A Review on the Evolving Roles of MiRNA-Based Technologies in Diagnosing and Treating Heart Failure

Round 1

Reviewer 1 Report

This is a review article focusing on microRNAs in cardiac diseases. The topic covered is very broad and, as expected, it misses some studies that should be included. Diagnosis part is better with some details, but the treatment part is very superficial. I suggest focusing on diagnosis only and cover more studies. Below are more specific comments.

 

There are several review papers with similar focus. How it differs from others and why this paper is worth reading may be highlighted in the abstract.

Ischemic heart disease refers to variety of different pathologies including MI, ACS, chronic ischemia etc. These should be separately discussed.

Only 4 microRNAs are discussed in the ischemic heart disease section, although there are several more miRNAs that have been shown to be useful markers.

While the article seems to mostly focus on serum/blood miRNA expression for diagnosis, there are description of some miRNAs in the myocardium. These should be clearly separated and the source of miRNAs should be described both in the text and the Table.

Therapeutic part is very superficial. For example, miR-132 inhibitor comes out of blue without explaining its target. I do not think the manuscript is able to cover all the miRNA treatments in development and I suggest focusing on diagnostics.

Author Response

There are several review papers with similar focus. How it differs from others and why this paper is worth reading may be highlighted in the abstract.

We thank the reviewers for this comment: the manuscript was an invited review from the publisher with the request to summarize current knowledge on miRNA-based technologies in diagnosis and treatment of heart failure

Ischemic heart disease refers to variety of different pathologies including MI, ACS, chronic ischemia etc. These should be separately discussed.

We thank the reviewer for this comment: We clarified the term “ischemic heart disease” in the manuscript, referring to myocardial ischemia, as from a molecular perspective we interpret miRNA being releases from ischemic myocardium. Independent of the cause of myocardial ischemia, miRNA based biomarkers of ischemic heart disease are based on measuring miRNA levels in circulation caused by the release of myocardially-expressed miRNAs from ischemic myocardium.

Only 4 microRNAs are discussed in the ischemic heart disease section, although there are several more miRNAs that have been shown to be useful markers.

Thank you for this important comment. We limited our review on this aspect on miRNAs with the most evidence and highest likelihood to progress to valuable miRNA-based assays. As noted by the reviewer, there are in fact dozens of miRNAs that have been described in a great number of studies. However, many of these studies are small, single center, with heterogeneous methods and no confirmatory subsequent studies. Aiming to present a concise and high-yield review on this aspect of miRNA-based biomarkers, we prefer to limit the number of miRNAs to the most promising nucleotides.

While the article seems to mostly focus on serum/blood miRNA expression for diagnosis, there are description of some miRNAs in the myocardium. These should be clearly separated and the source of miRNAs should be described both in the text and the Table.

Thank you for this important comment: we have added this information to Table 1.

Therapeutic part is very superficial. For example, miR-132 inhibitor comes out of blue without explaining its target. I do not think the manuscript is able to cover all the miRNA treatments in development and I suggest focusing on diagnostics.

We thank the reviewer for this comment: We have revised the paragraph to improve readability. As currently research on miRNA based therapeutics is in early stages, in the review we provide an outlook on potential paths towards cardiac miRNA based therapeutics, providing examples of miRNA-therapeutics currently in development in other fields. We expanded this paragraph further, as per reviewer suggestion

Reviewer 2 Report

To the authors,

This is a comprehensive review paper which focused on diagnostic ability and potential therapeutic options regarding micro-RNAs in various cardiac diseases including ischemic heart disease, hypertrophic cardiomyopathy, cardiac amyloidosis, sarcoidosis, ARVC, myocarditis, and stress cardiomyopathy. Basically, this manuscript seems well written, but several points and concerns need to be fixed. Please see my comments as follows.

• The contents focused on acute coronary syndrome (mainly diagnostic ability for ACS detection at emergent setting) and several non-ischemic cardiomyopathy without mentioning heart failure condition or not. Thus, better to fix the title as “A Review on the Evolving Role of miRNA-Based Technologies in Diagnosis and Treatment of Cardiac Disease”.
• (Page 2-3) All miRNAs in the chapter of “Ischemic Heart Disease” are raised for the purpose for detecting ACS. Are there any miRNAs available for high-risk (vulnerable) patient identification and/or for stratification of IHD prognosis after initial ischemic event?
• (Table 1) Similar to above mentioned point. miRNAs might be used for several purposes including 1) earlier disease detection (e.g. in the setting of ACS with chest pain), 2) identifying high-risk patients, 3) differentiate disease subtype, or 4) prognosis assessment such as response to therapy. The role of each miRNA in diseased condition seems difficult to be understood In the current Table 1 form. Moreover, some miRNAs are detected in serum/blood, while others are in the tissue (e.g. myocardium). Please make the point clearer.
• The association between HCM and other miRNAs such as miR133, miR1, and miR208 seems to be reported previously (J Am Coll Cardiol. 2016 Dec 13;68(23):2577-2584.).
• (Page 6, line 255-) The paragraph of “Cardiac Sarcoidosis” should be moved from “2.2.4. Myocarditis” and can be put between 2.2 Cardiac Amyloidosis and 2.2.3. ARVC as an independent chapter as shown in Table 1.
• (Page 7 line 310) “Alport Syndrome (miR-21, Lademirsen)” should be “Lademirsen (miR-21, Alport Syndrome)” to keep consistency.
• (Page 7, line 334-) What is the biological function of miR-132? Some explanations need to be added.
• Figure legend explaining the whole illustration should be put in Figure 1.
• ACS, MI, CMP, HOCM, HNCM, and DCM need to be spelled out.
• (Page 3, line 105) “(among other cardiac….” The sentence seems incomplete (there is no “)”). 

