Search Results (17)

Cardiotoxicity related to anthracyclines and trastuzumab represents a significant clinical challenge in cancer therapy, often limiting treatment efficacy and patient survival. The underlying mechanisms of cardiotoxicity involve the activation of NLRP3 and the MyD88-dependent signaling pathway. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), such as inclisiran, are known for their lipid-lowering effects, but emerging data indicate that they may also exert pleiotropic benefits beyond cholesterol reduction. This study investigates whether inclisiran can mitigate the cardiotoxic effects of anthracyclines and trastuzumab through reduction of NLRP3 activation and MyD88 signaling, independently of its effects on dyslipidemia. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were exposed to subclinical concentrations of doxorubicin (1 µM) and trastuzumab in sequential therapy (200 nM), alone or in combination with inclisiran (100 nM) for 24 h. After the incubation period, we performed the following tests: determination of cardiomyocytes apoptosis, analysis of intracellular reactive oxygen species, lipid peroxidation products (including malondialdehyde and 4-hydroxynonenal), intracellular mitofusin-2 and Ca⁺⁺ levels. Troponin and BNP were quantified through selective ELISA methods. A confocal laser scanning microscope was used to study cardiomyocyte morphology and F-actin staining after treatments. Moreover, pro-inflammatory studies were also performed, including the intracellular expression of NLRP-3, MyD-88 and twelve cytokines/growth factors involved in cardiotoxicity (IL-1α, IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12, IL17-α, IFN-γ, TNF-α, G-CSF, GM-CSF). Inclisiran co-incubated with doxorubicin and trastuzumab exerts significant cardioprotective effects, enhancing cell viability by 88.9% compared to only DOXO/TRA treated cells (p < 0.001 for all). Significant reduction of oxidative stress, and intracellular levels of NLRP-3, MyD88, IL-1α, IL-1β, IL-6, IL-12, IL17-α, TNF-α, G-CSF were seen in the inclisiran group vs. only DOXO/TRA (p < 0.001). For the first time, PCSK9i inclisiran has been shown to exert significant anti-inflammatory effects to reduce anthracycline-HER-2 blocking agent-mediated cardiotoxicity through NLRP-3 and Myd-88 related pathways. The overall conclusions of the study warrant further investigation of the use of PCSK9i in primary prevention of CTRCD in cancer patients, independently from dyslipidemia. Full article

Certain anticancer therapies inevitably increase the risk of cardiovascular events, now the second leading cause of death among cancer patients. This underscores the critical need for developing effective drugs or regimens for cardiovascular protection. Statins possess properties such as antioxidative stress, anti-inflammatory effects, antifibrotic activity, endothelial protection, and immune modulation. These pathological processes are central to the cardiotoxicity associated with anticancer treatment. There is prospective clinical evidence confirming the protective role of statins in chemotherapy-induced cardiotoxicity. Numerous preclinical studies have demonstrated that statins can ameliorate heart and endothelial damage caused by radiotherapy, although clinical studies are scarce. In the animal models of trastuzumab-induced cardiomyopathy, statins provide protection through anti-inflammatory, antioxidant, and antifibrotic mechanisms. In animal and cell models, statins can mitigate inflammation, endothelial damage, and cardiac injury induced by immune checkpoint inhibitors. Chimeric antigen receptor (CAR)-T cell therapy-induced cardiotoxicity and immune effector cell-associated neurotoxicity syndrome are associated with uncontrolled inflammation and immune activation. Due to their anti-inflammatory and immunomodulatory effects, statins have been used to manage CAR-T cell therapy-induced immune effector cell-associated neurotoxicity syndrome in a clinical trial. However, direct evidence proving that statins can mitigate CAR-T cell therapy-induced cardiotoxicity is still lacking. This review summarizes the possible mechanisms of anticancer therapy-induced cardiotoxicity and the potential mechanisms by which statins may reduce related cardiac damage. We also discuss the current status of research on the protective effect of statins in anticancer treatment-related cardiovascular disease and provide directions for future research. Additionally, we propose further studies on using statins for the prevention of cardiovascular disease in anticancer treatment. Full article

