System Dysfunction Research Articles

Regulation of Stress-Induced Immunosuppression in the Context of Neuroendocrine, Cytokine, and Cellular Processes.

Understanding the regulatory mechanisms of stress-induced immunosuppression and developing reliable diagnostic methods are important tasks in clinical medicine. This will allow for the development of effective strategies for the prevention and treatment of conditions associated with immune system dysfunction induced by chronic stress. The purpose of this review is to conduct a comprehensive analysis and synthesis of existing data on the regulatory mechanisms of stress-induced immunosuppression. The review is aimed at identifying key neuroendocrine, cytokine, and cellular processes underlying the suppression of the immune response under stress. This study involved a search of scientific literature covering the neuroendocrine, cellular, and molecular mechanisms of stress-induced immunosuppression regulation, as well as modern methods for its diagnosis. Major international bibliographic databases covering publications in biomedicine, psychophysiology, and immunology were selected for the search. The results of the analysis identified key mechanisms regulating stress-induced immunosuppression. The reviewed publications provided detailed descriptions of the neuroendocrine and cytokine processes underlying immune response suppression under stress. A significant portion of the data confirms that the activation of the hypothalamic-pituitary-adrenal (HPA) axis and subsequent elevation of cortisol levels exert substantial immunosuppressive effects on immune cells, particularly macrophages and lymphocytes, leading to the suppression of innate and adaptive immune responses. The data also highlight the crucial role of cortisol and catecholamines (adrenaline and noradrenaline) in initiating immunosuppressive mechanisms under chronic stress.

Animal Models of Non-Respiratory, Post-Acute Sequelae of COVID-19.

Post-acute sequelae of COVID-19 (PASC) are a diverse set of symptoms and syndromes driven by dysfunction of multiple organ systems that can persist for years and negatively impact the quality of life for millions of individuals. We currently lack specific therapeutics for patients with PASC, due in part to an incomplete understanding of its pathogenesis, especially for non-pulmonary sequelae. Here, we discuss three animal models that have been utilized to investigate PASC: non-human primates (NHPs), hamsters, and mice. We focus on neurological, gastrointestinal, and cardiovascular PASC and highlight advances in mechanistic insight that have been made using these animal models, as well as discussing the sequelae that warrant continued and intensive research.

Skin Microbiota: Mediator of Interactions Between Metabolic Disorders and Cutaneous Health and Disease.

Metabolic disorders, including type 2 diabetes mellitus (T2DM), obesity, and metabolic syndrome, are systemic conditions that profoundly impact the skin microbiota, a dynamic community of bacteria, fungi, viruses, and mites essential for cutaneous health. Dysbiosis caused by metabolic dysfunction contributes to skin barrier disruption, immune dysregulation, and increased susceptibility to inflammatory skin diseases, including psoriasis, atopic dermatitis, and acne. For instance, hyperglycemia in T2DM leads to the formation of advanced glycation end products (AGEs), which bind to the receptor for AGEs (RAGE) on keratinocytes and immune cells, promoting oxidative stress and inflammation while facilitating Staphylococcus aureus colonization in atopic dermatitis. Similarly, obesity-induced dysregulation of sebaceous lipid composition increases saturated fatty acids, favoring pathogenic strains of Cutibacterium acnes, which produce inflammatory metabolites that exacerbate acne. Advances in metabolomics and microbiome sequencing have unveiled critical biomarkers, such as short-chain fatty acids and microbial signatures, predictive of therapeutic outcomes. For example, elevated butyrate levels in psoriasis have been associated with reduced Th17-mediated inflammation, while the presence of specific Lactobacillus strains has shown potential to modulate immune tolerance in atopic dermatitis. Furthermore, machine learning models are increasingly used to integrate multi-omics data, enabling personalized interventions. Emerging therapies, such as probiotics and postbiotics, aim to restore microbial diversity, while phage therapy selectively targets pathogenic bacteria like Staphylococcus aureus without disrupting beneficial flora. Clinical trials have demonstrated significant reductions in inflammatory lesions and improved quality-of-life metrics in patients receiving these microbiota-targeted treatments. This review synthesizes current evidence on the bidirectional interplay between metabolic disorders and skin microbiota, highlighting therapeutic implications and future directions. By addressing systemic metabolic dysfunction and microbiota-mediated pathways, precision strategies are paving the way for improved patient outcomes in dermatologic care.

Immunometabolic alterations in type 2 diabetes mellitus revealed by single-cell RNA sequencing: insights into subtypes and therapeutic targets.

