Can short-term fasting protect against doxorubicin-induced cardiotoxicity?

Doxorubicin(Dox) is one of the most effective chemotherapeutic agents used in the treatment of several types of cancer. However the use is limited by cardiotoxicity. Despite extensive investigation into the mechanisms of toxicity and preventative strategies, Dox-induced cardiotoxicity still remains a major cause of morbidity and mortality in cancer survivors. Thus, continued research into preventative strategies is vital. Short-term fasting has proven to be cardioprotective against a variety of insults. Despite the potential, only a few studies have been conducted investigating its ability to prevent Dox-induced cardiotoxicity. However, all show proof-of-principle that short-term fasting is cardioprotective against Dox. Fasting affects a plethora of cellular processes making it difficult to discern the mechanism(s) translating fasting to cardioprotection, but may involve suppression of insulin and insulin-like growth factor-1 signaling with stimulated autophagy. It is likely that additional mechanisms also contribute. Importantly, the literature suggests that fasting may enhance the antitumor activity of Dox. Thus, fasting is a regimen that warrants further investigation as a potential strategy to prevent Dox-induced cardiotoxicity. Future research should aim to determine the optimal regimen of fasting, confirmation that this regimen does not interfere with the antitumor properties of Dox, as well as the underlying mechanisms exerting the cardioprotective effects.

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.

Advances of MicroRNA in the diagnosis and mechanism of doxorubicin-induced cardiotoxicity

Doxorubicin is a highly effective anthracycline chemotherapy drug,but its dose-dependent cardiotoxicity limits its clinical application.There are still many problems such as lack of sensitive biomarkers、effective therapeutic drugs and incomplete explanation of the mechanism.Because MicroRNA is expressed stably in human body fluid and especially in human tissue,and increasing evidence indicates that MicroRNA is not only involved in regulating cardiac electrical conduction,myocardial contraction process,but also can be used as a noninvasive biomarker,so this review will focus on the advances of MicroRNA in diagnosis and mechanism of doxorubicin-induced cardiotoxicity.

Protective role of concomitant administration of flax lignan concentrate and omega-3-fatty acid on myocardial damage in doxorubicin-induced cardiotoxicity

The severe cardiotoxicity incurred due to doxorubicin limits the use of their therapeutic potential.The current study aims to investigate the cardioprotective effect of concomitant administration of flax lignan concentrate(FLC)and omega-3-fatty acid(ω-3-FA)on myocardial damage in doxorubicin-induced cardiotoxicity in Wistar rats.Cardiotoxicity was induced by intraperitoneal injection of doxorubicin(4 mg/kg)on day 7th,14th,21st and 28th day in normal saline.Concomitant administration of FLC(500 mg/kg)andω-3-FA(1 mL/kg)lowered TNF-αlevel,normalized ST,QT and mean arterial blood pressure,elevation in endogenous enzymes levels such as glutathione and lowering in malondialdehyde,super oxide dismutase followed by normalized lipid profile and reduced the mortality rate.The treatment had antiapoptotic potential at cellular level also histopathology of heart tissue(light and electron microscopical).Thus concomitant action of FLC andω-3-FA may be antioxidant,antihyperlipidemic,anti-inflammatory and anti-apoptotic actions seem to the probable mechanisms in doxorubicin induced cardiotoxicity.It can be concluded that FLC andω-3-FA both have distinct mechanism for cardioprotection and hence the additive effect was observed in the present study due to concomitant administration of FLC andω-3-FA.©2013 Beijing Academy of Food Sciences.Production and hosting by Elsevier B.V.All rights reserved.

Idebenone alleviates doxorubicin-induced cardiotoxicity by stabilizing FSP1 to inhibit ferroptosis

