Echocardiographic studies have shown an increase in LV mass with advanced age. However, autopsy and MRI studies demonstrate that with aging, LV mass is unchanged or slightly decreased, with a decrease in LV volume and an increase in wall thickness consistent with concentric remodeling. LV structural remodeling with aging may lead to an overestimation of LV mass in older adults when using standard echocardiography measurements and calculations. This study compared CT and echocardiographic LV mass calculation in younger and older patients and parameters associated with age-related LV remodeling.Same subject modality comparison of echocardiographic and cardiac CT LV measurement with derivation of LV mass was performed retrospectively. Echocardiographic measurements were performed by a single observer in accordance with European Association of Cardiovascular Imaging (EACI)/American Society of Echocardiography (ASE) guidelines. CT measurements were performed in end-diastole on multiplanar reformatted image planes corresponding to those typically used in echocardiography. Calculated CT measurements were based on automatic segmentation of heart chambers via edge-tracing algorithms.129 patients were identified. In patients age 65 and older, LV mass was significantly higher when calculated using echocardiographic measurements compared to CT. Patients 65 years of age and older were found to have increased average wall thickness measurements with echocardiography but not with CT. The discrepancy between calculated echo and CT LV mass was reduced when using the mid-septal instead of proximal wall width for the EACI convention.In the elderly, increased echo-derived LV mass may reflect remodeling rather than a true increase in LV mass. Echocardiographic assessment of left ventricular hypertrophy (LVH) predicts increased cardiovascular morbidity and mortality–3. The iCT and MRI-based measurement of LV mass utilizes edge-detection software to measure the inner and outer boundaries of the LV at different levels, and includes direct measurement of a 3-dimensional data set in the calculations, thus minimizing the geometric assumptions utilized in echocardiographic measurements. MRI based measurement is considered the “gold standard,” and has been shown to be highly reproducible . ValidatCross-sectional and longitudinal studies have found that calculated echocardiographic LV mass increases with advanced age, with up to 43% of otherwise healthy adults above age 70 considered to have LVH, 16. At This discrepancy may be explained by the change in LV geometry seen in older age patients. Structural remodeling of the left ventricle is part of the normal aging process, even in the absence of disease. With aging, LV length decreases with an increase in wall thickness, and theThis study compared assessment of LV mass by CT and echocardiographic in patients 65 and older vs. younger patients.This study was approved by the Helsinki committee of Hadassah University Medical Center (0480-14-HMO) and was performed in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The ethics committee waived the requirement for informed consent.The study was a same-subject modality comparison study of patients aged 18 years and older who underwent a cardiac gated-CT scan between January 2010 and December 2013 and underwent transthoracic echocardiography at our institution within 6 months before or after the CT scan. Subjects with poor image quality were excluded from the study.Demographic data were obtained from the computerized hospital patient management system.Echocardiographic studies were performed on Vivid 7, Vivid 9, Vivid I or Vivid Q systems (GE) or IE33 (Philips). Echocardiographic measurements were performed off-line by a single observer in accordance with ASE/EACI guidelines using thMeasurements made in the parasternal long axis view included: septal wall thickness (SWTd), inferolateral wall thickness (PWTd), and left ventricular internal dimension (LVID.) Mid septal wall thickness (MSWTd) was measured in the mid ventricle at the level of the papillary muscles. See . AortoseComputed measurements included:LV mass was calculated using the European Association of Cardiovascular Imaging linear cube formula:Cardiac CT was performed on the Philips 256 Brilliance Scanner  using prospective gating volumetric acquisition during diastole. CT measurements were performed in end-diastole on multiplanar reformatted (MPR) image planes corresponding to those typically used in echocardiography. One reaLeft ventricular out flow tract angulation was measured at the intersection of a line parallel to the aorta and a line from the mitral annulus to the apex .Aortoseptal angulation was measured at the intersection between a line parallel to the aorta and a line parallel to the septal wall .Calculated CT measurements were based on automatic segmentation of heart chambers via edge-tracing algorithms with manual correction when necessary, utilizing the Philips Intellispace Portal Comprehensive Cardiac Package v4.02.51006 (2012) .The volume of each heart segment was calculated by counting the overall pixels of the segment. The mass was then calculated by multiplying volume by myocardial density.Continuous variables are presented as mean ± standard deviation. Student’s t-test was used to compare differences between two groups. Pearson’s correlation was used to determine the correlation between measures. Systematic error and the degree of agreement were assessed with Bland Altman’s analysis, and pre129 patients were retrospectively identified and included in the study. Patient age ranged from 18 to 90, with a mean age of 59 ±17. 64% of the subjects were men, of whom 35% were 65 and older. 55% of the women were 65 and older. Median number of days between CT and echo studies was 3 with an interquartile range of 34 days.Comparison of basic LV measurements on echocardiography and CT was notable for an average proximal:mid septal ratio that was on average 11% higher (p = 0.0001) on echocardiography compared to CT. Additionally, average LV length was 8% higher  on CT when compared to echo . There wAverage LV mass was found to be 12% higher (174 vs 155g) when calculated using echocardiographic measurements compared to the CT edge-detection based measurement (P = 0.0043).A comparison between the older (age 65 years and above) and younger (age less than 65) patient group measurements using echocardiography and CT is presented in Several significant differences were found on imaging between the older and the younger groups. When comparing the older to the younger group, there was a greater increase in average proximal septal wall thickness measurements on echocardiography (25%:2.3mm) compared to CT (9.5%:1mm). Estimates of average LV length were found to be 5% (echo) and 7% (CT) shorter in the older age group compared to the younger patients. The aortoseptal angulation was decreased in the older age groups compared to the younger group on both echo and CT.Statistically significant increases were seen on echo when comparing average septal mid wall thickness (0.8mm) and inferolateral wall thickness (0.7mm) between older and younger patients, whereas non-significant decreases on mid septal and inferolateral wall thickness were seen on CT. No differences between age groups in either modality were seen in left ventricular internal diameter, volume or sphericity index.A comparison of calculated LV mass values for the different age groups as derived from echocardiography measurements and CT is presented in Absolute deviation of ASE LV mass from CT derived LV mass (19 ±52g) by age group is presented using Bland-Altman analysis in Average ASE LV mass increased with age in women  as well as men . When using CT derived LV mass, no such correlation was found  in either gender.Increased proximal septal wall thickness in the older age group is seen on both echo and CT, leading to a higher proximal:mid septal wall ratio  which was found to be positively correlated with age (R = 0.42). A negative correlation was found between the proximal:mid septal wall ratio and the LV length per CT ; as well as with the aortoseptal angulation . A strong positive correlation was found between the proximal:mid septal wall ratio and the difference between echo and CT derived LV mass .When using the mid-septal instead of proximal wall width for the ASE formula, the average LV mass was significantly lower for the older age group  but remained relatively unchanged for the younger group . Accordingly, the positive correlation between LV mass and age disappeared when calculations were performed based on the mid-septal wall thickness . Using the mid-wall thickness also eliminated the significant difference between LV mass on echo and on CT .Mountain plots for both age groups comparing the differences between CT and echocardiographic LV mass using proximal vs. mid septum measurements are shown in Bland-Altman plots startified by age group comparing CT and echocardiographic LV mass measurement using proximal and mid septum are presented in A similar correction of LV mass in the older age group was achieved when applying the proximal:mid septal ratio as a correction factor onto mass calculated from the ASE formula.This study demonstrates a discrepancy between echo and CT calculations of LV mass, primarily in patients age 65 and older. Our findings using CT data are similar to those of a large MR based study, which also demonstrated no increase in LV mass with older age . In thatWhen examining other LV measures for their correlation with age, this study found a decrease in LV length, increased thickening of the proximal septum with a lesser degree of thickening of the posterior wall. The LV was found to shorten with prominent thickening of the proximal septum with advancing age. This buckling phenomenon, known as discrete upper septal hypertrophy, also known as a septal bulge, has been well-described in the elderly, and is found in up to 10% of large echocardiographic cohorts., 27 ThisAs the ASE formula assumes a universal prolate ellipse shape of the LV, the formula is unlikely to take into account the septal bulge associated with aging. The original studies used to determine the equations for echo derived LV mass , 30, 31,When mid rather than proximal septal wall thickness was used in the ASE formula much of the echo-CT discrepancy was eliminated. The change in measurement region was insignificant for the younger age group, since the septum is usually the same width throughout in healthy young hearts, but it did make a difference in the presence of subtle thickening of the proximal septum, or in the presence of a discrete upper septal thickening. Clinical laboratories frequently measure distal to the septal knuckle, though the measurements may be done more proximally than what was performed in this study. As the proximal septal thickening is not necessarily focal but may have a somewhat gradual attenuation, this study suggests that even measurements immediately distal to the septal bulge may lead to overestimation of LV mass. Although