Review Reports - Hypertensive Left Ventricular Hypertrophy: Pathogenesis, Treatment, and Health Disparities

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Pathological left ventricular hypertrophy (LVH) can be induced by a number of stressors including hypertension and often leads to heart failure. Despite advances in our understanding of the LVH process, therapeutic options remain limited. As such, a better understanding of the mechanisms of LVH is important in development of novel treatment options for pathological LVH and heart failure. The author presents a review of apoptosis in LVH and some treatment considerations.

In general, the manuscript is well-written and addresses an important health concern, as cardiovascular disease remains the leading cause of death in much of the world. That being said, the review is relatively superficial and a deeper review of the relevant literature would be beneficial to individuals in the cardiovascular field.
It would be helpful to include an expanded discussion of the different types of cardiac hypertrophy (eccentric versus concentric and physiological versus pathological).
A figure illustrating the processes taking place in the heart during LVH and the transition to heart failure may help the reader better understand LVH and its consequences.
The manuscript focuses on apoptosis with a brief mention of necrosis. It would be beneficial to include a brief discussion of the diverse forms of cell death and the limited information about other forms of cell death in the heart.
The title of the manuscript suggests the review will focus on apoptosis in LVH; however, the manuscript focuses largely on LVH itself. Extensive studies have illustrated a role for cardiomyocyte apoptosis in the progression to heart failure. What is the role of cardiomyocyte apoptosis in the structural remodeling resulting in LVH?
The author discusses community health efforts to address disparities in access to treatment. This is an interesting and growing area. Specifics about some of these efforts may stimulate readers to become more engaged in this area.
While the focus of the manuscript is on cardiomyocyte apoptosis and LVH, there is no discussion of apoptosis in clinical studies. Is there literature in this area?
Many of the references are out of date. For instance, the reviews cited on LVH are all almost 15 years old or older.

Author Response

Comment 1: It would be helpful to include an expanded discussion of the different types of cardiac hypertrophy (eccentric versus concentric and physiological versus pathological).

Response 1: Thank you for your valuable feedback. I have expanded the manuscript to include a discussion of the different types of cardiac hypertrophy, distinguishing between eccentric and concentric hypertrophy, as well as physiological and pathological forms. This addition helps clarify the structural and functional differences among these hypertrophic responses and their relevance to disease progression.

Comment 2: A figure illustrating the processes taking place in the heart during LVH and the transition to heart failure may help the reader better understand LVH and its consequences.

Response 2: Thank you for your suggestion. I have included a new figure (Figure 2) illustrating the key structural and functional changes occurring during the progression from left ventricular hypertrophy (LVH) to heart failure. The figure highlights mechanisms such as pressure overload, cardiomyocyte remodeling, apoptosis, and subsequent ventricular dysfunction to help readers better visualize and understand the pathological transition.

Comments 3: The manuscript focuses on apoptosis with a brief mention of necrosis. It would be beneficial to include a brief discussion of the diverse forms of cell death and the limited information about other forms of cell death in the heart.

Response 3: Thank you for your helpful feedback. I have expanded the manuscript to include a brief discussion of additional forms of regulated cell death and their emerging roles in cardiac pathology. This addition acknowledges the complexity of cardiomyocyte death beyond apoptosis and highlights the need for further investigation into these less-studied pathways in the context of heart disease.

Comment 4: The title of the manuscript suggests the review will focus on apoptosis in LVH; however, the manuscript focuses largely on LVH itself. Extensive studies have illustrated a role for cardiomyocyte apoptosis in the progression to heart failure. What is the role of cardiomyocyte apoptosis in the structural remodeling resulting in LVH?

Cardiomyocyte apoptosis contributes to left ventricular hypertrophy by reducing viable myocytes, promoting fibrosis, and driving maladaptive structural remodelling that impairs cardiac function. Finding sustainable approaches to reduce apoptosis prevents disease progression and improves long-term cardiac outcomes.

