Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The proposed mechanobiological continuum is intellectually attractive and may provide a useful conceptual framework. However, many mechanistic links are inferred from experimental vascular biology rather than directly demonstrated in endurance athletes. The manuscript would benefit from clearer separation of established evidence from hypothesis-generating concepts.

2. The discussion of calcification as lesion maturation or healing should be balanced by emphasizing that CAC remains a robust marker of total atherosclerotic burden and future cardiovascular risk. Current evidence does not establish that elevated CAC in athletes carries fundamentally different prognostic implications than in non-athletic populations.

3. Insufficient selection of bias: There should be a dedicated paragraph discussing:

• healthy athlete effect,
• survivor bias,
• referral bias,
• volunteer bias

These factors may substantially influence observed plaque phenotypes.

4. plaque burden ≠ functional impairment -> This is reasonable, but the evidence base is actually quite small. Therefore, statements regarding preserved ischemic threshold should be softened.

5. 

For a narrative review this is acceptable, but:

• only PubMed was searched,
• no PRISMA framework,
• no study selection diagram,
• no assessment of bias.

The review is therefore vulnerable to citation selection bias.

6. Figure 1 and Figure 2 add little scientific value. The figures simply display prevalence of CAC >100 across studies. 

The studies differ substantially regarding:

• age,
• risk profile,
• imaging methodology,
• athlete definition.

Direct visual comparison may be misleading.

7. 

Master@Heart is arguably the most important contemporary dataset.

The manuscript mentions it repeatedly but does not fully explore the implications that lifelong athletes exhibited:

• more mixed plaque,
• more proximal plaque,
• more non-calcified plaque.

These findings challenge the "benign calcification" narrative and deserve more emphasis.

8. Female athletes section is underdeveloped. The review appropriately highlights sex differences. 

However, the section appears brief relative to the importance of the topic.

Additional discussion of:

• menopause,
• hormonal influences,
• underrepresentation of women,

would strengthen the manuscript.

9. The manuscript cites studies from 2026 despite being submitted in 2025. The authors should clarify publication status and ensure all references are citable.

 

Author Response

We sincerely thank the Reviewer for the careful and constructive evaluation of our manuscript. We have revised the text extensively to clarify the evidentiary strength of the proposed framework, to avoid overinterpretation of athlete-specific calcification, and to better acknowledge methodological limitations and potential sources of bias.

In the revised version, all changes made in response to the Reviewer’s comments have been highlighted in yellow to facilitate review.

Below, we provide a point-by-point response.

 

Reviewer’s comment: 1. The proposed mechanobiological continuum is intellectually attractive and may provide a useful conceptual framework. However, many mechanistic links are inferred from experimental vascular biology rather than directly demonstrated in endurance athletes. The manuscript would benefit from clearer separation of established evidence from hypothesis-generating concepts.

 

Response. We agree with the Reviewer. We now explicitly state that the mechanobiological continuum should be interpreted as a hypothesis-generating framework rather than as a proven causal model in endurance athletes.

 

Reviewer’s comment: 2. The discussion of calcification as lesion maturation or healing should be balanced by emphasizing that CAC remains a robust marker of total atherosclerotic burden and future cardiovascular risk. Current evidence does not establish that elevated CAC in athletes carries fundamentally different prognostic implications than in non-athletic populations.

Response. We fully agree. We have revised the Introduction, Section 5.3, Figure 4 caption, and Conclusions to emphasize that CAC remains an established marker of total atherosclerotic burden and cardiovascular risk. We now avoid implying that athlete CAC is intrinsically benign or prognostically distinct. Instead, we state that dense calcification may coexist with higher total plaque burden and that current evidence is insufficient to conclude that CAC has fundamentally different prognostic implications in athletes than in non-athletes.

 

 

Reviewer’s comment: 3. Insufficient selection of bias: There should be a dedicated paragraph discussing:

• healthy athlete effect,
• survivor bias,
• referral bias,
• volunteer bias

These factors may substantially influence observed plaque phenotypes.

Response. We thank the Reviewer for this important suggestion. We have added a dedicated methodological paragraph addressing selection bias, including healthy athlete effect, survivor bias, referral bias, and volunteer bias. We also discuss how these biases may influence observed plaque prevalence, plaque phenotype, and the apparent dissociation between plaque burden and clinical outcomes.