Trastuzumab, a monoclonal antibody which works against human epidermal growth factor receptor 2 (HER2), possibly causes cardiotoxicity through mitochondrial dysfunction. The usefulness of isolated peripheral blood mononuclear cells (PBMCs) in the assessment of trastuzumab-induced cardiotoxicity remains uncertain. This study aimed to determine the temporal changes in mitochondrial function, oxidative stress, and cell death in the isolated PBMCs of HER2-positive breast cancer patients during breast cancer treatment and to compare the changes with HER2-negative breast cancer patients who did not receive trastuzumab therapy. Eighteen newly diagnosed HER2-positive breast cancer women who received sequential doxorubicin and trastuzumab were consecutively recruited. Age- and gender-matched controls with HER2-negative breast cancer were selected. Echocardiography was carried out, and blood samples for the study of cardiac biomarkers and PBMCs were collected periodically during treatment. Only one patient in our cohort developed asymptomatic left ventricular dysfunction during trastuzumab treatment. However, trastuzumab following doxorubicin aggravated subclinical cardiac injury, determined by cardiac troponin and echocardiography. Cellular and mitochondrial oxidative stress in isolated PBMCs remained unchanged throughout breast cancer treatment. Regarding mitochondrial respiration, the maximal respiration and spare respiration capacity was significantly increased in controls after doxorubicin treatment but not in patients who received trastuzumab therapy. Moreover, the percentage of apoptosis and necroptosis in isolated PBMCs was dramatically decreased in the control, compared to patients with trastuzumab treatment. In conclusion, trastuzumab caused subtle myocardial injury and impaired mitochondrial respiration and cell viability in isolated PBMCs. Full article

Cardiovascular diseases are a leading cause of mortality in the United States. The increasing number of cancer patients experiencing cardiovascular side effects from chemotherapeutic drugs is a cause for concern. Trastuzumab is a highly effective targeted therapy for HER2-positive cancers but its use is limited globally due to its cardiotoxic effects. The most severe adverse effect is cardiomyopathy, which is characterized by contractile dysfunction and reduced left ventricular systolic function. The electrophysiological side effects of trastuzumab are still not fully understood. Due to these life-threatening side effects, trastuzumab is routinely discontinued. This review aims to provide a comprehensive overview of trastuzumab-induced cardiomyopathy, including the mechanisms by which trastuzumab exerts its cardiotoxic effects, the clinical manifestations, diagnostic strategies, and potential interventions to protect the heart. By shedding light on the various aspects of this condition, we hope to emphasize the importance of early detection and effective management, as well as the urgent need for further research to optimize the balance between successful cancer treatment and cardiovascular well-being. Cardiologists, oncologists, and researchers are at the forefront of this critical intersection between oncology and cardiology, working collaboratively to enhance patient outcomes in the era of trastuzumab therapy. Full article

Background: During the physiological cardiac cycle, the helix orientation of the muscle fibres induces the rotation of the apex relative to the base of the left ventricular (LV). In heart failure, LV torsion is impaired, and rotation at basal and apical levels occurs in the same direction, a phenomenon called rigid body rotation (RBR). We aimed to evaluate whether the RBR pattern and GLS together could improve the diagnosis of cardiotoxicity in patients treated with anthracyclines and/or anti-HER2. Methods: With an observational, retrospective study involving 175 patients (mean age 55 ± 12 years, 94% females), we evaluated the development of cancer therapeutic–related cardiac dysfunction (CTRCD) defined according to ESC guidelines. We characterised LV dysfunction by echocardiographic standard and speckle-tracking (GLS and RBR pattern) measurements. Patients with a previous diagnosis of structural heart disease or atrial fibrillation were excluded. Results: At the time of enrolment, the chemotherapy regimen included trastuzumab (96%), pertuzumab (21%), and anthracyclines (13%). Twenty-two patients (12.5%) developed cardiotoxicity, and thirteen patients developed an RBR within 6 months of follow-up. In all cases, the RBR pattern was associated with cardiotoxicity (p < 0.001), reporting an optimal specificity but poor sensitivity at three and six months. However, the addition of the RBR pattern to the global longitudinal strain (GLS) ≥ −16% increased the odds ratio (OR) from 25.6 to 32.6 at three months and from 32.5 to 49.6 at six months rather than GLS alone. Conclusions: The RBR pattern improves the diagnostic accuracy of GLS for the detection of cardiotoxicity secondary to anthracyclines and anti-HER2-based treatments. Full article

