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.

Aconitine-induced cardiotoxicity is a serious adverse effect of Aconitum-containing medicines, with myocardial injury and malignant ventricular arrhythmias representing important clinical manifestations. However, the molecular responses underlying aconitine-induced myocardial injury remain incompletely understood. This study aimed to construct an integrated molecular network and signaling pathway landscape of aconitine-induced cardiotoxicity through multi-cohort transcriptomic analysis and to identify key hub genes associated with myocardial injury and ventricular tachyarrhythmias. Rat myocardial transcriptomic datasets related to aconitine-induced cardiotoxicity were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the thresholds of |log2FC| > 1 and a false discovery rate (FDR) < 0.05. Weighted gene co-expression network analysis (WGCNA) was performed to identify cardiotoxicity-associated gene modules, and candidate genes were obtained by intersecting DEGs with module genes. Protein-protein interaction (PPI) network analysis was subsequently conducted to identify hub genes, followed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses to characterize their biological functions and signaling pathways. The expression patterns of the hub genes showed broadly concordant trends in the independent doxorubicin-induced cardiotoxicity dataset, suggesting that these genes may represent conserved transcriptional responses to myocardial injury (GSE42177). A total of 265 DEGs were identified, and WGCNA revealed one gene module significantly associated with cardiotoxicity (r = - 0.33, P < 0.001). Integration of DEGs with the cardiotoxicity-associated module yielded 18 candidate genes, from which 12 hub genes (Abcb11, Abcc6, Fez1, Ldha, Nr3c1, Nr3c2, Pc, Pdk2, Prkcz, Slc9a1, Vcam1, and Vtn) were identified through PPI network analysis. Functional enrichment analysis indicated that these genes were primarily involved in inflammatory responses, metabolic regulation, and stress-related signaling pathways, particularly the MAPK and TGF-β signaling pathways.

Methanol poisoning induces severe mitochondrial dysfunction through inhibition of mitochondrial respiration, excessive reactive oxygen species (ROS) generation and oxidative stress. The present study investigated whether injection of freshly isolated mitochondria, could attenuate methanol-induced cardiac mitochondrial dysfunction and oxidative damage in rat. Adult male Wistar rats were randomly allocated into five experimental groups: control, methanol, methanol plus single mitochondrial injection, methanol plus repeated mitochondrial injection (double) and mitochondria alone. Fresh functional mitochondria were isolated from healthy donor cardiac tissue and administered intravenously (250 µg/kg), 30 min after methanol intoxication. Serum cardiac injury biomarkers, including creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), were measured. Oxidative stress was evaluated by determining malondialdehyde (MDA) and glutathione (GSH) levels. Cardiac mitochondrial function was assessed by measuring succinate dehydrogenase (SDH) activity, mitochondrial swelling, mitochondrial ROS production, and mitochondrial membrane potential (MMP). Methanol intoxication significantly increased serum cardiac injury biomarkers, ROS generation, lipid peroxidation, and mitochondrial swelling while markedly reducing GSH content, SDH activity, and MMP compared with the control group. Mitochondrial injection significantly attenuated oxidative stress, decreased ROS production, restored antioxidant capacity, improved SDH activity, reduced mitochondrial swelling, and preserved MMP. Repeated mitochondrial administration showed relatively greater improvement than single administration, although no consistent dose-response relationship was observed. Also, histopathological examinations demonstrated significant recovery following mitochondrial injection. Fresh mitochondrial injection effectively ameliorated methanol-induced cardiotoxicity by reducing oxidative stress, preserving mitochondrial integrity, and restoring mitochondrial function in cardiac tissue. These findings suggest that mitochondrial injection represents a promising mitochondria-targeted therapeutic approach for methanol-induced cardiotoxicity.

Cardiovascular disease is the leading cause of death in chronic kidney disease (CKD), largely driven by accelerated atherosclerosis and vascular calcification. These complications cannot be fully explained by traditional cardiovascular risk factors, indicating that CKD-specific mechanisms may contribute to persistent vascular inflammation. Trained immunity, a long-lasting functional reprogramming of innate immune cells mediated by metabolic and epigenetic remodeling, has emerged as a plausible mechanistic framework linking uremic toxin accumulation to cardiovascular injury. However, the level of evidence differs substantially across individual toxins. Indoxyl sulfate currently has the most direct evidence for classical trained immunity, whereas the evidence for p-cresyl sulfate, homocysteine, S-adenosylhomocysteine, and parts of trimethylamine N-oxide (TMAO) biology remains more indirect or hypothesis-generating. Uremic toxins may therefore act as endogenous danger signals that potentially prime monocytes, macrophages, and endothelial cells toward a hyper-inflammatory state. Because these trained phenotypes may be epigenetically durable, conventional dialysis and downstream anti-inflammatory therapies may be insufficient to reverse cardiovascular risk in CKD. This review summarizes the graded mechanistic evidence potentially linking uremic toxin-induced trained immunity to atherosclerosis and vascular calcification and discusses emerging therapeutic strategies targeting toxin burden, metabolic pathways, epigenetic remodeling, and myeloid-specific drug delivery. These approaches remain investigational in this setting, and evidence that they specifically modify uremic toxin-induced trained immunity in patients is currently lacking.

