Cardiovascular Toxicology最新文献

{"title":"Non-canonical PPARα Agonism by Arjunolic Acid Mitigates Cardiomyocyte PANoptosis Through a Novel PPARα/CRYAB/IKKα Axis During Pathological Cardiac Hypertrophy.","authors":"Abhik Kar, Soumyadeep Gupta, Gagandeep Singh, Arkapravo Matilal, Soumika Roy, Braja Gopal Bag, Shailendra Asthana, Sagartirtha Sarkar","doi":"10.1007/s12012-026-10120-z","DOIUrl":"10.1007/s12012-026-10120-z","url":null,"abstract":"<p><p>Pathological cardiac hypertrophy is manifested by downregulated PPARα driven metabolic dysregulation which culminates into cardiomyocyte apoptosis. Emerging evidences indicate that additional regulated cell death mechanisms also operate during cardiac pathophysiology. Arjunolic acid (AA) has shown antifibrotic effect via tinkering PPARα. The study investigates the underlying noncanonical role of PPARα agonism by AA in amelioration of cardiomyocyte PANoptosis process during pathological hypertrophy. An integrative approach combining in silico, in vitro and in vivo studies using Wistar rat model to uncover the role of AA driven cardio-protection by regression of PANoptosis signaling mechanism via PPARα agonism. AA driven PPARα agonism does not perturb its canonical function of being a transcription factor as it forms a stable structure with RXR. PPARα agonism in hypertrophied cardiomyocytes by AA, drives a molecular rearrangement within cells in two major ways; by interacting with a molecular chaperon CRYAB to repress IKKα mediated activation of pyroptosis and its sequestration of p300 mediated repression of p53 acetylation driven apoptosis in hypertrophied cardiomyocytes. Additionally, repressed activation of NFκB-p65 by PPARα augmentation effectively reduces ROS accumulation that in turn downregulates activation of MLKL driven necroptotic prowess in diseased cardiomyocytes. The present study provides novel mechanistic insights into the existence of PANoptosis during hypertrophic pathophysiology, that drives the diseased cardiomyocytes in unison towards imminent cell death, which could be mitigated by AA driven PPARα agonism leading to improved cardiac function.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970628","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":"Iron Deficiency as an Important Predictor of Arterial and Venous Thrombosis, Myocarditis, and Atrial Fibrillation in COVID-19 and Influenza.","authors":"Ana Cirovic, Nemanja Brankovic, Gorjana Antelj, Aleksandar Cirovic","doi":"10.1007/s12012-026-10128-5","DOIUrl":"10.1007/s12012-026-10128-5","url":null,"abstract":"<p><p>Arterial and venous thrombosis, atrial fibrillation, and viral myocarditis are potentially life-threatening conditions and well-documented complications of both COVID-19 and influenza. Therefore, clinicians should be aware of all factors that may promote their occurrence, particularly those related to common viral infections such as influenza and SARS-CoV-2. Both influenza and SARS-CoV-2 utilize transferrin receptor 1 (TfR1) to enter host cells; notably, SARS-CoV-2 has been detected in tissues that do not express ACE2. TfR1 is highly expressed on cardiomyocytes, as well as on endothelial cells. Iron deficiency -a common disorder in the general population- promotes overexpression of TfR1, thereby facilitating the entry of SARS-CoV-2 and influenza viruses into cardiomyocytes and endothelial cells. Therefore, an increased expression of the TfR1 on cardiomyocytes may consequently contribute to the development of viral myocarditis, and atrial fibrillation. Finally, TfR1 is involved in viral uptake by endothelial cells and in molecular pathways implicated in thrombus formation. Clinicians should recognize that individuals with iron deficiency and concomitant SARS-CoV-2 or influenza infection may be at increased risk of arterial and venous thrombosis, atrial fibrillation, and viral myocarditis. Given that approximately two billion people worldwide have some degree of iron deficiency-especially older adults and young children-appropriate preventive strategies should be considered.