While patients with cardiac transthyretin amyloidosis are easily diagnosed with bone scintigraphy, the detection of cardiac light chain (AL) amyloidosis is challenging. Cardiac magnetic resonance (CMR) analyses play an essential role in the differential diagnosis of cardiomyopathies; however, limited data are available from cardiac AL-Amyloidosis. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac AL-amyloidosis.We included 35 patients with proved cardiac AL-amyloidosis and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination. The phenotype and degree of left ventricular (LV) hypertrophy and the amount and pattern of late gadolinium enhancement (LGE) were evaluated. In addition, global and regional LV strain parameters were also analyzed using feature-tracking techniques. Sensitivity and specificity of several CMR parameters were analyzed in diagnosing cardiac AL-amyloidosis.The sensitivity and specificity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% and 100%, respectively. Likewise, the sensitivity and specificity of septal myocardial nulling prior to blood pool was 71% and 100%, respectively. In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT . On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing  had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%).The findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. Hence, further larger studies are warranted to validate the findings from this study. Cardiac involvement of light chain (AL) amyloidosis is characterized by impaired cardiac function, left ventricular (LV) hypertrophy and tissue specific changes of the myocardium. In a background of increased LV wall thickness or LV hypertrophy, several primary and secondary causes can be detected besides cardiac AL-amyloidosis, such as hypertrophic cardiomyopathy (HCM), endomyocardial fibrosis, cardiac involvement of Fabry disease, and pressure overload of the LV , 2. SincStrain analysis is a useful and reliable method for assessing global and regional myocardial function. Myocardial strain abnormalities assessed by echocardiography have been described and widely accepted to occur in myocardial diseases with LV hypertrophy –8. HowevDespite the advantages of CMR imaging in the diagnosis of cardiac AL-amyloidosis, there is a lack of comprehensive studies with large study populations that have investigated the role of CMR-based strain analysis in this patient population. Therefore, we conducted a study with the aim of investigating the importance of CMR parameters including feature-tracking strain analysis in differentiating cardiac AL-amyloidosis from HCM and cardiac AL-amyloidosis from myocardial consequences of arterial hypertension.We retrospectively identified all patients with myocardial disease causing LV hypertrophy or increased LV wall thickness who were referred to The Heart and Vascular Center of Semmelweis University between 2009 and 2019 for CMR examination. Patients with significant aortic stenosis, or athletes with left ventricular hypertrophy due to physiological sport adaptation were not involved in the study. The indications for CMR imaging were the assessment of LV hypertrophy identified with other imaging modalities, the detection of cardiac involvement from a known systemic amyloidosis, or the presence of electrocardiographic abnormalities. Patients with HCM or cardiac AL-amyloidosis were involved in the study. Patients with serum amyloid A (n = 1) and transthyretin amyloidosis (n = 3), or if the exact type of amyloidosis was unknown (n = 7) were excluded from the study. Additionally, patients with Fabry disease (n = 12), endomyocardial fibrosis (n = 16), previous kidney transplantation (n = 2), unsuitable strain analysis (n = 9) or an uncertain CMR-based diagnosis (n = 15) were excluded from the study .As a control group, we selected from our database 70 patients with (treated or untreated) arterial hypertension (HT) without history of cardiomyopathy and with similar LV ejection fraction than the group with cardiac AL-amyloidosis.Informed consent was obtained from each patient. Ethical approval was obtained from the Hungarian National Institute of Pharmacy and Nutrition (OGYEI/29174-4/2019), and this study was performed in accordance with the ethical standards in the 1964 Declaration of Helsinki and its later amendments.CMR examinations were conducted with a 1.5 T MR scanner  using a 5-channel cardiac coil. Retrospectively gated balanced steady-state free precession (bSSFP) cine images were acquired in 2-chamber, 4-chamber and LV outflow tract views. Additionally, short-axis (SA) images with full coverage of the LV were obtained. If no contraindications for contrast agent administration were present, a bolus of gadobutrol (0.15 mmol/kg) was injected at a rate of 2–3 ml/s through an antecubital intravenous line. LGE images were acquired using a segmented inversion recovery sequence with additional phase-sensitive reconstructions in the same views used for the cine images 10–20 minutes after contrast administration.CMR data were analyzed using Medis Suite 3.1 software . The left ventricular ejection fraction (LVEF), volumes , and mass (LVM) were quantified. The LV volumes and LVM were standardized to the body surface area (BSA), yielding LVEDVi, LVESVi, LVSVi, and LVMi. End-diastolic wall thickness (EDWT) measurements were taken in an SA slice perpendicular to the myocardial centerline, excluding trabeculation. The amount of LGE was quantified at a grayscale threshold of 5 standard deviations (SDs) above the mean signal intensity for normal myocardium. LV strain analysis was performed with the feature-tracking application of the MedisSuite: QStrain module. Endocardial contour detection was manually performed on the three long-axis (LA) and SA cine images on basal, midventricular and apical slices during the end-systolic and end-diastolic phases. Global longitudinal (GLS), circumferential (GCS) and radial (GRS) LV strain parameters were measured. Strain values for the six basal, six midventricular, and five apical segments were averaged to obtain regional longitudinal and circumferential strain values  . The apeThe CMR diagnosis was made based on the extracted morphologic features and LGE pattern  and was Continuous data are expressed as the mean ± SD. The normality of the distribution of the data was investigated with the Shapiro-Wilk test. Group characteristics were compared with an independent t-test or Mann-Whitney test, as appropriate; and with a Chi-squared test for nominal values. Receiver operating characteristic (ROC) curve analysis was performed to analyze the diagnostic accuracy of a parameter and to identify optimal cut-off values. Differences were considered statistically significant when p<0.05. All analyses were performed by using MedCalc software (version 17.9.5).Over a 10-year period, 330 patients were diagnosed with HCM, and 46 patients were diagnosed with cardiac AL-amyloidosis. The most common form of HCM was asymmetric hypertrophy with a septal or an anterior distribution, which was found in 257 patients (77.9%). There were 47 (14.2%) patients with apical HCM, 21 (6.4%) patients with concentric HCM and five (1.5%) patients with midventricular HCM. Among cardiac AL-amyloidosis patients, concentric hypertrophy was found in 16 cases (35%), and hypertrophy showed septal dominance in 30 patients (65%). CMR imaging provided a different diagnosis from the referral diagnosis for 8% of HCM and 26% of cardiac AL-amyloidosis patients.A control group of 70 patients with HT (treated or untreated) were selected who had similar age, sex rate and LVEF than the cardiac AL-amyloidosis patient group.The demographic and CMR data of the patient groups are summarized in When comparing cardiac AL-amyloidosis and control group with HT, we found more pronounced LV hypertrophy and higher amount of LGE in patients with cardiac AL-amyloidosis. Cardiac AL-amyloidosis patients had impaired global and regional LS values, while CS parameters were in absolute value higher in this patient group than in controls with HT. The apex-to-base CS and LS values were higher in cardiac AL-amyloidosis patients.In the differentiation of cardiac AL-amyloidosis and HCM, the pattern and amount of LGE, the abnormal contrast kinetics had the highest diagnostic accuracies, followed by basal CS, basal LS, and GRS. The sensitivity and specificity of CMR parameters to differentiate cardiac AL-amyloidosis from HCM are shown in 2 , basal LS cut-off of -21% , apex-to-base LS cut-off of 1.17 .In the differentiation of cardiac AL-amyloidosis and controls with HT, the degree of hypertrophy, the pattern and amount of LGE, the abnormal contrast kinetics, basal LS and the apex-to-base LS ratio had the highest diagnostic accuracies . The speAnalyzing a cohort of 35 patients with proved cardiac AL-amyloidosis and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination, the findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. In this respect, the sensitivity and specificity of diffuse septal subendocardial LGE and of septal myocardial nulling prior to blood pool in diagnosing cardiac AL-amyloidosis was excellent. In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT. On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%).The diagnosis of cardiac AL-amyloidosis with CMR examination is traditionally based on the LV hypertrophy phenotype and the pattern of LGE , 18. In However, in case of a contraindication for contrast agent administration, further diagnostic methods are needed. In recent years, novel CMR techniques, such as mapping measurements, have been developed for the quantitative assessment of myocardial changes. Cardiac amyloidosis is characterized by pronouncedly increased native T1 values. In the case of contrast administration, the extracellular volume of the myocardium can be evaluated with T1 mapping. An increase in extracellular volume is an early marker of cardiac amyloidosis even before the appearance of LGE , 29. UnfWe found that strain parameters have relatively high diagnostic accuracy. In the differentiation