Doxorubicin(DOX)-mediated cardiotoxicity can exacerbate mortality in oncology patients,but related pharmacotherapeutic measures are relatively limited.Ferroptosis was recently identified as a major mechanism of DOX-induced cardiotoxicity.Idebenone,a novel ferroptosis inhibitor,is a well-described clinical drug widely used.However,its role and pathological mechanism in DOX-induced cardiotoxicity are still unclear.In this study,we demonstrated the effects of idebenone on DOX-induced cardiotoxicity and elucidated its underlying mechanism.A single intraperitoneal injection of DOX(15 mg/kg)was administrated to establish DOX-induced cardiotoxicity.The results showed that idebenone significantly attenuated DOX-induced cardiac dysfunction due to its ability to regulate acute DOX-induced Fe^(2+)and ROS overload,which resulted in ferroptosis.CESTA and BLI further revealed that idebenone's anti-ferroptosis effect was mediated by FSP1.Interestingly,idebenone increased FSP1 protein levels but did not affect Fsp1 mRNA levels in the presence of DOX.Idebenone could form stable hydrogen bonds with FSP1 protein at K355,which may influence its association with ubiquitin.The results confirmed that idebenone stabilized FSP1 protein levels by inhibiting its ubiquitination degradation.In conclusion,this study demonstrates idebenone attenuated DOX-induced cardiotoxicity by inhibiting ferroptosis via regulation of FSP1,making it a potential clinical drug for patients receiving DOX treatment.

Overexpressed SIRT6 ameliorates doxorubicin-induced cardiotoxicity and potentiates the therapeutic efficacy through metabolic remodeling

Since the utilization of anthracyclines in cancer therapy, severe cardiotoxicity has become a major obstacle. The major challenge in treating cancer patients with anthracyclines is minimizing cardiotoxicity without compromising antitumor efficacy. Herein, histone deacetylase SIRT6 expression was reduced in plasma of patients treated with anthracyclines-based chemotherapy regimens. Furthermore,overexpression of SIRT6 alleviated doxorubicin-induced cytotoxicity in cardiomyocytes, and potentiated cytotoxicity of doxorubicin in multiple cancer cell lines. Moreover, SIRT6 overexpression ameliorated doxorubicin-induced cardiotoxicity and potentiated antitumor efficacy of doxorubicin in mice, suggesting that SIRT6 overexpression could be an adjunctive therapeutic strategy during doxorubicin treatment.Mechanistically, doxorubicin-impaired mitochondria led to decreased mitochondrial respiration and ATP production. And SIRT6 enhanced mitochondrial biogenesis and mitophagy by deacetylating and inhibiting Sgk1. Thus, SIRT6 overexpression coordinated metabolic remodeling from glycolysis to mitochondrial respiration during doxorubicin treatment, which was more conducive to cardiomyocyte metabolism, thus protecting cardiomyocytes but not cancer cells against doxorubicin-induced energy deficiency. In addition, ellagic acid, a natural compound that activates SIRT6, alleviated doxorubicininduced cardiotoxicity and enhanced doxorubicin-mediated tumor regression in tumor-bearing mice.These findings provide a preclinical rationale for preventing cardiotoxicity by activating SIRT6 in cancer patients undergoing chemotherapy, but also advancing the understanding of the crucial role of SIRT6 in mitochondrial homeostasis.

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.

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.

Chrysophanol protects against doxorubicin-induced cardiotoxicity by suppressing cellular PARylation

The clinical application of doxorubicin(DOX) in cancer chemotherapy is limited by its lifethreatening cardiotoxic effects. Chrysophanol(CHR), an anthraquinone compound isolated from the rhizome of Rheum palmatum L., is considered to play a broad role in a variety of biological processes.However, the effects of CHR’s cardioprotection in DOX-induced cardiomyopathy is poorly understood. In this study, we found that the cardiac apoptosis, mitochondrial injury and cellular PARylation levels were significantly increased in H9 C2 cells treated by Dox, while these effects were suppressed by CHR. Similar results were observed when PARP1 activity was suppressed by its inhibitors 3-aminobenzamide(3 AB)and ABT888. Ectopic expression of PARP1 effectively blocked this CHR’s cardioprotection against DOX-induced cardiomyocyte injury in H9 C2 cells. Furthermore, pre-administration with both CHR and 3 AB relieved DOX-induced cardiac apoptosis, mitochondrial impairment and heart dysfunction in Sprague–Dawley rat model. These results revealed that CHR protects against DOX-induced cardiotoxicity by suppressing cellular PARylation and provided critical evidence that PARylation may be a novel target for DOX-induced cardiomyopathy.

