Role of Early Left Atrial Functional Decline in Predicting Cardiotoxicity in HER2 Positive Breast Cancer Patients Treated With Trastuzumab.

Trastuzumab is widely used in HER2 breast cancer. However, it may cause left ventricular (LV) dysfunction. A decrease in LV global longitudinal strain (GLS) has been previously demonstrated to be a good predictor of subsequent cancer therapy related dysfunction (CTRCD). Left atrial morphological remodeling during Trastuzumab therapy has also been shown. The aim of this study is exploring the relationship between early changes in left atrial function and the development of Trastuzumab-induced cardiotoxicity. Consecutive patients with diagnosis of HER2+non-metastatic breast cancer treated with Trastuzumab were prospectively enrolled. A clinical, conventional, and advanced echocardiographic assessment was performed at baseline and every three months, until a one-year follow-up was reached. One-hundred-sixteen patients completed the 12 months follow-up, 10 (9%) cases of CTRCD were observed, all after the sixth month. GLS and LVEF significantly decreased in the CTRCD group at 6 months of follow-up, with an earlier (3 months) significant worsening in left atrial morpho-functional parameters. Systolic blood pressure, early peak atrial longitudinal strain (PALS), peak atrial contraction (PACS) and left atrial volume (LAVI) changes resulted independent predictors of CTRCD at multivariable logistic regression analysis. Moreover, early changes in PALS and PACS resulted good predictors of CTRCD development (AUC 0.85; p = 0.008, p < 0.001 and 0.77; p = 0.008, respectively). This prospective study emphasizes that the decline in PALS and PACS among trastuzumab-treated patients could possibly increase the accuracy in identifying future CTRCD in non-metastatic HER2 breast cancer cases, adding predictive value to conventional echocardiographic assessment.

Beneficial Effects of Oral Carbon Monoxide on Doxorubicin-Induced Cardiotoxicity.

BACKGROUND: Doxorubicin and other anthracyclines are crucial cancer treatment drugs. However, they are associated with significant cardiotoxicity, severely affecting patient care and limiting dosage and usage. Previous studies have shown that low carbon monoxide (CO) concentrations protect against doxorubicin toxicity. However, traditional methods of CO delivery pose complex challenges for daily administration, such as dosing and toxicity. To address these challenges, we developed a novel oral liquid drug product containing CO (HBI-002) that can be easily self-administered by patients with cancer undergoing doxorubicin treatment, resulting in CO being delivered through the upper gastrointestinal tract. METHODS AND RESULTS: HBI-002 was tested in a murine model of doxorubicin cardiotoxicity in the presence and absence of lung or breast cancer. The mice received HBI-002 twice daily before doxorubicin administration and experienced increased carboxyhemoglobin levels from a baseline of ≈1% to 7%. Heart tissue from mice treated with HBI-002 had a 6.3-fold increase in CO concentrations and higher expression of the cytoprotective enzyme heme oxygenase-1 compared with placebo control. In both acute and chronic doxorubicin toxicity scenarios, HBI-002 protected the heart from cardiotoxic effects, including limiting tissue damage and cardiac dysfunction and improving survival. In addition, HBI-002 did not compromise the efficacy of doxorubicin in reducing tumor volume, but rather enhanced the sensitivity of breast 4T1 cancer cells to doxorubicin while simultaneously protecting cardiac function. CONCLUSIONS: These findings strongly support using HBI-002 as a cardioprotective agent that maintains the therapeutic benefits of doxorubicin cancer treatment while mitigating cardiac damage.

Betaine Protects Mice from Cardiotoxicity Triggered by Sodium Arsenite Through Antioxidative and Anti-inflammatory Pathways.

