Duchenne muscular dystrophy (DMD) manifests in males mainly by skeletal muscle impairment, but also by cardiac dysfunction. The assessment of the early phases of cardiac involvement using echocardiography is often very difficult to perform in these patients. The aim of the study was to use cardiac magnetic resonance (CMR) strain analysis and mitral annular plane systolic excursion (MAPSE) in the detection of early left ventricular (LV) dysfunction in DMD patients.In total, 51 male DMD patients and 18 matched controls were examined by CMR. MAPSE measurement and functional analysis using feature tracking (FT) were performed. Three groups of patients were evaluated: A/ patients with LGE and LV EF < 50% (n = 8), B/ patients with LGE and LVEF ≥ 50% (n = 13), and C/ patients without LGE and LVEF ≥ 50% (n = 30). MAPSE and global LV strains of the 3 DMD groups were compared to controls (n = 18).p < 0.05). The values of MAPSE (11.6 ± 1.9 v 13.7 ± 2.7 mm) and GCS (− 26.2 ± 4.2 v − 30.0 ± 5.1%) were significantly reduced in group C compared to the controls (p < 0.05).Groups A and B had significantly reduced values of MAPSE, global longitudinal strain (GLS), global circumferential strain (GCS), and global radial strain (GRS) in comparison to controls (DMD patients had decreased LV systolic function measured by MAPSE and global LV strain even in the case of normal LV EF and the absence of LGE. FT and MAPSE measurement provide sensitive assessment of early cardiac involvement in DMD patients. Duchenne and Becker muscular dystrophy (DMD and BMD) is an X-linked inherited muscular disease that can also severely affect the heart muscle with manifestation as a cardiomyopathy. Although the cardiac care of DMD patients has recently greatly improved, there are only limited data about detailed development of cardiomyopathy, with certain influence of specific mutation in the DMD gene , 2. DespCardiovascular magnetic resonance (CMR) has become a main non-invasive diagnostic tool for DMD patients as the quality of echocardiographic gradually deteriorate during the disease progression, partially due to disease related skeletal deformities, but also narrow intercostal spaces , 10. In The aim of the study was to use CMR strain analysis and MAPSE in the detection of early LV dysfunction in DMD patients.http://ready.registry.cz) [The cohort of the Czech male population with genetically diagnosed DMD dystrophin mutation was screened in cooperation with the Muscular Dystrophy Registry REaDY (stry.cz)  and enrostry.cz) . All eliCMR studies were performed according to the standard protocol using a 1.5 T scanner  and included functional imaging using balanced steady-state free precession  cine sequences and LGE images acquired 10 min after an intravenous bolus of 0.2 mmol/kg of the gadolinium-based contrast agent gadobutrol . CMR data acquisition was described in detail in the previous study .For the detailed retrospective analysis, the patients were divided into groups based on LV EF and the presence or absence of LGE as an established marker. Four groups were compared – 1/ DMD patients with LGE and LV EF < 50% (group A), 2/ DMD patients with LGE and LV EF ≥ 50% (group B), 3/ DMD patients without LGE and preserved LV EF (group C), 4/ controls. MAPSE and global strain values were compared among the groups both unadjusted and after an adjustment for age. Further, the association of MR parameters with corticosteroid treatment was evaluated in DMD patients, to exclude possible confounding of the results.To assess interobserver and intraobserver agreement, 13 random patients were blindly evaluated by two experienced observers (T.H and R.P.), one of them performed the analysis twice.Septal and lateral MAPSE was measured as previously described , 11 by dMyocardial strain analysis was performed using the feature tracking (FT) method by a commercially available software Image Arena . Analyses were performed in a random and blinded order regarding the patient clinical characteristics. Both the endocardial and epicardial contours were manually traced in long-axis  and short-axis images  during end-diastole (ED) and end-systole (ES). The basal level of the short-axis was taken as the first slice that showed the entire cardiac cycle without the appearance of the left ventricle outflow tract. The middle level of the short-axis was a slice located at the level of the papillary muscles, and the apical level was the last slice that showed the blood pool cavity throughout the entire cardiac cycle. The papillary muscles were excluded from the contours. The manually traced contours were propagated throughout the images for the complete cardiac cycle. The accuracy of this process was visually validated and corrected if necessary. In the case of significant suboptimal tracking, the analysis was repeated from the start to minimize variability .The global LV strains were automatically measured and calculated. Short-axis images were used to determine the global circumferential strain (GCS) and global radial strain (GRS), while long-axis images  for the global longitudinal strain (GLS).2 test for categorical variables. In the case of a statistically significant result, the ANOVA was followed by Dunnet post hoc test and χ2 test by a series of 3 Fisher exact tests with Bonferroni correction. In the case of MAPSE and global strain values, the effect of age was also considered and Analysis of Covariance (ANCOVA) was employed with age as a cofactor. Normality was tested by the Kolmogorov–Smirnov test and visual inspection of the histograms.For basic characteristics, the Fisher exact test was used to compare the binary parameters in DMD patients and controls, while the Student’s t-test for unmatched data was used to compare the continuous variables with a normal distribution. When comparing the CMR results and other data obtained in different groups of DMD patients to the control group, an ANOVA was used for continuous variables and χTo assess intraobserver and interobserver agreement in 10 randomly selected subjects, the intraclass correlation coefficient (ICC) was used. Pearson correlation coefficient was used for other correlations.p value < 0.05 were considered statistically significant.In all cases, results with a Table 2), group A had larger LV (88.5 ml/m2) in comparison to the controls (64.8 ml/m2), and indexed LV stroke volume was lower in all 3 DMD groups.Of the total 51 DMD patients, LV EF < 50% was found in 8 patients (16%), and LGE in 21 subjects (41%). Intramural and subepicardial LGE was found typically in the lateral wall  with differing extension to other LV walls—to the inferior wall (9 patients) and/or to the interventricular septum and anterior wall (5 patients) . In addition, values of MAPSE (11.6 ± 1.9 v 13.7 ± 2.7 mm), and GCS (− 26.2 ± 4.2 v − 30.0 ± 5.1%) were significantly reduced even in group C compared to the control group (p < 0.05), although both groups had similar LV EF . The comparison of global strain values and MAPSE is shown in Table p = 0.91) or controls, where a weak, but nonsignificant negative trend was found . Similarly, no significant correlation with age was found for global strain values in DMD patients and controls , with the exception of GCS in DMD patients .Groups A and B had significantly reduced values of MAPSE, GCS, and GRS in comparison to the controls , with the exception of septal MAPSE in group C, where a trend towards lower value in corticosteroid-treated patients , insignificant at α = 0.05, was observed.To evaluate the possible association of corticosteroid treatment, which could stand as a confounder, with MAPSE and global strain values, the parameters were compared between the corticosteroid-treated and untreated patients. All patients except of one belonged to group B or C. The MAPSE and global strain values of patients from groups B and C who were treated or not by corticosteroids are shown in Table Inter- and intra-observer variability analysis was performed retrospectively on 13 subjects. In almost all parameters, the intraobserver ICC was > 80% and interobserver ICC was > 70%, with the notable exception of GRS, where the agreement was poor (ICC < 10%). Therefore, the results of GRS must be interpreted with caution. The values for lateral and septal MAPSE, as well as for GCS, GLS and GRS are shown in Table To the best of our knowledge, this is the first study assessing CMR-derived MAPSE in the DMD population and so far one of the largest studies using CMR-derived FT in DMD males. The study highlights some remarkable findings. Firstly, it confirmed a premise that the myocardium of DMD patients presents with early, subclinical cardiomyopathy long before detectable LV EF decline and/or LGE. GCS and MAPSE were significantly reduced in DMD patients even at the stage of normal LV EF and absence of LGE. Secondly, it showed the utility of CMR FT strain analysis and MAPSE measurement in these patients and their potential as new imaging biomarkers of early myocardial involvement in DMD subjects.Regarding FT-derived myocardial strain in DMD subjects, there are only a few published studies for comparison. Siegel et al.  demonstrA similar CMR technique for myocardial strain analysis, tissue tracking was used in a study by Buddhe  for compIn agreement with previous studies, circumferential strain seems to be the most sensitive strain marker for early myocardial changes in DMD. In comparison to the longitudinal and radial ones, the circumferential strain was also significantly reduced in LGE negative patients with normal LV EF. The reason for this fact is not fully understood. Nevertheless, it was previously speculated that a gradual loss of sarcomeres could lead to changes in contractility, at first manifesting by the deterioration of circumferential function , 32. In Several antecedent studies have used CMR tagging for strain assessment in the DMD population , 32, 38.Until now, no study using CMR-derived MAPSE assessment in DMD patients has been published. However, LV long axis dysfunction is known as an early biomarker of some pathological states as well as an independent prognostic predictor incremental to common risk factors including LV EF –18. MAPSThe study supported the evidence that the relatively simple CMR parameters, FT-derived strain and MAPSE could recognize early myocardial changes in DMD patients even without the use of a contrast agent or at least limit the frequency of gadolinium-based contrast agent exposure . BesidesThe study has several limitations. This is a single-center, retrospective study, with a limited number of patients because DMD is a rare disease. Actually, almost the whole cohort of the Czech male population with genetically diagnosed DMD dystrophin mutation  was screened, and all eligible patients fulfilling inclusion criteria were examined using CMR. Another limitation is the fact that only global myocardial strains were evaluated. Nevertheless, it is known that the FT technique has limited reproducibility of segmental strain measurements, thus FT regional analysis is not recommended for clinical and research purposes , althougDMD patients had decreased LV longitudinal systolic function measured by MAPSE and GCS even in the case of normal LV EF and absence of LGE. CMR-derived FT and MAPSE measurement provide a sensitive assessment of early cardiac involvement in DMD patients.


