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.

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.

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 (INa-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 Nav1.5 expressed in Human Embryonic Kidney (HEK293) cells, and significantly increases INa-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.

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.

Particulate matter exposure, particularly PM2.5 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.

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.

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.

Doxorubicin cardiotoxicity limits anthracycline chemotherapy, and mechanism-directed pharmacological protection remains limited. We investigated the cardioprotective action of sodium butyrate and its receptor-associated signaling mechanisms in doxorubicin-treated mice and H9c2 rat cardiomyoblasts. Targeted short-chain fatty acid profiling showed time- and compartment-dependent changes in endogenous butyrate after doxorubicin exposure. Oral sodium butyrate (300 mg/kg) improved left ventricular ejection fraction and fractional shortening, reduced circulating cardiac troponin I, creatine kinase-MB and lactate dehydrogenase, preserved myocardial ATP and mitochondrial ultrastructure, and decreased TUNEL positivity and the Bax/Bcl-2 ratio. In H9c2 cells, sodium butyrate (1 mM) increased viability and ATP content, preserved mitochondrial membrane potential, and reduced the Annexin V-positive fraction. Transcriptomic analysis and pathway perturbation implicated PI3K/Akt signaling. LY294002 attenuated sodium-butyrate-mediated protection in vivo and in vitro. GPR41 knockdown or GPR43 antagonism reduced cytoprotection and Akt phosphorylation. Sox4 loss- and gain-of-function experiments placed Sox4 upstream of Akt phosphorylation. A full-length Akt1 promoter reporter and co-immunoprecipitation further supported Sox4-associated transcriptional regulation and treatment-dependent co-precipitation of phosphorylated Akt with Sox4. These findings indicate that sodium butyrate attenuates doxorubicin cardiotoxicity through a receptor-associated Sox4-PI3K/Akt survival mechanism. Direct receptor-to-Sox4 coupling and direct Sox4 binding to the Akt1 promoter remain to be established.

Environmental thallium exposure is a growing public health concern, but evidence regarding its association with cardiovascular mortality remains limited. We evaluated this association in NHANES and used public disease-context single-cell transcriptomic datasets to generate candidate hypotheses for future experimental study. In the fully adjusted original-scale analysis, urinary thallium concentration showed a nominal positive association with cardiovascular mortality (OR = 2.13, 95% CI: 1.21-3.75; unadjusted P = 0.011). The multi-metal screening analyses were exploratory, and P values were not adjusted for multiple comparisons. After natural-log transformation of urinary thallium, the association with cardiovascular mortality was not statistically significant (OR = 1.53, 95% CI: 0.71-3.28; P = 0.264). Exploratory analyses of public disease-context single-cell datasets identified expression patterns of database-derived thallium-related candidate genes across vascular smooth muscle cells (VSMCs), macrophages, and other cell types. These candidate genes overlapped with disease-associated transcriptional programs annotated to VSMC phenotypic state and lipid metabolism. Because neither dataset included donor-level thallium measurements, these observations were used only to nominate hypotheses for future studies and were not interpreted as evidence of thallium-induced cellular changes or regulatory pathways. Because donor-level thallium measurements were unavailable, these transcriptomic observations are hypothesis-generating and do not establish that thallium exposure directly caused the observed cellular changes or activated specific regulatory pathways. In this exploratory cross-sectional analysis, higher urinary thallium concentration was positively associated with cardiovascular mortality in the original scale, but this association was not robust to natural-log transformation. Single-cell transcriptomic analyses of disease-context datasets identified candidate genes and pathways expressed in vascular smooth muscle cells and macrophages, but these findings are hypothesis-generating and require validation in studies with repeated exposure assessment and experimental models. The present results should be interpreted as preliminary and not as evidence of a causal relationship.