Type 2 Diabetes Mellitus (T2DM) represents a major global health challenge, marked by chronic hyperglycemia, insulin resistance, and immune system dysfunction. Immune cells, including T cells and monocytes, play a pivotal role in driving systemic inflammation in T2DM; however, the underlying single-cell mechanisms remain inadequately defined. Single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from 37 patients with T2DM and 11 healthy controls (HC) was conducted. Immune cell types were identified through clustering analysis, followed by differential expression and pathway analysis. Metabolic heterogeneity within T cell subpopulations was evaluated using Gene Set Variation Analysis (GSVA). Machine learning models were constructed to classify T2DM subtypes based on metabolic signatures, and T-cell-monocyte interactions were explored to assess immune crosstalk. Transcription factor (TF) activity was analyzed, and drug enrichment analysis was performed to identify potential therapeutic targets. In patients with T2DM, a marked increase in monocytes and a decrease in CD4+ T cells were observed, indicating immune dysregulation. Significant metabolic diversity within T cell subpopulations led to the classification of patients with T2DM into three distinct subtypes (A-C), with HC grouped as D. Enhanced intercellular communication, particularly through the MHC-I pathway, was evident in T2DM subtypes. Machine learning models effectively classified T2DM subtypes based on metabolic signatures, achieving an AUC > 0.84. Analysis of TF activity identified pivotal regulators, including NF-kB, STAT3, and FOXO1, associated with immune and metabolic disturbances in T2DM. Drug enrichment analysis highlighted potential therapeutic agents targeting these TFs and related pathways, including Suloctidil, Chlorpropamide, and other compounds modulating inflammatory and metabolic pathways. This study underscores significant immunometabolic dysfunction in T2DM, characterized by alterations in immune cell composition, metabolic pathways, and intercellular communication. The identification of critical TFs and the development of drug enrichment profiles highlight the potential for personalized therapeutic strategies, emphasizing the need for integrated immunological and metabolic approaches in T2DM management.

Influencing fracture healing by specific osteoporosis medications

Osteoporosis is a widespread disease defined by areduction in bone mass and structure, thereby increasing the risk of fragility fractures. Treatment typically involves specific medications, which either inhibit bone resorption (antiresorptive) or stimulate bone formation (anabolic) and may potentially influence the healing of osteoporotic fractures. On the other hand, metabolic disorders, immune system dysfunctions or circulatory problems can impair fracture healing. Therefore, the targeted use of osteoporosis medications could be astrategy to promote the healing of impaired fractures. The aim of this study is to provide acurrent overview of the effects of osteoporosis medications approved in Germany on fracture healing. The focus is on the potential influence of these medications in the context of osteoporosis treatment. Additionally, the current state of research is examined to explore to what extent the targeted use of these medications could improve fracture healing. Aliterature search was conducted in the PubMed database using topic-specific keywords. Preclinical studies, clinical trials, review articles and meta-analyses were considered to present the current scientific knowledge with clinical relevance. Preclinical and clinical studies suggest that specific osteoporosis medications do not have aclinically relevant negative impact on the healing of fragility fractures. Osteoanabolic substances even tend to have apositive effect on fracture healing in both normal and impaired healing processes; however, the available studies are limited and none of the medications have been approved for this specific use. Osteoporosis medications with antiresorptive or osteoanabolic effects are primarily used to treat osteoporosis, especially after fragility fractures, to reduce the risk of further fractures. There is no clinically relevant impairment of fracture healing due to these medications. Further studies would be required to obtain approval for these medications specifically to improve fracture healing.

Functional Tests and Surveys Used to Assess Nervous System Dysfunction in Patients with Fabry Disease – A Review

Functional Tests and Surveys Used to Assess Nervous System Dysfunction in Patients with Fabry Disease – A Review

UNVEILING THE POTENTIAL OF SALIVARY EXOSOMAL BIOMARKERS IN CARDIOVASCULAR DISEASE:INSIGHTS AND FUTURE DIRECTIONS

Cardiovascular disease (CVD) is the primary cause of mortality world wide, necessitating innovative diagnostic approaches due to the limitations of current tools. The growing significance of salivary exosomes as biomarkers for CVD detection and treatment is explored in this narrative review. Salivary diagnostics offer a non-invasive alternative, with exosomes-small extracellular vesicles containing proteins, lipids, and nucleic acids—serving as potential indicators of cardiovascular health. The review highlights how salivary exosomes reflect the physiological states of their parent cells and can indicate systemic inflammation, oxidative stress, and endothelial dysfunction, all critical factors in CVD progression. Furthermore, it discusses specific exosomal biomarkers linked to different cardiovascular diseases such as valvular heart disease, coronary artery disease, cardiac fibrosis, arrhythmias, and heart failure. By integrating salivary exosome analysis into clinical practice, there is potential for enhanced early detection, risk stratification, and monitoring of cardiovascular diseases, ultimately paving the way for more personalized treatment strategies. This exploration underscores the transformative potential of salivary exosomes in improving cardiovascular disease management and patient outcomes.

