Blood metal concentrations and cardiac structure and function in total joint arthroplasty patients

BACKGROUND There is concern regarding potential long-term cardiotoxicity with systemic distribution of metals in total joint arthroplasty(TJA)patients.AIM To determine the association of commonly used implant metals with echocardiographic measures in TJA patients.METHODS The study comprised 110 TJA patients who had a recent history of high chromium,cobalt or titanium concentrations.Patients underwent two-dimensional,three-dimensional,Doppler and speckle-strain transthoracic echocardiography and a blood draw to measure metal concentrations.Age and sex-adjusted linear and logistic regression models were used to examine the association of metal concentrations(exposure)with echocardiographic measures(outcome).RESULTS Higher cobalt concentrations were associated with increased left ventricular end-diastolic volume(estimate 5.09;95%CI:0.02-10.17)as well as left atrial and right ventricular dilation,particularly in men but no changes in cardiac function.Higher titanium concentrations were associated with a reduction in left ventricle global longitudinal strain(estimate 0.38;95%CI:0.70 to 0.06)and cardiac index(estimate 0.08;95%CI,-0.15 to-0.01).CONCLUSION Elevated cobalt and titanium concentrations may be associated with structural and functional cardiac changes in some patients.Longitudinal studies are warranted to better understand the systemic effects of metals in TJA patients.

Geraniol alleviates cyclophosphamide-induced cardiotoxicity in mice

Objective:To explore the effect of geraniol on cyclophosphamide-induced cardiotoxicity.Methods:Mice were divided into five groups:the control group,the cyclophosphamide group(200 mg/kg cyclophosphamide,i.p.on day 7),the group treated with geraniol 100 and 200 mg/kg from day 1 to day 14,along with a single dose of cyclophosphamide on day 7,and the geraniol alone group(200 mg/kg geraniol from day 1 to day 14).At the end of the study,animals were sacrificed,and blood and heart were collected and analyzed for biochemical,histopathological,and immunohistochemical changes.Results:Treatment with 200 mg/kg geraniol significantly reduced the levels of cardiac injury markers,malondialdehyde,and inflammatory and apoptotic markers,while increasing antioxidant activities in mice with cyclophosphamide-induced cardiotoxicity.Moreover,it remarkably alleviated histopathological aberrations in cardiac tissue.Conclusions:Geraniol attenuates cyclophosphamide-induced cardiotoxicity via antioxidant,anti-inflammatory,and antiapoptotic effects.

Thrombopoietin ameliorates doxorubicin-induced toxicities in H9c2 myocardiocytes by inhibiting oxidative stress through the SIRT1/p38 MAPK signaling pathway

Objective:To explore whether thrombopoietin can exert a protective effect against doxorubicin-induced cardiotoxicity by modulating the sirtuin 1(SIRT1)signaling pathway.Methods:H9c2 cell viability was determined by CCK-8 and cardiomyocyte apoptosis was detected by TUNEL assay.The protein expressions of SIRT1 and p38 MAPK were measured by Western blot.RT-qPCR was also used to determine SIRT1 mRNA expression.In addition,intracellular reactive oxygen species levels and antioxidant enzyme activities were evaluated.Results:Thrombopoietin treatment reversed doxorubicin-induced decline in H9c2 cell viability.It also increased SIRT1 and decreased p-p38 MAPK protein expressions.In addition,thrombopoietin significantly attenuated doxorubicin-induced apoptosis and oxidative stress,and enhanced antioxidant enzyme activities.However,silencing SIRT1 abrogated the protective effects of thrombopoietin,as evidenced by reduced cell viability and increased oxidative stress and reactive oxygen species levels.Conclusions:Thrombopoietin alleviates doxorubicin-induced cardiomyocyte injury by reducing oxidative stress and apoptosis via the SIRT1/p38 MAPK pathway.However,its protective effects need to be further verified in animal tests.

Cardiotoxicity induced by fluoropyrimidine drugs in the treatment of gastrointestinal tumors

In this editorial,we review the article published in World J Gastrointest Oncol 2019,11:1031-1042.We specifically focus on the occurrence,clinical characteristics,and risk factors of fluoropyrimidine drug-related cardiotoxicity in patients with gastrointestinal tumors.Despite significant advancements in diagnostic and therapeutic techniques that have reduced mortality rates associated with digestive system tumors,the incidence and mortality rates of treatment-related car-diotoxicity have been increasing,severely impacting the survival and prognosis of cancer patients.Fluoropyrimidine drugs are widely used as antimetabolites in the treatment of malignant tumors,including gastrointestinal tumors,and they represent the second largest class of drugs associated with cardiotoxicity.However,there is often a lack of awareness or understanding regarding their cardiotoxic effects and associated risks.