Protective effect of chrysoeriol against doxorubicin-induced cardiotoxicity in vitro

Background The use of doxorubicin （DOX） is limited by its dose-dependent cardiotoxicity. Reactive oxygen species （ROSs） play an important role in the pathological process of DOX-induced cardiotoxicity. The aim of this study was to evaluate the protective effect of chrysoeriol, a flavone compound, against DOX-induced apoptosis and death in H9c2 cells and to find out its preliminary mechanism. Methods We used 3-（4,5-dimethylthiazol-2-yl）-2,5-diphenyl-2H-tetrazolium bromide （MTT） assay, Hoechst33258 staining and measurement of lactate dehydrogenase （LDH） release to evaluate the protective effect of chrysoeriol against DOX-induced apoptosis and death in H9c2 cells. To find out the mechanism of this protective effect, we observed the immunofluorescence of intracellular ROS and measured the activities of malondialdehyde （MDA）, superoxide dismutase （SOD） and glutathione peroxidase （GPx）. Furthermore, we evaluated the effect of chrysoeriol on the antitumor activity of DOX in HeLa cells with MTT assay. Results The results of MTT assay, Hoechst 33258 staining and measurement of LDH release showed that chrysoeriol significantly reduced doxorubicin-induced apoptosis and cell death. Chrysoeriol at a dose of 20 μg/ml notably reduced intracellular ROS, decreased the concentration of MDA in the supernatant of DOX-treated H9c2 cells and increased SOD and GPx activities to their normal levels. Further study showed that the addition of chrysoeriol did not affect the antitumor activity of DOX. Conclusion Chrysoeriol could potentially serve as a novel cardioprotective agent against DOX-induced cardiotoxicity without affecting the antitumor activity of DOX.

Isorhapontigenin protects against doxorubicin-induced cardiotoxicity via increasing YAP1 expression

As an effective anticancer drug, the clinical limitation of doxorubicin(Dox) is the time-and dose-dependent cardiotoxicity. Yes-associated protein 1(YAP1) interacts with transcription factor TEA domain 1(TEAD1) and plays an important role in cell proliferation and survival. However, the role of YAP1 in Dox-induced cardiomyopathy has not been reported. In this study, the expression of YAP1 was reduced in clinical human failing hearts with dilated cardiomyopathy and Dox-induced in vivo and in vitro cardiotoxic model. Ectopic expression of Yap1 significantly blocked Dox-induced cardiomyocytes apoptosis in TEAD1 dependent manner. Isorhapontigenin(Isor) is a new derivative of stilbene and responsible for a wide range of biological processes. Here, we found that Isor effectively relieved Doxinduced cardiomyocytes apoptosis in a dose-dependent manner in vitro. Administration with Isor(30 mg/kg/day, intraperitoneally, 3 weeks) significantly protected against Dox-induced cardiotoxicity in mice. Interestingly, Isor increased Dox-caused repression in YAP1 and the expression of its target genes in vivo and in vitro. Knockout or inhibition of Yap1 blocked the protective effects of Isor on Dox-induced cardiotoxicity. In conclusion, YAP1 may be a novel target for Dox-induced cardiotoxicity and Isor might be a new compound to fight against Dox-induced cardiotoxicity by increasing YAP1 expression.

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.

MicroRNAs participate in the cardioprotective activity of dexrazoxane against doxorubicin-induced cardiotoxicity

