Pathophysiological Mechanisms Research Articles

Vascular Impairment, Muscle Atrophy, and Cognitive Decline: Critical Age-Related Conditions

The triad of vascular impairment, muscle atrophy, and cognitive decline represents critical age-related conditions that significantly impact health. Vascular impairment disrupts blood flow, precipitating the muscle mass reduction seen in sarcopenia and the decline in neuronal function characteristic of neurodegeneration. Our limited understanding of the intricate relationships within this triad hinders accurate diagnosis and effective treatment strategies. This review analyzes the interrelated mechanisms that contribute to these conditions, with a specific focus on oxidative stress, chronic inflammation, and impaired nutrient delivery. The aim is to understand the common pathways involved and to suggest comprehensive therapeutic approaches. Vascular dysfunctions hinder the circulation of blood and the transportation of nutrients, resulting in sarcopenia characterized by muscle atrophy and weakness. Vascular dysfunction and sarcopenia have a negative impact on physical function and quality of life. Neurodegenerative diseases exhibit comparable pathophysiological mechanisms that affect cognitive and motor functions. Preventive and therapeutic approaches encompass lifestyle adjustments, addressing oxidative stress, inflammation, and integrated therapies that focus on improving vascular and muscular well-being. Better understanding of these links can refine therapeutic strategies and yield better patient outcomes. This study emphasizes the complex interplay between vascular dysfunction, muscle degeneration, and cognitive decline, highlighting the necessity for multidisciplinary treatment approaches. Advances in this domain promise improved diagnostic accuracy, more effective therapeutic options, and enhanced preventive measures, all contributing to a higher quality of life for the elderly population.

Takotsubo cardiomyopathy in patients with borderline stenosis of the left anterior descending (LAD) and vasospastic angina. To stent or not to stent? A case report

Abstract Introduction Takotsubo cardiomyopathy (TCM) is a complex disease that resembles the clinical presentation of acute myocardial infarction with non-obstructive coronary arteries (MINOCA). The etiology remains elusive despite the comprehensive nature of current guidelines meticulously detailing the diagnostic process. Case summary We present the case of a 64-year-old female who presented with a clinical profile consistent with non-ST elevation myocardial infarction (NSTEMI), confirmed by elevated cardiac enzyme levels. Echocardiography raised suspicions of TCM. Angiography presented a challenge, revealing a 65% stenosis of the left anterior descending (LAD) artery. Based on the collected evidence, we decided to delay and ultimately forgo LAD revascularization while identifying epicardial vasospasm through a provocation test as a possible cause underlying TCM. Discussion Conducting an acetylcholine provocation test, as recommended by the European Society of Cardiology (ESC) guidelines for patients with Ischemia and No Obstructive Coronary Artery Disease (INOCA), unveiled severe diffuse vasospasm affecting both the left anterior descending artery and circumflex arteries. The intricate interplay of pathophysiological mechanisms and clinical presentations necessitates ongoing exploration to uncover the mysteries and refine our diagnostic and therapeutic strategies.

Application of computational fluid dynamics to investigate pathophysiological mechanisms in exercise-induced laryngeal obstruction.

The underlying pathophysiological mechanisms of exercise-induced laryngeal obstruction (EILO) remain to be fully established. It is hypothesised that high inspiratory flow rates can exert a force on laryngeal airway wall that contributeto its inward collapse causing obstruction. Computational fluid dynamics (CFD) presents an opportunity to explore the distribution of forces in a patient specific upper airway geometry. The current study combined exercise physiological data and CFD simulation to explore differences in airflow and force distribution between an EILO patient and a healthy-matched control. Subjects underwent incremental exercise testing with continuous recording of respiratory airflow and laryngoscopic video, followed by an MRI scan. The respiratory and MRI data were used to generate a subject specific CFD model of upper respiratory airflow. In the EILO patient, the posterior supraglottis experiences an inwardly directed net force, whose magnitude increases nonlinearly with larger flow rates, with slight changes in the direction toward the centre of the airway. The control demonstrated an outwardly directed force at all regions of the wall, with a magnitude that increases linearly with larger flow rates. A comparison is made between the CFD results and endoscopic visualisation of supraglottic collapse, and very good agreement is found. We present the first hybrid physiological / computational approach to investigate the pathophysiological mechanisms of EILO. The method shows great potential and the preliminary findings should be confirmed in larger sample sizes.

