A Study on Protective Action of Astragalus Injection(黄芪注射液)in Ouabain-Induced Cardiac Toxicity of Guinea Pigs

Objective: To study the protective action of Astragalus Injection (AI) on ouabain induced cardiac toxicity. Methods: Forty guinea pigs were randomly divided into the AI group and the control group, AI injected intravenously in the AI group and 0.9% normal saline injected in the control group, ouabain was injected in contralateral of both groups intravenously 8 mins later. The time of cardiac ventricular tachycardia (VT) and cardiac ventricular fibrillation (VF), and the dose of ouabain were documented.Results: Compared with the control group AI could markedly prolong the time of VT and VF, and increase the dose of ouabain induces VT and VF ( P <0.01). Conclusion: AI decreases the incidence of digitalism.

Anti-HER-2 therapy following severe trastuzumab-induced cardiac toxicity

The human epidermal growth factor receptor 2(HER2)is overexpressed in 25%e30%of breast cancer patients.Anti-HER2 therapies have changed the aggressive course of HER2t breast cancer.In spite of the therapeutic benefits,their cardiotoxicities are major concerns,especially when used concurrently with anthracyclines.Here we present an elderly patient with relapsed HER2t breast cancer.Her presentation for relapsed disease was unusual for the physical finding as well as the history of trastuzumabinduced severe cardiotoxicity while requiring additional anti-HER2 therapy.She received neoadjuvant anti-HER2 treatment for stage III breast caner.Due to severe reduction of cardiac ejection fraction(EF),she only received five doses of adjuvant transtuzumab.Unfortunately her disease relapsed one year later with chest wall lesions and a persistent low EF.We treated the patient with lapatinib combined with capecitabine which resulted rapid resolution of her chest wall lesion.More importantly,the patient had one year of disease control without deterioration in her ejection fraction.We discussed the management of recurrent HER2t breast cancer with chest wall disease and the choice of anti-HER2 therapy in patients with a history of transtuzumab-induced cardiac dysfunction.

Real-time three-dimensional echocardiography predicts cardiotoxicity induced by postoperative chemotherapy in breast cancer patients

BACKGROUND The anthracycline chemotherapeutic drugs are cardiotoxic.Studies have found some indicators related to cardiotoxicity.However,there is currently no accurate indicator that can predict cardiac toxicity early.AIM To explore the diagnostic value of real-time three-dimensional echocardiography(RT3DE)in predicting cardiac toxicity in breast cancer patients undergoing chemotherapy.METHODS Female breast cancer patients who underwent radical mastectomy and postoperative chemotherapy at the Affiliated Hanzhou First People’s Hospital,Zhejiang University School of Medicine were recruited.All patients were routinely administered with chemotherapy for four cycles(T1-T4)after surgery.Two-dimensional(2D)echocardiography,RT3DE,and serological examinations were performed after each cycle of chemotherapy.Patients were divided into a toxic group and a non-toxic group based on whether patients hadΔleft ventricular ejection fraction>10%after one year of chemotherapy.Repeated measurement analysis of variance was used to compare the changes in 2D echocardiographic indicators,serological indicators,and RT3DE indicators before independent predictive indicators for cardiac toxicity in postoperative chemotherapy patients.Receiver operating characteristics(ROC)curve analysis was performed to analyze the diagnostic value of potential indicators in the diagnosis of cardiotoxicity.RESULTS A total of 107 female breast cancer patients were included in the study.T4 maximum peak velocity in early diastole(E peak)/mitral annulus lateral tissue Doppler(e'peak)(E/e'),serological indicators[T4 cardiac troponin I(cTnI)and T4 pro-brain natriuretic peptide(Pro-BNP)],T3 minimum left atrial volume(LAV),T4 LAVmin,T3 LAV before the start of the P wave(LAVprep),and T4 LAVprep in the toxicity group were significantly higher than those in the nontoxic group.Multivariate logistic regression found that T4 cTnI,T4 Pro-BNP,T3 LAVmin,T4 LAVmin,T3 LAVprep,and T4 LAVprep had potential predictive value for cardiac toxicity(P<0.05).ROC results showed that T4 LAVmin had the highest accuracy for diagnosing cardiac toxicity[area under the curve(AUC)=0.947;sensitivity=78.57%;specificity=94.62%],followed by T4 LAVprep(AUC=0.899;sensitivity=100%;specificity=66.67%).The accuracies of LAVprep and LAVprep in predicting cardiac toxicity were higher than those of T3 LAVmin and T3 LAVprep.CONCLUSION RT3DE of left atrial volume can be used to predict the cardiotoxicity caused by chemotherapy,and it is expected to guide the clinical adjustment of dose and schedule in time.