P > 0.05). However, longitudinal PS was significantly lower in the preserved-LVEF group than in the control group (P = 0.005). Multivariate linear and logistic regression analyses showed that global longitudinal PS was independently associated  with the LV remodeling index. In conclusion, early quantitative evaluation of cardiac deformation can be successfully performed using CMR tissue tracking in T2DM patients. In addition, global longitudinal PS can complement LVEF in the assessment of cardiac function.To quantify the global and regional left ventricular (LV) myocardial strain in type 2 diabetes mellitus (T2DM) patients using cardiac magnetic resonance (CMR) tissue-tracking techniques and to determine the ability of myocardial strain parameters to assessment the LV deformation. Our study included 98 adult T2DM patients  and 35 healthy controls. Conventional LV function, volume-time curve parameters and LV remodeling index were measured using CMR. Global and regional LV myocardial strain parameters were measured using CMR tissue tracking and compared between the different sub-groups. Receiver operating characteristic analysis was used to assess the diagnostic accuracy. Regression analyses were conducted to determine the relationship between strain parameters and the LV remodeling index. The results show that global radial peak strain (PS) and circumferential PS were not significantly different between the preserved-LVEF group and control group ( T2DM is presently a rapidly growing global public health problem. According to the 2015 data of the International Diabetes Federation (IDF), more than 450 million people worldwide have DM2. Moreover, the number of T2DM patients is still increasing. The IDF predicts that the number of DM patients will reach 600 million by 20402. Cardiovascular disorders have been reported to be the leading causes of death and disability in T2DM patients3.Type 2 diabetes mellitus (T2DM) is a metabolic disease associated with high morbidity. It is characterized by insufficient or non-effective utilization of insulin, resulting in chronic hyperglycemia4. These findings suggest that histological changes, LV remodeling, myocardial hypertrophy, and fibrosis occur, which may lead to cardiac diastolic dysfunction and eventually to systolic heart failure4. Early studies have also suggested that T2DM might be associated with concentric LV remodeling which may lead to systolic or diastolic dysfunction6. Concentric LV remodeling itself has been reported to be an adverse prognostic marker of cardiovascular events, and such remodeling may explain why T2DM patients with heart failure have such a poor prognosis8. However, early myocardial damage is slow and difficult to detect in T2DM patients, and symptoms are not specific, leading to an increase in the risk of hospitalization and adverse outcomes10. Therefore, early evaluation of myocardial damage using imaging approaches is extremely important in making an early diagnosis, commencing treatment promptly, and hopefully preventing a poor prognosis in T2DM patients.T2DM patients have been found to have different types of cardiovascular issues, such as increased oxidative stress, endothelial dysfunction, mitochondrial dysfunction, impaired calcium handling, and extracellular matrix remodeling11. However, in the early stages of many cardiac diseases, LVEF is preserved despite impaired myocardial contractility13. Myocardial strain is an important method to evaluate the clinical or subclinical deformation of the cardiac14. Current methods for measuring myocardial strain include echocardiography, MR tagging and CMR tissue tracking. Echocardiography has been used extensively for strain analysis, but the accuracy of echocardiographic results depends substantially on operator skill and is limited by narrow acoustic windows. MR tagging require special sequences, and post-processing is complex. CMR has been regarded as the golden standard for the accurate quantification of cardiac function. In recent years, CMR tissue tracking has rapidly developed into a quantitative technique for the quick evaluation of myocardial strain15. CMR tissue tracking assesses the movement of the myocardial voxel and provides unique information about myocardial strain in subclinical conditions and potentially identifies myocardial damage before a significant reduction in LVEF occurs17. Traditional SSFP cine sequences  are suitable for CMR tissue tracking and only require a relatively quick and easy post-processing approach making these sequences ideal for the quantitative evaluation of LV myocardial strain characteristics. Presently, few studies are focusing on the assessment of myocardial strain damage using CMR tissue tracking in T2DM patients18. Thus, in the present study, we aimed to quantify myocardial strain using CMR tissue tracking, in T2DM patients, especially in patients with preserved LVEF, and to determine the ability of myocardial strain parameters to assessment the LV deformation. We explore the relationship between myocardial strain parameters with LV remodeling index.Clinically, left ventricular ejection fraction (LVEF) is widely used to evaluate cardiac function and thus myocardial statusThis study was approved by the Ethics Committee of Clinical Trials and Biomedicine at the West China Hospital of the Sichuan University (No-2016-24) and we pledged to abide by the declaration of Helsinki (2000 EDITION) in accordance with the relevant medical research rules in the study. Informed consent was obtained from all participants prior to study participation. All participant-sensitive information was kept confidential and was used solely for the purpose of this study.19. The exclusion criteria were history of cardiovascular disease , symptoms of possible cardiovascular disease , malignant tumors, uncontrollable hypertension, thyroid disease, other systemic diseases, and contraindications to CMR. Eventually, 98 T2DM patients of the original 103 fulfilled these criteria and were assessed in the study. Exclusion criteria for the healthy controls were history of diabetes mellitus, hypertension, hyperlipidemia, cardiovascular diseases, malignant tumors, thyroid diseases, other systemic diseases, and contraindications of CMR. Concurrently, thirty-five individuals from our healthy volunteer database, with similar sex, age and body mass index [BMI] distribution to those of our patients, were recruited to constitute the control group.One hundred and three adult T2DM patients from West China Hospital of Sichuan University were enrolled in this study between March 2016 and May 2018. Inclusion criteria were diagnosis of T2DM in accordance with the criteria of the American Diabetes AssociationFor all T2DM patients, we recorded age, sex, disease duration, blood pressure, height, and weight; we then calculated BMI. Additionally, we collected the following laboratory data from each T2DM patient: HbA1c, triglyceride (TG) level, total cholesterol, high-density lipoprotein (HDL) cholesterol, and low-density lipoprotein cholesterol (LDL).All patients and normal controls underwent CMR on the 3 T whole-body MR scanner MAGNETOM Skyra  with an 18-channel body phased-array coil combined with a spine coil (12 of 32 channels used). All participants were examined in the supine position and were required to hold their breaths at predefined portions of the exam. The manufacturer’s electrocardiographic (ECG) gating device was used during the entire examination. Following local transverse, coronal, and sagittal imaging, a series of short-axis cine images were acquired from the mitral valve level to the LV apex using the steady-state free-precession sequence with retrospective ECG gating . In addition, four-chamber and two-chamber long-axis cine images were acquired.42 . Image analysis was performed to evaluate conventional cardiac function and myocardial strain.All CMR data were analyzed using the commercially available software cviA set of short-axis and long-axis two-chamber and four-chamber slices were uploaded into the tissue-tracking module. Only short-axis slices were used to analyze cardiac function while both short- and long-axis slices were used to analyze strain parameters. An experienced radiologist manually delineated the endocardial and epicardial borders in the LV end-diastolic and end-systolic phases for each series involving short-axis two-chamber and four-chamber cine images; the moderator bands and papillary muscles were carefully excluded. Finally, reference lines were marked in the LV long-axis two-chamber and four-chamber cine images, and the short-axis reference points were defined as shown in Fig. 42 short-3D module. Cardiac function indexes, including LV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), stroke volume (SV), cardiac output (CO), and cardiac mass, were then automatically computed. The LV end-diastolic dimension (LVEDD) was measured on a four-chamber cine image. The LV remodeling index was obtained by calculating the ratio of the LV mass to the LV EDV. cvi42 software was used to automatically calculate the time-volume curve parameters, including the peak ejection rate (PER) and peak filling rate (PFR).Short-axis cine images were used to analyze cardiac function with the cvi21.The different strain parameters of each phase were automatically calculated by tracking the myocardial voxel points. The end-diastolic phase was the initial point of strain tracking. The LV global and regional  tissue-tracking variables, including the radial, circumferential, and longitudinal peak strain (PS), peak systolic strain rate (PSSR), and peak diastolic strain rate (PDSR), were automatically computed. Radial strain and circumferential strain represent movement in the cardiac short-axis direction. Radial strain reflects the thickening of the ventricular wall in the systolic phase, and circumferential strain is defined as circular motion in the direction of the short axis. Longitudinal strain refers to strain in the cardiac long-axis direction, which is the average strain of each longitudinal myocardial fiber segment. As LV wall thickening increases with wall contraction, radial strain is expressed as a positive value. Conversely, as the myocardium shortens in the longitudinal and circumferential directions during LV contraction, circumferential strain and longitudinal strain are expressed as negative valuesThe reproducibility of the global LV PS parameters was assessed by two experienced radiologists. To assess intra-observer variability, a single observer completed measurements of 24 random cases at two different time points with an interval of 1 month; these measurements from the two different time points were compared. To assess inter-observer variability, measurements from two independent experienced observers blinded to each other’s findings were compared.t-test or the one-way analysis of variance. The Mann–Whitney U-test was used to compare data not showing a normal distribution. Pearson’s correlation analyses were used to evaluate possible correlations of tissue-tracking variables with LVEF and time-volume curve parameters. Univariate and multivariate linear regression analyses were used to identify independent correlates of LV strain parameters and the LV remodeling index (LVMVR:LV mass to LV end diastolic volume). Multivariate logistic regression analyses were performed to explore the influence factor of LV remodeling. Receiver operating characteristic (ROC) analysis was performed to determine optimal cut-off values for LV strain parameters to identify LV dysfunction in T2DM patients. The intra-observer and inter-observer variabilities (reproducibility) were assessed using intraclass correlation coefficients (ICCs). All statistical tests were two-tailed. All statistical analyses were performed using SPSS  and GraphPad Prism . A P-value < 0.05 was considered to indicate a statistically significant difference.All data were analyzed using the Kolmogorov–Smirnov test. Normal data are presented as mean values with standard deviations. The homogeneity of variance assumption was assessed using Levene’s test. Comparisons were made regarding all cardiac function indexes and strain parameters between the reduced-LVEF group, the preserved-LVEF group, and the control group. Continuous variables were compared using the independent Student’s P > 0.05).Of the 98 T2DM patients, 72 had preserved LVEF , and 26 had reduced LVEF . The 35 healthy controls consisted of 17 men with a mean age of 53.2 ± 10.3 years. The baseline characteristics of the T2DM patients and normal controls are presented in Table P < 0.001). The mass was significantly higher in the T2DM patients as compared to the control group .LVEF were lower in the T2DM patients as compared to the control group . On the other hand, LVEDV, LVESV, SV, and CO were not significantly different between the control group and the preserved-LVEF group (P > 0.05). The time-volume curve parameter PER was significantly lower in the reduced-LVEF group as compared to the control group (P = 0.002). This index was numerically lower in the preserved-LVEF group as compared to the control group, but the difference was not significant (P = 0.586). PFR was significantly lower in both the reduced- and preserved-LVEF groups as compared to the control group .Conventional LV function and time-volume curve parameters of subgroups were obtained and compared Table . Among aP < 0.05). Although there were no significant differences between the T2DM patients and the control group in the LV global radial and circumferential PDSR (P > 0.05), global longitudinal PDSR was lower in the T2DM patients as compared to the control group (0.83 ± 0.21(1/S) vs. 0.93 ± 0.16(1/S), P < 0.05). There were no significant differences between the T2DM patients and the control group in the LV global radial, circumferential and longitudinal PSSR (P > 