A Scoping Review of the Association between Hemoglobinopathies and Male Infertility

Worldwide, infertility is a prevalent problem that poses a threat to couples, either the male or female partner, or both spouses, may be the cause of infertility. Numerous elements about the patient's general health or way of life may be to blame. Systemic or gonadal dysfunction may be the cause of the patient's health issues. Hematological factors may be one of the systemic reasons. Thalassemia major (TM) and sickle cell disease (SCD) are the two most prevalent hemoglobinopathies that are suspected to be the cause of infertility, particularly male infertility. Through pathophysiological changes, these two hemoglobinopathies result in male infertility. In particular, they change red blood cells' (RBCs') capacity to carry oxygen, resulting in tissue hypoxia that impacts spermatogenesis and the body's natural process of producing new cells, ultimately leading to infertility. Semen analyses and other systemic blood testing can be used to investigate male infertility. Both hemoglobinopathies can be helped by blood transfusions, which can then alleviate male infertility. This paper aims to explore the relationship between hemoglobinopathies (SCD and TM) and their role in contributing to male infertility, in addition to the role of blood transfusions in addressing male infertility by correcting the root cause.

Long COVID in Children and Adolescents: Mechanisms, Symptoms, and Long-Term Impact on Health-A Comprehensive Review.

Long COVID, also known as post-acute sequelae of SARS-CoV-2 infection (PASC), is increasingly recognized as a condition affecting not only adults but also children and adolescents. While children often experience milder acute COVID-19 symptoms compared to adults, some develop persistent physical, psychological, and neurological symptoms lasting for weeks or months after initial infection. The most commonly reported symptoms include debilitating fatigue, respiratory issues, headaches, muscle pain, gastrointestinal disturbances, and cognitive difficulties, which significantly impact daily activities, schooling, and social interactions. Additionally, many children with long COVID experience psychological symptoms, such as anxiety, depression, mood swings, and irritability, likely exacerbated by prolonged illness and lifestyle disruptions. Risk factors for long COVID in children include pre-existing health conditions such as asthma, obesity, and neurological disorders, with adolescents and females seemingly more affected. Hypothesized mechanisms underlying long COVID include chronic immune dysregulation, persistent viral particles stimulating inflammation, autonomic nervous system dysfunction, and mitochondrial impairment, which may collectively contribute to the variety of observed symptoms. Long-term outcomes remain uncertain; however, long COVID can lead to school absenteeism, social withdrawal, and psychological distress, potentially affecting cognitive development. Severe cases may develop chronic conditions such as postural orthostatic tachycardia syndrome (POTS) and reduced exercise tolerance. This review synthesizes the existing literature on long COVID in children, examining its prevalence, symptomatology, risk factors, and potential mechanisms, with an emphasis on the need for further clinical studies. While existing research largely relies on surveys and self-reported data, clinical assessments are essential to accurately characterize long COVID in pediatric populations and to guide effective management strategies.

A comprehensive review of computational diagnostic techniques for lymphedema.

