider’s average PA volume. An a priori power analysis indicated that a sample of 1,150 providers would appropriately power the study analyses.Supplementary Table 1).Respondent individual and practice characteristics are reported in P = 0.011) and providers of Hispanic/Latino ethnicity (P = 0.006) reported using ePA. Providers who report using ePA platforms come from practices with fewer prescribers but with higher patient loads (P < 0.001 for both). Dermatology providers were more likely to use ePA (P < 0.001), whereas internal medicine and oncology providers reported lower ePA use (P < 0.05 for both). Note, the survey questions queried the provider’s personal experience with PA volume and workload and their use of ePA and not that of the overall practice.In evaluating respondents by ePA use, greater proportions of women (P < 0.001) and spent more time on PA submissions (P = 0.003) than providers who reported not using ePA. Sixty percent reported that from start to finish, it takes 1 day or less to complete a PA submission, including gathering clinical documentation; 29% reported that the start-to-finish duration is 1 to 2 weeks. However, the duration of time from start to finish for a PA submission did not differ by ePA use (P = 0.211).Overall, 88% of providers reported personally submitting at least 1 PA in a typical week, with 5.4% submitting more than 20 PAs in a week . Most prP < 0.05 for both). A majority (58.5%) reported that manual PA is often to extremely often required by health plans/PBMs, although those using ePA reported that manual PA is required less frequently than those who do not use ePA (P = 0.012).When providers were asked how difficult they find it to identify step therapy requirements for PA, 60% reported that it is moderately to extremely challenging to identify step therapy requirements. In addition, a majority (77%) reported that they often, very often, or extremely often need to provide additional documentation for PA approval. These challenges were more frequently noted by ePA users compared with nonusers (P = 0.194). The overall time to a PA decision differed by ePA use; those using ePA responded that the typical response time from the health plan is shorter (P = 0.004).When asked how long they wait on average from the health plan for a PA response, 36% report receiving a PA response in 1 business day or less. When evaluated by ePA use, 38.0% of providers who use ePA report that they receive a PA response in 1 business day or less vs 33.9% of those who report not using ePA .The findings of the descriptive analyses were upheld in multivariable logistic regression analyses examining the association between PA experiences and ePA use, controlling for provider characteristics, including specialty, patient load, and PA volume  reported that medical practices complete an average of 41 PA requests per week per physician,4 whereas a majority of providers responding to the current study reported that they personally submit 5 or fewer PAs in a typical week. The difference in PA burden between studies may reflect that a portion of the practice PA burden is handled by administrative and other clinical staff. Considering this context, our survey explores the prescriber’s unique personal experience and helps to highlight if and how incorporation of ePA into their workflows influences that experience.This survey contributes to the existing research.6 Further, without a real-time clinical benefit check at the time of prescribing, a PA requirement may not be realized until a prescription claim is denied at the pharmacy. In such cases, even with the use of ePA, this process falls outside of the clinical workflow, which may be offset by other efficiency gains.Several expected benefits of ePA use were not noted by survey respondents, such as our expectation that providers using ePA would spend less of their time on PA submissions. However, prior research has highlighted barriers to the implementation of ePA in the United States by providers that may help explain this finding. One recent survey reported that despite the substantial integration of ePA software into EHR, pharmacy, and payer system platforms, providers report maintaining multiple processes, including submitting some PA requests manually.The current study identified other issues with PA that appear to be either more evident or more problematic for providers who use ePA software. This includes challenges in identifying step therapy requirements and how often providers find it necessary to send additional clinical documentation for coverage authorization. This finding highlights that although ePA can facilitate the completion and submission of PA request forms, real-time access to current PA clinical criteria and documentation requirements is lacking. The standardization of PA requirements and adoption of data standards for real-time communication between providers and plans/PBMs, including benefit checks, will be essential to minimize the administrative burden of PA.13 Others have noted issues leading to breakdowns in communication, such as providers not