Review Reports - Integrating Cardiopulmonary Exercise Testing in the Assessment of Aortic Stenosis: A Comprehensive Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The subject of CEPT (cardio-pulmonaire exercise testing) in aortic stenosis (AS) is of great interest

The paper should focus on the field; therefore paragraphs 2-3-4-5-6-7 should be removed as well as figures 3 page 5 (figures 1&2 are missing) and table 1

The authors should remind the indications for AVR (aortic valve replacement) and focus on the issue of symptoms as many patients report no symptoms due to sedentary lifestyle.

Conversely many AS patients report symptoms due to other causes than the valvular disease such as COPD, poor physical conditions, peripheral artery disease, impaired chronotropic response etc...

The authors should provide CEPT examinations from control and AS patient with abnormal circularoy response and from AS patient with impaired respiratory response

These figures are of importance for indicating the main parameters of CEPT : AT, O2 pulse, peak VO2, VE/VCO2, VE/VO2 etc...

In brief the authors should focus on the issue of diagnosing symptoms in AS patients and the potential prognostic role of CEPT in AS disease.

A PICO table summarizing the existing literature of CEPT in AS patients should be also provided

In my opinion combination of CEPT with stress echocardiography might not be feasible in routine

Author Response

We would like to thank you for taking the time to read this draft review article and providing constructive feedback. We have provided comments for the queries you have raised below:

The paper should focus on the field; therefore paragraphs 2-3-4-5-6-7 should be removed as well as figures 3 page 5 (figures 1&2 are missing) and table 1.

Thank you and we agree with these comments, therefore we have removed paragraphs 2-4 & 6-7. We have decided to leave in paragraph three as it provides some context around aortic stenosis prior to discussing CPET. The figures have been adjusted accordingly.

The authors should remind the indications for AVR (aortic valve replacement) and focus on the issue of symptoms as many patients report no symptoms due to sedentary lifestyle.

We have provided and made specific reference for where you can find the indications for aortic valve replacement. We wanted to provide a table of indications but the journal would not allow us to re-publish or modify the table due to copyright issues.

Conversely many AS patients report symptoms due to other causes than the valvular disease such as COPD, poor physical conditions, peripheral artery disease, impaired chronotropic response etc...

We have made specific reference to the comments made above. Thank you as this has strengthened the discussion within the article.

The authors should provide CEPT examinations from control and AS patient with abnormal circulatory response and from AS patient with impaired respiratory response

We agree. As such, we have added a normal example (Figure 2 & 3) but I’m afraid due to GDPR issues, we could not locate an example of a CPET with severe AS. Sadly, they are seldomly done (hence the review article) and those where we do have examples, we were unable to contact the patient to request permission to use their study. We have added Table 1 which contains key CPET parameters with normal physiology and with AS to address this.

These figures are of importance for indicating the main parameters of CEPT : AT, O2 pulse, peak VO2, VE/VCO2, VE/VO2 etc...

Thank you for this comment. We have added Figures 2 & 3 along with table 1 to support this point.

In brief the authors should focus on the issue of diagnosing symptoms in AS patients and the potential prognostic role of CEPT in AS disease.

This is an important point. As such, we have added comments and discussed the issues around relying on resting symptoms in AS and the benefits of CPET in identifying those who have hidden symptoms.

A PICO table summarizing the existing literature of CEPT in AS patients should be also provided.

I have added a PICO table which contains all primary studies that investigate the benefits of CPET in severe AS – Please review Table 3.

In my opinion combination of CEPT with stress echocardiography might not be feasible in routine.

We have added a comment questioning whether CPET is feasible in this population due to patient frailty and fitness. This provides a balanced argument for the potential adoption of CPET-SE.

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for the opportunity to review this manuscript.

I was very impressed by the quality of this manuscript. The data around appropriate use of exercise testing in AS was well presented. Much of what we send for surgery is very dependent on patients symptoms and we are often guided by this independent of "numbers" from the echo. My only comment would be to provide a citation for line 37, otherwise I found this a well presented, comprehensive review.

