The Neuro-Immune Axis in Cardiomyopathy: Molecular Mechanisms, Clinical Phenotypes, and Therapeutic Frontiers

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript concerns the mechanisms by which the  neuroimmune axis plays in cardiomyopathy and describes helpful therapies. The authors explain the range of cardiomyopathies and suggest the neuroimmune axis explains some of the treatment ineffectiveness.  The authors explain how overactivation of the sympathetic system results in an inflammatory environment. Careful consideration is given to the different cardiomyopathies and the role of sex differences and the microbiome in pathogenesis. Novel new therapies are described that improve patient outcomes. The manuscript contains several excellent figures that aid the readers understanding.

Suggestions line 264 insert ref.

The authors write about macrophage polarization and it would be helpful for the reader to include the characteristics of M1 and M2s perhaps in a figure.

Author Response

Reply to the Reviewers
We sincerely thank the reviewers for their constructive feedback. Their comments have further improved the clarity, balance, and rigor of the manuscript. Below, we provide detailed, point-by-point responses.

 

Reviewer 1

Comment 1: "Suggestions line 264 insert ref."

Response: The reference has been updated accordingly.

 

Comment 2: "The authors write about macrophage polarization and it would be helpful for the reader to include the characteristics of M1 and M2s perhaps in a figure."

Response: A new paragraph and a Figure (Figure 1) have been added as per the reviewer’s recommendation as follows:

Macrophage polarization is central to this metabolic-immune crosstalk, wherein metabolic dysfunction drives a decisive shift toward the M1 (classically activated) phenotype. M1 macrophages are characterized by enhanced glycolytic metabolism, elevated production of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), increased inducible nitric oxide synthase activity, and promotion of Th1-mediated responses that amplify tissue damage. This starkly contrasts with the cardioprotective M2 (alternatively activated) phenotype, which relies on oxidative metabolism, produces anti-inflammatory mediators, including IL-10 and arginase-1, supports tissue repair through growth factor secretion, and promotes Th2 responses conducive to healing. In cardiomyopathy, the metabolic milieu systematically favors M1 over M2 polarization, creating a self-perpetuating cycle of inflammation that impairs cardiac repair mechanisms and accelerates disease progression (Figure 1). (Page 11, Line 161 to 172).

 

 

 

 

Figure 1. Macrophage polarization and its impact on cardiomyopathy.

Naïve M0 macrophages differentiate into M1 (classically activated) or M2 (alternatively activated) states depending on the specific stimuli. M1 macrophages induced by IFN-γ, TNF-α, GM-CSF, and LPS express CD80, CD86, and MHC-II, secrete pro-inflammatory mediators (TNF-α, IL-1β, IL-6, IL-12, ROS, and NO), rely on glycolytic metabolism, and contribute to cardiomyocyte injury. M2 macrophages are induced by IL-4, IL-13, TLR ligands, and adenosine, express CD163, CD206, and Arg1, secrete IL-10, TGF-β, VEGF, and chemokines (CCL17, CCL22), utilize oxidative metabolism, and promote anti-inflammation and cardiac repair.  (Created with BioRender.com)

Abbreviations: ROS, reactive oxygen species; NO, nitric oxide; TME, tumor microenvironment.

Reviewer 2 Report

Comments and Suggestions for Authors

Saha et al have presented elaborate review on the neuro-immune axis in cardiomyopathy, highlighting the molecular mechanisms, clinical phenotypes and therapeutic frontiers. In order to complement the manuscript, I would suggest authors address couple of major and minor comments, before this manuscript can be accepted for the publication

Major comments

• Please provide the methodology section describing the search strategy, inclusion/exclusion criteria which was used for this review manuscript.
• Please elaborate each of the sections 3.1-3.6: for each type of CM please provide the traditional pathophysiology, CM etiology, prevalence and standard diagnostic criteria.
• Table 1 shows key neuro-immune pathways in CM, however it lacks clear correspondence to each CM type. Please complement the table associating the specific CM type for each of the pathways.
• Please provide a additional sections to section 4 describing current treatment strategies of each CM type their advantages and disadvantages and how novel neuro-immune therapies can address these limitations

 

Minor comments

• Please consider adding a figure summarizing different types of CM, prognosis, treatments strategies
• Please standardize the citation format for all references presented

Author Response

Reply to the Reviewers
We sincerely thank the reviewers for their constructive feedback. Their comments have further improved the clarity, balance, and rigor of the manuscript. Below, we provide detailed, point-by-point responses.

