Interrelationship Between Sarcopenia, Frailty and Cardiovascular Disease—The Crucial Role of Obesity in Hypothesis Generation—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript represents a partial literature review of risk factors for cardiovascular disease including sarcopenia, frailty, and obesity.

Systematic reviews should include a Prisma flow diagram, absent in this manuscript.

The authors do not define sarcopenia or frailty nor control for studies which meet inclusion criteria.  It is generally excepted that sarcopenia, frailty, and obesity are known risk factors for cardiovascular disease,  however determining the contribution of each factor toward this risk is difficult in heterogeneous populations.  The authors especially do not discuss the obesity survival paradox in older adults with sarcopenia.

The authors utilize selected references to support a hypothesis that sarcopenia and frailty are a continuum as opposed to overlapping conditions and further posit that obesity appears to be crucial in determining cardiovascular risk in both conditions.  Unfortunately these hypotheses remain untested contractures.

The fatal flaws discussed above preclude this manuscript from being a contribution to the literature.

Author Response

Many thanks for your comments and suggestions to improve the manuscript. We have attempted to answer each point.

 

1. Systematic reviews should include a Prisma flow diagram, absent in this manuscript.

 

Response: We agree that systematic reviews should now include a Prisma flow diagram as a gold standard. However, our manuscript is a narrative review which does require such a precise flow diagram as we did not employ a rigid, step-by-step database search strategy. We have, nevertheless, appropriately clarified the methods section and the title of our manuscript that it is a narrative review. We also added a simple flow diagram of study selection for completeness. Thank you again for this comment.  

 

2. The authors do not define sarcopenia or frailty nor control for studies which meet inclusion criteria.

 

Response:  Thanks, we have added these definitions early on, in the manuscript. For this point of inclusion and exclusion criteria, we have made it clear that our aim is not the main outcome of the studies.  We have proposed a hypothesis that sarcopenia and frailty are metabolically heterogeneous conditions and we believe, from clinical observation and our previous publications (please see below), that these conditions span across a metabolic spectrum with sarcopenic obese frail phenotype at one end of the spectrum and anorexic malnourished phenotype at the other end.  

 

Therefore, our main aim was to look at the anthropometric characteristics of the participants of the studies to prove our hypothesis.  To clarify this point further, we have:

 

1. Added Box 1 to make the aim of the review clear.

 

1. Re-arranged to tow tables. Instead of sarcopenia in table 1 and frailty table 2, changed to high BMI participants in table 1 (showing association with cardiovascular disease) and low BMI participants in table 2 (showing less association with cardiovascular disease).

 

3. It is generally expected that sarcopenia, frailty, and obesity are known risk factors for cardiovascular disease, however determining the contribution of each factor toward this risk is difficult in heterogeneous populations.

 

Response: Yes, we agree that it is fundamentally difficult (without more research in this area) to quantify contributions/impact of these risk factors. However, please see above as our main aim is not centred precisely on cardiovascular risk but to demonstrate that when sarcopenia or frailty was suspected to be a risk factor for cardiovascular disease, the participants of these studies were either overweight or obese in line with our hypothesis that the obese end of the sarcopenia-frailty syndrome is associated with cardiovascular risk.  The anorexic participants with significant weight loss and low insulin resistance and less prevalent cardiovascular risk factors are consequently less associated with cardiovascular risk.

 

4. The authors especially do not discuss the obesity survival paradox in older adults with sarcopenia.

 

Response: Thank you for this observation and our omission. We are not certain that such a benefit operates in complex, older or frail adults. Survival benefit in the obese sarcopenic phenotype would be difficult to observe because of the heightened CV risk, increased rate of frailty, and functional loss. Nevertheless, we have added a brief comment on this point in the future perspective section, but we feel this is a very important point, and a new future review addressing this topic is warranted.  

 

5. The authors utilize selected references to support a hypothesis that sarcopenia and frailty are a continuum as opposed to overlapping conditions and further posit that obesity appears to be crucial in determining cardiovascular risk in both conditions.

 

Response: Thank you. We feel justified in doing this. We feel that existing datasets routinely look at both conditions separately and by doing so, create an artificial divide – we speculate that this divide does not exist biologically!

 

We have already discussed that there is a significant overlap between sarcopenia and frailty, in terms of the diagnosis of each condition.  From metabolic and cardiovascular risk points, we have introduced the term sarcopenia-frailty syndrome to combine both conditions as the studies on their cardiovascular risk did not differentiate between each condition as we have mentioned above.  In other words, sarcopenia subjects in sarcopenia studies may well have frailty as well but not diagnosed and vice versa in frailty studies.  So, it is difficult to quantify the cardiovascular risk of one condition independent of the other.  Future research may elucidate this point.

 

6. Unfortunately, these hypotheses remain untested contractures. The fatal flaws discussed above preclude this manuscript from being a contribution to the literature.

 

Response: We are disappointed you feel this way and we wonder if this represents an over-critical comment?  We therefore do not agree that this narrative review will not be a useful addition to the literature.

 

We accept that this manuscript provides indirect evidence from literature.  None of the studies were set to test the effect of body composition on cardiovascular risk in sarcopenic or frail participants.  We have provided enough evidence in table 1 and table 2 to divide the studies by body weight and metabolic profile of the participants and it appears that there is a consistency among the studies.  High BMI participants have high cardiovascular risk and low BMI participants have low cardiovascular risk.  As before, we believe that, this is a contribution to the literature as no manuscript exists, which examines this area in any detail is available in the literature. 