Author Response

We would like to thank you for you positive comments. As recommended, we have attached two new references to support the statement that CPET is effective at risk stratifying AS patients.

Reviewer 3 Report

Comments and Suggestions for Authors

This narrative review provides a comprehensive overview of aortic stenosis, spanning normal aortic valve anatomy and physiology, pathophysiological mechanisms, epidemiology, diagnostic assessment, and the evolving role of cardiopulmonary exercise testing in clinical practice. The manuscript emphasizes the utility of cardiopulmonary exercise testing, including submaximal testing and combined cardiopulmonary exercise testing with stress echocardiography, for risk stratification and management of patients with aortic stenosis. The topic is clinically relevant and timely, and it aligns with current guideline-directed management; however, several substantive issues limit the manuscript’s clinical applicability and clarity in its current form.

The sections describing gross anatomy, leaflet microstructure, and normal aortic valve dynamics are highly detailed and extend beyond what is necessary for a clinically oriented review focused on cardiopulmonary exercise testing. While scientifically accurate, these sections occupy a substantial proportion of the manuscript without directly informing the later CPET-based risk stratification and management discussion. Condensation of these sections is recommended, with a clearer linkage to how structural and mechanical alterations of the aortic valve translate into exercise intolerance and abnormal CPET findings in aortic stenosis.
The manuscript summarizes multiple observational and prospective studies evaluating CPET parameters in aortic stenosis; however, these studies are largely presented descriptively. Greater critical synthesis is required, including discussion of heterogeneity in patient populations, severity definitions, CPET protocols, and outcome measures. Limitations such as small sample sizes, selection bias, and lack of standardized cut-off values for CPET parameters should be more explicitly acknowledged to avoid overinterpretation of findings.
Despite extensive discussion of CPET-derived variables, the manuscript does not provide a clear framework illustrating how CPET results should influence clinical decision-making. The addition of a structured clinical algorithm or flowchart outlining the role of CPET in asymptomatic and minimally symptomatic moderate-to-severe aortic stenosis would substantially enhance the manuscript’s translational value. This should include potential thresholds or patterns that may prompt closer surveillance, referral for intervention, or further imaging.
Although major international guidelines are cited, the manuscript does not sufficiently integrate CPET findings into guideline-based management pathways. A clearer discussion of where CPET complements standard echocardiographic parameters, particularly in patients with discordant symptoms or preserved left ventricular ejection fraction, is warranted. Explicit reference to how CPET may refine risk stratification beyond conventional metrics would strengthen the clinical relevance.
The section on combined CPET and stress echocardiography introduces an important and innovative concept; however, it remains relatively exploratory. The authors should further clarify the incremental value of this combined approach over standard CPET or stress echocardiography alone, including practical considerations such as feasibility, reproducibility, image quality limitations, and availability. Clear identification of patient subgroups most likely to benefit from CPET-SE would also be valuable.
The manuscript would benefit from summary tables that consolidate key CPET variables, their physiological interpretations, and their expected behavior in normal subjects versus patients with aortic stenosis. Such tables would improve readability and facilitate clinical interpretation, particularly for readers less familiar with CPET.

Author Response

We would like to thank you for taking the time to offer this insightful and very thought provoking review of our work. Your feedback give us some important points to consider on how this article could be improved. Please see the responses to individual comments below:

The sections describing gross anatomy, leaflet microstructure, and normal aortic valve dynamics are highly detailed and extend beyond what is necessary for a clinically oriented review focused on cardiopulmonary exercise testing. While scientifically accurate, these sections occupy a substantial proportion of the manuscript without directly informing the later CPET-based risk stratification and management discussion. Condensation of these sections is recommended, with a clearer linkage to how structural and mechanical alterations of the aortic valve translate into exercise intolerance and abnormal CPET findings in aortic stenosis.

Thank you for this comment. We agree with this and therefore we have removed the bulk of the first paragraphs, with the exception of “pathophysiology of AS” which we believe it offers context of AS before introducing CPET.