mid-ventricular measurement did not specifically adjust for the geometric changes, the estimate of LV mass correlated better with the 3-dimensional assessment performed by CT. This study suggests that mid-septal rather than standard proximal septal measurement may increase the accuracy of echocardiographic assessment of LV mass, as the septal bulge reflects remodeling and compression rather than an increase in overall ventricular mass.This study's findings in no way minimize the well-established predictive power of echo-derived LV mass for cardiovascular prognosis and its positive correlation with age. Discrete upper septal wall thickening has been described as a risk factor even without LVH, though not independent of other risk factors like hypertension. The proWith further exploration of LV remodeling with echo and other imaging studies, it may be possible to derive other more accurate descriptors of LV remodeling that improve the prognostic capabilities of what is now described as echo-derived LV mass.Our study does have several limitations. MRI is considered the gold standard for measurements of LV mass , 11. CT The initial inclusion criteria were patients with a cardiac CT on record; this population may not reflect the overall general population. Patients with technically difficult echocardiographic studies were excluded from the study, which may lead to other biases in findings. Due to incomplete height and weight data, LV mass was not indexed to body size. However as both CT and echo measurements were performed on the same population of subjects, this should not bias the results. The 2D echocardiographic measurements chosen for the study were the measurements of the septum and inferolateral wall, which are obtained for the calculation of LV mass as per the ASE and the European Association of Cardiovascular Imaging. Further analyses using additional LV measurements may provide further insight.In this study comparing echo and cardiac CT, measurement of mid-septal wall thickness instead of proximal septal thickness significantly improved the correlation in calculations of LV mass in the elderly. This finding or alternative adjustments that correct for the 5–7% decrease in LV length should be evaluated in larger scale studies. This will also allow for appropriate gender analyses, as there are differences in remodeling between women and men. The ratio between the proximal and mid-septal wall thickness, and aortoseptal angulation may provide alternate methods of correcting LV mass.Based on this study’s findings, further understanding of age-related cardiovascular remodeling and how it is reflected on the various imaging modalities, will bring a deeper understanding of its prognostic implications.In conclusion, the calculated echocardiographic LV mass remains one of the most powerful predictors of cardiovascular prognosis but may not accurately reflect actual myocardial mass. Echocardiographic LV mass is likely to overestimate LV mass, particularly in older patients, likely due to LV remodeling with aging. Simple adjustments to the calculation may improve the correlation. Analysis of echo, CT and MR changes with aging may help clarify the patterns of remodeling and elucidate predictors of prognosis.S1 DatasetThis is the dataset of measurements taken from echo and CT stratified by age and gender.(XLS)Click here for additional data file.S1 FigA. Echo Parasternal long axis view: Left ventricular outflow tract angulation (133.5) and aortoseptal angulation (127.1). B. CT three chamber view–left ventricular internal dimension (green), left ventricular outflow tract angle (blue), aortoseptal angle (red)(TIF)Click here for additional data file.S2 FigCT four chamber view–left ventricular internal dimension (green), septal wall thickness (blue), posterior wall thickness (yellow), LV length (red)(TIF)Click here for additional data file. 11 Jul 2019PONE-D-19-15733Echocardiography Overestimates LV Mass in the Elderly as Compared to Cardiac CTPLOS ONEDear Dr. Zwas,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.https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.We would appreciate receiving your revised manuscript by Aug 25 2019 11:59PM. When you are ready to submit your revision, log on to If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocolsTo enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. 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If eligible, we will contact you to opt in or out.We look forward to receiving your revised manuscript.Kind regards,Giacomo PucciAcademic EditorPLOS ONEJournal Requirements:1. When submitting your revision, we need you to address these additional requirements.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found athttp://www.journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and http://www.journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf2. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.Comments to the Author1. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: NoReviewer #2: Yes**********2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: Yes**********3. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: NoReviewer #2: Yes**********4. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********5. Review Comments to the AuthorPlease 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. Reviewer #1: The main findings of this study is to correlate measurement of LV mass made by CT with traditional measurement made with echocardiography. Authors demonstrated that there is a good correlation with the 2 way of measurement but in elderly the echo systematically overestimate LV mass.The main problem with the study is related to the methodological and related to the wrong way of measurement of LV septal wall thickness. As they report in figure 1 they both use proximal and and mid septum measurements and when using mid septum measurement much of the echo-CT discrepancy is eliminated. But this is just because using the proximal measurement in old patients with septal bulge is just uncorrected and the main finding is justified by the high prevalence of septal bulge in old patients. This is a main issue to be solved.Minor Issue:- the characteristics of the study population is not described. Are all patients hypertensive? what was the reason of the CT scan? what was the prevalence of hypertension or aortic valve disease in the two groups? Have you excluded patients with severe aortic stenosis?- in the results section, please report the median and IQR of the time between CT and Echo. It seems that in some patients the echo and CT have been within more than 3 months-in the discuss section there is a long paragraph related to the fibrosis and increase cardiac collagen content. this is not pertinent to the this study.Reference: Please updateReviewer #2: In the article entitled "Echocardiography Overestimates LV Mass in the Elderly as Compared to Cardiac CT" the authors present the results of a cohort of 129 patients which had undergone both echocardiography and cardiac CT as part of their clinical workup. Analysis consisted of comparing LV geometric measurement between modalities in two cohorts of patients: younger than 65 yo and older. The main conclusion of this work is that LV mass correlates well between modalities, but agreement is better in young populations than in the older population. The authors convincingly argue that overestimation of echo-derived LV mass in the elderly is due to inaccurate assumptions of LV remodeling with age and briefly propose alternative methods to increase agreement between modalities.The article is well written and easy to follow. Study design, data analysis and statistical analysis are all appropriate. Nevertheless several important improvements should be made to the manuscript to help with readability and completeness:1) In general the tables should be reformatted to avoid character spillover between lines.2) Figures 3, 4 and 5, need to be reworked to make them more legible (larger font size), include measurement units on axis titles, and appropriate number of decimal places 3) Throughout the document measurement units are absent in several places (e.g. LV mass in g) or erroneous 4) Table 2 - should include LV mass data as this is the main metric discussed in the study.5) There is mention of LV volumes briefly in the Discussion section, but these data are not shown. Consider adding the data to the tables and analysis if available or explaining its absence in more detail.6) Readers may be interested in having measures LV mass correlation between modalities (for each cohort separately and combined). In addition, the linear regression function may be of interest as a method to calibrate between the two modalities. These data should be easily derived from the analysis in Figure 3.7) On the Bland-Altman plots - please add the p-value for mean difference (bias) different from 0? These are presented in the text and should correspond.8) The text refers to Figure 4 as an appendix - I believe this is a typo.9) Some readers may benefit of an explanation of why you analyzed only the septum and posterior wall thicknesses .10) The discussion mentions several adjustments to echo LV mass measurements to improve agreement with CT and CMR, but falls short of making firm recommendations. Should echo LV mass be calibrated with an age adjusted function? should mid septum measurements be used? Or perhaps this data is too preliminary to make a firm recommendation?**********what does this mean?). If published, this will include your full peer review and any attached files.6. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  11 Aug 201911 August 2019Joerg HeberEditor-in-Chief, PLOS ONE – Public Library of ScienceDear Prof. Heber:We very much appreciate the opportunity to revise and resubmit our paper “Echocardiography Overestimates LV Mass in the Elderly as Compared to Cardiac CT”PONE-D-19-15733to PLOS ONE. We have addressed the concerns of the academic editor and reviewers, as described below.Academic Editor:1. When submitting your revision, we need you to address these additional requirements.Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. Authors’ response: We have edited the manuscript to meet PLOS ONE’s style requirements.2. In ethics statement in the manuscript and in the online submission form, please provide additional information about the patient records used in your retrospective study. Specifically, please ensure that you have discussed whether all data were fully anonymized before you accessed them and/or whether the IRB or ethics committee waived the requirement for informed consent. If patients provided informed written consent to have data from their medical records used in research, please include this information.Authors’ response: We have added the IRB ethics committee number and added the statement:“The ethics committee waived the requirement for informed consent.”Response to ReviewersReviewer #1: The main findings of this study is to correlate measurement of LV mass made by CT with traditional measurement made with echocardiography. Authors demonstrated that there is a good correlation with the 2 way of measurement but in elderly the echo systematically overestimate LV mass.The main problem with the study is related to the methodological and related to the wrong way of measurement of LV septal wall thickness. As they report in figure 1 they both use proximal and and mid septum measurements and when using mid septum measurement much of the echo-CT discrepancy is eliminated. But this is just because using the proximal measurement in old patients with septal bulge is just uncorrected and the main finding is justified by the high prevalence of septal bulge in old patients. This is a main issue to be solved.Authors’ response: The authors agree with the reviewers that measurements performed according to present guidelines necessitate the inclusion of the septal bulge which leads to overestimation of LV mass. This study seeks to address precisely the concern raised by the reviewer.Minor Issues:- the characteristics of the study population is not described. Are all patients hypertensive? what was the reason of the CT scan? what was the prevalence of hypertension or aortic valve disease in the two groups? Have you excluded patients with severe aortic stenosis?Authors’ response: As this was a retrospective study, the indications for imaging were not available to the investigators. Patients with severe aortic stenosis were included. The investigators believe that this broadens the spectrum of ventricular hypertrophy seen in the study, making the findings more robust and reflecting clinically relevant situations where estimation of LV mass is of importance. - in the results section, please report the median and IQR of the time between CT and Echo. It seems that in some patients the echo and CT have been within more than 3 monthsAuthors’ response: The authors appreciate this concern. The manuscript was updated with the correct information in the first paragraph of the results section. The sentence in the results section now reads: “ Mean number of days between CT and echo studies was 3 with IQR of 34 days. “-in the discussion section there is a long paragraph related to the fibrosis and increase cardiac collagen content. this is not pertinent to the this study. Authors’ response:The authors respect the reviewers comment. The two sentences discussing fibrosis, and myocardial stiffness were removed from the manuscript.Reviewer #2: 1) In general the tables should be reformatted to avoid character spillover between lines.Authors’ response: The tables have been updated so as to avoid character spillover between lines.2) Figures 3, 4 and 5, need to be reworked to make them more legible (larger font size), include measurement units on axis titles, and appropriate number of decimal places Authors’ response: Figures 3,4, and 5 have been reworked with larger font sizes, measurement units and decimal places, as suggested by the reviewer. 3) Throughout the document measurement units are absent in several places (e.g. LV mass in g) or erroneous Authors’ response: The authors appreciate the reviewer’s comment and have placed the measurement units in the appropriate places in the document. 4) Table 2 - should include LV mass data as this is the main metric discussed in the study.Authors’ response: The authors agree that the LV mass data is the main metric in the document. We have, however, placed this data in Table 3, as it permits a clearer and more informative presentation of the core findings of the study. 5) There is mention of LV volumes briefly in the Discussion section, but these data are not shown. Consider adding the data to the tables and analysis if available or explaining its absence in more detail.Author’s response: The authors appreciate this comment as it is an important point. The data have been added to the table, and comments have been added in the results section. The addition reads: “There was no significant difference between LV volumes as calculated by echocardiography and CT.”and“No differences between age groups in either modality were seen in left ventricular internal diameter, volume or sphericity index.”6) Readers may be interested in having measures LV mass correlation between modalities (for each cohort separately and combined). In addition, the linear regression function may be of interest as a method to calibrate between the two modalities. These data should be easily derived from the analysis in Figure 3.Authors’ response: This comment is well taken. We have incorporated the reviewer’s comment into the results section and Figure 3 which now reads:“Relative correlation coefficient between ASE and CT derived LV mass was 0.89; correlations by age group are presented in the scatter plot in figure 3. “ 7) On the Bland-Altman plots - please add the p-value for mean difference (bias) different from 0? These are presented in the text and should correspond.Authors’ response: As the reviewer suggested ,this was incorporated into Figure 4. 8) The text refers to Figure 4 as an appendix - I believe this is a typo.Authors’ response; This was a typo and has been corrected. 9) Some readers may benefit of an explanation of why you analyzed only the septum and posterior wall thicknesses . Authors’ response: The authors chose to use the measurements that are standardly obtained in echocardiography laboratories and are required for calculation of LV mass according to ASE and European Association of Cardiovascular Imaging. . We added this valid point to the study limitations. 10) The discussion mentions several adjustments to echo LV mass measurements to improve agreement with CT and CMR, but falls short of making firm recommendations. Should echo LV mass be calibrated with an age adjusted function? should mid septum measurements be used? Or perhaps this data is too preliminary to make a firm recommendation? Authors’ response. The authors appreciate the reviewer’s acceptance of our findings. We believe that a larger follow up studies is needed to confirm these findings before making a firm recommendation for updating the guidelines to use mid-septal measurements. We appreciate the interest that you and the reviewers have taken in this manuscript.Attachmentresponse to reviewers.docxSubmitted filename: Click here for additional data file. 13 Sep 2019PONE-D-19-15733R1Echocardiography Overestimates LV Mass in the Elderly as Compared to Cardiac CTPLOS ONEDear Dr. Zwas,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 processhttps://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.We would appreciate receiving your revised manuscript by Oct 28 2019 11:59PM. When you are ready to submit your revision, log on to If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter.http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocolsTo enhance the reproducibility of your results, we recommend that if applicable you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see: Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). This letter should be uploaded as separate file and labeled 'Response to Reviewers'.A marked-up copy of your manuscript that highlights changes made to the original version. This file should be uploaded as separate file and labeled 'Revised Manuscript with Track Changes'.An unmarked version of your revised paper without tracked changes. This file should be uploaded as separate file and labeled 'Manuscript'.Please note while forming your response, if your article is accepted, you may have the opportunity to make the peer review history publicly available. The record will include editor decision letters (with reviews) and your responses to reviewer comments. If eligible, we will contact you to opt in or out.We look forward to receiving your revised manuscript.Kind regards,Giacomo PucciAcademic EditorPLOS ONE[Note: HTML markup is below. Please do not edit.]Reviewers' comments:Reviewer's Responses to QuestionsComments to the Author1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.Reviewer #1: (No Response)Reviewer #2: All comments have been addressed**********2. Is the manuscript technically sound, and do the data support the conclusions?The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. Reviewer #1: YesReviewer #2: Yes**********3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: YesReviewer #2: Yes**********4. Have the authors made all data underlying the findings in their manuscript fully available?PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: YesReviewer #2: Yes**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: YesReviewer #2: Yes**********6. Review Comments to the AuthorPlease 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. Reviewer #1: The comments have been correctly answered by the Authors, but the discuss section needs to be better focused on the main concern raised by the reviewer. IF the main point is to address the issue of incorrect measurement of LV mass in older people with septal bulge, this should be better underlined.Regarding the days between the ECHO and CT, please report median and not mean.Reviewer #2: The authors have generally addressed this reviewers’ comments, however few corrections are still required:1) Page 9 - reference "{Lang, 2015 #34}" should be corrected.2) Page 9 - after " Page 10 - comma missing after "IBM".4) Page 10 - Results - mean number of days between CT and echo was previously reported as 19 and now as 3. What is the reason for this change? Is there a typo and mean should be median???5) Figure 3 caption - the line of identity is descried as black but, on my screen, appears blue . Please ensure consistency.6) Figure 4 caption - refers to multiple Bland-Altman plots, but only 1 was included in this revision .7) Page 19 there is an erroneous line break before references .**********what does this mean?). If published, this will include your full peer review and any attached files.7. PLOS authors have the option to publish the peer review history of their article  digital diagnostic tool,  24 Sep 2019Dear Prof. Heber:We very much appreciate the opportunity to revise and resubmit our paper “Echocardiography Overestimates LV Mass in the Elderly as Compared to Cardiac CT”PONE-D-19-15733to PLOS ONE. We have addressed the concerns of the reviewers, as described below.Reviewer #1: The comments have been correctly answered by the Authors, but the discuss section needs to be better focused on the main concern raised by the reviewer. IF the main point is to address the issue of incorrect measurement of LV mass in older people with septal bulge, this should be better underlined.Authors response: Two sections have been added to the discussion section to address the concern of the reviewer.The first on page 17 now reads:“This buckling phenomenon, known as discrete upper septal hypertrophy, also known as a septal bulge, has been well-described in the elderly, and is found in up to 10% of large echocardiographic cohorts. This finding is associated with hypertension and diastolic dysfunction, but not with increased cardiovascular mortality.