Metabolically Healthy Obesity Versus Metabolic Obesity on Long-Term Major Adverse Cardiovascular Events and Mortality in Women with Suspected Ischemic Heart Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have conducted interesting original research with follow-up that demonstrated the differences in CVD risks, MACE, and mortality between female patients with obesity and MS depending on weight. The article is well-structured and well-conducted; however, the discussion and conclusion could be improved.

 

Major points,

 

-In the discussion, this paragraph, lines 202-204, “ In this study, compared to MH-NW, women with stable IHD and 202 MH-obesity had a significantly lower risk of long-term MACE and all-cause mortality. We 203 also found a similar trend towards lower risk of MACE and all-cause mortality in MH-204 overweight women”)… seems repetitive in information as the first paragraph in this section (line 198-200). I suggest rephrasing and including in this section a small paragraph in which the connection between obesity and coronary artery disease, obstructive CAD, and IHD; and between MS and CAD is detailed (example: the impact of insulin resistance and BP in accelerated aortic stiffening, adipose cells, and endothelial dysfunction);

 

-Additionally, the authors found that MS-NW has the lowest systolic and diastolic blood pressure, and the highest fasting blood glucose; these aspects are interesting and worth discussing in relation to CAD, and higher rates of MACE and mortality. Moreover, the demographic/baseline characteristics mentioned that 24 out of 31 patients in post-menopause in the MS-NW group, and a higher proportion of History of HRT in the MH-obesity group. Given the hormonal changes over the years and their influence, data about this relationship and CVD can be highlighted.

 

-The Limitations could include the more specific: lack of medication and doses, such as antihypertensive of statin, or changes over time, lack of disease severity.

-The conclusions can be rephrased and enriched with new perspectives opened by this research, including studies that should investigate these differences in male gender. 

 

There are some grammatical mistakes throughout the manuscript that need correction:

Abstract “ Line 39 – the “ :” can be deleted.

Figure 1. Line 189” free survival [A] and surivial [B] needs correction.

Line 250 “ medial treatment …” needs correction.

Supplimentary Table 1. “Metabolic Sydrome”

Comments on the Quality of English Language

There are some grammatical mistakes throughout the manuscript that need correction, as well as duplicated phrases. Check the manuscript for any other errors.  

Author Response

Reviewer 1

 

The authors have conducted interesting original research with follow-up that demonstrated the

differences in CVD risks, MACE, and mortality between female patients with obesity and MS depending on weight. The article is well-structured and well-conducted; however, the discussion and conclusion could be improved.

           Response: We thank the reviewer for their review and suggestions to strengthen the

manuscript. We have revised the discussion and conclusion as suggested.

 

1. In the discussion, this paragraph, lines 202-204, “In this study, compared to MH-NW, women with stable IHD and 202 MH-obesity had a significantly lower risk of long-term MACE and all-cause mortality. We 203 also found a similar trend towards lower risk of MACE and all-cause mortality in MH-204 overweight women”)… seems repetitive in information as the first paragraph in this section (line 198-200). I suggest rephrasing and including in this section a small paragraph in which the connection between obesity and coronary artery disease, obstructive CAD, and IHD; and between MS and CAD is detailed (example: the impact of insulin resistance and BP in accelerated aortic stiffening, adipose cells, and endothelial dysfunction).

Response: Thank you for this suggestion to improve the discussion. We have completely revised paragraph 2 and 3 in the discussion. In paragraph 2 we have elaborated the relationship between obesity and CAD and IHD. In paragraph 3 we have elaborated the relationship between MS and CAD and IHD.

 

2. Additionally, the authors found that MS-NW has the lowest systolic and diastolic blood pressure, and the highest fasting blood glucose; these aspects are interesting and worth discussing in relation to CAD, and higher rates of MACE and mortality. Moreover, the demographic/baseline characteristics mentioned that 24 out of 31 patients in post-menopause in the MS-NW group, and a higher proportion of History of HRT in the MH-obesity group. Given the hormonal changes over the years and their influence, data about this relationship and CVD can be highlighted.

           Response: Thank you for this important suggestion. We have rewritten paragraph 2  

and 3 to include these observations in the context of our results.

 

3. The Limitations could include the more specific: lack of medication and doses, such as antihypertensive of statin, or changes over time, lack of disease severity.

Response: We have expanded the limitations to include all the limitations outlined by the reviewer. We do have disease severity which is captured by the CAD severity score reported in Table 1 and adjusted for this in our models for MACE and mortality.

 

4. The conclusions can be rephrased and enriched with new perspectives opened by this research, including studies that should investigate these differences in male gender.

           Response: We have rewritten the conclusion to address this important comment.

