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Doxorubicin treatments induce significant changes on the cardiac autonomic nervous system in childhood acute lymphoblastic leukemia long-term survivors

Clinical Research in Cardiology volume 108, pages 1000–1008 (2019)Cite this article

Abstract

Aims

Acute lymphoblastic leukemia (ALL) is one of the leading malignancies in children worldwide. The cardiotoxicity of anti-cancer treatments leads to a dysfunction of the cardiac autonomic nervous system. Protection strategies, with dexrazoxane treatments, were used to counter these adverse effects. The aim of this study was to investigate the effects of the treatments on the cardiac autonomic nervous system.

Methods and results

A total of 203 cALL survivors were included in our analyses and were classified into 3 categories based on the prognostic risk group: standard risk, high risk with and without dexrazoxane. A 24-h Holter monitoring was performed to study the cardiac autonomic nervous system. The frequency domain heart rate variability (HRV) was used to validate the cardiac autonomic nervous system modifications. Other analyses were performed using linear HRV indexes in the time domain and non-linear indexes. A frequency domain HRV parameters analysis revealed significant differences on an overall time-period of 24 h. A repeated measures ANOVA indicated a group-effect for the low frequency (p = 0.029), high frequency (p = 0.03) and LF/HF ratio (p = 0.029). Significant differences in the time domain and in the non-linear power spectral density HRV parameters were also observed.

Conclusion

Anti-cancer treatments induced significant changes in the cardiac autonomic nervous system. The HRV was sensitive enough to detect cardiac autonomic nervous system alterations depending on the cALL risk category. Protection strategies (i.e., dexrazoxane treatments), which were used to counter the adverse effects of doxorubicin, could prevent changes observed in the cardiac autonomic nervous system.

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References

  1. Iarussi D, Indolfi P, Casale F, Martino V, Di Tullio MT, Calabro R (2005) Anthracycline-induced cardiotoxicity in children with cancer: strategies for prevention and management. Paediatr Drugs 7(2):67–76

    Article  PubMed  Google Scholar 

  2. Lipshultz SE, Lipsitz SR, Mone SM, Goorin AM, Sallan SE, Sanders SP, Orav EJ, Gelber RD, Colan SD (1995) Female sex and higher drug dose as risk factors for late cardiotoxic effects of doxorubicin therapy for childhood cancer. N Engl J Med 332(26):1738–1743. https://doi.org/10.1056/nejm199506293322602

    Article  CAS  PubMed  Google Scholar 

  3. Lipshultz SE, Cochran TR, Franco VI, Miller TL (2013) Treatment-related cardiotoxicity in survivors of childhood cancer. Nat Rev Clin Oncol 10(12):697–710. https://doi.org/10.1038/nrclinonc.2013.195

    Article  CAS  PubMed  Google Scholar 

  4. Lipshultz SE, Colan SD, Gelber RD, Perez-Atayde AR, Sallan SE, Sanders SP (1991) Late cardiac effects of doxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 324(12):808–815. https://doi.org/10.1056/NEJM199103213241205 doi

    Article  CAS  PubMed  Google Scholar 

  5. Van Brussel M, Takken T, Lucia A, van der Net J, Helders PJ (2005) Is physical fitness decreased in survivors of childhood leukemia? A systematic review. Leukemia 19(1):13–17. https://doi.org/10.1038/sj.leu.2403547

    Article  PubMed  Google Scholar 

  6. Tilemann LM, Heckmann MB, Katus HA, Lehmann LH, Muller OJ (2018) Cardio-oncology: conflicting priorities of anticancer treatment and cardiovascular outcome. Clin Res Cardiol 107(4):271–280. https://doi.org/10.1007/s00392-018-1202-x

    Article  PubMed  PubMed Central  Google Scholar 

  7. Søgaard M, Thomsen RW, Bossen KS, Sørensen HT, Nørgaard M (2013) The impact of comorbidity on cancer survival: a review. Clin Epidemiol 5(Suppl 1):3–29. https://doi.org/10.2147/clep.S47150

    Article  PubMed  PubMed Central  Google Scholar 

  8. Walsh D, Nelson KA (2002) Autonomic nervous system dysfunction in advanced cancer. Support Care Cancer 10(7):523–528. https://doi.org/10.1007/s00520-002-0376-x

    Article  PubMed  Google Scholar 

  9. Viniegra M, Marchetti M, Losso M, Navigante A, Litovska S, Senderowicz A, Borghi L, Lebron J, Pujato D, Marrero H et al (1990) Cardiovascular autonomic function in anthracycline-treated breast cancer patients. Cancer Chemother Pharmacol 26(3):227–231

    Article  CAS  PubMed  Google Scholar 

  10. Kremer LC, van Dalen EC (2015) Dexrazoxane in children with cancer: from evidence to practice. J Clin Oncol 33(24):2594–2596. https://doi.org/10.1200/jco.2015.61.7928

    Article  CAS  PubMed  Google Scholar 

  11. Guo Y, Koshy S, Hui D, Palmer JL, Shin K, Bozkurt M, Yusuf SW (2015) Prognostic value of heart rate variability in patients with cancer. J Clin Neurophysiol 32(6):516–520. https://doi.org/10.1097/wnp.0000000000000210

