Cardiovascular Toxicology最新文献

{"title":"Arsenic Plasma Concentrations and Methylation Efficiency as Key Factors of Arsenic Trioxide-Related Cardiac Toxicity in Acute Promyelocytic Leukemia.","authors":"Meihua Guo, Chenli Yue, Yutong Liu, Tianyu Zhao, Xiaoting Ni, Zhibo Guo, Shi'ao Ren, Zengliang Gao, Wenlei Zhang, Longyu Li, Al-Mhmody Husam, Xin Hai","doi":"10.1007/s12012-026-10141-8","DOIUrl":"10.1007/s12012-026-10141-8","url":null,"abstract":"<p><p>Arsenic trioxide (ATO) is highly effective for acute promyelocytic leukemia (APL), but ATO-induced cardiac adverse events (CAEs) frequently cause treatment interruption or fatal outcomes, and real-world evidence linking arsenic species levels, methylation capacity, and CAE risk remains limited. In this study, we included 547 APL patients treated with ATO between 2014 and 2024 (4741 treatment cycles). Plasma concentrations of inorganic arsenic (iAs), monomethylated arsenic (MMA), and dimethylated arsenic (DMA) were measured in 374 patients using HPLC-HG-AFS. Primary (PMI = MMA/iAs) and secondary (SMI = DMA/MMA) methylation indices were calculated. Univariate and multivariate Cox regression identified independent CAE determinants, ROC analysis evaluated predictive values and cutoffs, and a risk nomogram was constructed. CAEs occurred in 297 patients (54.3%) and 554 treatment cycles (11.7%). Plasma arsenic distribution followed DMA, MMA > iAs, with PMI > SMI (all P < 0.05). Patients with CAEs had significantly higher DMA, iAs, total arsenic (tAs), and aberrant methylation profiles (all P < 0.05). Concomitant cardiotoxic drug use, DMA, tAs, SMI, DMA%, and MMA% were independent determinants. ROC analysis demonstrated good predictive performance for these markers (AUCs 0.708-0.869). The nomogram showed favorable discrimination (C-index = 0.823) and clinical net benefit. ECG abnormalities were the most common CAEs. ATO-induced cardiotoxicity is closely related to arsenic species concentration and methylation metabolism; importantly, impaired primary methylation (lower PMI, lower MMA%) appears to be the key bottleneck, with secondary methylation enhanced as a compensatory response (higher SMI, higher DMA%). Arsenic toxicokinetic and methylation markers effectively predict CAEs, supporting routine therapeutic drug monitoring in APL patients receiving ATO.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403680","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":"Plant and Mushroom Toxicity as an Under Recognized Cause of Cardiac Arrest and Arrhythmia.","authors":"Jessica T Kent, Lisa Albertini, Sara Bober, Cyrille De Halleux, Michael H Gollob","doi":"10.1007/s12012-026-10148-1","DOIUrl":"10.1007/s12012-026-10148-1","url":null,"abstract":"","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366957","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":"Effects of Low-Intensity Aaerobic Training on Cardiac Dysfunction and Myocardial Fibrosis Induced by Doxorubicin in Wistar Rats.","authors":"Talita Cristina Rodrigues Pereira, Alinne Tatiane Faria Silva, Matheus Matioli Mantovani, Simone Ramos Deconte, Bruno Antônio Ferreira, Mariane Marques da Guarda Pinto, Paulo Ricardo Lopes, Taysa Machado Menezes, Thiago Montes Fidale, Yara Cristina de Paiva Maia, Elmiro Santos Resende","doi":"10.1007/s12012-026-10150-7","DOIUrl":"10.1007/s12012-026-10150-7","url":null,"abstract":"<p><p>Doxorubicin-induced cardiotoxicity is a major limitation in cancer therapy. Physical exercise has been proposed as a non-pharmacological strategy capable of mitigating these effects through cardiovascular adaptations. This study evaluated whether low-intensity aerobic training attenuates cardiac dysfunction induced by doxorubicin. Twenty-five adult male Wistar rats (450 and 500 g) were allocated and divided into four groups: Control (C), Doxorubicin (D), Doxorubicin and Trained (DT), and Trained (T). The D and DT groups received weekly intraperitoneal injections of doxorubicin over a four-week period, totaling a cumulative dose of 8 mg/kg. The DT and T groups underwent low-intensity aerobic training for 25 weeks, three times a week, with sessions lasting 10 to 20 min at 50 and 60% of maximum aerobic speed. Statistical analysis was performed using GraphPad Prism software (version 8.0). The D group showed a significant increase in myocardial collagen deposition and a reduction in S wave values (parietal and septal) on echocardiography, compared to the control group. The values observed were 0.040 for group D and 0.065 for group C in the parietal S wave (overall p = 0.0248), and 0.040 for group D and 0.070 for group C in the septal S wave (overall p = 0.0389). Regarding exercise tolerance, group D showed the greatest reduction in performance from Test 0 to Test 5 (65.06%; p < 0.0001), followed by group C (23.60%; p = 0.0103). Group DT showed a smaller numerical reduction in performance (23.07%), but this change did not reach statistical significance (p = 0.1256), while group T showed a non-significant numerical improvement (10.99%; p = 0.2020). The results suggest that low-intensity aerobic training may attenuate cardiac fibrosis and partially preserve functional capacity in rats with doxorubicin-induced cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319301/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350875","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":"Cardiovascular Nanomedicine: Breakthroughs in Therapy-Challenges in Safety and Cardiotoxic Risks: A Comprehensive Review of Inorganic Nanoparticles.","authors":"Laila Rejali, Mahsa Lotfi, Pegah Pourakbar, Mohammadreza Masoudiankhouzani, Ali Hassanpoor Haghighi, Kimia Maleki, Negin Yousefi Chermehini","doi":"10.1007/s12012-026-10151-6","DOIUrl":"10.1007/s12012-026-10151-6","url":null,"abstract":"<p><p>The unique physicochemical properties of nanoparticles (NPs) have facilitated the development of targeted therapies for cardiovascular diseases (CVDs). According to World Health Organization estimates, CVDs are the predominant contributors to global mortality, accounting for approximately 17.9 million deaths annually. Conventional treatments, including pharmacological interventions and surgical procedures, face significant barriers such as systemic toxicity due to non-targeted delivery, incomplete efficacy, and high financial burdens. Nanoscale innovations address these limitations through mechanisms such as targeted drug delivery and controlled release. Despite these advancements, concerns regarding NPs-induced cardiotoxicity remain unresolved. As nanomedicine advances rapidly, understanding NP functions within the cardiovascular system is essential for optimizing therapeutic outcomes in parallel to minimize unintended risks. Metal-based NPs, including gold, silver, and iron oxide, have demonstrated promising applications in cardiovascular imaging, regenerative therapy, and drug delivery; however, emerging evidence indicates their potential to induce oxidative stress, inflammatory responses, and endothelial dysfunction, contributing to atherosclerosis, myocardial injury, and arrhythmias. Inhaled and intravenously administered NPs exhibit dose-dependent toxicities that influence mitochondrial function and calcium homeostasis within cardiomyocytes. This review comprehensively analyzes in vitro and in vivo studies and notable clinical trials such as the NANOM-FIM trial. Furthermore, we discuss the role of specific antioxidants in cardioprotection and mitigating NPs-induced cardiotoxicity.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350915","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":"Prenatal and Lactational Exposure to Polystyrene Nanoplastics Induces Lipid Accumulation in Vascular Smooth Muscle Cells of Male Offspring via the MAPK/ERK/UHRF1 Signaling Pathway.","authors":"Tan Ma, Chenghao Shen, Siliang Li, Ruiping Hu, Hongliang Li, Jingyan Liang, Yingge Wang","doi":"10.1007/s12012-026-10147-2","DOIUrl":"10.1007/s12012-026-10147-2","url":null,"abstract":"<p><p>Nanoplastics (NPs) have been shown to cross the placental barrier and disrupt systemic metabolism, raising concerns about their potential impact on developmental health. Despite accumulating evidence implicating NPs in metabolic toxicity, the effect of early-life NPs exposure on offspring vascular lipid metabolism has not been fully elucidated. In this study, pregnant mice were exposed to 100-nm PS-NPs at drinking-water concentrations of 0.1, 1, and 10 µg/mL throughout embryonic-lactational, and male offspring were examined at postnatal day 21. Our findings demonstrated that exposure to PS-NPs during the embryonic and lactational periods induced lipid accumulation in the medial layer of the aorta in male offspring, accompanied by elevated serum