Doxorubicin (DOX)-induced cardiotoxicity converges on oxidative-nitrosative stress, TLR4/NF-κB-driven inflammation, and caspase-3-mediated apoptosis, and remains a major dose-limiting complication of anthracycline therapy. Dexpanthenol (DEX), a coenzyme A precursor, has shown anti-oxidative, anti-inflammatory, and anti-apoptotic activity in diverse organ-injury models, but its cardioprotective potential against DOX has not been systematically evaluated. The present study aimed to investigate the protective effects of DEX against DOX-induced cardiotoxicity in Wistar rats. Twenty-eight male Wistar rats were randomly allocated to four groups (n = 7): Control, DOX (single 25 mg/kg i.p. on day 1), DOX + DEX (DOX on day 1 followed by 500 mg/kg/day DEX for eight days), and DEX (500 mg/kg/day for eight days). TLR4, NF-κB p65, TNF-α, MDA, SOD, and GSH were quantified by ELISA in both serum and cardiac tissue; caspase-3 and GFAP were quantified in cardiac tissue. Cardiac TAS, TOS, OSI, NO, and iNOS were also measured. Myocardial sections were graded for seven histopathological parameters by a blinded pathologist. DOX produced a robust cardiotoxic phenotype, with elevations in inflammatory, oxidative, nitrosative, and apoptotic markers, depletion of antioxidant defenses, and marked histopathological injury. Co-administration of DEX attenuated TLR4/NF-κB/TNF-α signaling in both compartments, reduced caspase-3 and GFAP, normalized TAS and OSI, and significantly improved five of seven histopathological parameters after multiplicity adjustment. Protection was selective: cardiac SOD, GSH, NO, and total oxidant status were only partially restored, and inflammatory cell infiltration was unchanged. DEX exerts a partial but mechanistically coherent cardioprotective effect against DOX-induced cardiotoxicity, chiefly through attenuation of TLR4/NF-κB-driven inflammation and caspase-3 signaling. These findings support its evaluation as a multi-target adjunct in cardio-oncology.

Omecamtiv mecarbil is a cardiac-selective myosin activator and potential heart failure treatment, but its electrophysiological profile remains incompletely characterized. We investigated omecamtiv mecarbil in a Langendorff-perfused rabbit heart model. Forty-eight rabbit hearts were retrogradely perfused; twenty-four in a ventricular and twenty-four in an atrial setup. In the ventricular setup, action potential duration at 90% repolarization (APD90), QT interval, and dispersion of repolarization were assessed during pacing at seven cycle lengths. After baseline recordings, Group 1 (n = 12) received 1, 5 and 10 µM omecamtiv mecarbil sequentially, while Group 2 (n = 12) received 100 µM sotalol followed by 5 µM omecamtiv mecarbil. In the atrial setup, Group 3 (n = 12) received 5 and 10 µM omecamtiv mecarbil, and Group 4 (n = 12) received isoproterenol/acetylcholine (IsoACh) to increase atrial fibrillation (AF) susceptibility, followed by 5 µM omecamtiv mecarbil. Omecamtiv mecarbil alone shortened ventricular APD90 and QT interval, increased dispersion of repolarization, and raised ventricular arrhythmia incidence. Sotalol prolonged APD90, QT interval, and dispersion, with a marked rise in VT episodes; additional omecamtiv mecarbil did not further prolong repolarization but increased arrhythmia susceptibility further. In the atrial setup, omecamtiv mecarbil alone prolonged conduction time and increased AF inducibility. Under IsoACh, which shortened atrial APD and refractoriness and increased AF episodes, additional omecamtiv mecarbil slowed atrial conduction and markedly suppressed AF. In summary, omecamtiv mecarbil was proarrhythmic at the ventricular level, particularly under reduced repolarization reserve, but showed antiarrhythmic effects in an IsoACh-induced AF model and proarrhythmic properties in the healthy atrium, indicating a substrate-dependent electrophysiological profile.

Primary percutaneous coronary intervention restores epicardial flow after ST-segment elevation myocardial infarction, but tissue perfusion may remain impaired. Coronary microvascular dysfunction, angiographic no-reflow, cardiac magnetic resonance-defined microvascular obstruction, and intramyocardial hemorrhage are overlapping but non-equivalent phenotypes. This review examines reduced mitochondrial aldehyde dehydrogenase 2 (ALDH2) activity as a susceptibility amplifier rather than an established independent cause of these outcomes. Reperfusion generates reactive oxygen species that initiate lipid peroxidation and produce electrophilic aldehydes, including 4-hydroxy-2-nonenal, malondialdehyde, and acrolein. Their effects are shaped by compartmental generation, competing clearance systems, protein-adduct persistence, and positive feedback between mitochondrial injury and inflammation. Methylglyoxal is considered a parallel, glyoxalase-dominant dicarbonyl pathway rather than a principal ALDH2 substrate. The resulting network may impair endothelial nitric oxide signaling and barrier integrity, promote platelet activation and neutrophil extracellular trap formation, and increase cardiomyocyte edema and damage-associated molecular-pattern release. Pericyte constriction contributes to experimental no-reflow, whereas pericyte sensitivity to 4-hydroxy-2-nonenal remains a theoretical hypothesis awaiting direct experimental confirmation. We also assess adductomics, proteomics, lipidomics, and time-resolved sampling strategies. Free aldehydes are chemically and preanalytically unstable; protein-bound adducts provide longer detection windows but lack the clinical standardization of cardiac troponin. ALDH2 activation remains preclinical for reperfusion microvascular injury. Prospective studies should further integrate genotype, enzyme activity, local carbonyl measurements, thromboinflammatory phenotyping, invasive physiology, and cardiac magnetic resonance endpoints.