Lymphedema is localized swelling due to lymphatic system dysfunction, often affecting arms and legs due to fluid accumulation. It occurs in 20% to 94% of patients within 2 to 5 years after breast cancer treatment, with around 20% of women developing breast cancer-related lymphedema (BCRL). This condition involves the accumulation of protein-rich fluid in interstitial spaces, leading to symptoms like swelling, pain, and reduced mobility that significantly impact quality of life. The early diagnosis of lymphedema helps mitigate the risk of deterioration and prevent its progression to more severe stages. Healthcare providers can reduce risks through exercise prescriptions and self-manual lymphatic drainage techniques. Lymphedema diagnosis currently relies on physical examinations and limb volume measurements, but challenges arise from a lack of standardized criteria and difficulties in detecting early stages. Recent advancements in computational imaging and decision support systems have improved diagnostic accuracy through enhanced image reconstruction and real-time data analysis. The aim of this comprehensive review is to provide an in-depth overview of the research landscape in computational diagnostic techniques for lymphedema. The computational techniques primarily include imaging-based, electrical, and machine learning approaches, which utilize advanced algorithms and data analysis. These modalities were compared based on various parameters to choose the most suitable techniques for their applications. Lymphedema detection faces challenges like subtle symptoms and inconsistent diagnostics. The research identifies Bioimpedance Spectroscopy (BIS), Kinect sensor and Machine Learning integration as the promising modalities for early lymphedema detection. BIS can effectively identify lymphedema as early as four months post-surgery with sensitivity of 44.1% and specificity of 95.4% in diagnosing lymphedema whereas in Machine learning, Artificial Neural Network (ANN) achieved an impressive average cross-validation accuracy of 93.75%, with sensitivity at 95.65% and specificity at 91.03%. Machine learning and imaging can be integrated into clinical practice to enhance diagnostic accuracy and accessibility.

Sleep and circadian disturbances in children with neurodevelopmental disorders.

Sleep is essential for brain development and overall health, particularly in children with neurodevelopmental disorders (NDDs). Sleep disruptions can considerably impact brain structure and function, leading to dysfunction of neurotransmitter systems, metabolism, hormonal balance and inflammatory processes, potentially contributing to the pathophysiology of NDDs. This Review examines the prevalence, types and mechanisms of sleep disturbances in children with NDDs, including autism spectrum disorder, attention-deficit hyperactivity disorder and various genetic syndromes. Common sleep disorders in these populations include insomnia, hypersomnia, circadian rhythm disorders, sleep-related breathing disorders and parasomnias, with underlying factors often involving genetic, neurobiological, environmental and neurophysiological influences. Sleep problems such as insomnia, night awakenings and sleep fragmentation are closely linked to both internalizing symptoms such as anxiety and depression, and externalizing behaviours such as hyperactivity and aggression. Assessment of sleep in children with NDDs presents unique challenges owing to communication difficulties, comorbid conditions and altered sensory processing. The Review underscores the importance of further research to unravel the complex interactions between sleep and neurodevelopment, advocating for longitudinal studies and the identification of predictive biomarkers. Understanding and addressing sleep disturbances in NDDs is crucial for improving developmental outcomes and the overall quality of life for affected individuals and their families.

Lysine acetylation and its role in the pathophysiology of acute pancreatitis.

Acute pancreatitis (AP) represents a severe inflammatory condition of the exocrine pancreas, precipitating systemic organ dysfunction and potential failure. The global prevalence of acute pancreatitis is on an ascending trajectory. The condition carries a significant mortality rate during acute episodes. This underscores the imperative to elucidate the etiopathogenic pathways of acute pancreatitis, enhance comprehension of the disease's intricacies, and identify precise molecular targets coupled with efficacious therapeutic interventions. The pathobiology of acute pancreatitis encompasses not only the ectopic activation of trypsinogen but also extends to disturbances in calcium homeostasis, mitochondrial impairment, autophagic disruption, and endoplasmic reticulum stress responses. Notably, the realm of epigenetic regulation has garnered extensive attention and rigorous investigation in acute pancreatitis research over recent years. One of these modifications, lysine acetylation, is a reversible post-translational modification of proteins that affects enzyme activity, DNA binding, and protein stability by changing the charge on lysine residues and altering protein structure. Numerous studies have revealed the importance of acetylation modification in acute pancreatitis, and that it is a favorable target for the design of new drugs for this disease. This review centers on lysine acetylation, examining the strides made in acute pancreatitis research with a focus on the contributory role of acetylomic alterations in the pathophysiological landscape of acute pancreatitis, thereby aiming to delineate novel therapeutic targets and advance the development of more efficacious treatment modalities.

The future of flourishing in veterinary medicine: a systems-informed positive psychology approach in veterinary education.

