Assessment of Right Ventricular Pressure in Chronic Thromboembolic Pulmonary Hypertension: Comparison of Diagnostic Modalities and Balloon Pulmonary Angioplasty Outcomes

1. Summary

Dear Reviewers! We would like to thank you for the prompt review and the insightful comments. We hope that the draft was of interest to you as well. In response to the points raised, we have provided detailed, point-by-point answers below. Where appropriate, we have revised or expanded the relevant sections of the manuscript accordingly.

Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Yes/Can be improved/Must be improved/Not applicable

Are all the cited references relevant to the research?

Yes/Can be improved/Must be improved/Not applicable

Is the research design appropriate?

Yes/Can be improved/Must be improved/Not applicable

Limitations section was expanded concerning methods, Simultaneous Multimodal Assessments were evaluated in detail in the article

Are the methods adequately described?

Yes/Can be improved/Must be improved/Not applicable

Limitations section was expanded concerning methods

Are the results clearly presented?

Yes/Can be improved/Must be improved/Not applicable

Are the conclusions supported by the results?

Yes/Can be improved/Must be improved/Not applicable

3. Point-by-point response to Comments and Suggestions for Authors

·         Comments 1:  At line 313 is mentioned: The table contains the data of 16 CTEPH patients during the follow-up period. Why 16 patients? At line 320 N: 17 patients.

Response 1: A typographical error occurred; the correct number of patients was 17.  

Thank you for pointing this out. We totally agree with this comment. Although we reviewed the draft several times, we unfortunately overlooked this typo. We appreciate you bringing it to our attention. change can be found in the revised article – page 11, paragraph 1, and line 318]

·         Comments 2: Figure 3 – Test Combination – How did the authors assess the number of patients (25,13,22,11)?

Response 2: A prospective analysis was performed to evaluate the correlation between invasive and noninvasive methods used for RV pressure assessment. Measurements were conducted on CTEPH patients within a 48-hour window during the same hospital stay to minimize physiological variability. Pulmonary angiography, Swan-Ganz catheterization, and transthoracic echocardiography were all performed in accordance with routine clinical practice. In cases where pressure values were assessed using more than one modality, we compared the measured or estimated right ventricular systolic pressures, provided that the time interval between the examinations did not exceed 48 hours and no therapeutic intervention or clinical deterioration occurred in the meantime. This 48-hour time window was defined artificially; however, in our opinion, it still allows for a valid comparison of the hemodynamic parameters obtained through different modalities.

During the study period, a total of 97 echocardiographic examinations, 50 balloon pulmonary angioplasties (BPAs), and 43 Swan-Ganz catheterizations were recorded. Within the 48-hour time frame, all three modalities—echocardiography, Swan-Ganz catheterization, and pulmonary angiography—were available for pressure comparison in 11 cases. Echocardiographic and Swan-Ganz-derived pressures were available for comparison in 25 cases, while pulmonary angiography and echocardiographic pressure estimations were performed within 48 hours in 22 cases. In 13 cases, both Swan-Ganz catheterization and pulmonary angiography-derived pressure measurements were available within the defined time window.

Agree. We have accordingly answered the question here in detail and modified the article to emphasize this point. (page number 11, paragraph 1, and line 332-340.]

“[updated text in the manuscript]”

Point 1: The English is fine and does not require any improvement.

Response 1:   

5. Additional clarifications

Response to Reviewer 2 Comments

1. Summary

Dear Reviewers! We would like to thank you for the prompt review and the insightful comments. We hope that the draft was of interest to you as well. In response to the points raised, we have provided detailed, point-by-point answers below. Where appropriate, we have revised or expanded the relevant sections of the manuscript accordingly.

Please find the detailed responses below and the corresponding revisions/corrections highlighted/in track changes in the re-submitted files.

2. Questions for General Evaluation

Reviewer’s Evaluation

Response and Revisions

Does the introduction provide sufficient background and include all relevant references?

Yes/Can be improved/Must be improved/Not applicable

Are all the cited references relevant to the research?