knowing to or forgetting to check an inbox for PA denials.14 Thus, communication issues may not be driven by failure to communicate per se, rather the communication of decisions may not be optimally integrated into clinical workflows. Thus, plans/PBMs and ePA developers should work with providers to integrate PA decisions into existing provider workflows.Another issue that could be reduced by reciprocal communication with ePA use is effective and accurate communication of PA decisions between health plans/PBMs and providers. In the current study, providers reported that they are often not made aware of PA decisions or were informed by their ePA platform that a medication request was denied when, in fact, it was approved by the health plan. This survey does not examine causes of communication delays and failures. However, a recent initiative to facilitate ePA adoption by plans/PBM and providers found that the level of ePA adoption may impact providers’ ability to navigate ePA for information. Notably, providers who used ePA for most patients reported that they found it easier to view PA decisions than providers who used ePA for some or a few of their patients.12 We contend that these steps are interrelated, as transparency and communication must be improved overall and supported by ePA solutions for optimal provider adoption. This is not to minimize the importance of other recommendations regarding PA improvement, including the judicious use of PA and the regular review of PA medications with volume adjustment.12 For instance, we identified differences in PA volume and provider burden by provider specialty (data not shown). These findings indicate the need to examine PA burden at the specialty and/or therapeutic level to avoid over burdening select providers and, by extension, their patients.Overall, the current survey identifies opportunities for ePA process improvements that are aligned with a consensus statement on improving the PA process sponsored by the AMA, BlueCross BlueShield Association, American’s Health Insurance Plans, and others regarding greater transparency and communication and the automation of PA processes with ePA solutions.18 Designed using a human-centered approach, the optimal ePA solution would consider the unique needs of providers, other health professionals involved in the PA process, and patients, as well as the requirements of plans/BPMs.We believe that plans/PBMs can play a key role in reducing PA burden for providers as well as their own organizations by standardization and support for real-time benefit check technology. However, if the ePA solutions fail to consider existing clinical workflows, providers may find it impractical to integrate ePA into their practice. Ideally, the development of ePA solutions should take a user-centered approach. Design thinking is one such mechanism, defined as “a human-centered approach to innovation that draws from the designer’s toolkit to integrate the needs of people, the possibilities of technology, and the requirements for business success.”19 it may diminish the representativeness of the survey responses. The demographic profile of those who responded matched well to national physician characteristics, but there is a risk of nonresponse bias based on unmeasured factors. Second, this survey was cross-sectional and can be used to examine associations, but it does not establish temporal relations or causation. Further, we asked if providers used ePA software but did not specifically ask providers for the proportion of PA submissions that they submit electronically or to differentiate their PA experiences by ePA vs manual submissions. Thus, the findings reflect their overall experience, and findings may be confounded by unmeasured factors that led providers to adopt an ePA tool. Finally, this survey represents provider perceptions of their experience. Future research that also includes clinic staff, that uses a prestudy-poststudy design, and that has more objective measures of PA volume and burden would be insightful for exploring causal relationships between ePA use, PA burden, and communication challenges.This survey-based study identified differences in provider experience with PA processes by ePA use. Its strengths are a large, nationwide sample with more than 1,000 usable survey responses, making it one of the largest provider surveys examining the effects of PA. However, the survey response rate was low. Although low survey participation by physicians is well documented,This large, nationwide survey of providers identified that providers who use ePA do not report spending less time preparing and submitting PA requests and do not face fewer challenges with PA submissions than those who do not use ePA. However, ePA use was associated with a shorter average time for a PA decision by the plan/PBM once submitted. Efforts to standardize PA and support real-time clinical benefits checks in a manner that is optimally integrated into provider workflows should help to reduce the burden of PA on providers and ultimately help reduce PA-related delays in treatment.


