{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:54:24Z","timestamp":1783598064743,"version":"3.55.0"},"reference-count":47,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T00:00:00Z","timestamp":1699747200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Anthracycline treatments are known to cause cardiotoxic long-term side effects in cancer survivors. Recently, a decrease in heart rate variability (HRV) has been identified in these patients, signaling autonomic dysfunction and altered cardiac fitness. This study aimed at evaluating changes in HRV in children treated with anthracyclines. A total of 35 pediatric patients with acute lymphoblastic leukemia were evaluated by means of a 24 h Holter ECG, at baseline and after reaching half the total cumulative dose of doxorubicin equivalent (120 mg\/m2). Parameters of HRV were assessed, as well as any arrhythmic episodes, bradycardia and tachycardia percentages. The results showed a significant decrease in both time-domain and frequency-domain HRV parameters, following anthracycline treatment. The low-frequency (LF) to high-frequency (HF) parameters\u2019 ratio also displayed a significant difference (p = 0.035), suggestive of early cardiac autonomic dysfunction. Of note, none of the patients presented symptoms of heart disease or elevated troponins, and only two patients presented echocardiographic signs of diastolic dysfunction. The present study showed that cardiac autonomic nervous system regulation is compromised in children treated with anthracyclines even before reaching the total cumulative dose. Therefore, HRV parameters could be the first indicators of subclinical cardiac toxicity, making Holter ECG monitoring of the oncological patient a necessity.<\/jats:p>","DOI":"10.3390\/jcm12227052","type":"journal-article","created":{"date-parts":[[2023,11,13]],"date-time":"2023-11-13T02:46:47Z","timestamp":1699843607000},"page":"7052","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Anthracycline\u2019s Effects on Heart Rate Variability in Children with Acute Lymphoblastic Leukemia: Early Toxicity Signs\u2014Pilot Study"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7000-9949","authenticated-orcid":false,"given":"Diana R.","family":"Lazar","sequence":"first","affiliation":[{"name":"Department No. 11, Oncology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Department of Pediatric Cardiology, Emergency Hospital for Children, 400394 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simona","family":"Cainap","sequence":"additional","affiliation":[{"name":"Department of Pediatric Cardiology, Emergency Hospital for Children, 400394 Cluj-Napoca, Romania"},{"name":"Department of Mother and Child, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3759-6544","authenticated-orcid":false,"given":"Dana","family":"Maniu","sequence":"additional","affiliation":[{"name":"Biomolecular Physics Department, Faculty of Physics, \u201cBabes-Bolyai\u201d University, 400347 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4111-1295","authenticated-orcid":false,"given":"Cristina","family":"Blag","sequence":"additional","affiliation":[{"name":"Department of Mother and Child, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Department of Pediatric Oncology and Hematology, Emergency Hospital for Children, 400394 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Madalina","family":"Bota","sequence":"additional","affiliation":[{"name":"Department of Mother and Child, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Department of Pediatric Oncology and Hematology, Emergency Hospital for Children, 400394 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florin-Leontin","family":"Lazar","sequence":"additional","affiliation":[{"name":"Department No. 5, Internal Medicine, Medical Clinic Number 1, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5540-3478","authenticated-orcid":false,"given":"Alexandru","family":"Achim","sequence":"additional","affiliation":[{"name":"Department of Cardiology, \u201cNiculae Stancioiu\u201d Heart Institute, Motilor 19-21, 400001 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8023-2631","authenticated-orcid":false,"given":"Marius C.","family":"Colceriu","sequence":"additional","affiliation":[{"name":"Department of Functional Biosciences, Discipline of Physiology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9461-987X","authenticated-orcid":false,"given":"Mihnea","family":"Zdrenghea","sequence":"additional","affiliation":[{"name":"Department No. 11, Oncology, \u201cIuliu Hatieganu\u201d University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania"},{"name":"Department of Hematology, \u201cIon Chiricuta\u201d Oncology Institute, 400015 