Cardiotoxicity concerns in total joint arthroplasty

This editorial examines the cardiotoxic effects of elevated metal concentrations in patients who received total joint arthroplasty,as detailed in the study of Brennan et al.The study findings reveal that elevated cobalt and titanium levels may affect the cardiac structure and function,providing crucial insights for clinical practice and research.This editorial suggests that the close monitoring of metal ion levels in patients undergoing arthroplasty is necessary to reduce cardiovascular risk.

Hydroxychloroquine in SARS-CoV-2 infection:Understanding the misadventure

The widespread outbreak of SARS-CoV-2 was declared a public health emergency by the World Health Organization and various governments worldwide.This prompted the implementation of stringent infection control measures to curb the spread of the virus.Amidst this,the medical community faced the challenge of treating the virus without specific therapies or a vaccine,leading to reliance on empirical treatment approaches.In this context,hydroxychloroquine,an antimalarial and antirheumatic drug,gained attention as a potential treatment option.Despite its theoretical benefits,such as inhibiting viral entry,reducing inflammation,and modulating immune responses,empirical studies yielded inconsistent results.Some indicated a potential for symptom relief,while others showed no significant improvement in patient outcomes.The initial enthusiasm waned as the lack of substantial evidence led to revoking its Emergency Use Authorization,and several clinical trials were prematurely halted.The review in question critically examines the factors contributing to the ineffectiveness of hydroxychloroquine in treating SARS-CoV-2 infection,highlighting the complexities of drug repurposing during a rapidly evolving pandemic.

Screening of Myocardial Cardiotoxicity Induced by Anticancer Chemotherapy and the Importance of Global Longitudinal Strain

Introduction: The improvement of survival in patients with cancer and the expansion of therapeutic options have led to the emergence of a new profile of cardiotoxicity, specifically associated with antimitotic agents. Our study aimed to assess the incidence of chemotherapy-induced myocardial toxicity in patients with cancer. Patients and Methods: We conducted a looking-forward longitudinal cohort study including all patients admitted to the Cardiology departments of Aristide le Dantec Hospital and Dalal Jamm National Hospital Centre for apre-chemotherapy check-up. The included patients did not undergo any pre-existing cardiopathy. Results: Over a period of two years ranging from January 2019 to December 2021, a total of 37 patients were included in the study. Notably, there was a female predominance (92%) with an average age of 49.7 years ± 13.69. Breast cancer accounted for 70% of the neoplasms. Laboratory findings revealed moderate anemia in 19 patients (51%). At inclusion, the left ventricle (LV) was of normal size (LV diastole at 44.46 ± 4.97 mm). The systolic function of the left ventricle was normal in all patients, with an average ejection fraction (EF) of 63.1% ± 5.80 and a mean global longitudinal strain (GLS) of −20.4% ± 2.58. The most commonly used agents were anthracyclines. During follow-up, 3 patients (8.1%) developed clinical symptoms of left heart failure, and LV dysfunction on echocardiography was observed in 5 (13.5%) patients, with a significant decrease in EF Conclusion: The incidence of cardiac toxicity is not negligible, hence the importance of early screening. Strain imaging is an essential tool that should be performed as part of the assessment before chemotherapy and re-evaluated during treatment.

IGF1-PI3K-induced physiological cardiac hypertrophy:Implications for new heart failure therapies,biomarkers,and predicting cardiotoxicity

Heart failure represents the end point of a variety of cardiovascular diseases.It is a growing health burden and a leading cause of death worldwide.To date,limited treatment options exist for the treatment of heart failure,but exercise has been well-established as one of the few safe and effective interventions,leading to improved outcomes in patients.However,a lack of patient adherence remains a significant barrier in the implementation of exercise-based therapy for the treatment of heart failure.The insulin-like growth factor 1(IGF1)phosphoinositide 3-kinase(PI3K)pathway has been recognized as perhaps the most critical pathway for mediating exercisedinduced heart growth and protection.Here,we discuss how modulating activity of the IGF1PI3K pathway may be a valuable approach for the development of therapies that mimic the protective effects of exercise on the heart.We outline some of the promising approaches being investigated that utilize PI3K-based therapy for the treatment of heart failure.We discuss the implications for cardiac pathology and cardiotoxicity that arise in a setting of reduced PI3K activity.Finally,we discuss the use of animal models of cardiac health and disease,and genetic mice with increased or decreased cardiac PI3K activity for the discovery of novel drug targets and biomarkers of cardiovascular disease.

