Background: Children with sickle cell anemia (SCA) are at an increased risk of cardiovascular complications. The aim of this study was to assess the role of speckle tracking echocardiography in detecting subclinical myocardial damage in children with SCA.Methods: A cross-sectional case–control study was conducted at the echocardiography laboratory of the military hospital of Tunis between July and December 2018. Thirty patients with SCA were included. A control(C) group including 30 normally developing children was selected and matched to the SCA group by sex and age. We compared between the two groups: conventional echocardiographic parameters including cardiac output, left ventricular ejection fraction (LVEF), thickness and the global longitudinal strain (GLS). The echocardiographic measurements were indexed according to body surface area. The left ventricular (LV) GLS association with clinical characteristics and echocardiographic parameters were also evaluated.Results: Patients and controls were matched for age and sex: the mean age was (11± 2years) in SCA group versus (12± 1 years) in C group with a sex ratio of . Body surface area was comparable. LV hypertrophy and dilation were revealed in the SCA group, whereas measurements were normal in the C group. No significant differences were observed for cardiac output (p=0.4). LVEF were preserved in both groups. However, two-dimensional (2D) LVGLS was impaired in 46% of SCA group (n=14) with mean value of .In SCA group, impaired LVGLS was significantly associated with LV mass , LV tele diastolic diameter and left atrial volume . In multivariate analysis, LV mass was the only independent factor.Conclusions: In the present study, LVGLS measurement revealed subclinical LV systolic impairment in patients with SCA. Therefore, 2D strain could be beneficial to detect the natural history of LV dysfunction in SCA. Globally, hemoglobin disorders are responsible for about 3.4% of death among children under 5 years old.Sickle cell disease or sickle cell anemia (SCA) is an autosomal recessive genetic disease linked to a hemoglobin abnormality leading to the deformation of red blood cells. The development of cardiac complications in SCA are multifactorial including anemia related chronic volumetric overload, endothelial dysfunction, altered microcirculation, and myocardial iron overload. All these mechanisms contribute to severe clinical manifestations, ranging from pulmonary arterial hypertension to left ventricular diastolic dysfunction and dilated or hypertrophic cardiomyopathy. Nowadays, with the advent of new echocardiographic techniques such as two-dimensional (2D) strain, it is possible to detect systolic and diastolic dysfunction earlier than with conventional echocardiography.The prognosis of this serious chronic disease depends on the occurrence of complications, particularly cardiovascular diseases. However, these complications usually occurred in adulthood, largely due to a lack of regular cardiological follow-up during childhood. Local tissue motion is represented by the geometric displacement of each speckle. Several software packages have been developed to allow temporal and spatial processing of the image obtained by the 2D strain.The advent of 2D strain has provided early detection of cardiac damage in many chronic diseases and has increasingly become essential to stratify prognosis. In fact, it is a new technique that studies myocardial motion by tracking speckles, which are acoustic markers of the myocardium.The aim of the present study was to assess the contribution of 2D strain to the detection of subclinical left ventricular (LV) myocardial damage in children with SCA.A cross sectional case-control study was conducted in the cardiology department at the Military Hospital of Tunis between July and December 2018.•Samplesize calculation:Knowing that 2.4% of patients followed up on at the pediatric department were referred for pediatric cardiology consultation during the study period, it was deemed that a sample size of 35 patients, calculated using a predictive formula, would be required to achieve statistical significance .•SCA group:Inclusion and non-inclusion criteria: The SCA group included children (2-18 years) followed up at the pediatric department of the military hospital of Tunis for homozygous SCA during the study period. Patients with a history of heart disease or those who had undergone cardiac surgery were not included.Exclusion criteria: The patients with poor echogenicity on transthoracic echocardiography (TTE) and those who were lost to follow-up during the study period were excluded.•Control group:For the control (C) group, we selected 30 children with no history of cardiovascular or respiratory pathology or presenting anemia at the time of the study. Those children were hospitalized in the pediatric department and referred to a pediatric cardiologist for assessment of a heart murmur or for exploration of atypical chest pain. All the control patients had normal echocardiography. Then, the control group was matched with the SCA group based on age and gender.Data were collected by a single physician (? For example SC or AN …) using the patient information sheet. Parents accepted to participate in the study and informed consents were given. They also accepted that their children underwent an echocardiographic examination since it is noninvasive.•Clinical and anthropometric data2) was calculated.Data collected were age, sex, medical history, age of onset of disease, hemoglobin level, rate of transfusion, complications, and current treatment. The height was measured with a standing stadiometer (Seca 217), barefoot or in socks, in a standing position, heels joined, well balanced, and back straight. Weight (±1 kg) was measured with a digital scale , and then body surface area  using a vivid E7 ultrasound system  with a S5-1 probe according to the guidelines of the American Society of Echocardiography and the European Association of Cardiovascular Imaging.All echocardiographic examinations were analyzed by the same cardiologist who was not aware about the collected clinical data . Measurements were performed in the parasternal long axis, parasternal short axis, and apical views . An electrocardiogram with a velocity scale between 12 and 20 cm/sec was performed to avoid aliasing.Each incidence was performed so that the angle between the examined myocardial wall and the ultrasound beam did not exceed 30 degrees. All echocardiographic data were stored on a central memory unit, allowing post processing and adjustment of measurements, including pulsed Doppler tissue imaging (DTI), measured, and averaged over 3 to 5 continuous cardiac cycles.Left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), interventricular septal wall thickness, and posterior wall thickness (PWT) were measured with 2D targeted M-mode tracing. The left ventricular mass (LVM) was estimated using the Devereux formula.Left ventricular ejection fraction (LVEF) was calculated using Simpson's biplane method of discs, and systolic mitral annulus velocity (S’) was assessed using DTI in 2D mode of the mitral annulus in the four-chamber view.•Strain analysis by speckle-tracking echocardiography: myocardial deformation assessmentSpeckle tracking analysis was performed offline on views of the four apical chambers, the apical long axis, and the apical two chambers that were previously stored in Digital Imaging and Communications in Medicine format. Analysis of echocardiographic images was performed offline using Echo PAC . Three cardiac cycles were recorded in cine loop format at a frame rate between 50 and 80 frames per second as 2D grayscale views. The quality of myocardial tracking was visually checked in real time and then manually corrected to ensure optimal tracking. The software then tracks the deformation of the myocardium during the cardiac cycle to calculate peak systolic segmental strain. The global longitudinal strain (GLS) is determined as the average of the segmental strains . Quantitative variables were tested for normal distribution using the Shapiro-Wilk tests and then expressed as medians and interquartile. Qualitative variables were expressed as numbers and percentages. For the case-control study, the Mann-Whitney test was used to compare categorical data. The optimal cutoff value of GLS in the SCA group was determined based on receiver-operator characteristics (ROC) curve analysis.A linear regression model was used to evaluate the relationship between impaired LVGLS and clinical and echocardiographic measurements. Pearson correlation analysis and Spearman rank correlation analysis were performed to assess dependence.The multivariate linear regression for assessing independent correlations in the impaired GLS was performed by including significant variables from the univariate model. A p<0.05 indicated statistical significance.For bibliographic research, we used PubMed through MESH research based on the following keywords: Sickle cell anemia, heart disease, echocardiography, speckle tracking echocardiography, global longitudinal strain, left ventricular systolic function, and child. We included publications in French and English between 1970 and 2020.The study was approved by the ethics committee of the military hospital in Tunis. Written informed consent was collected from the parents. Anonymity was respected during data treatment.•Baseline characteristics of the two groupsPatients and controls were matched for age and sex . The meaThe average hemoglobin level in the SCA group was 8.6±0.5 g/dl. The mean serum ferritin value was 824±32 μg/l. The treatment received by SCA children included intravenous penicillin in 43% (n=13), Hydroxycarbamide in 46% (n=14), Deferoxamine in 16% (n=5) and vitamin E in 96% (n=29) of the patients. All patients received folic acid.The symptoms of the SCA group and reported complications are summarized in•Echocardiographic measurementsMorphological characteristics and LV systolic function are summarized inNo significant differences were revealed between the 2 groups for mitral annular plane systolic excursion (MAPSE) and LV systolic mitral annulus velocity (S') wave measurements. The calculation of the indexed cardiac output was comparable in both groups.•Study of longitudinal myocardial deformation using the speckle tracking techniqueAccording to this study, the optimal cutoff value of GLS was -21.3% . The sensitivity, specificity, positive predictive value, and negative predictive value were 48%, 82%, 96%, and 65%, respectively, for predicting altered LV contractile function .In the SCA group, LVGLS was estimated at -21.2±3%. It was significantly reduced (-20%) in 46% of the children (n=14), whereas it was significantly higher (-25.03±2.9%) in the C group with no decreased value .