An Overview of Adverse Outcome Pathway Links between PM_(2.5)Exposure and Cardiac Developmental Toxicity

Fine particulate matter(PM_(2.5))is a significant risk factor for birth defects.As the first and most important organ to develop during embryogenesis,the heart’s potential susceptibility to PM_(2.5)has attracted growing concern.Despite several studies supporting the cardiac developmental toxicity of PM_(2.5),the diverse study types,models,and end points have prevented the integration of mechanisms.In this Review,we present an adverse outcome pathway framework to elucidate the association between PM_(2.5)-induced molecular initiating events and adverse cardiac developmental outcomes.Activation of the aryl hydrocarbon receptor(AhR)and excessive generation of reactive oxygen species(ROS)were considered as molecular initiating events.The excessive production of ROS induced oxidative stress,endoplasmic reticulum stress,DNA damage,and inflammation,resulting in apoptosis.The activation of the AhR inhibited the Wnt/β-catenin pathway and then suppressed cardiomyocyte differentiation.Impaired cardiomyocyte differentiation and persistent apoptosis resulted in abnormalities in the cardiac structure and function.All of the aforementioned events have been identified as key events(KEs).The culmination of these KEs ultimately led to the adverse outcome,an increased morbidity of congenital heart defects(CHDs).This work contributes to understanding the causes of CHDs and promotes the safety evaluation of PM_(2.5).

Is there a window of opportunity to optimize trastuzumab cardiac monitoring?

BACKGROUND It remains unclear whether the current arbitrary screening recommendations of trastuzumab-related cardiotoxicity provides an adequate balance between preventing heart damage and curtailing a curative treatment.AIM To determine the incidence rate and consequences of trastuzumab-induced cardiotoxicity as adjuvant treatment in a real-world scenario.METHODS We present a retrospective analysis of cardiac function measured by echocardiogram at baseline and every 3 mo during trastuzumab treatment.Cardiotoxicity was defined as a drop in left ventricular ejection fraction(LVEF)≥10%from baseline and/or any drop<50%.RESULTS Between January 2011 and December 2014,407 patients were selected.Most(93.6%)were treated with an anthracycline followed by a taxane-based regimen and trastuzumab for 12 mo.Forty patients(9.8%)had cardiotoxicity.None of them were symptomatic,and 28(72.5%)completely recovered LVEF.Cardiotoxicity happened early as shown by LVEF measured on echocardiogram 2 to 4 as compared to 5 to 7(odds ratio=2.47,95%confidence interval:1.09,5.63,P=0.024).There were 54 deaths(13.3%)during the 70-mo follow-up period;1(0.2%)was attributed to late cardiotoxicity(4 years after treatment).The absence of symptomatic cardiotoxicity during trastuzumab treatment and moreover the early occurrence on the treatment period may translate into a strategy to evaluate less frequently.CONCLUSION We observed a 10%rate of asymptomatic cardiotoxicity,which mirrors the results from the large adjuvant trials.Despite being transient,an LVEF drop led to frequent treatment delays and interruptions.It remains unclear whether LVEF decline is predictive of late cardiotoxicity,and treatment efficacy is compromised.

Cardiac Safety with High Cumulative Dose of Pegylated Liposomal Doxorubicin in Patients with Metastatic Breast Cancer Previously Treated with Conventional Anthracyclines