Cardiac toxicity of trastuzumab in elderly patients with breast cancer

Breast cancer （BC） is diagnosed in 〉 65 year old women in about half of cases. Experts currently recommend that systemic therapy is offered to elderly patients with BC, if, based on their overall conditions and life expectancy, it can be reasonably anticipated that the benefits will outweigh the risks of treatment. Like for young subjects, the monoclonal antibody against human epidermal growth factor receptor-2 （HER-2）, trastuzumab, represents a valid therapeutic option when BC over-expresses this receptor. Unforttmately, administration of trastu- zumab is associated with the occurrence of left ventricular dysfunction and chronic heart failure （CHF）, possibly because of interference with the homeostatic functions of HER-2 in the heart. Registry-based, retrospective analyses have reported an incidence of CHF around 25% in elderly women receiving trastuzumab compared with 10%-15% in those not given any therapy for BC, and the risk of CHF has been estimated to be two-fold higher in 〉 60455 year old trastuzumab users vs. non-users. Extremely advanced age and preexisting cardiac disease have been shown to predispose to trastuzumab cardiotoxicity. Therefore, selection of older patients for treatment with trastuzumab should be primarily based on their general status and the presence of comorbidities; previous chemotherapy, especially with anthracyclines, should be also taken into account. Once therapy has started, efforts should be made to ensure regular cardiac surveillance. The role of selected biomarkers, such as cardiac troponin, or new imaging techniques （three-dimension, tissue Doppler echocardiography, magnetic resonance imaging） is promising, but must be further investigated especially in the elderly. Moreover, additional studies are needed in order to better understand the mechanisms by which trastuzumab affects the old heart.

Enhanced myocardial fluorodeoxyglucose uptake following Adriamycin-based therapy: Evidence of early chemotherapeutic cardiotoxicity?

AIM: To analyze changes in myocardial glucose metabolism using fluorodeoxyglucose (FDG)-positron emission tomography (PET) in patients treated with adriamycin and to investigate the clinical significance of these changes.METHODS: Considering that FDG-PET scanning has the ability to show changes in glucose metabolism in the myocardium, we retrospectively analyzed the FDGPET studies of 18 lymphoma patients treated with adriamycin-based chemotherapy in both the preand posttherapy setting. Cardiac contractile parameters such as left ventricular ejection fraction were not available for correlation in all patients due to the short duration and the level of cumulative dose administered in these patients during the time of the follow-up FDG-PET study. The change in myocardial glucose utilization was estimated by change in standard uptake values (SUV) in the myocardium.RESULTS: We observed a significant change in SUVmean values in the myocardium (defined as more than change in cardiac SUVmean between pre-and post-chemotherapy PET) in 1 patients, whereas 6 patients did not show any significant cardiac FDG uptake in both preand post-therapy PET scans. Patients were divided into three groups based on the changes observed in myocardial tracer uptake on the followup 18 F-FDG-PET study. Group A (n = 8): showed an increase in cardiac 18 F-FDG uptake in the post-therapy scan compared to the baseline scan carried out prior to starting adriamycin-based chemotherapy. Group B (n = 6): showed no significant cardiac 18 F-FDG uptake in post-therapy and baseline PET scans, and group C (n = 4): showed a fall in cardiac 18 F-FDG uptake in the posttherapy scan compared to the baseline scan. Mean cumulative adriamycin dose (in mg/m 2 ) received during the time of the follow-up FDG-PET study was 256. 25, 250 and 137.5, respectively.CONCLUSION: Our study shows three different trends in the change in myocardial glucose metabolism in patients undergoing adriamycin-based chemotherapy. A further prospective study with prolonged follow-up of ventricular function is warranted to explore the significance of enhanced FDG uptake as a marker of early identification of adriamycin-induced cardiotoxicity.

Ratiometric delivery of doxorubicin and berberine by liposome enables superior therapeutic index than Doxil?

Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine(BER) and doxorubicin(DOX), which was called Lipo Be Do. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, Lipo Be Do, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The Lipo Be Do significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil(P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.

