Myocardial injury caused by Doxorubicin has limited its clinical application. Our research has demonstrated that doxorubicin induces various forms of cell death, oxidative stress, and metabolic abnormalities. We have confirmed, through both in vitro and in vivo studies, that apoptosis, iron overload, inflammatory responses, and arachidonic acid metabolism contribute to doxorubicin's cardiotoxic effects. Treatment with quercetin effectively reduces iron accumulation and preserves mitochondrial structural integrity by inhibiting oxidative stress and inflammatory responses. Using molecular docking and surface plasmon resonance (SPR) techniques, our study suggests that quercetin activates the HO-1/PGC-1α pathway, which may involve downregulation of ALOX5 expression, thereby alleviating oxidative stress, inhibiting iron-dependent lipid peroxidation and ferroptosis-like changes, mitigating inflammatory responses, and modulating arachidonic acid metabolism. Additionally, quercetin enhances energy availability and supports mitochondrial function. We propose quercetin, a promising active compound derived from traditional Chinese medicine, as a potential mitigator of doxorubicin-induced cardiotoxicity.

Doxorubicin (DOX) is a cytotoxic chemotherapeutic drug, the clinical value of which is limited by its cardiotoxicity. Krüppel-like factor 9 (KLF9) is known to modulate cell proliferation, differentiation, and apoptosis and plays critical roles in cardiovascular diseases. Here, we aimed to explore the potential effect of KLF9 on DOX-induced cardiotoxicity. C57BL/6J mice with cardiac-specific overexpression or silencing of KLF9 received single intraperitoneal injections of DOX to establish a DOX-induced cardiotoxicity model. The cardiac function of the mice was monitored by echocardiography, cardiac morphology was evaluated by histopathological staining, biomarkers of myocardial injury were detected using ELISA, and TUNEL staining and Western blotting were performed to evaluate apoptosis. In addition, H9c2 cells were used to validate the function of KLF9 in vitro. To test the involvement of thioredoxin reductase 2 (Txnrd2), ROS and p53 in the observed effects, siRNAs directed against p53 and Txnrd2 and the ROS inhibitor N-acetyl cysteine (NAC) were used. KLF9 expression was upregulated in the hearts of DOX-treated mice and H9c2 cells. Cardiac-specific KLF9 overexpression exacerbated, while cardiac-specific KLF9 silencing alleviated, DOX-induced apoptosis, acute myocardial injury and dysfunction. Mechanistically, KLF9 deficiency resulted in upregulation of Txnrd2 expression and subsequent suppression of apoptosis through modulation by ROS/p53 signalling. KLF9 exerts a pro-apoptotic effect on DOX-induced cardiotoxicity by inhibiting Txnrd2 and regulating the ROS/p53 signalling pathway. KLF9 deficiency may be a promising target for mitigating DOX-induced cardiotoxicity.

Cardiac toxicity from QT-prolonging drugs can precipitate malignant ventricular arrhythmias in susceptible individuals, and family screening may clarify inherited risk. We report a 33-year-old woman with a history of postpartum cardiac arrest treated with a secondary-prevention implantable cardioverter-defibrillator (ICD) who developed an electrical storm after self-administration of a single low dose of amitriptyline (12.5mg). ICD interrogation documented 176 episodes of ventricular fibrillation requiring repeated shocks, followed by complete battery depletion, hemodynamic collapse, and the need for venoarterial extracorporeal membrane oxygenation and continuous renal replacement therapy. The admission electrocardiogram showed marked QT prolongation (QTc 651 ms), with previously documented prolonged baseline QTc values. Targeted next-generation sequencing identified a novel SCN5A missense variant (NM_000335.5:c.5738G > A) and a rare pathogenic KCNQ1 splice variant (NM_000218.3:c.1032G > C), cascade testing across the family demonstrated variable expressivity among carriers. Given a suspected contribution of late sodium current, a mechanism-based strategy was implemented with mexiletine added to propranolol and overdrive pacing (90bpm). This case underscores the risk of malignant ventricular arrhythmias after exposure to QT-prolonging agents even at low doses, and supports genotype-informed, mechanism-based therapy to mitigate arrhythmic risk in patients with marked QT prolongation.