NaAsO2 is known as a harmful pollutant all over the world, and many chronic heart diseases can be attributed to its prolonged exposure in NaAsO2-contaminated water. Therefore, considering the anti-inflammatory and antioxidant effects of betaine (BET), in this study, our team investigated the cardioprotective effects of this phytochemical agent on sodium arsenite (NaAsO2)-induced cardiotoxicity. Forty male mice were randomly divided into 4 groups: (I) Control; (II) BET (500 mg/kg); (III) NaAsO2 (50 ppm); and (IV) NaAsO2 + BET. NaAsO2 was given to the animals for 8 weeks, but BET was given in the last two weeks. After decapitation, inflammatory factors and biochemical parameters were measured, and Western blot analyses were performed. BET decrease the activity level of alanine aspartate aminotransferase, creatine kinase MB, thiobarbituric acid reactive substances level, inflammatory factors (tumor necrosis factor-α) content, and nuclear factor kappa B expression. Furthermore, BET increased cardiac total thiol and activity levels of catalase, superoxide dismutase, and glutathione peroxidase and nuclear factor erythroid-2 expression. Hence, the administration of BET ameliorated the deleterious effects stemming from the imbalance of oxidative and antioxidant pathways and histopathological alterations observed in NaAsO2-intoxicated mice, thereby attenuating oxidative stress-induced damage and inflammation.

Assessment of Native Myocardial T1 Mapping for Early Detection of Anthracycline-Induced Cardiotoxicity in Patients with Cancer: a Systematic Review and Meta-analysis.

Anthracycline antibiotic is one of the most effective anti-tumor drugs used to manage certain types of breast cancers, lymphomas, and leukemias. However, anthracyclines induce a dose-dependent cardiotoxicity that may progress to heart failure. Thus, using a sensitive predictor of early cardiac dysfunction in patients treated with anthracyclines can help detect subclinical cardiac dysfunction early and help initiate interventions to protect these patients. Among parameters of myocardial measure, cardiac magnetic resonance (CMR)-measured native myocardial T1 mapping is considered a sensitive and accurate quantitative measure of early subclinical cardiac changes, particularly cardiac inflammation and fibrosis. However, to understand the quality and the validity of the current evidence supporting the use of these measures in patients treated with anthracyclines, we aimed to conduct a systematic review of clinical studies of this measure to detect early myocardial changes in cancer patients treated with anthracyclines. The primary outcome was the level of native T1 mapping. We performed fixed-effects meta-analyses and assessed certainty in effect estimates. Of the 1780 publications reviewed (till 2022), 23 were retrieved, and 9 articles met the inclusion criteria. Our study showed that exposure to anthracycline was associated with a significant elevation of native myocardial T1 mapping from baseline (95% CI 0.1121 to 0.5802; p = 0.0037) as well as compared to healthy control patients (95% CI 0.2925 to 0.7448; p < 0.0001). No significant publication bias was noted on the assessment of the funnel plot and Egger's test. According to the Q test, there was no significant heterogeneity in the included studies (I2 = 0.0000% versus healthy controls and I2 = 14.0666% versus baseline). Overall, our study suggests that native myocardial T1 mapping is useful for detecting anthracycline-induced cardiotoxicity in patients with cancer.

Early myocardial injury in children on doxorubicin for cancer chemotherapy: a cross-sectional study in a tertiary referral centre in Kenya.

INTRODUCTION: Use of doxorubicin, an anthracycline chemotherapeutic agent has been associated with late-occurring cardiac toxicities. Detection of early-occurring cardiac effects of cancer chemotherapy is essential to prevent occurrence of adverse events including toxicity, myocardial dysfunction, and death. OBJECTIVE: To investigate the prevalence of elevated cardiac troponin T (cTnT) and associated factors of myocardial injury in children on doxorubicin cancer chemotherapy. METHODS: Design: A cross-sectional study. SETTING AND SUBJECTS: A hospital-based study conducted on children aged 1-month to 12.4-years who had a diagnosis of cancer and were admitted at Kenyatta National Hospital (KNH). INTERVENTIONS AND OUTCOMES: The patients underwent Echocardiography (ECHO) before their scheduled chemotherapy infusion. Twenty-four (24) hours after the chemotherapy infusion the patients had an evaluation of the serum cardiac troponin T (cTnT) and a repeat ECHO. Myocardial injury was defined as cTnT level > 0.014 ng/ml or a Fractional Shortening (FS) of < 29% on ECHO. RESULTS: One hundred (100) children were included in the final analysis. Thirty-two percent (32%) of the study population had an elevated cTnT. A cumulative doxorubicin dose of > 175 mg/m2 was significantly associated with and elevated cTnT (OR, 10.76; 95% CI, 1.18-97.92; p = 0.035). Diagnosis of nephroblastoma was also associated with an elevated cTnT (OR, 3.0; 95% CI, 1.23-7.26) but not statistically significant (p = 0.105). Nine percent (9%) of the participants had echocardiographic evidence of myocardial injury. CONCLUSION: When compared to echocardiography, elevated levels of cTnT showed a higher association with early-occurring chemotherapy-induced myocardial injury among children on cancer treatment at a tertiary teaching and referral hospital in Kenya.