Antipsychotics cardiotoxicity:What's known and what's next

Chronic use of antipsychotic medications entails a dilemma between the benefit of alleviating psychotic symptoms and the risk of troubling,sometimes lifeshortening adverse effects.Antipsychotic-induced cardiotoxicity is one of the most life-threatening adverse effects that raises widespread concerns.These cardiotoxic effects range from arrhythmia to heart failure in the clinic,with myocarditis/cardiomyopathy,ischemic injuries,and unexplained cardiac lesions as the pathological bases.Multiple mechanisms have been proposed to underlie antipsychotic cardiotoxicity.This review aims to summarize the clinical signs and pathological changes of antipsychotic cardiotoxicity and introduce recent progress in understanding the underlying mechanisms at both the subcellular organelle level and the molecular level.We also provide an up-to-date perspective on future clinical monitoring and therapeutic strategies for antipsychotic cardiotoxicity.We propose that third-generation antipsychotics or drug adjuvant therapy,such as cannabinoid receptor modulators that confer dual benefits—i.e.,alleviating cardiotoxicity and improving metabolic disorders—deserve further clinical evaluation and marketing.

Thyme oil and thymol abrogate doxorubicin-induced nephrotoxicity and cardiotoxicity in Wistar rats via repression of oxidative stress and enhancement of antioxidant defense mechanisms

This study aimed to assess the preventive effects of thyme oil and thymol on doxorubicin(DOX)-induced renotoxicity,cardiotoxicity,and oxidative stress in Wistar rats.Thyme oil was subjected to GC-MS analysis,which indicated that thymol was the major constituent representing 33.896%.Rats intraperitoneally injected with DOX at a dose of 2 mg/kg b.w./one per week for 7 weeks were co-treated with thyme oil and its major constituent,thymol,at doses 250 and 100 mg/kg b.w./every other day,respectively,by oral gavage for the same period.Thyme oil and thymol markedly ameliorated the raised levels of serum urea,uric acid,and creatinine in DOX-administered rats.They also reduced the elevated activities of serum CK-MB and LDH.Thyme oil was more effective than thymol in decreasing the elevated serum creatinine level and serum CK-MB activity in DOX-administered rats,thereby reflecting its more potent effect on kidney and heart functions.Lipid peroxidation significantly decreased while GSH level and GST and GPx activities significantly increased in kidney and heart of DOX-administered rats treated with thyme oil and thymol.The DOX-induced perturbed kidney histological changes including congestion of glomerulus tuft,inflammatory cells infiltration,protein cast in lumina of the renal tubule,and thickening of the parietal layer of Bowman’s capsule were remarkably ameliorated as a result of treatment with thyme oil and thymol;thyme oil was more effective.In addition,DOX-induced deleterious heart histological alterations,including intramuscular infiltration of inflammatory cells,focal necrosis of cardiac myocytes,and edema,were remarkably reduced by treatment with thyme oil and thymol.Thus,it can be concluded that DOX could induce marked toxicity in kidney and heart,and the treatment with thyme oil or thymol produced potential improvement of kidney and heart function and histological integrity via repression of oxidative stress and enhancement of antioxidant defense mechanisms.

Induced pluripotent stem cells for therapy personalization in pediatric patients:Focus on drug-induced adverse events

Adverse drug reactions(ADRs)are major clinical problems,particularly in special populations such as pediatric patients.Indeed,ADRs may be caused by a plethora of different drugs leading,in some cases,to hospitalization,disability or even death.In addition,pediatric patients may respond differently to drugs with respect to adults and may be prone to developing different kinds of ADRs,leading,in some cases,to more severe consequences.To improve the comprehension,and thus the prevention,of ADRs,the set-up of sensitive and personalized assays is urgently needed.Important progress is represented by the possibility of setting up groundbreaking patient-specific assays.This goal has been powerfully achieved using induced pluripotent stem cells(iPSCs).Due to their genetic and physiological species-specific differences and their ability to be differentiated ideally into all tissues of the human body,this model may be accurate in predicting drug toxicity,especially when this toxicity is related to individual genetic differences.This review is an up-to-date summary of the employment of iPSCs as a model to study ADRs,with particular attention to drugs used in the pediatric field.We especially focused on the intestinal,hepatic,pancreatic,renal,cardiac,and neuronal levels,also discussing progress in organoids creation.The latter are three-dimensional in vitro culture systems derived from pluripotent or adult stem cells simulating the architecture and functionality of native organs such as the intestine,liver,pancreas,kidney,heart,and brain.Based on the existing knowledge,these models are powerful and promising tools in multiple clinical applications including toxicity screening,disease modeling,personalized and regenerative medicine.

