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. Pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA) increased the late sodium current in Nav1.5 expressed in Human embryonic kidney 293 and delayed the recovery from inactivation. Also, 3-PBA in relevant concentration to human toxicology reduced the maximal rate of action potential depolarization (dV/dt) in rat ventricular cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocyte. In the ECG of ex vivo heart preparation 3-PBA 1 μM caused non-effect. This provides 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. Created by Servier Medical Art ( https://smart.servier.com ), licensed under CC BY 4.0 ativecommons.org/licenses/by/4.0/). Gemini 3.1 Pro was used to refine the layout and visual presentation of the graphical abstract. The authors reviewed, verified, and approved all generated content.
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.