Research prospect of cyclic nucleotide phosphodiesterase 3/4 inhibitors in chronic obstructive pulmonary disease

Current treatments for chronic obstructive pulmonary disease (COPD) are relatively limited and cannot meet the needs of all patients. Ensifentrine (development code RPL554), a representative drug of cyclic nucleotide phosphodiesterase 3/4 (PDE 3/4) inhibitors, has shown promising developments in the treatment of COPD in recent years, which need to be summarized. This article reviews the mechanism and clinical research progress of ensifentrine, focusing on its chemical structure, pharmacokinetics, pathophysiological mechanism, efficacy, and safety. Additionally, we provide clinical application suggestions and future research prospects.

Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to functionina range of pathologicalconditions,such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodelingfollowingAMI. Following AMI in mice, MDSCsfrequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following theadoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-β1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-β1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly,blockade of IL-10 partially abolished the cardioprotectiverole of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

Exploring research trends and hotspots on oxidative stress and bronchopulmonary dysplasia: Insights from bibliometric and visualized study.

Bronchopulmonary dysplasia (BPD) is a severe chronic lung disease primarily affecting premature infants, often resulting from prolonged mechanical ventilation and oxygen therapy. Oxidative stress plays a critical role in the pathogenesis of BPD, contributing to lung injury, inflammation, and impaired lung development. Despite extensive research, there is a need to systematically map out the research trends and hotspots in this field to inform future studies and therapeutic strategies. This study utilized bibliometric and visualized analysis to explore global research trends and hotspots on oxidative stress and BPD from 2004 to 2024. A comprehensive literature search was conducted in the Web of Science Core Collection, focusing on publications related to oxidative stress and BPD. Tools such as VOSviewer, Citespace, and the R package Bibliometrix were employed to analyze Coauthorship, co-citation, and keyword co-occurrence networks, as well as to identify emerging research fronts and influential studies. The analysis identified 597 relevant publications, showing a steady increase in research output over the 20-year period, with a significant surge in the last decade. The United States led in research contributions, followed by China and Germany, with notable collaborations among these countries. Coauthorship analysis highlighted key research institutions, such as Harvard University and the University of California, as central nodes in the research network. Thematic clustering revealed five major research areas: antioxidant mechanisms, inflammation, molecular pathways, lung development, and therapeutic interventions. The keyword co-occurrence analysis showed a shift in research focus over time. Early studies concentrated on basic pathophysiological mechanisms, while recent research has increasingly focused on advanced molecular techniques, such as gene expression and targeted therapies. Notably, the study identified emerging research hotspots, including the role of extracellular vesicles and cellular senescence in BPD, as well as the potential therapeutic applications of antioxidants like superoxide dismutase mimetics. This bibliometric study provides a comprehensive overview of the research landscape on oxidative stress and BPD, identifying key trends, influential authors, and emerging research topics. The findings underscore the importance of continued research in this field, particularly in translating basic scientific insights into clinical applications to improve outcomes for infants affected by BPD. The study also highlights potential areas for future investigation, including the development of novel therapeutic strategies targeting oxidative stress in BPD.

AGTR1 variant rs2638355 is associated with increased salt sensitivity of blood pressure: a female-specific effect in individuals from the HyperPath cohort.