of cardiac AL-amyloidosis from HCM, the sensitivities of GLS (cut-off of -23%) and GRS (cut-off of 63%) were 89% and 83%, respectively, while the specificities of basal LS (cut-off of -16%), basal CS (cut-off of -31%) were 85% and 83%, respectively. In the differentiation of cardiac AL-amyloidosis from controls with HT, the sensitivity and specificity of basal LS (cut-off of -21%) were 94% and 79%, respectively, the sensitivity and specificity of apex-to-base LS ratio (cut-off of 1.17) were 83% and 76%, respectively.In the diagnosis of cardiac amyloidosis, echocardiography-based strain analysis is widely accepted. A well-known typical sign of cardiac amyloidosis is apical sparing, in which basal LS is severely impaired while apical LS is relatively spared , 18. HowWe found that cardiac AL-amyloidosis patients have more impaired global and regional LS values than controls with HT or HCM patients. Furthermore, our results demonstrate that feature-tracking strain analysis is applicable for detecting apical sparing in cardiac AL-amyloidosis patients, as they had significantly higher apex-to-base LS and CS ratios than controls with HT and HCM patients. However, in the differentiation of cardiac AL-amyloidosis from HCM, the apex-to-base CS and LS ratios were less accurate than the global and basal strain values, while the diagnostic accuracy of apex-to-base LS ratio was relatively high when differentiating cardiac AL-amyloidosis from controls with HT.The main advantage of feature-tracking strain analysis is that it needs no additional dedicated CMR sequences, and the evaluation is performed using the standard cine images. However, this method has some limitations: previously published data showed that reliability and accuracy of feature-tracking analysis is dependent on reader experience more than tagging-based strain analysis, and the reproducibility of segmental assessment of strain is lower –36.Another limitation of our study includes its single-center setting. Additionally, myocardial T1 and T2 mapping and myocardial extracellular volume measurements were available only in a few cases of the study population. Finally, in the vast majority of HCM patients, no genetic testing was performed.The findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. In this respect, the sensitivity and specificity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% and 100% and of septal myocardial nulling prior to blood pool was 71% and 100%, respectively. In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT . On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing (apex-to-base LS > 2) had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%). Hence, further larger studies are warranted to validate the potential key role of CMR in the diagnosis of cardiac AL-amyloidosis.S1 TableIntraclass correlation analysis for interobserver variability in strain parameters.(DOCX)Click here for additional data file.S2 TableResults of the ROC curve analyses.(DOCX)Click here for additional data file.S1 Dataset(XLSX)Click here for additional data file. 8 Oct 2021 <div> PONE-D-21-24457 </div>  <div> The Role of Cardiac Magnetic Resonance-based Feature-tracking Strain Analysis in the Differential Diagnosis and Prognostic Assessment of Patients with Left Ventricular Hypertrophy. </div>  <div> PLOS ONEDear Dr. Vago,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.plosone@plos.org. 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For instructions see: We look forward to receiving your revised manuscript.Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONEAdditional Editor Comments:Thank you very much for submitting this large study to PlosOne. While the cohort and analyses performed are analyzed interesting, several pending serious and major limitations should be addressed in order to get adequate clinical applicability of the findings from this study.Pending Major Limitations and Comments:1) Concerns stated by the reviewer:- The reviewer has addressed important limitations from this study, which should be mandatorily addressed in the revised version.3) Uncertainty of the clinical applicability of the LV strain parameters:- As it is shown in table 2, the rate of false positives and false negatives varied from 20 to 40% between the diverse strain parameters, which obligates to research alternative parameters to accurately differentiate HCM from CA. Hence, the authors should further analyze the diagnostic performance of ECV, T1 native mapping time, and LV phenotype to mainly differentiate HCM from CA.4) Lack of incremental value analyses:- The authors should show the sensibility, specificity, accuracy of the following parameters or findings to differentiate HCM from CA:- Mid Septal ECV > 0,40- Mid Septal ECV > 0,30- Mid septal T1 native mapping time > 1200 ms- Mid septal T1 native mapping time > 1000 ms- Septal and posterior wall thickness ≥ 15mm- Septal wall thickness ≥ 25mm- Septal wall thickness ≥ 15mm- Septal wall thickness ≥ 14mm- Septal wall thickness ≥ 12mm- Septal and posterior diffuse subendocardial LGE- Septal diffuse subendocardial LGE- Septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling.- Septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling.- Apical sparing using LV global longitudinal strain (GLS) .- GLS < 15% and apical sparing- Septal and posterior wall thickness ≥ 14mm + GLS < 15% and apical sparing + pericardial effusion- Septal and posterior wall thickness ≥ 14mm + GLS < 15% and apical sparing + RV free wall thickness ≥ 7mm- Septal and posterior wall thickness ≥ 12mm + GLS < 15% and apical sparing + RV free wall thickness ≥ 5mmJournal requirements:When submitting your revision, we need you to address these additional requirements.1. 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Thank you for stating the following in the Funding Section of your manuscript:“Project no. NVKP_16-1–2016-0017  has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. The research was financed by the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University; and by the Ministry of Innovation and Technology NRDI Office within the framework of the Artificial Intelligence National Laboratory Program. LS was supported by the ÚNKP-20-3-II-SE-61 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. ZD and LS were supported by the „Development of scientific workshops of medical, health sciences and pharmaceutical educations” project. Project identification number: EFOP-3.6.3-VEKOP-16-2017-00009.We note that you have provided additional information within the Funding Section. Please note that funding information should not appear in other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:“Project no. NVKP_16-1–2016-0017  has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. The research was financed by the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University; and by the Ministry of Innovation and Technology NRDI Office within the framework of the Artificial Intelligence National Laboratory Program. LS was supported by the ÚNKP-20-3-II-SE-61 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. ZD and LS were supported by the „Development of scientific workshops of medical, health sciences and pharmaceutical educations” project. Project identification number: EFOP-3.6.3-VEKOP-16-2017-00009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”Please include your amended statements within your cover letter; we will change the online submission form on your behalf.http://journals.plos.org/plosone/s/supporting-information.4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: 5) In order to refine and focus the findings, please exclude patients with Fabry disease and endomyocardial fibrosis.Reviewers' comments: <font color="black"> Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics.  </font> Reviewer #1: In the present paper Dohy and Merkely et al investigate the ability of myocardial strain by feature tracking analysis for the diagnostic classification and risk stratification of patients with myocardial hypertrophy due to HCM, cardiac amyloidosis (AL and ATTR), Fabry disease and endomyocardial fibrosis. Myocardial strain variables were able to differentiate between HCM and cardiac amyloidosis, whereas risk stratification could also be provided. The paper is surely of interest since strain is an important issue with cardiac imaging and the differentiation between diseases causing hypertrophy has nowadays important therapeutic implications for the specific management of such patients more than ever. However, some specific points definitely need to be clarified.1. The percentage of patients with HCM is strikingly high compared to those with cardiac amyloidosis. Especially ATTR patients are expected to be found much more frequently in a tertiary setting and AL patients in conjunction with hematology / oncology units. Please explain and consider reporting / acknowledging referral biases.2. In the same direction, the number of ATTR patients is strikingly low with 3 patients in total! This is certainly not in agreement with current trends of diagnosis this entity in 30-fold more patients than in the last decade. The prevalence especially in elderly patients with hypertrophy of unknow origin is very high, if correctly diagnosed based on current algorithms.3. In the same line the authors did not include patients with hypertensive heart disease, where in many cases differential diagnosis regarding HCM and cardiac amyloidosis may be very challenging, especially in those with progressed hypertensive heart disease, where focal LGE may be present, mimicking HCM. This needs to be explained by the authors, since inclusion of such patients would have been clinically meaningful and since inclusion of patients has performed retrospectively, which means that such patients could have been easily included and considered for feature tracking analysis too.4. The same restrictions also apply for individuals with athletes’ heart, while in this case referral may be an issue.5. Figure 1. It is striking that patients with hypertensive heart