triglyceride (TG) levels, suggesting that early-life exposure disrupts vascular lipid homeostasis. In vitro findings further confirmed that PS-NPs exposure led to lipid accumulation in mouse aortic vascular smooth muscle (MOVAS) cells, accompanied by elevated intracellular TG levels. Mechanistically, PS-NPs exposure activated the MAPK/ERK signaling pathway, accompanied by the upregulation of UHRF1, a key epigenetic regulator of lipid metabolism. Further pharmacological inhibition of ERK using PD98059 significantly attenuated both UHRF1 expression and lipid accumulation, providing additional evidence supporting the critical role of the MAPK/ERK/UHRF1 axis in PS-NPs-induced lipid dysregulation. Additionally, siRNA-mediated knockdown of UHRF1 alleviated PS-NPs-induced lipid accumulation, supporting the pivotal role of UHRF1 in the cellular response to PS-NPs exposure. Overall, these findings demonstrate that prenatal and lactational exposure to PS-NPs disrupts early vascular lipid homeostasis in male offspring by activating the MAPK/ERK/UHRF1 signaling pathway in vascular smooth muscle cells.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315582","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 Zinc Levels in Early Life and Risk of Elevated Carotid Intima-Media Thickness: An 8-Year Prospective Study.","authors":"Zahra Bahadoran, Farhad Hosseinpanah, Pooneh Dehghan, Fereidoun Azizi","doi":"10.1007/s12012-026-10146-3","DOIUrl":"10.1007/s12012-026-10146-3","url":null,"abstract":"<p><p>The association between serum zinc (SZn) concentration in adolescence-early adulthood and the risk of elevated carotid intima-media thickness (CIMT) in adulthood was investigated. A total of 519 participants (12-29 years) from the Tehran Lipid and Glucose Study with complete baseline data (2009-2011), including SZn concentrations, were recruited and followed through 2015-2018. CIMT was measured using high-resolution B-mode ultrasonography, and high-CIMT was defined as values above the sex-specific 90th percentile (i.e., 0.65 mm for men, 0.70 mm for women). Binary logistic regression models were used to estimate odds ratio (ORs) and 95% confidence intervals (CIs) for the association between baseline SZn and high-CIMT, considering SZn both as a continuous variable (per SD) and in tertiles [< 90, 90-120 (reference), ≥ 120 µg/dL), adjusted for potential confounders. Over a median follow-up of 8.6 years, 10.0% of participants developed high CIMT (7.0% of men, and 12.5% of women). Mean baseline age was 21.1 ± 4.2 years, mean SZn was 116 ± 49.2 µg/dL, and 23.9% were zinc deficient (18.7% of men, and 28.0% of women). In multivariable logistic regression models, each 50 µg/dL increase in baseline SZn was associated with a 43% lower odds of high CIMT at follow-up, although the association did not reach conventional statistical significance (OR = 0.57, 95% CI = 0.0.32-1.01, P = 0.056). Participants in the highest compared to the lowest SZn tertile (≥ 120 vs. <90 µg/dL) showed a 63% lower odds of high-CIMT (HR = 0.37, 95% CI = 0.14-1.00, P = 0.050). Higher SZn levels in adolescence-early adulthood may be associated with high-CIMT in adulthood, highlighting the potential importance of adequate zinc status for early-life vascular health.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315863","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":"Integrative Bioinformatics and Experimental Validation Identify LOX as a Glycolysis-Related Biomarker in Myocardial Ischemia-Reperfusion Injury.","authors":"Liying Wang, Zhian Chen, Tianying Liu, Yan Cui, Rui Zhang, Yong Cui, Zhi Liu","doi":"10.1007/s12012-026-10145-4","DOIUrl":"10.1007/s12012-026-10145-4","url":null,"abstract":"<p><p>Reprogramming of glycolytic metabolism plays a critical role in the pathogenesis of myocardial ischemia-reperfusion injury (MIRI). Although transient glycolysis activation may alleviate energy deficits, excessive glycolytic flux can worsen myocardial damage. This study aimed to identify specific biomarkers and therapeutic targets by investigating glycolysis-related genes in MIRI. We analyzed differentially expressed genes (DEGs) from GEO datasets GSE61592 and GSE160516 and constructed co-expression modules using weighted gene co-expression network analysis (WGCNA). By intersecting DEGs, WGCNA modules, and glycolysis-related genes, we identified glycolysis-related DEGs (GR-DEGs). Machine learning (support vector machine-recursive feature elimination and Random Forest) was applied to GR-DEGs; LOX emerged as the top intersecting feature (log2FC = 3. 