•Univariate and multivariate analyses of factors associated with abnormal LVGLSIn the SCA group, impaired LVGLS was significantly associated with left ventricular mass (LVM), LV tele diastolic diameter, and left atrial volume .No significant correlations were noted between the altered LVGLS, clinical symptoms, complications, and hemoglobin level. The multivariate analysis found a correlation between LVM and impaired GLS .The main finding of the present study was that performing 2D speckle echocardiography in SCA patients may allow early detection of subclinical left ventricular morphological modifications such as hypertrophy and dilation. Even though both groups had preserved LVEF, the systolic function as measured by 2D speckle tracking imaging was impaired in 46% of the SCA group. In addition, the chronic intravascular hemolysis is commonly associated with vaso-occlusive event that also results in hypoxia and further increase in cardiac output. In some studies, the degree of LV dilation has been described as proportional to the degree of anemia. However, increased cardiac output in non-sickle cell anemia usually occurs when the hemoglobin level is less than or equal to 7 g/100 ml. A few studies have been performed using hemodynamic measurements of cardiac output in homozygous SCA and have confirmed the existence of a significant increase in resting cardiac output in most patients, even for hemoglobin levels of 9 to 10 g/100 ml. Thus, for the same hemoglobin level, resting cardiac output was higher in sickle cell patients than that of persons with chronic anemia from other etiologies. This is most likely due to hypoxemia caused by hemoglobin S's decreased affinity for oxygen and intrapulmonary shunts caused by vaso-occlusive crisis. Therefore, this increase in cardiac output has long been implicated in the prime cause of cardiac damage in sickle cell patients. It has been also associated with morbidity and mortality in these patients.In fact, the greater dilation of the LV in the SCA group could be explained by several mechanisms. First, the chronic anemia due to hemolysis leads to an increase in cardiac output, systolic ejection volume, and baseline heart rate. All these contribute to a significant dilation of the LV.This study has also revealed features of left ventricular eccentric hypertrophy in SCA patients. The LVM may expand in the setting of SCA to accommodate the increase in tele diastolic diameter of LV. In addition, iron overload may develop during transfusions and boost myocardial development. For example, no significant difference in LVEF was also observed in a meta-analysis involving 841 patients with SCA and 554 controls. Otherwise, Lamers et al. have reported a decreased in fractional shortening in SCA children while studying myocardial contractility. Several studies that have assessed left ventricular systolic function in sickle cell patients have concluded that myocardial contractility was impaired independently of left ventricular preload and after load. The load-dependent parameters would be compensated at early stage and would progressively deteriorate with age. Chronic left ventricular volume overload and repeated ischemic events represent the main mechanisms of cardiomyopathy in SCA patients. It leads to myocardial dilation and remodeling that progressively impair left ventricular systolic function overtime.In this study, LV systolic function was preserved in all patients with a decreased mean value of LVEF in the SCA group. No significant differences were found for the rest of parameters, including cardiac output value. This result was in line with several studies and meta-analyses. In fact, altered strain in sickle cell patients could be the result of myocardial ischemia, fibrosis, myocardial iron deposition, and ventricular hypertrophy which could be associated with a preserved LVEF during the early stage of the disease. Therefore, LVGLS could indicate the progression to cardiac disorders and myocardial damage at a subclinical stage.The present study revealed that the LVGLS was significantly impaired in sickle cell patients compared to controls. Indeed, LVGLS is a more specific predictor of myocardial remodeling than LVEF. It is extremely sensitive in detecting early systolic function impairment despite a preserved LVEF. Thus, the GLS seems to bea useful tool for the follow-up of sickle cell patients. Recent genetic studies in SCA have identified certain genotypes associated with cardiovascular disease. Therefore, it is maybe important to couple echocardiography with genetic analyses in order improve the follow-up and long-term prognosis of SCA patients.In line with this study result, Sachdev et al. described a correlation between impaired LVGLS and LV dilation and hypertrophy.This study primarily supports the use of 2D strain in the assessment of LV function in SCA. However, the interpretation of these results was limited by the absence of recognized standard norms of strain in the pediatric population and by the complexity of using Z-score reference values in the morphological analysis of the LV. Larger scale studies are therefore required to improve the role of LV strain for early evaluation of myocardial damage in children with SCA and to predict the risk of progression to heart failure in these patients.Written informed consent was obtained from the parents.Each author has contributed to this work as follows:Sarra Chenik: Conceptualization, Data Curation, Methodology, Resources, Validation, Writing – Original Draft Preparation, Writing – Review & EditingAymen Noamen: Data Curation, Methodology, Resources, Validation, Writing – Original Draft PreparationAbyr Bouslimi: Data Curation, Methodology, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & EditingHouaida Mahfoudhi: Supervision, Validation, Visualization, Writing – Review & EditingSadok Hannachi: Conceptualization, Data Curation, Methodology, Resources, Supervision, Validation, Writing – Original Draft Preparation, Writing – Review & EditingHager Barakizou: Resources, Validation, VisualizationIslem Mejri: Validation, Visualization, Writing – Review & EditingTasnim znegui: Visualization, Writing – Review & EditingWafa Fehri: Supervision, Validation, Visualization, Writing – Review & Editinghttps://doi.org/10.6084/m9.figshare.20949031.v4.Figshare: ECHOCARDIOGRAPHIC EVALUATION IN CHILDREN WITH SICKLE CELL ANEMIA: CONTRIBUTION OF 2D STRAIN.xlsx.Creative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of the The authors have addressed the raised points in an appropriate way. The manuscript is well improved. Then, the current version of paper is suitable for indexing.Is the work clearly and accurately presented and does it cite the current literature?NoIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Cardiovascular diseaseI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. I have reviewed the submitted paper entitled “Evaluation of left ventricular systolic function in children with sickle cell anemia: contribution of 2D strain”. The authors showed that left ventricular global longitudinal strain is significantly altered in the SCD-group. They also suggested that treatment with hydroxycarbamide is a predictive factor.English editing is needed through all the manuscript.The authors must define each abbreviation before its first use in the text (C means control in the abstract section).Conclusion in abstract section is out of nowhere. In the introduction section, the authors should cite the potential cardiac complications of sickle cell disease and explain in detail the two-dimensional strain technique.Methods section. It is completely unclear how the authors have performed this study. First, it is a case control study. Inclusion and exclusion criteria are not well defined. They mentioned among inclusion criteria: “having SCA and a performed TTE”, then they mentioned in the text that they performed TTE for all patients. So why do they fix the performance of TTE during follow-up as an inclusion criterion? When have they performed TTE? Did they compare the performed TTE to the previous ones?What was the indication for TTE in SCA or controls group? What was the indication for hospital admission in controls group?A comparative table with 4 columns should be added in the result section . This table should figure baseline characteristics , treatment, dose, mean of LVGLS, LVEF, etc.).How much was the proportion of patients with impaired LVGLS? Also, a clear definition of impaired LVGLS is lacking.Multivariable logistic regression investigating the association between impaired LVGLS and other parameters  was not performed. Then, a conclusion only based on bivariate analysis is extremely weak.I suggest putting 3 main tables in the results section: Table 1 (point 6), Table 2 , Table 3 (multivariable logistic regression).Was a single TTE performed to each study participant? Or were repeated TTE performed?Clear definitions of left ventricular dilation and hypertrophy were missed. All these terms must be defined in the method section including for threshold of normal LVGLSThe authors should mention in the result section that LVGLS was normal in all study participants in C-group.It is true that there was a significant difference in echocardiographic parameters between study groups, but the represented values are within range of normal in both groups. They were not suitable for neither hypertrophic nor dilated cardiomyopathy diagnosis.The authors should represent their results in the first paragraph of the discussion section. Then, they must focus on discussing their findings based on literature data.They claim that hydroxycarbamide treatment is the predictor of LVGLS impairment, but in fact, the hydroxycarbamide dosage differs significantly between study groups. In the concerned table, the authors differ hydroxycarbamide treatment from hydroxycarbamide dose.The authors should explain what this study adds to what is already known in the field. Previous studies investigate the role of LVGLS to predict cardiac outcomes in SCD patients.Re-write the conclusion (rephrase the first sentence which must highlight your take-home message).It is unclear if a LVGLS below -20% is a predictor for cardiac disease in the future. It could be an incidental finding without clinical relevance. Usually, A GLS higher than 18% is considered normal.  This paper is not well written and not suitable for indexing in the current form. Major revision is required before being considered for further evaluation. Herein, I addressed the main points:Is the work clearly and accurately presented and does it cite the current literature?NoIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?PartlyAre the conclusions drawn adequately supported by the results?PartlyAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Cardiovascular diseaseI confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. 1. English editing is needed through all the manuscript. We revised the manuscript.2. The authors must define each abbreviation before its first use in the text (C means control in the abstract section). We rectified all abbreviations in the text.3. Conclusion in abstract section is out of nowhere.  