Left Atrial Volume Correlates with Mitral Annulus Size: An MDCT Study

Round 1

Reviewer 1 Report

Here, Dr. Cismaru and colleagues investigated the association between the dimensions of the left atrium (LA) and the mitral annulus (MA) based on CT imaging in patients with atrial fibrillation undergoing catheter ablation. The authors find a relatively strong correlation between different parameters of LA and MA size and conclude that “Dilation of the left atrium leads to increased mitral annulus diameters and area in patients with paroxysmal/persistent AF.”

Conceptually, the association between LA diameter and properties of the mitral annulus are well established, with several studies relating alterations in MA size to MA dysfunction and MA dysfunction to LA size. The authors claim that LA dilation leads to increased MA diameter, but this cannot be concluded from the current retrospective cross-sectional study design. I don’t doubt that there is an association between both parameters, but causality cannot be inferred and it may very well be that subtle subclinical MV dysfunction in the presence of larger MA may drive LA dilation. As such, the current study provides little novel insight. However, as indicated by the authors, most of the previous studies were based on echocardiography. Furthermore, the current study provides a more complete assessment of different parameters related to LA and MA size. Nonetheless, several issues need to be addressed:

1) Throughout the manuscript, statements suggesting a causal relation between LA diameter and MA size need to be rephrased, as this cannot be deduced from the current data. Examples include, but are not limited to: title lines 1-2; abstract lines 52-54; discussion lines 166-167; discussion lines 212-214

2) The authors should provide a multivariable analysis to analyze whether there is an independent relationship between LA diameter and MA size (in particular, independence from age, body size and AF type, all of which are known to affect LA and/or MA dimensions, should be assessed).

3) It is not clear why information on AF ablation is provided. All of the results could have similarly been obtained in patients not selected for AF ablation, as long as CT images are available. If ablation provided the clinical indication for performing CT then only this has to be mentioned.

4) The quality of figures 2-3 needs to be improved. Resolution is suboptimal (it appears to be a screenshot rather than a true plot of the data), units are missing from the axis labels, lines surrounding the figures should be removed.

5) Lines 174-176: “Because the discrepancies within the means are not clinically significant, the two techniques of LAV estimate can be employed interchangeably and a simple mitral valve area measurement can thus predict the dilation of the left atrium”. It should be noted that this only applies for the current group of patients without LV dysfunction or mitral valve pathology.

6) Lines 231-233: For the balance of the manuscript, it may be good to emphasize that the relationship between LA diameter/volume and MA size is likely bidirectional, with MV dysfunction promoting atrial stretch and dilatation and atrial dilatation due to subsequent AF potentially increasing MA size and dysfunction. In this regard, the impact of irregular ventricular contraction (irregular RR intervals) during AF on the stretch of the MA is also of interest.

7) More affiliations are provided in the affiliation list than numbers in the list of authors

8) Please fix numbering of headings (both introduction and materials and methods currently start with 1.)

Author Response

We'd like to express our gratitude to the three reviewers for their thoughtful review of the manuscript. They raise important issues, and their inputs are very helpful for improving the manuscript. We agree with almost all their comments, and we have revised our manuscript accordingly.

We marked with red color the modifications we have made in the revised manuscript.

Please, find below the referees’ comments repeated and our responses inserted in after each comment.

Reviewer No 1.

Comments and Suggestions for Authors

Here, Dr. Cismaru and colleagues investigated the association between the dimensions of the left atrium (LA) and the mitral annulus (MA) based on CT imaging in patients with atrial fibrillation undergoing catheter ablation. The authors find a relatively strong correlation between different parameters of LA and MA size and conclude that “Dilation of the left atrium leads to increased mitral annulus diameters and area in patients with paroxysmal/persistent AF.”