Cluj-Napoca, Romania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,11,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"81","DOI":"10.6004\/jnccn.2020.0001","article-title":"Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology","volume":"18","author":"Brown","year":"2020","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2801","DOI":"10.3109\/10428194.2014.894191","article-title":"Excellent outcomes for adolescents and adults with acute lymphoblastic leukemia and lymphoma without allogeneic stem cell transplant: The FRALLE-93 pediatric protocol","volume":"55","author":"Hocking","year":"2014","journal-title":"Leuk. Lymphoma"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3499","DOI":"10.1200\/JCO.22.01760","article-title":"Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Acute Lymphoblastic Leukemia Intercontinental-Berlin-Frankfurt-M\u00fcnster 2009 Trial","volume":"41","author":"Campbell","year":"2023","journal-title":"JCO"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.3389\/fphar.2018.01262","article-title":"Updates in Anthracycline-Mediated Cardiotoxicity","volume":"9","author":"Nebigil","year":"2018","journal-title":"Front. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1038\/nrclinonc.2013.195","article-title":"Treatment-related cardiotoxicity in survivors of childhood cancer","volume":"10","author":"Lipshultz","year":"2013","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s00392-018-1202-x","article-title":"Cardio-oncology: Conflicting priorities of anticancer treatment and cardiovascular outcome","volume":"107","author":"Tilemann","year":"2018","journal-title":"Clin. Res. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1056\/NEJM199103213241205","article-title":"Late Cardiac Effects of Doxorubicin Therapy for Acute Lymphoblastic Leukemia in Childhood","volume":"324","author":"Lipshultz","year":"1991","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s12265-020-10042-3","article-title":"The Role of Biomarkers in Cardio-Oncology","volume":"13","author":"Ananthan","year":"2020","journal-title":"J. Cardiovasc. Trans. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1007\/s11886-022-01834-x","article-title":"Recent Advances in Serum Biomarkers for Risk Stratification and Patient Management in Cardio-Oncology","volume":"25","author":"Joolharzadeh","year":"2023","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"e15226","DOI":"10.1016\/j.heliyon.2023.e15226","article-title":"Role of advanced cardiovascular imaging in chemotherapy-induced cardiotoxicity","volume":"9","author":"Cannizzaro","year":"2023","journal-title":"Heliyon"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1007\/s10741-020-09952-w","article-title":"Cardiac imaging in cardiotoxicity: A focus on clinical practice","volume":"26","author":"Makavos","year":"2021","journal-title":"Heart Fail. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"104542","DOI":"10.1016\/j.phrs.2019.104542","article-title":"Doxorubicin and its proarrhythmic effects: A comprehensive review of the evidence from experimental and clinical studies","volume":"151","author":"Benjanuwattra","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Li, H., Yang, W., Yu, Z., Peng, Y., Huang, M., Long, L., Lu, A., Tan, L., Deng, M., and Qu, H. (2023, August 04). Risk of Arrhythmia with Exposure to Anthracyclines: A Systematic Review, Meta-Analysis, and Network Meta-Analysis. In Review. Available online: https:\/\/www.researchsquare.com\/article\/rs-2318045\/v1.","DOI":"10.21203\/rs.3.rs-2318045\/v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"914","DOI":"10.5603\/KP.2018.0098","article-title":"Heart rate variability during and after chemotherapy with anthracycline in patients with breast cancer","volume":"76","author":"Stachowiak","year":"2018","journal-title":"Kardiol. Pol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1620\/tjem.211.121","article-title":"Cardiac Autonomic Functions are Altered in Patients with Acute Leukemia, Assessed by Heart Rate Variability","volume":"211","author":"Nevruz","year":"2007","journal-title":"Tohoku J. Exp. