Cardiovascular Toxicology最新文献

{"title":"Study on the Protective Effect of Sodium Ferulate Against Doxorubicin-Induced Cardiotoxicity in Zebrafish.","authors":"Yuehua Yao, Xiaoyu Yin, Hao Chen, Hongsong Chen, Xinru Bo, Zhe Han, Yuting Zhang, Tonglaga Li, Haiping Liu, Meirong Bai, Xiaohua Lei, Jingli Mu, Jianhua Yu, Wu Dong","doi":"10.1007/s12012-026-10215-7","DOIUrl":"https://doi.org/10.1007/s12012-026-10215-7","url":null,"abstract":"<p><p>Doxorubicin (DOX) is a widely used first-line chemotherapeutic agent with potent antitumor efficacy. However, its irreversible and dose-dependent cardiotoxicity severely limits its clinical application. Sodium ferulate (SF), a bioactive ingredient extracted from traditional Chinese medicinal herbs such as Rheum palmatum L., Cimicifuga foetida L., and Ligusticum chuanxiong Hort., possesses antioxidant and antithrombotic properties, suggesting potential cardioprotective effects. In this study, a DOX-induced cardiotoxicity model was established using transgenic zebrafish, and the protective effects of SF were systematically evaluated through transcriptomic profiling, histopathological examination, and molecular validation.The results demonstrated that DOX exposure reduced the survival rate of zebrafish, triggered cardiac dysfunction characterized by decreased heart rate and pericardial edema, and caused myocardial structural damage and cardiomyocyte death. Notably, SF intervention significantly alleviated the above DOX-induced cardiotoxic phenotypes, including myocardial pathological damage and cardiomyocyte loss. Transcriptomic profiling revealed that DOX disrupted pathway related to oxidative stress, apoptosis, cardiac contraction, and PPAR signaling, while SF intervention effectively reversed these altertions. Quantitative PCR further confirmed that SF upregulated antioxidant genes (Nrf2, HO-1, and Sod2), downregulated pro-apoptotic genes (Bax, Caspase 3, andp53), and restored expression of key myocardial structural genes (Vmhc, Cmlc2, and Tnnt2).Collectively, SF protects against DOX-induced cardiotoxicity by modulating oxidative stress and apoptotic signaling pathways, offering a promising therapeutic strategy for chemotherapy-associated cardiac injury.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Perfluorooctanoic Acid and Elevated Atherosclerosis Index: NHANES Associations and Exploratory Ceramide-Related Analyses.","authors":"Qianran Hong, Yibo He, Yiwei Feng, Ci Wang, Dongming Lin, Shuwei Huang","doi":"10.1007/s12012-026-10219-3","DOIUrl":"https://doi.org/10.1007/s12012-026-10219-3","url":null,"abstract":"<p><p>Perfluorooctanoic acid (PFOA) exposure has been associated with lipid abnormalities, but its potential links to ceramide-related processes in atherosclerosis remain incompletely characterized. This study examined the association between serum PFOA and atherosclerosis-related lipid status and explored candidate molecular links. Survey-weighted cross-sectional analyses of National Health and Nutrition Examination Survey data evaluated the atherosclerosis index (AI) as the primary outcome. AI was analyzed continuously and as elevated AI, defined as AI ≥ 4. Complementary analyses integrated network toxicology, machine learning, and bulk and single-cell transcriptomics. When serum PFOA was modeled continuously, higher concentrations were associated with elevated AI, and this association persisted after adjustment for confounders. After further adjustment for survey cycle, the association with elevated AI remained, whereas the association with continuous AI was attenuated. Integrative analyses prioritized candidate genes involved in lipid regulation and inflammatory signaling, with APOE showing prominent expression in macrophages and foam cells. Cell-cell communication analysis identified stronger inferred macrophage migration inhibitory factor (MIF) signaling from APOE-low macrophages to foam cells. An independent PFOA-exposure dataset further showed APOE upregulation in macrophages. Together, these findings suggest that higher serum PFOA concentrations are associated with an adverse atherogenic lipid profile, as reflected by greater odds of elevated AI. They also highlight ceramide-related molecular candidates and APOE-associated communication patterns for further mechanistic investigation.