Conceptually, the association between LA diameter and properties of the mitral annulus are well established, with several studies relating alterations in MA size to MA dysfunction and MA dysfunction to LA size. The authors claim that LA dilation leads to increased MA diameter, but this cannot be concluded from the current retrospective cross-sectional study design. I don’t doubt that there is an association between both parameters, but causality cannot be inferred and it may very well be that subtle subclinical MV dysfunction in the presence of larger MA may drive LA dilation. As such, the current study provides little novel insight. However, as indicated by the authors, most of the previous studies were based on echocardiography. Furthermore, the current study provides a more complete assessment of different parameters related to LA and MA size. Nonetheless, several issues need to be addressed:

1) Throughout the manuscript, statements suggesting a causal relation between LA diameter and MA size need to be rephrased, as this cannot be deduced from the current data. Examples include, but are not limited to: title lines 1-2; abstract lines 52-54; discussion lines 166-167; discussion lines 212-214

Response to Comment 1: We agree with the reviewer's assessment. We can't prove a direct link between LA and MA size. As a result, we replaced the phrase within the text and also the title:  Left Atrial Volume Correlates with Mitral Annulus Size. A MDCT study.

 2) The authors should provide a multivariable analysis to analyze whether there is an independent relationship between LA diameter and MA size (in particular, independence from age, body size and AF type, all of which are known to affect LA and/or MA dimensions, should be assessed).

Response to Comment 2: In multivariate analysis, transverse diameter of the mitral valve  (p=0.004, 95% CI=1.8-9.4) was independently associated with LA volume,  after adjusting for confounding factors sex, age and type of atrial fibrillation. 

3) It is not clear why information on AF ablation is provided. All of the results could have similarly been obtained in patients not selected for AF ablation, as long as CT images are available. If ablation provided the clinical indication for performing CT then only this has to be mentioned.

Response to Comment 3: We agree with the reviewer. We changed the Materials and Methods section and catheter ablation was mentioned as clinical indication for computed tomography.

4) The quality of figures 2-3 needs to be improved. Resolution is suboptimal (it appears to be a screenshot rather than a true plot of the data), units are missing from the axis labels, lines surrounding the figures should be removed.

Response to Comment 4: Thank you. We changed figures 2 and 3.

5) Lines 174-176: “Because the discrepancies within the means are not clinically significant, the two techniques of LAV estimate can be employed interchangeably and a simple mitral valve area measurement can thus predict the dilation of the left atrium”. It should be noted that this only applies for the current group of patients without LV dysfunction or mitral valve pathology.

Response to Comment 5:  We added the following text: „This applies exclusively to patients without LV dysfunction, organic valvular disease  or  replacement of the mitral valve.” 

6) Lines 231-233: For the balance of the manuscript, it may be good to emphasize that the relationship between LA diameter/volume and MA size is likely bidirectional, with MV dysfunction promoting atrial stretch and dilatation and atrial dilatation due to subsequent AF potentially increasing MA size and dysfunction. In this regard, the impact of irregular ventricular contraction (irregular RR intervals) during AF on the stretch of the MA is also of interest.

Response to Comment 6: We added the following text: “The relationship between LA volume and MA size is likely bidirectional: Mitral valve dysfunction causes atrial stretch with cellular and tissue  alterations that can lead to  fibrosis[1]. Atrial stretch leads to conduction slowing across the pulmonary veins-left atrial junction, predisposing to local reentry[2]. The effective refractory period of the left atrium is affected by heterogeneous tissue changes which further increase the risk of atrial fibrillation. Subsequently AF increases LA size, mitral annulus diameter and leads to MV dysfunction and regurgitation.”

7) More affiliations are provided in the affiliation list than numbers in the list of authors

Response to Comment 7: Thank you. We corrected the affiliations.

8) Please fix numbering of headings (both introduction and materials and methods currently start with 1.)

Response to Comment 8: Thank you. We corrected the numbering.

[1] Quinn TA, Kohl P. Cardiac Mechano-Electric Coupling: Acute Effects of Mechanical Stimulation on Heart Rate and Rhythm. Physiol Rev. 2021 Jan 1;101(1):37-92. doi: 10.1152/physrev.00036.2019. Epub 2020 May 7. PMID: 32380895.

