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Heart Failure Clinics Jul 2022Targeting cardioprotective strategies to patients at the highest risk for cardiac events can help maximize therapeutic benefits. Dexrazoxane, liposomal formulations,... (Review)
Review
Targeting cardioprotective strategies to patients at the highest risk for cardiac events can help maximize therapeutic benefits. Dexrazoxane, liposomal formulations, continuous infusions, and neurohormonal antagonists may be useful for cardioprotection for anthracycline-treated patients at the highest risk for heart failure. Prevalent cardiovascular disease is a risk factor for cardiac events with many cancer therapies, including anthracyclines, anti-human-epidermal growth factor receptor-2 therapy, radiation, and BCR-Abl tyrosine kinase inhibitors, and may be a risk factor for cardiac events with other therapies. Although evidence for cardioprotective strategies is sparse for nonanthracycline therapies, optimizing cardiac risk factors and prevalent cardiovascular disease may improve outcomes.
Topics: Anthracyclines; Antineoplastic Agents; Cardiovascular Diseases; Heart; Heart Failure; Humans; Risk Factors
PubMed: 35718414
DOI: 10.1016/j.hfc.2022.02.001 -
Rare Tumors 2022Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from...
BACKGROUND
Patient-reported outcomes (PROs), including health-related quality of life, are recommended to be routinely collected in clinical trials, but data are limited from trials of sarcoma patients. In this analysis, pooled PRO data are reported from patients with advanced or metastatic soft tissue sarcoma (STS) enrolled to the ANNOUNCE phase III trial of doxorubicin-based therapy.
METHODS
ANNOUNCE was a phase III trial that randomized 509 patients with STS to receive up to eight cycles of doxorubicin with olaratumab or placebo, followed by single-agent olaratumab or placebo. Dexrazoxane was allowed at any cycle of treatment. Participants completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30, which is scored 0-100), and Brief Pain Inventory Short Form Modified (mBPI-sf, scored from 0-10) at each treatment cycle. A descriptive analysis of the longitudinal data was conducted overall and by cumulative dose of doxorubicin received to inform the clinical care of patients with STS. Worsening on the QLQ-C30 was defined as a change of 10 points or more at any post-baseline assessment. Worsening on the mPBI-sf was defined as an increase of ≥2 points from baseline.
RESULTS
The majority of participants completed the baseline and at least one subsequent PRO assessment within the trial ( = 460, 90.4% EORTC QLQ-C30; = 454, 89.2%, mBPI-sf). Patients with STS enrolled to the ANNOUNCE trial had clinically meaningful problems with physical function and pain before initiating doxorubicin. Overall, those with fewer symptoms or better function at baseline received higher cumulative doxorubicin dose throughout the study. At baseline, mean QLQ-C30 fatigue was 29.9 with a median time to first worsening of 0.9 months, and mean nausea/vomiting was 6.5 with 1.4 months until worsening; mean physical function was 78.3 with median time to worsening of 2.1 months and mean health status was 66.8 with median time to first worsening of 1.6 months. Median time to worsening of pain was 7.9 months.
CONCLUSION
Patients with advanced or metastatic sarcoma reported a relatively rapid decline in PROs during doxorubicin-based treatment, with patients with poorer symptoms at baseline (specifically fatigue), subsequently receiving less doxorubicin therapy. The availability of detailed summary data from the patient perspective during doxorubicin-based treatment may inform future care of these patients and can provide a resource for the development of PRO endpoints in future trials.
PubMed: 35547106
DOI: 10.1177/20363613221100033 -
Frontiers in Cardiovascular Medicine 2022Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease.... (Review)
Review
Anthracyclines remain an essential component of the treatment of many hematologic and solid organ malignancies, but has important implications on cardiovascular disease. Anthracycline induced cardiotoxicity (AIC) ranges from asymptomatic LV dysfunction to highly morbid end- stage heart failure. As cancer survivorship improves, the detection and treatment of AIC becomes more crucial to improve patient outcomes. Current treatment modalities for AIC have been largely extrapolated from treatment of conventional heart failure, but developing effective therapies specific to AIC is an area of growing research interest. This review summarizes the current evidence behind the use of neurohormonal agents, dexrazoxane, and resynchronization therapy in AIC, evaluates the clinical outcomes of advanced therapy and heart transplantation in AIC, and explores future horizons for treatment utilizing gene therapy, stem cell therapy, and mechanism-specific targets.