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149340982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From Macroenvironmental Context to Individual Proximal Exposure: Multiscale Mechanisms Linking Environmental Factors to Blood Pressure Homeostasis and Variability : Author.","authors":"Yi Yao, Xinyue Chen, Xiaohua An, Yang Jiao, Qianfeng Jiang","doi":"10.1007/s12012-026-10221-9","DOIUrl":"https://doi.org/10.1007/s12012-026-10221-9","url":null,"abstract":"<p><p>Hypertension is a major contributor to the global burden of cardiovascular disease. In addition to genetics, age, and lifestyle, environmental exposures can disrupt blood pressure homeostasis. Compared with air pollution and ambient temperature, evidence concerning psychosocial factors, noise, light, chemical pollutants, micro- and nanoplastics, and the individual proximal residential environment is more fragmented, and studies often conflate mean blood pressure, incident hypertension, and blood pressure variability (BPV) as equivalent outcomes. Using a continuum from macroenvironmental context to individual proximal exposure, this review integrates evidence from human studies, animal experiments, and in vitro research to compare associations of air pollution, temperature, greenspace, noise, chemical pollutants, micro- and nanoplastics, light exposure, and psychosocial stress with distinct blood pressure phenotypes. We further summarize shared pathways involving autonomic and neurohumoral regulation, oxidative stress-inflammation-endothelial injury, the renin-angiotensin-aldosterone system (RAAS), circadian rhythms, and metabolic/microbiome mechanisms. Human evidence is relatively substantial for air pollution, temperature, noise, and greenspace, whereas direct evidence linking micro- and nanoplastics and some chemical pollutants to human hypertension and BPV remains limited, with mechanistic understanding derived mainly from experimental models. Multiple exposures, genetic and epigenetic backgrounds, and socioeconomic conditions may jointly modify environmental effects. Clarifying exposure dose, level of evidence, and the relevant BPV time scale will help identify environmentally susceptible populations and provide a conceptual basis for stratified prevention and future intervention studies.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149332661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Protective Effects of Gap26, a New Connexin-43 Inhibitor, on Doxorubicin-Induced Cardiotoxicity in Rats.","authors":"Arash Khodadoostan, Arefeh Tabashiri, Seyed Mohammad Tavangar, Ana Ghazanfari, Farahnaz Jazaeri","doi":"10.1007/s12012-026-10216-6","DOIUrl":"https://doi.org/10.1007/s12012-026-10216-6","url":null,"abstract":"<p><p>Doxorubicin (Dox) is a potent chemotherapeutic agent. Its clinical use is limited by severe cardiotoxicity, driven largely by oxidative stress. Gap junctions, formed by connexin-43 (Cx43), are vital for cardiac function, and pathological stress can open Cx43 hemichannels, exacerbating cellular damage. We hypothesized that Gap26, a Cx43 inhibitor, could protect against Dox-induced cardiotoxicity. Male Wistar rats were randomly assigned to four groups: Control/Saline, Control/Gap26, Dox/Saline, and Dox/Gap26 (receiving Gap26 pretreatment). After 14 days, cardiac function was assessed by electrocardiography (ECG) and inotropic studies. Myocardial histopathology and levels of malondialdehyde (MDA) and glutathione (GSH) were also evaluated. Dox significantly impaired cardiac contractility, markedly reducing atrial contractile force compared to the Control/Saline group. Histopathological analysis showed that Dox treatment led to severe myopathy and fibrosis. Dox also significantly increased MDA and depleted GSH. In contrast, Gap26 pretreatment significantly restored atrial contractility, attenuated histopathological damage, and ameliorated both MDA and GSH levels. Gap26 also demonstrated a shift towards less severe arrhythmias in subjects receiving Dox. Gap26 exhibited significant protection against Dox-induced cardiotoxicity by preserving atrial function, reducing oxidative damage, and improving myocardial histopathology. These findings suggest Gap26 may be a promising therapeutic candidate for preventing Dox cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149285422","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of Blood Heavy Metal Concentrations with Angiographic Coronary Artery Disease in a Consecutive Single-Center Cardiac Catheterization Cohort.","authors":"Jeffrey D Taylor, Pal Shah, Aaron Specht, Maitri Shah, Melissa Duckett, Christine Locquiao, Ken Lizama, Edward Salem, Hannah McKown, Peter Glynn, Mladen I Vidovich","doi":"10.1007/s12012-026-10214-8","DOIUrl":"10.1007/s12012-026-10214-8","url":null,"abstract":"<p><p>Environmental heavy metal exposure is increasingly recognized as a potentially important but underappreciated contributor to cardiovascular disease, yet its relationship to directly observed coronary artery disease (CAD) remains poorly defined. In this single-center cohort of 52 consecutive adults undergoing cardiac catheterization at an urban Chicago tertiary care center, we paired elemental exposure profiles with direct angiographic assessment in a racially