67, adjusted P = 1. 44 × 10⁻⁵, validation set AUC = 0. 97). Diagnostic value was assessed using gene set enrichment analysis (GSEA), decision curve analysis (DCA), and nomogram modeling. Immune infiltration was evaluated using CIBERSORT. Experimental validation was conducted in a rat MIRI model and H9c2 hypoxia-reoxygenation (H/R) cells. GR-DEGs were enriched in pathways including ribose phosphate metabolism, collagen binding, and apoptosis. Machine learning identified LOX as a hub gene, significantly upregulated in both models. Functional analysis suggested LOX expression was significantly associated with extracellular matrix (ECM) receptor interaction pathways, with its upregulation coinciding with myocardial injury progression. LOX expression correlated positively with CD8⁺ T cells and activated memory CD4⁺ T cells, indicating its potential association with metabolic and immune microenvironment remodeling in MIRI. Our findings suggest that LOX may serve as a key candidate gene associated with MIRI pathogenesis in preclinical models, with a potential value for preclinical research exploration.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315903","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":"Gastrodin Ameliorates Blood Pressure by Targeting the PPAR-γ/NF-κB/NLRP3 Signaling Axis in the Hypothalamic Paraventricular Nucleus.","authors":"Yu Yang, Xiao-Jing Yu, Li-Yan Fu, Jie Qi, Kai-Li Liu, Xiu-Yue Jia, Wei Cui, Qing Su, Ting Huang, Yan-Feng Liang, Hua Tian, Huan Liu, Hong-Li Gao, Yu-Ming Kang","doi":"10.1007/s12012-026-10139-2","DOIUrl":"10.1007/s12012-026-10139-2","url":null,"abstract":"<p><p>Hypertension increases the risk for cardiovascular and cerebrovascular diseases and both its preventive and current therapeutics measures require extensive investigations. Despite that Gastrodin, a neuroprotective compound extracted from a Traditional Chinese medicine (TCM), reportedly has preventive and curative potentials in hypertensive patients, its molecular mechanisms in lowering blood pressure still remain obscure. This study was designed to test the hypothesis that gastrodin lowers blood pressure by targeting the PPAR-γ/NF-κB/NLRP3 signaling axis in the hypothalamic paraventricular (PVN). Gastrodin or vehicle (artificial cerebrospinal fluid, aCSF) was directly infused into the PVN through a mini osmotic pump for 28 days to Spontaneous hypertensive rats (SHRs) and Wistar Kyoto (WKY). Four groups of rats were set: WKY + PVN vehicle; WKY + PVN Gastrodin; SHR + PVN vehicle; and SHR + PVN Gastrodin. Blood pressure was monitored and at the conclusion of experiment, plasma and PVN samples were collected and processed for ELISA, PCR, Western blotting and Immunofluorescence analyses. SHRs had elevated blood pressure (BP), heart rate (HR) and plasmatic norepinephrine (NE) validating their hypertensive status. PVN micro-infusion of gastrodin markedly reversed these hypertensive features in SHRs. At molecular level, gastrodin attenuated the local production of reactive oxygen species (ROS), reduced NADPH Oxidases (NOX)2 and NOX4 messenger RNA (mRNA) level and attenuated the activation of PPAR-γ in the PVN. In addition, gastrodin reduced the inflammasome activation and the expression of interleukin-1β (IL-1β). Furthermore, pretreatment with gastrodin reduced the expression of caspase-1 p10 and inflammation (IL-1β and MCP-1), the ratio of phosphorylated kappa B kinase (p-IKK)/IKK, and that of p-p65/p65 in the PVN of SHRs. In conclusion, gastrodin-lowered blood pressure is associated with balanced PPAR-γ/NF-κB/NLRP3 signaling axis within the PVN local highlighting its promising properties in the management of hypertension.