0.05).The LV global radial, circumferential, and longitudinal PS were lower in the T2DM patients as compared to the control group . Although there were no significant differences between the preserved-LVEF group and the control group in the LV global radial and circumferential PS (P > 0.05), global longitudinal PS was lower in the preserved-LVEF group as compared to the control group  . However, the global systolic strain indexes were not significantly different between the control group and the preserved-LVEF group (P > 0.05). With regard to the global diastolic strain indexes, the global radial, circumferential, and longitudinal PDSR were significantly lower in both the preserved- and reduced-LVEF groups than in the control group  (Supplementary Information).With regard to the global systolic strain indexes, the global radial, circumferential, and longitudinal PSSR were significantly lower in the reduced-LVEF group than in the control group . Longitudinal and circumferential PDSR of the basal segment and longitudinal PDSR of the mid segment were lower in the preserved-LVEF group as compared to the control group . In addition, the radial PS of the apical segment was higher in the preserved-LVEF group as compared to the control group   of the three groups were compared (Supplementary table). Most regional radial, circumferential, and longitudinal LV strain parameters were significantly different between the reduced-LVEF group and control group , circumferential PS , and longitudinal PS   Fig. .Table 3CP = 0.014) and that radial PS was not associated with LVMVR  (Table P = 0.042) . We attempted to determine whether global longitudinal PS would be significantly associated with LVMVR after adjusting for baseline characteristics and whether it would be significantly associated with the CMR indexes that were independently related to the occurrence of LVMVR. In the final multivariate model, global longitudinal PS was found to be associated with LVMVR  and intra-observer correlation coefficients (ICC: 0.832–0.920) of radial, circumferential, and longitudinal PS were considered to have good reliability.23. Although LVEF is traditionally used to monitor cardiac function, it is often preserved or increased in the early stages of diabetes despite the development of global and regional cardiac deformation and dysfunction, indicating that LVEF cannot be reliably used to monitor early subclinical changes in the diabetic heart25.Diabetic cardiomyopathy is one of the most common cardiovascular complications, yet no standardized guidelines exist to make the diagnosis and consequently potential cardiovascular complications are often overlooked in the early stages of T2DM. Furthermore, previous studies have mentioned that diabetes has a silent, slow, and early impact on cardiac functionThe present study adopted traditional CMR cardiac function indexes and time-volume curve parameters and included CMR tissue tracking to assess deteriorated myocardial deformation, including global and regional myocardial strain in the diastolic and systolic periods, in order to comprehensively explore cardiac dysfunction in T2DM, especially those changes occurring in the setting of a preserved LVEF. We demonstrated the value of CMR-derived global longitudinal PS in T2DM patients. Additionally, we found that myocardial strain was closely related to impaired cardiac function and provided imaging information for the early identification of cardiac damage in T2DM patients.In this study, 72 (73%) out of 98 T2DM patients showed preserved systolic function (LVEF ≥ 55%) and had no clinical cardiac symptoms. We found no significant differences in conventional cardiac function indexes, such as LVEDV, LVESV, LVSV, CO, and LVEDD, between the preserved-LVEF group and the control group. These findings indicate that conventional CMR function parameters might not be of assistance in the early detection of cardiac damage in T2DM patients.26.As expected, most CMR tissue-tracking parameters were lower in the reduced-LVEF group as compared to the control group and the preserved-LVEF group, suggesting that T2DM patients with reduced LVEF show both morphological and functional impairments. These findings are consistent with the study by Liu et al. which reported decreased PS in Ebstein’s anomaly with reduced LVEFThe systolic strain parameters were not significantly lower in the preserved-LVEF group as compared to the control group. However, it is worth noting that the global longitudinal PS and the diastolic strain indicators, such as radial, circumferential, and longitudinal PDSR, were lower in the preserved-LVEF group than the control group. The index PFR for diastolic function in the time-volume curve also decreased, which corresponded to the resulting strain values. In the correlation analysis, there were weak correlations between strain parameters and time-volume curve parameters. A possible reason for the weak correlations is that the principles of evaluation behind these parameters differed. The time-volume curve is based on the change trend of LV volume in a certain period; however, it cannot be used to monitor the systolic and diastolic ability of the myocardium itself. On the other hand, CMR tissue tracking is based on movement of the myocardial voxels for the evaluation of myocardial strain.28. Previous studies on other heart diseases have shown that most global strain abnormalities first appear in the longitudinal direction, suggesting that longitudinal strain damage may occur early31. A study about speckle tracking imaging in myocardial infarction also suggested that longitudinal strain damage occurs early14. The same abnormal manifestation was observed in this study in T2DM patients. Previous studies have suggested that myocardial interstitial fibrosis and cardiac activity characteristics are closely related to longitudinal strain, which is an important pathophysiological basis of LV remodeling33 Considering a previous finding that longitudinal PS is better than LVEF for predicting cardiac events34, we can assume that the early detection of myocardial strain is of great significance to the clinical prognosis of T2DM patients. ROC curve analysis demonstrated that the performance of global radial, circumferential, and longitudinal PS in detecting T2DM was moderate.Most abnormal global strain parameters occur in the longitudinal direction and are associated with diastolic function, which indicates that strain in the longitudinal direction, and in the diastolic period, becomes impaired in the early stage. These results are consistent with the results of the study by Habek et al. and Nakai et al., which identified cardiac dysfunction in conditions of early diastolic function and late systolic dysfunction in diabetic patients and found that it was associated with heart rate and its variability35.The segmental analysis found that most apical, mid, and basal strain parameters were lower in the reduced-LVEF group as compared with the control group. The trend of change in segmental strain parameters was consistent with that of global LV strain parameters. These results are similar to the findings in the study by Li et al. on cardiac strain in myocardial amyloidosis36.The regional myocardial strain of the basal and mid segments was lower in the preserved-LVEF group as compared with the control group. However, the radial PS of the apical segment was higher in the preserved-LVEF group as compared with the control group. This result may be related to a compensatory increase in the apical radial PS in the early stage, which is consistent with the findings of a previous reportWe found that global strain parameters were positively correlated with LVEF, which indicates that LVEF may decrease with a decrease in global strain. Good correlations were noted between myocardial strain and traditional cardiac function indexes, and high reproducibility and consistency were noted in the diagnosis of cardiac deformation, especially with regards to the early evaluation of subclinical diastolic dysfunction in T2DM.5. Our results indicate that patients with diabetes have an increased LV remodeling index (LVMVR) when compared with the value in normal individuals. In our study, we also explore the relationship between strain parameters and the LV remodeling index. Global longitudinal PS, radial PDSR, circumferential PDSR, and longitudinal PDSR were the only strain parameters independently related to LVMVR. A previous study has suggested that longitudinal PS is better than LVEF for predicting cardiac events31. Based on these findings, we only included global longitudinal PS in subsequent multivariate logistic regression analyses.Previous studies have shown that diabetes is correlated with LV remodeling, which may lead to systolic or diastolic dysfunctionIn the multivariate logistic regression analyses, we found that global longitudinal PS (derived from strain parameters) was associated with the occurrence of LVMVR. After comprehensive adjustments for baseline and traditional CMR indexes, only global longitudinal PS was associated with LV remodeling.The present study has some limitations. First, this study did not provide long-term follow-up data. Second, this study only evaluated LV myocardial strain; right ventricular strain characteristics are currently being considered in a follow-up study. Finally, CMR tissue tracking is a technology that involves increased automatization and robustness of the qualitative analysis of cardiac LV strain dysfunction. Although high reproducibility was achieved in our study, the accuracy of this approach needs to be further validated owing to the lack of a reference standard.The assessment of strain parameters obtained via CMR tissue tracking, allows for the evaluation of early cardiac deformation in T2DM patients. In addition, global longitudinal PS can complement LVEF in the assessment of cardiac function.Supplementary Information.


Ebstein’s anomaly is a rare congenital heart disorder that causes displacement of the tricuspid valve towards the apex of the heart. Patients with this anomaly rarely survive beyond the age of 70 without surgical correction. When such patients survive till adulthood, they tend to present with atrial arrhythmias. Although radiofrequency ablation is harder to successfully complete due to disrupted anatomy of the heart, it can be the best choice for terminating arrhythmias in such patients. Here, we present a case of a 76-year-old patient with an uncorrected Ebstein’s anomaly that presented with atrial flutter and was treated successfully with radiofrequency ablation. Ebstein’s anomaly is a rare congenital heart disorder characterized by an apical displacement of the tricuspid valve. This disorder accounts for less than 1% of all cases of congenital heart disease . AlthougA 76-years-old Caucasian man with known Ebstein’s anomaly and coronary artery disease was admitted to the hospital for left-sided chest pain associated with some lightheadedness. Years ago, the patient was evaluated at a tertiary center for Ebstein’s anomaly, and the decision was not to operate at that time because he was unfit for surgery. Upon admission, an electrocardiogram was done and showed atrial flutter Figure .The patient had negative cardiac enzymes and was hemodynamically stable. Echocardiogram showed reduced left ventricular systolic function, with an estimated ejection fraction (EF) of 20-30%. The tricuspid valve was ventricularly displaced consistent with Ebstein’s anomaly. The next day the patient underwent a transesophageal echocardiogram that showed no left atrial appendage clot. After informed consent, the patient underwent an electrophysiological study. Under sedation with midazolam, access was established via the right femoral vein. Upon advancement of the catheter into the heart, it showed that the flutter was right-sided and counterclockwise. We were unable to place the coronary sinus (CS) catheter in place due to an enlarged right atrium (RA) and possible rotation. We placed the CS catheter on the posterior septal region. Entrainment was used to confirm that the flutter was typical and Cavo-tricuspid isthmus (CTI) dependent. Ablation of the CTI was done with conventional mapping only. An 8mm Blazer™ Catheter  was used as well as RAMP™ sheath . Post ablation, the patient had a bidirectional block with lateral RA to the medial  interval was 200 msec and atrial flutter terminated. This was true in the reverse fashion as well. The procedure was completed without any complications, and the patient was discharged on the second day postoperatively. The patient was followed up serially for two years and showed no recurrence of arrhythmias until his death at the end of the second year.Ebstein’s anomaly is a very rare congenital heart disorder that was first described by Wilhelm Ebstein in 1886 . This anRadiofrequency catheter ablation is a safe and effective method to treat such arrhythmias. However, in patients with Ebstein’s anomaly, catheter ablation is much harder to successfully complete. This is because the normal anatomy of the right atrium is markedly disrupted due to dilation. In addition to dilation, tricuspid regurgitation will prevent stabilization of the catheter during the procedure, causing failure of the ablation and recurrence of arrhythmias . In thisEbstein’s anomaly is associated with an increased incidence of heart failure and arrhythmias. Only 5% of patients with Ebstein’s anomaly survive till the age of 50 without surgical correction . It is eRadiofrequency ablation is a suitable method to treat supraventricular tachycardias in patients with Ebstein’s anomaly. Although it is harder to complete and associated with an increased recurrence rate compared to the normal population, it is a minimally invasive procedure that is extremely safe, especially in patients that are unfit for cardiac surgery.