Toxic elements and metalloids exposure is an important environmental contributor to cardiometabolic disease, yet the gut-mediated mechanisms linking toxic elements to systemic metabolic and vascular injury remain incompletely understood. Lead, cadmium, arsenic, and mercury can enter the gastrointestinal tract through contaminated food, water, dust, smoking, seafood, and occupational sources, allowing direct interaction with the intestinal lumen, epithelial barrier, immune system, and gut microbiome. This narrative review examines the gut-cardiometabolic axis as a mechanistic framework connecting toxic metal exposure to microbiome dysbiosis, barrier dysfunction, endotoxemia, microbial metabolite imbalance, and chronic metabolic inflammation. Available evidence, derived from human, animal, and in-vitro studies of varying quality, suggests that toxic elements may alter microbial diversity and function, affect tight-junction integrity, and increase intestinal permeability; however, a consistent metal-specific signature and a complete causal chain have not been established. These changes may promote lipopolysaccharide passage through the intestinal barrier, activate innate immune pathways, and maintain systemic inflammatory signaling. At the same time, disruption of microbial metabolite profiles, including lower short-chain fatty acid production and altered trimethylamine N-oxide, bile acid and uremic toxin pathways, may promote insulin resistance, dyslipidemia, endothelial dysfunction, hypertension, atherosclerosis and overall cardiometabolic vulnerability. Viewing toxic-metal exposure through the gut-cardiometabolic axis provides a hypothesis-generating framework for integrating exposure reduction with conventional cardiometabolic risk management; the clinical value of microbiome-targeted strategies remains to be established. Longitudinal and multi-omics studies are still needed to define causal relationships and identify populations at greatest susceptibility.

Chemotherapeutic agents, including 5-fluorouracil (5-FU), are widely used to treat various types of malignant disorders, but cardiac injury limits their clinical benefit. Thus, we aimed to evaluate the usefulness of diacerein (DIA) in alleviating 5-FU myocardial and ocular injury. 50 male Wistar rats were included in the current model, and 5-FU was administered as a single intraperitoneal dose (150 mg/kg) on the first day of the study to induce myocardial and ocular injury, followed by co-administration of DIA (25, 50 mg/kg/day) by oral gavage for 7 days. 5-FU-induced myocardial and ocular injury was detected as structural changes in cardiac, corneal, and retinal tissues, with significant increases in the cardiac injury biomarkers, toll-like receptor 4 (TLR4), extracellular signal-regulated kinase (ERK), total oxidant status (TOS), oxidative stress index (OSI), nuclear factor kappa b (NF-κB), interleukin 1β (IL-1β), caspase-3, and caspase-1 expressions. Conversely, there were marked decreases in the serum total antioxidant capacity (TAC) and toxic features in the histopathological evaluation. However, co-administration of DIA ameliorated 5-FU-induced toxic effects and improved biochemical and structural changes. This beneficial effect of DIA is attributed to its ability to modulate the NF-κB/TLR4/ERK/caspase-1/IL-1β pathway, suppressing apoptosis and oxidative stress. DIA may be a future adjuvant medical therapy to reduce 5-FU side effects.

Polyethylene microplastics (PE-MPs), the most globally abundant plastic polymer, accumulate in rodent tissues following experimental exposure and have been implicated in multi-organ biochemical disruption. Whether mitochondrial bioenergetic failure and redox collapse represent a convergent, organ-transcendent mechanism of PE-MP toxicity has not been quantitatively established. We conducted a PRISMA 2020-guided systematic review and random-effects meta-analysis, searching four electronic databases for controlled rodent studies reporting oxidative phosphorylation enzyme activities and redox markers following PE-MP exposure. Risk of bias was evaluated with SYRCLE, and evidence certainty was graded using a preclinical adaptation of GRADE. Thirteen studies (160 experimental arms, seven organ systems) met inclusion criteria; four studies across five organs supplied quantitative TCA cycle and electron transport chain data for the primary analysis, while the remaining nine contributed redox biomarker data. PE-MPs produced large, significant suppression of all four TCA cycle enzymes (CS: g = -2.69 to -3.82; p ≤ 0.009) and electron transport chain Complexes I, III, and IV (g = -3.08 to -3.70; p < 0.0001); Complex II showed non-significant, organ-specific adaptive upregulation. Pro-oxidant markers MDA and NO rose significantly, with NO showing near-perfect cross-organ homogeneity (I[2] = 4.5%). Antioxidants GSH, SOD, and CAT were markedly depleted (g = -2.48, -2.93, -3.86; p < 0.0001). After mandatory GRADE/OHAT downgrades for unclear allocation concealment and single-group data dominance, certainty was Low for ten outcomes and Very Low for six. PE-MPs elicits the potency of being a mitochondrial toxicant via coherent tripartite axis throttling of TCA cycle, electron-leak amplification of the electron transport chain, and peroxynitrite-driven antioxidant exhaustion converging across renal, cardiac, pulmonary, neural, and gonadal tissues, with cardiac and cardiopulmonary mitochondrial injury emerging as a particularly consequential. These findings establish the mitochondrial-redox axis as a defining biochemical fingerprint of PE-MP multi-organ toxicity and provide mechanistic grounding for microplastic-associated cardiovascular risk.