 

Major Comments

1: "Please provide the methodology section describing the search strategy, inclusion/exclusion criteria which was used for this review manuscript."

 

Response: As per the reviewer’s recommendation methodology section has been added as follows:

2. Review Methodology

We conducted a systematic search using PubMed with established systematic review guidelines to evaluate the role of the neuroimmune axis in cardiomyopathy pathogen-esis and therapeutic interventions, with particular focus on autonomic dysfunction, in-flammatory mechanisms, and bioelectronic medicine applications.

2.1 Search strategy

A comprehensive literature search was performed across multiple databases, including PubMed, covering studies published between January 2010 and August 2025, yielding a total of 3511 records. The search strategy employed both Medical Subject Headings (MeSH) terms and free-text keywords to ensure broad coverage of relevant studies. The primary search terms included:

• "CARDIOMYOPATHY AND NEUROIMMUNE AXIS" (n = 14)
• "CARDIOMYOPATHY, NEUROIMMUNE AXIS AND AUTONOMIC NERVOUS SYSTEM" (n = 4)
• "CARDIOMYOPATHY, NEUROIMMUNE AXIS, AUTONOMIC NERVOUS SYSTEM AND INFLAMMATION" (n = 4)
• "CARDIOMYOPATHY, NEUROIMMUNE AXIS AND INFLAMMATION" (n = 10)
• "CARDIOMYOPATHY, NEUROIMMUNE AXIS AND HEART FAILURE" (n = 4)
• “CARDIOMYOPATHY AND IMMUNE SYSTEM” (n=2524)
• "CARDIOMYOPATHY AND VAGUS NERVE" (n = 96)
• “CARDIOMYOPATHY AND HEART RATE VARIABILITY” (n=851)
• "CARDIOMYOPATHY AND BIOELECTRONIC MEDICINE" (n = 2)
• "CARDIOMYOPATHY, BIOELECTRONIC MEDICINE AND HEART FAILURE" (n = 2)

2.2 Study selection

The search was refined to prioritize studies published between January 1, 2010 and August 31, 2025, focusing exclusively on peer-reviewed articles in indexed journals, while also included landmark foundational studies from earlier periods. After removing duplicates, 42 studies were identified as linking cardiomyopathy and neuroimmune mechanisms. Screening was conducted based on titles and abstracts, leading to the exclusion of studies due to irrelevance to cardiac neuroimmunology. A full-text re-view of the remaining articles was then performed, resulting in the exclusion of additional studies for the following reasons:

Studies focusing solely on cardiomyopathy development (n = 26)

Reviews without original data contribution (n = 62)

Irrelevant information (n=3381)

Ultimately, 42 studies met the inclusion criteria and were selected for analysis.

 

2.3 Inclusion criteria

Studies were included if they provided experimental evidence on the role of neuro-immune mechanisms in cardiomyopathy pathogenesis, progression, or therapeutic intervention. Additionally, research exploring molecular mechanisms such as autonomic dysfunction, inflammatory cytokine signaling, vagal nerve modulation, and bioelectronic medicine applications was considered. Clinical studies and observational investigations evaluating autonomic dysfunction and inflammatory markers in cardiac dis-ease were also included to ensure a comprehensive analysis from both mechanistic and clinical perspectives.

