Cardiovascular Toxicology最新文献

Sepsis-induced cardiomyopathy (SICM) is a life-threatening complication characterized by cardiac dysfunction, inflammation, oxidative stress, and mitochondrial impairment, with limited therapeutic options. Taurine, a naturally occurring amino acid with known anti-inflammatory and mitochondrial-stabilizing properties, may offer therapeutic benefits. However, its role in SICM is not well defined. This study aimed to evaluate the protective effects of taurine against SICM and elucidate its underlying mechanisms. A murine model of SICM was established via cecal ligation and puncture (CLP), and AC16 cardiomyocytes were stimulated with lipopolysaccharide (LPS) to mimic septic injury in vitro. Cardiac function was assessed by echocardiography; inflammatory cytokines and cardiac injury markers were measured via ELISA. Mitochondrial integrity and function were evaluated using transmission electron microscopy (TEM), oxygen consumption rate (OCR), and mitochondrial membrane potential (MMP). Apoptosis was analyzed by TUNEL staining, flow cytometry, and Western blot. Rescue experiments using an NF-κB activator were conducted to validate pathway involvement. The results showed that taurine treatment significantly improved cardiac function and survival rates in SICM mice, attenuated myocardial inflammation and oxidative stress, restored mitochondrial structure and function, and suppressed apoptosis. These beneficial effects were reversed upon NF-κB activation, indicating that taurine exerts its cardioprotective role primarily through inhibition of the NF-κB signaling pathway. In conclusion, this study provides the first evidence that taurine protects against SICM by alleviating NF-κB-driven inflammation, oxidative stress, mitochondrial dysfunction, and apoptosis, suggesting its potential as a therapeutic agent for sepsis-induced cardiac injury.

Metal-on-metal (MoM) joint replacements were designed to improve durability in younger, active patients. However, cobalt-induced cardiomyopathy (CIC) has emerged as a rare but serious complication, often misattributed to idiopathic or ischemic causes. We systematically reviewed published case reports, case series, and laboratory studies describing CIC in patients with MoM implants. Data extraction included clinical presentation, diagnostic criteria, treatment, and outcomes. Methodological quality and risk of bias were assessed qualitatively. Eighteen cases were included. Implant wear and corrosion released systemic cobalt, which localised in myocardial tissue. Pathophysiological mechanisms included mitochondrial dysfunction, oxidative stress, impaired calcium handling, and apoptotic injury. Patients commonly presented with non-specific cardiac symptoms such as fatigue, dyspnoea, orthopnoea, arrhythmias, and heart failure, alongside extra-cardiac features including hearing loss, thyroid dysfunction, and neurocognitive changes. Diagnostic confirmation required serum cobalt levels typically exceeding 30-100 µg/L, with cardiac MRI demonstrating non-ischemic fibrosis and oedema. Chelation therapy reduced cobalt burden but was rarely effective alone. Revision of the MoM implant consistently led to clinical improvement when performed early; delayed intervention was associated with irreversible myocardial damage and poorer outcomes. CIC is an under-recognised but potentially reversible form of cardiomyopathy. Routine cobalt screening and early implant revision are essential to prevent progression to heart failure or sudden cardiac death. Multidisciplinary collaboration between cardiology and orthopaedics is critical for the timely diagnosis and management of these conditions.

Heavy metal exposure is an emerging major environmental risk factor associated with metabolic and cardiometabolic disorders. Arsenic exposure via drinking water leads to cardiotoxicity through lipid metabolism. Exposure to arsenic can cause various heart conditions by activating oxidative stress and inflammatory pathways. Pioglitazone is a thiazolidinedione that activates PPARγ and is an approved clinical drug for the treatment of type 2 diabetes, widely used. Pharmacokinetics results indicate pioglitazone has good oral bioavailability. In this study, we employed a network pharmacology approach and a molecular docking approach to identify the potential mechanism by which pioglitazone may mitigate arsenic-induced cardiotoxicity via lipid metabolism. Key genes that target arsenic-induced cardiotoxicity via lipid metabolism and pioglitazone have been identified using the Swiss Target Prediction, Gene Cards, OMIM, and CTD databases. A protein-protein interaction (PPI) network was generated by analysing frequently intersecting genes with the STRING and Cytoscape tools. Shiny GO was used to conduct pathway enrichment analysis for the KEGG and Gene Ontology databases. Pioglitazone and arsenic-related cardiotoxicity shared 54 common targets. Enrichment analysis pathways involved fluid and shear stress atherosclerosis, NAFLD, lipid, and atherosclerosis. Molecular docking was performed using ten targets. The binding affinity of the ten targets was ALB (6M4R) -8.6 Kcal/mol, BCL2 (2YXJ) -8.0 Kcal/mol, CASP3 (4JJE) -7.1 Kcal/mol, EGFR (2ITO) -7.8 Kcal/mol, HSP90AA1 (6GP8) -7.3 Kcal/mol, PPARα (4UND) -8.4 Kcal/mol, PPARγ (5Y20) -8.6 Kcal/mol, SRC (2SRC) -8.1 Kcal/mol, TNF (5UUI) -6.5 Kcal/mol, and TP53 (4MZI) -5.6 Kcal/mol. And also, we carried out docking with known inhibitors (Asciminib, Emricasan, Navitoclax, Osimertinib, Geldanamycin, GW6471, GW9662, Dastinib, Balinatufnib, and pifithrin), and resveratrol as a positive control. Pioglitazone as a multi-target potential against arsenic-induced cardiotoxicity via lipid metabolism by modulating mitochondrial dysfunction. Overall, this study provides a system-level assumption that indicates lipid metabolism to arsenic-induced cardiotoxicity and identifies key molecular targets that show a way to further experimental validation.