diverse, socioeconomically vulnerable population. While no individual metal independently explained obstructive CAD, circulating metal exposure patterns were more revealing: Bayesian Kernel Machine Regression demonstrated that increasing overall metal burden was associated with worse coronary phenotypes, suggesting that environmental exposures may act collectively rather than in isolation. Lead and mercury emerged as the strongest contributors and were enriched relative to National Health and Nutrition Examination Survey (NHANES) reference populations. Taken together, these findings offer early but meaningful evidence that environmental toxicant burden may represent an underrecognized layer of cardiovascular risk, particularly in urban communities where industrial history, aging infrastructure, and socioeconomic disadvantage intersect. This work highlights the importance of viewing cardiovascular disease not only through the lens of traditional risk factors, but also through the environments in which patients live.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13714016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149285405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Pesticide Pyrethroid Metabolite 3-Phenoxybenzoic Acid (3-PBA) Impairs Human Cardiac Na_v1.5 and Action Potential Depolarization.","authors":"Michael Ramon de Lima Conceição, Leisiane Pereira Marques, Fabiana da Silva Alcantara, Rafael Leite Tavares de Morais, Vinicius Fogaça-Santos, Diego Jose Belato Orts, João Bosco Pesquero, Diego Santos de Souza, Danilo Roman-Campos","doi":"10.1007/s12012-026-10212-w","DOIUrl":"10.1007/s12012-026-10212-w","url":null,"abstract":"<p><p>Pyrethroid insecticides (PYRs) are widely used worldwide, and their primary metabolite, 3-phenoxybenzoic acid (3-PBA), serves as a near-ubiquitous biomarker of human exposure to PYRs. While epidemiological data consistently link urinary 3-PBA to increased cardiometabolic risk and coronary heart disease, the underlying electrophysiological mechanisms of its direct potential cardiotoxicity remain unexplored. Parent PYRs are known to exert cardiotoxic effects by enhancing the late sodium current (I_Na-L) and inducing arrhythmia, but the direct effect of 3-PBA on heart excitability has not been previously investigated. This study demonstrates that 3-PBA interacts with human cardiac Na_v1.5 expressed in Human Embryonic Kidney (HEK293) cells, and significantly increases I_Na-L in a concentration-dependent manner with an EC₅₀ of 51.3 ± 5.1 µM. The metabolite does not alter the voltage dependence of activation and inactivation, but it significantly delays the recovery from inactivation of the peak sodium current. In human induced pluripotent stem cell-derived cardiomyocytes (CM-hiPSCs) and adult rat ventricular myocytes, 3-PBA reduced maximal depolarization rate (dV/dt), indicating impaired depolarization dynamics and reduced peak sodium current. At the organ level, acute exposure in isolated rat hearts did not significantly alter standard ECG parameters. Collectively, these findings suggest that 3-PBA is not electrophysiologically inert but directly modulates cardiac sodium channel function, although at supraphysiological concentration. This provides new evidence of the biological activity of 3-PBA and suggests that its cardiotoxic potential may become clinically relevant under conditions of high dose and chronic exposure or in susceptible populations.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13696605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149263152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serum Proteoglycan Alterations Associated with Cardiovascular Risk in Pb-Battery Recycling Workers Using Exploratory Proteomics and Independent ELISA Validation.","authors":"Kartikey Matte, Shubhangi Pingle, Rajani Tumane, Manjula Kannasandra Ramaiah, Kalahasthi Ravibabu","doi":"10.1007/s12012-026-10213-9","DOIUrl":"https://doi.org/10.1007/s12012-026-10213-9","url":null,"abstract":"<p><p>Lead (Pb) is a prevalent environmental and occupational toxin that disrupts several biological systems. Its toxicological effects are well known but serum proteomic alterations associated with Pb remain insufficiently characterized. This study investigated serum proteomic changes in Pb-battery recycling workers (Pb-BRW) to identify the candidate proteins associated with Pb exposure using high-resolution mass spectrometry (HRMS). Blood samples (5 mL) were collected from Pb-BRW (n = 78) and age-matched unexposed controls (n = 65) from three industries in Karnataka, India. Blood Pb levels were assessed using inductively coupled plasma-optical emission spectroscopy. Serum samples (n = 10) pooled from each group were analyzed using quantitative discovery HRMS. Data are