 

2.4 Exclusion criteria

Non-peer-reviewed sources, conceptual frameworks lacking experimental validation, studies without full-text access (to maintain methodological rigor) and research unrelated to cardiomyopathy. These criteria ensured that only studies with direct relevance and high methodological quality were included in the final analysis. These criteria ensured that only studies with direct relevance to cardiac neuroimmunology and high methodological quality were included in the final analysis.

 

In addition to the primary database search, we conducted a comprehensive review of published literature examining the role of autonomic nervous system dysfunction, vagal nerve stimulation, inflammatory cascades, and bioelectronic medicine in cardio-myopathy. Studies were included based on detailed descriptions of neuroimmune mechanisms contributing to cardiac pathology, including cytokine-mediated inflammation, autonomic imbalance, and novel therapeutic approaches targeting the cardiac neuroimmune axis. We also evaluated clinical trials assessing neuromodulation interventions and inflammatory biomarkers in cardiomyopathy patients to provide com-prehensive coverage of both mechanistic insights and therapeutic applications. ” (Page: 2-4, Line No.92-153).

 

2: "Please elaborate each of the sections 3.1-3.6: for each type of CM please provide the traditional pathophysiology, CM etiology, prevalence and standard diagnostic criteria."

Response: To address the revier’s sugesstion, we have substantially expanded Sections 4.1-4.6, (previously it was 3.1-3.6) as follows:

 

4. Clinical Phenotypes and Neuro-Immune Signatures

The clinical manifestations of cardiomyopathy are shaped by specific neuroimmune signatures that can guide personalized management strategies.

4.1 Dilated Cardiomyopathy and Chronic Heart Failure

Dilated cardiomyopathy (DCM) is a prototypical neuroimmune disorder characterized by marked autonomic imbalance and systemic inflammation. DCM affects approximately 1:250 individuals globally and is the leading indication for cardiac transplantation [32]. The hallmark pathophysiology involves progressive ventricular dilatation and systolic dysfunction (ejection fraction <40%) driven by myocyte loss, interstitial fibrosis, and compensatory neurohormonal activation [33]. Genetic mutations account for 30–50% of cases, with titin (TTN) truncating variants being the most common cause (15–25%), followed by lamin A/C (LMNA) and desmin mutations [12]. Acquired causes include viral myocarditis (particularly coxsackievirus B3 and parvovirus B19), cardiotoxins (anthracyclines and alcohol), and peripartum cardiomyopathy [34]. Despite advances in neurohormonal blockade, which have achieved a 20–35% reduction in mortality, traditional hemodynamic-focused therapies fail to address the underlying neuroimmune dysfunction [35,36]. The hallmark of this condition is severe sympathetic nervous system overactivation, with norepinephrine levels directly correlating with the degree of heart muscle dysfunction and patient outcomes [37]. Concurrently, patients display persistently elevated levels of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, which serve as prognostic biomarkers of disease progression and mortality. Vagal withdrawal further contributes to autonomic dysregulation, as evidenced by significantly reduced heart rate variability (HRV) and impaired baroreflex function, both of which are independent predictors of sudden cardiac death and heart failure-related morbidity.   This neuroimmune signature explains why conventional RAAS inhibition and beta-blockade, while providing symptomatic relief, often fail to halt disease progression in 60% of patients with treatment resistance [38].            

 

4.2 Hypertrophic Cardiomyopathy and Genetic Neuro-Immune Interactions     

Hypertrophic cardiomyopathy (HCM) affects approximately 1:500 individuals and is characterized by asymmetric left ventricular hypertrophy (wall thickness ≥15 mm) without a hemodynamic cause [39]. Over 1,400 mutations in 11 sarcomeric genes have been identified, with MYH7 (β-myosin heavy chain) and MYBPC3 (myosin-binding protein C) accounting for approximately 70% of cases [40]. The pathophysiology centers on sarcomeric protein mutations, causing myofibrillar disarray, diastolic dysfunction, and dynamic outflow obstruction in 70% of cases [41]. Traditional management focuses on symptom control through negative inotropic agents (beta-blockers and calcium channel blockers) and septal reduction therapy; however, these approaches do not prevent fibrotic progression or address arrhythmic risk [42].