Salt-sensitive hypertension (SSH) affects approximately half of the hypertensive population, increasing the risk of vascular complications. The underlying pathophysiological mechanisms of SSH remain complex and need to be fully elucidated. Our prior research has identified genetic factors contributing to the salt sensitivity of blood pressure (SSBP), particularly involving genes regulating volume and blood pressure. We also observed enhanced peripheral vascular response to angiotensin II in humans with salt-sensitive hypertension. Given the pivotal role of the angiotensin II receptor type-1 (AT1R or AGTR1) in blood pressure and intravascular volume regulation, we hypothesized a genetic association between AGTR1 and SSBP. Our study involved 240 individuals of European ancestry from the HyperPATH cohort, examined under restricted and high dietary salt conditions. We employed a tagging single nucleotide variant approach to genotype participants at AGTR1. Our regression model revealed a significant association between the rs2638355 (A/G) variant and salt-sensitive systolic blood pressure (SS-SBP), and rs2638355 increased AGTR1 gene expression. Notably, carriers of the risk-allele of the noncoding regulatory variant rs2638355 exhibited higher systolic blood pressure under high salt diet conditions than nonrisk allele individuals. A sex-stratified analysis showed this salt-driven effect on systolic blood pressure was significant only in females, underscoring the role of dietary salt in modulating genetic effects in this group. Furthermore, a restricted salt diet in these individuals diminished blood pressure and negated the blood pressure phenotype-genotype association. Overall, our findings could aid in pinpointing individuals with salt-sensitive blood pressure among hypertensive patients, especially considering dietary and sex-specific factors.

Hypertension and menopause: physiopathology and impact of the hormonal therapy

Menopause, as a consequence of ovarian follicular decline, induces estrogen deficiency and metabolic changes that increase the cardiovascular risk in women. In particular, there is an increase in blood pressure during menopause. Menopausal hormonal therapy can be prescribed to women with symptoms of menopause to improve their quality of life. This article reviews the current literature on the pathophysiological mechanisms that explain blood pressure changes at menopause and describes the impact of menopausal hormone therapy on blood pressure.

Obesity, Metabolic Syndrome, and Sugar-Sweetened Beverages (SSBs) in America: A Novel Bioethical Argument for a Radical Public Health Proposal.

The prevalence of obesity, metabolic syndrome, and the associated long-term chronic diseases (cardiovascular disease, type II diabetes, cancer, Alzheimer's disease, depression) have reached epidemic levels in the United States and Western nations. In response to this public health calamity, the author of this paper presents and defends a novel bioethical argument: the consistency argument for outlawing SSBs (sugar-sweetened beverages) for child consumption (the "consistency argument"). This argument's radical conclusion states that the government is justified in outlawing SSBs consumption for child consumption. The reasoning is as follows: if one accepts that the physical harm caused by chronic alcohol consumption justifies the government outlawing alcoholic beverages for child consumption, and there is strong evidence that comparable physical harms result from chronic SSBs consumption, then, mutatis mutandis, the government is also justified in outlawing child consumption of SSBs. To support this argument, the author provides extensive evidence based on epidemiological observational studies, interventional studies, controlled trials, large meta-analyses, and the pathophysiology and biological mechanisms of action behind SSBs and chronic disease. Chronic consumption of large doses of SSBs and alcoholic beverages both drive the same diseases: obesity and insulin resistance, cardiovascular disease, hypertension, and cancer. Chronic SSB consumption carries the additional risk of Alzheimer's disease, dementia, and depression. The author concludes this paper by considering prominent objections to the consistency argument, and then demonstrating that each objection is unsound.

Gender-specific characteristics of heart failure with preserved ejection fraction in women: focus on pregnancy factors

The prevalence of heart failure with preserved ejection fraction (HFpEF) is relentlessly increasing, especially in women. Therefore, an important task is search for novel markers and early predictors of the disease. Evaluation of the association between physiological factors and complications of pregnancy and the development both early and longterm heart failure (HF) is also a substantial question. The younger women cohort is of particular interest because of the high prevalence of HFpEF among women in Russia. The purpose of the review is to assess gender differences in the HF, as well as to summarize the results of studies on the association of adverse pregnancy outcomes and development of HFpEF. The article describes the gender characteristics of the development of various HF types. We considered the morphofunctional, neurohumoral and age factors associated with the HF development in women, as well as the differences in the influence of the leading risk factors for HF between men and women. Particular attention is paid to the role of pregnancy factors in the development of various HF types. The following HF development variants in women have been identified: early (peripartum) and late (diagnosed in postmenopause). The pathophysiological mechanisms of the impact of extragenital pregnancy complications on HF development are described separately. Particular attention is paid to studying the relationship between pregnancy complications and HFpEF development in the long-term prognosis, as the most characteristic form of HF for women. The leading pregnancy complications associated with HFpEF development in postmenopause are hypertensive disorders (including preeclampsia and eclampsia) and gestational diabetes mellitus. A wider study of the association of pregnancy complications with HFpEF in a woman’s future is necessary to identify new mechanisms for its development.