We corrected the conclusion in the abstract section.4. In the introduction section, the authors should cite the potential cardiac complications of sickle cell disease and explain in detail the two-dimensional strain technique. We added a paragraph to explain this.5. Methods section. It is completely unclear how the authors have performed this study. First, it is a case control study. Inclusion and exclusion criteria are not well defined. They mentioned among inclusion criteria: “having SCA and a performed TTE”, then they mentioned in the text that they performed TTE for all patients. So why do they fix the performance of TTE during follow-up as an inclusion criterion? When have they performed TTE? Did they compare the performed TTE to the previous ones? It’s a cross sectional case-control study The (SCA) group included children followed up at the pediatric department of the Tunis military hospital for sickle cell disease during the study period. We did not include patients with SCA with history of heart diseases, or those who had undergone cardiac surgery. The control (C) group selected 30 children with no history of cardiovascular or respiratory pathology and not presenting anemia at the time of the study.  Then, C group was matched to the SCA group by age, sex and body mass index.6. What was the indication for TTE in SCA or controls group? What was the indication for hospital admission in controls group? These children had been hospitalized in the pediatric department and referred to a pediatric cardiology consultation for assessment of a heart murmur or for exploration of atypical chest pain, and who had a normal echocardiography.7. A comparative table with 4 columns should be added in the result section . This table should figure baseline characteristics , treatment, dose, mean of LVGLS, LVEF, etc.). We added a table untitled ‘Comparison of baseline characteristics of the two groups’.8. How much was the proportion of patients with impaired LVGLS? Also, a clear definition of impaired LVGLS is lacking. In SCA group, LVGLS was estimated at -21.2±3%. It was significantly decreased (< -20%) in 46% of children (n=14) referring to ‘Reference Ranges of Left Ventricular Strain Measures by Two-Dimensional Speckle-Tracking Echocardiography in Children A Systematic Review and Meta-Analysis. J Am Soc Echocardiogr. 2016 Mar;29(3):209-225.e6. Epub 2015 Dec 30.9. Multivariable logistic regression investigating the association between impaired LVGLS and other parameters  was not performed. Then, a conclusion only based on bivariate analysis is extremely weak. In multivariate analysis we found a correlation between LVM and impaired GLS 10. I suggest putting 3 main tables in the results section: Table 1 (point 6), Table 2 , Table 3 (multivariable logistic regression). We have organized the results section.11. was a single TTE performed to each study participant? Or were repeated TTE performed? A single TTE was performed to each study participant.12. Clear definitions of left ventricular dilation and hypertrophy were missed. All these terms must be defined in the method section including for threshold of normal LVGLS We revised the methodology.13. The authors should mention in the result section that LVGLS was normal in all study participants in C-group. We mentioned this result.14. It is true that there was a significant difference in echocardiographic parameters between study groups, but the represented values are within range of normal in both groups. They were not suitable for neither hypertrophic nor dilated cardiomyopathy diagnosis. We added a Table to compare the LV morphological parameters and LV systolic function in the two groups.15. the authors should represent their results in the first paragraph of the discussion section. Then, they must focus on discussing their findings based on literature data. We corrected the first paragraph of the discussion section.16. they claim that hydroxycarbamide treatment is the predictor of LVGLS impairment, but in fact, the hydroxycarbamide dosage differs significantly between study groups. In the concerned table, the authors differ hydroxycarbamide treatment from hydroxycarbamide dose. We corrected the correlation between treatment and LVGLS impairment.17. the authors should explain what this study adds to what is already known in the field. Previous studies investigate the role of LVGLS to predict cardiac outcomes in SCD patients.with abnormal LVGLS. The aim of this study was to assess the contribution of 2D strain to the detection of subclinical LV myocardial damage in children with SCA and to reveal associated factors18. Re-write the conclusion (rephrase the first sentence which must highlight your take-home message). We have corrected the conclusion. We are grateful to the reviewers for their insightful comments. Sickle cell disease is endemic in north Africa. It used to be a life-threatening disease with reduced life expectancy which improved in the recent years due to healthier lifestyles, medical monitoring, and new therapies. Nevertheless, we attest to an increase of chronic multi-systemic complications in addition to acute complications, mainly cardiovascular ones. The authors highlighted in this paper the importance of early detection of myocardial damage using echocardiographic techniques such as two-dimensional (2D) strain during childhood. It is a patient control study with a predictive factor analysis for alteration of the global longitudinal strain of the left ventricle. Generally, the manuscript is well written and the topic is quite interesting for the reader. The paper seems suitable for indexing in its actual version.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:cardiology, echocardiographyI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


Cardiac magnetic resonance (CMR) has been used to diagnose and risk-stratify patients with left ventricular noncompaction (LVNC). The prognostic value of CMR parameters for LVNC, especially feature tracking (CMR-FT), is not well known in LVNC patients with left ventricular dysfunction. The present study aimed to investigate whether the combination of CMR-FT with traditional CMR parameters can increase the prognostic value of CMR for LVNC patients with reduced left ventricular ejection fraction (LVEF).A total of 123 candidates were retrospectively included in this multicenter study and 55 LVNC patients  remained after applying the exclusion criteria. Clinical features, left ventricular (LV) function parameters, global and segment myocardial strain, and late gadolinium enhancement (LGE) were evaluated. The outcomes include the composite events of cardiovascular death, heart transplantation, hospitalization for heart failure, thromboembolic events, and ventricular arrhythmias.p = 0.029) was a strong predictor of MACEs and significantly improved the predictive value . However, myocardial strain parameters were not statistically significant for the prediction of MACEs after adjusting for age, body mass index, LVEF and the presence of LGE and did not increase the prognostic value  in the multivariate model.After a median follow-up of 5.17 years (interquartile range: 0.17 to 10.58 years), 24 (36.8%) patients experienced at least one major adverse cardiovascular event (MACE). The myocardial strain parameters of patients with events were lower than those of patients without events. In the univariable Cox analysis, LVEF, the presence of LGE, global longitudinal strain (GLS) and segmental strains, including longitudinal strain at the apical level and radial and circumferential strain at the basal level, were significantly associated with MACEs. In the multivariate analysis, LGE (hazard ratio (HR) 3.452, 95% CI 1.133 to 10.518, The combination of CMR-FT with traditional CMR parameters may not increase the prognostic value of CMR in LVNC patients with reduced LVEF, while the presence of LGE was a strong independent predictor of MACEs and significantly improved the predictive value.The online version contains supplementary material available at 10.1186/s12872-022-02963-5. Left ventricular noncompaction (LVNC) is a rare congenital disorder that is characterized by a bilayer myocardium with compacted and noncompacted layers, prominent trabeculations, and deep intertrabecular recesses connected with the left ventricular cavity . LVNC isCardiac magnetic resonance (CMR) is the technique of choice for the diagnosis, and early detection of cardiomyopathy and the severity grading of LVNC . Left veThe present study aimed to investigate whether the combination of CMR-FT with traditional MRI parameters can increase the prognostic value of MRI in an LVNC patient cohort with left ventricular dysfunction and to determine the optimal prediction model.This multicenter retrospective cohort study identified patients with the LVNC phenotype via a Boolean search of contrast-enhanced CMR reports between March 2009 and January 2020. Patients were queried in the CMR report database by searching the following keywords that describe LVNC: “left ventricular noncompaction”, “left ventricular hypertrabeculation”, and “spongiform cardiomyopathy”. The inclusion criteria were patients who fulfilled the following diagnostic criteria for LVNC: 1) bilayer myocardium with thin compacted and a thick noncompacted layers; 2) marked trabeculations with deep endomyocardial recesses; and 3) an end-diastolic noncompacted/compacted ratio > 2.3 in any LV segment in any long axis view . The excA total of 123 candidates were identified from the CMR report database and 55 subjects remained after exclusion applying the exclusion criteria. The inclusion and exclusion criteria of the patients are summarized in Fig. CMR images were obtained with the same type of scanner in two centers by using a 3.0-T whole body scanner . An 18-channel cardiac phased array coil and electrocardiogram triggering were used for CMR scanning. The adopted CMR protocol was the same in the two centers. Steady-state-free precession (SSFP) cine images were acquired for the assessment of left ventricular function and morphology before the contrast agent was injected, and they included two orientations, the short-axis view covering the full left ventricle from basis to apex and the 2-, 3- and 4-chamber long-axis views. LGE images for detecting myocardial scarring or fibrosis were obtained using a contrast-enhanced inversion recovery TrueFISP sequence for 10 ~ 15 min after an intravenous bolus of gadobenate dimeglumine . The dose of contrast agent was 0.1–0.2 ml/kg body weight at a flow rate of 2.5–3.0 ml/s and then injected with 20 ml of saline flush at a rate of 3.0 ml/s. The scan parameters of the two sequences were as follows: (1) SSFP sequence: slice thickness 6–8 mm, slice gap 0 mm, repetition time 3.42 ms, echo time 1.5 ms, flip angle 60°, and voxel