 

5. There are some grammatical mistakes throughout the manuscript that need correction:

Abstract “ Line 39 – the “ :” can be deleted.

Figure 1. Line 189” free survival [A] and surivial [B] needs correction. Line 250 “ medial treatment …” needs correction.

Supplemental Table 1. “Metabolic Sydrome”

           Response: Thank you. We have corrected the grammatical mistakes.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents an observational analysis of women with suspected ischemic heart disease (IHD), investigating the relationship between metabolic status, body weight, and long-term cardiovascular outcomes. The topic is relevant and clinically important, particularly given the ongoing debate on "metabolically healthy obesity” and the obesity paradox in cardiovascular disease. Overall, this is a well-conducted secondary analysis of a valuable cohort. The findings challenge simplistic BMI-based risk paradigms and emphasize metabolic status over weight alone. However, I have some concerns:

1. MACE is not clearly defined in the methods section. Please specify components (e.g., MI, stroke, revascularization, cardiovascular death).
2. The cohort consists of women referred for angiography, not a general population. This limits extrapolation to asymptomatic or lower-risk women.

 

Author Response

Reviewer 2

This manuscript presents an observational analysis of women with suspected ischemic heart disease (IHD), investigating the relationship between metabolic status, body weight, and long-term cardiovascular outcomes. The topic is relevant and clinically important, particularly  given the ongoing debate on "metabolically healthy obesity” and the obesity paradox in cardiovascular disease. Overall, this is a well-conducted secondary analysis of a valuable cohort. The findings challenge simplistic BMI-based risk paradigms and emphasize metabolic status over weight alone. However, I have some concerns:

           Response: We appreciate the reviewers positive review of our study. We have

addressed the two concerns raised by the reviewer as outlined below.

 

1. MACE is not clearly defined in the methods section. Please specify components (e.g., MI, stroke, revascularization, cardiovascular death).

Response: MACE was defined in the Methods section titled Follow-up and Cardiovascular Events. MACE included all-cause death, nonfatal myocardial infarction, stroke, or congestive heart failure.

 

2. The cohort consists of women referred for angiography, not a general population. This limits

extrapolation to asymptomatic or lower-risk women.

           Response: We have added this important point to our limitations paragraph in the

discussion.

Reviewer 3 Report

Comments and Suggestions for Authors

 This manuscript investigates a clinically important and timely topic by examining the relationship between metabolic status, body weight, and long-term cardiovascular outcomes in women with suspected ischemic heart disease. The subject is relevant, particularly because the interaction between obesity, metabolic syndrome, and cardiovascular risk remains complex, and sex-specific data are still limited. The study benefits from the use of a well-characterized cohort, clearly defined metabolic and body weight categories, angiographic assessment of coronary artery disease, and long-term follow-up for major adverse cardiovascular events and all-cause mortality. The finding that metabolically healthy obesity was associated with lower risk of MACE and mortality, whereas metabolic syndrome in normal-weight women was associated with higher odds of obstructive CAD and greater cardiovascular risk, is interesting and potentially impactful.

However, several minor issues should be addressed before publication. First, the manuscript would benefit from careful language editing, as there are multiple grammatical errors, awkward phrases, spacing inconsistencies, and typographical issues throughout the text that reduce readability. For example, some sentences in the abstract and discussion could be made more concise and clearer, and terminology should be standardized across the manuscript. Second, although the discussion addresses the “obesity paradox” and compares the findings with previous reports, it would be helpful if the authors more clearly distinguished between hypothesis-generating interpretation and evidence-based conclusions, especially when discussing the possible protective role of metabolically healthy obesity. The mechanistic explanation is interesting, but it should be presented more cautiously.

Third, the limitations section should be expanded slightly and emphasized more clearly. The authors do mention the limitations of BMI and the lack of visceral fat assessment, as well as the possibility that metabolic status and body weight may have changed over time, but these are highly important issues and deserve stronger emphasis because they directly affect interpretation of the results. In particular, the absence of longitudinal reassessment of metabolic phenotype may be important when drawing conclusions about long-term outcomes. In addition, the potential influence of treatment differences after angiography should be stated more explicitly in the discussion, not only in the limitations section.

Fourth, the statistical methodology is generally appropriate, but the presentation of the multivariable modeling strategy could be clarified further for readers. The use of stepwise selection is reported, yet a short justification for this approach and a brief comment on possible overfitting or residual confounding would improve transparency. Similarly, it may be useful to make clearer in the results or figure legends exactly which covariates remained in the final adjusted models for MACE and mortality, so that readers can interpret the effect estimates more easily.

Finally, the overall presentation of the manuscript could be improved by simplifying certain tables and figures, and by ensuring that the central message is more directly highlighted. Table 1 is detailed and informative, but a more focused presentation of the most clinically relevant differences between groups may help readability. In the discussion and conclusion, the authors should also avoid overstating the implications of observational associations and instead underline that these findings are hypothesis-generating and require confirmation in other cohorts. 