Fluoropyrimidine-induced cardiotoxicity

Cardio-oncology is a discipline based on early screening,monitoring,and treating chemotherapy-induced cardiotoxicity.There are many chemotherapeutics known for their cardiac toxic effects,including fluoropyrimidines.Fluoropyrimidine represents the cornerstone of many types of cancer and each year almost two million cancer patients undergo this treatment.Fluoropyrimidine-induced cardiotoxicity can be manifested in several forms,from angina pectoris to sudden death.This paper is a review of how the cardiotoxicity of fluoropyrimidines is presented,the mechanisms of its occurrence,its diagnosis,and management.

Evaluation of Epirubicin-induced Cardiotoxicity by Two-dimensional Strain Echocardiography in Breast Cancer Patients

The value of two-dimensional strain echocardiography for assessing left ventricular regional systolic function in breast cancer patients who were treated with epirubicin was evaluated. A total of 116 breast cancer patients were divided into 3 groups： Thirty-eight patients in group A were given epirubicin （Epi） of 120-340 mg/m^2, 42 patients in group B received epimbicin of≥ 360 mg/m^2, and 36 patients after surging without chemotherapy served as the control group C. High frame rate two-dimensional images were recorded from apical long-axis view, four-chamber view, two-chamber view of left ventricle. Peak systolic strain of left ventricular subendocardial myocardium was measured using two-dimensional strain software. The conventional echocardiographic parameters were also obtained. Conventional echocardiography showed there was no significant changes in conventional echocardiographic parameters among the three groups （P〉0.05）. Two-dimensional strain echocardiography revealed that the peak systolic strain of left ventricular subendocardial myocardium in group A was reduced in some segments as compared with the controls （P〈0.05）. The peak systolic strain of left ventricular subendocardial myocardium in group B was reduced significantly as com- pared with group C （P〈0.05）, but that was reduced in group B just in some of the segments as compared with group A （P〈0.05）. It was concluded that two-dimensional strain echocardiography could early and sensitively display the effects of epirubicin-induced cardiotoxicity on the systolic function of left ventricular subendocardial myocardium, and early monitor the epirubicin-induced cardiotoxicity.

Nuclear imaging in detection and monitoring of cardiotoxicity

Cardiotoxicity as a result of cancer treatment is a novel and serious public health issue that has a significant impact on a cancer patient’s management and outcome.The coexistence of cancer and cardiac disease in the same patient is more common because of aging population and improvements in the efficacy of antitumor agents.Left ventricular dysfunction is the most typical manifestation and can lead to heart failure.Left ventricular ejection fraction measurement by echocardiography and multigated radionuclide angiography is the most common diagnostic approach to detect cardiac damage,but it identifies a late manifestation of myocardial injury.Early non-invasive imaging techniques are needed for the diagnosis and monitoringof cardiotoxic effects.Although echocardiography and cardiac magnetic resonance are the most commonly used imaging techniques for cardiotoxicity assessment,greater attention is focused on new nuclear cardiologic techniques,which can identify high-risk patients in the early stage and visualize the pathophysiologic process at the tissue level before clinical manifestation.The aim of this review is to summarize the role of nuclear imaging techniques in the non-invasive detection of myocardial damage related to antineoplastic therapy at the reversible stage,focusing on the current role and future perspectives of nuclear imaging techniques and molecular radiotracers in detection and monitoring of cardiotoxicity.

Long Term Perinatal Deltamethrin Exposure Alters Electrophysiological Properties of Embryonic Ventricular Cardiomyocyte