size: 1.6 mm × 1.6 mm × 0.8 mm; (2) inversion recovery TrueFISP sequence: slice thickness 8 mm, repetition time 2.81 ms, echo time 1.04 ms and flip angle 55°.All collected images were transferred to the dedicated postprocessing software Cvi42  and analyzed at center A by two expert radiologists blinded to patient baseline characteristics and radiological information. The left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESV), stroke volume (SV), and LVEF were calculated from the short-axis cine images in the short 3D module. EDV, ESV, and SV were corrected using BSA . Left ventricular epicardial and endocardial borders were manually traced in the 2-, 3-, and 4-chamber views of cine images at the end-diastole and the short-axis view at the end-diastole and end-systole by using the semiautomated feature tracking module. Global radial strain (GRS), global circumferential strain (GCS), and segmental radial and circumferential strain at the three levels, including apex, mid, and base, were calculated from the average of the peak strain of the short axis, and the global longitudinal strain (GLS) and segmental longitudinal strain at the three levels were calculated from the average of the peak strain of the long axis. Papillary muscles and noncompacted myocardium were excluded when the endocardial border was drawn. LGE extent was calculated as a percentage enhancement of myocardial mass from the LGE images. The presence of LGE was defined as myocardial enhancement with a signal intensity of > 5 SD above the mean signal intensity of the remote normal myocardium. The pattern and location of LGE were visually assessed by two experienced radiologists and classified as subendocardial, mid-wall, subepicardial, or transmural in distribution using standard American Heart Association 17 segment model.All patients were followed up on the telephone by using the standard questionnaire interview and the clinical medical records, electrocardiogram, ultrasound and the results of laboratory tests of all patients after CMR examination were queried, which was performed at center A by experienced physicians blinded to the CMR data. The clinical endpoints were major adverse cardiovascular events (MACEs), including cardiovascular death, heart transplantation, hospitalization for heart failure, thromboembolic events and ventricular arrhythmias defined as sustained or non-sustained ventricular tachycardia and ventricular fibrillation. The duration of follow-up was calculated from the date of the first CMR examination to the first occurrence of an endpoint.Statistical analysis was performed using GraphPad Prism version 9.0 , IBM SPSS Statistics 23.0 software , and R software version 4.1.0 . Continuous variables are presented as the mean ± standard deviation. Categorical variables are presented as absolute numbers (percentage). To compare the patient characteristics and CMR data in the groups, we compared continuous data by the Mann‒Whitney U test or independent Student’s t test and used chi-square analysis for categorial data. Correlations between LVEF and global strain parameters were assessed based on the Pearson correlation coefficient.p value ≤ 0.1 were included in multivariate Cox regression analysis to determine the independent predictors of the MACE. The hazard ratio (HR) and 95% confidence interval (CI) were calculated to estimate the risk associated with a particular variable. First, a baseline clinical Cox model building was performed as model 1. To investigate the incremental role, we sequentially added the traditional CMR markers, mainly including LVEF and the presence of LGE, to building model 2 and model 3. Finally, the parameters of CMR-FT  were added into model 3 to build other nested regression models. The -2Loglikelihood and c-index of each model for the prediction of MACEs were calculated. The likelihood ratio test and continuous net reclassification improvement (NRI) were used to evaluate the incremental prognostic value of these nested regression models. The intra- and interobserver reliability and agreement for continuous CMR variables were evaluated using the interclass correlation coefficients (ICCs) and Bland‒Altman analysis.The cutoff value of the optimal receiver operating characteristic (ROC) curve for predicting MACEs was selected as the value for maximizing sensitivity and specificity. The survival rate was evaluated by Kaplan–Meier analysis. Univariate Cox regression analysis was used to identify potential clinical and CMR predictors of MACEs. Then these variables with p = 0.012).The baseline clinical characteristics for the controls and the patients with and without MACEs are shown in Table p < 0.001). In patients’ group, the LVEF values were lower in patients with MACEs . All global and segmental strain parameters in patients’ group were significantly lower than in the controls . Compared with the patients without MACEs, global strain parameters were mainly attenuated in patients with MACEs, GRS , GCS , and GLS ; Segmental strain parameters were also reduced, and the longitudinal strain at the apical level, radial and longitudinal strain at the mid level, and radial and circumferential strain at the basal level were significantly lower in patients with events . The decrease in global and segment strain at three different levels  in the same group are illustrated in Additional file The CMR findings are shown in Table p = 0.02) and the LGE extent  were higher in patients with MACEs. The most common pattern was subendocardial LGE and mid-wall LGE in all LVNC patients, the number of LGE segments was 84 (14.5%) and 91 (15.7%), respectively. The transmural LGE was more prevalent in patients with MACEs than in patients without MACEs (40 (12.4%) vs. 11 (4.3%), p < 0.001). However, no statistical significance was observed in the LGE extent between the two groups. The clinical characteristics and CMR parameters in LVNC patients with or without LGE are shown in Additional file The presence of LGE . The cutoff values for GRS, GLS, and LVEF were ≤ 11.41%, > -6.23%, and ≤ 23.89%, respectively.ROC analysis was performed for CMR parameters with significant differences between groups, and the results are displayed in Additional file p = 0.033) and LVEF  were univariate predictors of MACEs. Longitudinal strain at the apical level and radial and circumferential strain at the basal level were also univariate predictors of MACEs. The presence of LGE  was significantly associated with adverse events. However, the LGE extent  did not have prognostic value in the univariate Cox regression analysis.In univariate Cox regression analysis , LGE was a strong and independent predictor of MACEs in model 3 and model 4. The presence of LGE (in model 3) significantly improved the model fit compared with model 2, including the clinical characteristics and LVEF . Moreover, the continuous NRI increased significantly . In comparison with model 3, which includes the traditional CMR imaging markers of LVEF and the presence of LGE, the addition of GLS did not improve the model fit  and GLS was no longer statistically significant for the prediction of MACEs in model 4. Figure The different models by multivariate analysis are shown in Table p = 0.0335). The survival rates free from MACEs were 55.2% and 33.1% in patients without and with LGE, respectively. The median survival time was 4.25 years in patients with LGE.The Kaplan‒Meier survival curve of the presence of LGE is displayed in Fig. p < 0.0001)  the presence of LGE was a significant independent predictor of MACEs and can effectively improve the predictive ability of the risk prediction model in LVNC patients with reduced LV systolic function, 2) the global and segmental strain were lower in LVNC patients with MACEs than in those without MACEs, and 3) LV strain parameters from CMR-FT had no significant incremental prognostic value in these patients with reduced LV systolic function.Strain parameters are the main noninvasive strategy for assessing systolic function of the left ventricle and are useful for the early detection and outcome evaluation of some heart diseases , 19. OurIn comparison with the global strain parameters, the segmental strain parameters can reveal the change in myocardial deformation in each segment. However, the inter- and interobserver reproducibility of some segmental strain values, such as apical radial strain, were not good and they should be used with caution within clinical studies. In the present study, the reduction of global strains was moderate compared with the three segmental strains. The reduction in circumferential and longitudinal strain at the mid and apical levels were more pronounced than that at the basal level. This result supported that myocardial noncompaction often occurs in the apical and middle segments , 31, andLGE by cardiac MRI is a reference method for the noninvasive detection and quantification of myocardial fibrosis; moreover, it is a robust independent predictor of poor prognosis and is used extensively in various cardiomyopathy studies . The resMyocardial fibrosis can lead to changes in myocardial electrical properties. Wan J et al. showed that ventricular arrhythmias are common in patients with LGE . In the In the present study, the quantitative extent of LGE was considered, but no significant correlation was observed with clinical results. The discrepancy with some previous studies may be associated with the different study populations, small sample size, definitions of different outcomes, or the use of different statistical methods –8. More This study has some limitations. First, although this study was a multicenter study, the final patient cohort included in the study was limited. Uncontrollable confounders and selection bias may have been present. Second, most LVNC patients were treated with drugs because of cardiac dysfunction. However, we did not explore whether the different types and doses of drugs would affect the prognosis. Third, considering that the population of the study included the LVNC patients with reduced LVEF, the findings may not be universally applicable to all LVNC populations. In the future, we will further study the prognostic value of myocardial strain in patients with normal left ventricular function.This study further reinforces the predictive value of CMR-LGE in LVNC patients with reduced LVEF, while LV strain parameters from CMR-FT could not increase the prediction efficiency of the risk prognostic model in these patients.Additional file 1 : Fig. S1. Absolute value of global and segmental peak strain difference between controls and LVNC patients. Table S1 Clinical characteristics and CMR parameters in LVNC patients with or without LGE. Table S2 The ROC analysis for traditional CMR features and CMR feature tracking. Table S3 Incremental value of the segmental strain. Table S4 Intra- and inter-observer reproducibility for the myocardial strain parameters in LVNC patients.