Response: Thank you for your insightful comment. In response, I have revised the manuscript to clarify the role of cardiomyocyte apoptosis in structural remodeling during the development of left ventricular hypertrophy (LVH). Specifically, I now explain that apoptosis reduces the number of viable cardiomyocytes, which promotes interstitial fibrosis, alters myocardial architecture, and contributes to maladaptive hypertrophic remodeling

Comments 5: The author discusses community health efforts to address disparities in access to treatment. This is an interesting and growing area. Specifics about some of these efforts may stimulate readers to become more engaged in this area.

Response 5: Thank you for your thoughtful feedback. I have added a new section that highlights specific community health initiatives aimed at reducing hypertension among African American populations. This includes culturally tailored programs such as barbershop-based health interventions, faith-based outreach, and community-led physical activity and nutrition education campaigns. These examples illustrate how community-based strategies can improve access to care, promote engagement, and address disparities in cardiovascular health outcomes.

Comment 6: While the focus of the manuscript is on cardiomyocyte apoptosis and LVH, there is no discussion of apoptosis in clinical studies. Is there literature in this area?

Response 6: Thank you for your insightful comment. I have revised the manuscript to include a recent clinical study. Including this clinical perspective helps bridge the gap between experimental findings and real-world patient outcomes and highlights the translational relevance of apoptosis in LVH progression.

Comment 7: Many of the references are out of date. For instance, the reviews cited on LVH are all almost 15 years old or older.

Response 7: Thank you for your helpful comment. I have revised the reference list to include more recent and relevant literature. Outdated review articles have been replaced or supplemented with studies published within the past 5–7 years to ensure the manuscript reflects current evidence and understanding in the field.

Reviewer 2 Report

Comments and Suggestions for Authors

This review focuses on the link between hypertension-induced left ventricular hypertrophy (LVH) and cardiomyocyte apoptosis. It delves into LVH's pathogenesis, the role of apoptosis, and pharmacological/non-pharmacological treatments. It proposes multi-dimensional treatment strategies including lifestyle changes. It also pays attention to the health disparity of hypertension LVH among African Americans and emphasizes the necessity of culturally appropriate treatment.

However, there are several areas in which the authors should consider further revisions. The specific revisions are listed below:

Introduction section:

The logic of the first paragraph needs to be enhanced. When discussing hypertension's cardiac impact, start with general cardiovascular effects, then narrow down to LVH for better clarity.
The relationship between apoptosis and myocardial hypertrophy in the second paragraph is not explained clearly. Apoptosis is a form of cell death that leads to a reduction in cell number, while myocardial hypertrophy is characterized by an increase in cell volume and number. The connection between these two needs to be more explicitly explained. Although the third paragraph does mention it, for the sake of logical coherence, it is recommended to explain it earlier so that readers can understand how apoptosis leads to myocardial hypertrophy on the basis of understanding apoptosis.
The introduction of the apoptosis mechanism in the third paragraph is not detailed enough. It only mentions its energy dependence and regulation, as well as the two main pathways, but does not elaborate further. In addition, the article should also mention the role of other types of cell death in cardiac injury, such as necroptosis and pyroptosis, in order to more comprehensively reflect the complexity of cardiac cell death and its impact on heart diseases. The following references are recommended:

Yang F, Qin Y, Lv J, et al. Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis. 2018;9(10):1000.

Li L, Gao P, Tang X, et al. CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity. Signal Transduct Target Ther. 2022;7(1):190.

Cardiomyocyte apoptosis in hypertension section:

When introducing the occurrence of cardiomyocyte apoptosis in the first paragraph, it is advisable to follow a logical sequence. Start with physiological apoptosis (e.g., tissue remodeling in embryonic development), then discuss pathological apoptosis (e.g., gene mutations, diseases, injuries).
In the second paragraph, the expression "cardiomyocyte activation" may be incorrect and should be changed to "apoptosis activation". Moreover, this paragraph only lists the occurrence of apoptosis in several animal models without delving into its specific roles, such as how apoptosis is initiated and its specific effects on cardiomyocyte function and cardiac structure. It is recommended to add relevant content to address these aspects.
In the third paragraph, the author attempts to demonstrate that the novel coronavirus affects cardiovascular function through angiotensin II, but it is not clear whether this occurs through apoptosis. It is suggested to modify the article structure by adding an explanation of the mechanism of cardiovascular injury caused by novel coronavirus infection and exploring the role of apoptosis in this process. Additionally, relevant references should be provided to support the argument.