PubMed: 35528842
DOI: 10.3389/fcvm.2022.863314 -
European Journal of Cancer (Oxford,... Jul 2022Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration, strategy and long-term efficacy of empiric cardio-protection remains unknown.
METHODS
Leveraging the MEDLINE/Pubmed, CENTRAL and clinicaltrials.gov databases, we identified all randomised controlled trials investigating cardioprotective therapies from inception to November 2021 (PROSPERO-ID:CRD42021265006). Cardioprotective classes included ACEIs, ARBs, Beta-blockers, dexrazoxane (DEX), statins and mineralocorticoid receptor antagonists. The primary end-point was new-onset heart failure (HF). Secondary outcomes were the mean difference in left ventricular ejection fraction (LVEF) change, hypotension and all-cause mortality. Network meta-analyses were used to assess the cardioprotective effects of each therapy to deduce the most effective therapies. Both analyses were performed using a Bayesian random effects model to estimate risk ratios (RR) and 95% credible intervals (95% CrI).
RESULTS
Overall, from 726 articles, 39 trials evaluating 5931 participants (38.0 ± 19.1 years, 72.0% females) were identified. The use of any cardioprotective strategy associated with reduction in new-onset HF (RR:0.32; 95% CrI:0.19-0.55), improved LVEF (mean difference: 3.92%; 95% CrI:2.81-5.07), increased hypotension (RR:3.27; 95% CrI:1.38-9.87) and no difference in mortality. Based on control arms, the number-needed-to-treat for 'any' cardioprotective therapy to prevent one incident HF event was 45, including a number-needed-to-treat of 21 with ≥1 year of therapy. Dexrazoxane was most effective at HF prevention (Surface Under the Cumulative Ranking curve: 81.47%), and mineralocorticoid receptor antagonists were most effective at preserving LVEF (Surface Under the Cumulative Ranking curve: 99.22%).
CONCLUSION
Cardiotoxicity remains a challenge for patients requiring anticancer therapies. The initiation of extended duration cardioprotection reduces incident HF. Additional head-to-head trials are needed.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bayes Theorem; Cardiotoxicity; Dexrazoxane; Female; Heart Failure; Humans; Hypotension; Male; Mineralocorticoid Receptor Antagonists; Network Meta-Analysis; Stroke Volume; Ventricular Function, Left
PubMed: 35524992
DOI: 10.1016/j.ejca.2022.03.024 -
Phytomedicine : International Journal... Jul 2022Doxorubicin-induced myocardiopathy is a massive obstacle in administering chemotherapeutic drugs in cancer patients.
BACKGROUND
Doxorubicin-induced myocardiopathy is a massive obstacle in administering chemotherapeutic drugs in cancer patients.
PURPOSES
In the present study, we aim to investigate the effects of spinacetin, a flavonoid glycoside, on doxorubicin-induced cardiotoxicity.
STUDY DESIGN
The doxorubicin-induced cardiotoxicity mice model was established to evaluate the cardioprotective effects of SP. The H9C2 cell line was used to study SP's potential mechanisms of action. Dexrazoxane (180 mg/kg) was used as the positive control.
METHODS
The CCK-8 cell proliferation assay, hematoxylin and eosin (HE) staining, detection of serum biomarkers, flow cytometry for apoptosis, dansylcadaverine (MDC) staining, and Western blot for crucial molecules were conducted in the present study.
RESULTS
SP significantly increased the survival rate of primary cardiomyocytes and decreased the serum LDH, CK-MB, TrT, and myocardial MDA level. The apoptosis of cardiomyocytes significantly decreased by SP, with upregulation of autophagy. In the H9C2 cell line, SP protects the cells from doxorubicin-induced cytotoxicity, decreases apoptosis, and increases autophagy. The subsequent mechanism study showed that the activation of AMPK/mTOR signaling was involved in the protective effects of SP on doxorubicin-induced cardiotoxicity through upregulating the expression level of SIRT3.