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 7","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148315908","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":"Micro-nanoplastics in Cardiovascular Disease: A Critical Update from Environmental Exposure to Clinical Implications.","authors":"Zeeba Saeed, Marco Gatta, Annalisa Bruno, Melania Dovizio, Cristina Milillo, Amedeo Amedei, Giulia Renda, Patrizia Ballerini","doi":"10.1007/s12012-026-10149-0","DOIUrl":"10.1007/s12012-026-10149-0","url":null,"abstract":"<p><p>Micro- and nanoplastics (MNPs) are emerging environmental contaminants that may contribute to cardiovascular risk. Observational human studies have reported the presence of MNPs in patients with myocardial infarctions, acute coronary syndrome, coronary artery disease, extracranial artery stenosis, and asymptomatic extracranial internal carotid artery stenosis, where higher MNP levels have been associated with inflammatory and coagulation-related biomarkers and disease severity. Moreover, experimental in vivo and in vitro studies provide biological plausibility for these associations by showing that MNP exposure may promote endothelial dysfunction, oxidative stress, inflammation, platelet activation, coagulation abnormalities, cardiometabolic alterations, myocardial remodeling, fibrosis, and hypertension. However, major uncertainties remain regarding environmentally relevant exposure levels, long-term human effects, and the translational relevance of current experimental findings. This review critically summarizes the current evidence on the potential cardiovascular effects of MNPs, focusing mainly on endothelial dysfunction, platelet activation, the coagulation cascade, inflammation, gut dysbiosis, and alterations in lipid metabolism. We also discuss emerging therapeutic perspectives, iatrogenic exposure through cardiovascular medical devices, and the major methodological and translational limitations that currently hinder definitive cardiovascular risk assessment in humans.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 8","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13427906/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148629591","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":"Interpretable Machine Learning in Heavy Metal-Associated Cardiovascular and Metabolic Disease: A Review of Current Methodologies, Toxicological Insights, and Clinical Implications.","authors":"Ahmed Farid Gadelmawla, Amal A Alsubaiei, Najat Y AlSejari, Mohanad A Alkuwaiti, Bayan Mahafdah, Hamza A Abdul-Hafez, Ahmed Elmorsy Mohamed, Ahmed W Hageen, Abdullah M Alharran, Giuseppe Andò, Wilbert S Aronow","doi":"10.1007/s12012-026-10142-7","DOIUrl":"10.1007/s12012-026-10142-7","url":null,"abstract":"<p><p>Heavy metals, including lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg), are pervasive environmental toxicants increasingly recognized as nontraditional contributors to cardiovascular and cardiometabolic disease. Large-scale epidemiology and mechanistic studies link chronic low-to-moderate exposure to hypertension, atherosclerosis, coronary heart disease (CHD), stroke, heart failure (HF), and premature cardiovascular mortality. Concurrently, exposure science has shifted from single-pollutant models to high-dimensional \"exposome\" frameworks that must address correlated mixtures, non-linear dose-response, and subgroup heterogeneity. Machine learning (ML) methods can; learn these complex patterns, but clinical and policy translation requires interpretability: understanding which metals drive risk, how risk changes across exposure ranges, and where interactions amplify harm. This narrative review synthesizes contemporary interpretable ML approaches as SHapley Additive exPlanations (SHAP), partial dependence tools, Bayesian kernel machine regression (BKMR), and mixture-caausal methods, with toxicological mechanisms and clinically relevant outcomes. We integrate evidence from recent NHANES analyses, electronic medical record (EMR) mining, and the All of Us Research Program, highlighting a consistent ML-derived hierarchy wherein cadmium and lead frequently reported as dominant risk drivers for cardiovascular disease (CVD) outcomes and mortality prediction improvements when metal biomarkers augment standard risk models. We discuss current limitations, cross-sectional designs, residual confounding, measurement error, and variability in model development, and propose a future research agenda highlighting longitudinal cohorts, standardized reporting, causal validation, and integration of omics and real-time exposure monitoring to enable personalized environmental prevention.</p>","PeriodicalId":9570,"journal":{"name":"Cardiovascular Toxicology","volume":"26 6","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148249403","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}