(28) It has been associated with increased LV mass in echocardiographic studies.(29)”The second on page 18 now reads:“As the proximal septal thickening is not necessarily focal but may have a somewhat gradual attenuation, this study suggests that even measurements immediately distal to the septal bulge may lead to overestimation of LV mass. Although mid-ventricular measurement did not specifically adjust for the geometric changes, the estimate of LV mass correlated better with the 3-dimensional assessment performed by CT. This study suggests that mid-septal rather than standard proximal septal measurement may increase the accuracy of echocardiographic assessment of LV mass, as the septal bulge reflects remodeling and compression rather than an increase in overall ventricular mass. “Regarding the days between the ECHO and CT, please report median and not mean.Authors response: The manuscript now reports the median and not the mean.Reviewer #2: The authors have generally addressed this reviewers’ comments, however few corrections are still required:1) Page 9 - reference "{Lang, 2015 #34}" should be corrected.Corrected in manuscript.2) Page 9 - after " Page 10 - comma missing after "IBM".Corrected in manuscript.4) Page 10 - Results - mean number of days between CT and echo was previously reported as 19 and now as 3. What is the reason for this change? Is there a typo and mean should be median???As pointed out by the reviewer, it should be median. Corrected in manuscript.5) Figure 3 caption - the line of identity is descried as black but, on my screen, appears blue . Please ensure consistency.Corrected in manuscript.6) Figure 4 caption - refers to multiple Bland-Altman plots, but only 1 was included in this revision .The second Bland-Altman was by mistake not uploaded in the initial revision, and will be uploaded now.7) Page 19 there is an erroneous line break before references .Corrected in manuscript.Thanks very much. 7 Oct 2019Echocardiography Overestimates LV Mass in the Elderly as Compared to Cardiac CTPONE-D-19-15733R2Dear Dr. Zwas,We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.Within one week, you will receive an e-mail containing information on the amendments required prior to publication. 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If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.The Reviewer #1: (No Response)**********5. Is the manuscript presented in an intelligible fashion and written in standard English?PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.Reviewer #1: Yes**********6. Review Comments to the AuthorPlease 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. Reviewer #1: (No Response)**********what does this mean?). If published, this will include your full peer review and any attached files.7. 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A substantial number of patients with Takotsubo syndrome (TTS) exhibit right ventricular (RV) dysfunction which has been associated with adverse outcome. The aim of this study was to assess the clinical and prognostic value of RV myocardial strain in TTS using cardiovascular magnetic resonance myocardial feature tracking (CMR-FT).CMR-FT was performed in a core laboratory to determine RV longitudinal strain in 134 TTS patients undergoing CMR in median 2 days after admission to 2 experienced centers. For comparison, RV involvement was evaluated by sole visual assessment concerning RV contraction abnormalities. Both approaches were analyzed regarding their long-term prognostic value.The peak global RV longitudinal strain was in median -19%. Segmental analyses located contraction abnormalities primarily in the apical parts of the right ventricle. Sole visual assessment identified 38 patients (28%) with RV involvement. These patients showed a numerically higher long-term mortality without reaching statistical significance . The optimal RV strain cutoff value for risk prediction was -17.24%. Stratification according to this threshold categorized 41% of TTS patients (n = 55) in the high-risk group which demonstrated a significantly increased long-term mortality compared to patients with preserved global RV strain .The assessment of RV myocardial strain using CMR-FT enables an accurate evaluation of RV involvement in TTS and represents a promising approach for optimized risk stratification. Takotsubo syndrome (TTS) is a form of acute heart failure due to circumscribed left ventricular (LV) contraction abnormalities constituting the morphological picture of apical, midventricular, or basal ballooning. –3 In addThis international multi-center study included 141 patients with TTS presenting to the University of Leipzig—Heart Center n = 125) or the King’s College London—St. Thomas’ Hospital (n = 16). All patients met the established diagnostic criteria for TTS: (a) hypokinesia, akinesia, or dyskinesia of the apical and/or midventricular or basal LV segments extending beyond a single epicardial vessel distribution territory with complete recovery during follow-up; (b) absence of acute plaque rupture or significant obstructive coronary artery disease explaining the extent of wall motion abnormalities; (c) new electrocardiographic changes or modest elevation in cardiac troponin levels; and (d) absence of pheochromocytoma and myocarditis. 5 or the  ClinicalThe study was conducted according to the principles of the Declaration of Helsinki and approved by the institutional review boards of the participating study centers . Written informed consent was obtained.CMR imaging was performed on 1.5- or 3.0-T magnetic resonance scanners using a standardized protocol which included (a) ECG-gated balanced steady state—free precession (SSFP) sequences for functional analyses; (b) T2-weighted triple short-tau inversion recovery images for edema assessment; and (c) early as well as late gadolinium enhancement sequences for the detection of inflammation or fibrosis/necrosis. , 19 One t-test. Non-normally distributed continuous data are presented as median . Testing for differences was performed with the Mann-Whitney U test. Since CMR-FT data were non-normally distributed, the Kruskal-Wallis test was used to compare TTS patients with different LV ballooning patterns. Correlation between LV ejection fraction and global RV strain was analyzed with the Spearman method. Comparison of global RV strain between the acute phase and after recovery within the cohort of patients with serial CMR data was performed with the Wilcoxon signed rank test. The prognostic implications of RV involvement were assessed by dichotomizing the study population according to (a) visual assessment and (b) global RV strain. The optimal cutoff point for global RV strain was defined with the Youden index after application of receiver operating characteristic curve. Long-term mortality was compared between groups using Chi-square test as well as Kaplan-Meier analysis and log-rank testing. Furthermore, hazard ratios (HR) and corresponding 95% confidence intervals (CI) were calculated. Statistical analyses were performed with SPSS . A two-sided probability ≤0.05 was considered statistically significant.Categorical variables are presented as number (percentage) of patients and were compared with the Chi-square test. The Shapiro-Wilk test was used to test continuous variables for normal distribution. If normally distributed, variables are reported as mean ± standard deviation and were compared with the student Of the 141 eligible TTS cases, 7 patients (5%) were excluded due to severe breathing artefacts in long-axis 4-chamber ECG-gated balanced SSFP images that did not allow for reliable tracking. Consequently, the final study population consisted of 134 TTS patients. Coronary angiography was performed in all patients and excluded significant obstructive coronary artery disease. CMR was performed in median 2 days  after initial presentation and confirmed TTS in all patients.Baseline characteristics are summarized in Global and segmental RV longitudinal strain values are reported in Serial CMR data in median 3.5 months  after the initial event were available in 21 TTS patients. Global RV longitudinal strain improved from -17%  to -25% . Consistently, these patients demonstrated significantly lower global RV strain values compared to patients without RV ballooning  after a median of 3.1 years . A total of 15 patients died (11.2%) due to non-cardiovascular (n = 6), cardiovascular (n = 4), or unknown causes of death (n = 5). Compared to patients without RV ballooning in visual assessment, long-term mortality was numerically higher in patients with RV involvement without reaching statistical significance . Using the cutoff for global RV strain resulted in a significantly increased long-term mortality in TTS patients with a strain value > -17.24% (10/50 [20.0%]) compared to ≤ -17.24% (5/71 [7.0%]; HR 2.98 [95% CI 1.02–8.73]; p = 0.03; The present study is the first to investigate RV myocardial strain in patients with TTS using CMR-FT. The results suggest that this novel technique allows for a reliable and optimized detection of RV involvement in patients with TTS and a more accurate risk stratification compared to sole visual assessment.Since its first description more than 25 years ago, TTS has been increasingly recognized worldwide and research efforts have been directed to enhance the understanding of the disease.  In the cThe feasibility of echocardiographic strain imaging to assess RV involvement in TTS has been investigated previously.  Our firsThe observation of severe complications and substantial mortality rates in various TTS populations challenged the previously prevalent opinion of a benign disease. –13 EfforThe present study is subject to an unavoidable selection bias regarding stable patients without contraindications to undergo CMR imaging. This resulted in a low-risk study population with a moderate number of events during follow-up which does not entirely reflect the actual prognosis of TTS patients. Nevertheless, since fewer events generally impede risk prediction our results underscore the potential of the utilized approach. The observed RV strain cutoff value for increased risk has to be validated in independent TTS cohorts. The lack of a healthy control population impedes the comparative interpretation of the observed RV strain values and recovery of myocardial deformation was only analyzed in a small sub-population of patients with follow-up CMR data. These aspects require further evaluation in future trials. The presence of tricuspid valve regurgitation was assessed in 4-chamber view CMR images which might be inferior compared to systematic echocardiographic evaluation in multiple views. Several software solutions to perform CMR-FT are available and demonstrated some differences in strain measurements. , 24 HoweThe assessment of RV myocardial deformation using CMR-FT enables an accurate evaluation regarding RV involvement in patients with TTS. Furthermore, this novel technique represents a promising approach for optimized risk stratification in TTS based on RV myocardial strain.