Individuals in the veterinary profession are experiencing significant mental health and wellbeing challenges. A holistic view of wellbeing, which encompasses both physical and mental health, underscores their interconnected nature. This integrated approach reduces the artificial separation of wellbeing facets, and highlights how mental states influence not only individuals, but also their interactions with animals, the environment, and others in the workplace. Wellbeing challenges in veterinary medicine may contribute to negative impacts in animal, human, and environmental health. Veterinary education institutions and systems are also experiencing complex challenges as they adapt to rapidly changing societal, workforce, and professional wellbeing related pressures. This review paper explores the field of positive psychology and its application in educational contexts, commonly known as positive education. A thorough exploration of the systems-informed positive education approach and ways in which it can proactively enhance veterinary professional wellbeing from within the veterinary education ecosystem are presented. It is important to recognize that individual self-care, while valuable, cannot compensate for systemic dysfunctions such as poor team dynamics, ineffective leadership, or organizational culture issues. Addressing these systemic factors is critical for creating environments that support sustained flourishing. Positive psychology interventions delivered through the pathways of individuals, groups, and organizations specifically within a veterinary education context are discussed. Limitations, considerations, and proposed measurement strategies are reviewed. The implications of implementing a systems-informed positive psychology approach to enhance wellbeing in veterinary education include creating curriculum and cultures that enable flourishing within veterinary education institutions. Strengthening the individual and collective wellbeing of veterinary professionals has the potential to enhance the quality of care provided to animals, which has myriad positive implications for animal caregivers, their communities, the environment, and society.

Choroid plexus enlargement in patients with rapid eye movement sleep behavior disorder: relevance to glymphatic system dysfunction

Choroid plexus enlargement in patients with rapid eye movement sleep behavior disorder: relevance to glymphatic system dysfunction

Depressive symptoms in older adults are associated with changes in stress-related markers, functional connectivity and brain volume

BackgroundSubclinical depressive symptoms increase the risk of developing Alzheimer’s disease (AD). The neurobiological mechanisms underlying this link may involve stress system dysfunction, notably related to the hippocampus which is particularly sensitive to AD. We aimed to investigate the links between blood stress markers and changes in brain regions involved in the stress response in older adults with or without subclinical depressive symptoms.MethodsThis cross-sectional study was conducted using baseline data from the Age-Well trial. Cognitively unimpaired (CU) older adults with (DepS; n = 73) or without (NoDepS; n = 58) subclinical depressive symptoms (defined using the 15-item Geriatric Depression Scale) were included in the analyses. Blood cortisol, epinephrine and norepinephrine were measured; as well as the resting-state functional connectivity (rs-FC) between, and gray matter (GM) volume of, the hypothalamus, hippocampus and hippocampal subfields. Blood stress markers levels and neuroimaging measures were compared between groups; then regression analyses were conducted between these measures.ResultsDepS participants showed higher plasma epinephrine levels, which was associated with greater rs-FC between the CA1 and Subiculum hippocampal subfields and the hypothalamus. Lower GM volume in the CA1 and DG/CA2-3–4 subfields was also found in DepS. No between-group differences were observed for blood cortisol and norepinephrine.ConclusionsOur findings show that subclinical depressive symptoms are associated with increased sympatho-adrenomedullary axis activity, together with lower GM volume in a hippocampal subfield (i.e., CA1) particularly sensitive to AD. While causation cannot be inferred, these results suggest that screening and treating subclinical depressive symptoms in CU older adults could reduce AD risk.Trial registrationClinicalTrials.gov Identifier: NCT02977819, Registration Date: 2016–11-25.

The Impact of Levothyroxine and Testosterone Administration on Bladder Contractility in the Rat Model of Propylthiouracil-Induced Hypothyroidism.

To investigate the effects of testosterone (T) treatment, with or without levothyroxine, the most widely used and least effective medication for managing hypothyroidism, on the functional and histological changes in propylthiouracil (PTU)- induced hypothyroid rat bladders. Male rats (n=35) were split into control, hypothyroid, hypothyroid rats treated with levothyroxine (20 µg/kg/day, oral, 2-weeks), hypothyroid rats treated with Sustanon (10 mg/kg,iIM, once/week, 2-weeks), and hypothyroid rats treated with combined treatment groups. Hypothyroidism was induced by PTU (0.05% in drinking water, 6 weeks). The serum concentration of triiodothyronine (T3), thyroxine (T4), total T, and the detrusor muscle's contractile responses were determined. A morphological study was conducted using Masson trichrome staining. Triiodothyronine, T4, and T levels were considerably reduced in rats with hypothyroidism; however, these hormones were restored by levothyroxine and Sustanon. Compared to controls, the combination therapy improved the ratio of smooth muscle to collagen and the contractile responses to carbachol, electrical field stimulation, and adenosine triphosphate in the hypothyroid bladder. The authors' research suggests that hypothyroidism may affect the contractility and morphology of the bladder. In males with hypothyroidism and urogenital system dysfunction, combination therapy with thyroid hormones and T has a major impact on repairing detrusor smooth muscle contractility and bladder histomorphology.