Author Response

Reviewer 3

This manuscript investigates a clinically important and timely topic by examining the relationship between metabolic status, body weight, and long-term cardiovascular outcomes in women with suspected ischemic heart disease. The subject is relevant, particularly because the interaction between obesity, metabolic syndrome, and cardiovascular risk remains complex, and sex-specific data are still limited. The study benefits from the use of a well-characterized cohort, clearly defined metabolic and body weight categories, angiographic assessment of coronary artery disease, and long-term follow-up for major adverse cardiovascular events and all-cause mortality. The finding that metabolically healthy obesity was associated with lower risk of MACE and mortality, whereas metabolic syndrome in normal-weight women was associated with higher odds of obstructive CAD and greater cardiovascular risk, is interesting and potentially impactful. However, several minor issues should be addressed before publication.

           Response: We appreciate the reviewers positive review of our study. We have

addressed the minor issues raised by the reviewer as outlined below.

 

1. First, the manuscript would benefit from careful language editing, as there are multiple grammatical errors, awkward phrases, spacing inconsistencies, and typographical issues throughout the text that reduce readability. For example, some sentences in the abstract and discussion could be made more concise and clearer, and terminology should be standardized across the manuscript.

Response: Thank you for raising this important point. We have carefully reviewed and edited the language. We have standardized terms to be in line with current literature using the terms metabolically health obesity (MHO) which represents obesity but no metabolic syndrome and metabolically obese, normal weight (MO-NW) which represent individual with metabolic syndrome and normal BMI. We have also rewritten the abstract and discussion to make more concise and clearer.

 

2. Second, although the discussion addresses the “obesity paradox” and compares the findings with previous reports, it would be helpful if the authors more clearly distinguished between hypothesis-generating interpretation and evidence-based conclusions, especially when discussing the possible protective role of metabolically healthy obesity. The mechanistic explanation is interesting, but it should be presented more cautiously.

Response: Thank you for raising this important point. We have added a sentence to make it clear that this is hypothesis generating and future studies are needed to determine the role of MHO in the obesity paradox. We have rewritten paragraph 4 on the mechanistic explanation to indicate that these are hypothesis generating and warrant investigation is future studies.

 

3. Third, the limitations section should be expanded slightly and emphasized more clearly. The authors do mention the limitations of BMI and the lack of visceral fat assessment, as well as the possibility that metabolic status and body weight may have changed over time, but these are highly important issues and deserve stronger emphasis because they directly affect interpretation of the results. In particular, the absence of longitudinal reassessment of metabolic phenotype may be important when drawing conclusions about long-term outcomes. In addition, the potential influence of treatment differences after angiography should be stated more explicitly in the discussion, not only in the limitations section.

           Response: We have expanded the limitations to emphasize the absence of

longitudinal reassessment of metabolic phenotype. We also stated in the discussion the

influence of treatment difference after angiography on the results.   

 

4. Fourth, the statistical methodology is generally appropriate, but the presentation of the multivariable modeling strategy could be clarified further for readers. The use of stepwise selection is reported, yet a short justification for this approach and a brief comment on possible overfitting or residual confounding would improve transparency.

Response: Thank you for this thoughtful comment. To address this, we have expanded our explanation in the Methods section and added a dedicated acknowledgment in the limitations section. Specifically, we now clarify that stepwise selection was used as an exploratory variable selection approach to identify a parsimonious set of independent predictors from a large pool of candidate variables. This was done with the ultimate goal of building streamlined final models, which should ideally be validated in independent cohorts.

 

5. Similarly, it may be useful to make clearer in the results or figure legends exactly which covariates remained in the final adjusted models for MACE and mortality, so that readers can interpret the effect estimates more easily.

           Response: We have now added the variables included in each model in the table

and figure legends.

 

6. Finally, the overall presentation of the manuscript could be improved by simplifying certain tables and figures, and by ensuring that the central message is more directly highlighted. Table 1 is detailed and informative, but a more focused presentation of the most clinically relevant differences between groups may help readability.

Response: We agree that by accounting for the 6 groups our tables and figures are busy. We have removed some variables in Table 1 that were not significant and reduced the Table to 1 page. However, we think it is important to show all 6 groups. We can remove the p-value if the reviewer recommends.

 

7. In the discussion and conclusion, the authors should also avoid overstating the implications of observational associations and instead underline that these findings are hypothesis-generating and require confirmation in other cohorts.

           Response: We have edited the discussion and conclusion to emphasize that these

findings are hypothesis-generating and require confirmation in other cohorts.