Left ventricular untwisting generates an early diastolic intraventricular pressure gradient (DIVPG) than can be quantified by echocardiography. We sought to confirm the quantitative relationship between peak untwisting rate and peak DIVPG in a large adult population.From our echocardiographic database, we retrieved all the echocardiograms with a normal left ventricular ejection fraction, for whom color Doppler M-Mode interrogation of mitral inflow was available, and left ventricular untwisting rate was measurable using speckle tracking. Standard indices of left ventricular early diastolic function were assessed by Doppler  and speckle tracking (peak strain rate Esr). Load dependency of DIVPG and untwisting rate was evaluated using a passive leg raising maneuver.P <  0.001). On multivariate analysis, peak DIVPG was the only diastolic parameter that was independently associated with untwisting rate. Age and gender were the clinical predictive factors for peak untwisting rate, whereas only age was independently associated with peak DIVPG. Untwisting rate and DIVPG were both load-dependent, without affecting their relationship.We included 154 subjects, aged between 18 to 77 years old, 63% were male. Test-retest reliability for color Doppler-derived DIVPG measurements was good, the intraclass correlation coefficients were 0.97 [0.91–0.99] and 0.97 [0.67–0.99] for intra- and inter-observer reproducibility, respectively. Peak DIVPG was positively correlated with peak untwisting rate (r = 0.73, Color Doppler-derived peak DIVPG was quantitatively and independently associated with peak untwisting rate. It thus provides a reliable flow-based index of early left ventricular diastolic function. Left ventricular (LV) untwisting is a key component of diastolic function . This unThe echocardiographic laboratory of the CHUM  has a research database in which healthy volunteers and patients have consented to participate, authorizing access to their clinical information. We retrospectively retrieved from this database all echocardiograms performed over one year and meeting the following criteria: 1) an LV ejection fraction (LVEF) ≥ 50%, 2) an available color M-Mode tracing in apical four-chamber view as usually acquired for the assessment of the propagation flow velocity, and 3) the appropriate short-axis views to measure the untwisting rate using speckle tracking. Studies with the following criteria were excluded: known history of cardiac disease, regional wall motion abnormality, moderate or severe valvular heart disease, atrial fibrillation, or paced rhythm. Cardiovascular risk factors, physical activity behavior, and medical history were abstracted from either the questionnaire linked to our research database or from their medical records. The transthoracic echocardiograms were performed using one of our commercially available ultrasound machines: Vivid E9, Vivid 7 or Vivid q , equipped with a 2.5 MHz transducer. Acquisitions were performed in left lateral decubitus during an apnoea on three consecutive cardiac cycles with a stable ECG signal. All measurements were archived offline on a remote workstation .A passive leg raising maneuver had been performed by lifting the subject’s legs to a 45° angle to assess the load dependency of DIVPG and untwisting rate measurements, evaluated during the maneuver after heart rate stabilization. Lifting the legs passively from the horizontal position induces a gravitational transfer of blood from the lower limbs toward the intrathoracic compartment resulting in increased cardiac preload.LV function was evaluated according to the current guidelines of the American Society of Echocardiography , 14. LVELV untwisting rate was measured by two-dimensional speckle tracking on the parasternal short-axis views at the basal  and the apical  levels, as previously described . To ensuρ is constant since blood is incompressible in the investigated conditions. This simplified equation shows that the pressure gradient (∂P/∂s) is the result of inertial (∂v/∂t) and convective (∂v/∂s) components , and the relative percentage difference was 4.28 ± 4.52%. For inter-observer reproducibility, the intraclass correlation coefficient was 0.97 [0.67–0.99], and the relative percentage difference was 8.96 ± 5.28%.P <  0.001) in our population . Multivariate analysis revealed that peak DIVPG was the only variable that was independently associated with peak untwisting rate .There was a positive and significant correlation between peak DIVPG and peak untwisting rate , and that peak untwisting rate was inversely associated with body mass index (Table P = 0.81). The median age was similar between sexes .Univariate analysis showed that peak untwisting rate significantly decreased with aging, that peak untwisting rate differed significantly between males and females  and untwisting rate , with inter-individual variability . The heart rate was slightly but significantly increased after leg raising .During passive leg raising maneuver performed in 20 healthy male volunteers, we observed simultaneously significant variations of mean DIVPG  and patients with hypertrophic cardiomyopathy (n = 7) [First human studies that have demonstrated the relationship between LV untwisting (assessed by tissue Doppler imaging) and DIVPGs were conducted on small groups of healthy volunteers ( (n = 7) , 13. LV  (n = 7) . Studies (n = 7) , 20. Sig (n = 7) , 13. LV  (n = 7) . NonetheIn this study, age similarly affected the untwisting rate and DIVPG. We found that age was an independent predictor for both peak untwisting rate and peak DIVPG. Therefore, the relationship between untwisting rate and DIVPG remained similar in younger and older subgroups. Impairment in LV diastolic function is part of the aging process of the heart, which affects myocardial intrinsic relaxation proprieties and disturbs cellular calcium homeostasis . PreviouPrevious observations in healthy volunteers have suggested that the load dependency of LV untwisting rate may be a physiological compensatory mechanism to minimize the effects of load variations on LV filling and stroke volume , 28. ExpThe first limitation is related to the techniques used for non-invasive assessment of intraventricular pressure gradients and untwisting rate. Since color Doppler is a one-dimensional imaging technique (only velocity vector projections are returned), flow needs to be coaxially interrogated by the ultrasound M-mode scan-line so as not to underestimate blood velocity. Thus, we cannot preclude some misalignment in the course of this study. However, based on our past experience with this approach, the DIVPG calculation is only marginally or not affected by a slight misalignment of the Doppler scanline with respect to the flow streamline . MoreoveDIVPG measured by color Doppler M-mode was well correlated and independently associated with LV untwisting rate. Their interdependence indicates a strong physiological coupling between the intraventricular fluid forces and the myocardium relaxation. This echocardiographic approach to DIVPG estimation, highly feasible and reproducible, could improve the assessment of LV diastolic function. Our team is currently working on the development of turnkey clinical software for computing DIVPG, to further study its diagnostic value in patients with heart diseases.


The American Society for Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) 2016 guidelines for assessment of diastolic dysfunction (DD) are based primarily on the effects of diastolic dysfunction on left ventricular filling hemodynamics. However, these measures do not provide quantifiable mechanistic information about diastolic function. The Parameterized Diastolic Filling (PDF) formalism is a validated theoretical framework that describes DD in terms of the physical properties of left ventricular filling.We hypothesized that PDF analysis can provide mechanistic insight into the mechanical properties governing higher grade DD.Patients referred for echocardiography showing reduced left ventricular ejection fraction (< 45%) were prospectively classified into DD grade according to 2016 ASE/EACVI guidelines. Serial E-waves acquired during free breathing using pulsed wave Doppler of transmitral blood flow were analyzed using the PDF formalism.n = 20 vs grade 1, n = 30) was associated with increased chamber stiffness , increased filling energy  and greater peak forces resisting filling . DD grade was unrelated to chamber viscoelasticity . Stiffness was inversely correlated with ejection fraction .Higher DD grade (grade 2 or 3, Higher grade DD was associated with changes in the mechanical properties that determine the physics of poorer left ventricular filling. These findings provide mechanistic insight into, and independent validation of the appropriateness of the 2016 guidelines for assessment of DD. The prevalence of HF in adults is 1–2% in developed countries, and approximately 10% among people above 70 years of age . ImportaDiastolic function assessed by Doppler echocardiography can be categorized by severity, which is related to prognosis –7. In 200) can be determined . Categorical data was presented as number and percentage. A n = 30) or grade 2–3 (n = 20) . Patient demographic and conventional echocardiographic data are described in Table Applying the 2016 ASE/EACVI guidelines to the echocardiographic evaluation of diastolic function , patient0 , and chamber stiffness, k , while viscoelasticity, c, did not differ between the groups . As a consequence, the high DD group had a higher filling energy  and peak driving force of filling . Similarly, the damping index β was more negative in the high DD group, indicating greater damping relative to recoil . The high DD group had a greater peak resistive force of filling , and this can be attributed to a greater atrioventricular pressure gradient as denoted by higher E-wave maximum velocity . By comparison, the higher peak resistive force was not due to greater intrinsic damping properties within the ventricle as denoted by the lack of difference in viscoelasticity. The predicted peak driving force at zero resistive force (B intercept) was also increased in the group with high DD grade . There were no differences between the two groups with regards to the load-independent index of filling, M  or the kinematic filling efficiency index . Curiously, tau was lower in the high DD group . The stiffness constant k was inversely correlated with ejection fraction .Comparison of the PDF parameters between groups is displayed in Fig. All parameters had good to excellent intra-observer variability (intraclass correlation coefficient 0.69 to 0.95). Inter-observer variability was good to excellent for all parameters except the derived parameters KFEI, M, and β.The unique finding of this study is that higher grade DD in the setting of reduced LVEF was associated with non-invasively quantifiable changes in the mechanical properties that determine the physics of poorer left ventricular filling. Specifically, more severe DD was associated with a higher load, greater ventricular stiffness, higher energy of filling, and greater peak driving and peak resistive forces. These findings provide mechanistic insight into, and independent validation of the appropriateness of the 2016 ASE/EACVI guidelines for assessment of DD.Mechanistic validation of these guidelines in the HFrEF population to date is limited. DD grade has been shown to not be associated with prolonged Tau (> 48 ms) in patients with systolic LV dysfunction, though there was an association between DD grade and left ventricular end diastolic pressure (LVEDP) . The E/AThe relationship between E-wave velocity and diastolic function is represented by a J-shaped curve: tall E-waves in the setting of a high atrioventricular pressure gradient due to strong ventricular suction in normal diastolic function, short E-waves when relaxation is impaired but atrial pressure is normal, and tall E-waves again with impaired relaxation and elevated atrial pressure. The E-wave itself is a sum of several processes, namely, the load placed on the elastic elements during contraction as well as their stiffness, and early relaxation due to actin-myosin cross-bridge uncoupling. Measuring peak E-wave velocity alone therefore does not allow for the evaluation of the components of diastolic function. Other measurements such as E-wave deceleration time, early diastolic mitral annular velocity, and transmitral flow propagation velocity provide limited mechanistic insight, but the PDF formalism allows for noninvasive assessment of ventricular relaxation with considerably greater detail and with the added benefit of providing mechanistic understanding with regards to the physical properties of diastolic filling.The current study found no difference in the load-independent index of diastolic filling (M) between our low and high DD groups. This index has been previously shown to be higher in a cohort with LVEF > 60% and LVEDP > 19 mmHg compared to normal controls . By compΔP/ΔV measure of stiffness as determined by invasive measurements [Compared to the low DD grade cohort, the high DD group had higher stiffness (k), lower time-constant of isovolumic relaxation (tau), and shorter deceleration time. Prior work has shown patients with normal LVEF can have increased invasively determined end-diastatic chamber dP/dV stiffness , and it urements . Given turements , 25, 28.urements . In addiurements . Contracurements . Stiffneurements . The majurements . All theThe current study has several limitations that deserve to be acknowledged. Though our measurements were not directly compared to invasively derived data, these PDF methods have been validated in prior studies , 26, 27.In conclusion, higher grade DD was associated with a deterioration of the mechanical properties that determine the physics of left ventricular filling. These findings provide mechanistic insight into, and independent validation of the appropriateness of the 2016 guidelines for assessment of DD.