 

 

Reviewer’s comment: 4. plaque burden ≠ functional impairment -> This is reasonable, but the evidence base is actually quite small. Therefore, statements regarding preserved ischemic threshold should be softened.

Response. We agree. We have softened statements suggesting preserved ischemic threshold or preserved coronary flow reserve. We now state that limited available data suggest that plaque burden and functional ischemia may not always align in athletes, but that this evidence is based on small cohorts, limited functional testing, and relatively few outcome data. The revised text avoids generalizing this concept to all endurance athletes.

 

 

Reviewer’s comment: 5. For a narrative review this is acceptable, but:

• only PubMed was searched,
• no PRISMA framework,
• no study selection diagram,
• no assessment of bias.

The review is therefore vulnerable to citation selection bias.

Response. We agree and have revised the Literature Search Strategy section accordingly. We now explicitly state that this is a narrative, non-systematic review and that no PRISMA flow diagram, formal risk-of-bias assessment, or meta-analysis was performed. We also acknowledge that the PubMed/MEDLINE-only strategy and selective inclusion of mechanistically relevant studies may introduce citation selection bias. To mitigate this limitation, we have added a dedicated statement explaining that we prioritized major athlete cohorts, longitudinal imaging studies, and contemporary reviews while acknowledging the non-systematic nature of the evidence synthesis.

 

 

Reviewer’s comment: 6. Figure 1 and Figure 2 add little scientific value. The figures simply display prevalence of CAC >100 across studies. 

The studies differ substantially regarding:

• age,
• risk profile,
• imaging methodology,
• athlete definition.

Direct visual comparison may be misleading.

Response. We agree with the Reviewer. We have removed the direct prevalence-comparison bar charts from the revised manuscript. To avoid misleading cross-study visual comparisons, we now summarize heterogeneity in Tables 1 and 2, including athlete definitions, age, comparator strategy, imaging method, key findings, and limitations. We have also added text cautioning against direct numerical comparison across heterogeneous cohorts.

 

 

Reviewer’s comment: 7. Master@Heart is arguably the most important contemporary dataset.

The manuscript mentions it repeatedly but does not fully explore the implications that lifelong athletes exhibited:

• more mixed plaque,
• more proximal plaque,
• more non-calcified plaque.

These findings challenge the "benign calcification" narrative and deserve more emphasis.

 

Response. We agree. We have expanded the discussion of the Master@Heart study in Section 3.1 and Section 3.2. The revised manuscript now emphasizes that Master@Heart challenges a simplified benign-calcification narrative by showing higher overall plaque burden and more proximal, mixed, and non-calcified plaques in lifelong endurance athletes compared with healthy controls. We now discuss this dataset as a central reason why athlete plaque phenotype should be interpreted as heterogeneous rather than uniformly benign.

 

 

Reviewer’s comment: 8. Female athletes section is underdeveloped. The review appropriately highlights sex differences. 

However, the section appears brief relative to the importance of the topic.

Additional discussion of:

• menopause,
• hormonal influences,
• underrepresentation of women,

would strengthen the manuscript.

Response. We agree. We have expanded the section on female athletes to include underrepresentation of women in available cohorts, the possible influence of estrogen and androgen profiles, menopause-related loss of vascular protection, atypical presentation of ischemic symptoms, and the need for dedicated prospective imaging and outcome studies in female athletes.

 

 

Reviewer’s comment: 9. The manuscript cites studies from 2026 despite being submitted in 2025. The authors should clarify publication status and ensure all references are citable.

 

Response. We thank the Reviewer for raising this point. We have clarified in the revised Literature Search Strategy that the manuscript was updated during revision to include studies published or available online ahead of print up to the final revision date. We have verified that the 2026 references cited in the manuscript are citable publications with journal details and DOI. Where any reference was not fully citable, it has been removed or replaced by the final published version.

 

Reviewer 2 Report

Comments and Suggestions for Authors

I congratulate the authors for pursing a proposed mechanobiological continuum that may reconcile imaging findings with physiological performance and provide a translational basis for monitoring and risk interpretation. This a proposed “unified framework”. The manuscript is very informative and well written.

