Constrictive Pericarditis and Protein-Losing Enteropathies: Exploring the Heart–Gut Axis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

- the tables are not easy to consult: perhaps they can be divided into more  units (i.e. symptoms, exams) or organized differently

 

- the pediatric case reported by Savilhati seems to differ from the others and does not appear to be affected strictly by constrictive pericarditis (only pericardial effusion with electrocardiographic anomalies are reported); this may require discussion

 

- given the limited number of reports present in the literature, in your research it was necessary to go back to the 1960s, so it could be useful to consider whether there have been changes and evolutions over time in the techniques and diagnostic criteria for both constrictive pericarditis and PLE. This is also to avoid confusion in the reported case series.

 

 

Author Response

Reviewer(s)' Comments to Author:

Rev#1

 

1. The tables are not easy to consult: perhaps they can be divided into more units (i.e. symptoms, exams) or organized differently

To improve readability and avoid redundancy of information, we removed clinical information (i.e., symptoms and lab findings) from the two tables because it is clearly expressed in the main text. We believe that the other information cannot be separated because it would provide the reader with a fragmented vision.

 

2. The pediatric case reported by Savilhati seems to differ from the others and does not appear to be affected strictly by constrictive pericarditis (only pericardial effusion with electrocardiographic anomalies are reported); this may require discussion

       We thank the reviewer for his insightful comments. We addressed the disparities between this case and the others.

 

3. Given the limited number of reports present in the literature, in your research it was necessary to go back to the 1960s, so it could be useful to consider whether there have been changes and evolutions over time in the techniques and diagnostic criteria for both constrictive pericarditis and PLE. This is also to avoid confusion in the reported case series.

We thank the reviewer for raising this important point. Regardless, the techniques and diagnostic criteria for constrictive pericarditis did not change or evolve significantly over time, except for the replacement of previous radioisotopic techniques (131I-polyvinylpyrrolidone, 131I-albumin tests, and 51Cr albumin stool clearance) with Tc-GSA scintigraphy for PLE diagnosis. We mentioned this concept in the discussion section. 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Thank you for inviting me to evaluate the article titled "Constrictive Pericarditis and Protein-Losing Enteropathies: Exploring the Heart-Gut Axis." This study compiles pediatric and adult cases of protein-losing enteropathy (PLE) caused by constrictive pericarditis, suggesting that pericardiectomy may be an effective treatment for PLE. Given the limited number of specific studies examining the relationship between PLE and constrictive pericarditis, the results of this study, which present all clinical cases and analyze the impact of pericardiectomy on PLE outcomes, contribute valuable insights to this area of research. However, several issues must be addressed before the manuscript can be considered for publication. The following suggestions are provided for improvement:

1. The study includes both pediatric and adult cases; please add a separate paragraph discussing the similarities and differences between these two populations. This should encompass aspects such as case characteristics, clinical manifestations, intestinal pathological changes, and prognoses following pericardiectomy. Rather than merely summarizing the case reports, consider the distinct characteristics present in different patients.

2. Please clarify why pericardiectomy may not be effective for some patients. What factors might predict the effectiveness of the procedure? Consider discussing the types of primary disease, disease severity, intestinal involvement, and other relevant factors.

3. Tables 1 and 2 list the clinical characteristics of each case. Please indicate whether any of the cases reported a long follow-up period. Additionally, if there are studies that have observed the recurrence of PLE after improvement following pericardiectomy, please include those findings. If such studies do not exist, please describe this gap in the literature.

4. Previous studies on the cardio-intestinal axis have primarily concentrated on the relationship between intestinal flora and cardiovascular disease. Constrictive pericarditis, a chronic inflammatory condition characterized by pericardial calcification and fibrinoid exudation, raises important questions regarding its etiology. In addition to factors such as abnormalities in lymphatic system reflux and elevated venous pressure, it is essential to explore the potential involvement of immune regulatory responses and immune-related factors in the development of protein-losing enteropathy (PLE). Please elaborate on this topic in the Discussion section and incorporate the relevant details into Fig. 2.

5. The conclusion section is overly lengthy, please summarize the article's conclusions in clear and concise language.

 

Comments on the Quality of English Language

Minor editing of English language is suggested.

Author Response

Rev#2

Thank you for inviting me to evaluate the article titled "Constrictive Pericarditis and Protein-Losing Enteropathies: Exploring the Heart-Gut Axis." This study compiles pediatric and adult cases of protein-losing enteropathy (PLE) caused by constrictive pericarditis, suggesting that pericardiectomy may be an effective treatment for PLE. Given the limited number of specific studies examining the relationship between PLE and constrictive pericarditis, the results of this study, which present all clinical cases and analyze the impact of pericardiectomy on PLE outcomes, contribute valuable insights to this area of research. However, several issues must be addressed before the manuscript can be considered for publication. The following suggestions are provided for improvement:

 

1. The study includes both pediatric and adult cases; please add a separate paragraph discussing the similarities and differences between these two populations. This should encompass aspects such as case characteristics, clinical manifestations, intestinal pathological changes, and prognoses following pericardiectomy. Rather than merely summarizing the case reports, consider the distinct characteristics present in different patients.

We thank the reviewer for making the appropriate suggestions. As a result, we've included a new paragraph 4 that details the requested similarities and differences between these two populations.

 

2. Please clarify why pericardiectomy may not be effective for some patients. What factors might predict the effectiveness of the procedure? Consider discussing the types of primary disease, disease severity, intestinal involvement, and other relevant factors.

