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Background Cardiotoxicity is the most significant adverse event associated with trastuzumab (T), the main component of HER2-positive breast cancer (BC) treatment. Less is known about the cardiotoxicity of dual HER2 blockade with T plus lapatinib (L), although this regimen is used in the metastatic setting. Methods This is a sub-analysis of the ALTTO trial comparing adjuvant treatment options for patients with early HER2-positive BC. Patients randomised to either T or concomitant T + L were eligible. Cardiac events (CEs) rates were compared according to treatment arm. Results With 6.9 years of median follow-up (FU) and 4190 patients, CE were observed in 363 (8.6%): 166 (7.9%) of patient in T + L arm vs. 197 (9.3%) in T arm (OR = 0.85 [95% CI, 0.68–1.05]). During anti-HER2 treatment 270 CE (6.4%) occurred while 93 (2.2%) were during FU (median time to onset = 6.6 months [IQR = 3.4–11.7]). While 265 CEs were asymptomatic (73%), 94 were symptomatic (26%) and four were cardiac deaths (1%). Recovery was observed in 301 cases (83.8%). Identified cardiac risk factors were: baseline LVEF < 55% (vs > 64%, OR 3.1 [95% CI 1.54–6.25]), diabetes mellitus (OR 1.85 [95% CI 1.25–2.75]), BMI > 30 kg/m 2 (vs < 25 mg/kg 2 , OR 2.21 [95% CI 1.40–3.49]), cumulative dose of doxorubicin ≥240 mg/m 2 (OR 1.36 [95% CI 1.01–1.82]) and of epirubicin≥ 480 mg/m 2 (OR 2.33 [95% CI 1.55–3.51]). Conclusions Dual HER2 blockade with T + L is a safe regimen from a cardiac perspective, but cardiac-focused history for proper patient selection is crucial. Trial registration number ClinicalTrials.gov Identifier: NCT00490139 (registration date: 22/06/2007); EudraCT Number: 2006–000562–36 (registration date: 04/05/2007); Sponsor Protocol Number: BIG2–06 /EGF106708/N063D.

Trastuzumab has improved the prognosis of HER2 positive breast cancer, but cardiotoxicity remains a concern. We aimed to identify risk factors for trastuzumab-induced cardiotoxicity, with an emphasis on the HER2 Ile655Val single nucleotide polymorphism. This single-center case–control study included 1056 patients with early-stage HER2 positive breast cancer that received adjuvant trastuzumab. Cardiotoxicity was defined as a decline in left ventricular ejection fraction (LVEF) > 15% in patients without previous cardiomyopathy, or > 10% in patients with baseline LVEF of < 50%. Patient characteristics and cardiac parameters were compared in 78 (7.38%) cases and 99 randomly assigned controls, and the polymorphism was genotyped using real-time polymerase chain reaction. Cardiotoxicity was independently associated with advanced age ( P  = 0.024), lower body mass index ( P  = 0.023), left breast involvement ( P  = 0.001), N3 status ( P  = 0.004), diabetes ( P  = 0.016), and a family history of coronary artery disease ( P  = 0.019). Genotype distribution was as follows: A/A (Ile/Ile) was found in 111 (62.7%) patients, A/G (Ile/Val) in 60 (33.9%) patients, and G/G (Val/Val) in 6 (3.4%) patients. The genotype was not associated with cardiotoxicity or the severity of heart failure, reversibility, and recovery time. We found no association between the HER2 Ile655Val polymorphism and trastuzumab-induced cardiotoxicity; therefore, we do not recommend routine cardiotoxicity-risk stratification using this polymorphism.