HCM presents a unique model of how genetic mutations in heart muscle proteins can trigger neuro-immune dysfunction through biomechanical stress, where inherited mutations in contractile proteins cause disorganized muscle architecture and mechanical stress which activates local inflammatory responses.  This mechanical stress promotes the recruitment of inflammatory cells and the activation of fibroblast cells that produce scar tissue, creating an electrical substrate that predisposes to dangerous arrhythmia [40]. LMNA mutations increase susceptibility to inflammation, elevating interleukin-6, tumor necrosis factor alpha, and macrophage infiltration, even in the early stages of the disease [43]. Autonomic imbalance further compounds this risk, with exaggerated sympathetic activity and impaired vagal modulation fostering an arrhythmogenic neuroimmune milieu that increases susceptibility to sudden cardiac death and adverse electrical remodelling.  This mechanistic understanding explains why traditional negative inotropic therapy, while controlling symptoms, fails to modify the underlying inflammatory substrate driving disease progression [44].             

4.3 Takotsubo Cardiomyopathy- An Acute Neuro-Immune Crisis

Takotsubo cardiomyopathy (TTC) presents as acute reversible cardiac dysfunction triggered by emotional or physical stress, predominantly affecting postmenopausal women (90% of cases), with plasma norepinephrine levels 2-3-fold higher than those in acute myocardial infarction[45]. TTC accounts for 1-2% of acute coronary syn-drome presentations, with in-hospital mortality of 9% and a rate of recurrence reaching 2.9% per year [45]. The characteristic apical ballooning pattern reflects cate-cholamine-mediated myocardial stunning, with the traditional pathophysiology attributing the syndrome to coronary microvascular dysfunction and direct catecholamine toxicity [46]. Diagnosis follows the modified Mayo Clinic criteria of transient wall motion abnormalities extending beyond a single coronary territory, absence of obstruc-tive coronary disease, and emotional/physical triggers [47].TTC exemplifies acute neuroimmune dysregulation triggered by extreme emotional or physical stress, leading to a sudden surge in catecholamines. This surge directly damages the myocardial tissue and activates systemic inflammatory responses [48]. Acute-phase features include elevated inflammatory markers, including C-reactive protein, IL-6, and TNF-α, contributing to myocardial stunning and ballooning. This condition demonstrates how acute stress-induced sympathetic overactivation can overwhelm normal cardiac adaptive mechanisms, creating a cascade of neuroimmune activation that manifests as reversible cardiac dysfunction. The predominance in postmenopausal women reflects the loss of estrogen's cardioprotective effects on autonomic regulation and inflammatory modulation, highlighting the intersection between hormonal status, neuroimmune function, and cardiac vulnerability[49].

 

4.4 Arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) affects 1:2,000-5,000 individuals, characterized by progressive fibrofatty replacement of the myocardium and a high risk of arrhythmia [50]. Mutations in five desmosomal genes (PKP2, DSG2, DSC2, DSP, JUP) account for 50-60% of cases, with plakophilin-2 (PKP2) most frequently involved [51]. Traditional pathophysiology focused on desmosomal protein dysfunction causing cell-cell adhesion defects and mechanical stress-induced myocyte death [52]. The right ventricle is predominantly affected (classical ARVC), though biventricular and left-dominant variants are increas-ingly recognized [53]. Exercise restriction is paramount given the role of physical activity in disease progression, though current therapies remain largely supportive. ACM is distinguished by complex neuroimmune pathophysiology driven by mutations in desmosomal proteins, which disrupt structural integrity and initiate inflammatory and autonomic dysregulation [54]. Histologically, ACM is marked by T-lymphocyte and macrophage infiltration, contributing to progressive cardiomyocyte loss and the hallmark fibrofatty myocardial replacement that predisposes patients to malignant arrhythmias [55].

