Deciphering the Involvement of the Epicardium in Cardiac Diseases

Round 1

Reviewer 1 Report

The review by Carmona et al. provides a comprehensive summary of the potential role of the developing epicardium in cardiac morphogenesis. Impairment of the epicardium or its derivatives leads to cardiac developmental defects, including dysfunction of the myocardium and coronary vasculature, as well as morphological features reminiscent of congenital heart defects. This review summarizes how the epicardium may be implicated in the congenital defects that lead to adult heart diseases.

Although the connection between epicardial dysfunction and congenital heart disorders is intriguing, the authors mention that there is no direct evidence to support the claim that inadequate epicardial cell function leads to the development of CHD.

In Holt-Oram syndrome, the authors suggest that decreased interstitial cell recruitment from the epicardium leads to defects in the myocardium, such as thinning. While it has been shown that Tbx5 loss in the epicardium can lead to impaired coronary vasculature formation, the epicardium does not directly form the vasculature. The authors allude to paracrine-mediated factors, which are more likely.

Sections 2.1 and 2.2 need to be expanded further. The authors merely correlate epicardial gene mutations and the emergence of CHD. Additionally, many of these gene mutations are associated with defects or alterations in EMT, which are not mentioned.

The authors may also consider mentioning recent technological advances that have illuminated the molecular knowledge of the developing epicardium and its spatial patterning.

Author Response

We would like to thanks the reviewer for his/her kind report of our review manuscript

Following his/her recommendation, we have modified the subheading concerning Holt-Oram syndrome as suggested by the reviewer and we have also expanded sections 2.1 and 2.2 

Similarly we have added information in the Conclusion and Perspectives subheading regarding the recent technological advances in the field as suggested by the reviewer.

Reviewer 2 Report

Here, Carmona et al reviewed the the current knowledge on epicardium development and its role in heart formation and disease. The manuscript is written in a clear, concise and objective manner, and explores a link between congenital heart defects and adult heart disease (e.g. AF) and defects in epicardial EMT. I found this approach original and thought-provoking. I have no further comments or suggestions.

The manuscript is well-written and the only suggestions/corrections are:

line 156: thought instead of though

EPDCs=epicardium-derived cells, not epicardial-derived cells

Author Response

We would like to thanks the reviewer for his/her kind report of our review manuscript. Following his/her recommendation, we have modified the text according in the revised version of the manuscript.

Reviewer 3 Report

In this review by Carmona et al., the authors give a concise yet informative overview of the epicardium during heart development and its potential roles in contributing to and/or modulating cardiac disorders and syndromes.  The embryonic epicardium yields multiple cardiac lineages and is a source of paracrine signaling during heart development and after ischemic injury.  Defects to this cardiac progenitor population may have profound impacts on its derivatives and, in turn, impact cardiac physiology. Indeed, epicardial adipose tissue has increasingly been recognized as a potential substrate for arrhythmogenesis in various cardiac disorders.  This review examines the links between multiple pathologies and the potential involvement of the epicardium.  This reviewer feels this review is well suited for publication and a useful resource to the field.  There are no major concerns.

 Minor edit:

Line 183 – “PHP2 knockdown” should be PKP2 knockdown.

Author Response

We would like to thanks the reviewer for his/her kind report of our review manuscript. Following his/her recommendation, we have modified the text according in the revised version of the manuscript.