However, there are a few details that need to be considered to both increase the readability but also to be transparent (avoid bias) and acknowledge earlier perspectives in the field that contribute to this approach. The quality of the article will be improved based on the following given the authors have not identified any limitations in the manuscript.

Major Concern: Article Type, Novelty Framing, and Literature Search Methodology

This manuscript is framed as a review—it is a narrative review—of exercise-induced coronary remodeling and adaptive vascular morphology in endurance athletes, with a focus on the so-called atherosclerotic paradox. However, several issues must be addressed before this manuscript can be considered.

1. Article Type Misalignment and Overstated Novelty

The title does not indicate that this is a narrative review, which may mislead readers about the article type.

Additionally, the introduction appears to overstate the novelty of describing this topic by focusing on a binary perspective. (The abstract does not mention this as a narrative review). Closely related reviews already exist on vascular adaptation in athletes, coronary atherosclerosis in endurance populations, and the exercise–coronary calcification paradox, all of which address related aspects of the atherosclerotic paradox in endurance athletes and even the multifactorial aspects of vascular adaptations. For example, Möhlenkamp et al. published a series of studies on marathon runners (2006, 2008, yes these are cited) examining coronary atherosclerosis and cardiovascular risk in master male marathon runners. Yet the article that gained significant attention was: Möhlenkamp S, Böse D, Mahabadi A, et al. On the paradox of exercise: coronary atherosclerosis in an apparently healthy marathon runner. (Nat Rev Cardiol. 2007;4:396–401. doi:10.1038/ncpcardio0926). Green et al. should also be mentioned, given its relevance and 2012 publication date (Green DJ, Spence A, et al., Vascular adaptation in athletes: is there an 'athlete's artery'? Exp Physiol. 2012 Mar;97(3):295–304. doi:10.1113/expphysiol.2011.058826). More recent reviews are included in the reference list (Hus et al., 2025; Celeski et al., 2024).

A more historically grounded introduction would appropriately acknowledge this existing literature and clarify the specific conceptual gap this review addresses. Suggest that the authors revise the framing to more accurately reflect the article type, explicitly acknowledge this existing literature, and clarify the distinction between coronary remodeling and broader vascular adaptation, and how this review differs from prior discussions of athlete plaque and calcification.

The title could also be revised to explicitly indicate that this is a narrative review and to clarify that the manuscript proposes a “unified framework”. For example: 'Exercise-Induced Coronary Remodeling and the Atherosclerotic Paradox in Endurance Athletes: A Narrative Review Proposing a Unified Framework.' This would improve transparency and align the title with the article type and aims.

2. Aim Statement Should Acknowledge Historical Context

The current aim statement reads: "The aim of this review is to integrate mechanical loading, endothelial mechanotransduction, structural remodeling, and functional performance into a unified framework. Specifically, we examine coronary remodeling as a load-conditioned biological response in endurance athletes."

A revised version: "The aim of this review is to integrate mechanical loading, endothelial mechanotransduction, structural remodeling, and functional performance into a unified framework. We begin by acknowledging the historical perspective on vascular adaptation in athletes and coronary atherosclerosis in endurance populations, including key work by Möhlenkamp et al. and Green et al., and then examine coronary remodeling as a load-conditioned biological response in endurance athletes, proposing a mechanobiological continuum to distinguish adaptive remodeling from pathological atherosclerosis." This actually gives the authors credit for their proposed work.

3. Literature Search Methodology Falls Below Scoping Review Standards

The literature search described in this manuscript falls well below even scoping review standards and introduces significant selection bias. This is a difficult situation as even narrative reviews should follow transparent methods (e.g., PRISMA-NR)

• Single database only: PubMed/MEDLINE only, excluding Embase, Scopus, Web of Science — introduces database bias
• No reproducible search strategy: Search terms listed but no actual search string, Boolean operators, or combination logic provided — impossible to replicate
• No dual review process: No mention of which authors screened the studies, were their any independent reviewers involved, or how disagreements were resolved to include or not include studies— introduces selection bias
• Vague selection criteria: "Prioritized according to clinical relevance, methodological rigor, imaging depth" without explicit thresholds — subjective and non-replicable
• Unjustified exclusions: 2000 start date excludes earlier foundational work; English-language only not justified

Recommendation: The authors should either:

• (a) Revise the search to meet at least scoping review standards (multiple databases, reproducible search string, dual review process, protocol registration per PRISMA-ScR), OR
• (b) Explicitly acknowledge that this is a selective narrative review with significant limitations in comprehensiveness, and reframe all conclusions as based on "selected evidence" rather than implying comprehensive synthesis.

