Autonomic Nervous System Regulation of Epicardial Adipose Tissue: Potential Roles for Regulator of G Protein Signaling-4
Round 1
Reviewer 1 Report
This is a nice review article which highlights a link between epicardial adipose tissue (EAT), autonomic nervous system regulation and atrial fibrillation (AFib). They also introduced and discuss the potential role of RGS4 protein in EAT regulation and its therapeutic potential. The concept and the topic of the paper are very important, discussion of the literature are timely and readers can learn a lot from reading the paper. I have just few minor comments:
1. page 2, line 44. was „visceral“ meant instead of „viscera“?
2. top of page 3 - passage regarding the expression of M2 receptors in ventricular myocytes. Mostly old Literature is cited here for absence of M2 expression. Is it species dependent and the authors refer to human myocardium. In rodent cells there is quite some functional M2 described - ironically, the ref 46 cited a bit later shows examples of M2 responses in Guinea pig myocytes.
3. Also, in human and mouse hearts, parasympathetic fibres and their functional effects were found also in ventricles though with lower abundance than in atria. On the other hand, it is correct that they have Minute effects on contractility. See e.g. PMID 28128201
Author Response
- page 2, line 44. was „visceral“ meant instead of „viscera“?
Author response: We thank this reviewer for the overall kind and positive comments about the quality of our work. This is a pertinent remark. We have corrected to “visceral” in the revised text.
- top of page 3 - passage regarding the expression of M2 receptors in ventricular myocytes. Mostly old Literature is cited here for absence of M2 expression. Is it species dependent and the authors refer to human myocardium. In rodent cells there is quite some functional M2 described - ironically, the ref 46 cited a bit later shows examples of M2 responses in Guinea pig myocytes.
Author response: The reviewer is right again about this pertinent remark. Regardless of the actual expression levels of M2 mAChR in the ventricles, the point we were trying to make in that paragraph was that the effect of ACh on overall cardiac contractility is minimal, at least in humans (as reviewed in Refs. #4 & #33 of the revised manuscript). We have now rephrased that part of the text in our revised manuscript (lines 97-102 of our revised manuscript, highlighted in yellow) to bring this point across more clearly. We hope this now satisfies this reviewer.
- Also, in human and mouse hearts, parasympathetic fibres and their functional effects were found also in ventricles though with lower abundance than in atria. On the other hand, it is correct that they have Minute effects on contractility. See e.g. PMID28128201
Author response: We thank this reviewer for this excellent remark, which is exactly what we argued in our response to the immediately preceding comment above. We have also cited this interesting study in our revised manuscript (new Ref. 40).
Reviewer 2 Report
In this review, authors discuss the regulation of the epicardial fat tissue by the autonomous nervous system. Although the topic is very interesting, the information is not easy to extract.
The brief introduction section only mentions EAT and atrial fibrillation (an excellent recent review can be found in Ernault et al. J Am Coll Cardiol. 2021; 78 (17) 1730–1745). However, an overview of the topics to be discussed is needed. That will contextualize the ANS and the RGS-4 protein (the other two players in the review) and highlight the relevance of the manuscript.
Figure 1 is confusing. It would be more clear to separate the effects of autonomic dysregulation in the heart in one figure; and the interactions between the ANS and the EAT in another. For the latter, it would be helpful to show the plexi and the cellular components of the EAT, as well as the involved mechanisms (neurotransmitters, receptors…). This separation is important since the focus of the review is precisely the autonomic regulation of Epicardial Adipose Tissue.
Sections 2 and 3 discuss general information and can be summarized to give more prominence to the regulation of the EAT.
As the authors mention in section 5, the role of RGS-4 in autonomic regulation of EAT is speculative. A figure showing the potential mechanisms would help justify its presence in the title.
14 % of the references are self-citations. Some are redundant and can be removed.
Author Response
In this review, authors discuss the regulation of the epicardial fat tissue by the autonomous nervous system. Although the topic is very interesting, the information is not easy to extract.
The brief introduction section only mentions EAT and atrial fibrillation (an excellent recent review can be found in Ernault et al. J Am Coll Cardiol. 2021; 78 (17) 1730–1745). However, an overview of the topics to be discussed is needed. That will contextualize the ANS and the RGS-4 protein (the other two players in the review) and highlight the relevance of the manuscript.
Author response: We thank this reviewer for the overall kind and positive comments about the quality of our work. This is a pertinent remark and we have now included the excellent recent review article suggested by the reviewer (new Ref. 2 of our revised manuscript). However, our present review is focused on autonomic nervous system regulation of EAT, not on the link between EAT and atrial fibrillation. Extensive discussion of all the cardiac conditions EAT is involved in is beyond the scope of our present manuscript. We hope the reviewer understands.
Figure 1 is confusing. It would be more clear to separate the effects of autonomic dysregulation in the heart in one figure; and the interactions between the ANS and the EAT in another. For the latter, it would be helpful to show the plexi and the cellular components of the EAT, as well as the involved mechanisms (neurotransmitters, receptors…). This separation is important since the focus of the review is precisely the autonomic regulation of Epicardial Adipose Tissue.
Author response: We thank this reviewer for this excellent suggestion, which we have followed. Our revised manuscript is now showing the autonomic signaling of the heart and the interplay between EAT, autonomic neurons, and cardiomyocytes in two separate figures. We hope this satisfies now this reviewer.
Sections 2 and 3 discuss general information and can be summarized to give more prominence to the regulation of the EAT.
Author response: Thank you for the suggestion. We tried to shorten these two sections as much as we could in our revised manuscript.
As the authors mention in section 5, the role of RGS-4 in autonomic regulation of EAT is speculative. A figure showing the potential mechanisms would help justify its presence in the title.
Author response: The potential mechanisms are depicted in Figure 1. It should also be pointed out that, although the role of RGS4 in regulation of EAT is speculative at present, its involvement in autonomic regulation of the heart in general, via the mechanisms illustrated in Figure 1, has been documented. In other words, RGS4 has already been shown, and is known to regulate calcium transients/signaling and M2 mAChR signaling in cardiac atria (e.g., Refs. 78, 81, 85, and 86 of the revised manuscript), as schematically depicted in Figure 1.
14 % of the references are self-citations. Some are redundant and can be removed.
Author response: Thank you for the observation. This is because we are among the experts in the field, which is why we were invited to contribute this review article in the first place! We respectfully disagree that any of them is redundant; perhaps if the reviewer could be more specific as to which one(s) should be removed (and why), we would be happy to accommodate him/her.
Round 2
Reviewer 2 Report
I think the review has improved significantly with the second figure and the modifications in the text and I have no further comments to add.
