Anthracycline Cardiotoxicity
2019; Lippincott Williams & Wilkins; Volume: 12; Issue: 3 Linguagem: Inglês
10.1161/circheartfailure.119.005910
ISSN1941-3297
Autores Tópico(s)Cancer Treatment and Pharmacology
ResumoHomeCirculation: Heart FailureVol. 12, No. 3Anthracycline Cardiotoxicity Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAnthracycline CardiotoxicityOne Step Closer to Reversing the Irreversible Anna Narezkina, MD and Khoban Nasim, BS Anna NarezkinaAnna Narezkina Anna Narezkina, MD, Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, 9300 Campus Point Dr, La Jolla, CA 92037. Email E-mail Address: [email protected] Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego. and Khoban NasimKhoban Nasim Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego. Originally published15 Mar 2019https://doi.org/10.1161/CIRCHEARTFAILURE.119.005910Circulation: Heart Failure. 2019;12:e005910This article is a commentary on the followingDoxorubicin Exposure Causes Subacute Cardiac Atrophy Dependent on the Striated Muscle–Specific Ubiquitin Ligase MuRF1See Article by Willis et alThe discovery of anthracyclines in the 1960s was a major breakthrough in oncology. And although the field of cancer therapeutics has undergone dramatic changes over subsequent decades, anthracyclines remain the cornerstone of contemporary chemotherapeutic regimens for a variety of cancers. Although very effective, the use of anthracyclines has been limited by significant dose-dependent cardiotoxicity. In the contemporary cohort of 2625 anthracycline-treated patients, who were followed for a median time of 5.2 years after chemotherapy, the incidence of cardiotoxicity was 9% (cardiotoxicity was defined as reduction in left ventricular [LV] ejection fraction >10% from baseline and <50%).1 Although anthracycline-induced cardiotoxicity was initially thought to be irreversible,2 there is increasing evidence of myocardial recovery after anthracycline-induced damage. In the study of 201 patients with anthracycline-induced cardiomyopathy (LV ejection fraction <45%), treatment with enalapril and carvedilol within 2 months after the completion of chemotherapy was associated with normalization of the LV ejection fraction in 64% of the patients.3 In contrast, LV ejection fraction did not normalize in any of the patients who started treatment later than 6 months after the completion of chemotherapy.3Understanding the biological mechanisms underlying anthracycline-induced cardiac toxicity is critical to developing successful strategies for prevention, early detection, and treatment. Previously, anthracycline-induced cardiotoxicity was primarily attributed to iron-dependent generation of reactive oxygen species and subsequent oxidative damage.4 More recent data indicate that anthracycline-induced generation of reactive oxygen species is dependent on topoisomerase-2β.5 Doxorubicin-bound topoisomerase-2β suppresses transcription of antioxidative and electron transport genes, leading to marked increase in reactive oxygen species and defective mitochondrial biogenesis. Mice with a cardiac-specific deletion of Top2b are protected against doxorubicin-related cardiomyopathy.5Many recent clinical studies indicated that LV mass reduction is seen early in the course of anthracycline-induced cardiotoxicity. In a study by Jordan et al,6 76 patients receiving chemotherapy were evaluated by a cardiac magnetic resonance imaging (CMR) before and 6 months after receiving chemotherapy. Patients who received anthracyclines demonstrated a 5% reduction in LV mass, which was not seen among patients receiving other types of chemotherapy. In another CMR-based study of 91 patients with anthracycline-induced cardiomyopathy decrease in LV mass index correlated with the cumulative dose of anthracycline.7 Moreover, LV mass index was a strong predictor of major adverse cardiac events, composed of death, heart failure admissions, and appropriate defibrillator therapy.7 This reduction in LV mass may be caused by apoptosis as well as myocyte atrophy. In a CMR-based imaging study of breast cancer patients, a reduction in LV mass index after anthracycline therapy was associated with an ≈30% decrease in intracellular lifetime of water (τic),8 which is a noninvasive way for measuring cardiomyocyte size. τic estimates the time it takes a water molecule to diffuse to the cell membrane, and in cardiomyocytes, τic is primarily determined by the cell diameter.9 This suggests that reduction in LV mass with anthracycline therapy is at least partly related to myocyte atrophy.In the current issue of Circulation: Heart Failure, Willis et al10 demonstrate subacute anthracycline-induced myocyte atrophy in humans and a mouse model and describe its potential mechanism. They showed a significant decrease in cardiac mass measured by CMR in 70 human subjects 1 month after anthracycline treatment, and this effect persisted through the 6-month follow-up period. They also noted a dose-dependent decrease in cardiac mass and myocardial fractional shortening in wild-type