Background: Measurement of myocardial T1 is increasingly incorporated into standard cardiovascular magnetic resonance (CMR) protocols, however accuracy may be reduced in patients with metallic cardiovascular implants. Measurement is feasible in segments free from visual artifact, but there may still be off-resonance induced error.Aim: To quantify off-resonance induced T1 error in patients with metallic cardiovascular implants, and validate a method for error correction for a conventional MOLLI pulse sequence.Methods: Twenty-four patients with cardiac implantable electronic devices ; and 31 patients with aortic valve replacement (AVR)  were studied. Paired mid-myocardial short-axis MOLLI and single breath-hold off-resonance field maps were acquired at 1.5 T. T1 values were measured by AHA segment, and segments with visual artifact were excluded. T1 correction was applied using a published relationship between off-resonance and T1. The accuracy of the correction was assessed in 10 healthy volunteers by measuring T1 before and after external placement of an ICD generator next to the chest to generate off-resonance.Results: T1 values in healthy volunteers with an ICD were underestimated compared to without , but were similar after correction . Artifact was visible in 4 ± 12, 42 ± 31, and 53 ± 27% of AHA segments in patients with ILRs, PPMs, and ICDs, respectively. In segments without artifact, T1 was underestimated by 63 ms (interquartile range: 7–143) per patient. The greatest error for patients with ILRs, PPMs and ICDs were 79, 146, and 191 ms, respectively. The presence of an AVR did not generate T1 error.Conclusion: Even when there is no visual artifact, there is error in T1 in patients with CIEDs, but not AVRs. Off-resonance field map acquisition can detect error in measured T1, and a correction can be applied to quantify T1 MOLLI accurately. Parametric mapping using cardiovascular magnetic resonance (CMR) permits non-invasive quantitative myocardial tissue characterization. T1 quantification, performed by sampling the longitudinal relaxation to steady-state, is a useful tool to evaluate patients undergoing CMR for suspected myocardial pathology –4. CMR cThe modified Look-Locker inversion recovery (MOLLI) sequence using a balanced steady-state free precession (SSFP) readout is a widely used, commercially available, T1 mapping method and normally has high precision and reproducibility , 10. OffThe relationship between off-resonance frequency and changes to measured T1 values has previously been described , with myWe hypothesized that the extent of error in T1 is beyond the visual artifact generated by a metallic cardiovascular implant, and is relative to the size of the implant. In patients with either CIEDs or aortic valve replacements (AVRs), we therefore aimed to quantify the off-resonance frequency induced T1 MOLLI error. By generating CIED metallic artifact in healthy volunteers, we also tested the hypothesis that a T1 correction curve for off-resonance frequency, previously derived by Bloch simulations, would permit accurate T1 MOLLI quantification in the presence of off-resonance artifact.Ten healthy volunteers were recruited to assess the impact of off-resonance from the presence of a CIED on T1 values, and to test whether correction for off-resonance enabled accurate T1 measurement. The study was approved by the UK National Research Ethics Service 07/H0715/101); conformed to the principles of the Helsinki Declaration, and all subjects gave written informed consent. Body surface area (BSA) was measured before the CMR study. All CMR scans were performed at 1.5 Tesla . After pilot imaging, a second order shim was performed over a volume encompassing the left ventricle. A mid-ventricular short-axis MOLLI 5s(3s)3s map (Siemens MyoMaps) was then acquired /101; con. In brieFollowing acquisition of the initial “reference” T1 map and field map, an implantable cardioverter-defibrillator (ICD) generator  was secured to a weighted phantom and placed adjacent to the left chest wall without performing a repeat isocenter. Positioning of the ICD generator was adjusted to mimic off-resonance frequency similar to that expected in patients with CIEDs. Repeat paired MOLLI and field maps were acquired in the same slice position as the reference imaging.To evaluate the extent of T1 error and the application of an error correction, 24 patients with CIEDs and 31 patients with AVRs who were undergoing CMR tissue characterization were studied. Clinical indications were typically for suspected cardiomyopathy or cardiac sarcoidosis, for assessment of substrate for arrhythmia or viability imaging. Paired MOLLI and field maps were acquired using the same protocol as described for the healthy volunteers above. For patients with AVRs, additional paired maps were acquired in the base and apical short-axis orientations. Post contrast T1 mapping was not routinely acquired in patients and so the accuracy of extra-cellular volume fraction was not studied. The CMR safety protocol for patients with CIEDs has been described elsewhere and is in accordance with international guidance , 17. In Because the presence of an ICD also results in artifact manifest as SSFP hyperintensity bands or signal void, segments with visual artifact were excluded from analysis . As prevImage analysis was performed using CVI42 . For each T1 map, endocardial and epicardial borders were manually contoured and the superior and inferior RV insertion points were marked to measure T1 in six segments according to the American Heart Association (AHA) classification. A conservative 30% erosion was applied to both borders, avoiding error from endocardial blood-pool partial voluming and increased off-resonance at the epicardial tissue-air interface . BecauseWhilst measuring segmental artifact is straightforward and its ease facilitates clinical use, an off-line tool was also developed for illustrative purposes using Matlab R2013 . T1 correction based on off-resonance was calculated from field maps and integrated into the automated tool to produce voxel-wise corrected T1 maps .Microsoft Office 2010, Microsoft, Redmond, WA) and SPSS version 22 . Data are presented as mean ± sd or median  according to distribution. Categorical variables are presented as absolute numbers or frequencies. A paired Student's t-test was used for within group comparisons. Repeated measures and one-way ANOVA was used for multiple measurements from the same and between different groups, respectively. Pearson's correlation coefficient (r) was used to assess correlation. All tests were two-tailed and p < 0.05 was considered statistically significant.Analysis was performed in Excel . An average of five out of six segments per volunteer were free of visual artifact. In the segments free of visual artifact, the mean segmental off-resonance frequency induced by the ICD was 70 ± 41 Hz, and the maximal segmental off-resonance frequency per volunteer was 113 ± 25 Hz. T1 in the presence of the ICD was underestimated compared to reference T1 by 30 ± 51 ms , and the offset was greater with larger off-resonance frequency (p = 0.57).Ten healthy volunteers were scanned, age 33 ± 2 years old and 80% male  segments. There was greater underestimation of T1 compared to reference T1 by 87 ± 50 ms . Correction remained successful, and corrected T1 was similar to reference T1 with a mean difference of −6 ± 29 ms .The same analysis and correction was also applied to only those segments with large off-resonance error , Twenty-four patients with CIEDs were scanned, age 54 ± 19 years old, 54% male. Implanted CIEDs were 11 (46%) permanent pacemakers (PPMs), 8 (33%) ILRs and 5 (21%) ICDs; 20 (83%) were MRI-conditional.One patient with an ICD had completely non-diagnostic T1 mapping due to extensive banding artifact, and overall patients with ICDs had 53 ± 27% of segments with banding artifact. Patients with PPMs had 42 ± 31% of segments with banding artifact. One patient with an ILR had banding artifact, affecting two out of six segments.r = 0.44, p = 0.03).In the segments free of visual artifact, the maximal absolute off-resonance frequency per patient was 114 (48–147) Hz. The anterior wall and anterior-septum had the greatest proportion of segments with significant frequency >85 Hz , whilst the inferior wall had the least proportion (12.5%). The inferior-septum, inferior-lateral and lateral walls had significant frequency in 29, 20, and 33% of segments, respectively. T1 was underestimated in the presence of off-resonance frequency, and as predicted by Bloch simulation the T1 offset was greater with larger frequency, Correction of maximal off-resonance resulted in an increase in T1 per patient of 63 (7–143) ms. The greatest correction in T1 required for patients with ILRs, PPMs and ICDs was 79, 146, and 191 ms, respectively . Figure Thirty-one patients with AVRs were scanned, age 69 ± 8 years. AVRs were 14 (45%) metallic; 17 (55%) bioprosthetic. No banding artifact was noted on T1 mapping.p = 0.48). There was no gradient between basal, mid and apical short-axis orientation off-resonance .The maximal absolute off-resonance frequency per patient was 48 ± 16 Hz. There were no segments with significant frequency >85 Hz. There was no difference between mechanical or bioprosthetic AVRs . Accurate measurement in one or two segments should be sufficient to investigate global infiltrative pathologies such as cardiac amyloidosis and cardiac iron loading . Failure to correct for off-resonance risks underestimation of measured T1 values which, in the case of cardiac amyloidosis may risk misdiagnosis, or for patients with normal T1 over-diagnosis of Anderson-Fabry disease or iron loading.Alternative strategies have been applied for T1 mapping in patients with CIEDs including adapting the sequence to include a wideband inversion pulse , 22. TheThere are alternative approaches to decrease sensitivity to off-resonance in patients with CIEDs, at a cost of reduced spatial resolution and signal to noise. These include using a shorter echo time, lower flip angle or smaller matrix size . Applicain-vivo Bloch simulations accurately described the measured T1 underestimation. The correction curves improve measurement accuracy whilst maintaining similar precision. When comparing corrected T1 values to a reference T1 of the same patient, the sd of the residual difference was 27 ms, and is comparable to an inter-study difference sd of 28 ms . The patients/participants provided their written informed consent to participate in this study.AB drafted the manuscript and all co-authors critically reviewed and amended the manuscript. All authors contributed to this study by conceiving and designing the study, performing the data collection and the statistical analysis, or assisting in data interpretation.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a past co-authorship with several of the authors JM and PK.