This structural degeneration is accompanied by autonomic remodelling, characterized by abnormal sympathetic innervation and cycles of denervation and re-innervation, creating spatial heterogeneity in neural control. The neuroimmune axis plays a pivotal role in this process, where cytokine signaling influences neural sprouting and survival [56]. Notably, physical exertion amplifies disease progression by intensifying sympathetic output and mechanical stress, which in turn escalates local inflammation via neuro-immune crosstalk, accelerating fibrofatty transformation and arrhythmogenesis [57]. This mechanistic framework explains why exercise restriction remains a cornerstone of management and highlights the need for therapies targeting both the inflammatory pathways and autonomic dysfunction [58].

 

4.5 Pediatric and Developmental Cardiomyopathy

The incidence of pediatric cardiomyopathy is 0.57-1.13 per 100,000 children, with distinct etiological and prognostic profiles compared to adult disease[59]. Genetic causes predominate (60-70%), including metabolic disorders (glycogen storage diseases, mitochondrial cardiomyopathies) and sarcomeric mutations[60]. Infants present primarily with dilated cardiomyopathy (50% of cases), often secondary to met-abolic or genetic disorders, while hypertrophic cardiomyopathy in children frequently associates with inborn errors of metabolism or malformation syndromes [61]. Traditional management emphasizes heart failure optimization and consid-eration for mechanical support or transplantation, with 5-year survival rates of 65-75%, though diagnostic workup requires comprehensive metabolic screening and genetic testing [62].

It  represents unique neuro-immune dynamics due to age-related differences in immune maturation, autonomic regulation, and genetic predisposition. Children are more susceptible to developing cardiomyopathy secondary to metabolic disorders, genetic syndromes, or post-infectious immune problems, with parvovirus B19 and human herpesvirus 6 being the main viral causes [63]. Multisystem Inflammatory Syndrome in Children (MIS-C) associated with SARS-CoV-2 represents a perfect example of neuro-immune cardiomyopathy, characterized by acute myocarditis and dilated cardiomyopathy through hyperinflammatory cytokine storm involving IL-6, IL-1β and TNF-α [64,65]. Patients with MIS-C show profound autonomic dysfunction with reduced heart rate variability and elevated sympathetic tone, mirroring adult neuroimmune cardiomyopathy patterns [66]. Recent multicenter studies have revealed that 72% of patients with MIS-C develop low blood pressure and cardiac dysfunction, with 96% showing elevated brain natriuretic peptide and 64% demonstrating increased cardiac troponin levels [67]. Heightened neuroplasticity in pediatric autonomic circuits suggests unique opportunities for early intervention through vagal stimulation or targeted immunomodulatory strategies [68].

 

4.6 COVID-19 and Post-Viral Neuro-Immune Cardiomyopathy

The COVID-19 pandemic has provided unprecedented insights into the mechanisms through which viral infections can trigger persistent neuroimmune cardiac dysfunction.