[2] Walters TE, Lee G, Spence S, Larobina M, Atkinson V, Antippa P, Goldblatt J, O'Keefe M, Sanders P, Kistler PM, Kalman JM. Acute atrial stretch results in conduction slowing and complex signals at the pulmonary vein to left atrial junction: insights into the mechanism of pulmonary vein arrhythmogenesis. Circ Arrhythm Electrophysiol. 2014 Dec;7(6):1189-97. doi: 10.1161/CIRCEP.114.001894. Epub 2014 Nov 5. PMID: 25516579.

Reviewer 2 Report

The authors assessed the link between left atrial dilation and the dimensions of the mitral annulus. They concluded, that dilation of the left atrium leads to increased mitral annulus diameters and area in patients with 53
paroxysmal/persistent AF.

I have the following concerns:

1. The small size of the cohort, single-site, and retrospective study seriously limits its value.
2. How many patients had the second or another catheter ablation?
3. Definitions of normal mitral annulus, and left atrium should be included.
4. What was the patient's mean weight or body mass index?

Author Response

We'd like to express our gratitude to the three reviewers for their thoughtful review of the manuscript. They raise important issues, and their inputs are very helpful for improving the manuscript. We agree with almost all their comments, and we have revised our manuscript accordingly.

We marked with red color the modifications we have made in the revised manuscript.

Please, find below the referees’ comments repeated and our responses inserted in after each comment.

Reviewer No 2.

Comments and Suggestions for Authors

The authors assessed the link between left atrial dilation and the dimensions of the mitral annulus. They concluded, that dilation of the left atrium leads to increased mitral annulus diameters and area in patients with 53
paroxysmal/persistent AF.

I have the following concerns:

1. The small size of the cohort, single-site, and retrospective study seriously limits its value.

Response to Comment 1: The retrospective, single-site study type is acknowledged as an essential weakness in the Limitations section. Because of the small size of the cohort, it is possible that significant correlations between the mitral valve and the size of the left atrium will not be discovered.

1. How many patients had the second or another catheter ablation?

Response to Comment 2: A second ablation procedure was performed in  3 of the 107 patients.

1. Definitions of normal mitral annulus, and left atrium should be included.

Response to Comment 3: Stojanovska's work described normal left atrium in MDCT

for both men and women[1]: 74 ml for women, 86 ml for men and 80 ml for all subject.

According to Grover et al.[2] and  Naoum et al[3]. normal mitral valve dimensions differ between male and female: area=8.4+/-1.2 for female;  9.3+/-1.6 for male; and 8.9 +/- 1.5 cm² overall; perimeter=107.0+/-7.0 mm for female, 113+/-10 mm for male and  110+/-9.0 mm overall; longitudinal diameter=36.1+/-2.9 for female, 38.8+/-3.9 for male and  37.6+/-3.7 mm  overall; transversal diameter = 27.1+/-2.3 for female; 27.8+/0 3.0 for men and 27.5+/-2.7 mm  overall.

1. What was the patient's mean weight or body mass index?

Response to Comment 4: Mean weight was 80.3 +/-15.5 kg and mean BMI=29.6+/-6.0

[1] Stojanovska J, Cronin P, Gross BH, Kazerooni EA, Tsodikov A, Frank L, Oral H. Left atrial function and maximum volume as determined by MDCT are independently associated with atrial fibrillation. Acad Radiol. 2014 Sep;21(9):1162-71. doi: 10.1016/j.acra.2014.02.018. Epub 2014 Jul 9. PMID: 25022763.

[2] Grover R, Ohana M, Arepalli CD, Sellers SL, Mooney J, Kueh SH, Kim U, Blanke P, Leipsic JA. Role of MDCT Imaging in Planning Mitral Valve Intervention. Curr Cardiol Rep. 2018 Mar 6;20(3):16. doi: 10.1007/s11886-018-0960-4. PMID: 29511849.