In contrast, HCM risk score and left ventricular maximal thickness (LVMT) were similar in NCP and CP patients. No left ventricular outflow tract obstruction (LVOTO) was observed in the NCP group. Left ventricular outflow tract diameter (LVOT), aortic valve diameter (Ao), and LVOT/Ao ratio were significantly higher and anterior mitral leaflet (AML)/LVOT ratio was lower in the NCP compared to the CP group. In conclusion, significant differences in nonstandard CMR parameters were noted between the nonclassic and classic HCM phenotypes that may contribute to future studies on disease stages and risk stratification in HCM.Patients with nonclassic phenotypes (NCP)—more advanced stages of hypertrophic cardiomyopathy (HCM)—constitute an intriguing and heterogeneous group that is difficult to diagnose, risk-stratify, and treat, and often neglected in research projects. We aimed to compare cardiac magnetic resonance (CMR) parameters in NCP versus classic phenotypes (CP) of HCM with special emphasis given to the parameters of established and potential prognostic importance, including numerous variables not used in everyday clinical practice. The CMR studies of 88 patients performed from 2011 to 2019 were postprocessed according to the study protocol to obtain standard and non-standard parameters. In NCP, the late gadolinium enhancement extent expressed as percent of left ventricular mass (%LGE) and left ventricular mass index (LVMI) were higher, left atrium emptying fraction (LAEF) was lower, minimal left atrial volume (LAV min) was greater, and myocardial contraction fraction (MCF) and left ventricular global function index (LVGFI) were lower than in CP ( Hypertrophic cardiomyopathy (HCM) is defined in the European guidelines by the presence of increased left ventricular (LV) wall thickness, which is not solely explained by abnormal loading conditions , with noThe most important achievements are more effective risk stratification and the use of the implantable cardioverter defibrillator (ICD) for primary prevention of sudden cardiac death (SCD). It was estimated that only about 25% of patients with HCM ultimately died of their disease, predominantly those who were <30 years of age at presentation . The othIt is indicated that certain subgroups of the HCM patients face a worse prognosis: the patients with a high risk of SCD with no symptoms of heart failure, those with progressive symptoms of congestive heart failure (CHF) with or without left ventricle outflow tract obstruction (LVOTO) in the absence of systolic dysfunction, and the so-called end-stage disease characterized by LV systolic dysfunction or apical aneurysms. The development of atrial fibrillation (AF) has an unfavorable hemodynamic impact on the clinical course of HCM and is associated with a significant risk of thromboembolism and stroke ,4,7. CHFThe assessment of an individual patient’s risk for SCD is nuanced and actively being refined; it continues to evolve as new imaging prognostic markers emerge ), with some variability in recommendations from different society guidelines ,2,10. ThThe aim of our study was the comparison of CMR parameters of nonclassic versus classic phenotypes of HCM with special emphasis given to the markers of established and potential prognostic importance, based on the CMR studies of the patients referred to our center, mostly outpatients. It was a single-center observational study in the “real world” setting. To the best of our knowledge, this was the first comparison of prognostic CMR parameters in the population of HCM patients grouped according to the nonclassic versus classic phenotype.The investigated group consisted of 88 patients referred for CMR in our hospital from 2011 to 2019. The inclusion criteria were as follows: LV wall thickness ≥15 mm or ≥13 mm with family history of HCM, according to the 2014 European Society of Cardiology (ESC) Guidelines  > 65%), stage III: adverse remodeling, the presence of unfavorable structural modifications, superimposed to the “classic” HCM phenotype with LVEF in the low to normal range of 50% to 65%, and stage IV: overt dysfunction defined by an LVEF < 50% [For the purpose of our study, the nonclassic phenotype (NCP) was defined as ejection fraction (EF) ≤ 65%, and classic phenotype (CP) as EF > 65% [All the CMR studies were performed on a 1.5 T scanner  using the standard protocol. Long- and short-axis stack cine images were acquired for assessment of myocardial function. The routine LGE imaging included a breath-hold segmented inversion recovery sequence covering the entire myocardium obtained 10 min after administration of a commercially available gadolinium-based contrast agent at a standard dosage (0.1 mmol/kg), with the inversion time adjusted to null the normal myocardium.syngo.via MR Cardiac Analysis . The left ventricular semi-automated segmentation algorithm included the papillary muscles and trabeculae in the blood pool, and excluded them from the left ventricular mass. The LV contours were corrected by the investigator (M.S.) when appropriate. Apart from routine LV functional parameters and mean segmental thickness, volume–time curves were derived automatically by the software for the estimation of the following: PER (peak ejection rate), PET (peak ejection time), PFR (peak filling rate) and PFT (peak filling time). The maximal wall thickness of the left and right ventricles (LVMT and RVMT) were determined in each patient in short-axis slices manually.All the CMR studies were postprocessed according to the study protocol with a dedicated software, i.e., Myocardial contraction fraction (MCF) and left ventricular global function index (LVGFI) were calculated manually according to the formulas given in , with paLGE areas were quantitated in all of our patients as LGE volume and as a percentage of the total LV mass with the manual visual method included in the analysis package. Segmental distribution of LGE was also noted.Left atrium (LA) endocardium was traced manually and LA long axis was measured in standard 4-chamber and 2-chamber cine long-axis acquisitions, excluding the left atrial appendage and pulmonary veins. Parameters were taken at the end of ventricular systole  and when the size of the chamber was minimal by visual assessment. Additionally, LA volumes were calculated manually by the biplane area method as in ,16. LA pLeft ventricle outflow tract (LVOT), aortic valve diameter (Ao), anterior mitral leaflet (AML), posterior mitral leaflet (PML), and LA 3-chamber (LA 3Ch) dimensions were measured manually from routine cine three-chamber images, as in ,18,19. Lp value < 0.05 was considered as statistically significant. Statistical analysis was performed using Statsoft Statistica 13 software  and R statistical software .Quantitative variables are expressed as median (interquartile range) and the differences between the groups were tested by the Mann–Whitney U tests. For correlation calculations, Spearman’s rank correlation coefficient was used. Chi-square Pearson tests (with Yates correction where appropriate) were used for categorical variables. The The study group consisted of 88 patients , and 61% of them were men. A total of 62 (70%) of the patients had EF > 65% and were classified as CP, while NCP presented in 26 of patients with EF ≤ 65% . The resThere were two patients with ventricular aneurysms and midventricular hypertrophy in the NCP group and only one patient with a notably small aneurysm in CP . No apicSignificant differences were noted regarding the following CMR parameters.Compared to CP, the NCP patients had significantly more LGE% , and the2 (IQR 101–150) compared to 93 g/m2 (IQR 80–113) in the CP group, p < 0.0001. The LV segmental thickness was greater in segments 1, 7–11, and 15 (mostly midsegments)—see The median left ventricular mass index (LVMI) in the NCP group was 111 g/mp < 0.0001.The NCP patients had significantly lower values of MCF . Both grThe differences in LAVmax, LAVI, and LAA between the NCP and CP patients were not statistically significant. In contrast, the LAEF difference was strikingly significant . The minp = 0.0012, probably due to impaired systole in nonclassic phenotypes. The peak ejection rate (PER), peak filling rate (PFR), and peak filling time (PFT) differences did not reach statistical significance  was observed: median 128 ms (IQR 114–149) versus 110 ms (IQR 91–125) in CP, ificance . On the ificance .p = 0.0013—probably due to more advanced disease.The right ventricular maximal thickness (RVMT) appeared greater in NCP—median value of 4.5 mm (IQR 3–6) versus 3 mm (IQR 2–4), No LVOTO was observed in our NCP group, as a result of progressive LV remodeling. Consequently, LVOT, Ao, and LVOT/Ao were significantly higher, and AML/LVOT was lower in NCP . Good coAccording to the available data, this was the first report comparing advanced CMR parameters, not routinely used, in nonclassic phenotype (NCP) and classic phenotype (CP) groups of HCM patients. A comprehensive profile of the disease stages may facilitate optimal management and better prognostication ,6,22. OnOur results indicated the significant differences in quantitative LGE, LVMI, and LA parameters, MCF and LVGFI, between the nonclassic and classic HCM phenotypes. We believe this may be useful in clinical practice. We assumed that if numerous parameters are more frequent in advanced stages of the disease, it is likely that they reflect progression of heart dysfunction and may help in clinically relevant staging of the disease. Due to the complex pathological mechanisms involved, new prognostic parameters, beyond EF, seem to be promising in risk stratification and deserve further prospective evaluation. Of note is that a significant proportion of research on HCM risk stratification concentrates