The manuscript summarizes multiple observational and prospective studies evaluating CPET parameters in aortic stenosis; however, these studies are largely presented descriptively. Greater critical synthesis is required, including discussion of heterogeneity in patient populations, severity definitions, CPET protocols, and outcome measures. Limitations such as small sample sizes, selection bias, and lack of standardized cut-off values for CPET parameters should be more explicitly acknowledged to avoid overinterpretation of findings.

Thank you for this point. We have attempted to discuss the points raised above which includes the limitations of such studies highlighting the potential benefits of CPET. This has created a more balanced discussion along with an important points around the small, single centre, observational studies being available at the moment.

Despite extensive discussion of CPET-derived variables, the manuscript does not provide a clear framework illustrating how CPET results should influence clinical decision-making. The addition of a structured clinical algorithm or flowchart outlining the role of CPET in asymptomatic and minimally symptomatic moderate-to-severe aortic stenosis would substantially enhance the manuscript’s translational value. This should include potential thresholds or patterns that may prompt closer surveillance, referral for intervention, or further imaging.

This was a very useful point. We discussed in depth about creating a flow chart and we believe we successfully created one following this comment – please see figure 4.

Although major international guidelines are cited, the manuscript does not sufficiently integrate CPET findings into guideline-based management pathways. A clearer discussion of where CPET complements standard echocardiographic parameters, particularly in patients with discordant symptoms or preserved left ventricular ejection fraction, is warranted. Explicit reference to how CPET may refine risk stratification beyond conventional metrics would strengthen the clinical relevance.

Thank you for this comment. We agree and as such, we have included comments around the complementary benefits of CPET to improve the risk stratification of asymptomatic AS patients.

The section on combined CPET and stress echocardiography introduces an important and innovative concept; however, it remains relatively exploratory. The authors should further clarify the incremental value of this combined approach over standard CPET or stress echocardiography alone, including practical considerations such as feasibility, reproducibility, image quality limitations, and availability. Clear identification of patient subgroups most likely to benefit from CPET-SE would also be valuable.

We have included these discussion points and integrated them into the CPET-SE paragraph. This further strengthens the discussion around the adoption of CPET-SE.

The manuscript would benefit from summary tables that consolidate key CPET variables, their physiological interpretations, and their expected behavior in normal subjects versus patients with aortic stenosis. Such tables would improve readability and facilitate clinical interpretation, particularly for readers less familiar with CPET.

Thank you for this comment. We agree and therefore, we have added an example from a normal CPET to support how the parameters are measured and Table 1 which highlights key CPET parameters which are influenced and modified by AS.

Reviewer 4 Report

Comments and Suggestions for Authors

In line 20, authors stated that AS is degenerative form of valvular heart disease, however AS could be rheumatic disease or non-degenerative too, especially in developing countries

Author Response

We would like to thank the reviewer for their comment. We did have a paragraph dedicated to the pathophysiology of AS which discussed rheumatic and bicuspid aortic valve disease in our original article submission but other reviewers felt it detracted from the main feature of CPET.

We have removed the term 'degenerative' from the introduction (line 20) and abstract and included a statement within the introduction briefly mentioning rheumatic and bicuspid aortic valve anatomy as other derivatives of aortic stenosis.

Many thanks once again.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript has been significantly improved

However the paragraph "pathogenesis of aortic stenosis" should be removed as the main topic of this paper is Cardiopulmonary exercise testing (CPET).

The role of CPET in aortic stenosis risk stratification should be first introduced

Author Response

Thank you once again for your review and comments. We are pleased to hear you feel the manuscript has been significantly improved. We have reluctantly removed the suggested "pathogenesis of aortic stenosis" paragraph following your recommendations.

As for your other recommendation - We discussed at length replacing "the role of CPET in aortic stenosis risk stratification" with the pathogenesis AS paragraph - however, we felt that this would negatively influence the overall flow of the written work. The risk stratification paragraph discusses key CPET parameters before they are introduced in "the role of cardiopulmonary exercise testing in clinical practice" paragraph. As such, the article becomes disjointed. Therefore, while we considered this alteration, we have decided to keep the format of the article as it is.