Anabolic-Androgenic Steroid Abuse Causes Cardiac Dysfunction.

This article aims to review available literature evidence about the harmful effects of long-term anabolic-androgenic steroid (AAS) abuse on the heart. A review of 11 existing literature articles regarding this association has been used in the development of this review article. There is increasing medical literature documentation of the eventual harmful effect of AAS misuse or abuse on the heart. Individuals who misuse these steroids are susceptible to significant debilitation and loss of productive person-hours, and in severe cases, it can lead to death. Raising awareness about this potentially deleterious effect of anabolic steroids is crucial to prevent its misuse or abuse.

Inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by astragalus polysaccharide protects against transport stress-induced cardiac injury in chicks.

Transport stress (TS) not only weakens poultry performance but also affects animal welfare. Additionally, TS can evoke cardiac damage by triggering sterile inflammation in chicks, but the underlying mechanism is not fully understood. Here, we aimed to elucidate how TS induces sterile inflammation and heart injury and to clarify the antagonism effect of astragalus polysaccharides (APS). We randomly divided 60 chicks (one-day-old female) into 5 groups (n = 12): Control_0h (Con_0h) group (chicks were slaughtered at initiation), Control group (stress-free control), TS group (simulated TS exposure for 8 h), TS plus water (TS+W) group, and TS plus APS (TS+APS) group. Before simulation transport, the chicks of TS+W and TS+APS groups were, respectively, dietary with 100 µL of water or APS (250 µg/mL). H&E staining was employed for cardiac histopathological observation. ELISA assay was used to measure oxidative stress marker levels (GSH, GPX, GST, and MDA). A commercial kit was used to isolate the mitochondrial portion, and qRT-PCR was employed to measure the mitochondrial DNA (mtDNA) levels. Furthermore, we evaluated the activity of mtDNA-mediated NF-κB, NLRP3 inflammasome, and cGAS-STING inflammatory pathways and the expression of downstream inflammatory factors by Western Blotting or qRT-PCR. Our findings revealed that APS notably relieved TS-induced myocardial histopathological lesions and infiltrations. Likewise, the decrease in proinflammatory factors (TNF-α, IL-1ß, and IL-6) and IFN-ß by APS further supported this result. Meanwhile, TS caused severe oxidative stress in the chick heart, as evidenced by decreased antioxidant enzymes and increased MDA. Importantly, APS prevented mtDNA stress and leakage by reducing oxidative stress. Interestingly, TS-induced mtDNA leakage caused a series of inflammation events via mtDNA-PRRs pathways, including TLR21-NF-κB, NLRP3 inflammasome, and cGAS-STING signaling. Encouragingly, all these adverse changes related to inflammation events induced by mtDNA-PRRs activation were all relieved by APS treatment. In summary, our findings provide the first evidence that inhibition of mtDNA-PRRs pathway-mediated sterile inflammation by APS could protect against TS-induced cardiac damage in chicks.

Should Glucokinase be Given a Chance in Diabetes Therapeutics? A Clinical-Pharmacological Review of Dorzagliatin and Lessons Learned So Far.

