Molecular Pathology of Cardiomyopathies: Bridging Morphology, Genomics, and Clinical Phenotypes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a well-written review on causes and consequences of cardiomyopathies. It nicely catalogs genetic, function/structural/clinical manifestations of major cardiomyopathy sub-types. It serves as a valuable resource for basic, translational, & clinical scientist and physicians.

Two minor comments.

1. Be sure all acronyms are appropriately defined.
2. Consider a bit more breadth in Clinical implications and targeted therapies (i.e., any promising clinical studies using gene editing, what are the major hurdles that need to be overcome for precision-gene therapies, and what are some other avenues for precision/semi-precision therapies (e.g., small molecule therapy).

Author Response

Dear Reviewer1,

 Thank you very much for your positive and constructive comments on the manuscript. We have addressed both minor comments with the following revisions:

Question 1) Be sure all acronyms are appropriately defined.

Answer 1: All acronyms have been double-checked and explicitly defined upon their first occurrence in the text.

Question 2) Consider a bit more breadth in Clinical implications and targeted therapies (i.e., any promising clinical studies using gene editing, what are the major hurdles that need to be overcome for precision-gene therapies, and what are some other avenues for precision/semi-precision therapies (e.g., small molecule therapy).

Answer 2: We have expanded the section on clinical implications and targeted therapies to include a more detailed discussion of emerging precision medicine approaches, such as gene editing, gene therapies, and small molecule therapies, also highlighting the main translational and clinical challenges. (highlighted in green)

Thank you and Happy New Year!

Best regards,

The Authors

Reviewer 2 Report

Comments and Suggestions for Authors

This review offers a comprehensive, well-structured examination that effectively integrates morphology, genetics, and molecular mechanisms across the subtypes of cardiomyopathy. The manuscript synthesizes a substantial body of contemporary literature and includes valuable tables that summarize genotype-phenotype correlations. However, there are a few areas where further clarification and deeper synthesis could enhance the overall narrative and clinical applicability.

First, while the description of each cardiomyopathy subtype is thorough, including a more explicit unifying discussion highlighting the shared and divergent molecular mechanisms across these conditions would be very beneficial. A brief integrative paragraph at the end of Section 3 could succinctly summarize how sarcomeric dysfunction, cytoskeletal instability, impaired proteostasis, and maladaptive signaling pathways (such as Wnt, Hippo, and TGF-β) manifest differently in DCM, HCM, RCM, ACM, and LVNC. This addition could reinforce the theme of "bridging morphology, genomics, and clinical phenotypes," providing readers with a clearer understanding of the disease continuum and the interconnectedness of mechanisms.

Second, the section on LVNC effectively presents the current debate but may benefit from a more definitive interpretive conclusion. Considering the ongoing discussion about whether LVNC is a distinct cardiomyopathy or a morphological trait arising from various genetic backgrounds, it would be helpful for the authors to offer a concise, evidence-based perspective. A brief statement acknowledging that LVNC may be a heterogeneous entity, sometimes viewed as a primary developmental disorder and at other times a phenotypic variant of HCM/DCM, could assist clinicians in avoiding overdiagnosis and help contextualize the genetic heterogeneity discussed.

Third, although the manuscript provides an in-depth discussion of genetic testing, making a more explicit connection to clinical decision-making could enhance its translational impact. Outlining how specific pathogenic variants can influence management, for instance, earlier ICD consideration for LMNA, DSP, FLNC carriers; implications for family screening; or surveillance strategies for genotype-positive/phenotype-negative individuals, would offer practical value and help bridge the gap between genetic findings and patient care.

Fourth, the section on molecular autopsy is well-supported and rich in content, but a brief acknowledgment of practical limitations could provide a more balanced perspective. Mentioning issues such as DNA degradation in post-mortem samples, challenges in interpreting VUS in decedents, variability in genetic panels across institutions, and ethical considerations for family communication would present a realistic picture of the current capabilities and challenges in post-mortem genomics.

Finally, the discussion on precision medicine and gene therapy would benefit from a nuanced framing. While emerging RNA and CRISPR-based therapies are indeed promising, including a statement to acknowledge current limitations, such as delivery vectors, off-target effects, and early developmental stages, would temper expectations and provide a balanced scientific view. This enhancement would align the manuscript more closely with current therapeutic realities. I would like to thank the authors for their excellent work and consider these suggestions to strengthen it further.