Aging and insulin resistance are intertwined factors in the development of metabolic diseases such as type 2 diabetes and cardiovascular disorders. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown promising cardioprotective effects in preclinical and clinical studies of metabolic diseases. Yet, its action on insulin-resistant aged subjects is not clearly defined. This study aimed to investigate the effects of liraglutide on intracellular zinc levels, including its modulation of oxidative stress, mitochondrial function, and Endoplasmic Reticulum (ER) stress in a novel insulin-resistant senescent model. Insulin resistance and senescence were confirmed by reduced glucose uptake and increased β-Galactosidase Staining and increased p-H2A.X (Ser139) levels after 24 h of co-incubation with bovine serum albumin (BSA) conjugated palmitic acid (PA; 50 µM) and 278 mM D-galactose (D-Gal) in human AC16 cells. Our findings showed upregulated expression of ER and mitochondrial proteostasis markers in the early minutes of liraglutide treatment. In addition, chronic but not acute liraglutide treatment significantly increased intracellular zinc levels, accompanied by improved mitochondrial membrane potential and reduced reactive oxygen species in the insulin-resistant senescent model. Casein kinase 2 inhibition completely abolished liraglutide-induced zinc elevation and mitochondrial improvements in the chronic context, highlighting the role of casein kinase 2 in the subcellular signaling of liraglutide. These findings indicate that liraglutide alters intracellular zinc and modulates endoplasmic reticulum-mitochondria communication, giving insight into its therapeutic potential in metabolic cardiomyopathies linked to insulin resistance and aging.

Childhood cancer survivors (CCS) are at increased risk of developing heart disease due to the cardiotoxic effects of oncological treatment. This study aimed to investigate the long-term cardiotoxic effects of cancer therapy in CCS using a multimodal approach combining cardiac magnetic resonance (CMR) imaging and circulating blood biomarkers. A total of 117 CCS (mean age 24.7 ± 5.2 years), at least five years post-treatment and in complete remission, were prospectively enrolled. All participants underwent CMR, including T1 mapping, and blood analysis for biomarkers of endothelial damage and oxidative stress. Parameters were compared with sex- and age-matched healthy control groups. Anthracycline treatment was administered in 82.9% of CCS (mean cumulative doxorubicin equivalent dose 231.7 ± 92.0 mg/m²). Left ventricular ejection fraction and mitral annular plane systolic excursion were significantly reduced in CCS compared to controls (59.0 ± 5.5% vs. 67.2 ± 6.9%, p < 0.001; 12.5 ± 1.7 mm vs. 13.9 ± 2.2 mm, p = 0.001). Late gadolinium enhancement was detected in four CCS. No significant differences in global native T1 relaxation time or extracellular volume were observed. N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels remained within normal limits but correlated with native T1, ECV, and MAPSE. Levels of myeloperoxidase, big endothelin-1, and ischemia-modified albumin were significantly higher than in controls. Subclinical myocardial changes were detected in long-term CCS using CMR and circulating biomarkers. These findings support the utility of a multimodal approach for the early identification of individuals at increased cardiovascular risk after childhood cancer treatment.

Doxorubicin (DOX), a widely used anthracycline in cancer therapy, is associated with significant cardiovascular toxicity. While its cardiotoxic effects are well documented, the mechanisms and prevention of DOX-induced vascular toxicity remain insufficiently explored. Angiotensin-converting enzyme inhibitors (ACEIs), such as perindopril (PER), are commonly used in cardiovascular disease management and may offer vascular protection during chemotherapy. Female ovariectomized Wistar rats were treated with i.v. DOX and/or p.o. PER over five weeks. Cardiac and vascular function were assessed using high-frequency ultrasound and ECG. Vascular reactivity was evaluated in isolated aortal rings using phenylephrine (PE), acetylcholine (ACh), L-N-Nitro arginine methyl ester hydrochloride (L-NAME), and verapamil (VER). Oxidative stress was assessed via plasma 4-hydroxy-2-nonenal (4-HNE) levels, and structural changes were monitored through intima-media thickness (IMT) measurements. DOX administration significantly impaired vascular reactivity, as evidenced by increased contractile responses to PE and reduced endothelium-dependent relaxation. These functional alterations were accompanied by elevated plasma 4-HNE levels, indicating enhanced oxidative stress. Co-treatment with PER preserved vascular responsiveness, reduced contractile tension, and significantly lowered 4-HNE concentrations. Structurally, IMT increased in control and PER-only groups, likely due to post-ovariectomy remodelling, while DOX-treated groups showed no IMT progression. PER co-treatment appeared to stabilize IMT values. PER mitigates DOX-induced vascular toxicity, likely through endothelial protection and reduction of oxidative stress. These findings support the potential use of ACEIs as prophylactic agents in patients undergoing anthracycline-based chemotherapy and highlight the need for further translational studies in cardio-oncology.