The ending is not the end: Lymph node metastasis in oral squamous cell carcinoma.

Lymph node metastasis is an important biological feature of oral squamous cell carcinoma, bearing poorly prognostic implications. However, the role of lymph node metastasis in cancer progression remains inconclusive. On the one hand, lymph nodes are pivotal sites for initiating specific immunity, which is crucial for maintaining antitumor immune response. On the other hand, they also serve as primary conduits for tumor metastasis, with lymph node colonization potentially inducing systemic immune dysfunction, thereby further promoting tumor progression. Considering this paradoxical role of lymph nodes, comprehending their impact on the primary tumor and immunity becomes paramount. Furthermore, leveraging these distinctive attributes of lymph nodes presents novel avenues for enhancing current therapeutic strategies against oral squamous cell carcinoma. This review summarizes the anatomical and molecular profiles of lymph node metastasis in oral squamous cell carcinoma, elucidating how lymphatic involvement compromises antitumor immunity, thus facilitating primary tumor and distant metastases. Additionally, it explores avenues for harnessing these mechanisms to optimize clinical interventions.

Safety and efficacy of dapagliflozin in patients with systemic right ventricular dysfunction: Preliminary results

Safety and efficacy of dapagliflozin in patients with systemic right ventricular dysfunction: Preliminary results

Integrating Manual Therapy Techniques in the Treatment of Long COVID: A Case Report

Purpose: Growing evidence suggests long COVID in some can result in nervous system dysfunction, which translates to difficulty completing daily activities. Physical therapists play an important role in regulating the autonomic system through the use of manual techniques that can decrease sympathetic tone. The purpose of this case report was to outline the physical therapy management of a person with long COVID and associated autonomic nervous system dysfunction. This case report discusses a patient who is a 70-year-old man referred to physical therapy for fatigue and shortness of breath related to physician-diagnosed long COVID. Methods: The following manual therapy techniques were applied at each treatment session to address rib cage dysfunctions, muscle hypertonicity, and sympathetic tone for improved breathing: suboccipital release, cervical paraspinal release, and rib raising. Concurrently, the patient was instructed and prescribed a diaphragmatic breathing home exercise program. Results: After 11 physical therapy visits over 20 weeks, the patient demonstrated functional improvement with an associated decrease in symptoms. Conclusions: Manual therapy techniques, in combination with other physical therapy interventions, may be a first-line, less invasive means of addressing sympathetic tone and the downstream effects of nervous system dysfunction on daily living.

Poincaré plot analysis of electrocardiogram uncovers beneficial effects of omaveloxolone in a mouse model of Friedreich ataxia.

Friedreich ataxia (FA) is a rare inherited neuromuscular disorder whereby most patients die of lethal cardiomyopathy and arrhythmias. Mechanisms leading to arrhythmic events in patients with FA are poorly understood. This study aimed to examine cardiac electrical signal propagation in a mouse model of FA with severe cardiomyopathy and to evaluate effects of omaveloxolone (OMAV), the first Food and Drug Administration-approved therapy. Cardiac-specific MCK-Cre frataxin knockout (FXN-cKO) mice were used to mimic FA cardiomyopathy. Invivo surface electrocardiogram (ECG) recordings, Western blotting, quantitative real-time polymerase chain reaction analysis, and histochemistry were performed. Characteristics like long QT syndrome, interatrial block, and ST-segment abnormalities in patients with FA were identified in FXN-cKO mice. FXN-cKO mice exhibited sexual dimorphism in electrical signal propagation and cardiac structural integrity. Untreated FA males showed increased ventricular propagation intervals, whereas females exhibited delayed atrial propagation. OMAV showed no significant therapeutic effect on average ECG time intervals but improved chamber-specific waveforms when aggregated frequency distributions were analyzed. The J wave was absent in FXN-cKO male mice but reappeared with OMAV treatment. Poincaré plots revealed disparate idiopathic arrhythmias with multi-clustering events in individual mice with high incidence in FXN-cKO males. OMAV treatment reduced multi-clustering events to a single cluster; however, autonomic nervous system dysfunction still remained. Our study revealed significant electrical propagation disturbances and sexual dimorphism in FXN-cKO mice with severe cardiomyopathy. Poincaré plots identified irregularities in heart rhythm and autonomic nervous system dysfunction. OMAV improved heart function by stabilizing early repolarization and reducing disparate arrhythmias. This work stresses sex-specific ECG interpretations and alternative mathematical approaches for drug testing in FA models.