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147970613","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":"Cardiac Electrophysiologic Effects of Different Local Anesthetics in Langendorff-Perfused Rabbit Hearts.","authors":"Julian Wolfes, Amy Katthöfer, Felix Wegner, Benjamin Rath, Florian Doldi, Sati Güler-Eren, Lars Eckardt, Gerrit Frommeyer, Christian Ellermann","doi":"10.1007/s12012-026-10122-x","DOIUrl":"10.1007/s12012-026-10122-x","url":null,"abstract":"<p><p>Local anesthetics are widely used in medical care. However, their sodium channel blocking properties not only explain their analgesic potency but also their possible cardiotoxic effects. Due to the different pharmacodynamics and pharmacokinetics of different local anesthetics as well as the divergent cellular electrophysiological effects, we aimed to investigate and compare the electrophysiological effects of different local anesthetics in an established Langendorff model of the isolated rabbit heart. 50 hearts of New Zealand White rabbits were retrogradely perfused employing a Langendorff-setup. Eight catheters were placed endo- and epicardially, thereby recording monophasic action potentials. Hearts were paced at seven different cycle lengths (300-900 ms), thus obtaining cycle-length dependent action potential duration at 90% of repolarization (APD₉₀), QT intervals and dispersion of repolarization. In addition, burst pacing was utilized to assess ventricular vulnerability. Thereafter, bradycardic AV-blocked hearts were perfused with a hypokalemic solution to enhance the occurrence of triggered activity. After generating baseline data, the hearts were assigned to four groups: In group 1, hearts were treated with 25 µM, and 50 µM lidocaine. Group 2 was perfused with 25 µM, and 50 µM mepivacaine. Group 3 was perfused with 0.5 µM, and 1 µM bupivacaine. Group 4 was perfused with 5 µM, and 10 µM ropivacaine. As expected, perfusion with all local anesthetics led to a significant prolongation of the effective refractory period as a result of sodium channel blockade. Perfusion with bupivacaine and ropivacaine resulted in pronounced cardiotoxic effects, characterized by electromechanical uncoupling or loss-of-capture phenomena, in the majority of hearts. Perfusion with mepivacaine and ropivacaine resulted in the comparatively most pronounced prolongation of the effective refractory period. Accompanied by a pronounced dispersion of repolarization, the highest incidence of ventricular tachycardia and ventricular fibrillation episodes was observed during perfusion with bupivacaine. Perfusion with the local anesthetics showed pronounced electrophysiological effects, which differed between the various local anesthetics. Bupivacaine showed the most pronounced cardiotoxic effects even at low doses.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13183750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147962290","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":"KLF9 Aggravates Doxorubicin-Induced Cardiotoxicity by Regulating the ROS/p53 Signalling Pathway.","authors":"Jingfeng Peng, Jianhua Wang, Hui Feng, Bihan Zhou, Haoyu Zhou, Fangfang Li","doi":"10.1007/s12012-026-10121-y","DOIUrl":"10.1007/s12012-026-10121-y","url":null,"abstract":"<p><p>Doxorubicin (DOX) is a cytotoxic chemotherapeutic drug, the clinical value of which is limited by its cardiotoxicity. Krüppel-like factor 9 (KLF9) is known to modulate cell proliferation, differentiation, and apoptosis and plays critical roles in cardiovascular diseases. Here, we aimed to explore the potential effect of KLF9 on DOX-induced cardiotoxicity. C57BL/6J mice with cardiac-specific overexpression or silencing of KLF9 received single intraperitoneal injections of DOX to establish a DOX-induced cardiotoxicity model. The cardiac function of the mice was monitored by echocardiography, cardiac morphology was evaluated by histopathological staining, biomarkers of myocardial injury were detected using ELISA, and TUNEL staining and Western blotting were performed to evaluate apoptosis. In addition, H9c2 cells were used to validate the function of KLF9 in vitro. To test the involvement of thioredoxin reductase 2 (Txnrd2), ROS and p53 in the observed effects, siRNAs directed against p53 and Txnrd2 and the ROS inhibitor N-acetyl cysteine (NAC) were used. KLF9 expression was upregulated in the hearts of DOX-treated mice and H9c2 cells. Cardiac-specific KLF9 overexpression exacerbated, while cardiac-specific KLF9 silencing alleviated, DOX-induced apoptosis, acute myocardial injury and dysfunction. Mechanistically, KLF9 deficiency resulted in upregulation of Txnrd2 expression and subsequent suppression of apoptosis through modulation by ROS/p53 signalling. KLF9 exerts a pro-apoptotic effect on DOX-induced cardiotoxicity by inhibiting Txnrd2 and regulating the ROS/p53 signalling pathway. KLF9 deficiency may be a promising target for mitigating