Trastuzumab is the primary treatment for all stages of HER2-overexpressing breast cancer in patients. Though discovered over 20 years ago, trastuzumab-induced cardiotoxicity (TIC) remains a research topic in cardio-oncology. This review explores the pathophysiological basis of TIC and its clinical manifestations. Their understanding is paramount for early detection and cardioprotective treatment. Trastuzumab renders cardiomyocytes susceptible by inhibiting the cardioprotective NRG-1/HER2/HER4 signaling pathway. The drug acts on HER2-receptor-expressing cardiomyocytes, endothelium, and cardiac progenitor cells (see the Graphical Abstract). The activation of immune cells, fibroblasts, inflammation, and neurohormonal systems all contribute to the evolution of TIC. A substantial amount of research demonstrates that trastuzumab induces overt and subclinical left ventricular (LV) systolic failure. Data suggest the development of right ventricular damage, LV diastolic dysfunction, and heart failure with preserved ejection fraction. Further research is needed to define a chronological sequence of cardiac impairments to guide the proper timing of cardioprotection implementation. Full article

There are significant considerations about the prevention of cardiotoxicity caused by trastuzumab therapy in patients with breast cancer, leading to discontinuation. Recently, randomized controlled trials (RCTs) have evaluated the effects of early commitment of beta-blockers (BBs), angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) during trastuzumab chemotherapy in order to prevent the related cardiotoxicity. The present systematic review and meta-analysis of six RCTs included patients who have predominantly non-metastatic, HER2-positive, breast cancer and received trastuzumab as primary or adjuvant therapy. Those patients did not have any obvious cardiac dysfunction or any previous therapy with cardioprotective agent. We evaluated the efficacy of the aforementioned medications for primary prevention of cardiotoxicity, using random effects models. Any preventive treatment did not reduce cardiotoxicity occurrence compared to controls (Odds ratios (OR) = 0.92, 95% CI 0.54–1.56, p = 0.75). Results were similar for ACEIs/ARBs and beta-blockers. Treatment with ACEIs/ARBs led to a slight, but significant, increase in LVEF in patients compared to the placebo group. Only two studies reported less likelihood of discontinuation of trastuzumab treatment. More adequately powered RCTs are needed to determine the efficacy of routine prophylactic therapy. Full article

Trastuzumab-induced cardiotoxicity (TIC) can lead to early treatment discontinuation. The aim of this study was to evaluate: N-terminal brain natriuretic peptide (NT-proBNP), creatine kinase-MB (CK-MB), myoglobin, and selected biochemical and clinical factors as predictors of TIC. One hundred and thirty patients with HER2-positive BC receiving adjuvant trastuzumab therapy (TT) were enrolled. Measurement of cardiac markers and biochemical tests as well as echocardiography were performed prior to TT initiation and every three months thereafter. Cardiotoxicity leading to treatment interruption occurred in 24 patients (18.5%). While cardiotoxicity caused early treatment discontinuation in 14 patients (10.8%), the TIC resolved in 10 (7.7%) and TT was resumed. The most common complication was a decrease in left ventricular ejection fraction of more than 10% from baseline or below 50% (7.7%). In patients with TIC, there was no increase in the levels of NT-proBNP, myoglobin, and CK-MB. BMI, hypertension, ischemic heart disease, diabetes, age, cancer stage, type of surgery, use of radiotherapy, chemotherapy, and hormone therapy were shown to not have an effect on TIC occurrence. NT-proBNP, myoglobin, and CK-MB are not predictors of TIC. There is an ongoing need to identify biomarkers for TIC. Full article

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer. Full article

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancer cases, causing a more aggressive tumour growth and poor prognosis. Trastuzumab, the humanized antibody targeted to HER2, increased the life expectancy of patients, but severe cardiotoxicity emerged as a long-term adverse effect. Clinical evidence highlights that Trastuzumab-induced cardiotoxicity drastically increases in association with Doxorubicin; however, the exact mechanisms involved remain incompletely understood. In order to analyse the molecular mechanisms involved and the possible adaptative responses to Trastuzumab and Doxorubicin treatment, in this study, H9c2 cardiomyoblasts were used. Results showed that Trastuzumab and Doxorubicin sequential administration in cardiomyoblast increased cytosolic and mitochondrial ROS production, intracellular calcium dysregulation, mitochondrial membrane depolarization, and the consequent apoptosis, induced by both Trastuzumab and Doxorubicin alone. Furthermore, in these conditions, we observed increased levels of Connexin43 phosphorylated on Ser368 (pCx43). Since phosphorylation on Ser368 decreases gap junction intracellular communication, thus reducing the spread of death signals to adjacent cells, we hypothesized that the increase in pCx43 could be an adaptative response implemented by cells to defend neighbouring cells by Trastuzumab and Doxorubicin sequential administration. However, the other side of the coin is the resulting conduction abnormalities. Full article