Despite advances in the management of type 2 diabetes mellitus (T2DM), one-third of patients with diabetes do not achieve the desired glycemic goal. Considering this inadequacy, many agents that activate glucokinase have been investigated over the last two decades but were withdrawn before submission for marketing permission. Dorzagliatin is the first glucokinase activator that has been granted approval for T2DM, only in China. As overstimulation of glucokinase is linked with pathophysiological disturbances such as fatty liver and cardiovascular issues and a loss of therapeutic efficacy with time. This review aims to highlight the benefits of glucokinase activators vis-à-vis the risks associated with chronic enzymatic activation. We discuss the multisystem disturbances expected with chronic activation of the enzyme, the lessons learned with glucokinase activators of the past, the major efficacy and safety findings with dorzagliatin and its pharmacological properties, and the status of other glucokinase activators in the pipeline. The approval of dorzagliatin in China was based on the SEED and the DAWN trials, the major pivotal phase III trials that enrolled patients with T2DM with a mean glycosylated hemoglobin of 8.3-8.4%, and a mean age of 53-54.5 years from multiple sites in China. Patients with uncontrolled diabetes, cardiac diseases, organ dysfunction, and a history of severe hypoglycemia were excluded. Both trials had a randomized double-blind placebo-controlled phase of 24 weeks followed by an open-label phase of 28 weeks with dorzagliatin. Drug-naïve patients with T2DM with a disease duration of 11.7 months were enrolled in the SEED trial while the DAWN trial involved patients with T2DM with a mean duration of 71.5 months and receiving background metformin therapy. Compared with placebo, the decline in glycosylated hemoglobin at 24 weeks was more with dorzagliatin with an estimated treatment difference of - 0.57% in the SEED trial and - 0.66% in the DAWN trial. The desired glycosylated hemoglobin (< 7%) was also attained at more than two times higher rates with dorzagliatin. The glycemic improvement was sustained in the SEED trial but decreased over 52 weeks in the DAWN trial. Hyperlipidemia was observed in 12-14% of patients taking dorzagliatin versus 9-11% of patients receiving a placebo. Additional adverse effects noticed over 52 weeks with dorzagliatin included an elevation in liver enzymes, hyperuricemia, hyperlacticacidemia, renal dysfunction, and cardiovascular disturbances. Considering the statistically significant improvement in glycosylated hemoglobin with dorzagliatin in patients with T2DM, the drug may be given a chance in treatment-naïve patients with a shorter disease history. However, with the waning therapeutic efficacy witnessed in patients with long-standing diabetes, which was also one of the potential concerns with previously tested molecules, extended studies involving patients with chronic and uncontrolled diabetes are needed to comment upon the long-term therapeutic performance of dorzagliatin. Likewise, evidence needs to be generated from other countries, patients with organ dysfunction, a history of severe hypoglycemia, cardiac diseases, and elderly patients before extending the use of dorzagliatin. Apart from monitoring lipid profiles, long-term safety studies of dorzagliatin should involve the assessment of serum uric acid, lactate, renal function, liver function, and cardiovascular parameters.

Effect of angiotensin-converting enzyme inhibitors versus that of angiotensin receptor blockers on survival in patients undergoing hemodialysis: a nationwide observational cohort study.

BACKGROUND: This study aimed to evaluate the patient survival rates based on the use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) in a large cohort of patients undergoing maintenance hemodialysis (HD). METHODS: Data from a national HD quality assessment program were used in this retrospective study. The patients were classified into four groups based on the use of renin-angiotensin system blockers (RASBs) as follows: No group, patients without a prescription of any anti-hypertensive drugs including RASBs; Other group, patients with a prescription of anti-hypertensive drugs excluding RASBs; ACEI group, patients with a prescription of an ACEI; and ARB group, patients with a prescription of an ARB. RESULTS: The 5-year survival rates in the no, other, ACEI, and ARB groups were 68.6%, 67.8%, 70.6%, and 69.2%, respectively. The ACEI group had the best patient survival trend among the four groups. In multivariable Cox regression analyses, no differences were observed between the ACEI and ARB groups. Among young patients and patients without diabetes or heart disease, the ACEI group had the best patient survival among the four groups. However, among patients with DM or heart disease, the ARB group had the best patient survival. CONCLUSIONS: Our study found that patients receiving ACEI and ARB had comparable survival. However, patients receiving ARB had better survival in the subgroups of patients with DM or heart disease, and patients receiving ACEI had better survival in the subgroup of young patients or patients without diabetes or heart disease.