Effects of glycaemic control on memory performance, hippocampal volumes and depressive symptomology

BackgroundDiabetes and poor glycaemic control have been shown to negatively impact cognitive abilities, while also raising risk of both mood disorders and brain structural atrophy. Sites of atrophy include the hippocampus, which has been implicated in both memory performance and depression. The current study set out to better characterise the associations between poor glycaemic control, memory performance, and depression symptoms, and investigate whether loss of hippocampal volume could represent a neuropathological mechanism underlying these.Methods1331 participants (60.9% female, age range 18–88 (Mean = 44.02), 6.5% with likely diabetes) provided HbA1c data (as an index of glycaemic control), completed a word list learning task, and a validated depression scale. A subsample of 392 participants underwent structural MRI; hippocampal volumes were extracted using FreeSurfer.ResultsPartial correlation analyses (controlling for age, gender, and education) showed that, in the full sample, poorer glycaemic control was related to lower word list memory performance. In the MRI sub-sample, poorer glycaemic control was related to higher depressive symptoms, and lower hippocampal volumes. Total hippocampus volume partially mediated the association between HbA1c levels and depressive symptoms.ConclusionsResults emphasise the impact of glycaemic control on memory, depression and hippocampal volume and suggest hippocampal volume loss could be a pathophysiological mechanism underlying the link between HbA1c and depression risk; inflammatory and stress-hormone related processes might have a role in this.

10. Complex regional pain syndrome.

Complex regional pain syndrome (CRPS) is a clinical disorder that can develop following surgery or trauma. Based on the most prominent underlying pathophysiological mechanisms, CRPS can be classified into different subtypes, namely inflammatory, nociplastic/neuropathic, vasomotor, and motor. Depending on the subtype, personalized treatment can be applied. If conservative treatments are insufficient or ineffective, more invasive treatments may be recommended. This article provides an overview of the most recent insights into CRPS and discusses the most common invasive treatments. The literature regarding interventional treatments for CRPS has been systematically reviewed and summarized. Bisphosphonates are effective in treating the inflammatory subtype, while ketamine can provide pain relief for the nociplastic/neuropathic subtype. Sympathetic blocks are effective in addressing vasomotor disturbances. For patients with refractory symptoms, neurostimulation is a viable option due to its multimechanistic properties for all subtypes. End-of-line motor disturbances may benefit from intrathecal baclofen. CRPS is a debilitating condition with an unpredictable course. The effectiveness of treatment varies from patient to patient. When conservative approaches prove insufficient, gradual progression to invasive treatments based on the underlying subtype is recommended.

Baseline serum glutamate: Implications for diagnosis and prediction in mild cognitive impairment and Alzheimer’s disease of the Alzheimer’s Disease Neuroimaging Initiative

PurposeNumerous studies have highlighted a close link between metabolic imbalances and Alzheimer’s Disease (AD). The advancement of metabolomics has recently enabled the exploration of characteristic metabolic changes associated with AD. Studies indicate that serum glutamate (Glu) levels may correlate with mild cognitive impairment (MCI) and AD. This study aims to further elucidate the characteristics of baseline serum Glu levels in MCI and AD. MethodsThis study included 783 participants from the Alzheimer’s Disease Neuroimaging Initiative-1 (ADNI-1) cohort, categorized into cognitively normal (CN, n = 224), stable MCI (sMCI, n = 181), progressive MCI (pMCI, n = 193), and AD (n = 185). The study aimed to analyze the diagnostic value of baseline serum Glu, to explore its predictive capability for the progression from CN to MCI or AD, and from MCI to AD, and to analyze the relationship between serum Glu and cerebrospinal fluid (CSF) biomarkers and cognitive functions in different diagnostic groups. ResultsCompared to the CN and sMCI groups, the pMCI group showed significantly lower levels of serum Glu, and the AD group also had lower Glu levels compared to the sMCI group. However, serum Glu did not show significant diagnostic value for MCI and AD. Lower levels of serum Glu could predict the progression from MCI to AD. ConclusionSerum Glu levels can predict the progression from MCI to AD, suggesting that it could provide new insights into the pathophysiological mechanisms of AD. However, serum Glu may not be an ideal peripheral biomarker for AD.