DOX-induced cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13171662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926766","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":"Quercetin Antagonizes Doxorubicin-Induced Cardiotoxicity via HO-1/PGC-1α-ALOX5 Axis: Arachidonic Acid Metabolism-Ferroptosis Crosstalk as a Therapeutic Target.","authors":"Fangfang Duan, Xingying Zeng, Lijun Yi, Chen Wang, Chengyuan Huang, Liming Zhao, Junkai Duan, Hong Li","doi":"10.1007/s12012-026-10127-6","DOIUrl":"10.1007/s12012-026-10127-6","url":null,"abstract":"<p><p>Myocardial injury caused by Doxorubicin has limited its clinical application. Our research has demonstrated that doxorubicin induces various forms of cell death, oxidative stress, and metabolic abnormalities. We have confirmed, through both in vitro and in vivo studies, that apoptosis, iron overload, inflammatory responses, and arachidonic acid metabolism contribute to doxorubicin's cardiotoxic effects. Treatment with quercetin effectively reduces iron accumulation and preserves mitochondrial structural integrity by inhibiting oxidative stress and inflammatory responses. Using molecular docking and surface plasmon resonance (SPR) techniques, our study suggests that quercetin activates the HO-1/PGC-1α pathway, which may involve downregulation of ALOX5 expression, thereby alleviating oxidative stress, inhibiting iron-dependent lipid peroxidation and ferroptosis-like changes, mitigating inflammatory responses, and modulating arachidonic acid metabolism. Additionally, quercetin enhances energy availability and supports mitochondrial function. We propose quercetin, a promising active compound derived from traditional Chinese medicine, as a potential mitigator of doxorubicin-induced cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926718","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":"Low Dose Amitriptyline-Induced Electrical Storm Unmasking a Novel SCN5A and KCNQ1 Compound Genotype: Insights from Family Cascade Screening.","authors":"Thai Duy Vo, Ngoc Dung Kieu, Le Uyen Phuong Tran, Thi Van Khanh Nguyen, Tri Thuc Nguyen, Li-Wei Lo, Thi Thanh Binh Dao","doi":"10.1007/s12012-026-10125-8","DOIUrl":"10.1007/s12012-026-10125-8","url":null,"abstract":"<p><p>Cardiac toxicity from QT-prolonging drugs can precipitate malignant ventricular arrhythmias in susceptible individuals, and family screening may clarify inherited risk. We report a 33-year-old woman with a history of postpartum cardiac arrest treated with a secondary-prevention implantable cardioverter-defibrillator (ICD) who developed an electrical storm after self-administration of a single low dose of amitriptyline (12.5 mg). ICD interrogation documented 176 episodes of ventricular fibrillation requiring repeated shocks, followed by complete battery depletion, hemodynamic collapse, and the need for venoarterial extracorporeal membrane oxygenation and continuous renal replacement therapy. The admission electrocardiogram showed marked QT prolongation (QTc 651 ms), with previously documented prolonged baseline QTc values. Targeted next-generation sequencing identified a novel SCN5A missense variant (NM_000335.5:c.5738G > A) and a rare pathogenic KCNQ1 splice variant (NM_000218.3:c.1032G > C), cascade testing across the family demonstrated variable expressivity among carriers. Given a suspected contribution of late sodium current, a mechanism-based strategy was implemented with mexiletine added to propranolol and overdrive pacing (90 bpm). This case underscores the risk of malignant ventricular arrhythmias after exposure to QT-prolonging agents even at low doses, and supports genotype-informed, mechanism-based therapy to mitigate arrhythmic risk in patients with marked QT prolongation.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147926728","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":"Assessing the Risk of Myocarditis Post-COVID-19 Vaccination: A Systematic Review of Case Reports from 2023 to 2025.","authors":"Alessio Ardizzone, Charlaine A Agoy, Giuseppe Carota, Imma Altruda, Ilaria Erba, Marzia Del Re, Emanuela Esposito, Giuseppe Caruso","doi":"10.1007/s12012-026-10123-w","DOIUrl":"10.1007/s12012-026-10123-w","url":null,"abstract":"<p><p>COVID-19 vaccines covered a crucial role in mitigating the pandemic; however, rare adverse events such as myocarditis continue to raise safety concerns. This systematic review evaluated whether the clinical profile and outcomes of COVID-19 vaccine–associated