A review regarding the article 'The cardioprotective potential of sodium-glucose cotransporter 2-inhibitors in breast cancer therapy-related cardiac dysfunction-A systematic review'.

Breast cancer is one of the most common types of cancer, representing 15 % of all new cancer cases in the United States. Approximately 12.4 % of all women will be diagnosed with breast cancer during their lifetime. In the past decades, a decrease in cancer-related mortality is evident as a result of early screening and improved therapeutic options. Nonetheless, breast cancer survivors face long-term treatment side effects, with cardiotoxicity being the most significant one, which lead to increased morbidity and mortality. Breast cancer patients are particularly susceptible to cancer therapeutics-related cardiac dysfunction (CTRCD) as treatment regimens include cardiotoxic drugs, primarily anthracyclines and anti-human epidermal growth factor receptor 2 (anti-HER2) agents (recombinant humanized monoclonal antibodies directed against HER2 such as trastuzumab and pertuzumab). Cardiotoxicity is the most common dose-limiting toxicity associated with trastuzumab. Discontinuation of trastuzumab however, can lead to worse cancer outcomes. There have been case reports, registry-based, retrospective cohort-based and mechanistic studies suggesting the cardioprotective potential of SGLT2i in CTRCD. It is not known whether SGLT2i can prevent the development of incident HF or reduce the risk of HF in patients receiving trastuzumab with or without other concurrent anti-HER2 agent or sequential anthracycline for treatment of HER2 positive breast cancer. Based on these, there is now a call for randomized controlled trials to be performed in this patient cohort to advise guideline-directed therapy for CTRCD, which will in turn also provide detailed safety information and improve cancer and cardiovascular outcomes.

Late Cardiac Toxic Effects Associated With Treatment Protocols for Hodgkin Lymphoma in Children.

Importance: Contemporary North American trials for children with Hodgkin lymphoma (HL) have decreased radiation therapy (RT) use and increased pharmacologic cardioprotection but also increased the cumulative doxorubicin dose, making overall treatment consequences for late cardiac toxic effects uncertain. Objective: To estimate the risk of cardiac toxic effects associated with treatments used in modern pediatric HL clinical trials. Design, Setting, and Participants: For this cohort study, Fine and Gray models were fitted using survivors in the Childhood Cancer Survivor Study who were diagnosed with HL between January 1, 1970, and December 31, 1999, and were followed for a median of 23.5 (range, 5.0-46.3) years. These models were applied to the exposures in the study population to estimate the 30-year cumulative incidence of cardiac disease. The study population comprised patients with intermediate-risk or high-risk HL treated in 4 consecutive Children's Oncology Group clinical trials from September 2002 to October 2022: AHOD0031, AHOD0831, AHOD1331, and S1826. Data analysis was performed from April 2020 to February 2023. Exposures: All patients received chemotherapy including doxorubicin, and some patients received mediastinal RT, dexrazoxane, or mediastinal RT and dexrazoxane. Main Outcomes and Measures: Estimated 30-year cumulative incidence of grade 3 to 5 cardiac disease. Results: The study cohort comprised 2563 patients, with a median age at diagnosis of 15 (range, 1-22) years. More than half of the patients were male (1357 [52.9%]). All 2563 patients received doxorubicin, 1362 patients (53.1%) received mediastinal RT, and 307 patients (12.0%) received dexrazoxane. Radiation therapy use and the median mean heart dose among patients receiving RT decreased, whereas the planned cumulative dose of doxorubicin and use of dexrazoxane cardioprotection increased. For patients treated at age 15 years, the estimated 30-year cumulative incidence of severe or fatal cardiac disease was 9.6% (95% CI, 4.2%-16.4%) in the AHOD0031 standard treatment group (enrolled 2002-2009), 8.6% (95% CI, 3.8%-14.9%) in the AHOD0831 trial (enrolled 2009-2012), 8.2% (95% CI, 3.6%-14.3%) in the AHOD1331 trial (enrolled 2015-2019), and 6.2% (95% CI, 2.7%-10.9%) in the S1826 trial (enrolled 2019-2022), whereas the expected rate in an untreated population was 5.0% (95% CI, 2.1%-9.3%). Despite the estimated reduction in late cardiac morbidity, the frequency of recommended echocardiographic screening among survivors will increase based on current guidelines. Conclusions and Relevance: In this cohort study of sequential HL trials, reductions in the proportion of children receiving mediastinal RT and increases in dexrazoxane use were estimated to offset the increased doxorubicin dose and produce a net reduction in late cardiac disease. Further studies on dexrazoxane are warranted to confirm whether its role in reducing cardiac toxic effects is maintained long term. These findings suggest that survivorship follow-up guidelines should be refined to align with the risks associated with treatment.