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1007\/s00392-019-01427-9","article-title":"Doxorubicin treatments induce significant changes on the cardiac autonomic nervous system in childhood acute lymphoblastic leukemia long-term survivors","volume":"108","author":"Caru","year":"2019","journal-title":"Clin. Res. Cardiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1007\/BF02897205","article-title":"Cardiovascular autonomic function in anthracycline-treated breast cancer patients","volume":"26","author":"Viniegra","year":"1990","journal-title":"Cancer Chemother. Pharmacol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/oxfordjournals.eurheartj.a014868","article-title":"Heart rate variability: Standards of measurement, physiological interpretation, and clinical use","volume":"17","author":"Malik","year":"1996","journal-title":"Eur. Heart J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1845","DOI":"10.1111\/j.1540-8159.1996.tb03238.x","article-title":"Stepwise strategy of using short- and long-term heart rate variability for risk stratification after myocardial infarction","volume":"19","author":"Faber","year":"1996","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.pcad.2013.07.003","article-title":"Heart rate variability in risk stratification of cardiac patients","volume":"56","author":"Huikuri","year":"2013","journal-title":"Prog. Cardiovasc. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Benichou, T., Pereira, B., Mermillod, M., Tauveron, I., Pfabigan, D., Maqdasy, S., and Dutheil, F. (2018). Heart rate variability in type 2 diabetes mellitus: A systematic review and meta\u2013analysis. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0195166"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e28388","DOI":"10.1002\/pbc.28388","article-title":"Cardiac autonomic dysfunction in survivors of childhood acute lymphoblastic leukemia: The St. Jude Lifetime Cohort Study","volume":"67","author":"Christoffersen","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_23","first-page":"299","article-title":"Heart rate variability and myocardial infarction: Systematic literature review and metanalysis","volume":"13","author":"Buccelletti","year":"2009","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1046\/j.1540-8167.2005.04358.x","article-title":"Cast Investigators Traditional and nonlinear heart rate variability are each independently associated with mortality after myocardial infarction","volume":"16","author":"Stein","year":"2005","journal-title":"J. Cardiovasc. Electrophysiol."},{"key":"ref_25","first-page":"956","article-title":"Myocardial sympathetic nervous dysfunction detected with iodine-123-MIBG is associated with low heart rate variability after myocardial infarction","volume":"36","author":"Kuikka","year":"1995","journal-title":"J. Nucl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1111\/j.1540-8159.1996.tb03286.x","article-title":"Heart rate variability after cardiac transplantation in humans","volume":"19","author":"Ramaekers","year":"1996","journal-title":"Pacing Clin. Electrophysiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s00246-003-0387-5","article-title":"Evolution of heart rate control after transplantation: Conduction versus autonomic innervation","volume":"25","author":"Sanatani","year":"2004","journal-title":"Pediatr. Cardiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1007\/s00246-018-1881-0","article-title":"Heart Rate Variability and Cardiopulmonary Dysfunction in Patients with Duchenne Muscular Dystrophy: A Systematic Review","volume":"39","author":"Massetti","year":"2018","journal-title":"Pediatr. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Brusseau, V., Tauveron, I., Bagheri, R., Ugbolue, U.C., Magnon, V., Bouillon-Minois, J.-B., Navel, V., and Dutheil, F. (2022). Heart Rate Variability in Hyperthyroidism: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health, 19.","DOI":"10.3390\/ijerph19063606"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Letzkus, L., Picavia, R., Lyons, G., Brandberg, J., Qiu, J., Kausch, S., Lake, D., and Fairchild, K. (2023). Heart rate patterns predicting cerebral palsy in preterm infants. Pediatr. Res., Online ahead of print.","DOI":"10.1038\/s41390-023-02853-2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.jad.2023.05.022","article-title":"Heart rate variability in children and adolescents with major depressive disorder: A systematic review and meta-analysis","volume":"335","author":"Chen","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1016\/j.jad.2023.07.027","article-title":"Vagally-mediated heart rate variability and depression in children and adolescents\u2014A meta-analytic update","volume":"339","author":"Rothe","year":"2023","journal-title":"J. Affect. Disord."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1002\/aur.2437","article-title":"Heart Rate Variability in Children With Autism Spectrum Disorder and Associations With Medication and Symptom Severity","volume":"14","author":"Thapa","year":"2021","journal-title":"Autism Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"4679","DOI":"10.1007\/s10803-021-05244-w","article-title":"Heart Rate Variability in Children and Adolescents with Autism, ADHD and Co-occurring Autism and ADHD, During Passive and Active Experimental Conditions","volume":"52","author":"Bellato","year":"2022","journal-title":"J. Autism Dev. Disord."