NT-proBNP serum levels also decreased significantly  pg/mL vs. 792  pg/mL; p = 0.001). A total of 102 (45%) of patients responded favorably to ARNI  and 126 (55%) patients achieved ΔLVEF ≥ +5% (Group B). The two groups differed significantly in age, heart failure etiology, baseline LVEF and baseline NT-proBNP. On multivariable analysis, nonischemic heart failure, LVEF < 30% and NT-proBNP < 1500 pg/mL emerged as independent correlates of favorable response to ARNI therapy. Conclusion. ARNI therapy appears to improve echocardiographic parameters of left and right ventricular function in HFrEF patients above the effect of pre-existing optimal medical management. These effects may be particularly pronounced in patients with nonischemic heart failure, LVEF < 30% and lower degree of neurohumoral activation.Background. We sought to evaluate the long-term effects of angiotensin receptor blocker–neprilysin inhibitor (ARNI) therapy on reverse remodeling of the failing myocardium in HFrEF patients. Methods. We performed a prospective non-randomized longitudinal study on 228 HFrEF patients treated with ARNI at our center. Prior to ARNI introduction all patients received stable doses of ACEI/ARB for at least six months. Clinical, biochemical and echocardiography data were obtained at ARNI introduction and 12-month follow-up. Results At follow-up, we found significant improvements in LVEF (29.7% ± 8% vs. 36.5% ± 9%;  With the publication of paradigm-HF trial  in 2014 . HoweverStudies of guidelines-based optimal heart failure medical therapy using angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), beta receptor blocking agents (β-blockers) and mineralocorticoid receptor antagonists (MRA) have demonstrated that improved clinical outcomes of HFrEF patients were associated with the reverse remodeling of the failing myocardium  which laThe recently published prove-HF trial confirmed the association of reverse remodeling and neurohumoral modulation in HFrEF patients treated with ARNI, demonstrating a significant correlation between changes in serum NT-proBNP and parameters of left ventricular volume and function in these patients . While tThe aim of our study was therefore to evaluate the long-term effects of ARNI therapy on ventricular reverse remodeling in a HFrEF patient population.We performed a single-center open-label prospective non-randomized longitudinal study to explore the effects of ARNI on the ventricular reverse remodeling in HFrEF patients . The stuβ-blockers and MRAs. Clinical, biochemical and echocardiographic data were collected at baseline and 12-month follow-up. Favorable response to ARNI therapy was defined as an increase in left ventricular ejection fraction (LVEF) ≥5% at 12-month follow-up [At enrollment, all patients were started on a sacubitril/valsartan dose per our institution’s protocol : if the ollow-up .Laboratory tests  were collected at baseline and at 12-month follow-up. All samples were collected in accordance with the institutional protocols and delivered to the institutional laboratory that was blinded to patient clinical data for the analysis.Blood sample was collected at baseline and at 12-month follow-up. EDTA-coated, aprotinin-containing test tubes were used. Immediately after the blood sample was obtained, it was placed on ice (for up to 4 h) and centrifuged at 4500 rpm for 15 min at 0 °C. After centrifugation, the serum was extracted from the test tube and stored separately (at −80 °C). All NT-proBNP assays were done using a standard commercial kit  at a hospital’s central independent laboratory which was blinded to the patients’ clinical status and medication data.Transthoracic echocardiography was performed at baseline and 12 months according to American Society of Echocardiography (ASE) and European Association of Cardiovascular Imaging (EACVI) recommendations . A cardiThe primary end point was a change in LVEF between baseline and 12-month follow-up. Secondary end points were the changes in TAPSE, left ventricular outflow tract velocity–time integral (LVOT VTI) and left ventricular end-diastolic diameter (LVEDD) between baseline and 12-month follow-up. In exploratory data analysis, we aimed to identify predictors of favorable response to ARNI therapy.t-test, ANOVA or Mann–Whitney nonparametric test. Pearson correlation model was used to assess the potential correlation between two continuous variables. Shapiro–Wilk test was used to test for the normality of data distribution. Statistical significance was assumed for p-values of <0.05. All statistical analyses were performed with SPSS version 20.0 .Categorical variables are presented as count (percent) and were compared using a chi-squared test or nonparametric Fischer exact test. Continuous variables are reported either as mean (±SD) or median (IQR). Continuous variables were compared using Student’s Baseline patient characteristics are outlined in p < 0.001) and LVOT VTI . At the same time, a decrease in LVEDD  was noted. Importantly, our data also showed that in this patient cohort ARNI therapy was associated with a significant improvement in right ventricular function as TAPSE changed from 1.7 ± 0.5 cm at baseline to 2.1 ± 0.6 cm (p < 0.001) at 12-month follow-up.The effects of ARNI on the left and right ventricular reverse remodeling are outlined in p = 0.001). However, we did not find a correlation between changes in NT-proBNP serum levels and LVEF (Pearson’s r2 = 0.01) or TAPSE (Pearson’s r2 = 0.003).Our data also confirmed the beneficial effects of ARNI on neurohumoral modulation as NT-proBNP serum levels decreased significantly between baseline and 12-month follow-up  pg/mL vs. 792  pg/mL; N = 102, 45%) to patients, in whom an increase in LVEF of 5% or more was observed . In Group A 50% of patients displayed a less than 5% increase of LVEF, in 6% of patients LVEF remained unchanged and in 44% of patients LVEF decreased. In the latter subgroup the mean decrease of LVEF was −4.6%. Comparing the two groups, we found significant differences in age , heart failure etiology , baseline LVEF  and baseline NT-proBNP 1612  pg/mL vs. 1112  pg/mL; p = 0.03). Our data also showed that more patients in Group A received low dose of ARNI , while there were no differences regarding the intermediate  and high  ARNI doses between the two groups. On multivariable analysis, nonischemic heart failure, baseline LVEF < 30% and baseline NT-proBNP serum levels less than 1500 pg/mL emerged as independent predictors of favorable response to ARNI therapy  were introduced for the treatment of HFrEF. Inhibiting the renin–angiotensin–aldosterone axis they have significantly improved the morbidity and mortality of these patients ,15,16,17While emerging data suggest a significant benefit of ARNI therapy on left ventricular reverse remodeling there are currently almost no data available on the effects of ARNI on right ventricular function in HFrEF patient population. Bayard et al. failed to establish any benefit of ARNI therapy on right ventricular function in 52 patients with HFrEF as no changes in TAPSE were observed throughout the study period (3 months) . ContrarIn accordance with previously published literature ,2,19 ourConsidering the response to ARNI therapy our data suggest that patients with non-ischemic heart failure, patients with left ventricular ejection fraction less than 30% and with less pronounced neurohumoral activation may display particularly good response to ARNI therapy. In terms of left ventricular ejection fraction and neurohumoral activation these results are supported by paradigm-HF data that showed better clinical response to ARNI therapy in patients with lower left ventricular ejection fraction and with NT-proBNP levels below the median value . While tFinally, in our patient cohort a dose-dependent effect of ARNI therapy was noted as an increase in left ventricular ejection fraction and TAPSE was significantly lower in patients receiving low dose of ARNI than in patients receiving intermediate or high doses of ARNI. We did not observe any differences in response to ARNI between the groups of patients receiving intermediate or high ARNI doses. These observations are in line with the data from Mullens et al. who also demonstrated dose-dependent effect of ARNI therapy . ImportaOur study has several limitations that must be acknowledged. First is its single-group, open-label design. However, this study design may be justified due to a widespread bioavailability of ARNI, its class I clinical practice guideline recommendation and proven superiority over ACEI/ARB in most the HFrEF patients. Second, compared to some recently published heart failure trials, there may be an underrepresentation of the female gender in our study. Third, the size of our study sample—despite being second only to prove-HF considering the studies analyzing echocardiographic response to ARNI therapy—is still relatively small. Therefore, our study was likely not sufficiently powered for some performed analyses, such as a correlation between changes in serum NT-proBNP and left ventricular ejection fraction or TAPSE. Fourth, while many more informative and intricate echocardiographic parameters could be assessed, we chose only the most robust and easily accessible ones for our analysis in order to make our conclusions applicable not only to the tertiary centers with access to the advanced imaging technology, but also to the general cardiology practices. We acknowledge that adding other echocardiographic parameters to the analysis may add novel insights into the reverse-remodeling in the HFrEF patient population and fully support the verification of our preliminary data in such a trial.ARNI therapy appears to promote long-term reverse remodeling of both left and right ventricle in HFrEF patient populations, above and beyond the effect of pre-existing optimal medical management. These effects may be particularly pronounced in patients with nonischemic heart failure, LVEF < 30% and lower degree of neurohumoral activation.