disease are not included. Please see also my comment #3.6. Figure 2. It would be meaningful to parallel show the images of a normal volunteer for comparison to this cardiac amyloidosis patient with very progressed myocardial disease.7. Diagnosis of HCM. What about patients with septal wall thickness >13mm and family history of HCM?8. I am not sure if inclusion of patients with endomyocardial fibrosis is meaningful since hypertrophy is not necessarily associated with this entity. Possibly some overlap with hypertensive heart disease needs to be considered with these patients more than with other categories.9. The differential diagnosis of HCM versus cardiac amyloidosis is clinical meaningful and a strength of the article. It is correct to highlight this in the results, as shown in Table 2. Hereby, LGE seems to be the stronger predictor, which can be expected. However, the value of strain is also relevant since basal LS und CS also provide relatively high AUC values.10. Figure 4 demonstrates that patients with amyloidosis have poorer prognosis, which is expected due to the entity of the disease. However, much more meaningful would be a Kaplan-Maier analysis based on LGE and on strain values. Would one of the myocardial strain values be able to show prognostic relevance. If yes, this would surely contribute to the current literature.11. In the same direction, basal LS seems to bear independent prognostic implications for the estimation of mortality. This needs to be tested and adjusted for quantitative LGE and main diagnosis. The corresponding Kaplan-Maier analysis needs to be demonstrated.12. A recent study investigating the ability of strain based CMR (with fast-SENC) to differentiate between patients with HCM, amyloidosis and hypertensive heart disease needs to be reported and discussed by the authors .13. In addition, some limitations need to be reported with feature tracking acquisitions. Although, a big advantage of feature tracking is no need for additional dedicated CMR sequences, some disadvantages have been extensively mentioned in the recent literature, especially regarding the segmental assessment of strain . 22 Nov 20211) Concerns stated by the reviewer:- The reviewer has addressed important limitations from this study, which should be mandatorily addressed in the revised version.Thank you for your comment. The limitations section has been completed with the followings:“The main advantage of feature-tracking strain analysis is that it needs no additional dedicated CMR sequences, and the evaluation is performed using the standard cine images. However, this method has some limitations: previously published data showed that reliability and accuracy of feature-tracking analysis is dependent on reader experience more than tagging-based strain analysis, and the reproducibility of segmental assessment of strain is lower. There might be some referral bias that can explain the relatively low prevalence of CA patients, especially ATTR patients: ATTR patients are usually referred from community cardiac services or from other cardiology centers where diagnostic awareness is lower compared to hematology centers where myeloma and MGUS patients are monitored for CA and from where a great number of AL patients are referred. In recent years, cardiology centers have diagnosed TTR CA in a "non-biopsy" manner in many cases with the help of PYP scans. Many of these TTR CA pts did not have a CMR for the diagnosis.”3) Uncertainty of the clinical applicability of the LV strain parameters:- As it is shown in table 2, the rate of false positives and false negatives varied from 20 to 40% between the diverse strain parameters, which obligates to research alternative parameters to accurately differentiate HCM from CA. Hence, the authors should further analyze the diagnostic performance of ECV, T1 native mapping time, and LV phenotype to mainly differentiate HCM from CA.Thank you for your comment. We agree with the Editor that ECV and T1 mapping parameters increase the diagnostic accuracy of CMR in the differentiation of CA from HCM. Unfortunately, mapping measurements were not available in our center at the time of the investigated examinations. It has been signed in the limitation section. The discussion section has been completed with the followings: “In recent years, novel CMR techniques, such as mapping measurements, have been developed for the quantitative assessment of myocardial changes. CA is characterized by pronouncedly increased native T1 values. In the case of contrast administration, the extracellular volume of the myocardium can be evaluated with T1 mapping. An increase in extracellular volume is an early marker of CA even before the appearance of LGE. Unfortunately, mapping measurements were not available in our center for the current study.”Regarding LV phenotype, we have completed the results section with the followings: “The most common form of HCM was asymmetric hypertrophy with a septal or an anterior distribution, which was found in 257 patients (77.9%). There were 47 (14.2%) patients with apical HCM, 21 (6.4%) patients with concentric HCM and five (1.5%) patients with midventricular HCM. Among CA patients, concentric hypertrophy was found in 16 cases (35%), and hypertrophy showed septal dominance in 30 patients (65%).”“There was no difference in LVMi between HCM and CA patients; however, HCM patients had higher EDWT. Concentric hypertrophy was more frequent among CA patients.”4) Lack of incremental value analyses:- The authors should show the sensibility, specificity, accuracy of the following parameters or findings to differentiate HCM from CA:- Mid Septal ECV > 0,40- Mid Septal ECV > 0,30- Mid septal T1 native mapping time > 1200 ms- Mid septal T1 native mapping time > 1000 ms- Septal and posterior wall thickness ≥ 15mm- Septal wall thickness ≥ 25mm- Septal wall thickness ≥ 15mm- Septal wall thickness ≥ 14mm- Septal wall thickness ≥ 12mm- Septal and posterior diffuse subendocardial LGE- Septal diffuse subendocardial LGE- Septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling.- Septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling.- Apical sparing using LV global longitudinal strain (GLS) .- GLS < 15% and apical sparing- Septal and posterior wall thickness ≥ 14mm + GLS < 15% and apical sparing + pericardial effusion- Septal and posterior wall thickness ≥ 14mm + GLS < 15% and apical sparing + RV free wall thickness ≥ 7mm- Septal and posterior wall thickness ≥ 12mm + GLS < 15% and apical sparing + RV free wall thickness ≥ 5mmThank you for your advice. We added the required parameters to a new table  and completed the results section as follows. However, the results of the performed ROC curve analyses showed other cut-off values for GLS (>-23) and apex-to-base LS ratio (>1.36), as recommended by the Editor. Therefor we presented data with our cut-off values as well.“The frequencies of positive results of different diagnostic criteria in the patient groups are shown in Table 3. The presence of septal or septal and posterior diffuse subendocardial LGE had high specificity  and relatively high sensitivity (89% for both). The specificity of myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling was 100%, with a sensitivity of 68%.”Table 3Frequencies of positive diagnostic criteria in the HCM and CA patient groups compared with the chi-squared testJournal requirements:When submitting your revision, we need you to address these additional requirements.1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttps://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf andhttps://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdfWe have updated the manuscript’s style according to PLOS ONE’s style requirements.http://journals.plos.org/plosone/s/data-availability.2. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: We will update your Data Availability statement to reflect the information you provide in your cover letterWe have uploaded our study’s minimal underlying data set as Supporting Information file.3. Thank you for stating the following in the Funding Section of your manuscript:“Project no. NVKP_16-1–2016-0017  has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. The research was financed by the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University; and by the Ministry of Innovation and Technology NRDI Office within the framework of the Artificial Intelligence National Laboratory Program. LS was supported by the ÚNKP-20-3-II-SE-61 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. ZD and LS were supported by the „Development of scientific workshops of medical, health sciences and pharmaceutical educations” project. Project identification number: EFOP-3.6.3-VEKOP-16-2017-00009.We note that you have provided additional information within the Funding Section. Please note that funding information should not appear in other areas of your manuscript. We will only publish funding information present in the Funding Statement section of the online submission form.Please remove any funding-related text from the manuscript and let us know how you would like to update your Funding Statement. Currently, your Funding Statement reads as follows:“Project no. NVKP_16-1–2016-0017  has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the NVKP_16 funding scheme. The research was financed by the Thematic Excellence Programme (2020-4.1.1.-TKP2020) of the Ministry for Innovation and Technology in Hungary, within the framework of the Therapeutic Development and Bioimaging thematic programmes of the Semmelweis University; and by the Ministry of Innovation and Technology NRDI Office within the framework of the Artificial Intelligence National Laboratory Program. LS was supported by the ÚNKP-20-3-II-SE-61 New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund. ZD and LS were supported by the „Development of scientific workshops of medical, health sciences and pharmaceutical educations” project. Project identification number: EFOP-3.6.3-VEKOP-16-2017-00009. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.”Please include your amended statements within your cover letter; we will change the online submission form on your behalf.We have removed funding-related text from the manuscript. We have not changed our Funding Statement.http://journals.plos.org/plosone/s/supporting-information.4. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: We have included captions for the Supporting Information file at the end of the manuscript.5) In order to refine and focus the findings, please exclude patients with Fabry disease and endomyocardial fibrosis.Thank you for your advice. We excluded patients with Fabry disease and endomyocardial fibrosis from the study.Reviewers' comments:Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. Author comment:We would like to thank the reviewer for the thorough reading of our manuscript and the constructive suggestions. We believe that the manuscript has been improved by incorporating these comments and recommendations.Reviewer #1: In the present paper Dohy and Merkely et al investigate the ability of myocardial strain by feature tracking analysis for the diagnostic classification and risk stratification of patients with myocardial hypertrophy due to HCM, cardiac amyloidosis (AL and ATTR), Fabry disease and endomyocardial fibrosis. Myocardial strain variables were able to differentiate between HCM and cardiac amyloidosis, whereas risk stratification could also be provided. The paper is surely of interest since strain is an important issue with cardiac imaging and the differentiation between diseases causing hypertrophy has nowadays important therapeutic implications for the specific management of such patients more than ever. However, some specific points definitely need to be clarified.1. The percentage of patients with HCM is strikingly high compared to those with cardiac amyloidosis. Especially ATTR patients are expected to be found much more frequently in a tertiary setting and AL patients in conjunction with hematology / oncology units. Please explain and consider reporting / acknowledging referral biases.2. In the same direction, the number of ATTR patients is strikingly low with 3 patients in total! This is certainly not in agreement with current trends of diagnosis this entity in 30-fold more patients than in the last decade. The prevalence especially in elderly patients with hypertrophy of unknown origin is very high, if correctly diagnosed based on current algorithms.Thank you for your questions.Answer for question 1 and 2:There was certainly some referral bias. Myeloma and MGUS pts are monitored for CA in hematology centers, from where a great number of AL patients are referred. In other words, hematologists have a high awareness of AL. For them, CMR is ideal for the diagnosis of CA.On the other hand, ATTR patients are usually referred from community cardiac services or from other cardiology centers where diagnostic awareness is lower (see below). In recent years, these centers have diagnosed TTR CA in a "non-biopsy" manner in many cases with the help of PYP scans. Many of these TTR CA pts did not have a CMR for the diagnosis. Another possible explanation for the relatively low number of ATTRwt patients is that the expected life expectancy in Hungary is significantly lower than that in Western Europe and the US, and therefore fewer patients "live long enough" to obtain ATTRwt. Additionally, the severe comorbidity of the elderly population in Hungary is quite high; therefore, we speculate that CMR is not performed in many cases, as it would not change the disease course.In a very large series of systemic amyloid (not only CA) pts, Wechalekar et al published in 2016 in the Lancet that the ratio of AL was stable at approximately 67% over the past decades. The ratio of ATTR was growing simultaneously with the lowering number of AAs. In our retrospective study, the cause of CA remained unknown in 7 pts, but probably some of them also had ATTR. All together our data, i.e., the ratio of AL and ATTR, are not far from the data of Wechalekar et al.CA is considered to be a rare disease, and diagnostic awareness is still low in Hungary. It is nicely shown by a recent paper which found that the prevalence of ATTRv is just half of the prevalence observed in non-endemic regions of Western Europe, although the number of recognized cases is increasing. . This is also one cause, which explains the higher ratio of HCM and lower CA patients among LVH morphology pts in Hungary.We have completed the limitations sections with the followings: “There might be some referral bias that can explain the relatively low prevalence of CA patients, especially ATTR patients: ATTR patients are usually referred from community cardiac services or from other cardiology centers where diagnostic awareness is lower compared to hematology centers where myeloma and MGUS patients are monitored for CA and from where a great number of AL patients are referred. In recent years, cardiology centers have diagnosed TTR CA in a "non-biopsy" manner in many cases with the help of PYP scans. Many of these TTR CA pts did not have a CMR for the diagnosis.”3. In the same line the authors did not include patients with hypertensive heart disease, where in many cases differential diagnosis regarding HCM and cardiac amyloidosis may be very challenging, especially in those with progressed hypertensive heart disease, where focal LGE may be present, mimicking HCM. This needs to be explained by the authors, since inclusion of such patients would have been clinically meaningful and since inclusion of patients has performed retrospectively, which means that such patients could have been easily included and considered for feature tracking analysis too.Thank you for your comment. Differentiating hypertensive heart disease from HCM is highly clinically relevant. Patients with left ventricular hypertrophy obviously due to untreated hypertension are usually not referred to CMR in our center. Patients with hypertensive heart disease are usually referred for CMR if there is a suspicion of other underlying conditions behind LV hypertrophy. In these cases, differentiating hypertensive heart disease from mild phenotypic HCM is challenging. To avoid diagnostic uncertainty, we decided to exclude these patients from the study. As we involved in the study referred patients with clinical questions, we had only a few cases of LV hypertrophy certainly due to hypertensive heart disease.4. The same restrictions also apply for individuals with athletes’ heart, while in this case referral may be an issue.Thank you for your comment. We agree with the reviewer that differentiating athletes’ heart and pathological hypertrophy is crucial. As our clinic is a sports cardiology center, we perform CMR examinations in athletes in a large number. Nine athletes who were diagnosed with HCM were involved in the study. Athletes with physiological sport adaptation were not investigated in the current study.We completed the methods section with the followings: “Patients with untreated hypertension, significant aortic stenosis, or athletes with left ventricular hypertrophy due to physiological sport adaptation were not involved in the study.”5. Figure 1. It is striking that patients with hypertensive heart disease are not included. Please see also my comment #3.Thank you for your comment. According to our inclusion criteria, patients with hypertensive heart disease were not included in the study.6. Figure 2. It would be meaningful to parallel show the images of a normal volunteer for comparison to this cardiac amyloidosis patient with very progressed myocardial disease.Thank you for your advice. We added to Figure 2 the LGE images and the bull’s eye with segmental strain values of a patient without structural heart disease.7. Diagnosis of HCM. What about patients with septal wall thickness >13mm and family history of HCM?Thank you for your question. The diagnosis of HCM in first-degree relatives of patients with HCM was based on the presence of otherwise unexplained increased wall thickness ≥13 mm. We have completed the methods section with this information. HCM in the family history was known in 24 cases, and only 4 of them had a wall thickness of 13-14 mm. 8. I am not sure if inclusion of patients with endomyocardial fibrosis is meaningful since hypertrophy is not necessarily associated with this entity. Possibly some overlap with hypertensive heart disease needs to be considered with these patients more than with other categories.Thank you for your comment. On the advice of the Editor, patients with EMF or Fabry disease have been excluded from the study.9. The differential diagnosis of HCM versus cardiac amyloidosis is clinical meaningful and a strength of the article. It is correct to highlight this in the results, as shown in Table 2. Hereby, LGE seems to be the stronger predictor, which can be expected. However, the value of strain is also relevant since basal LS und CS also provide relatively high AUC values.Thank you for your comment. We have completed this section with the followings:“The frequencies of positive results of different diagnostic criteria in the patient groups are shown in Table 3. The presence of septal or septal and posterior diffuse subendocardial LGE had high specificity  and relatively high sensitivity (89% for both). The specificity of myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling was 100%, with a sensitivity of 68%.”Table 3 Frequencies of positive diagnostic criteria in the HCM and CA patient groups compared with the chi-squared test We have highlighted these results in the discussion section:“In the differentiation of CA from HCM, the amount and pattern of LGE have the highest diagnostic accuracy, followed by basal LS, basal CS and GRS. (…) In our study population, it was found that the amount and pattern of LGE had the highest diagnostic accuracy in the differentiation of CA and HCM. However, in case of a contraindication for contrast agent administration, further diagnostic methods are needed. We found that strain parameters have relatively high diagnostic accuracy. The