Cardiomyocyte Apoptosis and Cardiovascular Complications section:

The authors should focus on elaborating on which cardiovascular complications apoptosis has played a role in. Currently, it is only mentioned in a general way that apoptosis is related to cardiovascular diseases, but it does not specifically explain how apoptosis participates in different complications such as heart failure, arrhythmia, and coronary heart disease, nor does it detail its specific contribution in the progression of the diseases. It is recommended to provide a detailed account.

Author Response

Comments and Suggestions for Authors

However, there are several areas in which the authors should consider further revisions. The specific revisions are listed below:

Introduction section:

The logic of the first paragraph needs to be enhanced. When discussing hypertension's cardiac impact, start with general cardiovascular effects, then narrow down to LVH for better clarity.

Response: Thank you for your helpful suggestion. I have revised the first paragraph of the introduction to improve the logical structure by first outlining the general cardiovascular consequences of hypertension before narrowing the focus to the development and clinical significance of left ventricular hypertrophy. This adjustment enhances the clarity and progression of the discussion.

The relationship between apoptosis and myocardial hypertrophy in the second paragraph is not explained clearly. Apoptosis is a form of cell death that leads to a reduction in cell number, while myocardial hypertrophy is characterized by an increase in cell volume and number. The connection between these two needs to be more explicitly explained. Although the third paragraph does mention it, for the sake of logical coherence, it is recommended to explain it earlier so that readers can understand how apoptosis leads to myocardial hypertrophy on the basis of understanding apoptosis.

Response: Thank you for your insightful feedback. I have revised the section to improve the logical coherence between apoptosis and myocardial hypertrophy. In addition, I have incorporated a discussion of other forms of regulated cell death to provide a more comprehensive overview of cardiomyocyte loss in pathological conditions. A new figure has also been added to visually summarize the different forms of cell death and their roles in cardiac injury.

The introduction of the apoptosis mechanism in the third paragraph is not detailed enough. It only mentions its energy dependence and regulation, as well as the two main pathways, but does not elaborate further. In addition, the article should also mention the role of other types of cell death in cardiac injury, such as necroptosis and pyroptosis, in order to more comprehensively reflect the complexity of cardiac cell death and its impact on heart diseases. The following references are recommended:

Yang F, Qin Y, Lv J, et al. Silencing long non-coding RNA Kcnq1ot1 alleviates pyroptosis and fibrosis in diabetic cardiomyopathy. Cell Death Dis. 2018;9(10):1000.

Li L, Gao P, Tang X, et al. CB1R-stabilized NLRP3 inflammasome drives antipsychotics cardiotoxicity. Signal Transduct Target Ther. 2022;7(1):190.

Response: Thank you for your feedback and suggestions. I expanded the discussion to include other regulated forms of cell death to reflect the complexity of cardiomyocyte loss in heart disease. While I appreciate the suggested references, I have instead cited a more contextually appropriate source that aligns closely with the focus of this manuscript.

Cardiomyocyte apoptosis in hypertension section:

When introducing the occurrence of cardiomyocyte apoptosis in the first paragraph, it is advisable to follow a logical sequence. Start with physiological apoptosis (e.g., tissue remodeling in embryonic development), then discuss pathological apoptosis (e.g., gene mutations, diseases, injuries).

In the second paragraph, the expression "cardiomyocyte activation" may be incorrect and should be changed to "apoptosis activation". Moreover, this paragraph only lists the occurrence of apoptosis in several animal models without delving into its specific roles, such as how apoptosis is initiated and its specific effects on cardiomyocyte function and cardiac structure. It is recommended to add relevant content to address these aspects.

In the third paragraph, the author attempts to demonstrate that the novel coronavirus affects cardiovascular function through angiotensin II, but it is not clear whether this occurs through apoptosis. It is suggested to modify the article structure by adding an explanation of the mechanism of cardiovascular injury caused by novel coronavirus infection and exploring the role of apoptosis in this process. Additionally, relevant references should be provided to support the argument.