What is the variability in left ventricular ejection fraction (LVEF) as measured by different cardiac imaging modalities?r = 0.493 (for biplane echocardiography and cardiovascular magnetic resonance) to r = 0.660 (for cardiovascular magnetic resonance and gated single-photon emission computed tomography). There was no systematic overestimation or underestimation of LVEF for any modality.In this multicenter diagnostic study of 2032 patients with coronary artery disease and LVEF of 35% or less with imaging interpreted by core laboratories, correlation of LVEF between modalities ranged from There is substantial variability in LVEF assessment between modalities, which should be considered in trial design and clinical management. Clinical decisions are frequently based on measurement of left ventricular ejection fraction (LVEF). Limited information exists regarding inconsistencies in LVEF measurements when determined by various imaging modalities and the potential impact of such variability.To determine the intermodality variability of LVEF measured by echocardiography, gated single-photon emission computed tomography (SPECT), and cardiovascular magnetic resonance (CMR) in patients with left ventricular dysfunction.International multicenter diagnostic study with LVEF imaging performed at 127 clinical sites in 26 countries from July 24, 2002, to May 5, 2007, and measured by core laboratories. Secondary study of clinical diagnostic measurements of LVEF in the Surgical Treatment for Ischemic Heart Failure (STICH), a randomized trial to identify the optimal treatment strategy for patients with LVEF of 35% or less and coronary artery disease. Data analysis was conducted from March 19, 2016, to May 29, 2018.At baseline, most patients had an echocardiogram and subsets of patients underwent SPECT and/or CMR. Left ventricular ejection fraction was measured by a core laboratory for each modality independent of the results of other modalities, and measurements were compared among imaging methods using correlation, Bland-Altman plots, and coverage probability methods. Association of LVEF by each method and death was assessed.r = 0.601 (for biplane echocardiography and SPECT [n = 385]), r = 0.493 (for biplane echocardiography and CMR [n = 204]), and r = 0.660 (for CMR and SPECT [n = 134]). Bland-Altman plots showed only moderate agreement in LVEF measurements from all 3 core laboratories with no substantial overestimation or underestimation of LVEF by any modality. The percentage of observations that fell within a range of 5% ranged from 43% to 54% between different imaging modalities.A total of 2032 patients  with baseline LVEF data were included. Correlation of LVEF between modalities was In this international multicenter study of patients with coronary artery disease and reduced LVEF, there was substantial variation between modalities in LVEF determination by core laboratories. This variability should be considered in clinical management and trial design.NCT00023595Clinicaltrials.gov Identifier:  This multicenter diagnostic study determines the intermodality variability of left ventricular ejection fraction (LVEF) measured by echocardiography, gated single-photon emission computed tomography (SPECT), and cardiovascular magnetic resonance (CMR) in patients with coronary artery disease and left ventricular dysfunction. Whether LVEF is preserved or reduced currently forms the basis for the classification of patients with heart failure. Additionally, LVEF is an important predictor of prognosis in patients with myocardial infarction,14 As LVEF cut points are often the basis for clinical management decisions and trial eligibility, the implications of variability are substantial.Left ventricular ejection fraction can be determined by using multiple noninvasive imaging modalities, including echocardiography, cardiac magnetic resonance (CMR) imaging, and gated single-photon emission computed tomography (SPECT) imaging. All of these methods are routinely used for clinical decision making as well as research study enrollment. However, few data exist regarding the agreement between LVEF determined by these different methods. Prior studies have been limited by small numbers of participants, sometimes including only healthy volunteers, with imaging performed by a single center, and have compared only 2 imaging modalities.16 In this trial, any of 3 diagnostic methods  could be used by a local clinical site to measure LVEF in order to determine a patient’s trial eligibility. All patients enrolled in the STICH trial were required to have a baseline determination of LVEF, and a subset of patients underwent this determination by multiple modalities, including echocardiography, gated SPECT imaging, and/or CMR. All LVEF data obtained by echocardiography, CMR, and SPECT were measured by respective core laboratories. Therefore, the STICH trial provides a unique opportunity to correlate core laboratory assessment of LVEF data between different modalities.The Surgical Treatment for Ischemic Heart Failure (STICH) was an international multicenter trial aimed to compare coronary artery bypass grafting (CABG) and medical therapy for patients with heart failure, coronary artery disease (CAD), and left ventricular (LV) systolic dysfunction defined as LVEF of 35% or less.We conducted this study to determine the variability among imaging modalities and among different echocardiographic methods for assessing LVEF in patients with reduced LV systolic function, and to compare the association between these measurements and subsequent mortality in patients with ischemic cardiomyopathy.16 All patients provided written informed consent, as approved by the local institutional review board. Patients were enrolled at 127 clinical sites in 26 countries from July 24, 2002, to May 5, 2007; all had CAD amenable to CABG. Each of the 127 enrolling sites had to obtain institutional review board approval for STICH. We followed the Standards for Reporting of Diagnostic Accuracy (STARD) reporting guideline. A manual of operation for each modality was produced by the core laboratory for that modality to standardize imaging technique. Each site was required to submit 1 to 3 studies that fulfilled imaging requirements before enrollment. When studies did not meet these requirements, additional studies were requested until requirements were met. Patients with baseline imaging data received by the core laboratories for 1 or more imaging modalities were considered for inclusion. Patients with LVEF measured 90 days or more from study randomization or with study quality deemed by the core laboratory as being unusable for measurement were excluded. Determination of LVEF was performed by a separate core laboratory for each modality, independent of clinical information, treatment assignment, and data from other modalities.17 Each core laboratory provided oversight of quality control and assessed the quality of each study as excellent, good, fair, borderline, or unusable. Left ventricular end-systolic volume for each modality was indexed for body surface area.A total of 2136 patients with LVEF of 35% or less were enrolled in the STICH trial.Left ventricular ejection fraction was determined from LV end-diastolic volume and end-systolic volume using the following standard formula:18 using the Simpson method.17 Measurements were averaged over 3 cardiac cycles for patients in sinus rhythm, and 3 to 5 cardiac cycles for those in atrial fibrillation. If 2 apical views were not available for LV volume measurement, only 1 apical view (single-plane Simpson measurement) was used for determination of LVEF. For Simpson measurements, the LV endocardial border was traced contiguously from one side of the mitral annulus to the other side excluding the papillary muscles and trabeculations. Left ventricular ejection fraction was also estimated visually in most patients and when the definition of the LV endocardial border was not satisfactory from any of the apical views, visual estimate was the only echocardiographic determination of LVEF.19Echocardiography was performed at most sites for patient enrollment. Determination of LVEF was attempted according to the recommendations of the American Society of Echocardiography20Gated myocardial perfusion SPECT imaging, predominantly using sestamibi, was performed at clinical sites using a standard protocol. The gated raw projections were reconstructed by the radionuclide core laboratory using automatic software (AutoSPECT). When appropriate, an algorithm was applied to correct for motion. Resting studies accounted for 82% of measurements of LVEF; the remainder was obtained from poststress studies. Gated short-axis images were reviewed by a core laboratory technologist to optimize the accuracy of automatically determined LV contours, which were measured in end-systole and end-diastole. Manual adjustment addressed incorrect valve plane placement or contour deviations because of extracardiac radioactivity. Gated SPECT images were analyzed for LVEF by the radionuclide core laboratory using quantitative gated SPECT (QGS) software.21 A minimum of 2 data sets of short- and long-axis views were required to allow the core laboratory to select images of the highest quality. All gated data were displayed and reviewed by CMR core laboratory expert technologists to verify that LV boundaries were accurately demarcated. Short-axis images allowed determination of LVEF, using software developed by the CMR core laboratory at the University of Southern California (USC Cardio) and based on the Simpson method. Papillary muscles and trabeculations were considered to be part of the LV cavity. All short-axis data were reviewed by a technologist and adjusted manually, if necessary, to optimize accuracy of LV contour borders.Cardiac magnetic resonance imaging was performed by clinical sites that had the required CMR platform and software.22 and coverage probability.23 For determining LVEF by echocardiography, 3 methods  were included in this comparison. For the