sensitivity of GLS with a cut-off of -23% was 89%, while the specificities of basal LS (cut-off of -16%), basal CS (cut-off of -31%) and GRS (cut-off of 63%) were 85%, 83% and 83%, respectively.”10. Figure 4 demonstrates that patients with amyloidosis have poorer prognosis, which is expected due to the entity of the disease. However, much more meaningful would be a Kaplan-Maier analysis based on LGE and on strain values. Would one of the myocardial strain values be able to show prognostic relevance. If yes, this would surely contribute to the current literature.Thank you for your advice. Using ROC curve analysis, we calculated cut-off values of LGE, LVSVi, GLS, GCS and GRS regarding mortality. The survival probability of patient groups defined by the calculated cut-off parameters was analyzed and illustrated with Kaplan-Meier curves, which can be found in the revised Figure 4.11. In the same direction, basal LS seems to bear independent prognostic implications for the estimation of mortality. This needs to be tested and adjusted for quantitative LGE and main diagnosis. The corresponding Kaplan-Maier analysis needs to be demonstrated.Thank you for your comment. Our study population changed, as we excluded patients with EMF or Fabry disease from the analysis on the advice of the Editor. Furthermore, we completed the regional strain analysis of all HCM patients . These factors led to a changed result of the survival analysis: independent predictors of mortality with multivariable Cox proportional hazard regression are a diagnosis of CA, age and GLS. Variables with p<0.05 in the univariable analysis were analyzed in one multivariable model (after excluding highly correlated predictors). As quantitative LGE and the main diagnosis were included in this model, the prognostic significance of GLS is independent of these factors. We believe this result is more reliable than the previous one was with a smaller patient group.Kaplan-Meier curves based on LGE, LVSVi, GLS, GCS and GRS have been added to Figure 4.12. A recent study investigating the ability of strain based CMR (with fast-SENC) to differentiate between patients with HCM, amyloidosis and hypertensive heart disease needs to be reported and discussed by the authors .Thank you for your comment. We have added the required article to the references and completed the discussion section with the followings: “A recently published study investigated the ability of a single heartbeat fast-strain encoded (SENC) CMR-derived myocardial strain to discriminate between CA, HCM, hypertensive heart disease, athletes’ heart and healthy controls. CA patients had the most impaired GLS and GCS values, and the percentage of LV segments with a strain value < -17% was the lowest in this patient group; apical sparing was not investigated.”13. In addition, some limitations need to be reported with feature tracking acquisitions. Although, a big advantage of feature tracking is no need for additional dedicated CMR sequences, some disadvantages have been extensively mentioned in the recent literature, especially regarding the segmental assessment of strain .Thank you for your comment. We have completed the limitations section as follows: “The main advantage of feature-tracking strain analysis is that it needs no additional dedicated CMR sequences, and the evaluation is performed using the standard cine images. However, this method has some limitations: previously published data showed that reliability and accuracy of feature-tracking analysis is dependent on reader experience more than tagging-based strain analysis, and the reproducibility of segmental assessment of strain is lower.”AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 25 Nov 2021 <div> PONE-D-21-24457R1 </div>  <div> The role of cardiac magnetic resonance-based feature-tracking strain analysis in the differential diagnosis and prognostic assessment of patients with left ventricular hypertrophy. </div>  <div> PLOS ONEDear Dr. Vago,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. </div> A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.Please include the following items when submitting your revised manuscript:We look forward to receiving your revised manuscript.Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONE Editor Comments :I have read and revised again this interesting large study and appreciated the effort of the authors to address the suggestions of the editors and reviewers. While the data is interesting, there are pending major and serious limitations in this study, mainly regarding the clinical relevance, applicability, and presentation of this study.Hence, without addressing the below detailed major limitations, this study will have a low priority for publication in PlosOne.Major and Serious Pending Limitations:1) Presentation of the Manuscript and Results:- The most important and clinically relevant findings from this study are those linked to AL-Amyloidosis . In fact, while patients with cardiac ATTR-Amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the cardiac involvement in AL-Amyloidosis is challenging . In addition, the role of CMR in AL-Amyloidosis remains uncertain. Hence, the authors should make focus in patients with AL-Amyloidosis.- In line with the above-mentioned comments, it will necessary to include a control group of at least 70 patients  with arterial hypertension without history of cardiomyopathy and with similar LVEF than the group with AL-Amyloidosis. Including merely at least 70 control patients it would not mean a lot of effort in a normal CMR department.- Patients with other type of Amyloidosis other than AL should be excluded in order to get a homogenous and clinically relevant population.- The most important analyses and parameters to analyze are the sensibility and specificity of CMR parameters to determine cardiac involvement as compared to controls patients and also to differentiate from CMH. Hence, the authors should mandatorily analyze and show the sensibility and specificity of the following parameters to determine cardiac Al-Amyloidosis :Septal and posterior wall thickness ≥ 15mmSeptal and posterior wall thickness ≥ 14mmSeptal and posterior wall thickness ≥ 13mmSeptal and posterior wall thickness ≥ 12mmSeptal wall thickness ≥ 20mmSeptal wall thickness ≥ 18mmSeptal wall thickness ≥ 15mmSeptal wall thickness ≥ 14mmSeptal wall thickness ≥ 13mmSeptal wall thickness ≥ 12mmSeptal and posterior diffuse subendocardial LGESeptal diffuse subendocardial LGESeptal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nullingSeptal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nullingApical sparing using LV global longitudinal strain (GLS) .GLS < 15% and apical sparingGLS < 15%GLS < 13%GLS < 12%- Please provide the following cases examples:1- AL-Amyloidosis with septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling2- Arterial hypertension without septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling3- CMH without septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling4- AL-Amyloidosis with septal and posterior diffuse subendocardial LGE5- Arterial hypertension without septal and posterior diffuse subendocardial LGE6- CMH without septal and posterior diffuse subendocardial LGE- The outcome data is not of high relevance in this study, but if you consider important this data, please analyze only the mortality for HF or hospitalization for HF and in separated groups . 13 Dec 2021Editor Comments :I have read and revised again this interesting large study and appreciated the effort of the authors to address the suggestions of the editors and reviewers. While the data is interesting, there are pending major and serious limitations in this study, mainly regarding the clinical relevance, applicability, and presentation of this study.Hence, without addressing the below detailed major limitations, this study will have a low priority for publication in PlosOne.Major and Serious Pending Limitations:1) Presentation of the Manuscript and Results:- The most important and clinically relevant findings from this study are those linked to AL-Amyloidosis . In fact, while patients with cardiac ATTR-Amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the cardiac involvement in AL-Amyloidosis is challenging . In addition, the role of CMR in AL-Amyloidosis remains uncertain. Hence, the authors should make focus in patients with AL-Amyloidosis.Thank you for your comment. We have focused on patients with AL-Amyloidosis and have excluded patients with TTR or AA amyloidosis or if the exact type of amyloidosis was unknown.- In line with the above-mentioned comments, it will necessary to include a control group of at least 70 patients  with arterial hypertension without history of cardiomyopathy and with similar LVEF than the group with AL-Amyloidosis. Including merely at least 70 control patients it would not mean a lot of effort in a normal CMR department.Thank you for your advice. Hypertensive heart disease patients are usually not referred for CMR in our Center if there is no suspicion of cardiomyopathy. We can retrospectively collect patients, who have in their patient’s history arterial hypertension (mostly treated hypertension) and were referred for CMR with an other indication but CMR found no structural heart disease. However, these patients usually have no expressed hypertrophy as their hypertension is treated. If the Editor suggest that we could increase the scientific value of our study with analyzing this patient population, we will complete our study with pleasure.- Patients with other type of Amyloidosis other than AL should be excluded in order to get a homogenous and clinically relevant population.Thank you for your advice. We have excluded patients with TTR or AA amyloidosis and if the exact type of amyloidosis was unknown.