C57B6J mice treated with intraperitoneal doxorubicin. There was no convincing evidence for significant doxorubicin-induced apoptosis in this study. Instead, upon histological examination, there was a 44% decrease in cardiomyocyte cross-sectional area, suggesting that cell atrophy rather than apoptosis was the primary cause of myocardial mass loss. Molecular profiling of the myocardium of doxorubicin-treated mice revealed upregulation of MuRF1 (muscle-specific ubiquitin ligase muscle ring finger-1), and its upstream regulator, BNIP3 (BCL2 interacting protein 3). There was also switching of MHC (myosin heavy chain) from the α to the β isoform, as is typically seen in atrophy. MuRF1, a striated muscle-specific ubiquitin ligase, has been previously described as a mediator of cardiac atrophy in other mouse models.11 Here Willis et al10 developed global MuRF1-deficient mice to investigate the causal relationship between MuRF1 and doxorubicin-induced myocardial atrophy. Unlike wild-type mice, animals lacking MuRF1 were resistant to doxorubicin-induced cardiomyopathy. MuRF1−/− mice had preserved myocardial function and heart weight after anthracycline exposure. This study confirmed that cardiomyocyte atrophy plays a significant role in the pathogenesis of anthracycline-related cardiac injury and demonstrated that in mice doxorubicin-induced cardiac atrophy is dependent on MuRF1.The authors prove a direct effect of MuRF1 on cardiomyocyte atrophy but acknowledge that other signaling pathways may also be involved in the process. In their discussion, the authors also note that the single-dose model does not replicate clinical dosing. Further studies are needed to prove that these findings in a murine model are applicable to humans; additional experiments in human cardiomyocyte model systems could help bridge gaps in our understanding of anthracycline-induced myocardial atrophy.A decline in LV mass could potentially serve as a marker of early anthracycline-induced cardiac damage, but further research is needed to understand its utility in clinical practice. CMR availability in the community is limited at the present time, and echocardiography-based LV mass measurement might be easier to adopt in wide clinical practice. With CMR, LV mass is acquired from a 3-dimensional image of LV, whereas traditional echocardiographic estimation of LV mass from 2-dimensional images is based on geometric assumptions that may introduce a substantial error.12 Comparison of echocardiography- and CMR-derived LV mass index in 91 patients with anthracycline-induced cardiomyopathy showed that echocardiography overestimates LV mass index by an average of 20 g/m2.7 Additional studies are needed to confirm that echocardiographic measurement of LV mass is reproducible and sensitive for the small changes in LV mass among patients undergoing anthracycline therapy.LV mass loss caused by cardiomyocyte atrophy could be the underlying pathogenetic aspect that explains the reversibility of anthracycline-induced cardiomyopathy. This study advances our understanding of molecular mechanisms of anthracycline-induced atrophy and opens the door for new discoveries. Variations in MuRF1 expression in myocardium could determine individual susceptibility to doxorubicin-induced cardiotoxicity. Inhibitors of the MuRF1-mediated pathway could be tested in prevention and treatment of anthracycline-induced cardiomyopathy. In addition, we should explore effects of neurohormonal blocking agents on MuRF1-mediated cardiac atrophy.As survival of cancer patients continues to improve, long-term cardiovascular complications of chemotherapy are a major concern. The overarching goal of the emerging field of cardio-oncology is to make cancer treatments safer from cardiovascular perspective. Better understanding of the mechanisms of cardiotoxicity brings us closer to that ultimate goal of developing better techniques for surveillance, prevention, and treatment.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Anna Narezkina, MD, Division of Cardiovascular Medicine, Department of Medicine, University of California San Diego, 9300 Campus Point Dr, La Jolla, CA 92037. Email [email protected]eduReferences1. Cardinale D, Colombo A, Bacchiani G, Tedeschi I, Meroni CA, Veglia F, Civelli M, Lamantia G, Colombo N, Curigliano G, Fiorentini C, Cipolla CM. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy.Circulation. 2015; 131:1981–1988. doi: 10.1161/CIRCULATIONAHA.114.013777LinkGoogle Scholar2. Von Hoff DD, Layard MW, Basa P, Davis HL, Von Hoff AL, Rozencweig M, Muggia FM. 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Willis, et al. Circulation: Heart Failure. 2019;12 March 2019Vol 12, Issue 3 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.119.005910PMID: 30871350 Originally publishedMarch 15, 2019 KeywordsEditorialsmicedoxorubicincardiotoxicityPDF download Advertisement SubjectsAnimal Models of Human DiseaseCardio-OncologyCardiomyopathyHeart FailureMechanismsPathophysiology
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