Obstructive Sleep Apnea and Cardiovascular Disease: Mechanisms, Diagnostics, and Emerging Therapeutic Approaches

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

General Assessment

This manuscript provides a comprehensive and technically oriented review of the mechanistic links between sleep apnea (OSA and CSA) and cardiovascular disease, while also discussing emerging diagnostic and therapeutic innovations. The topic is timely and clinically relevant, particularly given the growing interest in precision medicine and device-based therapies.

The review is well-structured, logically organized, and integrates pathophysiological, translational, and technological perspectives. The inclusion of epigenetics, nerve stimulation, computational modeling, and artificial intelligence strengthens the manuscript’s interdisciplinary value.

However, several areas would benefit from clarification, deeper critical synthesis, and improved balance between mechanistic discussion and clinical evidence.

While the manuscript summarizes a broad range of studies, several sections remain largely descriptive. For example:

• The ROS/HIF-1 discussion (Section 3.1) presents dual roles of HIF-1α but does not fully reconcile the conflicting data.

• The epigenetics section (6.1) lists findings but would benefit from a clearer integrative model explaining how epigenetic mechanisms translate into cardiovascular phenotypes in OSA.

Suggestion:
The authors may consider adding brief integrative summary paragraphs at the end of major sections to critically synthesize the evidence rather than only reporting it.

The discussion of CPAP and cardiovascular endpoints (SAVE trial and related data) is accurate but could be more critically framed.

Points needing refinement:

• The distinction between symptomatic improvement and hard cardiovascular outcomes should be more explicitly emphasized.

• Adherence-related subgroup findings deserve clearer contextualization (e.g., causality vs. association).

• The ongoing debate about whether OSA is a modifiable cardiovascular risk factor via CPAP should be more critically addressed.

This is a key controversy in the field and deserves a slightly deeper analytical tone.

The manuscript is weighted more heavily toward OSA, particularly in mechanistic and therapeutic discussions. While this reflects epidemiology, the title suggests equal emphasis on sleep apnea broadly.

Suggestions:

• Consider expanding mechanistic depth for CSA beyond loop gain and Cheyne–Stokes respiration.

• Provide a clearer conceptual framework distinguishing OSA-driven cardiovascular injury from CSA in heart failure contexts.

Precision Medicine and AI Sections – Need for Clinical Framing

The precision medicine, CFD, and AI sections are forward-looking and technically interesting. However:

• The readiness for clinical implementation is not critically evaluated.

• Issues such as external validation, regulatory considerations, dataset bias, and reproducibility could be briefly acknowledged.

A short paragraph outlining current translational barriers would strengthen credibility.

The animal models section is informative but somewhat isolated from the cardiovascular discussion.

Suggestion:
Briefly connect animal findings more explicitly to human translational implications (e.g., how CIH models inform arrhythmia or endothelial dysfunction mechanisms in patients).

• Clear organization and logical progression.

• Strong integration of engineering and biomedical perspectives.

• Inclusion of emerging therapeutic technologies.

• Comprehensive reference list.

• Good visual support with explanatory figures.

 

The manuscript addresses a highly relevant topic and has the potential to make a meaningful contribution. With moderate revision focused on deeper critical synthesis and stronger clinical contextualization, it would be suitable for publication.

 

Author Response

1. While the manuscript summarizes a broad range of studies, several sections remain largely descriptive. For example:
The ROS/HIF-1 discussion (Section 3.1) presents dual roles of HIF-1α but does not fully reconcile the conflicting data.
The epigenetics section (6.1) lists findings but would benefit from a clearer integrative model explaining how epigenetic mechanisms translate into cardiovascular phenotypes in OSA.
The authors may consider adding brief integrative summary paragraphs at the end of major sections to critically synthesize the evidence rather than only reporting it.

Thank you for this suggestion. We agree with this comment. We have included several summary paragraphs at the end of major sections including a summary after the ROS and epigenetics sections.

2. The discussion of CPAP and cardiovascular endpoints (SAVE trial and related data) is accurate but could be more critically framed. 