CONCLUSION
We concluded that SP could protect against doxorubicin-induced cardiotoxicity both in vitro and in vivo by initiating protective autophagy through SIRT3/AMPK/mTOR pathways, which has not been reported previously. SP could be treated as a potential candidate for cardioprotective usage during chemotherapy. The further clinical study is still urgently needed to investigate the safety and effectiveness of SP in patients.
Topics: Animals; Mice; AMP-Activated Protein Kinases; Apoptosis; Autophagy; Cardiotoxicity; Doxorubicin; Myocytes, Cardiac; Oxidative Stress; Sirtuin 3; TOR Serine-Threonine Kinases
PubMed: 35430482
DOI: 10.1016/j.phymed.2022.154098 -
Pharmaceutical Biology Dec 2022Shengmai injection (SMI) has been used to treat heart failure.
CONTEXT
Shengmai injection (SMI) has been used to treat heart failure.
OBJECTIVE
This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX).
MATERIALS AND METHODS
, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. , H9c2 cells were divided into control group, model group (2 mL 1 μM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed.
RESULTS
SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group . Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway.
CONCLUSIONS
This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.
Topics: Animals; Apoptosis; Cardiotoxicity; Cells, Cultured; Doxorubicin; Drug Combinations; Drugs, Chinese Herbal; Kelch-Like ECH-Associated Protein 1; Molecular Docking Simulation; Myocardium; NF-E2-Related Factor 2; Rats; Rats, Sprague-Dawley; Signal Transduction
PubMed: 35298357
DOI: 10.1080/13880209.2022.2046801 -
BioMed Research International 2022Doxorubicin (Dox) is an effective chemotherapeutic drug for the treatment of various cancers. Due to its potential fatal cardiotoxic side effects, the clinical... (Review)
Review
Doxorubicin (Dox) is an effective chemotherapeutic drug for the treatment of various cancers. Due to its potential fatal cardiotoxic side effects, the clinical application is often limited. Dexrazoxane (Dex) is the only drug approved by the Food and Drug Administration (FDA) for the prevention of Dox-induced cardiotoxicity but has side effects. Thus, more protective strategies should be explored. If NAD plays a role in maintaining heart function, its precursor prospectively alleviates Dox-induced cellular injury. Here, we studied the protective effects of nicotinic acid riboside (NAR) on Dox-induced cardiotoxicity and . We found that NAR significantly improved the cardiac function of Dox-treated mice by restoring ejection fraction (EF), fractional shortening (FS), and serum level of cardiac troponin (cTnI). NAR not only reduced malondialdehyde (MDA), lactate dehydrogenase (LDH), and reactive oxygen species (ROS) levels in Dox-treated cardiomyocytes but also further promoted the activities of cardiac superoxide dismutase (SOD) and glutathione (GSH). Following exposure to 5 M Dox, cotreatment with NAR exhibited increased cell viability with a decrease in the apoptosis cell population. Moreover, the levels of apoptosis-related proteins, as well as proteins involved in oxidative stress and autophagy, were altered after NAR treatment. Collectively, these findings underline the protective potential of NAR against Dox-induced cardiomyocyte injury by regulating Nrf-2/P62-related oxidative stress and autophagy, which could potentially promote survival.
Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Cardiotonic Agents; Cardiotoxicity; Dexrazoxane; Doxorubicin; Humans; Niacinamide; Oxidative Stress; Pyridinium Compounds
PubMed: 35242876
DOI: 10.1155/2022/6293329 -
European Heart Journal Supplements :... Oct 2021Prevention of left ventricular dysfunction predominantly induced by anthracyclines and/or trastuzumab still represents a challenge for cardio-oncology today. Indeed,...
Prevention of left ventricular dysfunction predominantly induced by anthracyclines and/or trastuzumab still represents a challenge for cardio-oncology today. Indeed, this complication threatens to limit the significant gain in cancer survival achieved to date. Oncology strategies with cumulative dose limitation, continuous infusion, dexrazoxane, and liposomal formulations have been shown to decrease the risk of anthracycline cardiotoxicity. The preventive use of ace inhibitors, sartans, and/or beta-blockers has not yet provided convincing evidence and the positive effect on left ventricular ejection fraction decline appears poor without a clear clinical relevance. Assessment of the cardiovascular risk profile is a key aspect of the baseline evaluation of any patient scheduled for cancer therapy. Control and/or correction of modifiable cardiovascular risk factors is the first form of primary prevention of cardiotoxicity. It will be necessary to select populations at higher risk of developing cardiac dysfunction, identify patients genetically predisposed to develop cardiotoxicity in order to build the most appropriate strategies to correctly and timely target cardioprotective therapies.