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Dias, R.M., Moraes, \u00cd.A.P., Dantas, M.T.A.P., Fernani, D.C.G.L., Fontes, A.M.G.G., Silveira, A.C., Barnab\u00e9, V., Fernandes, M., Martinelli, P.M., and Monteiro, C.B.M. (2021). Influence of Chronic Exposure to Exercise on Heart Rate Variability in Children and Adolescents Affected by Obesity: A Systematic Review and Meta-Analysis. Int. J. Environ. Res. Public Health, 18.","DOI":"10.3390\/ijerph182111065"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1002\/ppul.24714","article-title":"Cardiac autonomic modulation assessed by heart rate variability in children with asthma","volume":"55","author":"Franco","year":"2020","journal-title":"Pediatr. Pulmonol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.1002\/ppul.26340","article-title":"Impact of asthma on heart rate variability in children and adolescents: Systematic review and meta-analysis","volume":"58","author":"Schiwe","year":"2023","journal-title":"Pediatr. Pulmonol."},{"key":"ref_38","first-page":"1102","article-title":"Heart rate variability in children with myocarditis presenting with ventricular arrhythmias","volume":"22","author":"Ling","year":"2018","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Connell, P.S., Price, J.F., Rusin, C.G., Howard, T.S., Spinner, J.A., Valdes, S.O., Pham, T.D.N., Miyake, C.Y., and Kim, J.J. (2023). Decreased Heart Rate Variability in Children with Acute Decompensated Heart Failure is Associated with Poor Outcomes. Pediatr. Cardiol., Online ahead of print.","DOI":"10.1007\/s00246-023-03279-7"},{"key":"ref_40","unstructured":"Campbell, D.M. (2023, September 29). All IC-BFM 2009\u2014Trial Steering Committee. Available online: https:\/\/www.google.com.hk\/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwiv4t2XiLuCAxV_plYBHROIAmEQFnoECBcQAQ&url=https%3A%2F%2Fwww.bialaczka.org%2Fwp-content%2Fuploads%2F2016%2F10%2FALLIC_BFM_2009.pdf&usg=AOvVaw13HbMigLHAYgMqIeqtGwhK&opi=89978449."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1111\/j.1542-474X.1997.tb00325.x","article-title":"An Analysis of the Time-Relations of Electrocardiograms","volume":"2","author":"Bazett","year":"1997","journal-title":"Ann. Noninvasive Electrocardiol."},{"key":"ref_42","unstructured":"Maniu, D.R., Blag, C., Popa, G., Bota, M., Vlad, C., Cainap, C., Balacescu, O., Pop, L., and Cainap, S.S. (2017). The Role of Biomarkers and Echocardiography in the Evaluation of Cardiotoxicity Risk in Children Treated for Leukemia, Morressier."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"03000605221079547","DOI":"10.1177\/03000605221079547","article-title":"Predictive role of C-reactive protein in sudden death: A meta-analysis of prospective studies","volume":"50","author":"Zhou","year":"2022","journal-title":"J. Int. Med. Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"214","DOI":"10.2174\/157340311799960645","article-title":"Anthracycline Cardiotoxicity: Prevalence, Pathogenesis and Treatment","volume":"7","author":"Volkova","year":"2011","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Zeid, S., Buch, G., Velmeden, D., S\u00f6hne, J., Schulz, A., Schuch, A., Tr\u00f6bs, S.-O., Heidorn, M.W., M\u00fcller, F., and Strauch, K. (2023). Heart rate variability: Reference values and role for clinical profile and mortality in individuals with heart failure. Clin. Res. Cardiol., Online ahead of print.","DOI":"10.1007\/s00392-023-02248-7"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Poto\u010dnik, N., Per\u0161e, M., Cerar, A., Injac, R., and Finderle, \u017d. (2017). Cardiac autonomic modulation induced by doxorubicin in a rodent model of colorectal cancer and the influence of fullerenol pretreatment. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0181632"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1007\/s00520-019-05047-x","article-title":"Is heart rate variability a valuable method to investigate cardiac autonomic dysfunction in subjects with leukemia? A systematic review to evaluate its importance in clinical practice","volume":"28","author":"Kirizawa","year":"2020","journal-title":"Support. Care Cancer"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/22\/7052\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:21:55Z","timestamp":1760131315000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/12\/22\/7052"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,11,12]]},"references-count":47,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2023,11]]}},"alternative-id":["jcm12227052"],"URL":"https:\/\/doi.org\/10.3390\/jcm12227052","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,11,12]]}}}