available via ProteomeXchange with identifier PXD082567. Raw files were processed using Proteome Discoverer, and proteins were identified using the UniProt Homo sapiens reviewed database. Further data were analysed in Perseus with log₂ transformation and imputation. Gene ontology was used for functional enrichment analysis. Candidate proteins were selected (nominal p < 0.05 and |log₂FC| ≥ 1.2) as exploratory filtering criteria and visualized using a volcano plot and heatmap. Selected proteins were further validated using ELISA in an independent set of serum samples obtained from Pb-BRW (n = 68) and control subjects (n = 55). A total of 257 serum proteins were identified. Exploratory HRMS-based proteomic profiling identified 26 candidate proteins with nominal p < 0.05. Functional enrichment analysis suggested associations with cardiovascular-related processes. Of these, eight candidate proteins met both exploratory filtering criteria, including five showing higher and three showing lower abundance in Pb-BRW. Lumican (LUM) and Proteoglycan-4 (PRG4) were selected for ELISA-based validation based on their abundance patterns and biological relevance to extracellular matrix organisation and vascular homeostasis. Exploratory serum proteomic profiling revealed alterations in proteins involved in lipid transport and extracellular matrix organization in Pb-BRW. The identification and independent validation of LUM and PRG4 suggest their potential as candidate biomarkers associated with Pb-related cardiovascular alterations.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Particulate Matter Exposure and Accelerated Cardiovascular Aging: Mechanistic Evidence, Biomarker Integration, and the PACA Framework.","authors":"Pankaj Yadav, Dipita Bhakta-Guha, Devipriya Nagarajan, Krishna Priya Mani, Rosy Mondal, Gunjan Guha, Gino A Kurian","doi":"10.1007/s12012-026-10209-5","DOIUrl":"https://doi.org/10.1007/s12012-026-10209-5","url":null,"abstract":"<p><p>Particulate matter exposure, particularly PM_2.5 and ultrafine particles, is a well-established risk factor for cardiovascular morbidity. However, whether pollution-associated cardiovascular abnormalities represent transient toxicity, cumulative injury, developmental programming, aging-like phenotypes, or a genuine alteration in the trajectory of cardiovascular aging remains unresolved. Here, we propose the Pollution-Accelerated Cardiovascular Aging (PACA) framework as a conceptual, hypothesis-generating approach for interpreting this distinction. Rather than proposing new molecular mechanisms, we integrate established pathways, including mitochondrial and redox dysfunction, genomic and epigenetic alterations, cellular senescence and senescence-associated secretory phenotype signaling, impaired proteostasis, endothelial dysfunction, and autonomic dysregulation within an explicit evidentiary framework. We also consider the pulmonary neural cardiac axis as a potential route through which pulmonary sensory activation may influence autonomic regulation, calcium handling, and cardiac electrophysiological function. To distinguish exposure-associated toxicity from evidence consistent with altered cardiovascular aging, we introduce a Temporal-Evidence Matrix that integrates exposure kinetics, life-course timing, persistence and recovery after exposure cessation, exposure response relationships, and longitudinal change relative to age-referenced comparators. Persistence, incomplete recovery, or cumulative loss of cardiovascular reserve support chronic or sustained injury but do not independently establish accelerated aging. Stronger evidence for PACA requires repeated longitudinal demonstration that particulate exposure is associated with a greater rate or altered trajectory of aging-related cardiovascular or biological change than expected from chronological aging. Finally, we propose a tiered biomarker framework that separates candidate biological-aging integrators from mechanistic stress and injury indicators and contextual inflammatory markers, while treating vascular and cardiac functional or imaging measures as complementary cardiovascular phenotypes. The principal contribution of PACA is therefore evidentiary rather than mechanistic, providing a structured approach for testing whether particulate exposure is associated with cardiovascular toxicity alone or with an altered cardiovascular-aging trajectory.