myocarditis (CVAM) have changed in the post-2022 era. Following PRISMA guidelines, case reports published between 2023 and 2025 were identified through Web of Science, Embase, and PubMed (MEDLINE). Twenty-eight articles describing 35 patients were included. CVAM predominantly affected males, with the highest frequency among adolescents aged 10–19 years, and most cases occurred after the second vaccine dose, typically within two weeks. Chest pain was the most common presenting symptom, followed by tachycardia, fever, and dyspnea. Elevated cardiac biomarkers, electrocardiographic abnormalities, and myocardial edema on cardiac magnetic resonance imaging were frequently observed, with reduced left ventricular ejection fraction in a subset of patients. Management ranged from nonsteroidal anti-inflammatory drugs and colchicine to immunosuppressive therapy and mechanical circulatory support in severe cases. Although many patients experienced clinical improvement, fatal cases were documented, and follow-up revealed persistent late gadolinium enhancement and recurrent arrhythmias in several individuals, indicating incomplete myocardial recovery. Unlike earlier reviews reporting largely mild and self-limiting disease, this 2023–2025 case series documents fatal outcomes, persistent myocardial fibrosis, and recurrent arrhythmias, suggesting that CVAM may lead to long-term cardiac sequelae in a subset of patient. These findings indicate that contemporary clinical spectrum of CVAM may be broader and more severe than previously recognized, underscoring the need for prolonged surveillance and updated management strategies.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763357","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":"Inhalant Exposures and the Risk of Rheumatoid Arthritis and Rheumatoid Arthritis-Associated Interstitial Lung Disease.","authors":"Spencer Jones, Ted R Mikuls, Bryant R England","doi":"10.1007/s12012-026-10118-7","DOIUrl":"10.1007/s12012-026-10118-7","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a systemic autoimmune disease with substantial extraarticular morbidity and mortality, particularly from rheumatoid arthritis–associated interstitial lung disease (RA-ILD). Although advances in disease-modifying therapies have improved joint outcomes and overall survival, RA-ILD remains a major contributor to premature death. Emerging evidence supports the mucosal origins hypothesis, which proposes that RA-related autoimmunity may be initiated at extraarticular sites, particularly the lungs following inhalational exposures. This narrative review synthesizes the current body of literature linking various inhaled exposures, including cigarette smoking, particulate matter, gaseous air pollutants, silica, coal dust, military-related exposures and pesticides, to RA and RA-ILD risk. Cigarette smoking is the most well-established environmental risk factor for RA, demonstrating strong dose-dependent associations with disease risk, severity, and the development and progression of RA-ILD, especially in genetically susceptible individuals. Evidence for other airborne pollutants is mixed, with particulate matter and nitrogen dioxide showing emerging but inconsistent associations with RA and limited data for RA-ILD. Occupational exposures such as silica and coal dust demonstrate stronger links, particularly for seropositive RA. Translational models further support sex-specific immune and fibrotic responses to inhaled irritants. Collectively, current data suggest that inhaled environmental exposures may contribute to the pathogenesis of RA and RA-ILD, highlighting the lungs as a critical interface between environmental risk and autoimmunity and underscoring the need for prospective studies to clarify causality and prevention strategies.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147763376","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":"Targeting the Apelin-APJ Axis: A Promising Strategy to Mitigate Anthracycline-Induced Cardiotoxicity.","authors":"Varsha G Desai","doi":"10.1007/s12012-026-10107-w","DOIUrl":"10.1007/s12012-026-10107-w","url":null,"abstract":"<p><p>Anthracycline-induced cardiotoxicity remains a major clinical challenge, often progressing to heart failure years after therapy. Conventional cardioprotective agents, including angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and beta-blockers, are widely used to preserve cardiac function; however, their effectiveness is limited by