A Systematic Review on the Risk Modulators of Myocardial Infarction in the “Young”—Implications of Lipoprotein (a)

Round 1

Reviewer 1 Report (New Reviewer)

This manuscript reviewed the Risk Factors of Myocardial Infarction in the “young” – Implications of Lipoprotein (a).It’s rather important work. However, before it can be accepted for publication, there’re still several issues must be addressed:

 1. The main purpose of this review is to introduce a novel Risk Factors of Myocardial Infarction in the ”young” – Implications of Lipoprotein (a). However ,the authors have given too much detailed description about myocardial infarction related to traditional cardiovascular risk factors in young patients, which are already well known.

2.Lp(a) should be interpreted more as a “risk modulator”, rather than a distinct parameter of Myocardial Infarction. Hence, it should be better to change the title into “the Risk modulator of Myocardial Infarction in the “young” – Implications of Lipoprotein (a).”

Author Response

Dear Reviewer,

Our team would like to deeply thank you for the positive manuscript appreciation and for all your valuable suggestions. We have applied all the suggested text modifications, and we strongly believe your input was crucial to the global value of the manuscript. We have carefully addressed your comments and have revised our manuscript accordingly. Revised portions are highlighted in red.

Thanks again for your helpful comments.

We greatly appreciate your comments and suggestions and hope that with these alterations, our manuscript will be acceptable for publication. We remain prepared to further revise our manuscript should it be required.

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 2 Report (New Reviewer)

The present study represents an interesting short review of the classic risk factors for myocardial infarction from the perspective of the young population, respectively a synthesis of the role of lipoprotein A in myocardial infarction in young people.

I suggest the introduction of a short section related to the involvement of periodontal disease, a recently identified risk factor in the occurrence of acute coronary syndromes and which presents an increased incidence among young patients. From this point of view, I find an approach to the new risk factors for acute coronary syndrome, more actual and interesting and probably with greater implication in the young population. For this reason, I would not overlook at least the short review of other newer risk factors in the occurrence of acute coronary syndromes in young people.

I suggest the introduction of a short part about the involvement of COVID 19 in myocardial infarction in young people.

Author Response

Dear Reviewer,

Our team would like to deeply thank you for the positive manuscript appreciation and we strongly believe that your input was crucial to the global value of the manuscript. We have applied all the suggested text modifications, and we strongly believe your input was crucial to the global value of the manuscript. We have carefully addressed your comments and have revised our manuscript accordingly. Revised portions are highlighted in red.

Thanks again for your helpful comment.

We greatly appreciate your comments and suggestions and hope that with these alterations, our manuscript will be acceptable for publication. We remain prepared to further revise our manuscript should it be required.

Please see the attachment.

Author Response File: Author Response.docx

Reviewer 3 Report (New Reviewer)

A VERY INTERESTING REVIEW, REGARDING Lp(a) LEVELS IN YOUNG CVD PATIENTS. IT IS A WELL WRITTEN AND COMPREHENSIVE PAPER.

Author Response

Dear Reviewer,

Our team would like to deeply thank you for the positive manuscript appreciation and for all your valuable comments.

Thanks again for your helpful comment.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

In this review, Statescu provide a summary of literature pertinent to ASCVD risk in young patients, with special focus on Lp(a). The review is well-written, althought an English grammar revision is recommended.

Data should be added on pharmacological agents targeting directly Lp(a). For example, a Phase 1 trial with olpasiran has recently been published in NEJM (NCT04270760). Furthermore, the authors should gather data on whether Lp(a) is still a predictor in high-risk CVD patients with LDL values are on target.

The quotation marks around 'young' should be removed.

The figure contains no specific information. Its resolution is not compatible with publication.

Author Response

Dear Reviewer,

Our team would like to deeply thank you for the positive manuscript appreciation and for all your valuable suggestions. We have applied all the suggested text modifications, and we strongly believe your input was crucial to the global value of the manuscript. We have carefully addressed your comments and have revised our manuscript accordingly. Revised portions are highlighted in red.

Q1: The review is well-written, although an English grammar revision is recommended.

Response 1: Thank you for your suggestion. We revised the English grammar.

Q 2: Data should be added on pharmacological agents targeting directly Lp(a). For example, a Phase 1 trial with olpasiran has recently been published in NEJM (NCT04270760). Furthermore, the authors should gather data on whether Lp(a) is still a predictor in high-risk CVD patients with LDL values are on target.

Response 2: Thank you very much this suggestion. We added more information regarding this issue (lines 58-62, 533-538 and lines 551-554).