Yes/Can be improved/Must be improved/Not applicable

Is the research design appropriate?

Yes/Can be improved/Must be improved/Not applicable

Are the methods adequately described?

Yes/Can be improved/Must be improved/Not applicable

Are the results clearly presented?

Yes/Can be improved/Must be improved/Not applicable

Are the conclusions supported by the results?

Yes/Can be improved/Must be improved/Not applicable

3. Point-by-point response to Comments and Suggestions for Authors

Comments 1:  In the current paper, the authors compare RV pressure measurements obtained by noninvasive echocardiography with those derived from invasive techniques, including right heart catheterization and direct measurement during pulmonary angiography, in a cohort of patients with CTEPH. They also explored the impact of BPA on clinical and laboratory outcomes. The study sample size was very small, as the study population was particular. What about the BPA rate in patients with CTEPH at the current center?

Response 1: In our center, the clinical characteristics of the CTEPH patient population reflect those reported in Japanese cohorts, with nearly 80% of patients presenting with predominantly peripheral vascular lesions. This distribution contrasts with data from U.S. registries, where central and peripheral obstructions are reported in approximately equal proportions. In accordance with current ESC Guidelines, balloon pulmonary angioplasty (BPA) is indicated for patients with peripheral-type CTEPH in our practice.  The majority of our patients (approx. 70%) consistently accept this treatment approach following appropriate evaluation and shared decision-making within the multidisciplinary CTEPH team. Approximately 10% of patients are deemed ineligible for BPA, and an additional 15–20% refuse to undergo the procedure.

Thank you for pointing this out. We agree with this comment. Therefore, we have provided our response here and have updated the revised article accordingly. change can be found – page 2, last paragraph, and line 87-91.]

Comments 2: Please include the details of medications, including OACs and PH treatment strategies.

Response 2: Chronic thromboembolic pulmonary hypertension (CTEPH) is a distinct form of pulmonary hypertension (PH) classified under Group 4 of the WHO classification system. It is characterized by persistent obstruction of the pulmonary vasculature due to organized thromboembolic material, resulting in progressive pulmonary vascular remodeling and increased pulmonary vascular resistance. Management of CTEPH requires a comprehensive, multidisciplinary approach that includes anticoagulation, pulmonary endarterectomy (PEA) when feasible, balloon pulmonary angioplasty (BPA) in selected patients, and medical therapy for inoperable or residual PH.

Anticoagulation is the cornerstone of medical management in all patients with CTEPH, regardless of operability. Lifelong oral anticoagulation is strongly recommended to prevent further thromboembolic events and to stabilize the existing vascular lesions. Vitamin K antagonists (VKAs), such as warfarin, are the standard of care, there is growing evidence supporting the use of direct oral anticoagulants (DOACs) as an alternative in selected patients. However, current guidelines still favor VKAs due to the lack of large-scale randomized trials evaluating the efficacy and safety of DOACs specifically in CTEPH. We do favour VKA antagonists in our practice.

In patients who are not candidates for surgery or have persistent PH following PEA or BPA, targeted pulmonary hypertension therapy may be initiated. Riociguat, a soluble guanylate cyclase (sGC) stimulator, is currently the only drug approved specifically for the treatment of inoperable or persistent/recurrent CTEPH after surgery. Clinical trials have demonstrated that riociguat improves exercise capacity, WHO functional class in this patient population. improves hemodynamics and reduced complication  after BPA  In clinical practice, other PH-specific agents such as endothelin receptor antagonists (e.g., bosentan, macitentan), phosphodiesterase-5 inhibitors (e.g., sildenafil, tadalafil), and prostacyclin analogues or receptor agonists may be used off-label in selected cases, particularly in patients with severe or progressive disease under close specialist supervision.