Cuproptosis resulting from copper (Cu) overload has not yet been investigated in diabetic cardiomyopathy (DCM). Advanced glycosylation end products (AGEs) induced by persistent hyperglycemia play an essential role in cardiotoxicity. To clarify whether cuproptosis was involved in AGEs-induced cardiotoxicity, we analyzed the toxicity of AGEs and copper in AC16 cardiomyocytes and in STZ-induced or db/db-diabetic mouse models. The results showed that copper ionophore elesclomol induced cuproptosis in cardiomyocytes. It was only rescued by copper chelator tetrathiomolybdate rather than by other cell death inhibitors. Intriguingly, AGEs triggered cardiomyocyte death and aggravated it when incubated with CuCl2 or elesclomol–CuCl2. Moreover, AGEs increased intracellular copper accumulation and exhibited features of cuproptosis, including loss of Fe–S cluster proteins (FDX1, LIAS, NDUFS8 and ACO2) and decreased lipoylation of DLAT and DLST. These effects were accompanied by decreased mitochondrial oxidative respiration, including downregulated mitochondrial respiratory chain complex, decreased ATP production and suppressed mitochondrial complex I and III activity. Additionally, AGEs promoted the upregulation of copper importer SLC31A1. We predicted that ATF3 and/or SPI1 might be transcriptional factors of SLC31A1 by online databases and validated that by ATF3/SPI1 overexpression. In diabetic mice, copper and AGEs increases in the blood and heart were observed and accompanied by cardiac dysfunction. The protein and mRNA profile changes in diabetic hearts were consistent with cuproptosis. Our findings showed, for the first time, that excessive AGEs and copper in diabetes upregulated ATF3/SPI1/SLC31A1 signaling, thereby disturbing copper homeostasis and promoting cuproptosis. Collectively, the novel mechanism might be an alternative potential therapeutic target for DCM.

In the present study, we explored SA’s activity against DOX-induced cardiotoxicity and revealed its underlying mechanisms. Male Wistar rats (weight, 190-210g; n=6) were randomly divided into four groups: group I, normal control; group II, DOX 15 mg/kg via intraperitoneal (ip) route; group III, administered DOX+SA 20 mg/kg; and group IV, administered DOX+captopril (CAP 30 mg/kg). SA and CAP were administered orally for seven days, and DOX (15 mg/kg) was injected intraperitoneally an hour before SA treatment on the fifth day. Forty-eight hours after DOX administration, animals were anesthetized and sacrificed for molecular and histology experiments. SA significantly mitigated the myocardial effects of DOX, and following daily administration, it reduced serum levels of lactate dehydrogenase (LDH) and creatine kinase isoenzyme-MB to near normal values. Levels of oxidative stress markers, glutathione-peroxidase, superoxide dismutase, and catalase, in the cardiac tissue were significantly increased, whereas malondialdehyde levels decreased after SA treatment in DOX-administered rats. Furthermore, DOX caused an inflammatory reaction by elevating the levels of proinflammatory cytokines, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and endothelin- (ET-) 1, as well as nuclear factor kappa-B (NF-κB) expression. Daily administration of SA significantly repressed TNF-α, IL-1β, ET-1, and NF-κB levels. caspase-3 and Bax expression, bcl-2-like protein and caspase-3 activities and levels. Overall, we found that SA could inhibit DOX-induced cardiotoxicity by inhibiting oxidative stress, inflammation, and apoptotic damage.

Clinical therapy of doxorubicin (DOX) is limited due to its cardiotoxicity. miR-146a was proved as a protective factor in many cardiovascular diseases, but its role in chronic DOX-induced cardiotoxicity is unclear. The objective of this study was to demonstrate the role of miR-146a in low-dose long-term DOX-induced cardiotoxicity. Experiments have shown that DOX intervention caused a dose-dependent and time-dependent cardiotoxicity involving the increased of apoptosis and dysregulation of autophagy. The cardiotoxicity was inhibited by overexpressed miR-146a and was more severe when miR-146a was downgraded. Further research proved that miR-146a targeted TATA-binding protein (TBP) associated factor 9b (TAF9b), a coactivator and stabilizer of P53, indirectly destroyed the stability of P53, thereby inhibiting apoptosis and improving autophagy in cardiomyocytes. Besides, miR-146a knockout mice were used for in vivo validation. In the DOX-induced model, miR-146a deficiency made it worse whether in cardiac function, cardiomyocyte apoptosis or basal level of autophagy, than wild-type. In conclusion, miR-146a partially reversed the DOX-induced cardiotoxicity by targeting TAF9b/P53 pathway to attenuate apoptosis and adjust autophagy levels.