SARS-CoV-2–induced cardiomyopathy arises from a triad of direct viral cardiotropism, systemic hyperinflammation, and severe autonomic imbalance. Viral entry via ACE2 receptors facilitates myocardial infiltration, and the ensuing cytokine storm exacerbates tissue injury and immune-mediated damage. COVID-19–associated cardiomyopathy affects 0.146% of hospitalized patients, with mortality rates reaching 13.3% [70]. Similar to the emerging evidence linking human papillomavirus infection with coronary artery disease through shared inflammatory and metabolic pathways, viral triggers such as SARS-CoV-2 may induce chronic cardiovascular vulnerability via immune-metabolic dysregulation [71,72]. The syndrome ranges from acute myocarditis to chronic dilated cardiomyopathy, with the traditional pathophysiology encompassing direct viral cytotoxicity via ACE2 receptors, cytokine storm-mediated injury, and microvascular dysfunction[73]. Acute presentations include fulminant myocarditis requiring mechanical support, whereas chronic manifestations resemble dilated cardiomyopathy. Beyond the acute phase, post-COVID cardiac symptoms affect 10–30% of survivors and are characterized by persistent dyspnea, reduced exercise tolerance, and autonomic dysfunction, including POTS-like syndromes. Cardiac MRI demonstrates persistent inflammatory changes in 60% of recovered patients [74]. This prolonged neuroimmune dysregulation demonstrates how viral triggers can establish persistent pathological circuits that maintain cardiac dysfunction long after viral clearance [75]. The mechanistic parallels between COVID-19 cardiomyopathy and other viral myocarditis suggest common neuroimmune pathways that could be therapeutically targeted across multiple etiologies. . Table 1 summarizes the major immunoneural signaling components implicated in cardiomyopathy pathophysiology, their key mediators, and mechanistic pathways. Shared neuroimmune mechanisms underlie disease progression across all major cardiomyopathy phenotypes, whereas clinical outcomes remain highly variable. A summary of the etiology, prognosis, and current treatment strategies for each subtype is presented in Figure 3. (Page 15-22, Line 248-409 )                                                            

   

3: Table 1 shows key neuro-immune pathways in CM, however it lacks clear correspondence to each CM type. Please complement the table associating the specific CM type for each of the pathways.

Response: Table 1 has been updated as per the review’s recommendation s follows:  

 

Table 1. Key Neuro-immune Pathways in Cardiomyopathy

Axis Component	Key Mediators	Cardiomyopathy Role	Mechanistic Notes	Primary CM Associations
Sympathetic Nervous System [5,8]	Norepinephrine, Epinephrine, NPY	Promotes inflammation, oxidative stress, arrhythmogenesis	β2-AR activation on immune cells → ↑TNF-α, IL-1β, IL-6	DCM [141], HCM [142], TTC  [143], COVID-19 CM [144]
Parasympathetic System [25,115]	Acetylcholine, VIP	Anti-inflammatory, cardioprotective	α7-nAChR activation → ↓TNF-α, IL-1β via cholinergic anti-inflammatory pathway	DCM [145]
Central Neural Integration [5]	Cortisol, CRH, AVP	Coordinates neuro-immune responses	HPA axis activation, microglial activation, neuroinflammation	TTC [146]
Inflammatory Cytokines [8]	TNF-α, IL-1β, IL-6, IL-10	Impair contractility, promote fibrosis	Cross blood-brain barrier, affect autonomic centers	DCM [147], ACM [58], COVID-19 CM [148]
Damage Signals (DAMPs) [8]	HMGB1,	Trigger sterile inflammation	Activate TLRs, modulated by vagal tone	ACM [58]
Inflammasome Pathway [8]	NLRP3, Caspase-1, IL-1β	Mediates	Primed by β-adrenergic signaling, suppressed by cholinergic activity	DCM [149], HCM [150]
Complement System [151]	C3a, C5a, MAC	Amplifies inflammatory responses	Activated by DAMPs, modulated by neural signals	DCM [152], ACM [153]
Neurotransmitter  [5]	Dopamine, Substance P, GABA	Modulates immune cell function	Receptor-mediated effects on T-cells, macrophages	DCM [154]

 

4: Please provide additional sections to section 4 describing current treatment strategies of each CM type their advantages and disadvantages and how novel neuro-immune therapies can address these limitations.

 

Response: To address the reviewer’s comment, a new section has been added as followes:

 