Introduction: The treatment of metastatic breast cancer (MBC) is still challenging. Many studies documented the efficacy of pegylated liposomal doxorubicin (PLD) in patients with MBC, but there is a limited data about the cardiac safety with high cumulative dose (HCD) of PLD. Aim of the work: We conducted this trial to outline the cardiac safety of HCD of PLD in patients with MBC who previously received conventional anthracyclines. Methods: During the period of nine years (January 2011 to December 2019). We extracted the data of the patients with MBC receiving PLD at Medical Oncology Department, South Egypt Cancer Institute, Assiut University. These included patients’ demographics and therapeutic data including the full data of PLD, prior conventional anthracyclines, prior trastuzumab, and prior radiotherapy. Also, data about comorbidities as well as cardiac and other toxicities of PLD were obtained. The data was analysed using SPSS v. 21. Results: For all 81 eligible patients, the mean age was 43.9 years (±standard deviation (SD) 13.2). The mean cumulative dose of PLD was 378.4 mg/m2 (± SD of 250.2) and a range of 100 - 1200 mg/m2. About thirty-one (38.3%) patients received high cumulative dose (400 mg/m2 or more), while the remaining 50 patients did not. The decline in left ventricular ejection fraction (LVEF) was relatively rare;and of low grade. Grade 2 decline in LVEF occurred in only two patients who received high cumulative dose of PLD, and only one patient who did not reach HCD (p = 0.555). Grade 3 or 4 decline in LVEF did not occur in patients either with or without HCD. Regarding other toxicities, there was a significant increase in incidence of all grades palmar plantar erythrodysesthesia (PPE) in patients who received HCD of PLD when compared to those who did not reach the HCD (38.7% versus 16% respectively;p = 0.021). Conclusion: Our study concluded that the use of PLD seems to be a justified agent in the treatment of MBC who previously treated by conventional anthracyclines in the adjuvant, metastatic or both settings, even in patients reaching the cumulative dose of conventional anthracycline.

Impact of Cardiac Dose on Overall Survival in Lung Stereotactic Body Radiotherapy (SBRT) Compared to Conventionally Fractionated Radiotherapy for Locally Advanced Non-Small Cell Lung Cancer (LA-NSCLC)

Purpose: To examine possible association between heart irradiation and Overall Survival (OS) in lung SBRT patients and to compare observed associations with cardiac toxicity models previously derived in LA-NSCLC patient studies. Materials and Methods: 197 Patients treated with lung SBRT at Mayo Clinic Arizona were selected for this IRB-approved study. Multivariate Cox model with Akaike Information Criterion (AIC) was used to select patient specific covariates associated with OS. Heart dosimetry was represented by VD indices, which is a percentage of volume exposed to dose D or greater. Multivariate Cox models with patient specific covariates and single VD index per model was used to find a range of doses which were predictive for OS. A digital subdivision of the heart was further used to determine the spatial distribution of doses which were predictive for OS. A coarse subdivision divided heart into 4 segments, while the fine subdivision divided heart into 64 segments. Knowledge constrained Fused Lasso operator was used to derive a more complete model which correlated heart dosimetry with OS. Results of statistical analysis were compared to predictions of a model of cardiac toxicity in LA-NSCLC patients. Results: Higher age (p < 0.001), higher stage (p < 0.001) and squamous cell histology (p = 0.001) were associated with reduced OS. Whole heart DVH analysis did not reveal associations between heart irradiation and reduced OS. Coarse subdivision of the heart into four segments revealed that the irradiation of two inferior segments of the heart with low doses was associated with reduced OS, V2Gy in the right-inferior segment (HR = 1.012/1%, p = 0.02), and V1Gy in the left-inferior segment (HR = 1.01/1%, p = 0.04). Maximum dose in the right-inferior segment of the heart was also associated with reduced OS (HR = 1.02/Gy, p = 0.02). Fine subdivision of the heart into 64 segments revealed that approximately 25% of heart volume in the inferior part of the heart (15/64 segments), when irradiated to doses in the 1 Gy - 5 Gy range, were predictive for reduced OS (HR = 1.01/1%, p = 0.01). A previously derived model of cardiac toxicity in LA-NSCLC patients did not predict a reduction of OS due to heart irradiation in lung SBRT patients, because of relatively low doses to the heart in most lung SBRT patients. Conclusions: Doses lower than 5 Gy in the inferior segments of the heart may be associated with reduced overall survival in patients treated for lung lesions with SBRT. Stage and histology of the disease, as well as patients’ age, were also associated with overall survival. Comparisons of cardiac toxicity patterns in LA-NSCLC patients and lung SBRT patients suggest different etiology of cardiac toxicity in the two groups.