[3] Naoum C, Leipsic J, Cheung A, Ye J, Bilbey N, Mak G, Berger A, Dvir D, Arepalli C, Grewal J, Muller D, Murphy D, Hague C, Piazza N, Webb J, Blanke P. Mitral Annular Dimensions and Geometry in Patients With Functional Mitral Regurgitation and Mitral Valve Prolapse: Implications for Transcatheter Mitral Valve Implantation. JACC Cardiovasc Imaging. 2016 Mar;9(3):269-80. doi: 10.1016/j.jcmg.2015.08.022. Epub 2016 Feb 17. PMID: 26897676.

Author Response File: Author Response.docx

Reviewer 3 Report

General comments:

This is a retrospective study of 107 patients with multidetector CT (MDCT) prior to AF ablation evaluating the association of LA and mitral annulus (MA) size measured on Carto 3. The LA vol. was 139±56 ml and the MA diameters were 29.9±5.3 mm and 41.9±7.6 mm resulting in an area of 14±5 qcm. There was a significant correlation of the transverse MA with the AP-LA diameter (R=0.59), the longitudinal MA with the LL-LA diameter (R=0.576) and the MA area with the LA volume (R=0.639). Thus the authors conclude that LA dilation leads to greater MA size.

The manuscript is interesting. The introduction, the methods and the results are adequate; the discussion and the conclusions are supported by the data but they could be improved by some clarifications. Thus, some issues should be addressed before considering publication in the journal of Applied Sciences:

Specific comments:

1. Methods/Results/ Discussion: Given the nature of the study, the observed association cannot prove causation. The authors report that they excluded patients with mitral regurgitation but a functional regurgitation was not explicitly evaluated or excluded. Therefore, one cannot say for sure that LA dilatation leads to MA dilation or vice versa. Please correct and comment
2. Methods: Please provide a better description of the measurement methods, esp. for the MA and LA diameters. How did you ensure standardization of measurements? Are there any inter- or intra-observer variability measurements? What were the guiding points for setting the distance measurement points? Are they amenable to bias due to rotation of the heart axis?
3. Results: Please provide some more information or comment on baseline characteristics of the patients that could influence the results of the study e.g. LV systolic/diastolic function and size
4. Discussion: “The longitudinal diameter was 4.4 mm in 209 patients with functional MR and 3.9 mm in control subjects” -> Both are less than half a centimeter and not realistic for MA. Please correct (is it 44 and 39 mm?)
5. Figure 1: Please annotate which diameter is where on the figure. Consider using the “capture” tool by Carto 3 to create a Figure of higher quality/clarity.
6. Figure 3: The confidence intervals (1.96-SD lines) seem asymmetrical. Please explain and/or correct. Also consider reporting what the x-axis stands for (mean of predicted LAV?)
7. Please run a check for spelling/grammatical errors: e.g. the word “disparity” has usually an economic reference – consider discrepancy instead

Author Response

We would like to thank both reviewers for their thoughtful review of the manuscript. They raise important issues and their inputs are very helpful for improving the manuscript. We agree with all their comments and we have revised our manuscript accordingly.

We marked with red color the modifications we have made in the revised manuscript.

Please, find below the referees’ comments repeated and our responses inserted in after each comment.

General comments:

This is a retrospective study of 107 patients with multidetector CT (MDCT) prior to AF ablation evaluating the association of LA and mitral annulus (MA) size measured on Carto 3. The LA vol. was 139±56 ml and the MA diameters were 29.9±5.3 mm and 41.9±7.6 mm resulting in an area of 14±5 qcm. There was a significant correlation of the transverse MA with the AP-LA diameter (R=0.59), the longitudinal MA with the LL-LA diameter (R=0.576) and the MA area with the LA volume (R=0.639). Thus the authors conclude that LA dilation leads to greater MA size.