Response: Thank you for your feedback and recommendation. I have revised the section to follow a logical structure and to provide a more detailed discussion of the apoptosis mechanism, including its energy dependence, intrinsic and extrinsic pathways, and downstream effects on cardiac tissue. I have also revised the section to clarify the mechanism by which SARS-CoV-2 infection may contribute to cardiovascular injury, with specific attention to the role of the angiotensin II/ACE2 imbalance. I also elaborated on how this dysregulation can lead to increased oxidative stress and apoptosis, referencing recent studies that support this mechanistic link.

Cardiomyocyte Apoptosis and Cardiovascular Complications section:

Response: Thank you for your feedback. While cardiomyocyte apoptosis remains a significant factor in LVH pathogenesis, this paper prioritizes clinically actionable insights. Therefore, part of the focus is on advanced diagnostic and management strategies to better understand and intervene in LVH progression, particularly in high-risk populations. Therefore, I deleted this section and added a new subheading titled Advanced Approaches to Understanding and Managing LVH Progression.

Reviewer 3 Report

Comments and Suggestions for Authors

The present paper aimed to provide an overview of cardiomyocyte apoptosis in hypertensive left ventricular hypertrophy and to discuss the cardioprotective effects in inhibiting apoptosis-mediated cardiac remodeling of several drugs (angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)) as well as life-style changes.

A few changes are needed, as follows:

Please explain every abbreviation before using it, staring with “SHR” (line 83).

Please add a few words about other potential inducers of cardiomyocyte apoptosis in overloaded hearts, such as mechanical forces, neurohormonal activation, hypoxia, cytokines, downregulation of survival proteins or activation of death proteins.

Please mention the importance of apoptosis in the transition from compensatory hypertrophy to pump failure!

Please add a few words about caspase inhibition and left ventricular hypertrophy.

Several other possibilities to reduce apoptosis related to cardiac hypertrophy were reported such as Qingda granule), inhibition of apoptosis signal-regulating kinase 1 (ASK1), thyroxin (T4) treatment, Ivabradine, rapamycin, Hydroxysafflor yellow A (HSYA), Serelaxin. Please provide a table with experimental results, as well!

A figure with the main factors able to reduce apoptosis, would improve the paper.

Please provide gaps in knowledge and future research directions!

Author Response

Comment 1: Please explain every abbreviation before using it, starting with “SHR” (line 83).

Response 1: Thank you for this helpful observation. I have revised the manuscript to ensure that all abbreviations are defined upon their first mention, including “SHR” (Spontaneously Hypertensive Rat), as well as subsequent abbreviations throughout the text for improved clarity and consistency.

Comment 2: Several other possibilities to reduce apoptosis related to cardiac hypertrophy were reported such as Qingda granule), inhibition of apoptosis signal-regulating kinase 1 (ASK1), thyroxin (T4) treatment, Ivabradine, rapamycin, Hydroxysafflor yellow A (HSYA), Serelaxin. Please provide a table with experimental results, as well!

Response 2: Thank you for your valuable suggestion. In response, I have added a table summarizing recent experimental studies investigating some agents. The table outlines their reported effects on apoptosis reduction in cardiac hypertrophy models, including study design, key findings, and proposed mechanisms of action, to support a clearer comparative understanding.

Comment 3: A figure with the main factors able to reduce apoptosis would improve the paper.

Response 3: Thank you for your helpful suggestion. I agree that a visual summary would enhance the manuscript. While I have included a table summarizing recent experimental findings on therapeutic agents that reduce cardiomyocyte apoptosis. This Table is intended to provide readers with a clearer conceptual overview of the mechanisms discussed.

Comment 4: Please provide gaps in knowledge and future research directions!

Response 4: Thank you for highlighting this important point. I have expanded the conclusion to include identified gaps in the current understanding and suggestions for future research directions, particularly emphasizing the need for population-specific therapeutic studies and clinical translation of experimental findings.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have addressed my previous concerns and suggestions. The manuscript is very well done and will be of great interest to the field.

Reviewer 2 Report

Comments and Suggestions for Authors

Authors have addressed all my concerns.