on CP patients only.HCM risk score was retrospectively developed and first published in 2014 ; it is iLVMT is an important classic prognostic parameter analyzed in  and incoThere was only one notably small aneurysm in our CP group. However, two aneurysms were detected in stage III—adverse remodeling, and as usual, they were a consequence of LV adaptation to progressive midventricular obstruction. It was shown retrospectively that the HCM patients with LV apical aneurysms, developed in the evolution of midventricular obstruction phenotype, are at high risk for arrhythmic sudden death and thromboembolic events ,10,32. FLGE reflects the focal distribution of fibrosis in HCM . There iUnfortunately, a number of practical challenges prevent the routine use of LGE quantification in everyday clinical practice. The differences in CMR scanners, LGE sequences, contrast doses and types, inversion times, and software preclude universal agreement ,35. ChanOur study showed that 68% of our patients belonged to the lowest range 0–5%LGE cf.  and only2 for men and 69 g/m2 for women were suggested. In a recent retrospective study from Hungary, LVMI was confirmed as an independent predictor of major events with slightly different cutoffs (108 g/m2 for men and 86 g/m2 for women) [p < 0.001) and more myocardial segments were hypertrophied, mostly midsegments. In our opinion, it reflected the pattern of disease progression.Left ventricular mass index is a simple, routine, and well-known CMR parameter. Correlation with HCM-related mortality was demonstrated in the 2008 retrospective study by Olivotto et al. , and ther women) . In our A promising novel prognostic CMR parameter is myocardial contraction fraction (MCF). MCF was first described by King et al.  as the vThe values of MCF for healthy people are given in many population-based and clinical studies ,38,43,44Lower MCF can indicate worsening of LV function with preserved ejection fraction because of a reduction in ventricular capacitance, especially in hypertrophied ventricles .The researchers from Switzerland  suggesteIn echocardiography-based single-center studies of MCF in HCM patients published in 2019 and 2020 ,46, MCF The median MCP in our study was significantly below normal CMR values in both CP and NCP groups and it seemed to be a sensitive marker of pathological hypertrophy. The difference between CP and more advanced stages was also distinct; therefore, we believe that the MCP may prove to be particularly useful for HCM progression monitoring, reflecting the dysfunction in NCP patients, since it is considered to be a measure of myocardial shortening .Left ventricular global function index (LVGFI) is another novel prognostic parameter introduced in , derivedIn our study, there was a clear and significant difference between the groups, and we believe LVGFI might be well-suited to reflect the specific nature of LV remodeling in HCM. It would be interesting to evaluate LGFI in a properly designed and powered prognostic study as well as apply it retrospectively to patients from important registries, e.g., the Sarcomeric Human Cardiomyopathy Registry (SHaRe) or an ongoing HCM registry.In a recent paper by Huang S et al. , LVGFI wCMR-derived MCF and LGFI are promising parameters; however, further studies are needed to verify the clinical utility in HCM, with emphasis on including the NCP HCM population.Left atrial CMR parameters in the context of HCM have been frequently studied in recent years ,16,47,48The CMR measures of LA remodeling and dysfunction reliably identified the patients with HCM at risk for future development of AF; in , multivaIt would be interesting to analyze the prognostic potential of LAEF and LA not only in relation to AF but also to CHF progression, stroke, and combined cardiovascular endpoints.The practical application of these parameters is difficult ,54, partIn our study, a longer peak ejection time (PET) was observed in the NCP patients, probably due to impaired systole in nonclassic phenotypes. The normalized peak filling rate in NCP differed significantly, most likely reflecting diastolic dysfunction.p = 0.01) was observed in [Right ventricular involvement in our NCP patients was greater than in CP, probably because of more advanced disease. A weak positive association between RV hypertrophy and the estimated probability of SCD at 5 years  is appreciated ,18,56. TOur study showed that simple CMR parameters derived from routine three-chamber cine images (LVOT/Ao and AML/LVOT) are valuable for resting LVOTO assessment, even without dedicated flow sequences that prolong imaging duration.LVOTO disappearance is an important part of the disease progression in HCM; as LV remodeling develops, LVOT increases. In our NCP patients, no LVOTO was detectable.Recently in , it was To conclude, we believe that the various parameters investigated in our study may contribute to redefining the classification of HCM stages so that it is better suited for clinical practice and risk stratification purposes. If numerous parameters are more frequent in advanced stages of the disease, it is likely that they reflect pathophysiology of heart chamber remodeling in HCM leading to increasing dysfunction, and may serve as an adjunct to clinical staging and decision making.Our study also illustrated the notion that the frequent exclusions of the NCP patients from the HCM population in numerous research studies may lead to incorrect conclusions. We believe this population is a challenge in clinical practice.This study was a single-center observation study dealing with a relatively small number of patients. The small numbers of deaths and clinical adverse events (mentioned in our review paper ) precludOur results showed significant differences in validated and novel prognostically important CMR parameters between the nonclassic and classic HCM phenotypes that may contribute to future studies on risk stratification in HCM. CMR-derived MCF and LGFI were promising parameters; however, further studies are still needed to verify their clinical utility in HCM, with the emphasis on including the NCP HCM population.


Poor responders to chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) can still have a good prognosis if the treatment strategy is changed in time. However, no reliable predictor of early-treatment response has been identified. The purpose of this study was to investigate the role of T2 relaxation time in magnetic resonance imaging (MRI) for the early prediction of a pathological response to CRT in LARC.U test was used to compare the T2 relaxation time between pathological good responders (GR) and non-good responders (non-GR). The area under the curve (AUC) value was used to quantify the diagnostic ability of each parameter in predicting tumor response to CRT.A total of 123 MRIs were performed on 41 LARC patients immediately before, during, and after CRT. The corresponding tumor volume, T2 relaxation time, and apparent diffusion coefficient (ADC) values at different scan time points were obtained. The Mann–Whitney Twenty-one (51%) and 20 (49%) were GRs and non-GRs, respectively. T2 relaxation time showed an excellent intraclass correlation coefficient (ICC) of > 0.85 at three-time points. It was significantly lower in the GR group than in the non-GR group during and after CRT. The early T2 decrease had a high AUC of 0.91 in differentiating non-GRs and GRs, similar to 0.90 of the T2 value after CRT.T2 relaxation time may help predict treatment response to CRT for LARC earlier, rather than having to wait until the end of CRT, thereby alleviating the physical burden for patients with no good response.The online version contains supplementary material available at 10.1186/s13244-022-01254-z. T2 relaxation time in rectal cancer has high inter-observer agreement.The early T2 decrease is higher in good responders than non-good responders.The early T2 decrease enables excellent diagnostic accuracy in predicting CRT response.Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment modality for locally advanced rectal cancer (LARC) . The outSeveral studies have attempted to use magnetic resonance imaging (MRI) to predict early CRT response in LARC. Tumor size reduction on early MRI during CRT for LARCs can distinguish complete response (CR), partial response (PR), and non-response (NR) with high accuracy . A cliniT2-weighted images demonstrate the tissue's relative, not absolute, T2 signal intensity. T2 mapping calculates each tissue's intrinsic T2 relaxation time by fitting an exponential function to the signal intensity at different echo times. T2 relaxation time is an absolute quantitative value with high reproducibility  that mayThis prospective study was approved by the Medical Ethics Committee of our institution and conformed to the tenets of the Declaration of Helsinki. Written informed consent was obtained from all patients.n = 19); (b) refused preoperative chemoradiation or had received chemoradiation, but withdrew from treatment (n = 23); (c) did not undergo TME after CRT (n = 13); and (d) had poor quality of T2 mapping images, diffusion-weighted images, or both (n = 7), were excluded. Finally, 41 adult patients with pathologically proven rectal adenocarcinomas who underwent preoperative CRT and surgical resection were evaluated  did not satisfy the LARC diagnostic criteria on primary staging MRI scan  plus capecitabine , also known as CapeOx, once every 3 weeks before radiotherapy.Preoperative CRT included initial induction chemotherapy, subsequent CRT, and consolidation chemotherapy according to the National Comprehensive Cancer Network (NCCN) guidelines. Compared with short-course radiotherapy, a long-course radiotherapy was administered in our institution because it is a more