Trastuzumab (Trz) is a humanized monoclonal antibody targeting epidermal growth factor receptor 2 (HER2; ErbB2). The combined administration of Trz and doxorubicin (DOX) has shown potent anti-cancer efficacy; however, this regimen may be accompanied by severe cardiac toxicity. Mesenchymal stem cells (MSCs)-derived exosomes are nanosized vesicles that play a crucial role in cell–cell communication and have shown efficacy in the treatment of various diseases. In this study, we aim to investigate the cardioprotective effects of MSCs-derived exosomes in a DOX/Trz- mediated cardiotoxicity model, and the possible mechanisms underlying these effects are elucidated. Forty-nine male rats were randomly assigned into four groups: Group I (control); Group II (Dox/Trz); Group III (protective group); and Group IV (curative group). Cardiac hemodynamic parameters, serum markers of cardiac injury, oxidative stress indices, and cardiac histopathology were investigated. Further, transcript profile of specific cardiac tissue injury markers, apoptotic markers, and fibrotic markers were analyzed using qRT-PCR, while the protein expressions of pAkt/Akt, pERK/ERK, pJNK/JNK, pJNK/JNK, and pSTAT3/STAT3 were evaluated by ELISA. Additionally, cardiac mirR-21 and miR-26a were assessed. A combined administration of DOX/Trz disrupted redox and Ca²⁺ homeostasis in cardiac tissue induced myocardial fibrosis and myofibril loss and triggered cardiac DNA damage and apoptosis. This cardiotoxicity was accompanied by decreased NRG-1 mRNA expression, HER2 protein expression, and suppressed AKT and ERK phosphorylation, while triggering JNK phosphorylation. Histological and ultra-structural examination of cardiac specimens revealed features typical of cardiac tissue injury. Moreover, a significant decline in cardiac function was observed through biochemical testing of serum cardiac markers and echocardiography. In contrast, the intraperitoneal administration of MSCs-derived exosomes alleviated cardiac injury in both protective and curative protocols; however, superior effects were observed in the protective protocol. The results of the current study indicate the ability of MSCs-derived exosomes to protect from and attenuate DOX/Trz-induced cardiotoxicity. The NRG-1/HER2, MAPK, PI3K/AKT, PJNK/JNK, and PSTAT/STAT signaling pathways play roles in mediating these effects. Full article

Background: Two anti-cancer agents, doxorubicin (DOX) and trastuzumab (TRZ), are commonly used in the management of breast cancer in women. Despite their efficacy in reducing the morbidity and mortality of individuals with breast cancer, the use of these agents is limited by adverse cardiotoxic side effects. Both the nutraceutical agent flaxseed (FLX) and the pharmaceutical drug perindopril (PER) have been studied individually in the prevention of chemotherapy-mediated cardiac dysfunction. The objective of this study was to determine whether the prophylactic administration of FLX is comparable and/or synergistic with PER in preventing DOX + TRZ-induced cardiotoxicity. Methods: Over a six-week period, 81 wild-type C57Bl/6 female mice (8–12 weeks old) were randomized to receive regular chow (RC) or 10% FLX-supplemented diets with or without PER (3 mg/kg/week; oral gavage). Starting at week 4, mice were randomized to receive a weekly injection of saline or DOX (8 mg/kg) + TRZ (3 mg/kg). Serial echocardiography was conducted weekly and histological and biochemical analyses were performed at the end of the study. Results: In mice treated with RC + DOX + TRZ, left ventricular ejection (LVEF) decreased from 75 ± 2% at baseline to 37 ± 3% at week 6. However, prophylactic treatment with either FLX, PER, or FLX + PER partially preserved left ventricular systolic function with LVEF values of 61 ± 2%, 62 ± 2%, and 64 ± 2%, respectively. The administration of FLX, PER, or FLX + PER was also partially cardioprotective in preserving cardiomyocyte integrity and attenuating the expression of the inflammatory biomarker NF-κB due to DOX + TRZ administration. Conclusion: FLX was equivalent to PER at preventing DOX + TRZ-induced cardiotoxicity in a chronic in vivo murine model. Full article