Purpose Chemotherapeutic agents, though highly effective in eliminating tumor cells, frequently cause varying degrees of myocardial injury. Doxorubicin (DOX) is a leading extensively used anthracycline-based chemotherapy agents. The present research sought to explore the role of lncRNA FAF in chemotherapy-induced cardiotoxicity and to elucidate its regulatory function via the NLRP3-Caspase-1 axis. Methods A rat model of DOX-induced cardiac toxicity was generated by administering the drug intraperitoneally, and cardiac function in rats was subsequently evaluated by echocardiography. We assessed morphological changes in rat myocardial tissue by hematoxylin-eosin and Masson staining, and measured the expression of biomarkers associated with cardiac damage, including LDH and CK-MB, using ELISA. Proteins involved in pyroptosis (GSDMD, NLRP3, and C-Caspase-1) were evaluated through TUNEL assay, immunohistochemical staining, and Western blot experiments. Cell viability was determined using the CCK-8 assay, while pyroptosis was inspected by flow cytometry, and lncRNA FAF expression was quantified by qRT-PCR. Results DOX administration induced cardiac dysfunction, myocardial tissue structural disorders and fibrosis, as well as heightened serum concentrations of LDH and CK-MB. In both animal and cell-based experiments, DOX treatment led to a decrease in lncRNA FAF expression in cardiac myocytes, accompanied by a significantly up-regulation of NLRP3, C-Caspase-1, and GSDND-N, thereby promoting cardiomyocyte pyroptosis. In contrast, high expression of lncRNA FAF enhanced cardiac myocytes viability, inhibited pyroptosis, and down-regulated the expression of NLRP3, C-Caspase-1, and GSDND-N. Importantly, these effects were reversed by treatment with the NLRP3 agonist nigericin or the pyroptosis agonist polyphyllin VI in cardiomyocytes treated with lncRNA FAF overexpression. Conclusion lncRNA FAF alleviates DOX-induced cardiomyocyte injury by enhancing cardiomyocyte viability and suppressing pyroptosis by targeting the NLRP3-Caspase-1 axis.

Doxorubicin (DOX) could trigger congestive heart failure, which largely limited the clinical use of DOX. microRNAs (miRNAs) were closely involved in the pathogenesis of DOX-induced cardiomyopathy. Here, we aimed to investigate the effect of miR-152 on DOX-induced cardiotoxicity in mice. To study this, we used an adeno-associated viral vector to overexpress miR-152 in mice 6 weeks before DOX treatment, using a dose mimicking the concentrations used in the clinics. In response to DOX injection, miR-152 was significantly decreased in murine hearts and cardiomyocytes. After DOX treatment, mice with miR-152 overexpression in the hearts developed less cardiac dysfunction, oxidative stress, inflammation, and myocardial apoptosis. Furthermore, we found that miR-152 overexpression attenuated DOX-related oxidative stress, inflammation, and cell loss in cardiomyocytes, whereas miR-152 knockdown resulted in oxidative stress, inflammation, and cell loss in cardiomyocytes. Mechanistically, this effect of miR-152 was dependent on the activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in response to DOX. Notably, Nrf2 deficiency blocked the protective effects of miR-152 against DOX-related cardiac injury in mice. In conclusion, miR-152 protected against DOX-induced cardiotoxicity via the activation of the Nrf2 signaling pathway. These results suggest that miR-152 may be a promising therapeutic target for the treatment of DOX-induced cardiotoxicity.

Abstract Background BRCA1/2 genes play a critical role in genome stability and DNA repair. In animal models, loss of cardiomyocyte-specific BRCA1/2 is associated with DNA damage, apoptosis, cardiac dysfunction, and mortality following anthracycline exposure. However, whether these preclinical findings translate to humans remains unclear. Objective Assess the impact of germline BRCA1/2 (gBRCA1/2) status on anthracyclines-induced cardiotoxicity (AIC) in patients with early breast cancer and no prior anti-HER2 therapy. Methods This single-center retrospective/prospective cohort study focused on early breast cancer patients, treated with anthracycline-based chemotherapy in the neo/adjuvant setting, no prior anti-HER2 therapy, and known gBRCA1/2 status, normal baseline left ventricular ejection fraction (LVEF), and no previous cardiovascular disease. Follow-up assessments involved myocardial dysfunction blood biomarkers (MDBB), transthoracic echocardiography (TTE), and quality of life (QoL) questionnaires. The primary objective was LVEF changes comparing BRCA1/2 mutation carriers (gBRCA1/2m) vs non-carriers (gBRCA1/2wt). Secondary objectives included differences in MDBB and QoL. Results A total of 137 patients were included (103 gBRCA1/2wt and 34 gBRCA1/2m). Baseline characteristics were similar between groups. Compared to baseline, LVEF% reduction was −4.7[−12.0, 0.0] vs −9.5[−18.0, −5.0] in gBRCA1/2wt vs gBRCA1/2m, (P = .027). After adjusting for confounders, the difference in reduction in LVEF remained statistically significant at −4.5 [95%CI, −8.6, −0.4; P = .032]. No differences between MDBB (C-reactive protein, hsTnI, NT-proBNP, D-Dimer, ST-2, or Galectine-3) or QoL (MLHFQ and EQ5-D index) were detected. Conclusions gBRCA1/2m patients could represent a higher-risk population for AIC. gBRCA1/2 status should be one of the factors to consider in deciding on adjuvant anthracycline necessity. This population could benefit from a cardio-oncology closer follow-up and cardioprotective strategies. Graphical Abstract Graphical Abstract