To confirm the ability of native T1 and T2 values in detecting and monitoring early myocardial injuries of chest radiotherapy in neoplasm patients.Fifteen participants received non-anthracycline chemotherapy and chest radiotherapy, and 30 age/gender-matched controls were enrolled in this prospective study. Cardiac magnetic resonance scans were performed within 2 days, 3 months, and 6 months after chest radiotherapy. Myocardial native T1 and T2 values were measured in irradiated and nonirradiated areas. Meanwhile, the parameters of left ventricular function and left ventricular myocardial strain were obtained.P = 0.021), while the adjusted P-value was higher than 0.05 after Bonferroni correction, as well as other parameters. Native T1 values were elevated at 3 and 6 months in irradiated areas compared with baseline . However, T2 values only changed at 3 months in irradiated areas compared with baseline . Neither the native T1 nor T2 values changed in nonirradiated areas during the follow-up period . There were no significant differences in strain changes during the follow-up period .There were no significant differences in left ventricular function, native T1, T2, and strain between patients and controls before chest radiotherapy. In 15 participants who were followed up for 6 months, there was a significant change only in left ventricular ejection fraction (LVEF) among baseline and the first follow-up (Native T1 and T2 values elevated at 3 months after chest radiotherapy, whereas LVEF showed no significant change during the 6-month follow-up. The incidence of cancer is increasing and the age of onset is getting younger, but due to advances in medical care, patients are surviving significantly longer , 2. ChesT1 and T2 mapping is an emerging quantitative MRI technique that allows dynamic analysis of changes in myocardial tissue components by measuring T1 and T2 values, directly reflecting their pathophysiological statuses such as edema, fibrosis, and iron deposition without the use of contrast agents , and proPrevious studies –32 have All patients who received chest radiotherapy at our institution from March 2019 to September 2020 were included in this prospective study. Exclusion criteria included younger than 18 years old and older than 75 years, inappropriate irradiation field (whole heart exposed to radiation field or not exposed to radiation field), receiving anthracycline chemotherapy, and having known cardiac symptoms or diseases . Finally, our prospective observational study included 15 consecutive patients who received non-anthracycline chemotherapy and chest radiotherapy and 30 healthy controls with matched age and gender. To evaluate the changes in myocardial tissue, four cardiac MRI examinations were performed in patient groups before radiotherapy (baseline), as well as within 2 days, 3 months, and 6 months after chest radiotherapy. The healthy controls underwent cardiac MRI only once. This study was approved by the Ethical Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University, and all patients signed informed consent to participate in this study.All patients were receiving standard treatment according to Chinese guidelines at the time of inclusion, and they were treated with intensity-modulated radiation therapy (IMRT), in which multiple beams of uneven intensity are aimed at the tumor, which also improves the consistency of treatment and reduces the dose to normal tissue. Meanwhile, the hearts of all patients in this study were partly exposed to the radiation field. Thus, the heart could be divided into two parts, the irradiated areas (IA) and nonirradiated areas (NIA), see 2, acquisition matrix = 192 × 140, and voxel size = 1.6 × 1.6 × 6.0 mm3. Native T1 map was acquired with a 3 s(3 s)5 s modified Look-Locker inversion recovery (MOLLI) sequence with the following parameters: TR/TE = 2.4/1.1 ms, FA = 35°, FOV = 300 × 225 mm2, acquisition matrix = 256 × 192, and voxel size = 1.2 × 1.2 × 8.0 mm3. The T2 map was obtained using the SSFP sequence with three different T2 preparation times. Parameters were as follows: TE = 0 ms, 25 ms, 55 ms; TR = 3 × RR; FA = 50°; FOV = 300 × 225 mm2; acquisition matrix = 256 × 192, and voxel size = 1.2 × 1.2 × 8.0 mm3.All MRI examinations were performed using a 3.0 T Siemens Skyra scanner  with a 32-channel matrix coil. The cardiac magnetic resonance (CMR) imaging protocols included cine MRI, Native T1 map, and T2 map in four-chamber, three-chamber, two-chamber, and short-axis views. Steady-state free precession (SSFP) cine images were obtained with the following imaging parameters: TR/TE = 39.2/1.4 ms; FA = 80°, FOV = 300 × 225 mm42, circle cardiovascular imaging, Inc., Calgary, Canada). The contour of the myocardial endocardium and epicardium were drawn by the semiautomatic method provided by CVI42 to obtain global T1 values, global T2 values, and parameters about LV function and strain. To avoid blood pool and epicardial fat contamination, a 10% automated contour adjustment was applied to move both contours toward each other to eliminate potential in-plane partial volume effects. The global longitudinal strain (GLS) was measured as an average of peak diastolic longitudinal strain from all three long-axis views using a tissue tracking method. The global T1 values, global T2 values, global