Unravelling the interplay between Harmattan wind and baroreflex functions: implications on environmental health and cardiovascular pathophysiology

Harmattan is a season characterized by dust, cold, and sub-humid trade winds in Sub-Saharan countries. It’s similar to meteorological phenomena like Asian dust storms, Santa Ana winds, Australian bushfires, and Saharan dust in the Caribbean. It causes profound changes in the cardiorespiratory system in apparently healthy individuals and increases the risk of hospitalization in susceptible individuals. Exposure to these extreme conditions has been associated with alterations in autonomic function and baroreceptor sensitivity thus resulting in dysregulation of blood pressure control mechanisms. Baroreceptors are critical regulators of hemodynamics and cardiovascular function. They play a vital role in the short-term responses to blood pressure perturbation and are essential for acute restoration of blood pressure following cold exposure. Harmattan wind contains a barrage of chemicals, dust, and particulate matters depending on industrialization, natural and human activities. Particulate matter from Harmattan dust can trigger systemic inflammation and oxidative stress, exacerbating endothelial dysfunction and impairing vascular reactivity thus contributing to the pathogenesis of alterations in baroreceptor insensitivity, and cardiovascular diseases, including hypertension and atherosclerosis. Furthermore, fine particulate matter from dust may penetrate deep into the respiratory tract, activating pulmonary sensory receptors and eliciting reflex responses that influence autonomic tone. The presence of rich acrolein smokes and non-essential heavy metals such as cadmium, lead, and mercury in Harmattan wind also reduces baroreflex sensitivity, culminating in a sustained increase in diastolic and systolic blood pressure. This integrated review aims to provide valuable insights into how changes in each of these environmental constituents alter vital pathophysiologic and immunologic mechanisms of the body leading to baroreceptor instability and ultimately hemodynamic imbalance using available primary studies. Understanding this intricate interplay is crucial for implementing targeted interventions and informed public health strategies to mitigate the adverse effects of extreme environmental exposure and ultimately reduce poor health outcomes in the affected regions.

S-Nitrosylation of p39 promotes its degradation and contributes to synaptic dysfunction induced by β-amyloid peptide

Alzheimer’s disease (AD), characterized by cognitive decline, is increasingly recognized as a disorder marked by synaptic loss and dysfunction. Despite this understanding, the underlying pathophysiological mechanisms contributing to synaptic impairment remain largely unknown. In this study, we elucidate a previously undiscovered signaling pathway wherein the S-nitrosylation of the Cdk5 activator p39, a post-translational modification involving the addition of nitric oxide to protein cysteine residues, plays a crucial role in synaptic dysfunction associated with AD. Our investigation reveals heightened p39 S-nitrosylation in the brain of an amyloid precursor protein (APP)/presenilin 1 (PS1) transgenic mouse model of AD. Additionally, soluble amyloid-β oligomers (Aβ), implicated in synaptic loss in AD, induce p39 S-nitrosylation in cultured neurons. Notably, we uncover that p39 protein level is regulated by S-nitrosylation, with nitric oxide S-nitrosylating p39 at Cys265 and subsequently promoting its degradation. Furthermore, our study demonstrates that S-nitrosylation of p39 at Cys265 significantly contributes to amyloid-β (Aβ) peptide-induced dendrite retraction and spine loss. Collectively, our findings highlight S-nitrosylation of p39 as a novel aberrant redox protein modification involved in the pathogenesis of AD, suggesting its potential as a therapeutic target for the disease.

Beyond the Gut: Exploring Cardiovascular Implications of Celiac Disease.