Background The co-administration of dexrazoxane （DEX） with each dose of doxoruhicin （Dox） is an efficient strategy to relieve Dox-induced cardiotoxicity, however, the mechanisms underlying the cardioprotective effect of DEX have not been well elucidated. MieroRNAs （miRNAs） are endogenous, small non-coding RNAs that negatively regulate gene expression in diverse biological and pathological processes. The aim of the present study was to investigate whether the certain cardiac miRNAs were involved in DOX-induced cardiotoxicity. Methods Male SD rats were randomized into five groups, including the 4-week （cumulative dose： 16 mg/kg） and the 8-week （cumulative dose： 32 mg/kg） Dox-treated groups, and the corresponding 4-week and 8-week Dox plus DEX-treated groups and the normal control group. Heart functions of the animals were detected by echocardiography. Quantitative real-time PCR was used to determine the expression of cardiac remodeling, apoptosis-related genes and mature micoRNAs of interest. Results The echocardiography detection showed that cardiac remodeling and impaired heart function were observed after 4-week and 8-week Dox treatment, and the cardiac remodeling and decreased ejection fraction （EF%） and fractional shortening （FS%） were efficiently rescued in the corresponding 4-week and 8-week Dox plus DEX-treated groups. The myocardial expression of Anp and CTGF mRNA was significantly upregulated by Dox treatment, but the upregulation of Anp and CTGF mHNA was blocked in the Dox plus DEX-treated groups. IGF-1 mRNA was significantly up-regulated in rat myocardium in Dox plus DEX-treated groups, with no significant changes of Bcl-2 and BAX mRNA expression. Mature miRNAs determination demonstrated that the myocardial miR-1 and -30e were significantly down-regulated and miR-21 and -208b were significantly up-regulated in Dox treatment groups, but the above miRNA dysregulation could be efficiently reversed after DEX treatment. Conclusions DEX could tune the microRNAs dysregulation in Dox-treated rat myocardium, miRNAs participated in the cardioprotective activity of DEX against Dox-induced cardiotoxicity.

Didymin attenuates doxorubicin-induced cardiotoxicity by inhibiting oxidative stress

Objective:This study was designed to investigate the protective effects of didymin(Did)on doxorubicin(DOX)-induced cardiotoxicity.Methods:After pretreatment with Did(2,4,8 mg/kg intraperitoneal i.p.)for 7 d,the male C57 mice were injected with single dose of DOX(20 mg/kg i.p.).The cardioprotective effect of Did was observed on the 7th day after DOX treatment.Results:DOX delayed body growth and caused cardiac tissue injury,oxidative stress,and mitochondrial dysfunction.Similar experiments in H9C2 cardiomyocytes showed that DOX reduced cell viability,increased generation of reactive oxygen species(ROS)and fragmentation of DNA,decreased mitochondrial membrane potential,and induced cardiomyocyte apoptosis.However,all of these adverse effects were suppressed by Did pretreatment.Did increased protein expression of glutamate-L-cysteine ligase catalytic subunit(GCL),heme oxygenase 1(HO-1),and nuclear factor erythroid 2-related factor 2(Nrf2).Besides,Did also induced activation of PI3K/AKT.Conclusion:These findings indicated Did prevented DOX-induced cardiac injury and apoptosis via activating PI3K/AKT/Nrf2 signaling pathway.

Long Term Follow-Up of Cardiotoxicity in Breast Cancer Treatment: A Case Report

Background: Cardiac toxicity is currently defined as a symptomatic decrease in Left Ventricular Ejection Fraction (LVEF) of more than 5% or an asymptomatic decrease of at least 10% to a value of under 50% in repeated evaluations on conventional transthoracic echocardiogram (TTE), as well as a Global Longitudinal Strain (GLS) value Aims: To highlight using GLS rather than modified Simpson 2D-LVEF for the evaluation of long-term cardiotoxicity. Case Presentation: The case concerns a 73-year-old female patient with a history of breast cancer chemotherapy and anthracyclines-based therapy who presented symptoms of late cardiac toxicity related to the chemotherapeutic treatment. In the following years, the patient remained asymptomatic with a 2D-LVEF of 48%, dilation of the left atrium was found, and the reservoir phase strain was severely decreased. Conclusion: The preferred method for evaluating cardiovascular complications associated with chemotherapy is the TTE, which is performed prior to the start of treatment, during therapy, and in the follow-up. Myocardial deformation as a predictor of cardiotoxicity allows the identification of subclinical heart failure.

Research progress on cardiotoxicity mechanism of doxorubicin and prevention and treatment of traditional Chinese medicine

Doxorubicin is an anthracycline antibiotic.As a broad-spectrum antitumor drug,it is widely used in clinic.However,doxorubicin is dose-dependent and shows obvious cardiotoxicity,which limits its clinical application.At present,the mechanism of doxorubicin induced cardiotoxicity has not been fully clarified.Reducing cardiotoxicity and improving the scope of clinical application have become the focus of research in recent years.This paper reviews the mechanism of doxorubicin cardiotoxicity and the prevention and treatment of doxorubicin cardiotoxicity with traditional Chinese medicine,in order to provide reference for the combined application of doxorubicin.

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.

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.