Anthracycline-induced cardiotoxicity (AIC) persists as a significant cause of morbidity and mortality in cancer survivors. Although many protective strategies have been evaluated, cardiotoxicity remains an ongoing threat. The mechanisms of AIC remain unclear; however, several pathways have been proposed, suggesting a multifactorial origin. When the central role of topoisomerase 2β in the pathophysiology of AIC was described some years ago, the classical reactive oxygen species (ROS) hypothesis shifted to a secondary position. However, new insights have reemphasized the importance of the role of oxidative stress-mediated signaling as a common pathway and a critical modulator of the different mechanisms involved in AIC. A better understanding of the mechanisms of cardiotoxicity is crucial for the development of treatment strategies. It has been suggested that the available therapeutic interventions for AIC could act on the modulation of oxidative balance, leading to a reduction in oxidative stress injury. These indirect antioxidant effects make them an option for the primary prevention of AIC. In this review, our objective is to provide an update of the accumulated knowledge on the role of oxidative stress in AIC and the modulation of the redox balance by potential preventive strategies.

Doxorubicin (DOX) is an anthracycline chemotherapeutic drug used for tumour treatment. Due to DOX‐induced cardiotoxicity (DIC), its clinical application has been widely limited. Multiple studies have shown that ferroptosis is involved in the pathogenesis of DIC and that arachidonate 5‐lipoxygenase (Alox5) plays an important role in the occurrence and development of ferroptosis. The aim of this study was to provide evidence that silencing Alox5 alleviated DIC by affecting ferroptosis and identify mechanisms. Acute models of DIC were established in wild‐type (WT) C57BL/6 and Alox5‐deficient (Alox5 KO) mice and neonatal rat ventricular myocytes (NRVMs). Alox5 was upregulated in vivo and in vitro during DIC. Subsequently, we overexpressed the Alox5 gene in adult mice using a recombinant adenovirus expression vector (rAAV9). Compared with that in WT mice, overexpressing Alox5 accelerated DOX‐induced myocardial injury and cardiac dysfunction. This finding was also confirmed in vitro. In contrast, silencing the Alox5 gene protected against myocardial injury in the DIC model and reduced ferroptosis and inflammation, and this effect was confirmed in vitro. In addition, transcriptomics and GO enrichment analysis of adult mouse cardiomyocytes showed that Alox5 could ameliorate DIC by inhibiting ferroptosis and inflammation. Moreover, P53 was identified as a target of Alox5. Subsequently, in vivo and in vitro experiments showed that silencing Alox5 could alleviate ferroptosis and inflammation. Further in vivo and in vitro experiments demonstrated that dexrazoxane (DXZ) could ameliorate DIC caused by Alox5 overexpression by alleviating ferroptosis. Mechanistically, silencing Alox5 could reduce reactive oxygen species (ROS) production through the P53/SLC7A11 pathway. Furthermore, P53 inhibitors significantly inhibited the adverse effects of Alox5 overexpression on DIC. The final experiment showed that pharmacological inhibition of Alox5 could prevent DIC in vivo and in vitro. Our study showed that the downregulation of Alox5 alleviated myocardial damage associated with DIC via the P53/SLC7A11 pathway. Therefore, inhibiting Alox5 might be a potential strategy for the treatment of DIC.