4. Conclusion Overstates Certainty Given Methodological Limitations

The authors conclude that "lifelong endurance exercise does not uniformly prevent subclinical coronary atherosclerosis, particularly in older men with high cumulative exposure." However, as a narrative review with the methodological limitations described above, this manuscript may not have captured all available evidence. The conclusion should be framed more cautiously:

"The available evidence synthesized in this narrative review suggests that lifelong endurance exercise does not uniformly prevent subclinical coronary atherosclerosis, particularly in older men with high cumulative exposure, though systematic reviews and prospective data are needed to confirm this conclusion."

5. Figure Caption Language Is Imprecise for a Narrative Review

The figure caption states that the mechanisms shown are "hypothesis-generating rather than definitive." While narrative reviews can propose conceptual frameworks and suggest research questions, they do not generate hypotheses empirically. The authors should clarify that these are conceptually hypothesis-generating (i.e., suggesting future research directions) rather than empirically generated hypotheses, or rephrase to "conceptually informative and suggestive of future research" to avoid misleading readers.

Summary Recommendation

This manuscript requires substantial revision to:

1. Accurately identify the article type in the title and therefore revise the aim.
2. Acknowledge existing literature and foundational work with appropriate historical context
3. Either improve search methodology OR explicitly acknowledge limitations as a selective narrative review
4. Frame conclusions more cautiously given methodological limitations
5. Clarify figure caption language regarding "hypothesis-generating" claims.

Author Response

Reviewer’s comment:

I congratulate the authors for pursing a proposed mechanobiological continuum that may reconcile imaging findings with physiological performance and provide a translational basis for monitoring and risk interpretation. This a proposed “unified framework”. The manuscript is very informative and well written.

However, there are a few details that need to be considered to both increase the readability but also to be transparent (avoid bias) and acknowledge earlier perspectives in the field that contribute to this approach. The quality of the article will be improved based on the following given the authors have not identified any limitations in the manuscript.

 

Response:

We sincerely thank the Reviewer for the thoughtful and constructive comments, which helped us improve the clarity, transparency, and methodological framing of the manuscript.

In the revised version, all changes made in response to the Reviewer’s comments have been highlighted in yellow to facilitate review.

Below, we provide a point-by-point response.

 

 

Major Concern:

Reviewer’s comment: Article Type, Novelty Framing, and Literature Search Methodology

This manuscript is framed as a review—it is a narrative review—of exercise-induced coronary remodeling and adaptive vascular morphology in endurance athletes, with a focus on the so-called atherosclerotic paradox. However, several issues must be addressed before this manuscript can be considered.

1. Article Type Misalignment and Overstated Novelty

The title does not indicate that this is a narrative review, which may mislead readers about the article type.

Additionally, the introduction appears to overstate the novelty of describing this topic by focusing on a binary perspective. (The abstract does not mention this as a narrative review). Closely related reviews already exist on vascular adaptation in athletes, coronary atherosclerosis in endurance populations, and the exercise–coronary calcification paradox, all of which address related aspects of the atherosclerotic paradox in endurance athletes and even the multifactorial aspects of vascular adaptations. For example, Möhlenkamp et al. published a series of studies on marathon runners (2006, 2008, yes these are cited) examining coronary atherosclerosis and cardiovascular risk in master male marathon runners. Yet the article that gained significant attention was: Möhlenkamp S, Böse D, Mahabadi A, et al. On the paradox of exercise: coronary atherosclerosis in an apparently healthy marathon runner. (Nat Rev Cardiol. 2007;4:396–401. doi:10.1038/ncpcardio0926). Green et al. should also be mentioned, given its relevance and 2012 publication date (Green DJ, Spence A, et al., Vascular adaptation in athletes: is there an 'athlete's artery'? Exp Physiol. 2012 Mar;97(3):295–304. doi:10.1113/expphysiol.2011.058826). More recent reviews are included in the reference list (Hus et al., 2025; Celeski et al., 2024).