The prevention of sudden cardiac death (SCD) in cardiomyopathies (CM) remains a challenge. The current guidelines still favor the implantation of devices for the primary prevention of SCD only in patients with severely reduced left ventricular ejection fraction (LVEF) and heart failure (HF) symptoms. The implantation of an implantable cardioverter-defibrillator (ICD) is a protective barrier against arrhythmic events in CMs, but the benefit does not outweigh the cost in low risk patients. The identification of high risk patients is the key to an individualized prevention strategy. Cardiac magnetic resonance (CMR) provides reliable and reproducible information about biventricular function and tissue characterization. Furthermore, late gadolinium enhancement (LGE) quantification and pattern of distribution, as well as abnormal T1 mapping and extracellular volume (ECV), representing indices of diffuse fibrosis, can enhance our ability to detect high risk patients. CMR can also complement electro-anatomical mapping (EAM), a technique already applied in the risk evaluation and in the ventricular arrhythmias ablation therapy of CM patients, providing a more accurate assessment of fibrosis and arrhythmic corridors. As a result, CMR provides a new insight into the pathological substrate of CM. CMR may help identify high risk CM patients and, combined with EAM, can provide an integrated evaluation of scar and arrhythmic corridors in the ablative therapy of ventricular arrhythmias. Cardiac plasticity permits the heart to adjust its function and structure in response to environmental stimuli such as the increase in the wall thickness or the dilatation of the ventricles due to pressure or volume overload conditions . The terPatients diagnosed with any kind of CM are threatened by a variety of complications including progressive heart failure, need for cardiac transplantation or sudden cardiac death (SCD). Even if manifestations such as an episode of heart failure decompensation give time to seek medical help and are manageable, SCD leaves no room for reaction. SCD can be divided into two major categories—deaths that occur as a consequence of a mechanical complication, for instance, myocardial rupture or left ventricular outflow tract obstruction in HCM and deaths that have a malignant arrhythmic origin . The latAccurate and straightforward arrhythmic risk stratification algorithms for the primary prevention of major arrhythmic events (MAEs)—including, in this article, SCD and both sustained ventricular tachycardia (VT) and fibrillation (Vf)—constitute the holy grail of clinical electrophysiology. An effective and efficient approach allows for the rational targeted allocation of life-saving implantable cardioverter defibrillators (ICDs), with the expected benefit outweighing any device related complication and adverse events  . Based oThe aforementioned studies were not designed to stratify patients according to arrhythmic risk but rather, based on their LVEF; consequently, they only demonstrated that moderately-to-severely impaired LVEFs were associated with high arrhythmic risk, without including patients with mildly-to-moderately impaired contractility. Not unexpectedly, a two-fold disparity between ICD allocation and MAE occurrence in the primary prevention population has been noted, with an ever increasing trend, given that the majority of sudden deaths in the community occurs in people with mildly impaired LVEF ,21, and As contemporary studies ,21,22 raThe aim of this review is to present the CMR imaging patterns of the arrhythmogenic substrate, studied up to date in CMs, and examine the role of CMR findings in the clinical decision making of the electrophysiologist. The diagnostic imaging of the human body, independently of the modality used, enables the creation of contrast between tissues. The signal source that serves as contrast for magnetic resonance imaging (MRI) is the response of hydrogen atoms to the magnetic field. Each hydrogen atom is composed of a proton which carries its own spin. The human body does not spontaneously create magnetic signal since spins are oriented randomly . By placThe heart, as a constantly beating organ, which is also affected by respiration movements, makes CMR measurements challenging because of multiple artifacts. Techniques such as the Look Locker (LL) sequence, the Modified Look Locker Inversion Recovery Sequence (MOLLI), the shortened MOLLI (shMOLLI) and the Saturation recovery single-shot acquisition sequence (SASHA) overcome these difficulties by using protocols of supplement excitation RF pulses to extract T1 measurements and have significantly improved the reproducibility of the method .Regarding T1 mapping, it is created by the accumulation of multiple T1 measurements from many heart beats, all at the same phase of the cardiac cycle. Each T1 value is represented by a pixel in the map. T1 mapping images the entire myocardium and does not separate extracellular from cellular environments. The deposition of lipids, water, proteins or iron change T1 measurements and reveal early histological changes ,39. NatiWhen CMR imaging is being supplemented with intravenous contrast agents, the information derived is multiplied. Gadolinium-based contrast agents (GBCAs) are the most widely used agents approved for use .They areThe paramagnetic properties of gadolinium lead to a shorten T1 relaxation time in these areas. The most valuable information extracted by the use of GBCA is its pattern of removal from tissues. Normally, after its first distribution, a GBCA is progressively washed out. In areas of myocardial fibrosis, the wash out is delayed since the extracellular space is expanded, the capillary density is reduced and the distance between myocardial cells is augmented. Imaging the heart ”late” after the gadolinium has been washed out from healthy tissue can identify these areas with pathological response indicative of replacement fibrosis. It is noticeable that, by definition, late gadolinium enhancement (LGE)  expresseLast but not least, extracellular volume (ECV) is another useful parameter reflecting histological changes early in the CMs’ course, independently of their cause. It is measured by the native and postcontrast T1 mapping also including the hematocrit level ,46 Figu.The quantification of ECV by CMR is an excellent noninvasive method as the measurements are highly correlated with the results of biopsies ,48. ECV A common issue affecting all contrast-based scar detection lies in the definition of scar and its subtypes, given that it hinges on relative signal intensity. There is not a universal cutoff over which the high signal intensity in LGE-CMR reflects scar tissue. Subsequently, the definition of scar varies between different studies and researchers. Two major approaches have been pursued, one defining scars based on increased signal intensity  and the other defining healthy tissue based on less pronounced signal intensity . A few of the most popular scar definitions in studies are the followings: areas with signal intensity >6 standard deviations (SD) higher than the average intensity of remote areas , or withThe most well established parameter of an arrhythmogenic substrate in NIDCM is the LGE imaging ,29,30,31Furthermore, T1 mapping and ECV are also valuable tools in the arrhythmic risk stratification of NIDCM ,62,63,64Finally, CMR derived left ventricular longitudinal strain is a newly proposed marker of prognosis in patients with NIDCM with conflicting results ,66. In oThe scar tissue following an acute coronary syndrome (ACS) constitutes the most common arrhythmogenic substrate in ICM ,69,70. AFocal myocardial fibrosis detected by LGE imaging substantially increases the risk for life threatening arrhythmias in ICM ,33,34,72Regarding the role of T1 mapping and ECV measurements in the arrhythmic risk stratification of ICM, there are a few studies, including both ischemic and nonischemic CM patients, suggesting a correlation between their pathological values and an increased arrhythmic burden ,80.Here, it should be highlighted that another highly effective risk stratification approach with absolute negative predictive value, and a positive predictive one of 22% over a mean follow up of 32 months, is that of PVS response in post-myocardial infarction (MI) patients with a LVEF ≥ 40% having at least one out of seven noninvasive risk factors (NIRFs) present on ambulatory and signal averaged electrocardiography . This apIn a rare divergence between American and European guidelines ,85, primIndeed, there has been considerable debate concerning the value of the latest European risk score ,88 regarThe presence of scar, imaged by LGE in HCM patients is considered to be a strong independent predictor for ventricular arrhythmias, ventricular remodeling, all-cause mortality and cardiac death ,99,100. A relatively common finding during CMR imaging of HCM patients is the appearance of areas of T2-high signal spotted within LGE. Although its clinical significance is not well established, a study of 81 HCM patients concluded that high T2 signal is another parameter for VT manifestation in this group . ConcernInflammatory CM is the result of an inflammatory process due either to infective or autoimmune causes. Myocardial oedema and fibrosis as a result of macro-, micro-vascular coronary artery disease, vasculitis and autoimmune myocarditis may lead to SCD in patients with autoimmune diseases, even if the left ventricular ejection fraction (LVEF) is preserved . These cBetween various ARDs, polymyalgia rheumatica, the commonest rheumaticdisease in elderly people, may present with SCD, as a result of chronic inflammation. Several studies demonstrated that besides promoting structural heart disease, inflammatory activation may also be per se arrhythmogenic, via cytokine-mediated effects on cardiac electrophysiologic properties. Furthermore, there is increasing evidence that inflammation is a risk factor for QTc prolongation and associated life-threatening arrhythmias, specifically torsade de pointes (TdP) . AdditioAutonomic dysfunction, potentially leading to SCD, even in the absence of relevant symptoms or reduced LVEF, was documented in systemic lupus erythematosus, idiopathic juvenile arthritis patients and children with type 1 diabetes mellitus ,108,109.A significant limitation of VT ablation is its variable success rate. The HELP-VT study evaluated VT ablation outcomes among patients with ICM and NIDCM, demonstrating similar success rates in the short term, but with significant reappearance of the arrhythmia in the long term in the latter . The absElectroanatomic mapping (EAM) is the currently used approach to identify the arrhythmiologic substrate. However, in EAM the arrhythmogenic substrate is identified indirectly by collecting local voltage amplitudes of the myocardium. This method has some drawbacks: (a) it is time consuming, (b) it lacks sensitivity for scar substrates deep in the mapped surface and (c) it lacks specificity for scar detection in the case of poor catheter contact or thin myocardium. Therefore, the need for new strategies to define arrhythmogenic scar substrates is relevant . CMR exaThe first necessary step in this algorithm is to incorporate CMR into 3D-EAM in order to transfer anatomical data from one software environment to the other. Potential causes of a mismatch include different rhythms during different image acquisition timings, as well as different loading conditions, leading to slight geometric alterations in chamber geometry , as it hIn one of the first studies, to evaluate the integration of CMR to achieve the demanding task of scar definition in a clinical setting , this imGenerate anatomic images during the procedure. Consequently, any registration mismatch errors are avoided. The operator uses the CMR scanner virtually in the same manner as a fluoroscope, with an attached pedalfor image acquisition whenever e.g., tissue characterization is needed .Locate indwelling ablation catheters ,123,124.Produce substrate maps to be compared with those derived from the “classical” EAM module and improve area of interest targeting. Evaluate the formation of permanent, irreversible lesions ,125,126 In a more radical approach, the field of magnetic resonance electrophysiology (MR-EP) , alternaA multidisciplinary approach for the risk stratification of ICM and NIDCM patients seems to be more suitable than the proposed oversimplified one based on LVEF so far, in order to better define their complex substrate and support individualization. Towards this direction, several efforts have been made to update primary prevention arrhythmic risk stratification in ICM and NIDCM with rather well maintained LVEF, either by assessing the presence of an arrhythmogenic substrate through a two-step approach with noninvasive risk factor presence leading to PVSin both diseases ,89,133 oIn this direction, two prospective observational studies are currently underway: The CMR-Guide trial  (NCT0191The question of which is the best risk stratification approach among HCM patients with a low European risk score and/or a single conventional noninvasive risk factor present, remains a highly debatable issue. On the contrary, there is solid evidence that, in the presence of multiple NIRFs and/or a high European risk score, the justification of ICD insertion is well supported . AlthougThere is an urgent need to update our risk stratification criteria for the appropriate and timely selection of the ICD candidates among CM patients at all LVEF spectrum values. In this direction, CMR imaging may play a significant role. Indeed, LGE quantification and pattern of distribution, as well as abnormal T1 mapping and ECV, can further enhance our ability to identify patients susceptible to life threatening arrhythmogenesis. Currently, more sophisticated approaches combining a variety of noninvasive and invasive modalities are underway in the new era of the arrhythmic risk stratification among CM patients even at early heart failure stages with less impaired LV function. Furthermore, CMR in combination with EAM may assist in the effectiveness of demanding interventional EP procedures not uncommonly applied among such seriously affected high risk patients.