Points needing refinement:

• The distinction between symptomatic improvement and hard cardiovascular outcomes should be more explicitly emphasized.
• Adherence-related subgroup findings deserve clearer contextualization (e.g., causality vs. association).
• The ongoing debate about whether OSA is a modifiable cardiovascular risk factor via CPAP should be more critically addressed.

This is a key controversy in the field and deserves a slightly deeper analytical tone.

Thank you for this suggestion. We have updated section 4.1 to more critically frame the discussion of CPAP and cardiovascular endpoints. We have more clearly distinguished CPAP’s established benefits for symptom improvement and quality of life from the less consistent evidence supporting reductions in major cardiovascular outcomes.

3. 

The manuscript is weighted more heavily toward OSA, particularly in mechanistic and therapeutic discussions. While this reflects epidemiology, the title suggests equal emphasis on sleep apnea broadly.

Suggestions:

• Consider expanding mechanistic depth for CSA beyond loop gain and Cheyne–Stokes respiration.
• Provide a clearer conceptual framework distinguishing OSA-driven cardiovascular injury from CSA in heart failure contexts.

Thank you very much for this suggestion and we agree, since most of the discussion in the manuscript is about OSA, we have changed the title to reflect the manuscript's focus on OSA. To avoid indicating that the manuscript broadly addresses CSA and OSA we changed the title to indicate that the manuscript primarily discusses OSA.

4. Precision Medicine and AI Sections – Need for Clinical Framing
The precision medicine, CFD, and AI sections are forward-looking and technically interesting. However:
The readiness for clinical implementation is not critically evaluated.
Issues such as external validation, regulatory considerations, dataset bias, and reproducibility could be briefly acknowledged.
A short paragraph outlining current translational barriers would strengthen credibility.

Thank you for this suggestion and we agree that this is a very important aspect to discuss. We have elaborated on section 6.4 and wrote a summary paragraph discussing these important points.

5. The animal models section is informative but somewhat isolated from the cardiovascular discussion.
Suggestion:
Briefly connect animal findings more explicitly to human translational implications (e.g., how CIH models inform arrhythmia or endothelial dysfunction mechanisms in patients).

Thank you for this suggestion. We have added additional text to relate the human and animal models bringing attention to the fact that animal models do not fully reproduce OSA physiology in section 5. 

Additionally, we have better connected animal findings to human clinical findings. We have updated section 3.2 and section 5.

Reviewer 2 Report

Comments and Suggestions for Authors

I read this paper with great interest. 

This is comprehensive narrative review of OSA and CSA, focusing on mechanistic links to CVD and much more. The topic is highly relevant and the paper is well written.

However, i have some concerns which must be addressed: 

- Please add a framework diagram integrating mechanistic endotypes with therapeutic implications.

- Please expand loop gain section with things like mathematical definition, relation to Cheyne–Stokes respiration in HF and potential pharmacologic modulation strategies

- The AI needs clincial integration context. 

- Please better specify that animal models reproduce components, but not full OSA physiology.

Author Response

1. Please add a framework diagram integrating mechanistic endotypes with therapeutic implications.

Thank you for this suggestion. We have added a figure (Figure 2: Mechanistic framework for OSA and therapeutic targets) that shows OSA endotypes and the corresponding therapies.  

2. Please expand loop gain section with things like mathematical definition, relation to Cheyne–Stokes respiration in HF and potential pharmacologic modulation strategies

Thank you for this suggestion. We have added text to section 2.1 to further explain loop gain and discussed Cheyne-Stokes respiration in HF and pharmacologic modulation. 

3. The AI needs clinical integration context. 

Thank you for this suggestion. We have added text to the AI section (section 6.4) discussing clinical integration and have also added a summary paragraph that discusses some of the current barriers to AI implementation.  

4. Please better specify that animal models reproduce components, but not full OSA physiology.

Thank you for this suggestion. We have further brought attention to the fact that animal models do not fully reproduce OSA physiology (Section 5). Additionally, we have specifically provided context connecting animal models to translational implications throughout. (sections 3.2) and updated section 5.