Celiac disease (CD) is an autoimmune disorder that presents with gastrointestinal symptoms including diarrhea, weight loss, and abdominal bloating due to the inflammation in the small intestine. It has been associated with various extraintestinal manifestations, including mucocutaneous findings such as dermatitis herpetiformis, anemia, dental enamel defects, osteoporosis, and arthritis. Studies have revealed an increasing association between CD and cardiovascular diseases (CVDs), including atherosclerosis, cardiomyopathy, and arrhythmia. Chronic inflammation, nutritional deficiencies from malabsorption, endothelial dysfunction, thrombophilic autoantibodies, thrombocytosis, and protein C and S deficiency have been proposed as the probable mechanisms for the association between the 2 conditions. This article aims to provide a review of the pathophysiological mechanism of celiac disease causing various CVDs and to compare and contrast the existing studies suggesting both favorable and unfavorable CVD outcomes in patients with CD.

(Key1-001) congenital disorders of glycosylation: Glycobiology at the bedside.

Congenital disorders of glycosylation (CDG) are a group of rare monogenic human disorders caused by defects in the genes encoding the proteins that generate, attach, and modify glycans, thus disrupting cellular glycosylation machinery. Over 200 CDG caused by disruptions of 189 different genes are currently known. The multi-system disease manifestations of the CDG disorders highlight the importance of glycosylation across the organ systems. Clinical manifestations of CDG tend to group among genes contributing to the same glycosylation pathways, suggesting shared pathophysiology related to the glycosylation disruptions. However, the underlying glycosylation disruptions and pathophysiologic mechanisms responsible for specific CDG clinical manifestations have been determined for only a few hypoglycosylated proteins. The Frontiers in CDG Consortium (FCDGC) is an international network of clinical sites, laboratories, and patient advocacy groups established in 2019 to improve clinical symptoms, quality of life, and life expectancy for individuals with CDG. FCDGC seeks to answer decades of unresolved questions, address knowledge gaps, develop and validate new biochemical diagnostic techniques and therapeutic biomarkers, and explore novel therapeutic options for CDG. Over the past 5years, FCDGC has launched a Natural History Study with over 300 CDG patients, discovered novel biomarkers suggesting new mechanisms of disease, and launched clinical trials aiming to restore appropriate glycosylation and targeting newly identified potential mechanisms of disease. Technical advances in glycobiology are making it increasingly possible to comprehensively catalog glycoproteomic data and to probe functional impact of altered glycosylation. My laboratory applies glycoproteomic technologies to samples from human subjects and genetic model systems to identify glycosylation abnormalities and unlock new insights from translational glycobiology. Current findings and accomplishments highlight the ongoing bottlenecks and knowledge gaps at intersections of glycobiology and clinical care requiring further investigation.

Revealing alterations in heart rate fluctuations during the progression of Chagas disease

IntroductionThe heart rate variability (HRV) continually evolves throughout life, reflecting modifications in the architecture of the sinoatrial node (SAN) and in the regulation of heart rate by the autonomic nervous system (ANS). Both can be considerably affected by Chagas disease, causing important changes in the complex nature of HRV. We aim to evaluate the ability of an index based on the false nearest neighbors method (FN10) to reflect these changes during disease progression.MethodsWe perform a retrospective, descriptive, and cross-sectional study analyzing HRV time series of participants with Chagas disease. We determine the dependence of FN10 on age and sex in a healthy population, and then evaluate FN10 in individuals with Chagas disease.Results and discussionIn the healthy population, FN10 has a scaling behavior with age, which is independent of sex. In Chagas disease, some individuals show FN10 values significantly above those seen in the healthy population. We relate the findings to the pathophysiological mechanisms that determine the progression of the disease. The results indicate that FN10 may be a candidate prognostic biomarker for heart disease.