frequently chosen neoadjuvant CRT plan in China with fewer adverse events. The patients received a dose cycle of oxaliplatin  was administered during the radiotherapy sessions.The subsequent radiotherapy was administered once a day at 1.8–2.0 Gy/fraction per day, 5 days per week, for a total dose of 50–50.4 Gy in 25–28 fractions. A CT scan was acquired at 3 mm slice thickness for planning purpose. Most patients were immobilized in the prone position with an ankle-holder. The radiation clinical target volume (CTV) included the primary rectal cancer, perirectal and internal iliac nodes, mesorectum, pelvic sidewalls, and presacral space with the upper border at the sacral promontory. Intensity-modulated radiotherapy (IMRT) treatment with 6–10-MV X-rays delivered using a Varian linear accelerator was administered with daily image guidance. Oral capecitabine , in addition to the standard-of-care MRI scans, pre-CRT (at the beginning of treatment), and post-CRT (8 weeks after the end of radiation therapy). A 3.0 Tesla magnetic resonance (MR) system  with a 16-channel phased-array body coil was used for image acquisition. All the patients were scanned in the supine position with a feet-first orientation. Rectal preparation involved fasting and taking oral polyethylene glycol electrolyte solution to empty the intestinal contents 6–8 h before the examination. Polyethylene glycol electrolyte was used because, as we observed in the preliminary experiments, it can discharge not only waste but also the air in the rectum, thus producing better T2WI tissue contrast and reducing distortions in DWI  were obtained. The oblique axial planes were orthogonal to the tumor, based on the high-resolution T2W images. Coronal T2 mapping  was performed to cover all tumor layers in the shortest possible time with a location line parallel to the long axis of the tumor.Axial, sagittal, and coronal high-resolution T2-weighted  and axial echo-planar diffusion-weighted images  along the tumor border on each tumor slice about the corresponding T2W image. For the T2 relaxation time, the ROI was drawn freehand on the original T2 mapping image of 65 ms echo time, along the border of the tumor, on each slice.DWI and T2 maps were transferred to a workstation . A senior radiologist and a junior radiologist  who were blinded to the study design and diagnoses performed the measurements. The junior radiologist repeated the measurements 2 weeks later. To determine the ADC, the tumor's region of interest (ROI) was drawn freehand on high Vduring) was calculated using the Vpre and Vduring (Vduring − Vpre) × 100%/Vpre. The relative early ADCincrease (ΔADCduring) was calculated using the ADCpre and ADCduring (ADCduring − ADCpre) × 100%/ADCpre. The relative early T2 decrease (ΔT2during) was calculated using the following equation: ΔT2during = (T2pre − T2during) × 100%/T2pre.The relative early tumor volume decrease  TNM Classification of Malignant Tumors 8th edition. All the examinations were performed using resection specimens obtained by different experienced pathologists and reviewed by a single dedicated gastrointestinal pathologist who was blinded to the MRI data. The pathological tumor regression grade (TRG) was classified as follows, according to Mandard et al. : TRG 1, U test was used for ADC values, T2 relaxation time, tumor volume, and the corresponding ratios. The area under the receiving operating characteristic curves (AUC) was used to compare the diagnostic power of these test indicators. The cutoff values were determined, and their sensitivity and specificity were calculated. De Long's test was used to compare the difference between AUCs. The differences were considered statistically significant if the p-value was less than 0.05. The statistical analyses were performed using the Statistical Package for the Social Sciences  and MedCalc Statistical Software .Intra- and inter-observer correlations for the T2 and ADC values were analyzed by estimating the ICCs. The values obtained by the radiologists were used for further statistical testing only when the intra- and inter-observer ICC values were greater than 0.75, which indicated excellent consistency. The histopathological correlations were analyzed using Spearman's correlation test. The Mann–Whitney In total, 41 patients  with a mean age of 64 y (31–81 y) were included in the study. All the patients completed the long-course CRT and TME. After the histopathological examination, 21 patients (51%) were classified into the GR group; among them, six achieved pCR. Meanwhile, the remaining 19 patients (46%) were classified into the non-GR group. The patient characteristics are summarized in Table The T2 relaxation time displayed excellent intra- and inter-observer agreement before, during, and after CRT, with ICCs of 0.95, 0.92; 0.95, 0.95; and 0.94, 0.82, respectively. Comparable results were also found for the tumor volumes and ADC values. However, the ADC values after CRT showed the lowest ICCs, 0.82 and 0.64 for intra- and inter-observer agreements, respectively. Therefore, the ADC values after CRT were not used for further analyses. The details of ICCs are shown in Table during, T2post, and ΔT2during showed significant correlation with the pathologic TRG, with high correlation coefficients . The Vpost, ΔVduring, and ΔADCduring also demonstrated a moderate correlation coefficient . However, neither the tumor volume nor ADC values pre and during CRT correlated with pathology. The correlation coefficients are listed in Table T2p = 0.003) and post  CRT than the non-GR group , ΔADCduring , and ΔVduring . Meanwhile, there were no significant between-group differences in the ADC values and tumor volumes before and during CRT  and higher specificity (100%) compared to ΔT2during the procedure. Although ΔT2during achieved a higher AUC of 0.91, Delong's test showed no statistical difference between ΔT2during and ΔVduring, ΔADCduring, and post-T2 values   Table .Table 4CReliable and quantitative MRI values for the early monitoring of treatment responses are critical for individualized treatment decisions; however, no imaging markers have been established to distinguish the responders from non-responders in the early stages of CRT. This study found that T2 relaxation time is a potentially valuable indicator of treatment response to CRT for LARC, as shown by their excellent ICC values and high correlation coefficients with the pathologic TRG. The relative early T2 decrease during CRT was significantly higher in the GR group than in the non-GR group. It showed a diagnostic efficacy similar to the T2 relaxation time at the end of CRT. To the best of our knowledge, this study was the first to investigate the feasibility and reproducibility of T2 relaxation time for predicting a pathological response during CRT in patients with LARC.T2 mapping is considered a robust technology for myocardial , 17 and Several approaches have been attempted for the early evaluation of tumor response using quantitative MRI parameters, including tumor shrinkage-based T2WI , 23, radDifferent collagen fibers may appear during CRT in the tumor, especially in GRs . This deT2WI) showed an AUC of 0.899 for predicting CR after CRT [Some prospective exploratory studies reported that MRI during neoadjuvant RCT may predict early pCR in rectal cancer patients . A radiofter CRT . Our stuOur study had some limitations. First, the number of patients included in the present study was limited. More prospective studies with larger numbers of patients are needed to validate our results. Therefore, the proposed T2 cutoff values should be considered cautiously and need to be verified in larger, multicenter studies and other MRI scans. Second, using basic T2 mapping to evaluate the entire tumor area was time-consuming. However, accelerated T2 mapping may be more time-efficient than conventional T2 mapping in the prostate . Third, during was significantly higher in the GR group than in the non-GR group and provided a robust diagnostic efficacy in distinguishing non-GRs from GRs. This finding indicates that ΔT2during, calculated using T2 before and during CRT, can evaluate the CRT response early, rather than waiting until the end of CRT, alleviating the physical burden for patients with no good response.For the first time, this study investigated the clinical value of T2 mapping in predicting treatment response to CRT for LARC patients. Significantly different T2 values were found between GR and non-GR groups, and a high correlation relationship was revealed between T2 and pathologic TRG. Additionally, ΔT2Additional file 1: Fig. S1. Figures a, b, c were MR images of a patient with oral polyethylene glycol electrolyte solution. On sagittal T2 weighted images (a), the tumor contour was clearly shown against the water in the intestinal lumen. A region of interest (ROI) was outlined along the contour of the intestinal lumen at axial T2WI . Then, this ROI was copied onto the DWI (shown as the red dashed line). Subsequently, another ROI was outlined on DWI using the same method (shown as the green dashed line). The two ROIs were well matched (c). Figures d, e, f were MR images of a patient without any bowel preparation. The tumor contour was difficult to be distinguished from the surrounding tissues due to the influence of faeces and air in the intestinal lumen on sagittal T2WI (d). A ROI was outlined along the contour of the intestinal lumen at axial T2WI . Then, this ROI was copied onto the DWI (shown as the red dashed line). Subsequently, another ROI was outlined on DWI along the contour of the intestinal lumen (shown as the green dashed line). The two ROIs cannot be well matched with large morphological variation, suggesting significant DWI distortion. t: tumor; w: water; f: faeces.