PubMed: 35233212
DOI: 10.1093/eurheartj/suab085 -
Frontiers in Cell and Developmental... 2022Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the...
Doxorubicin (DOX) is one of the most effective chemotherapeutic agents. However, its clinical use is limited due to the severe risk of cardiotoxicity. One of the hallmarks of doxorubicin-induced cardiotoxicity (DICT) is the cascade of mitophagy deficiency-mitochondrial oxidative injury-apoptosis, while so far, there is no preventive strategy for alleviating DICT by targeting this molecular mechanism. Excitedly, based on our previous drug screen in DICT zebrafish model, harpagoside (HAR) showed dramatic anti-DICT efficacy superior to dexrazoxane (DXZ) only cardioprotectant approved by FDA. Therefore, its pharmacological effects and molecular mechanism on DICT mouse and rat cardiomyocytes were further discussed. , HAR significantly improved cardiac function and myocardial structural lesions with concomitant of diminished mitochondrial oxidative damage and recovered mitophagy flux. In parallel, HAR protected mitophagy and mitochondria homeostasis, and repressed apoptosis . Intriguingly, both nutlin-3 (agonist of p53) and Parkin siRNA reversed these protective effects of HAR. Additional data, including fluorescence colocalization of Parkin and MitoTracker and mt-Keima for the detection of mitophagy flux and coimmunoprecipitation of p53 and Parkin, showed that HAR promoted Parkin translocation to mitochondria and substantially restored Parkin-mediated mitophagy by inhibiting the binding of p53 and Parkin. Importantly, the results of the cell viability demonstrated that cardioprotective effect of HAR did not interfere with anticancer effect of DOX on MCF-7 and HepG2 cells. Our research documented p53-Parkin-mediated cascade of mitophagy deficiency-mitochondrial dyshomeostasis-apoptosis as a pathogenic mechanism and druggable pathway and HAR as a cardioprotection on DICT by acting on novel interaction between p53 and Parkin.
PubMed: 35223843
DOI: 10.3389/fcell.2022.813370 -
Journal of Applied Toxicology : JAT Sep 2022Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present...
Cardiotoxicity is a serious adverse effect of an anticancer drug, doxorubicin (DOX), which can occur within a year or decades after completion of therapy. The present study was designed to address a knowledge gap concerning a lack of circulating biomarkers capable of predicting the risk of cardiotoxicity induced by DOX. Profiling of 2083 microRNAs (miRNAs) in mouse plasma revealed 81 differentially expressed miRNAs 1 week after 6, 9, 12, 18, or 24 mg/kg total cumulative DOX doses (early-onset model) or saline (SAL). Among these, the expression of seven miRNAs was altered prior to the onset of myocardial injury at 12 mg/kg and higher cumulative doses. The expression of only miR-34a-5p was significantly (false discovery rate [FDR] < 0.1) elevated at all total cumulative doses compared with concurrent SAL-treated controls and showed a statistically significant dose-related response. The trend in plasma miR-34a-5p expression levels during DOX exposures also correlated with a significant dose-related increase in cardiac expression of miR-34a-5p in these mice. Administration of a cardioprotective drug, dexrazoxane, to mice before DOX treatment, significantly mitigated miR-34a-5p expression in both plasma and heart in conjunction with attenuation of cardiac pathology. This association between plasma and heart may suggest miR-34a-5p as a potential early circulating marker of early-onset DOX cardiotoxicity. In addition, higher expression of miR-34a-5p (FDR < 0.1) in plasma and heart compared with SAL-treated controls 24 weeks after 24 mg/kg total cumulative DOX dose, when cardiac function was altered in our recently established delayed-onset cardiotoxicity model, indicated its potential as an early biomarker of delayed-onset cardiotoxicity.
Topics: Animals; Biomarkers; Cardiotoxicity; Doxorubicin; Heart; Mice; MicroRNAs
PubMed: 35199358
DOI: 10.1002/jat.4309