Cancer-therapeutics-related cardiac dysfunction (CTRCD) is an important concern in women receiving trastuzumab therapy for HER2+ breast cancer. However, the ability to assess CTRCD risk remains limited. In this retrospective cohort study, we apply three published risk prediction models (Ezaz et al., NSABP-31 cardiac risk scores (CRS), and HFA-ICOS trastuzumab proforma) to 629 women (mean age 52.4 ± 10.9 years) with Stage I-III HER2+ breast cancer treated with trastuzumab ± anthracyclines to assess their performance to identify CTRCD during or immediately post treatment. Using these models, patients were classified into CTRCD risk categories according to the pre-treatment characteristics. With NSABP-31 CRS and HFA-ICOS proformas, patients in the highest risk category had a 1.7-to-2.4-fold higher relative risk of CTRCD than the low-risk category (p = 0.010 and 0.005, respectively). However, with all three risk models, those in the low-risk category had a high absolute risk of CTRCD (15.5–25.5%). The discrimination of the models for CTRCD (AUC 0.51–0.60) and their calibration was limited. NSAP-31 CRS and HFA-ICOS proformas can identify relative differences in CTRCD risk between patients, but when considering absolute risk, they are only able to identify the highest risk patients. There remains an ongoing need for accurate CTRCD risk prediction models in women with HER2+ breast cancer. Full article

Long-term cardiovascular complications of cancer therapy are becoming ever more prevalent due to increased numbers of cancer survivors. Cancer therapy-induced cardiotoxicity (CTIC) is an incompletely understood consequence of various chemotherapies, targeted anti-cancer agents and radiation therapy. It is typically detected clinically by a reduction in cardiac left ventricular ejection fraction, assessed by echocardiography. However, once cardiac functional decline is apparent, this indicates irreversible cardiac damage, highlighting a need for the development of diagnostics which can detect CTIC prior to the onset of functional decline. There is increasing evidence to suggest that pathological alterations to cardiac metabolism play a crucial role in the development of CTIC. This review discusses the metabolic alterations and mechanisms which occur in the development of CTIC, with a focus on doxorubicin, trastuzumab, imatinib, ponatinib, sunitinib and radiotherapy. Potential methods to diagnose and predict CTIC prior to functional cardiac decline in the clinic are evaluated, with a view to both biomarker and imaging-based approaches. Finally, the therapeutic potential of therapies which manipulate cardiac metabolism in the context of adjuvant cardioprotection against CTIC is examined. Together, an integrated view of the role of metabolism in pathogenesis, diagnosis and treatment is presented. Full article

Monoclonal antibodies including trastuzumab, pertuzumab, and antibody-drug conjugates, form the backbone of HER2-positive breast cancer therapy. Unfortunately, an important adverse effect of these agents is cardiotoxicity, occurring in approximately 10% of patients. There is increasing published data regarding prevention strategies for cardiotoxicity, though seldom used in clinical practice. We performed a systematic review and meta-analysis of randomized-controlled trials to evaluate pharmacotherapy for the prevention of monoclonal HER2-directed antibody-induced cardiotoxicity in patients with breast cancer. Online databases were queried from their inception until October 2021. Effects were determined by calculating risk ratios (RRs) and 95% confidence intervals (CI) or mean differences (MD) using random-effects models. We identified five eligible trials. In the three trials (n = 952) reporting data on the primary outcome of cardiotoxicity, there was no clear effect for patients assigned active treatment compared to control (RR = 0.90, 95% CI 0.63 to 1.29, p = 0.57). Effects were similar for ACE-I/ARB and beta-blockers (p homogeneity = 0.50). Active treatment reduced the risk of HER2 therapy interruptions (RR = 0.57, 95% CI 0.43 to 0.77, p < 0.001) with similar findings for ACE-I/ARB and beta-blockers (p homogeneity = 0.97). Prophylactic treatment with ACE-I/ARB or beta-blocker therapy may be of value for cardio-protection in patients with breast cancer prescribed monoclonal antibodies. Further, adequately powered randomized trials are required to define the role of routine prophylactic treatment in this patient group. Full article