coverage probability analysis, which is an assessment of the proportion of participants where a prespecified level of agreement is present, agreement was assumed to be present if the LVEF measures being compared were within 5% of each other. Because LVEF measures with SPECT performed after stress could be influenced by ischemia or stunning, Bland-Altman plots were repeated after exclusion of the 18% with SPECT LVEF assessed following stress. To assess the impact of nonsimultaneous imaging, the number of days between performances of various modalities was considered. Finally, the prognostic effect of the different measures of LVEF for association with all-cause mortality was assessed using Cox regression models. In each case, the relationship of LVEF with mortality was modeled using restricted cubic spline functions.24 The relative risk of every 5% LVEF increment, expressed as hazard ratio and 95% confidence interval, was also calculated using the Cox model. The longest available follow-up information was used for each patient.25 This was a 2-sided test with a P value less than .05 required for significance.In this secondary study of the STICH trial, agreement of the core laboratory determinations of LVEF between modalities were assessed using 5 indices of variability: mean signed difference, mean absolute difference, Pearson correlation coefficient, Bland-Altman plots in which the mean of 2 measurements was plotted against the difference,P < .001). For those with excellent echocardiographic image quality, 36.6% had CMR . Compared with those who had only imaging by echocardiography, patients who also had imaging by SPECT or CMR more often had prior myocardial infarction , prior percutaneous coronary revascularization , greater anterior akinesia or dyskinesia , and lower New York Heart Association heart failure class . Left ventricular ejection fraction was measured by all 3 modalities in 127 patients; these patients compared with those with LVEF measured by 1 or 2 modalities more often had prior myocardial infarction , prior percutaneous coronary revascularization , greater anterior akinesia or dyskinesia , and lower New York Heart Association heart failure class .The population included 2032 patients (95.1%)  of the 2136 patients in the STICH trial who had LVEF assessed by at least 1 imaging modality. A baseline echocardiographic assessment of LVEF was received by the core laboratory in 1978 patients. Of these, 30 (1.5%) were excluded (imaging was performed >90 days before or after randomization in 24 cases and images were unusable in 6 cases). The remaining 1948 patients constitute the population studied with echocardiography. Biplane Simpson method of determining LVEF was performed in 897 (46%) of the 1948 patients. Only 3 patients (<1%) received echo contrast. Gated SPECT images for assessment of LVEF were received by the core laboratory in 790 patients. Of these, 16 (2.0%) were excluded (imaging was performed >90 days before or after randomization in 14 cases and images were unusable in 2 cases). The remaining 774 patients constitute the population studied with SPECT. Cardiac magnetic resonance assessment of LVEF was performed and received by the core laboratory in 425 patients. Of these, 7 (1.6%) were excluded (imaging was performed >90 days before or after randomization in 6 cases and 1 patient with out-of-range LVEF measurement that could not be confirmed by the CMR core laboratory). The remaining 417 patients constitute the population studied with CMR. Although most patients had echocardiography, the population included 84 patients who had only gated SPECT or CMR. Thus, 1107 (57%) of the 1948 patients with echocardiographic determination of LVEF also had LVEF determined by a second modality. Characteristics of the patients who were evaluable are shown in The median time interval between echocardiography and SPECT was 3.0 days ; between echocardiography and CMR was 2.0 days ; and between SPECT and CMR was 1.0 days . All patients qualified for participation in the study based on LVEF of 35% or less as assessed by the recruiting site. Thus, in some patients, an alternative modality of determination of LVEF yielded a result of 35% or greater. The mean (SD) for the LVEF by the core laboratories for each modality and for the various echocardiographic methods and the numbers and percentages with LVEF of 35% or less for each modality are shown in Among 1948 patients who had LVEF assessed by echocardiography, 1437 (73.8%) of them had both visual estimate and quantitative LVEF. The mean absolute differences between LVEF as determined by quantitative vs visual echocardiographic methods were all less than 5% . The mean absolute differences of LVEF by echocardiography and by other modalities were all greater than 5% but were lowest when biplane echocardiography, rather than other echocardiographic methods, was used (data not shown). Mean absolute difference of LVEF between modalities was 5.9% for biplane echocardiography and SPECT (n = 385), 7.3% for CMR and biplane echocardiography (n = 204), and 5.9% for CMR and SPECT (n = 134). The variability measurements were similar in women and men (data not shown). When only data for studies performed within 3 days were considered, results were similar: mean absolute difference 5.8% for biplane echocardiography and SPECT (n = 213), 7.2% for CMR and biplane echocardiography (n = 126), and 5.9% for CMR and SPECT (n = 84). Even when only data for studies performed the same day were considered, results were similar: mean absolute difference 5.2% for biplane echocardiography and SPECT (n = 68 ), 8.6% for CMR and biplane echocardiography (n = 33), and 4.1% for CMR and SPECT (n = 10). When only data for studies rated as having excellent or good quality were included, mean absolute differences were again similar: 5.6% for biplane echocardiography and SPECT (n = 317), 7.3% for CMR and biplane echocardiography (n = 184), and 5.7% for CMR and SPECT (n = 116). For the 127 patients in whom LVEF was measured by all 3 modalities, mean absolute difference between modalities was 6.0% for echocardiography and SPECT, 6.8% for CMR and echocardiography, and 5.9% for CMR and SPECT.Bland-Altman comparisons between modalities for determining LVEF are shown in the r = 0.898 for biplane vs visual, r = 0.876 for single plane vs visual, r = 0.874 for biplane and single plane) were higher than the correlations of LVEF assessed between different modalities .Correlations between LVEF as determined by quantitative vs visual echocardiographic methods . The prognostic effect of LVEF by modality and outcome was assessed. During a mean (SD) follow-up of 5.0 (3.3) years, there were 966 deaths. Among 1948 patients who had echocardiographic LVEF assessment, the prognostic effect of LVEF by method  was examined. Left ventricular ejection fractions measured by different methods were all statistically significant in terms of their prognostic value with respect to all-cause mortality. The HR (0.83-0.89) and the associated 95% confidence intervals for every 5% LVEF increment were all similar and below 1.00. This indicates increased LVEF was associated with decreased mortality risk, regardless which modality for determining LVEF was used  than were correlations between different modalities, which ranged from r = 0.493 (for biplane echocardiography and CMR) to r = 0.660 (for CMR and SPECT). The good correlation between visual estimation and measurement of echocardiographic images is of interest; however, it should be noted that visual estimates were made by echocardiographic core laboratory staff, who had advanced training and extensive experience. Results might be worse with less experienced reviewers. Although the 3 echocardiographic methods assessed were well correlated, LVEF by biplane method of disks should be used when feasible as it correlated best with LVEF by other modalities.Correlations between various methods of determination of LVEF by a single modality, echocardiography, were similar and better . Ultrasonography contrast agents, recommended for use when imaging is suboptimal,33 Data regarding changes in pharmacologic therapy or blood pressure between tests were not available. The median time interval between studies was 3 days between echocardiography and SPECT studies, 2 days between echocardiography and CMR studies, and 1 day between SPECT and CMR studies. Correlations were not consistently improved when tests were performed within 3 days or on the same day. Reproducibility of LVEF determination may be affected by image quality,34 but correlations were not improved when only images of good or excellent quality were included.Assessments by different modalities were not simultaneous, and intervening medical therapy or ischemia may have affected LVEF. Left ventricular ejection fraction can be affected by changes in preload, afterload, and LV remodeling.Although LVEF is a widely reported measurement and is the cornerstone of many treatment decisions, there is substantial variability in its measurement using different modalities, even when assessed by core laboratories. In this international study in which LVEF imaging was performed at 127 clinical sites using up to 3 widely used imaging modalities and LVEF was independently measured by core laboratories according to standard protocols, the variability in LVEF measurement exceeded 5% in about half of the patients. Variability was less for different methods of determining LVEF when a single imaging modality  was used. Longitudinal assessments of a given patient may best be accomplished using a single imaging modality.The diagnostic and prognostic importance of LVEF as well documented in numerous studies is not disputed. Left ventricular ejection fraction by each modality was associated with mortality. However, variability in LVEF assessment by different imaging modalities should be considered in trial design and clinical management. Considering this variability, cut points in LVEF should not be the sole basis for decision making.