“ 5.1 Conventional Treatments of Cardiomyopathies and Their Limitations

Conventional management of cardiomyopathies remains phenotype-specific yet largely symptom-directed, with therapies that reduce mortality but fail to address the persistent neuroimmune dysfunction. In dilated cardiomyopathy (DCM), standard neurohormonal blockade with ACE inhibitors/ARBs, β-blockers, and mineralocorticoid receptor antagonists lowers mortality by 20–35% [76], with newer agents such as sacubitril–valsartan (ARNI therapy) and SGLT2 inhibitors offering incremental benefits [77]. Device therapies, including implantable cardioverter-defibrillators (ICDs) and cardiac resynchronization therapy (CRT),  improve survival in selected cases [78]. However, up to 60% of patients remain refractory, 25% are readmitted within 30 days, and 5-year mortality exceeds 50%[79], reflecting unresolved inflammatory and autonomic dysregulation [80]. In hypertrophic cardiomyopathy (HCM), β-blockers and calcium channel blockers relieve obstruction, and myectomy or alcohol ablation is used in refractory cases [81]. The advent of mavacamten has provided significant symptomatic improvement [82]; however, fibrosis, inflammatory remodelling, and sudden death risk (1–2% annually) remain unresolved [83,84]. Similarly, arrhythmogenic cardiomyopathy (ACM) is managed with exercise restriction, antiarrhythmics, and ICDs [53,85]; however, disease progression continues with fibrofatty replacement and declining antiarrhythmic efficacy [86].

 

Other subtypes have similar therapeutic limitations. Takotsubo cardiomyopathy is treated with supportive care, including ACE inhibitors and β-blockers [87]; however, recurrence affects 10% of patients, and cardiogenic shock arises in 10–15% of cases [88], as stress-induced neuroimmune activation remains unaddressed [89]. In pediatric cardiomyopathies, extrapolated adult therapies such as ACE inhibitors, β-blockers, and diuretics [90] are often ineffective, with mechanical support or transplantation required in advanced disease [91]. The 5-year survival rate is only 59% [92], underscoring the unique neuroimmune biology of developing hearts. Finally, COVID-19–related cardiomyopathy is managed with conventional heart failure therapies and, in severe inflammatory cases, with corticosteroids or immunosuppression [93]. However, the combined effects of viral cardiotropism, cytokine storm, and autonomic dysfunction generate sequelae that cannot be resolved by conventional treatments, including long-term autonomic dysregulation and exercise intolerance [94].

 

Together, these limitations reveal a shared gap across different cardiomyopathy phenotypes.  Although conventional therapies improve hemodynamics and reduce mortality, they fail to disrupt the persistent inflammatory and autonomic circuits that drive disease progression. This therapeutic inadequacy highlights the urgent need for neuroimmune-targeted intervention.” (Page  22-24, line 420- 459)

 

 

Minor Comments

1: Please consider adding a figure summarizing different types of CM, prognosis, treatments strategies

Response: The following figure has been added as per reviewers recommendation:

 

 

Figure 3. Overview of cardiomyopathy subtypes, including their characteristic etiologies, prognostic implications, and current treatment strategies.

Dilated cardiomyopathy is primarily driven by sympathetic overactivation, inflammatory cytokines, and vagal dysfunction, with poor long-term survival despite neurohormonal blockade. Hypertrophic cardiomyopathy involves macrophage/fibroblast activation and arrhythmogenic remodelling, with persistent sudden-death risk despite β-blockers and myosin inhibitors. Arrhythmogenic cardiomyopathy is associated with desmosomal mutations, immune cell infiltration, and neural remodelling, with treatment centered on arrhythmia suppression and ICD implantation. Takotsubo cardiomyopathy reflects acute catecholamine surge and autonomic dysfunction, with recurrence risk linked to stress, whereas pediatric cardiomyopathies reflect immune immaturity and viral triggers, requiring age-specific immune modulation. COVID-19 cardiomyopathy combines viral entry via ACE2, cytokine storm, and persistent autonomic dysfunction, with long COVID sequelae complicating management.

 

 

2: Please standardize the citation format for all references presented.

Response:  We have thoroughly reviewed and standardized all the references according to the journal's citation format.

 

 

 

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Saha et al have performed impressive adjustment for their manuscript and very carefully and successfully address my comments.  Congratulations for great work making this manuscript more comprehensive and complete. I also thank the authors for addressing my suggestions. I recommend accept this version of the manuscript in current form.