Identification of key immune-related genes and potential therapeutic targets in immune checkpoint inhibitor–associated myocarditis

Abstract Background Immune checkpoint inhibitors (ICIs) are widely used in cancer treatment; however, the emergence of ICI-associated myocarditis (ICI-MC) presents a severe and potentially fatal complication with poorly understood pathophysiological mechanisms. This study aimed to identify crucial immune-related genes in ICI-MC and uncover potential therapeutic targets using bioinformatics. Methods Using the GSE180045 dataset, which includes three groups—Group A: ICI patients without immune adverse events, Group B: ICI patients with non-myocarditis immune adverse events, and Group C: ICI patients with myocarditis—we analyzed differentially expressed genes (DEGs) between ICI-MC samples (Group C) and non-myocarditis controls (Groups A and B). These DEGs were then cross-referenced with 1796 immune-related genes from the immPort database to identify immune-related DEGs. We conducted functional enrichment analyses (Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, gene set enrichment analysis), constructed a protein–protein interaction network, and identified hub genes. Validation using the GSE4172 dataset led to the identification of optimal feature genes from the overlap between hub genes and DEGs. Predictions of target MicroRNAs (miRNAs) were made, and a competing endogenous RNA (ceRNA) network was constructed. Target drugs for hub genes were predicted using the Connectivity Map database. Results We identified 58 DEGs between ICI-MC and controls, which led to the identification of 32 immune-related DEGs after intersection with 1796 immune-related genes. Functional analyses revealed enrichment in cell lysis, CD8+ T-cell receptor, natural killer cell–mediated cytotoxicity, and RAGE signaling. Notably upregulated hub genes included IL7R, PRF1, GNLY, CD3G, NKG7, GZMH, GZMB, KLRB1, KLRK1, and CD247. In the validation dataset, 407 DEGs were uncovered, resulting in the identification of 3 optimal feature genes (KLRB1, NKG7, GZMH). The predicted target miRNAs, lincRNAs, and circRNAs constituted a comprehensive ceRNA network. Among the top 10 drugs with elevated connectivity scores was acetohydroxamic acid, indicating a need for caution in ICI treatment. Conclusion KG7, GZMH, and KLRB1 were identified as pivotal immune-related genes in ICI-MC. Biological enrichments included pathways involved in cell lysis, the CD8+ T-cell receptor pathway, natural killer cell–mediated cytotoxicity, RAGE signaling, and proinflammatory responses. The ceRNA network illuminated the role of critical molecules and underscored the importance of avoiding drugs such as acetohydroxamic acid in ICI treatment. Key message What is already known on this topic Myocarditis is recognized as a serious ICI-associated toxicity, seemingly infrequent yet often fulminant and lethal. The underlying mechanisms of ICI-associated myocarditis remain not fully understood. Although the significance of T cells and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) is evident, the inciting antigens, the reasons for their recognition, and the mechanisms causing cardiac cell injury are not well characterized. An improved understanding of ICI-associated myocarditis will provide insights into the equilibrium between the immune and cardiovascular systems. What this study adds Our study further validates the significance of T cells and CTLA-4 in ICI-associated myocarditis. More importantly, we identified three genes—NKG7, GZMH, and KLRB1—essential for the development of ICI-MC and proposed ceRNA networks involving these three key genes. How this study might affect research, practice or policy The newly discovered key genes and their intricate molecular interactions offer a comprehensive perspective on the mechanisms underlying ICI-MC. Furthermore, our findings advise caution regarding the use of drugs like acetohydroxamic acid during ICI treatment. As our understanding of these regulatory networks deepens, our study provides valuable insights that could inform future therapeutic strategies for ICI-MC.

PDE4B Missense Variant Increases Susceptibility to Post-Traumatic Stress Disorder-Relevant Phenotypes in Mice.

Large-scale genome-wide association studies (GWAS) have associated intronic variants in PDE4B, encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (ten tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b M220T mice. At 24 hours post-trauma, Pde4b M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b M220T mice also exhibited a slower decay in freezing at 15 days and 30 days post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes, and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.Significance Statement Human genetic studies have associated variants in the PDE4B gene, encoding the phosphodiesterase-4B (PDE4B) enzyme, with increased risk for post-traumatic stress disorder (PTSD) and other mental disorders that often occur with it. However, the underlying biological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effect of PDE4B variation on behaviors relevant to mental disorders, we studied male Pde4b M220T mice that carry a PDE4B variant (M220T), which is also present in humans. Pde4b M220T mice exhibited increased PTSD-like behavior in response to a traumatic event, as well as abnormal neuronal activity in the brain. Our findings provide substantive evidence linking PDE4B variation to PTSD-relevant behaviors, and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.