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149237029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterizing the Thrombotic Spectrum and Clinical Phenotypes of Tranexamic Acid-Associated Adverse Events: A Pharmacovigilance Study Based on the FAERS Database.","authors":"Yayuan Zou, Shuo Wang, Youping Yuan, Ye Cao, Jia Liu, Zhonghua Guan","doi":"10.1007/s12012-026-10210-y","DOIUrl":"https://doi.org/10.1007/s12012-026-10210-y","url":null,"abstract":"<p><p>Tranexamic acid (TXA) is widely used to reduce bleeding in surgical, trauma, obstetric, and gynecological settings. However, concerns remain regarding TXA-associated thrombotic adverse events, and their phenotypic heterogeneity and clinical severity have not been comprehensively characterized. This study investigated TXA-associated thrombotic events using the Food and Drug Administration Adverse Event Reporting System (FAERS) from 2004Q1 to 2026Q1. Thrombotic adverse events were identified using the Standardized MedDRA Query (SMQ) \"Embolic and thrombotic events\" and evaluated by disproportionality analysis based on reporting odds ratios (RORs). Qualifying thrombotic events were assigned to the SMQ vessel-type subgroups-arterial, vessel-type unspecified/mixed, and venous-and demographic characteristics, indications, clinical outcomes and time-to-onset were compared across subgroups; signal strength was further related to clinical severity. In all, 515 thrombotic cases associated with TXA and 26 selected thrombotic terms were found (arterial, 157; mixed, 168; venous, 190). Venous thromboembolism-pulmonary embolism (n = 128, ROR 13.94) and deep vein thrombosis (n = 58, ROR 9.09)-is the most frequent type and brings about the most severe and fatal consequences (death reported in 16.8% of venous versus 2.5% of arterial reports), whereas the strongest disproportionality signals were observed for rare site-specific events such as ovarian vein thrombosis (ROR 352.95) and cerebral venous sinus thrombosis (ROR 118.35). The three subgroups differed markedly in demographic and clinical characteristics: venous events occurred predominantly in women (73.7%) treated for menorrhagia (35.3%), whereas arterial events arose mainly in surgical or procedural settings (intravenous route 36.3%; surgery/prophylaxis 19.1%) and presented earliest after exposure [median time-to-onset (TTO) 0 versus 7 days]. Signal strength was not concordant with clinical severity across the thrombotic spectrum. These findings provide a deeper understanding of the thrombotic safety of TXA, indicate that the clinical background may influence the phenotypic differences among the different thrombotic types, and emphasize the necessity of enhanced attention and risk stratification in high-risk groups.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227372","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Role of Sodium Valproate in Clozapine-Associated Cardiotoxicities: The Importance of Cellular and Systemic Energetics.","authors":"Amanda Groenewald, Amelia S Power, Kathryn E Burns, Malcolm D Tingle, Marie-Louise Ward","doi":"10.1007/s12012-026-10204-w","DOIUrl":"10.1007/s12012-026-10204-w","url":null,"abstract":"<p><p>The antipsychotic drug clozapine is associated with one of the broadest spectra of cardiac adverse effects. Many of these are of unknown aetiology, hindering clinicians' ability to prevent, diagnose, and treat them. Risk factors for clozapine-associated cardiotoxicities include concomitant valproic acid therapy and comorbidities associated with the dysregulation of systemic metabolism, such as obesity and diabetes. Therefore, this review aims to summarise existing evidence for the adverse effects of these drugs on cellular and systemic energetics. Both drugs are strongly associated with mitochondrial dysfunction and oxidative stress, but in different tissues. Clozapine may be bioactivated within cardiomyocytes and their mitochondria, producing reactive species that damage these organelles, thus impairing oxidative phosphorylation. Valproate may have similar effects in hepatocytes but doesn't appear to be bioactivated in all cell types, though it reportedly has modest inhibitory effects on fatty acid oxidation. Both drugs affect substrate supply, altering serum lipid, carbohydrate, and ketone levels. In concert, these medications are likely to impair cardiac metabolic flexibility and energetics. Considering the absolute dependence of cardiomyocyte function on continuous energy supply, the dysregulation of cardiomyocyte energetics is likely to have a significant role in the development of clozapine-associated cardiotoxicities. However, limited investigation has been made of the effects of these drugs in cardiomyocytes specifically. Rectifying this could inform improved prevention, detection, and management of cardiotoxicities to facilitate the development of clinical strategies to enable the safer use of these medicines.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 11","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675322/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149206479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}