Author Response

Dear Reviewer2,

We would like to thank the Reviewer for his careful and thorough evaluation of the manuscript and for his constructive suggestions, which significantly contributed to improving its clarity, coherence and clinical relevance. Below we report the answers point by point.

Question 1) First, while the description of each cardiomyopathy subtype is thorough, including a more explicit unifying discussion highlighting the shared and divergent molecular mechanisms across these conditions would be very beneficial. A brief integrative paragraph at the end of Section 3 could succinctly summarize how sarcomeric dysfunction, cytoskeletal instability, impaired proteostasis, and maladaptive signaling pathways (such as Wnt, Hippo, and TGF-β) manifest differently in DCM, HCM, RCM, ACM, and LVNC. This addition could reinforce the theme of "bridging morphology, genomics, and clinical phenotypes," providing readers with a clearer understanding of the disease continuum and the interconnectedness of mechanisms.

Answer 1: We fully support this suggestion. A new supplementary paragraph has been added to the end of Section 3, summarizing the main shared molecular mechanisms (sarcomeric dysfunction, cytoskeletal instability, altered proteostasis, and maladaptive signaling pathways such as Wnt, Hippo, and TGF-β) and illustrating how their different modulations contribute to the phenotypic variability of cardiomyopathies. (light blue highlighted)

Question 2) Second, the section on LVNC effectively presents the current debate but may benefit from a more definitive interpretative conclusion. Considering the ongoing discussion about whether LVNC is a distinct cardiomyopathy or a morphological trait arising from various genetic backgrounds, it would be helpful for the authors to offer a concise, evidence-based perspective. A brief statement acknowledging that LVNC may be a heterogeneous entity, sometimes viewed as a primary developmental disorder and at other times a phenotypic variant of HCM/DCM, could assist clinicians in avoiding overdiagnosis and help contextualize the genetic heterogeneity discussed.

Answer 2: We revised the concluding section of the LVNC section to include a concise, evidence-based interpretative statement. The manuscript now explicitly recognizes LVNC as a heterogeneous condition, which may represent either a primary developmental cardiomyopathy or a phenotypic variant of HCM or DCM, emphasizing the relevant clinical implications of this view. (highlighted in light blue)

Question 3) Third, although the manuscript provides an in-depth discussion of genetic testing, making a more explicit connection to clinical decision-making could enhance its translational impact. Outlining how specific pathogenic variants can influence management, for instance, earlier ICD consideration for LMNA, DSP, and FLNC carriers; implications for family screening; or surveillance strategies for genotype-positive/phenotype-negative individuals would offer practical value and help bridge the gap between genetic findings and patient care.

Answer 3: We have expanded the section on genetic analysis to more explicitly highlight how the identification of specific pathogenic variants (e.g., in LMNA, DSP, and FLNC) can influence clinical management, including arrhythmic risk stratification, ICD evaluation, family screening, and surveillance strategies in genotype-positive individuals. (highlighted in light blue)

Question 4) Fourth, the section on molecular autopsy is well-supported and rich in content, but a brief acknowledgment of practical limitations could provide a more balanced perspective. Mentioning issues such as DNA degradation in postmortem samples, challenges in interpreting VUS in decedents, variability in genetic panels across institutions, and ethical considerations for family communication would present a realistic picture of the current capabilities and challenges in postmortem genomics.

Answer 4: We have added a paragraph dedicated to the main limitations of molecular autopsy, including the quality of postmortem DNA, the difficulties in interpreting variants of uncertain significance, the variability of gene panels, and ethical considerations in communicating results to family members. (highlighted in light blue)

Question 5) Finally, the discussion on precision medicine and gene therapy would benefit from a nuanced framing. While emerging RNA and CRISPR-based therapies are indeed promising, including a statement acknowledging current limitations, such as delivery vectors, off-target effects, and early developmental stages, would temper expectations and provide a balanced scientific view. This enhancement would align the manuscript more closely with current therapeutic realities. I would like to thank the authors for their excellent work and consider these su management to strengthen it further.

Answer 5: We have revised this section by introducing a more balanced framework that, while recognizing the potential of emerging RNA-based therapies and genome editing, highlights their current technical and clinical limitations. This approach allows the manuscript to be aligned with current therapeutic realities. (light blue highlighted)

Thank you and Happy New Year!

Best regards,

The Authors