These include natriuretic peptides, soluble suppressorof tumorigenicity 2 (ST-2), highly sensitive troponin, galectin-3, mid regional proadrenomedullin (MR-proADM), cystatin-C, interleukin-6 and procalcitonin. There is a needto further evaluate existing and novel markers for guiding therapy.Several biomarkers have been studied in the context of acute and chronic heart failure(HF). In 2016 the American Heart Association issued a statement on the Role ofBiomarkers for the Prevention, Assessment, and Management of Heart Failure.3 According to these guidelines other biomarkers such astroponins T and I, galectin-3 and ST-2 may add prognostic information in HFpatients.4The 2018 Brazilian Guidelines on Chronic and Acute Heart Failure recommends the use ofnatriuretic peptides with diagnostic and prognostic purposes.5 Nonetheless, NT-proBNP wasthe only biomarker to predict the risk of re-hospitalization due to cardiac causes.More recently Swedish investigators reported that elevated plasma levels of NT-proBNP,MR-proADM, copeptin, and cystatin C were associated with higher mortality afterdischarge in a cohort of 286 patients hospitalized for newly diagnosed or exacerbatedHF.5 In addition,they provided genetic evidence that this association was mediated at least partly viacoronary heart disease (CAD) and aortic valve stenosis.Lipoprotein(a) (Lp(a)) is a biomarker associated with increased risk of atheroscleroticdisease. In 2016 Kamstrup and Nordestgaard demonstrated a clear stepwise association ofelevated Lp(a) levels with increased risk of HF in a study with more than 98,000 danishparticipants.Arquivos Brasileiros de Cardiologia presents the paper ofJianlong et al.6 examining theprognostic value of Lp(a) in Chinese patients admitted for decompensated HF of ischemicorigin. An Lp(a) greater than 20,6 mg/dL was associated with 3 fold increase inreadmission for HF. Patients with higher Lp(a) levels also had higher NT-proBNP levels,higher NYHA class, lower left ventricle ejection fraction, more CAD. The results wereadjusted for theses covariates with a slight decrease in the hazard ratio.This issue of Lp(a) may be a prominent new biomarker in patients with HF of ischemic origin. Morestudies in different populations are needed to validate these results.


In this review, we discuss recent findings in SQTS molecular mechanisms and correlate these advances with clinical guidelines for SQTS diagnosis and treatment.Short QT syndrome (SQTS) is a myocardial conduction disorder characterized by a short QT interval on electrocardiogram and predisposition to familial atrial fibrillation and/or sudden cardiac death. Genetic SQTS is primarily caused by one or more cardiac ion channelopathies, in which either impaired depolarization currents, or enhanced repolarization currents, shorten cardiac action potential duration. Given that QT interval duration is not always predictive of arrhythmia burden and risk of death in SQTS, there is a need to understand the molecular mechanisms of the condition to improve risk prognostication and potential pharmacologic treatment. In the last decade, several computational advances and in vitro For instance, gain-of-function genetic mutations in voltage-gated potassium channel subunits KCNH2,6KCNQ1,7 and KCNJ27 are known to cause SQTS; conversely, loss-of-function mutations in cardiac voltage-gated calcium channels including CACNA1C,8CACNB2B,8 and CACNA2D9 cause SQTS and have phenotypic overlap with Brugada syndrome.9Short QT syndrome (SQTS) is a genetic cardiac channelopathy with a predisposition to life-threatening atrial and ventricular arrhythmias. Clinically, SQTS is associated with a variety of signs and symptoms including palpitations, presyncope, syncope, shortened atrial and ventricular effective refractory periods, and sudden cardiac death.10 hyperkalemia,11 acidosis,11 vagal or sympathetic hypertonia,11 effects of digitalis,12 and androgen misuse13 are all associated with QT interval shortening. In this review, we will discuss recent advances in understanding the consequences of genetic SQTS, pharmacotherapy, and diagnostic challenges. Given the relative paucity of genetic SQTS—fewer than 200 SQTS patients have been identified worldwide—preclinical models of cellular SQTS mechanisms are necessary for timely diagnosis and treatment of this potentially lethal disease.Aside from genetic channelopathies, other acquired causes of short QT interval must be considered before entertaining the diagnosis of genetic SQTS. For example, hypercalcemia,in silico modeling to determine the molecular underpinnings of QT interval shortening. The first mathematical model for human ventricular myocytes was established by Priebe and Beuckelmann in 1998.14 This model was derived via parameter variations from the Luo-Rudy phase II model (LR II model) of guinea pig ventricular cells.15 Priebe and Beuckelmann obtained experimental data for major ionic currents from human myocytes including IKr, IKs, ICa, Ito, and IK1, and adopted INa, INaCa, and INaK currents from the LR II model scaled to fit human ventricular cell data. Bernus et al. simplified the Priebe and Beuckelmann model by fixing the intracellular ionic concentrations and reformulating the currents that can be applied to any ionic model.16 This model is computationally efficient, less complex versus the second-generation Priebe and Beuckelmann ionic model, and more accurate for studying reentrant phenomena in human ventricular tissue.16 In 2004, ten Tusscher et al. developed a ventricular model that reproduced the detailed electrophysiological properties of single human ventricular cells for studying reentrant arrhythmias and performing large-scale spatial simulations.17 They have used new formulations for ionic currents and combined experimental data from human ventricular cells and ion channel expression experiments. While each of these approaches has been instrumental in understanding the mechanisms of ventricular arrhythmias, none of them incorporated the effects of specific genetic mutations. Thus, to better understand the molecular and cellular bases of specific mutations, experimental observations of ion channel-specific disease-causing mutations were included in subsequent in silico analyses.There is a lack of accurate cellular and tissue models of the human ventricles that recapitulate abnormal ion channel kinetics in SQTS. To overcome this limitation, several groups have established In silico models have replicated experimental data describing the loss of IKr inactivation, which leads to a gain in IKr function and shortens the QT interval in this syndrome.18 Priori et al. demonstrated that in the setting of SQTS 3 (SQT3), a gain-of-function mutation (D172N) in the KCNJ2 gene, encoding the inwardly rectifying KIR 2.1 (IK1) channel, is associated with an accelerated repolarization with a predisposition to ventricular reentry.19 Adeniran et al. reproduced this in SQTS 1 (SQT1)20 and SQT321 by simulating the data for wild-type and mutant versions of the KCNH2 and KCNJ2 genes. The group found that an N588K-hERG mutation in SQT1 initiates and maintains ventricular reentry, which increases the generation of reentrant spiral waves and stabilizes scroll waves in anatomical three-dimensional (3D) ventricular tissue.20 On the other hand, in SQT3, the gain-of-function KIR 2.1 D172N mutation increases IK1 ionic currents and increases arrhythmia risk due to enhanced tissue vulnerability, a reduced ventricular effective refractory period, and altered membrane excitability.21 Rice et al. developed a related myocyte contraction model primarily based on a cross-bridge cycling model of cardiac muscle contraction.22 This model simulates a wide variety of experimental cardiac muscle characteristics such as steady-state force-sarcomere length, force-calcium, and sarcomere length-calcium relations.22 At present, there is little information available regarding impaired cardiac contractile functions in SQTS patients. To address this limitation, Adeniran et al. coupled cardiac muscle contraction and ventricular cell models; SQTS mutations were simulated at the single-cell level and evaluated with respect to the potential electromechanical consequences.23 They also built experimental cellular data into predictions for mechanical activity in two-dimensional and 3D human ventricular tissue models, and these geometrical changes were incorporated into the electrophysiological computations.24 They found that shortening of the action potential in SQTS is associated with reduced ventricular mechanical function. Collectively, in silico modeling of the human heart has provided powerful insights into the mechanisms of arrhythmias and genetic consequences of physicomechanical interactions in SQTS.hERG K+ channel protein was identified in families with heritable SQTS. El Harchi et al. electrophysiologically characterized the T618I mutation, which exerts a more modest effect on cardiac action potential repolarization compared with other IhERG variants of SQT1.25 Additionally, the group was able to inhibit IhERG-T618I in SQT1 using quinidine, disopyramide, D-sotalol, and flecainide.25 Antzelevitch et al. genetically screened 82 probands with Brugada syndrome for ion channel abnormalities.8 They performed site-directed mutagenesis experiments for wild-type and mutant CACNB2B, CACNA2D1, and CACNA1C channels and electrophysiologically characterized the mutations in mammalian cells. They found that loss-of-function mutations in α1- and β-subunits encoding the cardiac L-type calcium channel are associated with QT interval shortening.8 Tse et al. characterized the ventricular arrhythmogenic properties of hyperkalemia in Langendorff-perfused mouse hearts.26 They found that hyperkalemia exerted proarrhythmic effects by shortening