Sex-related differences in delayed doxorubicin-induced cardiac dysfunction in C57BL/6 mice.

Cancer survivors may experience long-term cardiovascular complications due to chemotherapeutic drugs such as doxorubicin (DOX). The exact mechanism of delayed DOX-induced cardiotoxicity has not been fully elucidated. Sex is an important risk factor for DOX-induced cardiotoxicity. In the current study, we identified sex differences in delayed DOX-induced cardiotoxicity and determined the underlying molecular determinants of the observed sexual dimorphism. Five-week-old male and female mice were administered intraperitoneal injections of DOX (4 mg/kg/week) or saline for 6 weeks. Echocardiography was performed 5 weeks after the last dose of DOX to evaluate cardiac function. Thereafter, mice were sacrificed and gene expression of markers of apoptosis, senescence, and inflammation was measured by PCR in hearts and livers. Proteomic profiling of the heart from both sexes was conducted to determine differentially expressed proteins (DEPs). Only DOX-treated male, but not female, mice demonstrated cardiac dysfunction, cardiac atrophy, and upregulated cardiac expression of Nppb and Myh7. No sex-related differences were observed in DOX-induced expression of most apoptotic, senescence, and pro-inflammatory markers. However, the gene expression of Trp53 was significantly reduced in hearts of DOX-treated female mice only. The anti-inflammatory marker Il-10 was significantly reduced in hearts of DOX-treated male mice only, while the pro-inflammatory marker Il-1α was significantly reduced in livers of DOX-treated female mice only. Gene expression of Tnf-α was reduced in hearts of both DOX-treated male and female mice. Proteomic analysis identified several DEPs after DOX treatment in a sex-specific manner, including anti-inflammatory acute phase proteins. This is the first study to assess sex-specific proteomic changes in a mouse model of delayed DOX-induced cardiotoxicity. Our proteomic analysis identified several sexually dimorphic DEPs, many of which are associated with the anti-inflammatory marker Il-10.

Drug-induced cardiac toxicity and adverse drug reactions, a narrative review.

Drug-induced cardiotoxicity is a primary concern in both drug development and clinical practice. Although the heart is not a common target for adverse drug reactions, some drugs still cause various adverse cardiac events, with sometimes severe consequences. Direct cardiac toxicity encompasses functional and structural changes of the cardiovascular system due to possible exposure to medicines. This phenomenon extends beyond cardiovascular drugs to include non-cardiovascular drugs including anticancer drugs such as tyrosine kinase inhibitors, anthracyclines and immune checkpoint inhibitors (ICIs), as well as various antipsychotics, venlafaxine, and even some antibiotics (such as macrolides). Cardiac ADRs comprise an array of effects, ranging from heart failure and myocardial ischemia to valvular disease, thrombosis, myocarditis, pericarditis, arrhythmias, and conduction abnormalities. The underlying mechanisms may include disturbances of ionic processes, induction of cellular damage via impaired mitochondrial function, and even hypercoagulability. To mitigate the impact of drug-induced cardiotoxicity, multi-stage evaluation guidelines have been established, following the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for in vitro and in vivo testing. Despite preclinical safeguards, post-marketing surveillance remains critical, as certain cardiotoxic drugs may escape initial scrutiny. Indeed, historical data show that cardiovascular ADRs contribute to almost 10% of market withdrawals. The impact of drug-induced cardiotoxicity on cardiac issues, particularly heart failure, is often underestimated, with incidence rates ranging from 11.0% to over 20.0%. We here comprehensively examine different patterns of drug-induced cardiotoxicity, highlighting current concerns and emerging pharmacovigilance signals. Understanding the underlying mechanisms and the associated risk factors is critical in order to promptly identify, effectively manage, and proactively prevent drug-induced cardiac adverse events. Collaborative efforts between physicians and cardiologists, coupled with thorough assessment and close monitoring, are essential to ensuring patient safety in the face of potential drug-induced cardiotoxicity.