Major adverse cardiovascular events (MACE) in patients with liver cancer receiving vascular endothelial growth factor tyrosine kinase inhibitors (VEGF-TKI) remain uncertain. This retrospective cohort study aimed to evaluate the association between VEGF-TKIs and MACE and develop a risk prediction score. Using the Taiwan Cancer Registry linked with the Taiwan National Insurance Claim Database, 11,960 VEGF-TKI users were matched to 11,960 non-users by age and sex. Cause-specific hazard ratios (HRs) were estimated using multivariable Cox models with competing risk of non-cardiovascular death; propensity score (PS)-adjusted or PS-matched models were additionally conducted. During follow-up, the incidence of MACE was 49.5 versus 28.3 per 1,000 person-years in VEGF-TKI users and non-users. VEGF-TKI use was associated with increased MACE risk in multivariable analysis (adjusted HR 1.31; 95% CI 1.14-1.50); however, PS-adjusted and PS-matched models show non-significant associations. Because proportional hazards assumptions were violated, a 60-day landmark analysis was conducted, in which the increased risk was again significant across analytic approaches, including multivariable adjusted (HR 1.92; 95% CI 1.63-2.27), PS-adjusted (HR 1.35; 95% CI 1.00-1.82) and PS-matched models (HR 1.30; 95% CI 1.03-1.63). A point-based score was developed using a multivariable sub-distribution hazard model and assessed by a time-dependent c-index. The score demonstrated good discrimination with c-indices of 79.9% (3 months) and 74.2% (6 months). VEGF-TKIs were associated with increased risk of MACE among liver cancer patients. Landmark analyses indicated a persistently elevated risk among patients surviving beyond early treatment. A risk score based on prior cardiovascular history may help identify high-risk patients.

Electronic cigarettes (e-cigs) are major contributors to inflammatory-mediated responses, which are implicated in a vast array of pathophysiological conditions, including cardiovascular disease (CVD). More recently e-cigs have been recognized as a source of thirdhand exposure (THEC); the process by which expelled toxins settle on materials (i.e., carpets, curtains, clothes etc.) and undergo chemical reactions, rendering them more harmful overtime. Herein, mice were exposed to THEC for four months, and platelet reactivity, systemic mediated effects on platelet function, and cytokine expression profiles were analyzed in both sexes. Our data revealed a hyperactive platelet phenotype as determined by shortened bleeding and occlusion times, enhanced platelet aggregation, and dense granule secretion with no significant difference between males and females. Cytokines, amongst other inflammatory molecules, are well documented mediators by which platelet function is modulated and they also enhance susceptibility to CVD. To this end, and to elucidate the mechanism by which platelet reactivity was augmented, washed platelets that were exposed only to clean air (CA) and resuspended in THEC exposed plasma, displayed significantly increased platelet aggregation, dense granule secretion, and p-selectin expression. Indeed, this data suggests that THEC exposure elicits a systemic effect, enhancing platelet response, and was further validated by a dysregulated cytokine profile using plasma, free of platelets, in a sex-dependent manner. Collectively and for the first time, we highlight that both males and females are at similar risk of THEC-mediated prothrombotic phenotype, which is underlined-at least in part- by an indirect systemic effect of exposure on platelet reactivity that involves changes in the cytokine profile. These findings underscore this form of exposure as a threat to cardiovascular health.

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 24h 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.

Aluminum phosphide (ALP) is a highly toxic pesticide endangering the healthcare system. Higher central venous pressure (CVP) values may be linked to poorer outcomes in various medical conditions. This study evaluated the role of CVP and mean arterial pressure (MAP)/CVP ratio as prognostic factors for intensive care unit (ICU) admitted acute ALP-poisoned patients. This retrospective study included 145 acutely ALP-poisoned patients who were referred to the ICU during two years. Data regarding history, clinical manifestations, laboratory investigations, and outcome were collected and stratified by quartiles (Q1-Q4) of the measured CVP during the first 6 h after admission. In-hospital mortality and need for mechanical ventilation (MV) were significantly predominant in Q3 and Q4 groups of CVP levels (89.4% and 92% & 91.5% and 96%, respectively) (p-values < 0.001). After vasopressors administration, survivors demonstrated a significant mean reduction in CVP measurements (–4.5 mmHg), whereas non-survivors had a mean increase (+ 0.6 mmHg) (p = 0.011). MAP/CVP ratio has good discriminatory power (the areas under the curve (AUCs) = 0.836 and 0.846) for predicting the need for MV and in-hospital mortality, respectively. The CVP measurement (AUCs = 0.812 and 0.782, respectively) comes in second, followed by the poisoning severity score (AUCs = 0.778 and 0.768, respectively). There was a significant decrease in survival probability in patients with CVP ≥ 25 mmHg, and MAP/CVP ratio ≤ 2.48 (p-values < 0.001). Lower MAP/CVP ratios and higher CVP measurements are alarming signs, warranting a higher risk of the need for MV and in-hospital mortality in acute ALP poisoning.Graphical Supplementary InformationThe online version contains supplementary material available at 10.1007/s12012-026-10103-0.