the effective refractory period and action potential duration, which leads to a decrease in the excitation wavelength and predisposes to reentry of ventricular tachyarrhythmias.26 In contrast, hypercalcemia exerted antiarrhythmic effects by changing the ventricular effective refractory period, which is in accordance with the ventricular effective refractory period/latency ratio and critical intervals.26The mechanism of arrhythmogenesis in SQTS is less clear, and few SQTS cohorts have been identified. At present, electrophysiologic testing and genetic screening of patients and their families are performed to improve risk stratification for affected kindred. Several groups have established a link between preclinical models and a pharmacogenetic approach to treating patients with SQTS. For instance, a gain-of-function (T618I) mutation in the torsades de pointes, Extramiana and Antzelevitch developed a canine left ventricular wedge model that showed a heterogeneous distribution of action potentials in the left ventricular wall, increasing the transmural dispersion of repolarization.27 The group found that transmural dispersion is critical for inducing polymorphic ventricular tachycardia and is a significant trigger for SQTS-related arrhythmias.27 Further work by the group in 2008 evaluated a left ventricular wedge model that recapitulates electrocardiographic and arrhythmic manifestations of SQT1.28 The inclusion of potassium channel “openers” increases the transmural dispersion repolarization and reduces the ventricular effective refractory period.28 Evidence is also accumulating that patient-specific induced pluripotent stem cells could be used to test the potential of antiarrhythmic agents to prolong the QT interval.31 This technology could directly model rare forms of SQTS in patients and kindred for whom a pharmacogenetics approach is unclear. Experimental models have been critical to understanding SQTS pathogenesis and potential therapies.Given that patients with SQTS are prone to the development of polymorphic ventricular tachycardia, including 33 In 2011, Gollob et al. proposed four diagnostic criteria for SQTS, focusing on ECG findings of shortened QT interval, clinical history, family history, and genotyping.3 Initially, genetic screening and identification of the short QT interval on ECG would be helpful for affected individuals. Certainly, this will enable identification of the abnormal genetic variants that can be targeted for the optimal diagnosis and could help reduce the prevalence in at-risk family members. The European Society of Cardiology recently developed guidelines on SQTS diagnosis 34The number of identified congenital SQTS cohorts is small, and establishing the diagnosis is usually quite challenging. Additionally, there is no proper consensus on the exact cutoff value for shorter corrected QT intervals that could confer a higher risk of cardiac arrhythmia.36 Patients who have survived a previous cardiac arrest and/or those with documented occurrence of spontaneous sustained ventricular tachyarrhythmias with or without syncope have been suggested as candidates to receive ICDs for secondary prevention of cardiac arrest (class I recommendation) .34 Since ICD therapy has been implemented for high-risk patients, the recurrence rate of cardiac arrest has been estimated at 10% per year.32 However, an ICD implant may not be feasible in all patients, especially in those who are very young (infants) SQTS patients with severe phenotypes. Pharmacotherapy is a primary adjunctive modality to ICD to reduce arrhythmia burden and reduce potential ICD shocks. However, antiarrhythmic drug use requires a comprehensive risk stratification and management plan. Asymptomatic patients also require risk stratification, in which ICD implantation and/or pharmacotherapy is recommended. QT prolongation can be achieved by pharmacological agents that reduce outward potassium currents and/or enhance the inward flow of current. Gaita et al. tested four different antiarrhythmic agents  to prolong the QT interval and prevent arrhythmia recurrence in SQT1 patients.37 More specifically, hydroquinidine prolonged QT intervals to near-normal levels, from 263 ± 12 ms to 362 ± 25 ms, and was associated with an increase in ventricular effective refractory period, as well as the prevention of ventricular fibrillation.37 Notably, hydroquinidine-treated patients were followed for a year and remained asymptomatic without any episodes of ventricular arrhythmia. This suggests that hydroquinidine is the most effective antiarrhythmic agent for SQTS patients to date. Milberg et al. demonstrated that the antiarrhythmic effects of quinidine in SQTS are due to less repolarization dispersion and prolonged post-repolarization refractoriness.38 Another antiarrhythmic agent, flecainide, slightly prolonged the QT interval primarily due to prolongation of the QRS complex, which may be the second choice for patients who are intolerant to quinidine therapy.37 In contrast, sotalol and ibutilide have no effect on QT interval in this population.37 Propafenone prevents paroxysms of atrial fibrillation without arrhythmia recurrence in SQTS patients.36 The Vaughn-Williams class III antiarrhythmic drug nifekalant, a pure IKr blocker, is effective in treating ventricular tachycardia storm by prolonging atrial and ventricular effective refractory periods and normalizing the QT interval.40 In SQT1, disopyramide (a class Ia antiarrhythmic against the hERG channel) is effective in that it prolongs the QT interval and ventricular refractory period and abbreviates the Tpeak to Tend interval.41 Isoproterenol infusion has been effectively used to manage electrical storm in SQTS.42 Existing pharmacotherapy options for SQTS patients are still poorly defined due to the small number of affected cohorts, but, based on the accumulating evidence and guidelines, hydroquinidine may be the ideal choice.To date, an implantable cardioverter-defibrillator (ICD) is the first-line therapy for patients with symptomatic SQTS.43 At the single-cell level, they found that amiodarone use increased action potential duration, the effective refractory period, and the QT interval. This suggests that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis in SQT3 patients. The same group assessed the antiarrhythmogenic effects of E-4031, disopyramide, and quinidine on SQT1 using a mathematical model of human ventricular electrophysiology.44 They found that E-4031 and disopyramide exerted no significant effects on ventricular cell action potential duration, even at 90% repolarization, as compared with quinidine. Additionally, quinidine prolonged the QT interval by decreasing the T-wave amplitude, increasing the effective refractory period, and consequently terminating the reentrant ventricular arrhythmias in SQTS.44 They also simulated the pharmacological actions of quinidine that exhibited antiarrhythmic effects in SQT1. Their results revealed a causal link between quinidine and QT interval prolongation in SQT1, indicating that it may be a first-line antiarrhythmic agent for SQT1. Ji et al. developed an experimental compound, PA-6, which is a new drug candidate for targeting the inward rectifier potassium current IK1.45 They found that the KCNJ2 gain-of-function mutations V93I and D172N in the KIR 2.1 ion channel do not impair PA6-mediated inhibition of IK1. Additionally, PA6 enhances KIR 2.1 ion channel protein expression and intracellular accumulation, making it a drug candidate for SQT3. The clinical application of insights from molecular modeling and preclinical results could effectively translate information for the benefit of SQTS and congenital atrial fibrillation patients.To improve pharmacologic options for SQTS, we require a better understanding of arrhythmia mechanisms, which will allow us to tailor rational drug designs to specific underlying ion channelopathies. Computational models have been successfully utilized to assess effects on drug–ion channel interactions and screen the arrhythmogenic potential of pharmacological agents. Luo et al. utilized computational modeling to assess the antiarrhythmic effects of amiodarone on human ventricular electrophysiology in SQT3.in silico investigations and preclinical electrophysiological studies, we are better able to predict possible candidate drugs to treat genetic SQTS. That being said, a pharmacogenomic approach to SQTS is still in its infancy, and more studies are required. This review highlighted how the genetic characterization of cohorts with SQTS allows for the prediction of arrhythmia mechanisms and drug–gene interactions. Diagnosis remains challenging and is primarily based on ECG measurements of the QT interval, clinical and familial history, and genetic findings. Currently, the ICD is the first-choice prophylactic therapy for symptomatic SQTS patients at risk for sudden arrhythmic death. In recent years, various antiarrhythmic agents have been tested to prolong QT intervals, including flecainide, sotalol, ibutilide, and hydroquinidine. Numerous studies have indicated that hydroquinidine is the most promising antiarrhythmic agent. Future research should also focus on other factors such as electrolyte imbalances, epigenetics, and competitive physical activity in SQTS patients. This will help facilitate more timely diagnosis and is crucial to prevent the recurrence of life-threatening arrhythmias.SQTS is an inherited ion channelopathy characterized by high incidences of life-threatening atrial and ventricular arrhythmias and sudden cardiac death. The small number of cohorts and the overlapping range of ECG values between cohorts and healthy individuals sometimes make this syndrome difficult to diagnose. Despite the challenges, however, with the emergence of