Golgi Protein 73 Promotes LPS-Induced Cardiac Dysfunction via Mediating Myocardial Apoptosis and Autophagy.

ABSTRACT: Sepsis-induced cardiac dysfunction represents a major cause of high mortality in intensive care units with limited therapeutic options. Golgi protein 73 (GP73) has been implicated in various diseases. However, the role of GP73 in lipopolysaccharide (LPS)-induced cardiac dysfunction is unclear. In this study, we established a sepsis-induced cardiac dysfunction model by LPS administration in wild-type and GP73 knockout ( GP73-/- ) mice. We found that GP73 was increased in LPS-treated mouse hearts and LPS-cultured neonatal rat cardiomyocytes (NRCMs). Knockout of GP73 alleviated myocardial injury and improved cardiac dysfunction. Moreover, depletion of GP73 in NRCMs relieved LPS-induced cardiomyocyte apoptosis and activated myocardial autophagy. Therefore, GP73 is a negative regulator in LPS-induced cardiac dysfunction by promoting cardiomyocyte apoptosis and inhibiting cardiomyocyte autophagy.

Anti-tumor and cardiotoxic effects of microtubule polymerization inhibitors: The mechanisms and management strategies.

Microtubule polymerization inhibitors (MPIs) have long been used as anticancer agents because they inhibit mitosis. Microtubules are thought to play an important role in the migration of tumor cells and the formation of tumor blood vessels, and new MPIs are being developed. Many clinical trials of novel MPIs have been conducted in humans, while some clinical studies in dogs have also been reported. More attempts to apply MPIs not only in humans but also in the veterinary field are expected to be made in the future. Meanwhile, MPIs have a risk of cardiotoxicity. In this paper, we review findings on the pharmacological effects and cardiotoxicity of MPIs, as well as the mechanisms of their cardiotoxicity. Cardiotoxicity of MPIs involves not only the direct effects of MPIs on cardiomyocytes but also their effects on vascular function. For example, hypertension induced by impaired vascular function also contributes to the exacerbation of myocardial damage, and blood pressure control may be useful in reducing cardiotoxicity. By combined administration of MPIs and other anticancer agents, MPI efficacy may be enhanced, thereby potentially allowing to keep MPI dosage low. Measurement of myocardial injury markers in blood and echocardiography may be useful for monitoring cardiotoxicity. In particular, two-dimensional speckle tracking may have high sensitivity for the early detection of MPI-induced cardiac dysfunction. The exploration of the potential of new MPIs while understanding their toxicity and how to deal with them will lead to the further development of cancer chemotherapy.

Role of Statin Therapy in Prevention of Anthracycline-Induced Cardiotoxicity: A Three Dimentional Echocardiography Study.