            Lp(a) has some pleiotropic effects on atherosclerotic cardiovascular disease: promotes atherosclerosis due to its LDL moiety, promotes thrombosis due to its similarity with plasminogen, and promotes arterial wall inflammation due to the oxidized phospholipids [9,10]. Thus, targeting Lp(a) seems to be at least as important as LDLc reduction, even in patients with LDLc values on target.

            Another phase 2 trial designed to evaluate the efficacy and safety of olpasiran, a small interfering RNA molecule that prevents assembly of the lipoprotein (a) particle in the hepatocyte, was recently published. In this study, olpasiran led to a significant and sustained reduction in the Lp(a) concentration, when administered every 12 weeks, in patients with established atherosclerotic cardiovascular disease and a Lp(a) concentration of more than 150 nmol per litre [131].

            The impact of Olpasiran on major cardiovascular events in patients with atherosclerotic cardiovascular disease and elevated lipoprotein(a) is currently being studied in a phase 3 trial which is expected to be completed by the end of 2026.

Q3: The quotation marks around 'young' should be removed.

Response 3: Thank you very much for your suggestion. We revised the manuscript.

Q4: The figure contains no specific information. Its resolution is not compatible with publication.

Response 4: Thank you very much for your suggestion. We revised the figure.

Figure 1. Risk factors of myocardial infarction in the young.

AMI, acute myocardial infarction.

Thanks again for your helpful comment.

We greatly appreciate your comments and suggestions and hope that with these alterations, our manuscript will be acceptable for publication. We remain prepared to further revise our manuscript should it be required.

Author Response File: Author Response.docx

Reviewer 2 Report

It is a very extensive and detailed text with respect to acute myocardial infarction among young people. Thank you for this great effort.

However, the number of references can be reduced if possible. 

Author Response

Dear Reviewer,

Our team would like to deeply thank you for the positive manuscript appreciation and we strongly believe that your input was crucial to the global value of the manuscript.

Q1: The number of references can be reduced if possible.

Response 1: Thank you very much for your suggestion. We revised the references and reduced the number of references, as much as possible.

Thanks again for your helpful comment.

We greatly appreciate your comments and suggestions, and hope that with these alterations, our manuscript will be acceptable for publication. We remain prepared to further revise our manuscript should it be required.

Author Response File: Author Response.docx

Reviewer 3 Report

Authors summarized risk factors of AMI in younger patients, and this review is wide-ranging and very well compiled. Although authors presented one-third of CAD in Indian were <45 years and pose the well-known problem that distribution of AMI varies greatly depending on race or ethnicity, however this topic has not been discussed in this review. I recommend to add the statement on this topic. If necessary, please refer to the following current article on the association between incidence rates of AMI and  races/ethnicities; Gloria C. Chi et al. J Am Heart Assoc. 2020 Mar 3; 9(5): e013542.

Author Response

Dear Reviewer,

Our team would like to deeply thank you for the positive manuscript appreciation and for all your valuable suggestions. We have applied all the suggested text modifications, and we strongly believe your input was crucial to the global value of the manuscript. We have carefully addressed your comments and have revised our manuscript accordingly. Revised portions are highlighted in red.

Q1: Authors summarized risk factors of AMI in younger patients, and this review is wide-ranging and very well compiled. Although authors presented one-third of CAD in Indian were <45 years and pose the well-known problem that distribution of AMI varies greatly depending on race or ethnicity, however this topic has not been discussed in this review. I recommend to add the statement on this topic. If necessary, please refer to the following current article on the association between incidence rates of AMI and races/ethnicities; Gloria C. Chi et al. J Am Heart Assoc. 2020 Mar 3; 9(5): e013542.

Response 1: Thank you very much for your suggestion. We included this topic in our manuscript, as follows (lines 105-113):

Regarding the trends in acute myocardial infarction by race and ethnicity, in a recent study, Chi and coworkers observed a decline in acute myocardial infarction hospitalization incidence rates across all race/ethnic groups during a 15-year period (2000 to 2014). Declines were similar for most race/ethnic groups; however, blacks experienced an important decline in acute myocardial infarction rates during 2000 to 2009 that slowed during 2010 to 2014. Although acute myocardial incidence rates narrowed between black and white, and between Asian or Pacific Islander and Hispanic groups, differences persist [17]. Thus, further efforts are needed in primary prevention, to guide targeted interventions.

Thanks again for your helpful comment.

We greatly appreciate your comments and suggestions, and hope that with these alterations, our manuscript will be acceptable for publication. We remain prepared to further revise our manuscript should it be required.

Author Response File: Author Response.docx