their inability to comprehensively address the complex, multifactorial pathophysiology of anthracycline-induced cardiotoxicity. This underscores the critical need for more effective and mechanism-based cardioprotective strategies that directly target the underlying molecular mechanisms, particularly oxidative stress and mitochondrial dysfunction. In recent years, the apelin-APJ signalling axis has attracted increasing attention as a potential therapeutic target in cardiovascular diseases owing to its multifaceted biological actions, including positive inotropy, vasodilation, anti-inflammatory, anti-fibrotic, anti-apoptotic, antioxidant, and pro-angiogenic effects. These pleiotropic actions are primarily mediated through the activation of key signalling pathways such as phosphoinositide 3-kinase/protein kinase B, extracellular signal-regulated kinases 1/2, and AMP-activated protein kinase. Given that these signalling cascades are disrupted during anthracycline-induced cardiotoxicity, pharmacological activation of the apelin-APJ axis may represent a promising avenue to mitigate anthracycline-associated cardiac injury with greater efficacy than conventional therapies. While native apelin isoforms (apelin-12, -13, -17, and [Pyr¹]apelin-13) are limited by their short half-lives, chemically modified analogues such as LIT01-196 and apelin-17(A2) exhibit enhanced stability and efficacy, with demonstrated cardioprotective effects in preclinical cardiovascular models and patients with chronic heart failure. However, their therapeutic potential in anthracycline-induced cardiotoxicity remains largely unexplored. This review highlights its promise as a novel cardioprotective strategy for mitigating anthracycline-induced cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716024","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":"Sex-Specific Associations Between Cadmium Exposure and Mortality Risk in Cardiovascular Disease Patients: A Cohort Study Integrating Molecular Mechanisms of Myocardial Dysfunction.","authors":"Caili He, Kaiwen Wang, Ruiqi Yang, Xinyi Li, Zicong Shao, Li Ma, Yongbin Lu, Xiaowei Niu, Siyu Zhang, Yongxiang Wang","doi":"10.1007/s12012-026-10117-8","DOIUrl":"10.1007/s12012-026-10117-8","url":null,"abstract":"<p><p>Heavy metal cadmium (Cd) exposure is associated with increased cardiovascular disease (CVD) risk, yet sex-specific differences in Cd exposure’s impact on CVD patient mortality and underlying mechanisms remain unclear. Using the national health and nutrition examination survey (NHANES) database and its follow-up mortality data (1,413 CVD patients: 652 deaths [46.14%], 761 survivors [53.86%]), we investigated the specific roles of Cd exposure in CVD. Cox regression showed that elevated blood Cd were more strongly associated with increased all-cause mortality risk in males (HR = 1.67, 95% CI: 1.00-2.78), whereas higher urinary Cd conferred a greater risk in females (HR = 2.17, 95% CI: 1.20–3.92). Restricted cubic spline analysis showed that, in males, blood Cd exhibited a linear dose-response with all-cause mortality (P for nonlinear = 0.128), while urinary Cd demonstrated a significant nonlinear relationship (P for nonlinear = 0.016). Interaction models further revealed that the interactions between blood Cd and diabetes mellitus (DM) (P for interaction = 0.013), as well as between urinary Cd and DM (P for interaction = 0.017), significantly amplified all-cause mortality risk in males. Network toxicology and bioinformatics analyses identified formyl peptide receptor 1 (FPR1) as a key mediator of CdCl₂-associated CVD progression, with elevated expression in CVD patients (log2FC = 0.71, P < 0.001). Molecular docking (free energy = -2.620 kcal/mol), Western blot, and qPCR confirmed that FPR1 can bind CdCl₂ and is dose-dependently upregulated in AC16 cardiomyocytes. Overall, we found that male CVD patients exhibit a marked, dose-dependent increase in all-cause mortality risk associated with Cd exposure, which is further exacerbated by its synergy with DM. Mechanistically, Cd appears to promote CVD progression by disrupting FPR1 signaling in cardiomyocytes. These findings suggest that prevention strategies should integrate metabolic disease management with environmental Cd control, and highlight FPR1 as a promising therapeutic target.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 5","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147716038","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}