- The most important analyses and parameters to analyze are the sensibility and specificity of CMR parameters to determine cardiac involvement as compared to controls patients and also to differentiate from CMH. Hence, the authors should mandatorily analyze and show the sensibility and specificity of the following parameters to determine cardiac Al-Amyloidosis :Septal and posterior wall thickness ≥ 15mmSeptal and posterior wall thickness ≥ 14mmSeptal and posterior wall thickness ≥ 13mmSeptal and posterior wall thickness ≥ 12mmSeptal wall thickness ≥ 20mmSeptal wall thickness ≥ 18mmSeptal wall thickness ≥ 15mmSeptal wall thickness ≥ 14mmSeptal wall thickness ≥ 13mmSeptal wall thickness ≥ 12mmSeptal and posterior diffuse subendocardial LGESeptal diffuse subendocardial LGESeptal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nullingSeptal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nullingApical sparing using LV global longitudinal strain (GLS) .GLS < 15% and apical sparingGLS < 15%GLS < 13%GLS < 12%Thank you for your advice. We have added a table with the sensitivity and specificity of the required parameters to differentiate CA from HCM.- Please provide the following cases examples:1- AL-Amyloidosis with septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling2- Arterial hypertension without septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling3- CMH without septal and posterior myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling4- AL-Amyloidosis with septal and posterior diffuse subendocardial LGE5- Arterial hypertension without septal and posterior diffuse subendocardial LGE6- CMH without septal and posterior diffuse subendocardial LGEThank you for your comment. We provided examples of CA with myocardial nulling prior to blood pool nulling and diffuse subendocardial LGE, and a case of HCM with patchy mid-myocardial LGE in Figure 3.- The outcome data is not of high relevance in this study, but if you consider important this data, please analyze only the mortality for HF or hospitalization for HF and in separated groups .Thank you for your advice. We have no information about the hospitalization in most of the cases, and also the cause of death is unknown in a part of the cases. Therefore, we decided to leave out the Cox regression analysis for the assessment the prognostic value of CMR parameters.The Kaplan-Meier analyses are included the study later on, as it was the request of the Reviewer.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 15 Dec 2021 <div> PONE-D-21-24457R2 </div>  <div> The role of cardiac magnetic resonance-based feature-tracking strain analysis in the differential diagnosis and prognostic assessment of patients with left ventricular hypertrophy. </div>  <div> PLOS ONEDear Dr. Vago,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. </div> A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.Please include the following items when submitting your revised manuscript:We look forward to receiving your revised manuscript.Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONEAdditional Editor Comments:I would like to congratulate to the authors for the effort made to improve the manuscript following the suggestions of the Editors and Reviewers. In fact, the presentation of the study has significantly improved and it remains just some limitations to be addressed to get the final version of this interesting study.Minor Pending Limitations:1) It will absolutely necessary to include a control group of at least 70 patients  with arterial hypertension without history of cardiomyopathy and with similar LVEF than the group with AL-Amyloidosis.2) Please a table as table 3, comparing the sensibility and specificity of the parameters of table but comparing AL-Amyloidosis vs. control patients with arterial hypertension.3) Table 2 is not interesting and thus, it should be moved to data supplement.4) The section on prognosis is interesting, but out of the scope of the present study. Hence, it should be removed, but it would be very interesting to make a new study and analysis examining the main parameters linked to prognosis in patients with CMH in this large cohort of 330 patients. PlosOne Editors will evaluate with interest this potential further study.5) The most important and clinically relevant findings from this study are those linked to AL-Amyloidosis . In fact, while patients with cardiac ATTR-Amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the cardiac involvement in AL-Amyloidosis is challenging . In addition, the role of CMR in AL-Amyloidosis remains uncertain. Hence, the authors should make focus in patients with AL-Amyloidosis.6) In the line with above-mentioned suggestion, the authors should significantly change the title, abstract, introduction, and discussion of the study, focusing only in the findings on the detection and diagnosis of cardiac AL-Amyloidosis. In this respect, a potential title would be “Potential Clinical Relevance of CMR to Diagnose Cardiac AL-Amyloidosis”. By the way, a potential abstract would be:- Background: While patients with cardiac ATTR-Amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the detection of cardiac involvement in AL-Amyloidosis is challenging. In addition, the role of CMR in AL-Amyloidosis remains uncertain. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac involvement in patients with AL-Amyloidosis.Methods: We included 35 patients with proved cardiac AL-Amyloidosis and two control groups constituted by 330 patients with HCM and 70 patients with arterial hypertension, who underwent CMR examination. Phenotype and amount of LV wall thickness, strain, and late gadolinium enhancement (LGE) were evaluated. Sensibility and specificity of several CMR parameters were analyzed comparing patients with cardiac AL-Amyloidosis vs those with CMH and vs. those with arterial hypertension.Results: please describe the results of table 3 regarding AL-Amyloidosis vs CMH and vs. arterial hypertension.Conclusions: The findings from this study suggest that septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling or septal diffuse subendocardial LGE proving excellent sensibility and specificity to determine cardiac involvement in patients with AL-Amyloidosis. Further larger studies are warranted to validate the findings from this study.7) Please do not add the symbol % next to the parameters’ description, but next to the values of sensibility and specificity.8) Please add to the table 3 a file with the accuracy value.9) Please provide mandatorily the following cases/figures examples:1- AL-Amyloidosis with septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling2- Arterial hypertension without septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling3- CMH without septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling4- AL-Amyloidosis with septal diffuse subendocardial LGE5- Arterial hypertension without septal diffuse subendocardial LGE6- CMH without septal diffuse subendocardial LGhttps://pubmed.ncbi.nlm.nih.gov/?term=light%20chain%20(AL)%20amyloidosis%20AND%20diagnosis%20AND%20CMR&sort=date&page=410) Please provide a table comparing and describing the findings of the present study vs previous similar studies  Please discuss previous similar studies in the discussion section. 28 Jan 20221) It will absolutely necessary to include a control group of at least 70 patients  with arterial hypertension without history of cardiomyopathy and with similar LVEF than the group with AL-Amyloidosis.Thank you for your suggestion. We have added 70 patients with arterial hypertension to the study and analyzed the differential diagnostic significance of CMR parameters in CA patients vs. those with hypertension. We believe that the clinical relevance of our study increased with these findings.2) Please a table as table 3, comparing the sensibility and specificity of the parameters of table but comparing AL-Amyloidosis vs. control patients with arterial hypertension.Thank you for your suggestion. We have added a table with the sensitivity and specificity of CMR parameters to differentiate CA from controls with HT3) Table 2 is not interesting and thus, it should be moved to data supplement.Thank you for your advice. We have moved the results of ROC analysis to data supplement.4) The section on prognosis is interesting, but out of the scope of the present study. Hence, it should be removed, but it would be very interesting to make a new study and analysis examining the main parameters linked to prognosis in patients with CMH in this large cohort of 330 patients. PlosOne Editors will evaluate with interest this potential further study.Thank you for your suggestion. We have removed prognosis from the current study, and we will consider to publish it in a further study.5) The most important and clinically relevant findings from this study are those linked to AL-Amyloidosis . In fact, while patients with cardiac ATTR-Amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the cardiac involvement in AL-Amyloidosis is challenging . In addition, the role of CMR in AL-Amyloidosis remains uncertain. Hence, the authors should make focus in patients with AL-Amyloidosis.Thank you for your comment. We have made changes in the introduction and discussion section in order to direct the focus on the diagnosis of AL-amyloidosis. 6) In the line with above-mentioned suggestion, the authors should significantly change the title, abstract, introduction, and discussion of the study, focusing only in the findings on the detection and diagnosis of cardiac AL-Amyloidosis. In this respect, a potential title would be “Potential Clinical Relevance of CMR to Diagnose Cardiac AL-Amyloidosis”. By the way, a potential abstract would be:- Background: While patients with cardiac ATTR-Amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the detection of cardiac involvement in AL-Amyloidosis is challenging. In addition, the role of CMR in AL-Amyloidosis remains uncertain. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac involvement in patients with AL-Amyloidosis.Methods: We included 35 patients with proved cardiac AL-Amyloidosis and two control groups constituted by 330 patients with HCM and 70 patients with arterial hypertension, who underwent CMR examination. Phenotype and amount of LV wall thickness, strain, and late gadolinium enhancement (LGE) were evaluated. Sensibility and specificity of several CMR parameters were analyzed comparing patients with cardiac AL-Amyloidosis vs those with CMH and vs. those with arterial hypertension.Results: please describe the results of table 3 regarding AL-Amyloidosis vs CMH and vs. arterial hypertension.Conclusions: The findings from this study suggest that septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling or septal diffuse subendocardial LGE proving excellent sensibility and specificity to determine cardiac involvement in patients with AL-Amyloidosis. Further larger studies are warranted to validate the findings from this study.Thank you for your suggestion. We have changed the title and the abstract of the article. We agree with the Editor that LGE CMR has an important role in the diagnosis of cardiac AL-amyloidosis. Moreover, we believe that our findings regarding the CMR-based strain analysis have also clinical significance and novelty. Therefore, besides LGE results, we would like to focus on strain, as well.Full title: Potential clinical relevance of cardiac magnetic resonance including strain analysis to diagnose cardiac light chain amyloidosis.Short title: CMR-based diagnosis of patients with cardiac amyloidosis.Abstract:Background: While patients with cardiac transthyretin amyloidosis are easily diagnosed with bone scintigraphy (planar and/or SPECT), the detection of cardiac involvement in light chain amyloidosis (CA) is challenging. Cardiac magnetic resonance (CMR) examinations have an essential role in the diagnosis of myocardial diseases; however, limited data are available from CMR-based feature-tracking strain analysis in this patient population. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac involvement in patients with light chain amyloidosis (CA).Methods: We included 35 patients with proved CA and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination. The phenotype and degree of left ventricular (LV) hypertrophy, and the amount and pattern of late gadolinium enhancement (LGE) were evaluated. Global and regional LV strain parameters were calculated with feature-tracking strain analysis. Sensitivity and specificity of several CMR parameters were analyzed in diagnosing CA.Results: The sensitivity of diffuse septal subendocardial LGE in diagnosing CA was 88% with a specificity of 99% when differentiating it from HCM and 100% when differentiating it from HT. The sensitivity and specificity of myocardial nulling prior to blood pool was 77% and 100%, respectively, both vs. HCM and vs. HT. Basal longitudinal strain had also high diagnostic accuracy . CMR-based strain analysis was applicable for detecting apical sparing in CA patients.Conclusions: The findings from this study suggest that CMR has high diagnostic relevance in the diagnosis of CA. Besides the excellent sensitivity and specificity of diffuse subendocardial LGE pattern and abnormal contrast kinetics, CMR-based strain analysis has also an important role in differentiating CA from HCM and from controls with HT.7) Please do not add the symbol % next to the parameters’ description, but next to the values of sensibility and specificity.Thank you for your advice. We have added the symbol % next to the values instead of the parameters’ description.8) Please add to the table 3 a file with the accuracy value.Thank you for your advice. We added the AUC values to the table 3.9) Please provide mandatorily the following cases/figures examples:1- AL-Amyloidosis with septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling2- Arterial hypertension without septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling3- CMH without septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling4- AL-Amyloidosis with septal diffuse subendocardial LGE5- Arterial hypertension without septal diffuse subendocardial LGE6- CMH without septal diffuse subendocardial LGThank you for your suggestion. On Figure 3, we show a representative case of HCM without septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling and without septal diffuse subendocardial LGE (A), cases of CA with myocardial nulling prior to blood pool nulling (B) and diffuse subendocardial LGE (C), and a case of arterial hypertension without septal myocardial nulling prior to blood pool nulling or difficulty in achieving myocardial nulling and without septal diffuse subendocardial LGE (D).https://pubmed.ncbi.nlm.nih.gov/?term=light%20chain%20(AL)%20amyloidosis%20AND%20diagnosis%20AND%20CMR&sort=date&page=410) Please provide a table comparing and describing the findings of the present study vs previous similar studies  Please discuss previous similar studies in the discussion section.Thank you for your suggestion. We have completed the discussion section with the followings:“A recent meta-analysis based on 18 published studies included 1,108 CA patients (69% were AL) and 907 control subjects, estimated a sensitivity and specificity of 84% and 80%, respectively, for LGE in diagnosing CA (21). According to another meta-analysis of 7 studies, the sensitivity and specificity of LGE CMR in diagnosing CA were 85% and 92%, respectively (22). Expert consensus recommendations  state that CMR has a central role in the non-invasive diagnosis of CA referring to several studies in which typical LGE pattern has been shown to have a diagnostic sensitivity of 85% to 90% (23–27).”AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 1 Mar 2022 <div> PONE-D-21-24457R3 </div>  <div> Potential clinical relevance of cardiac magnetic resonance including strain analysis to diagnose cardiac light chain amyloidosis. </div>  <div> PLOS ONEDear Dr. Vago,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. </div> A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. <div> Please include the following items when submitting your revised manuscript:We look forward to receiving your revised manuscript.Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONEAdditional Editor Comments:Thank you very much for your time in addressing all suggested revisions. In effect, the paper has significantly improved and it is still only some minor revisions to get the final version of this interesting study.Pending Minor Revisions:1) Please use the term Al-Amyloidosis to refer to light chain amyloidosis. Hence, please use in the whole manuscript as well in the abstract and conclusion the term “cardiac AL-Amyloidosis”.2) Please make focus in the results section of the abstract and in the conclusion of the manuscript on the main findings of the study such as the high sensitivity and specificity of diffuse septal subendocardial LGE and myocardial nulling to differentiate cardiac AL-Amyloidosis from HCM and from HT as well as the low sensibility of a reduced GLS and of apical sparing to differentiate cardiac AL-Amyloidosis from HCM and from HT. Moreover, please highlight that a septum ≥ 14 mm has high sensitivity and specificity to differentiate cardiac AL-Amyloidosis from HT.3) The results on the diagnostic performance of LV basal segmental strain are additional or secondary findings given the high variability and low reproducibility of basal strain values in the LV. Hence, the manuscript should not be focused or centered on these findings and these findings should not be shown in the abstract or conclusion section.4) In line with the above-mentioned comments, please re-edit the title of the study as “Potential clinical relevance of cardiac magnetic resonance to diagnose cardiac light chain amyloidosis”. </div>   4 Apr 20221) Please use the term Al-Amyloidosis to refer to light chain amyloidosis. Hence, please use in the whole manuscript as well in the abstract and conclusion the term “cardiac AL-Amyloidosis”.Thank you for your suggestion. We have changed the term CA to cardiac AL-amyloidosis.2) Please make focus in the results section of the abstract and in the conclusion of the manuscript on the main findings of the study such as the high sensitivity and specificity of diffuse septal subendocardial LGE and myocardial nulling to differentiate cardiac AL-Amyloidosis from HCM and from HT as well as the low sensibility of a reduced GLS and of apical sparing to differentiate cardiac AL-Amyloidosis from HCM and from HT. Moreover, please highlight that a septum ≥ 14 mm has high sensitivity and specificity to differentiate cardiac AL-Amyloidosis from HT.Thank you for your advice. We have changed the results section of the abstract as follows:“The sensitivity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% with a specificity of 99% vs. HCM and 100% vs. HT. The sensitivity and specificity of myocardial nulling prior to blood pool was 77% and 100%, respectively, both vs. HCM and vs. HT. Maximal wall thickness with a cut-off of 14 mm had high diagnostic accuracy when differentiating cardiac AL-amyloidosis from HT: sensitivity 94%, specificity 89%. The sensitivities of reduced global longitudinal strain plus apical sparing were low with high specificities. CMR-based strain analysis was applicable for detecting apical sparing in cardiac AL-amyloidosis patients.”3) The results on the diagnostic performance of LV basal segmental strain are additional or secondary findings given the high variability and low reproducibility of basal strain values in the LV. Hence, the manuscript should not be focused or centered on these findings and these findings should not be shown in the abstract or conclusion section.Thank you for your advice. We have deleted the results regarding basal strain values from the abstract. Our results of interobserver analyses show that intraclass correlation of basal LS was good, near to excellent (0.87), the intraclass correlation of basal CS was excellent (0.92) (S1 Table). Thus we believe that the results regarding basal strain values are relevant enough to be included in the manuscript beside the main findings.4) In line with the above-mentioned comments, please re-edit the title of the study as “Potential clinical relevance of cardiac magnetic resonance to diagnose cardiac light chain amyloidosis”.Thank you for your suggestion, we have changed the title as requested.