Background: Influenza remains a major global health threat and, akin to "long COVID," has been linked to prolonged multi-organ comorbidities ("long flu"). Cardiovascular diseases (CVDs) are increasingly recognized in the pathogenesis of influenza, yet most prior work emphasizes acute or short-term outcomes and rarely contrasts multiple endpoints over extended horizons.

Methods: This study conducted a disease-wide association study (DWAS), assembling individuals with clinically coded influenza without pneumonia (n = 5136) and population comparators (n = 314,673). Using age- and sex-adjusted Cox models, this analysis screened 106 comorbid endpoints classified by ICD-10/ICD-O-3 and FinnGen disease taxonomy. Associations were evaluated bidirectionally-before influenza (predisposition) and after influenza (subsequent risk)-within prespecified 1-, 5-, and 15-year time windows.

Results: Influenza showed broad associations spanning circulatory, nervous, endocrine-metabolic, respiratory, musculoskeletal, and other organ systems. CVD endpoints demonstrated the most persistent and directionally consistent DWAS signals. In pre-influenza analyses, greater baseline cardiovascular burden-including heart failure, coronary atherosclerosis, hypertension, major coronary heart disease, atrial fibrillation/flutter, myocardial infarction, stroke, pulmonary embolism, and venous thromboembolism-was associated with higher susceptibility to subsequent influenza. In post-influenza analyses, elevated risks remained for key CVD outcomes-atrial fibrillation/flutter, heart failure, myocardial infarction, and stroke. Non-cardiovascular endpoints (e.g., migraine, sleep apnoea, spinal stenosis, osteoporosis, chronic obstructive pulmonary disease, diabetic nephropathy, and chronic kidney disease) also showed bidirectional associations with influenza, thereby situating CVD within a broader comorbidity and frailty context of influenza.

Conclusions: In this population-scale DWAS, CVDs emerged as the most significant comorbidities of influenza. Conceptualizing influenza as a "cardiovascular stress test" supports targeted prevention (e.g., vaccination prioritization) and intensified cardiovascular risk management around influenza seasons. While the biological mechanism remains unclear, this study will motivate future studies integrating biomarkers, cardiovascular imaging, and virologic-immunologic profiling to disentangle causal mechanisms.

Copper ions are essential metal ions that play a pivotal role in various biochemical processes. Recent studies have identified a novel copper-dependent form of cell death named cuproptosis, which differs significantly from other well-characterized modes of cell death, such as apoptosis, pyroptosis, necrosis and ferroptosis. Moreover, a series of researches indicate that cuproptosis may be related to the occurrence and aggravation of cardiovascular diseases (CVDs). This review aims to elucidate the molecular mechanisms underlying cuproptosis and to summarize the pathways through which cuproptosis contributes to the pathogenesis of various cardiovascular conditions, including atherosclerosis, heart failure, dilated cardiomyopathy, atrial fibrillation, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, acute myocardial infarction, and vascular aging. Additionally, we explore therapeutic approaches involving copper chelators, small-molecule inhibitors targeting copper chaperone proteins, and copper ionophores, which may mitigate these cardiovascular disorders by inhibiting cuproptosis. Collectively, effective suppression of cuproptosis may become a novel therapeutic strategy for the prevention and treatment of related CVDs.

Hypoxia is involved in severe cardiac conditions such as heart failure and myocardial infarction. Therefore, understanding the molecular mechanisms underlying hypoxia is crucial for developing effective therapeutic strategies. Specifically, one in vitro hypoxia model involves reducing oxygen concentration, thereby emulating many features observed in cardiac ischemia in rodents and patients. One way to overcome the infrastructure challenges in basic research laboratories (e.g., anaerobic chamber) is to use chemically-induced hypoxia models. Cobalt chloride (CoCl₂) treatment provides an inexpensive, accessible, and highly reproducible model in diverse cell types, as it mimics many of the cellular processes activated during hypoxia/ischemia. Paradoxically, no compendium addresses these processes beyond oxidative stress, let alone focusing on cardiac tissue. Hence, our objective was to describe how other processes, such as mitochondrial dysfunction, calcium handling, apoptosis, autophagy, inflammation, and endoplasmic reticulum stress, interact negatively in cardiac cells exposed to CoCl₂ and to examine their cardiomyocyte-level toxicological effects.