The manuscript is interesting. The introduction, the methods and the results are adequate; the discussion and the conclusions are supported by the data but they could be improved by some clarifications. Thus, some issues should be addressed before considering publication in the journal of Applied Sciences:

Specific comments:

1. Methods/Results/ Discussion: Given the nature of the study, the observed association cannot prove causation. The authors report that they excluded patients with mitral regurgitation but a functional regurgitation was not explicitly evaluated or excluded. Therefore, one cannot say for sure that LA dilatation leads to MA dilation or vice versa. Please correct and comment

Response to Comment 1: We agree with the reviewer's assessment. We can't prove a direct link between LA and MA size. As a result, we replaced the phrase within the text and the title:  Left Atrial Volume Correlates with Mitral Annulus Size. A MDCT study.

1. Methods: Please provide a better description of the measurement methods, esp. for the MA and LA diameters. How did you ensure standardization of measurements? Are there any inter- or intra-observer variability measurements? What were the guiding points for setting the distance measurement points? Are they amenable to bias due to rotation of the heart axis?

Response to Comment 2:  Transverse diameter of the mitral annulus was defined as  the longest septal to lateral  distance, perpendicular on the contact line between LVOT and mitral annulus. The longitudinal diameter of the mitral annulus was defined as the  longest distance measured between  intercumissural points, perpendicular on the transverse diameter. Supero-inferior diameter of the left atrium was defined as the distance between the point of intersection between longitudinal and transversal diameters of the mitral annulus and the highest left atrial point. Latero-lateral diameter of the left atrium was the longest distance between the lateral and septal walls of the left atrium, parallel to the mitral annulus. AP diameter of the left atrium was defined as the distance between the anterior and posterior walls of the LA, perpendicular on the LL diameter.

We believe that rotation of the heart axis will not affect MA and LA dimensions because an automatic contour tracking tool is included in the module, which is based on automated heart chamber detection with volume segmentation. The aorta, left and right atria and ventricles, pulmonary veins, and arteries are all separated during this process and LA is extracted from the heart volume.

Figure 1. Diameters of the mitral annulus are depicted in the image. With red color-transverse diameter; with green color-longitudinal diameter.

1. Results: Please provide some more information or comment on baseline characteristics of the patients that could influence the results of the study e.g. LV systolic/diastolic function and size

Response to Comment 3: LV systolic diameter=52.4+/-5.8 mm; LV diastolic diameter=37.6+/-6.8 mm; LVEF=54.2+/-4.2%.

1. Discussion: “The longitudinal diameter was 4.4 mm in 209 patients with functional MR and 3.9 mm in control subjects” -> Both are less than half a centimeter and not realistic for MA. Please correct (is it 44 and 39 mm?)

Response to Comment 4: Thank you for the correction. It is 44 and 39 mm.

1. Figure 1: Please annotate which diameter is where on the figure. Consider using the “capture” tool by Carto 3 to create a Figure of higher quality/clarity.

Response to Comment 5: We used “capture” tool and introduced new images in the manuscript. We marked the 2 diameters, area and perimeter of the mitral annulus.

Figure 2. Assessment of mitral valve dimensions using MDCT. 1A. White line shows measurement of the transverse diameter of the mitral annulus. 1B. White line shows measurement of the longitudinal diameter of the mitral annulus. 1C. Measurement of the mitral valve area and perimeter. The system calculates the perimeter and area based on the points defining the mitral annulus: perimeter = 12.2 cm, area = 10.8 cm²

1. Figure 3: The confidence intervals (1.96-SD lines) seem asymmetrical. Please explain and/or correct. Also consider reporting what the x-axis stands for (mean of predicted LAV?)

Response to Comment 6: We appreciate the reviewer bringing this calculation error to our attention. Mean value was -2.77 and SD = 58.73. Therefore superior green line should be: Mean+1.96SD=+56.96 and inferior green line: Mean-1.96DS= -62.5 

1. Please run a check for spelling/grammatical errors: e.g. the word “disparity” has usually an economic reference – consider discrepancy instead

Response to Comment 7: We made grammatical and spelling corrections.

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

I thank the authors for addressing my comments in this revised version. I have no additional suggestions.

Reviewer 2 Report

All my comments have been adequately addressed. I have no further comments.