Posterior reversible encephalopathy syndrome and heart failure tacrolimus-induced after liver transplantation: A case report

BACKGROUND Patients undergoing liver transplantation can develop posterior reversible encephalopathy syndrome(PRES)and acute heart failure(HF)in the postoperative period.But PRES with HF caused by tacrolimus has rarely been described.CASE SUMMAR A 40-year-old female patient who had a normal preoperative cardiac and neural evaluation developed PRES with acute heart failure tacrolimus-induced after liver transplantation.The challenges associated with both diagnosis and management in the setting of a newly implanted graft are discussed.CONCLUSION Tacrolimus can induce neurotoxicity and then cardiac toxicity.Magnetic resonance imaging,echocardiography,and increased brain natriuretic peptide may be predictive of post-operative PRES with acute heart failure.Further investigations are necessary to verify this finding.

Using Novel Statistical Techniques to Accurately Determine the Predictive Dose Range in a Study of Overall Survival after Definitive Radiotherapy for Stage III Non-Small Cell Lung Cancer in Association with Heart Dose

Purpose: Recent studies of radiotherapy (RT) for stage III non-small-cell lung cancer (NSCLC) have associated high dose to the heart with cardiac toxicity and decreased overall survival (OS). We used advanced statistical techniques to account for correlations between dosimetric variables and more accurately determine the range of heart doses which are associated with reduced OS in patients receiving RT for stage III NSCLC. Methods: From 2006 to 2013, 119 patients with stage III NSCLC received definitive RT at our institution. OS data was obtained from institutional tumor registry. We used multivariate Cox model to determine patient specific covariates predictive for reduced overall survival. We examined age, prescription dose, mean lung dose, lung V20, RT technique, stage, chemotherapy, tumor laterality, tumor volume, and tumor site as candidate covariates. We subsequently used novel statistical techniques within multivariate Cox model to systematically search the whole heart dose-volume histogram (DVH) for dose parameters associated with OS. Results: Patients were followed until death or 2.5 to 81.2 months (median 30.4 months) in those alive at last follow up. On multivariate analysis of whole heart DVH, the dose of 51 Gy was identified as a threshold dose above which the dose volume relationship becomes predictive for OS. We identified V55Gy (percentage of the whole heart volume receiving at least 55 Gy) as the best single DVH index which can be used to set treatment optimization constraints (Hazard Ratio = 1.044 per 1% increase in heart volume exposed to at least 55 Gy, P = 0.03). Additional characteristics correlated with OS on multivariate analysis were age, stage (IIIA/IIIB), and administration of chemotherapy. Conclusion: Doses above 51 Gy, applied to small volumes of the heart, are associated with worse OS in stage III NSCLC patients treated with definitive RT. Higher stage, older age and lack of chemotherapy were also associated with reduced OS.

Black phosphorus quantum dots induce myocardial inflammatory responses and metabolic disorders in mice

As an ultrasmall derivative of black phosphorus(BP)sheets,BP quantum dots(BP-QDs)have been effectively used in many fields.Currently,information on the cardiotoxicity induced by BP-QDs remains limited.We aimed to evaluate BP-QD-induced cardiac toxicity in mice.Histopathological examination of heart tissue sections was performed.Transcriptome sequencing,real-time quantitative PCR(RT–qPCR),western blotting,and enzyme-linked immunosorbent assay(ELISA)assays were used to detect the m RNA and/or protein expression of proinfammatory cytokines,nuclear factor kappa B(NF-κB),phosphatidylinositol3 kinase-protein kinase B(PI3K-AKT),peroxisome proliferator-activated receptor gamma(PPARγ),and glucose/lipid metabolism pathway-related genes.We found that heart weight and heart/body weight index(HBI)were significantly reduced in mice after intragastric administration of 0.1 or 1 mg/kg BP-QDs for 28 days.In addition,obvious infammatory cell infiltration and increased cardiomyocyte diameter were observed in the BP-QD-treated groups.Altered expression of proinfammatory cytokines and genes related to the NF-κB signaling pathway further confirmed that BP-QD exposure induced infammatory responses.In addition,BP-QD treatment also affected the PI3K-AKT,PPARγ,thermogenesis,oxidative phosphorylation,and cardiac muscle contraction signaling pathways.The expression of genes related to glucose/lipid metabolism signaling pathways was dramatically affected by BP-QD exposure,and the effect was primarily mediated by the PPAR signaling pathway.Our study provides new insights into the toxicity of BP-QDs to human health.