circumferential strain (GCS), and global radial strain (GRS) were calculated based on all short axis from bottom to apex.All analyses were using commercial software  of irradiated and nonirradiated areas in the native T1 map and T2 map independently to assess intra- and interrater reliability and to get regional T1 and T2 values. ROI was greater than 1.0 cmP < 0.05 was considered statistically significant. All discrete variables were reported as numbers of participants with percentages in parentheses. All continuous variables with a normal distribution  were reported as mean ± SD, and those without were reported as median with an interquartile range in parentheses. Intraclass correlation coefficient (ICC) and Bland–Altman analyses were used for evaluating the agreement of ROI measurements. Differences in count variables of demographic data were tested by using the χ2 test. The differences between baseline and controls were compared with the Student’s t-test or Mann–Whitney U test to eliminate the interference of chemotherapy partly. The differences in variables between IA and NIA were compared with paired sample t-test. Data were compared among baseline and follow-ups by using the Friedman rank test with post-hoc test with Bonferroni correction. Since adjusted P-values of the Friedman rank test were not reported when there were no significances in SPSS, it would be reported as not applicable (NA). For correlations between regional radiation dose and percent change of T1 and T2 values in the IA, Pearson correlation coefficients were computed.All statistical analyses were performed by using SPSS . Two-sided P < 0.01); however, there was no significant difference between the follow-up groups (see P = 0.037). There were no statistical differences between the two groups in terms of other variables.Of all 362 patients who would receive chest radiotherapy between March 2019 and September 2020 in our institution, 296 were excluded because of the reasons listed in oups see . The bodP < 0.001), shown in In terms of the oncological diagnosis of patients enrolled, six were squamous cell lung carcinoma, three were lung adenocarcinoma, two were small-cell lung carcinoma, and four were esophageal cancer, see P = 0.021), but the adjusted P-value was higher than 0.05 after the Bonferroni correction. There were no statistically significant changes in other LV function parameters, global native T1 and T2 values, GRS, GCS, and GLS at all follow-ups compared with baseline.The average values of mentioned parameters among controls, baseline, and follow-ups are shown in P = 0.144; T2: 39.14 ± 1.44 vs. 38.61 ± 1.62, P = 0.248) and between those of NIA at each time point. Native T1 values in IA were significantly elevated compared with that in NIA at all follow-ups . Although T2 values of IA at all time points were higher than that in NIA, only the second follow-up demonstrated a statistically significant difference .Native T1, T2 values, and their temporal percent changes are summarized in P = 0.006, P < 0.001, separately). As for T2 values in IA, they increased slightly at the first follow-up, elevated sharply and peaked at the second follow-up, and then decreased at the last follow-up, but only showed statistical difference at the second follow-up compared with baseline (P = 0.006). As for NIA, no significant changes were found in native T1 and T2 values at all follow-ups compared with baseline. The longitudinal trend of native T1 and T2 values in different radiation fields is shown in The native T1 values gradually increased since the first follow-up in IA but only showed significant differences since the second follow-up compared with baseline , but at the third follow-up, only the change in native T1 values was statistically significant . Furthermore, the correlation of the percent change of native T1 and T2 values with radiation dose in IA was evaluated and no statistical significance was found  found on IA in our study, and another study  was consOur study has several limitations. First, the sample size of this study was small and the follow-up period was short, thus late changes in parameters such as native T1, T2, LV function, and strain were unclear; and no participant had a cardiac event during the follow-up period, so the correlation between MRI performance and cardiac events after chemotherapy–radiotherapy remains unclear. Second, we did not perform enhancement scans, so additional cardiac MR data such as extracellular volume (ECV) and LGE could not be obtained for several reasons: on the one hand, the scans would have been longer and there was concern that the patients would not tolerate them; on the another hand, some of the chemotherapeutic agents may be nephrotoxic to reduce the patient's renal burden as well as to avoid contrast allergy or adverse reactions. Third, all of our participants received radiotherapy and chemotherapy, some of them with paclitaxel, which has been found to cause cardiac rhythm disturbances possibly through mechanisms such as organelle damage and histamine-induced release , so it mIn conclusion, native T1 and T2 mapping can detect early changes in the myocardium at 3 months after chest radiotherapy, which is earlier than LVEF. This may provide clinical evidence of the time point to early prevent cardiac injury during chest radiotherapy.