A more historically grounded introduction would appropriately acknowledge this existing literature and clarify the specific conceptual gap this review addresses. Suggest that the authors revise the framing to more accurately reflect the article type, explicitly acknowledge this existing literature, and clarify the distinction between coronary remodeling and broader vascular adaptation, and how this review differs from prior discussions of athlete plaque and calcification.

The title could also be revised to explicitly indicate that this is a narrative review and to clarify that the manuscript proposes a “unified framework”. For example: 'Exercise-Induced Coronary Remodeling and the Atherosclerotic Paradox in Endurance Athletes: A Narrative Review Proposing a Unified Framework.' This would improve transparency and align the title with the article type and aims.

 

Response:

We thank the Reviewer for this important comment and agree that the article type and conceptual framing should be made clearer. We have revised the title to explicitly identify the manuscript as a narrative review and to clarify that the manuscript proposes a unified mechanobiological framework. The revised title is: “Exercise-Induced Coronary Remodeling and the Atherosclerotic Paradox in Endurance Athletes: A Narrative Review Proposing a Unified Mechanobiological Framework.”

We have also revised the Abstract to explicitly state that this is a narrative review. In addition, the Introduction has been expanded to acknowledge the historical development of the field, including the early work by Möhlenkamp et al. on the paradox of exercise and coronary atherosclerosis in marathon runners, as well as the vascular adaptation framework proposed by Green et al. We also clarify that our manuscript does not claim to be the first to describe the athlete atherosclerotic paradox or vascular adaptation in athletes. Rather, its specific contribution is to integrate clinical coronary imaging findings, vascular mechanobiology, plaque phenotype, and functional performance into a coronary-focused adaptive–maladaptive continuum.

 

 

Reviewer’s comment:  2. Aim Statement Should Acknowledge Historical Context

The current aim statement reads: "The aim of this review is to integrate mechanical loading, endothelial mechanotransduction, structural remodeling, and functional performance into a unified framework. Specifically, we examine coronary remodeling as a load-conditioned biological response in endurance athletes."

A revised version: "The aim of this review is to integrate mechanical loading, endothelial mechanotransduction, structural remodeling, and functional performance into a unified framework. We begin by acknowledging the historical perspective on vascular adaptation in athletes and coronary atherosclerosis in endurance populations, including key work by Möhlenkamp et al. and Green et al., and then examine coronary remodeling as a load-conditioned biological response in endurance athletes, proposing a mechanobiological continuum to distinguish adaptive remodeling from pathological atherosclerosis." This actually gives the authors credit for their proposed work.

 

Response:

We agree. We have revised the aim statement in the Introduction to explicitly acknowledge the historical perspective on vascular adaptation in athletes and coronary atherosclerosis in endurance populations. The revised aim now clarifies that the review builds on prior work and proposes a coronary-specific mechanobiological continuum to distinguish adaptive remodeling from pathological atherosclerosis.

 

 

 

Reviewer’s comment: 3. Literature Search Methodology Falls Below Scoping Review Standards

The literature search described in this manuscript falls well below even scoping review standards and introduces significant selection bias. This is a difficult situation as even narrative reviews should follow transparent methods (e.g., PRISMA-NR)

• Single database only: PubMed/MEDLINE only, excluding Embase, Scopus, Web of Science — introduces database bias
• No reproducible search strategy: Search terms listed but no actual search string, Boolean operators, or combination logic provided — impossible to replicate
• No dual review process: No mention of which authors screened the studies, were their any independent reviewers involved, or how disagreements were resolved to include or not include studies— introduces selection bias
• Vague selection criteria: "Prioritized according to clinical relevance, methodological rigor, imaging depth" without explicit thresholds — subjective and non-replicable
• Unjustified exclusions: 2000 start date excludes earlier foundational work; English-language only not justified

Recommendation: The authors should either:

• (a) Revise the search to meet at least scoping review standards (multiple databases, reproducible search string, dual review process, protocol registration per PRISMA-ScR), OR
• (b) Explicitly acknowledge that this is a selective narrative review with significant limitations in comprehensiveness, and reframe all conclusions as based on "selected evidence" rather than implying comprehensive synthesis.