As reported in the new paragraph 4, the case of ref 7 may serve as an example for inferring some possible hypotheses about the inefficacy of pericardiectomy in some cases. Specifically, in the examined fatal young adult case (1963), the onset of a cardiac cirrhosis could have complicated the clinical course of the disease, especially in a historical era when diagnostic and therapeutic tools for the management of decompensated liver cirrhosis were far more limited than they are nowadays. Moreover, in another young adult case (1991- ref. 5), despite the fact that peripheral oedema had disappeared and serum protein had returned to normal in the short-term follow-up, there was a small enteric protein loss one year after surgery, most likely due to the patient's subtotal pericardiectomy, which may have resulted in incomplete healing of the constrictive pericarditis. Indeed, the cardio-intestinal abnormalities of PLE caused by constrictive pericarditis are frequently reversed in all cases that underwent a complete pericardiectomy, as we sharply emphasized in the conclusion section. Among the pediatric cases who did not undergo pericardiectomy, one died of mycotic sepsis after a loss of clinical response despite several and different treatment courses (ref. 17); and the other patient developed clinical signs of right heart failure on long-term follow-up (re. 3). We therefore detailed these considerations in the main text.

 

3. Tables 1 and 2 list the clinical characteristics of each case. Please indicate whether any of the cases reported a long follow-up period. Additionally, if there are studies that have observed the recurrence of PLE after improvement following pericardiectomy, please include those findings. If such studies do not exist, please describe this gap in the literature.

As shown in table 1 (ref. 20) and discussed in the new paragraph 4, the pediatric case had a 2-year follow-up after pericardiectomy, while another adult case had a 6-year follow-up (see ref. 7).  Regarding the question of whether there have been studies that have observed the recurrence of PLE after improvement following pericardiectomy, we found and discussed only one fatal case of a young adult (see also above) in which oedema and ascites were absent for six years, but a slight cardiac inflow-stasis persisted and developed a permanent hypoalbuminemia six years after the complete pericardiectomy (Tab. 2 - ref. 7). The hypothesis underlying this unexpected clinical course is described in the new paragraph 4.

 

4. Previous studies on the cardio-intestinal axis have primarily concentrated on the relationship between intestinal flora and cardiovascular disease. Constrictive pericarditis, a chronic inflammatory condition characterized by pericardial calcification and fibrinoid exudation, raises important questions regarding its etiology. In addition to factors such as abnormalities in lymphatic system reflux and elevated venous pressure, it is essential to explore the potential involvement of immune regulatory responses and immune-related factors in the development of protein-losing enteropathy (PLE). Please elaborate on this topic in the Discussion section and incorporate the relevant details into Fig. 2.

We expanded on this important topic in the discussion section and incorporated the necessary details into Fig. 2.

 

5. The conclusion section is overly lengthy, please summarize the article's conclusions in clear and concise language.

We provided the article's conclusions in simple and straightforward language.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The authors present a comprehensive review of reported cases associating constrictive pericarditis and secondary protein-losing enteropathy.

The paper is well-structured and the few cases identified in the literature are extensively presented. I do not have major concerns about the paper.

Minor issues:

1. The introduction seems to be too long and presents pathophysiology data that belong to the discussion section.

2. It is not clear if all selected patients had constrictive pericarditis. For example, the case from Ref 17 had pericardial effusion on echocardiography, with no other imaging data or right heart catheterization.

3. What are the learning points of the article?

4. Enteropathy secondary to constrictive pericarditis is a late complication of the disease and the focus should be on early diagnosis and treatment of the heart condition. Consequently, what is the usefulness of gastrointestinal investigations like videocapsule endoscopy which is not readily available in most centers?

Comments on the Quality of English Language

The language is of good quality.

Author Response

Rev#3

The authors present a comprehensive review of reported cases associating constrictive pericarditis and secondary protein-losing enteropathy.

The paper is well-structured and the few cases identified in the literature are extensively presented. I do not have major concerns about the paper.

 

Minor issues:

1. The introduction seems to be too long and presents pathophysiology data that belong to the discussion section.

We thank to the reviewer for the appropriate comment. Accordingly, we shortened the introduction section.

 

2. It is not clear if all selected patients had constrictive pericarditis. For example, the case from Ref 17 had pericardial effusion on echocardiography, with no other imaging data or right heart catheterization.

We appreciate the reviewer's precise comment. As requested by another reviewer, we addressed the differences between the cases in ref. 17 and the others.

 

3. What are the learning points of the article?

We provided the main learning points in the first paragraph of the discussion “...i) constrictive pericarditis is rarely associated with PLE, and ii) the cardio-intestinal ab-normalities of PLE caused by constrictive pericarditis are frequently reversed following a complete pericardiectomy.”

 

4. Enteropathy secondary to constrictive pericarditis is a late complication of the disease and the focus should be on early diagnosis and treatment of the heart condition. Consequently, what is the usefulness of gastrointestinal investigations like videocapsule endoscopy which is not readily available in most centers?

In the discussion we stated that “…To evaluate the small bowel distal to the ligament of Treitz, videocapsule endoscopy or double-balloon enteroscopy can be successfully used.” Indeed, in cases of high clinical suspicion, a videocapsule exam may be useful in detecting lymphangiectasias in anatomical sites that are difficult to access with conventional endoscopy; on the other hand, because lymphangiectasias can have a patchy distribution, normal endoscopic or histological findings do not rule out diagnosis. As suggested, we precised that GI investigations such as videocapsule endoscopy are not widely available in most centers.

 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The issues raised were discussed and clarified. Thank you for shining the spotlight on an uncommon pathology with complex implications, often unrecognized.