The effects of benzodiazepines (BZDs) for insomnia on heart failure (HF) remain unclear, particularly among high-risk populations. Relevant studies were retrieved by searching seven databases from inception to August 7, 2025. Hazard ratios (HRs) or risk ratios estimated for related HF outcomes were extracted. Meta-analyses were conducted using a random-effects model, and study quality was assessed using the Newcastle-Ottawa Scale (NOS). Eleven studies met the inclusion criteria, with follow-up durations ranging from 180 days to 15 years. The meta-analysis demonstrated that BZD use was associated with increased risks of HF incidence (HR = 1.41, 95% confidence interval (CI) 1.16-1.72) and HF hospitalization (HR = 1.29, 95% CI 1.01-1.65) compared to non-use. BZD use also suggested an increased risk of HF hospitalization and rehospitalization compared to antipsychotics, z-drugs, and suvorexant. Benzodiazepine use was associated with an increased risk of HF-related outcomes. Since most of the included studies were observational, these findings indicate associations rather than causal relationships. BZDs should be used with caution among populations at risk of HF when treating insomnia.

Environmental metal exposure has been increasingly recognized as a contributor to cardiovascular toxicity, yet the effects of single and mixed metal burdens, as well as susceptible population subgroups, remain insufficiently characterized. This study aimed to investigate the associations of blood copper (Cu), zinc (Zn), Cu/Zn ratio, selenium (Se), lead (Pb), cadmium (Cd), total mercury (HgT), and manganese (Mn) with cardiovascular disease (CVD), and to evaluate the joint association of multiple metal exposures and potential heterogeneity across population subgroups. Data from 1,967 participants (211 CVD cases) in the 2011-2016 NHANES were analyzed. Spearman correlation, logistic regression, restricted cubic spline (RCS), weighted quantile sum (WQS) regression, and quantile-based g-computation (QGcomp) were applied to assess associations of single metals and mixtures with CVD. Subgroup analyses were conducted by demographics and health conditions. Network pharmacology was applied to identify candidate pathways and toxicological targets. CVD patients had higher levels of Cu, Cu/Zn ratio, Pb, and Cd, but lower levels of Zn, HgT, and Mn. Spearman analyses showed Cd (rho = 0.114) and Pb (rho = 0.111) have positive associations with CVD, whereas Mn has a negative connection (rho=-0.069) (all P < 0.05). In quartile-based logistic regression, Cd showed the most consistent positive association with CVD, with participants in the highest quartile having higher odds of CVD in the fully adjusted model (OR = 2.29, 95% CI: 1.37-3.87, P = 0.002). The Cu/Zn ratio was positively associated with CVD in partially adjusted models, but the association was attenuated and no longer statistically significant after full adjustment (OR = 1.55, 95% CI: 0.94-2.57, P = 0.089). RCS revealed linear correlations between Pb, Cd and Mn with prevalent CVD. The WQS index was positively associated with higher odds of CVD (OR = 1.70, 95% CI: 1.16-2.52, P = 0.008), with Cd, the Cu/Zn ratio, and Pb showing the largest positive weights. QGcomp similarly indicated a positive overall mixture association (OR = 1.64, 95% CI: 1.10-2.45, P = 0.014), while Mn contributed in the negative direction. Subgroup analyses indicated that specific metals exerted positive contributions in vulnerable populations, including younger males, smokers, drinkers, elderly, hypertensive, and low-BMI groups. GAPDH, AKT1, CTNNB1, MYC, TNF, and TP53 were predicted to be key targets. Elevated blood Cd showed the most consistent positive association with CVD across individual and mixture-based analyses. The Cu/Zn ratio and Pb also contributed substantially to the positive association of the metal mixture with CVD, although the independent association of the Cu/Zn ratio was attenuated after full multivariable adjustment. Mn showed a potential inverse association. These findings highlight the toxicological relevance of metal mixtures in cardiovascular disease and underscore the need for mechanistic studies to establish causality.