Clinical diagnosis of myocardial injury is based on initial electrocardiogram, levels of circulating biomarkers, and perfusion imaging with single photon emission computed tomography (SPECT). Positron emission tomography (PET) is an alternative imaging modality that provides better resolution and sensitivity than SPECT, improves diagnostic accuracy, and allows therapeutic monitoring. The objective of this study was to assess the detection of drug‐induced cardiomyopathy by PET using 2‐deoxy‐2‐[18F]FDG/PET and [99mTc]MIBI/SPECT were performed before and after isoproterenol administration. [18F]FDG  and [99mTc]MIBI  were administered via the tail vein and imaging was performed 1 hour postinjection. Isoproterenol‐induced injury was confirmed by the plasma level of cardiac troponin and triphenyltetrazolium chloride (TTC) staining.Cardiomyopathy was induced in Sprague Dawley rats using high‐dose isoproterenol. Nuclear [18F]FDG, but not of [99mTc]MIBI. Image analysis revealed that myocardial uptake of [18F]FDG reduced by 60% after isoproterenol treatment, whereas that of [99mTc]MIBI decreased by 45%.Isoproterenol administration resulted in an increase in circulating cardiac troponin I and showed histologic damage in the myocardium. Visually, preisoproterenol and postisoproterenol images showed alterations in cardiac accumulation of [18F]FDG is a more sensitive radiotracer than [99mTc]MIBI for imaging of drug‐induced cardiomyopathy. We theorize that isoproterenol‐induced cardiomyopathy impacts cellular metabolism more than perfusion, which results in more substantial changes in [18F]FDG uptake than in [99mTc]MIBI accumulation in cardiac tissue.We conclude that [ PET and SPECT nuclear images of cardiomyopathy. The classification and diagnosis of these patients is primarily based on chest pain, electrocardiogram (ECG) changes, and serum cardiac troponin levels. ECG can be inconclusive in many instances,18F‐labeled perfusion agents such as Flurpiridaz.18F]‐fluorodeoxyglucose (FDG) might provide a sensitive and early indicator of drug‐induced myocardial injury. PET using [18F]FDG as radiotracer is an established technique to determine metabolic correlates in cancer tissue.18F]FDG and 99mTc‐Sestamibi (MIBI) in cardiac injury induced by isoproterenol. [99mTc]MIBI/SPECT is used in clinic to define perfusion of myocardial tissue.Positron emission tomography (PET) can also be employed to determine myocardial perfusion, especially after the recent introduction of 22.118F]FDG and [99mTc]MIBI were purchased from the University of Oklahoma‐Nuclear Pharmacy . Sprague Dawley rats were obtained from Envigo .Isoproterenol was purchased from Sigma‐Aldrich  and was used without further purification. Clinical grade FDG/PET and [99mTc]MIB/SPECT on the same day before isoproterenol administration. Imaging was repeated on the day after the second dose of isoproterenol  was administered and imaging was performed 1 hour postinjection. Helical SPECT of the thoracic region in 24 frames of 60 seconds each was acquired on a NanoSPECT machine . For PET, [18F]FDG  was injected and imaging was performed 1 hour postinjection on a PET‐CT dual modality machine . A fly‐mode CT of thoracic region was also acquired. After imaging, the rats were allowed to wake up and kept in their cage until the time of euthanasia.The sequence of treatment given to the rats is shown in Figure SPECT acquisitions were reconstructed with HiSPECT reconstruction algorithm provided with the NanoSPECT system. The acquired list‐mode PET data were reconstructed by filtered back projection algorithm and fused with the CT to generate a composite PET‐CT image.Standard uptake values (SUV) from the acquired PET and SPECT images were calculated by drawing a three‐dimensional volume of interest (VOI) around the heart using the CT image. Background was determined by placing a spherical VOI at the same level as the 4th sternebrae in the XY‐plane of the posterio‐medial region of the left lung. Background was subtracted from mean counts per voxel for the heart and the values were normalized to injected dose per gram bodyweight.2.5g for 5 minutes). Cardiac Troponin I (cTnI) levels were determined in plasma by using a rat‐specific enzyme‐linked immunoassay kit obtained from Life Diagnostics . Plasma samples were diluted in 1:2 ratio with PBS before estimation.Blood samples were collected before euthanasia via the tail vein and plasma was separated by centrifugation . The results have been presented as percent of control values.2.7After the final session of imaging and last blood sample collection, 1% percent Evan's blue was injected into the rats (2 mL/kg) before euthanasia. After 30 minutes, euthanasia was performed and their hearts were immediately collected. Whole hearts were pictured before freezing at −20°C for 2 hours. Afterwards, the hearts were sectioned into 2 mm slices and placed in 1% solution of TTC in PBS at 37°C with intermittent shaking. After 30 minutes of staining, the TTC solution was removed and replaced with 10% buffered formalin for overnight fixing. TTC stains viable tissue (red), but leaves dead/necrotic tissue unstained.2.8T Test. P value < .05 was the cut‐off for statistical significance. Data in figures are displayed as mean ± standard error of mean (SEM).For statistical comparisons we employed GraphPad Prism 6 Software . Two group comparisons were performed using an unpaired, two‐tailed Student's 33.1Figure 3.2Circulating levels of cardiac troponin are highly sensitive clinical markers of acute myocardial pathology. Cardiac troponin was undetectable in control/baseline plasma (n = 6), and was increased in isoproterenol‐treated rat plasma  Figure . While t3.399mTc]MIBI, for myocardial perfusion. The left‐oblique composite views and tomograms of thoracic region at baseline and after isoproterenol treatments are shown in Figure 99mTc]MIBI accumulation in isoproterenol‐treated hearts reduced by 45% as compared to the baseline values . At the same time, isoproterenol has been known to increase oxidative stress in myocardial tissue.18F]FDG/PET is perhaps a better technique than perfusion imaging with [99mTc]MIBI/SPECT. Thus, molecular imaging of glucose metabolism with PET may help to detect subclinical drug cardiotoxicity and complement traditional LVEF assessment. There have been very few clinical studies involving [18F]FDG/PET to evaluate drug‐induced cardiotoxicity.18F]FDG is substantially taken up by normal heart tissue. In isoproterenol‐treated hearts [18F]FDG accumulation was reduced as compared to the control values, but it was still detectable in surrounding tissues including brown fat. These results are in accordance with the clinical and preclinical findings reported about [18F]FDG accumulation in congestive heart failure.18F]FDG accumulation in isoproterenol‐treated rats is due to regions of nonviable tissue created by isoproterenol treatment. It is notable that smaller doses of isoproterenol have been shown to increase FDG uptake in brown fat and some tumor lines.Our imaging results indicate that [18F]FDG, [99mTc]MIBI is a cationic radiotracer with a significant ability to partition into the lipid phase. It accumulates in the myocardium in proportion to both the extent of myocardial perfusion and the viability of myocytes. It diffuses across the cell membrane and its intracellular trapping is dependent on mitochondrial membrane potentials present in viable cells.99mTc]MIBI is taken up by viable myocardial tissue, but not by necrotic tissue, we expected to see its reduced uptake in the isoproterenol‐treated hearts. However, the acquired SPECT images showed no visible differences. Only with quantitative VOI analysis of the images we could detect a significant reduction in uptake in isoproterenol hearts as compared to the normal hearts. Other groups have reported varying degrees of alterations in [99mTc]MIBI uptake as a result of cardiotoxic agents and myopathies. [99mTc]MIBI uptake has been shown to increase in patients with doxorubicin‐induced cardiotoxicity.99mTc]MIBI uptake were reported between controls and patients with statin‐induced myopathy or congestive heart failure.99m]MIBI uptake is dependent on cellular integrity and mitochondrial viability, it is likely that uptake in conditions of cardiomyopathy are dependent on how the injury alters mitochondrial function. The damage caused by isoproterenol treatment is diffuse and widespread in the heart. In the absence of a focal area of damage, we suspect that [99mTc]MIBI is not able to provide differential diagnosis of isoproterenol‐induced myocardial injury.Unlike [18F]FDG uptake than in [99mTc]MIBI accumulation in cardiac tissue. Although the quantitative uptake values of [18F]FDG were significantly altered, the [18F]FDG/PET images were more remarkable in showing reduced uptake in isoproterenol‐treated hearts. Previously, Heather et al showed that prolonged dosing of rats with isoproterenol resulted in generalized suppression of myocardial metabolism, including myocardial palmitate oxidation rate, citrate synthase activity, and insulin‐stimulated glycolysis as well as expression of glucose transporter GLUT4.As a sympathomimetic amine, isoproterenol has potent chronotropic and inotropic effects on the heart. Accordingly, it increases myocardial utilization of oxygen, creating imbalance in supply and demand and resulting in a hypertrophic heart. Isoproterenol‐induced hypertrophy is associated with arrhythmias, myocyte loss, myocardial ischemia, and fibrosis, with progression to heart failure.518F]FDG/PET to image myocardial damage in a rat model of isoproterenol‐induced injury. To our knowledge, this is the first study which investigated [18F]FDG and [99mTc]MIBI uptake in this model of drug‐induced cardiomyopathy. Because of the profound impact of accurate and early detection of MI on patient care, definitive diagnosis of drug‐induced MI is of critical importance. When compared to each other, [18F]FDG performed better than [99mTc]MIBI in delineating healthy from damaged myocardium. Although controlled trials will further unravel the role of new PET agents for perfusion imaging ([18F]Flurpiridaz and [18F]BFPET), it is noteworthy that imaging of myocardial viability, as indicated by intact perfusion, is not always able to predict clinical outcome of revascularization or therapy in MI.We demonstrated the utility of [None.VA conceived and designed the study; HH, AH, and VA performed the experiments and collected the data; HH and VA conducted the data analysis and wrote the manuscript. All authors have reviewed and approved this manuscript.