 

 

Response. We thank the Reviewer for this important methodological comment. We would like to clarify that the literature search was not limited to PubMed/MEDLINE. The original search strategy included PubMed/MEDLINE, Scopus, Web of Science, Embase, Cochrane Library, and Google Scholar, together with manual screening of references from major athlete cohorts, longitudinal imaging studies, contemporary state-of-the-art reviews, and relevant consensus documents. During manuscript revision and editing, only PubMed/MEDLINE was inadvertently reported in the Methods section. We apologize for this omission and have corrected the revised manuscript to accurately describe the full search strategy.

Nevertheless, we agree with the Reviewer that the manuscript was not designed as a scoping review or systematic review. Therefore, we have explicitly acknowledged this in the revised Methods section. Specifically, we now state that no PRISMA or PRISMA-ScR framework was applied, no protocol was registered, no formal dual-review screening process was performed, no PRISMA flow diagram was generated, and no structured risk-of-bias assessment was conducted. We also clarify that studies were selected and discussed according to their clinical relevance, methodological quality, imaging detail, mechanistic relevance, and contribution to the evolving concept of exercise-associated coronary remodeling and plaque phenotype in athletes. Accordingly, we have reframed the manuscript as a selective narrative review and have tempered the conclusions to indicate that they are based on selected evidence rather than on a comprehensive systematic synthesis.

 

Reviewer’s comment: 4. Conclusion Overstates Certainty Given Methodological Limitations

The authors conclude that "lifelong endurance exercise does not uniformly prevent subclinical coronary atherosclerosis, particularly in older men with high cumulative exposure." However, as a narrative review with the methodological limitations described above, this manuscript may not have captured all available evidence. The conclusion should be framed more cautiously:

"The available evidence synthesized in this narrative review suggests that lifelong endurance exercise does not uniformly prevent subclinical coronary atherosclerosis, particularly in older men with high cumulative exposure, though systematic reviews and prospective data are needed to confirm this conclusion."

 

Response. We agree. We have revised the Conclusions to avoid overstating certainty. Specifically, we now state that the available evidence synthesized in this narrative review suggests that lifelong endurance exercise does not uniformly prevent subclinical coronary atherosclerosis, particularly in older men with high cumulative exposure, while emphasizing that systematic evidence synthesis and prospective outcome studies are needed to confirm this conclusion.

 

 

Reviewer’s comment: 5. Figure Caption Language Is Imprecise for a Narrative Review

The figure caption states that the mechanisms shown are "hypothesis-generating rather than definitive." While narrative reviews can propose conceptual frameworks and suggest research questions, they do not generate hypotheses empirically. The authors should clarify that these are conceptually hypothesis-generating (i.e., suggesting future research directions) rather than empirically generated hypotheses, or rephrase to "conceptually informative and suggestive of future research" to avoid misleading readers.

 

Response. We agree with the Reviewer’s distinction. We have revised the figure captions to avoid implying that hypotheses were empirically generated by this review. We now describe the proposed mechanisms as “conceptually informative and suggestive of future research directions” rather than “hypothesis-generating.” This clarification has been applied to the captions of the mechanistic and sex-difference figures.

 

Reviewer’s comment: Summary Recommendation

This manuscript requires substantial revision to:

1. Accurately identify the article type in the title and therefore revise the aim.
2. Acknowledge existing literature and foundational work with appropriate historical context
3. Either improve search methodology OR explicitly acknowledge limitations as a selective narrative review
4. Frame conclusions more cautiously given methodological limitations
5. Clarify figure caption language regarding "hypothesis-generating" claims.

 

Response:

Overall, we have revised the manuscript to: (1) explicitly identify the article as a narrative review in the title and abstract; (2) provide a more historically grounded introduction acknowledging foundational and contemporary literature; (3) clarify the distinction between broader vascular adaptation and coronary-specific remodeling; (4) improve transparency regarding the literature search strategy while acknowledging the limitations of a selective narrative review; (5) frame conclusions more cautiously; and (6) revise figure caption language to avoid overstatement.