 

References:

 

Abdelhafiz AH, Emmerton D, Sinclair AJ. Impact of frailty metabolic phenotypes on the management of older people with type 2 diabetes mellitus. Geriatr. Gerontol. Int. 2021; 21: 614–622. https://doi.org/10.1111/ggi.14214

 

Abdelhafiz AH, Keegan GL, Sinclair AJ. Metabolic Characteristics of Frail Older People with Diabetes Mellitus-A Systematic Search for Phenotypes. Metabolites. 2023 May 29;13(6):705. doi: 10.3390/metabo13060705. 

 

Sinclair AJ, Abdelhafiz AH. Metabolic Impact of Frailty Changes Diabetes Trajectory. Metabolites. 2023 Feb 16;13(2):295. doi: 10.3390/metabo13020295. 

 

Reviewer 2 Report

Comments and Suggestions for Authors

The methodology should be strengthened by providing more detailed information regarding the literature search process. Specifically, the authors should clearly state the time period covered by the literature search (e.g., the years searched or the search end date). In addition, a flowchart illustrating the study selection process (e.g., identification, screening, eligibility, and inclusion of studies) should be included to improve the transparency and reproducibility of the review.

 

In addition, the authors frequently refer to "several studies" throughout the manuscript, yet only a single reference is often provided. Please carefully review the manuscript and ensure that all such statements are supported by the appropriate references.

Please define cardiovascular risk factors and provide them in the search terms. Further, the authors. The search strategy appears to be limited. Although the authors included terms such as "cardiovascular disease," or "cardiovascular risk," or "insulin resistance," additional cardiovascular-related search terms (e.g., cardiovascular events, coronary artery disease, heart failure, stroke, myocardial infarction) or insulin resistance-related search terms (e.g., diabetic) should be incorporated to ensure a more comprehensive identification of relevant studies.

Author Response

Many thanks for your comments and suggestions to improve the manuscript.

 

1. The methodology should be strengthened by providing more detailed information regarding the literature search process. Specifically, the authors should clearly state the time period covered by the literature search (e.g., the years searched or the search end date). In addition, a flowchart illustrating the study selection process (e.g., identification, screening, eligibility, and inclusion of studies) should be included to improve the transparency and reproducibility of the review.

 

Response: Thank you. We have previously made it clear that it is a narrative review.  In response to your comment, we have reviewed the methods section and we have added a flow chart diagram for study selection. We hope that this is sufficient.

 

2. In addition, the authors frequently refer to "several studies" throughout the manuscript, yet only a single reference is often provided. Please carefully review the manuscript and ensure that all such statements are supported by the appropriate references.

 

Response: Thank you. You will see that we have reviewed this important point across the manuscript.

 

3. Please define cardiovascular risk factors and provide them in the search terms. The search strategy appears to be limited. Although the authors included terms such as "cardiovascular disease," or "cardiovascular risk," or "insulin resistance," additional cardiovascular-related search terms (e.g., cardiovascular events, coronary artery disease, heart failure, stroke, myocardial infarction) or insulin resistance-related search terms (e.g., diabetic) should be incorporated to ensure a more comprehensive identification of relevant studies.

 

Response: Thank you. Yes, you are correct to point out these omissions. We have consequently added this in the methods section.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript is improved in terms of defining terms and with respect to methodology explaining the literature review. However, it continues to overstate the results and overspeculates on clinical treatment rationales.

 

My opinion is that the work represents generation of a hypothesis based on literature review.

I would organize the abstract in a fashion similar to below:

• Introduction: Sarcopenia and frailty are emerging independent risk factors for cardiovascular disease. Sarcopenia represents a decline in function associated with reduced muscle mass. Frailty defined as a phenotype or multiple stress model is associated with weakness and a decline in organ reserve with vulnerability to disease. Frailty and sarcopenia may overlap and have shared clinical risk factors including age and malnutrition.
• Methods: We performed a literature review of published studies on frailty and sarcopenia with respect to cardiovascular risk factors and body composition.
• Results: Studies demonstrated that obese sarcopenic or obese frail subjects had higher prevalence of cardiovascular risk factors such as hypertension, diabetes mellitus, dyslipidaemia, smoking and sedentary lifestyle, which was highly associated with cardiovascular disease. On the other hand, anorexic malnourished frail participants with unintentional weight loss or sarcopenic subjects without obesity had low prevalence of cardiovascular risk factors, which was less associated with cardiovascular disease. 
• Conclusion: Obesity appears to play a crucial role in mediating the cardiovascular risk of both sarcopenic or frail patients.

 

Recommend adding the word “hypothesis” to the title and shortening the manuscript avoiding over interpretation of the findings and extension to clinical treatment rationales. I would revise the manuscript according to the outline in the abstract above. Box 1 and Figure 2 are not helpful. If the authors wish to use the graphic abstract as their hypothesis, this may be presented in the discussion with recommendations to focus prevention on obesity sub populations and for future controlled studies.

Author Response

Thank you to Reviewer 1 for these further comments. We have re-written the abstract as directed by Reviewer 1 in his own design. We have changed the title to include reference to a 'hypothesis':

Interrelationship between sarcopenia, frailty and cardiovascular disease - the crucial role of obesity in hypothesis generation - a narrative review

I am afraid we disagree with this reviewer that Box 1 (it represents a concise summary of where we were before this work and how this work adds to the literature) and Figure 2 (a simple schematic representation of how multiple biological overlaps occur commonly in sarcopenia and frailty) and have therefore not removed them. 

We feel we have added significant changes to the manuscript already in the light of the Reviewers comments (particularly Reviewer 1) and do not feel that further changes the manuscript are necessary in this narrative review. 

We are submitting the 2nd revision (with changes in highlighted text). We cannot upload a 'clean' version as the site does not allow a second file. We hope that the responses we have given will lead to acceptance of our manuscript which has definitely improved in the light of the Reviewers and Editor's comments. 

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript is accepted. 

Author Response

Thank you indeed for your generous and supportive comments. Our manuscript has improved as a consequence of this.