Author Response

• The contents focused on acute coronary syndrome (mainly diagnostic ability for ACS detection at emergent setting) and several non-ischemic cardiomyopathy without mentioning heart failure condition or not. Thus, better to fix the title as “A Review on the Evolving Role of miRNA-Based Technologies in Diagnosis and Treatment of Cardiac Disease”.

 

We thank the reviewer for this comment: In the review, we attempt to describe the current knowledge on the major cardiac pathologies leading to heart failure, separated between ischemic CMP and non-ischemic casues, and therein idiopathic NICM, HCM, infiltrative disease, inflammatory CMP and more rare causes as ARVC and Tako-Tsubo (as there is some data on miRNAs in these specific conditions.) We clarified the structure in the manuscript and revised the introduction and paragraph on diagnostics accordingly

 

• (Page 2-3) All miRNAs in the chapter of “Ischemic Heart Disease” are raised for the purpose for detecting ACS. Are there any miRNAs available for high-risk (vulnerable) patient identification and/or for stratification of IHD prognosis after initial ischemic event?

 

Thank you for this interesting comment. As there is a pleitropy of data published on miRNAs in cardiac ischemia, in this review we highlighted only data from larger trials with stronger evidence and confirmed by multiple studies. A major limitation when attempting to compare studies in this field is the heterogeneous study design and importantly varying definition of ACS/ ischemic events in these studies. We have added a fairly robust study on miRNA biomarkers in high risk patients, as suggested by the reviewer.

 

• (Table 1) Similar to above mentioned point. miRNAs might be used for several purposes including 1) earlier disease detection (e.g. in the setting of ACS with chest pain), 2) identifying high-risk patients, 3) differentiate disease subtype, or 4) prognosis assessment such as response to therapy. The role of each miRNA in diseased condition seems difficult to be understood In the current Table 1 form. Moreover, some miRNAs are detected in serum/blood, while others are in the tissue (e.g. myocardium). Please make the point clearer.

 

As suggested by the reviewer, we have added this information to table 1

 

• The association between HCM and other miRNAs such as miR133, miR1, and miR208 seems to be reported previously (J Am Coll Cardiol. 2016 Dec 13;68(23):2577-2584.).

 

As the purpose of this review was to summarize the current knowledge on miRNA biomarkers in different etiologies of HF, we have included this study in our manuscript.

• (Page 6, line 255-) The paragraph of “Cardiac Sarcoidosis” should be moved from “2.2.4. Myocarditis” and can be put between 2.2 Cardiac Amyloidosis and 2.2.3. ARVC as an independent chapter as shown in Table 1

As cardiac sarcoidosis falls within the spectrum of inflammatory cardiomyopathies, we would suggest to discuss this disease within the “inflammatory CPM” paragraph.

 

• (Page 7 line 310) “Alport Syndrome (miR-21, Lademirsen)” should be “Lademirsen (miR-21, Alport Syndrome)” to keep consistency.

 

We apologize for this oversight and have corrected this as suggested

 

• (Page 7, line 334-) What is the biological function of miR-132? Some explanations need to be added

 

As per the reviewer’s suggestion, we have added a brief paragraph on what is know on the function of mir-132

 

• Figure legend explaining the whole illustration should be put in Figure 1

 

• We thank the reviewer for this great suggestion and have added detailed figure legends to figure 1

 

• ACS, MI, CMP, HOCM, HNCM, and DCM need to be spelled out.

 

We have added this information to the manuscript and apologize for this oversight

 

• (Page 3, line 105) “(among other cardiac….” The sentence seems incomplete (there is no “)”). 

 

We have corrected this typographical error and apologize for this oversight

Round 2

Reviewer 2 Report

To the authors,

Most of the questions I raised in the last round seem to be adequately answered.

I have some minor comments as follows.

At the part of "2.2.4 Myocarditis", three subcategory including viral myocarditis, cardiac sarcoidosis, and giant cell myocarditis were raised. But sarcoidosis and  myocarditis were separated in Table 1. Please fix the deviation to make more sense.

The font size of the description of ARVC and Myocarditis associated miRNA in Table 1 seems larger than other part, need to be fixed.

Author Response

At the part of "2.2.4 Myocarditis", three subcategory including viral myocarditis, cardiac sarcoidosis, and giant cell myocarditis were raised. But sarcoidosis and  myocarditis were separated in Table 1. Please fix the deviation to make more sense.

Thank you for this comment: to avoid confusion, we have changed the title of the subcategory to “Inflammatory cardiomyopathies”, under which we describe viral myocarditis, sarcoidosis and GCM.

 

The font size of the description of ARVC and Myocarditis associated miRNA in Table 1 seems larger than other part, need to be fixed.

We have now corrected this as suggested