The decision to initiate medical therapy should always be made within a specialized PH center, ideally in the context of a multidisciplinary CTEPH team, including PH physicians and interventionalists. Ongoing follow-up, including serial echocardiography, right heart catheterization, and imaging studies, is essential to guide treatment adjustments and monitor response to therapy. Optimal management of CTEPH requires not only pharmacologic treatment but also attention to comorbid conditions, rehabilitation, and psychosocial support to improve functional status and long-term outcomes

Agree. We have, accordingly answered the question here in detail and modified the article to emphasize this point. (page number 2, paragraph 3, and line 80-86.]

“[updated text in the manuscript]”

Comments 3:  Please include the intra- and inter-observer variability data for echocardiographic measurements.

Response 3:  All echocardiographic examinations in our patient cohort were performed using the same imaging platform, the Philips Epiq 5 Ultrasound System, ensuring consistency in image acquisition and reducing variability related to equipment differences. Our clinic also serves as a certified echocardiographic training center. All members of the echocardiographic imaging team participate in the same structured training and education program, which significantly contributes to reducing interobserver variability. The follow-up of patients with chronic thromboembolic pulmonary hypertension (CTEPH) is primarily conducted by members of the dedicated CTEPH team. Consequently, echocardiographic examinations in these patients are typically performed by the same group of physicians, who work in close collaboration and frequently consult with one another. All studies were validated by an expert CTEPH echocardiography specialist. This team-based approach includes the joint review of echocardiographic acquisitions, thereby further enhancing consistency and diagnostic reliability.

In the context of follow-up assessments, echocardiographic measurements are systematically performed prior to any review of previous studies. This sequence minimizes interpretive bias and allows for an objective comparison with prior data, facilitating accurate evaluation of disease progression or therapeutic response, and thus reducing intraobserver variability. In our department, the majority of echocardiographic examinations are archived and can be easily retrieved using the TomTec system, which enables standardized re-analysis and additional offline measurements when needed. The use of the TomTec platform contributes significantly to both inter- and intraobserver consistency due to its advanced technological capabilities.

TomTec software is vendor-neutral, allowing for standardized post-processing across different ultrasound systems and eliminating variability related to acquisition hardware. It provides automated and semi-automated tools for quantitative analysis, such as left ventricular ejection fraction, reducing the impact of manual tracing and operator dependence. Its advanced contour detection enable consistent and reproducible border delineation, minimizing subjectivity in measurements. The reliability of TomTec's quantitative tools has been validated in multiple peer-reviewed studies, which demonstrate excellent inter- and intraobserver agreement.

Beyond the advantages of advanced software, reducing observer variability in echocardiography also depends on the standardization of image acquisition protocols. Uniform acquisition following EACVI guidelines ensures consistency across operators. Structured operator training and certification further reduce interobserver variability, while the use of quantitative methods—such as Simpson’s biplane method instead of visual estimation—improves objectivity. Ensuring high image quality through optimal probe positioning, appropriate imaging settings, and avoidance of foreshortening, especially in apical views, is essential for reproducible measurements. Performing measurements blinded to previous results or clinical data helps to minimize cognitive bias. Repeating measurements and averaging can reduce random error, while the archiving of raw image data and cine loops allows for retrospective review and second-opinion assessments when necessary. Together, these elements form an integrated framework that enhances reproducibility in echocardiographic practice and strengthens the reliability of serial assessments, particularly in specialized patient populations such as those with CTEPH.

We have, accordingly answered the question here in detail and modified the article to emphasize this point. (page number 16, paragraph 3, and line 522-530.)

“[updated text in the manuscript]”

Comments 4: Please discuss the limitations of each measurement strategy more extensively.   

Response 4: Dear Reviewer, we fully agree that recognizing the limitations of the applied diagnostic methods is of critical importance in clinical practice. In response to your comment, we have expanded the relevant section of the manuscript accordingly. We hope that the revised version now provides sufficient detail and clarity.

In the revised manuscript this change can be found – page number 16, paragraph 3, and line 510-562.]

“[updated text in the manuscript]”

4. Response to Comments on the Quality of English Language

Point 1: The English is fine and does not require any improvement.

Response 1:   

5. Additional clarifications