Congenital diaphragmatic hernia (CDH) is a rare congenital anomaly, whose presentation is complicated by pulmonary hypertension (PH), pulmonary hypoplasia, and myocardial dysfunction, each of which have significant impact on short-term clinical management and long-term outcomes. Despite many advances in therapy and surgical technique, optimal CDH management remains a topic of debate, due to the variable presentation, complex pathophysiology, and continued impact on morbidity and mortality. One of the more recent management strategies is the use of prostaglandin E1 (PGE1) infusion in the management of PH associated with CDH. PGE1 is widely used in the NICU in critical congenital cardiac disease to maintain ductal patency and facilitate pulmonary and systemic blood flow. In a related paradigm, PGE1 infusion has been used in situations of supra-systemic right ventricular pressures, including CDH, with the therapeutic intent to maintain ductal patency as a “pressure relief valve” to reduce the effective afterload on the right ventricle (RV), optimize cardiac function and support pulmonary and systemic blood flow. This paper reviews the current evidence for use of PGE1 in the CDH population and the opportunities for future investigations. Congenital diaphragmatic hernia (CDH) is a rare anomaly, characterized by a defect in the diaphragm causing abdominal contents to protrude into the thoracic cavity. The incidence of CDH is 1 in 2,500 to 1 in 3,500 live births . DespiteProstaglandin E1 (PGE1), a prostaglandin analog administered by intravenous infusion, is typically used to maintain ductal patency in newborn infants in the setting of suspected duct-dependent congenital heart disease. In this setting, PGE1 infusion is used to ensure adequate systemic or pulmonary blood flow or mixing until definitive surgical repair is accomplished. In the setting of pulmonary hypertensive disease, including CDH, PGE1 may have other benefits, the most important being reduction of afterload of a failing right ventricle (RV).In this review, we will discuss the pathophysiology of CDH, the theoretical benefits of PGE1 therapy in the management of CDH, critically review existing evidence of its use, and identify key questions for future areas of research.Congenital diaphragmatic hernia is associated with pulmonary hypoplasia of varying extent typically affecting both the ipsilateral and contralateral lungs. This abnormal pathophysiology has been hypothesized to begin at ~8th to 10th-week of gestation, after failure of the normal physiological closure of the diaphragm and the establishment of the separation between abdominal and thoracic organs . AccompaThe pulmonary alveolar and vascular maldevelopment results in increased pulmonary vascular resistance and associated PH. Studies have shown that over 70% of CDH infants exhibit CDH-PH , which iIn addition, CDH has been described to be associated with both structural and functional left ventricular abnormalities , 21, 22.The combination and spectrum of pulmonary hypoplasia, pulmonary hypertension, and ventricular dysfunction makes CDH a unique clinical management challenge. Historically, PH therapeutic strategies in CDH have focused mainly on pulmonary vasodilation. The main therapeutic targets are cytokine pathways regulating pulmonary artery smooth muscle tone, specifically such the nitric oxide (NO) pathway, prostacyclin pathway and endothelin pathways .via the NO pathway, has been widely used in the management of CDH-PH , a potent pulmonary vasodilator, acts by stimulating guanylyl cyclase in the vascular smooth muscle cells to produce cyclic guanosine monophosphate (cGMP). Elevated intracellular concentrations of cGMP activate cGMP-dependent protein kinases and lower cytosolic calcium concentrations, which in turn promote vascular smooth muscle cell relaxation . Phosphof CDH-PH . Milrinof CDH-PH , 31. Anof CDH-PH , 32, 33. pathway . Endothe pathway .Among studies in adults with PH, the major cause of mortality of patients with PH was RV failure . ExperimSeveral important concepts regarding ventricular response to elevated pulmonary pressures investigated in animal models can be translated to clinical medicine. Firstly, as demonstrated by Urashima et al. , the RV Existing studies of RV function in CDH, though limited, indicate similar morphological and functional changes. Echocardiographic studies of early RV function have demonstrated RV systolic and diastolic dysfunction, and evidence of interdependent impairment of LV function , 48. FurAn important conclusion that can be drawn from these animal model studies and clinical studies in CDH is the importance of unloading the RV in the setting of elevated pulmonary pressures, and tailoring PH therapy to target both biomechanical and hemodynamic function with the aim of optimizing RV function and improving outcomes.Prostaglandin E1 is a potent dilator of the ductus arteriosus in human neonates . The firThe therapeutic benefits that PGE 1 offers in the setting of elevated pulmonary vascular resistance in CDH are theoretically three-fold. This has been summarized in By acting as pressure “blow-off” valve, reducing the effective afterload on the pressure loaded RV, alleviating RV dilatation and myocardial dysfunction. LV function in turn may also improve by mechanisms of ventricular interdependence. A similar strategy of having a “pop off” conduit in supra-systemic pulmonary pressures has been demonstrated by the use of the Pott's shunt (anastomosis between left pulmonary artery to descending aorta) in pediatric hypertension and in patients with Eisenmenger syndrome (1) syndrome . Evidencsyndrome .By augmenting systemic blood flow in the setting of LV failure, by facilitating right-to-left shunting via the ductus arteriosus. The evidence of the benefits of using PGE1 to augment systemic blood flow is best noted in single ventricle pathologies such as hypoplastic left heart syndrome, where there exists an uncertain balance among systemic, pulmonary and coronary blood flows, with the systemic and pulmonary circulations in parallel rather than in series. The use of PGE1 in this situation ensures systemic blood flow to the vital organs, and also balances the systemic and pulmonary cardiac output (2) c output .By its direct pulmonary vasodilating action in pulmonary artery smooth muscle. PGE1 increases intracellular cyclic AMP leading to decreased pulmonary vascular resistance (3) sistance , reducinsistance . The pulsistance  and in nsistance , 63.Animal studies support these potential benefits. Sakuma et al. , demonstThough the potential benefits of PGE1 use in the cardiopulmonary physiology of CDH appear compelling, there are potential adverse effects. In the short-term, PGE1 may induce apnea, peripheral vasodilation, fever and hypotension . With lowww.clinicaltrials.gov. Additionally, we also used PubMed's related citations feature to identify relevant studies. We included chart reviews, case control studies, case series and case reports. Once a list of studies was obtained, we analyzed the studies for methodology and outcomes measures as described below.To date, the investigation of PGE1 use in CDH has been limited to case reports and retrospective chart reviews. We performed a review of literature using the electronic bibliographic databases PubMed and Embase, and of ongoing trials in A summary of these studies is provided in via the DA was longer than that of left-to-right shunting, whereas Shiyanagi et al. , left ventricular end-diastolic diameter and LV-Tei index  , 69. One2 requirements , and improved circulatory function, thus preventing cardiorespiratory failure in this population. Echocardiographic markers for PH used in this study include ductal flow velocities and flow patterns and mean pulmonary arterial pressures in relation to systemic blood pressures and classified as suprasystemic when mean PAP > systemic blood pressure +10 mm Hg  Advocating for a more pronounced pathophysiology-based approach using serial echocardiograms.2) Promoting further research on the use of PGE1 in this patient population to address these clinical concerns.To our knowledge, there have not been any prospective studies investigating the effect of PGE1 on cardiorespiratory outcomes in CDH. Studies on significant and/or long-term outcomes, such as need for ECMO, duration of ventilation, length of stay, need for oxygen at discharge, need for additional PH medications and neurodevelopmental outcomes, are lacking. Use of PGE1 infusion either alone or in combination with other PH management strategies is a potential area for future research, which may further open the doors to other aspects of research such as the long-term effects of the presence of a ductus in patients with congenital diaphragmatic hernia.Ongoing areas of uncertainty about the use of PGE1 in CDH which require further investigation include:1) Appropriate timing of the PGE1 infusion in CDH .2) Dosing regimens of PGE1 for PH . The studies described above have used variable dosing patterns for PGE1 use in CDH. Although this area may need to be further investigated, higher doses of PGE1 may have utility in situations of acute severe PH with RV failure with duct closure, analogous to those used in resuscitation of infants presenting with duct closure in critical congenital heart disease.3) Potential side effects of its use in this population (both short- and long-term).4) Duration of therapy .5) Use of PGE1 in relation to ECLS.6) Impact of concomitant use of other pulmonary vasodilators, such as iNO, Sildenafil and/or Bosentan.7) Impact on LV/RV performance.8) The specific subset of CDH that might best benefit from it use, which may require a pathophysiology-based, targeted approach to PH management in CDH.In terms of “long-term” effects, areas of uncertainty ripe for further investigation include:1) Impact on short- and long-term outcomes, including survival, need for ECLS, duration of ventilation, duration of hospital stay, need for oxygen at discharge, and neurodevelopmental outcome.2) Timing and need for additional PH medications, such as Sildenafil and/or Bosentan at discharge.3) Impact on intervention for ductal management due to the potential effect from L–R shunting.With the evidence from a recent study that the severity of early postnatal PH has a significant impact on long-term outcome, an important question to be answered is the timing of the first echocardiogram in this population . This stTheoretically a well-designed clinical trial of PGE1 in CDH may help to address the current evidence gap. Ideally this would be a randomized double-blinded placebo trial of PGE1 in a priori risk-stratified subgroups of CDH patients with echocardiographic and clinical evidence of elevated PAP, biventricular dysfunction and a restrictive ductus and with outcome measures that include cardiopulmonary outcomes such as RV and LV performance, need for ECLS, effect of ventilatory needs, vasopressor needs, survival at discharge and mortality, managed using standardized management guidelines. Risk stratification should include prenatal imaging markers of severity, such as percent liver herniation (%LH), observed to expected Total Fetal Lung Volume (O/E TFLV), observed to expected Lung-Head Ratio (O/E LHR) , locatioPrevious milestone trials in CDH include Ventilation in Infants with Congenital diaphragmatic hernia (VICI), the TOTAL trial of fetal tracheal occlusion, and the Neonatal Inhaled Nitric Oxide Study (NINOS) –82. OtheIn conclusion, with continuing research to improve cardio-pulmonary and long-term outcomes in CDH, new management strategies are being proposed and studied. Supra-systemic RV pressures are associated with poor clinical outcomes in this population. There is a pathophysiological rationale for the use of PGE1 in CDH to maintain ductal patency and promote right-to-left shunting, thereby reducing effective RV afterload and supporting systemic blood flow. In addition, PGE1 may have direct pulmonary vasodilating actions. Although existing, single-center retrospective studies and case reports suggest benefit from the use of PGE1 in terms of reducing severity of PH and improving short-term cardiopulmonary stability, uncertainties remain around its optimal pragmatic clinical use in CDH, and current evidence from these studies may not strongly support clinical recommendations. Conducting pharmacological trials in neonates can be challenging due to physiological changes, variable pharmacokinetics in the early newborn period and the ethical considerations involved. However, a well-designed a-priori prospective study as outlined above should be considered to definitively understand the implications of the use of PGE1 in CDH and its impact on meaningful outcomes.SH: conceptualization, design, methodology, and drafting and revising. NP: design, methodology, and reviewing and revising. CF: conceptualization, design, reviewing and revising, and supervision. All authors contributed to manuscript revision, read, approved the submitted version and agreed to be accountable for all aspects of the work.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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.