Increased use of pyrethroids and the exposure to pyrethroids for pregnant women and children have raised the concerns over the potential effect of pyrethroids on developmental cardiotoxicity and other abnormalities.The purpose of this study was to investigate whether long tenn peri natal deltamethrin exposure altered embryonic cardiac electrophysiology in mice.Pregnant mice were administered with 0 or 3 mg/kg of deltamethrin by gavage daily from gestational day(gd)10.5 to gd 17.5.Whole cell patch-clamp technique was used in electrophysiological study,and real time RT-PCR was applied to analyze the molecular changes for the electrophysiological properties.Deltamethrin exposure resulted in increased mortality of pregnant mice and decreased viability of embryos.Moreover,deltamethrin slowed the maximum depolarization velocity(Vmax),prolonged the action potential duration(APD)and depolarized the maximuin diastolic potential(MDP)of embryonic cardiomyocytes.Additionally,perinatal deltamethrin exposure decreased the mRNA expression of Na^+channel regulatory subunit Navpl,inward rectifier K^+channel subunit Kir2.1,and delayed rectifier K^+channel subunit MERG while the L-type Ca^2+channel subunit,Cavl.2 expression was increased.On the contraiy,deltamethrin administration did not significantly alter the regulation ofβ-adrenergic or muscarinic receptor on embryonic cardiomyocytes.In conclusion,deltamethrin exposure at perinatal stage significantly alters mRNA expression of embryonic cardiac ion channels and therefore influences embryonic cardiac electrophysiological properties.This highlights the need to understand the persistent effects of pyrethroid exposure on cardiac function during embryonic development due to potential for cardiac arrhythmogenicity.

Phloretin-induced suppression of oxidative and nitrosative stress attenuates doxorubicin-induced cardiotoxicity in rats

Objective:To compare the cardioprotective efficacy of equimolar doses(50 mM/kg,p.o.)of phloretin and genistein against doxorubicin-induced cardiotoxicity in rats.Methods:Cardiotoxicity was induced in rats by intraperitoneal injection of 6 mg/kg doxorubicin on alternative days till the cumulative dose reached 30 mg/kg.This study included four treatment groups of rats(n=6):the control group(0.5%carboxymethyl cellulose solution-treated),the doxorubicin-treated group(0.5%carboxymethyl cellulose solution along with doxorubicin),the genistein-treated group(50 mM/kg/day;p.o.along with doxorubicin)and phloretin-treated group(50 mM/kg/day;p.o.along with doxorubicin).On the 10th day of dosing,rats were anesthetized for recording ECG,mean arterial pressure,and left ventricular function.Oxidative stress,nitric oxide levels,and inflammatory cytokines were estimated in the cardiac tissue.Cardiac function parameters(creatine kinase MB,lactate dehydrogenase,aspartate aminotransferase,and alanine transaminase)were estimated in the serum samples.Results:Phloretin treatment inhibited doxorubicin-induced oxidative stress and also reduced nitric oxide levels in cardiac tissues of rats.Phloretin administration attenuated doxorubicin-induced alterations in hemodynamic parameters(heart rate,mean arterial blood pressure,and left ventricular function)and suppressed the expression of pro-inflammatory cytokines.The cardiac injury markers like creatine kinase MB,lactate dehydrogenase,aspartate aminotransferase,and alanine transaminase were reduced by both genistein and phloretin.All these effects of phloretin were more prominent than genistein.Conclusions:Phloretin offers cardioprotection that is comparable to genistein,a clinically validated cardioprotectant against doxorubicin-induced cardiotoxicity.Further studies are needed to confirm and establish the therapeutic utility of phloretin as a chemopreventive adjuvant to doxorubicin chemotherapy.

Neuregulin-1/erbB activities with focus on the susceptibility of the heart to anthracyclines

Neuregulin-1(NRG1)signaling through the tyrosine kinase receptors erbB2 and erbB4 is required for cardiac morphogenesis,and it plays an essential role in maintaining the myocardial architecture during adulthood.The tyrosine kinase receptor erbB2 was first linked to the amplification and overexpression of erbb2 gene in a subtype of breast tumor cells,which is indicative of highly proliferative cells and likely a poor prognosis following conventional chemotherapy.The development of targeted therapies to block the survival of erbB2-positive cancer cells revealed that impaired NRG1 signaling through erbB2/erbB4 heterodimers combined with anthracycline chemotherapy may lead to dilated cardiomyopathy in a subpopulation of treated patients.The ventricular-specific deletion of either erbb2 or erbb4 manifested dilated cardiomyopathy,which is aggravated by the administration of doxorubicin.Based on the exacerbated toxicity displayed by the combined treatment,it is expected that the relevant pathways would be affected in a synergistic manner.This review examines the NRG1 activities that were monitored in different model systems,focusing on the emerging pathways and molecular targets,which may aid in understanding the acquired dilated cardiomyopathy that occurs under the conditions of NRG1-deficient signaling.