BACKGROUND: Recent advances in the treatment of breast cancer have resulted in improved overall cancer survival; however, cancer therapy related cardiac dysfunction is considered a major adverse effect of several chemotherapeutic agents, particularly anthracyclines. Hence, there is a need to develop proper cardioprotective strategies to limit myocardial injury following chemotherapy. OBJECTIVE: To evaluate the effect of statin therapy on prevention of anthracycline- induced cardiotoxicity in female patients with breast cancer. PATIENTS AND METHODS: The current study is a prospective, randomized, single-blind, placebo-controlled trial in which we enrolled a total of 110 female patients with newly diagnosed breast cancer who received anthracycline based chemotherapy. Patients were randomly assigned in 1:1 ratio into two groups, study group in which patients received 40 mg of oral atorvastatin and control group in which patients received placebo. A comprehensive echocardiographic examination was performed to all patients prior to receiving the chemotherapy and after 6 months, assessment of LV ejection fraction was done by 3D-echocardiography. All echocardiographers were blinded to all the patients' characteristics and assignment to either group. RESULTS: The mean age of patients assigned to the control group was 49.8±10.51 years old, while patients assigned to the intervention group had mean age of 47.84± 9.16 years old, both the control group and the intervention group were similar in demographic data and baseline clinical characteristics. There was a highly significant difference between the two groups regarding both the absolute LVEF assessed by 3D- echocardiography at 6 months and the percentage of change compared to baseline values, patients assigned to the control group had mean LVEF of 52.92% at 6 months with percentage of change reaching -7.06%, while those assigned to the intervention group had mean LVEF reaching 56.22% at 6 months with a percentage of change reaching -3.64% (P-value: 0.008 and 0.004 for the absolute value and percentage of change respectively). There was a significant difference between the two groups regarding incidence of development of cancer therapy related cardiac dysfunction (CTRCD); defined as drop in LVEF more than 10% and to a value below 53% assessed by 3D echocardiography, among the control group 15 patients (30%) developed CTRCD after 6 months from starting Anthracyclines based chemotherapy, while, among the intervention group only 6 patients (12%) developed CTRCD. (P-value= 0.027) CONCLUSION: Prophylactic use of atorvastatin may prevent the development of cancer therapy related cardiac dysfunction in breast cancer patients receiving anthracycline based chemotherapy.

Evaluation of cardiotoxicity of anthracycline-containing chemotherapy regimens in patients with bone and soft tissue sarcomas: A study of the FDA adverse event reporting system joint single-center real-world experience.

OBJECTIVES: To assess the occurrence of cardiotoxicity in patients with tumors receiving anthracycline-based chemotherapy, especially for sarcomas. METHODS: This study summarized the types and frequency of adverse events (AEs) for three anthracyclines from the FDA adverse event reporting system (FAERS) database. FAERS data from January 2004 to June 2022 were collected and analyzed. Disproportionality analyses, logistic regression, and descriptive analysis were used to compare the differences in cardiac disorders. A retrospective cohort study was conducted in a single center between December 2008 and May 2022. Our hospital-treated patients with bone and soft tissue sarcomas (BSTSs) with anthracycline-containing chemotherapy were analyzed. Serum markers, echocardiography, and electrocardiography have been used to evaluate cardiotoxic events. RESULTS: One hundred thousand and seventy-five AE reports were obtained for doxorubicin (ADM), epirubicin (EPI), and liposome doxorubicin (L-ADM) from the FAERS database. ADM (OR = 3.1, p < 0.001), EPI (OR = 1.5, p < 0.001), and sarcomas (OR = 1.8, p < 0.001) may increase the probability of cardiac disorders. Cardiac failure, cardiotoxicity, and cardiomyopathy were anthracyclines' top 3 frequent AEs. Among patients receiving ADM-containing therapy, those with ADM applied at doses ≥75 mg/m2 /cycle were more likely to develop cardiac disorders than the other subgroups (OR = 3.5, p < 0.001). Patients younger than 18 are more likely to benefit from dexrazoxane prevention of cardiac failure. Six hundred and eighty-three patients with BSTSs receiving anthracycline-based chemotherapy were analyzed in our center. Patients receiving ADM-containing chemotherapy were likelier to experience abnormalities in serum troponin-T and left ventricular ejection fraction (p < 0.05). 2.0% (6/300) of patients receiving ADM-containing chemotherapy required adjustment of the chemotherapy regimen because of cardiotoxicity, whereas none were in the EPI or L-ADM groups. CONCLUSIONS AND RELEVANCE: Among patients receiving anthracycline-containing therapy, patients with BSTSs were more likely to develop cardiac disorders than other tumors. In addition, patients with BSTSs receiving ADM chemotherapy had a higher likelihood of cardiotoxic events than those receiving EPI or L-ADM.