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 3 May 2022 <div> PONE-D-21-24457R4 </div>  <div> Potential clinical relevance of cardiac magnetic resonance to diagnose cardiac light chain amyloidosis. </div>  <div> PLOS ONEDear Dr. Vago,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. </div> A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. <div> If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.Please include the following items when submitting your revised manuscript:We look forward to receiving your revised manuscript.Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONEAdditional Editor Comments:1) Thank you very much for your efforts to improve the manuscript, which in fact has significantly improved. However, it remains the same issues as in the previous submissions. In this respect, the findings on the role of basal LS and CS to differentiate AL-Amyloidosis from CMH and HT are not clinically relevant. In this respect, a cutoff of basal LS at 21 and 16% and basal CS at 31% are within the range of normality, and thus, these cutoffs have low specificity . In addition, the variability day to day of basal LS and basal CS is well known in clinical practice. Hence, as it has been stated and highlighted in previous submissions, the findings of the diagnostic performance of basal LS and CS or any strain parameter are of low clinical relevance to differentiating Al-Amyloidosis from CMH or HT and thus, these findings should play a secondary role in the manuscript.2) Taking into consideration the above-mentioned issues please re-edit and refine the abstract, conclusions, and the first paragraph of the discussion section.3) Please consider using an abstract like this:- Background: While patients with cardiac transthyretin amyloidosis are easily diagnosed with bone scintigraphy, the detection of cardiac light chain (AL) amyloidosis is challenging. Cardiac magnetic resonance (CMR) analyses play an essential role in the differential diagnosis of cardiomyopathies; however, limited data are available from cardiac AL-Amyloidosis. Hence, the purpose of the present study was to analyze the potential role of CMR in the detection of cardiac AL-amyloidosis.Methods: We included 35 patients with proved cardiac AL-amyloidosis and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination. The phenotype and degree of left ventricular (LV) hypertrophy and the amount and pattern of late gadolinium enhancement (LGE) were evaluated. In addition, global and regional LV strain parameters were also analyzed using feature-tracking techniques. Sensitivity and specificity of several CMR parameters were analyzed in diagnosing cardiac AL-amyloidosis.Results: The sensitivity and specificity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% and 100%, respectively. Likewise, the sensitivity and specificity of septal myocardial nulling prior to blood pool was 71% and 100%, respectively. In addition, a maximal LV end-diastolic septal wall thickness ≥ 14 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT . On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%).Conclusions: The findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. Hence, further larger studies are warranted to validate the findings from this study.4) Please consider using a conclusion like this:- The findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. In this respect, the sensitivity and specificity of diffuse septal subendocardial LGE in diagnosing cardiac AL-amyloidosis was 88% and 100% and of septal myocardial nulling prior to blood pool was 71% and 100%, respectively. In addition, a maximal LV end-diastolic septal wall thickness ≥ 14 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT . On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%). Hence, further larger studies are warranted to validate the potential key role of CMR in the diagnosis of cardiac AL-amyloidosis.5) Please consider using in the first sentence and paragraph of the discussion section the following statements:- Analyzing a cohort of 35 patients with proved cardiac AL-amyloidosis and two control groups constituted by 330 patients with hypertrophic cardiomyopathy (HCM) and 70 patients with arterial hypertension (HT), who underwent CMR examination, the findings from this study suggest that CMR could have an optimal diagnostic performance in the diagnosis of cardiac AL-amyloidosis. In this respect, the sensitivity and specificity of diffuse septal subendocardial LGE and of septal myocardial nulling prior to blood pool in diagnosing cardiac AL-amyloidosis was excellent. In addition, a maximal LV end-diastolic septal wall thickness ≥ 14 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT. On the other hand, a reduced global LV longitudinal strain (< 15%) plus apical sparing had a very low sensitivity (6%) in detecting AL-Amyloidosis, but with very high specificity (100%).https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step. </div> While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool,  16 May 2022We thank the editor for his thorough work and detailed suggestions for improving the manuscript. We have changed the abstract, the conclusion, and the first sentence and paragraph of the discussion section as requested. We only deviated from the editor's proposal on one point: Data show that a LV end-diastolic septal wall thickness ≥ 15 mm had better diagnostic performance to differentiate cardiac AL-amyloidosis from HT than a cut-off of 14 mm . However, if maximal end-diastolic wall thickness is analysed , the optimal cut-off is 14 mm . Since the maximal end-diastolic wall thickness ≥ 14 mm had the highest diagnostic performance of the above mentioned parameters, we decided to highlight it. Max. EDWT has also been added to tables 2 and 3.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 23 May 2022 <div> PONE-D-21-24457R5 </div>  <div> Potential clinical relevance of cardiac magnetic resonance to diagnose cardiac light chain amyloidosis. </div>  <div> PLOS ONEDear Dr. Vago,Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process. </div> A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'. <div> If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.Please include the following items when submitting your revised manuscript:We look forward to receiving your revised manuscript.Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONEJournal Requirements:Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.Additional Editor Comments:I would like to congratulate again to the authors for the effort made to improve this interesting study. In fact, the study is of high interest for the Journal and it will be for all medical community, given the originality the findings regarding the potential usefulness of CMR in the diagnosis of cardiac Al-Amyloidosis.Just one last minor correction is pending. In this respect, please delete in the text, abstract, conclusions, and tables the “new” analysis titled “maximal LV end-diastolic wall thickness” since in clinical practice almost never are measured all walls thickness but only the septal and posterior wall thickness, which are easy correlated with the measurements from echocardiography. By the way, as the authors have been stated, please change / correct in the abstract, conclusion, and first paragraph of the discussion section the sentence “In addition, a maximal LV end-diastolic wall thickness ≥ 14 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT ” by “In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT ”. </div>   25 May 2022Journal Requirements:Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.Authors’ answer:We have reviewed the reference list and made no changes.Additional Editor Comments:I would like to congratulate again to the authors for the effort made to improve this interesting study. In fact, the study is of high interest for the Journal and it will be for all medical community, given the originality the findings regarding the potential usefulness of CMR in the diagnosis of cardiac Al-Amyloidosis.Just one last minor correction is pending. In this respect, please delete in the text, abstract, conclusions, and tables the “new” analysis titled “maximal LV end-diastolic wall thickness” since in clinical practice almost never are measured all walls thickness but only the septal and posterior wall thickness, which are easy correlated with the measurements from echocardiography. By the way, as the authors have been stated, please change / correct in the abstract, conclusion, and first paragraph of the discussion section the sentence “In addition, a maximal LV end-diastolic wall thickness ≥ 14 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT ” by “In addition, a LV end-diastolic septal wall thickness ≥ 15 mm had an optimal diagnostic performance to differentiate cardiac AL-amyloidosis from HT ”.Authors’ answer:We thank again the editor for his thorough work and detailed suggestions for improving the manuscript. We have changed the abstract, the conclusion, and the first sentence and paragraph of the discussion section as requested. We have deleted max. EDWT in tables 2 and 3.AttachmentResponse to Reviewers.docxSubmitted filename: Click here for additional data file. 30 May 2022Potential clinical relevance of cardiac magnetic resonance to diagnose cardiac light chain amyloidosis.PONE-D-21-24457R6Dear Dr. Vago,We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at onepress@plos.org.If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact Kind regards,Daniel A. Morris, M.DAcademic EditorPLOS ONE 3 Jun 2022PONE-D-21-24457R6 Potential clinical relevance of cardiac magnetic resonance to diagnose cardiac light chain amyloidosis. Dear Dr. Vago:I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. onepress@plos.org.If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact plosone@plos.org. If we can help with anything else, please email us at Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staffon behalf ofDr. Daniel A. Morris Academic EditorPLOS ONE