    Article  PubMed  PubMed Central  Google Scholar 

  12. Kamath MV, Halton J, Harvey A, Turner-Gomes S, McArthur A, Barr RD (1998) Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood. Int J Oncol 12(3):635–640

    CAS  PubMed  Google Scholar 

  13. Silverman LB, Stevenson KE, O’Brien JE, Asselin BL, Barr RD, Clavell L, Cole PD, Kelly KM, Laverdiere C, Michon B, Schorin MA, Schwartz CL, O’Holleran EW, Neuberg DS, Cohen HJ, Sallan SE (2010) Long-term results of Dana-Farber Cancer Institute ALL Consortium protocols for children with newly diagnosed acute lymphoblastic leukemia (1985–2000). Leukemia 24(2):320–334. https://doi.org/10.1038/leu.2009.253

    Article  CAS  PubMed  Google Scholar 

  14. Marcoux S, Drouin S, Laverdiere C, Alos N, Andelfinger GU, Bertout L, Curnier D, Friedrich MG, Kritikou EA, Lefebvre G, Levy E, Lippe S, Marcil V, Raboisson MJ, Rauch F, Robaey P, Samoilenko M, Seguin C, Sultan S, Krajinovic M, Sinnett D (2017) The PETALE study: late adverse effects and biomarkers in childhood acute lymphoblastic leukemia survivors. Pediatr Blood Cancer. https://doi.org/10.1002/pbc.26361

    Article  PubMed  Google Scholar 

  15. Akselrod S, Gordon D, Ubel FA, Shannon DC, Berger AC, Cohen RJ (1981) Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 213(4504):220–222

    Article  CAS  PubMed  Google Scholar 

  16. Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology (1996) Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 93(5):1043–1065

    Article  Google Scholar 

  17. Arab C, Vanderlei LCM, da Silva Paiva L, Fulghum KL, Fristachi CE, Nazario ACP, Elias S, Gebrim LH, Ferreira Filho C, Gidron Y (2018) Cardiac autonomic modulation impairments in advanced breast cancer patients. Clin Res Cardiol 107(10):924–936

    Article  PubMed  Google Scholar 

  18. Berntson GG, Bigger JT Jr, Eckberg DL, Grossman P, Kaufmann PG, Malik M, Nagaraja HN, Porges SW, Saul JP, Stone PH, van der Molen MW (1997) Heart rate variability: origins, methods, and interpretive caveats. Psychophysiology 34(6):623–648

    Article  CAS  PubMed  Google Scholar 

  19. Malik M (1996) Heart rate variability. Circulation 93(5):1043–1065

    Article  Google Scholar 

  20. Tarvainen MP, Niskanen JP, Lipponen JA, Ranta-Aho PO, Karjalainen PA (2014) Kubios HRV–heart rate variability analysis software. Comput Methods Progr Biomed 113(1):210–220. https://doi.org/10.1016/j.cmpb.2013.07.024

    Article  Google Scholar 

  21. Heart rate variability (1996) Standards of measurement, physiological interpretation, and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Euro Heart J 17(3):354–381

    Article  Google Scholar 

  22. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF 3rd, Dokainish H, Edvardsen T, Flachskampf FA, Gillebert TC, Klein AL, Lancellotti P, Marino P, Oh JK, Popescu BA, Waggoner AD (2016) Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 29(4):277–314. https://doi.org/10.1016/j.echo.2016.01.011

    Article  Google Scholar 

  23. Ueda T, Kawakami R, Nishida T, Onoue K, Soeda T, Okayama S, Takeda Y, Watanabe M, Kawata H, Uemura S, Saito Y (2015) Left ventricular ejection fraction (EF) of 55% as cutoff for late transition from heart failure (HF) with preserved EF to HF with mildly reduced EF. Circ J 79(10):2209–2215. https://doi.org/10.1253/circj.CJ-15-0425

    Article  PubMed  Google Scholar 

  24. Myerburg RJ, Kessler KM, Luceri RM, Zaman L, Trohman RG, Estes D, Castellanos A (1984) Classification of ventricular arrhythmias based on parallel hierarchies of frequency and form. Am J Cardiol 54(10):1355–1358

    Article  CAS  PubMed  Google Scholar 

  25. Lown B, Wolf M (1971) Approaches to sudden death from coronary heart disease. Circulation 44(1):130–142

    Article  CAS  Google Scholar 

  26. Bethge K-P (1991) Classification of arrhythmias. J Cardiovasc Pharmacol 17:S20

    Article  Google Scholar 

  27. Nevruz O, Yokusoglu M, Uzun M, Demirkol S, Avcu F, Baysan O, Koz C, Cetin T, Sag C, Ural AU, Isik E (2007) Cardiac autonomic functions are altered in patients with acute leukemia, assessed by heart rate variability. Tohoku J Exp Med 211(2):121–126

    Article  PubMed  Google Scholar 

  28. Potocnik N, Perse M, Cerar A, Injac R, Finderle Z (2017) Cardiac autonomic modulation induced by doxorubicin in a rodent model of colorectal cancer and the influence of fullerenol pretreatment. PLoS One 12(7):e0181632. https://doi.org/10.1371/journal.pone.0181632

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kleiger RE, Stein PK, Bigger JT Jr (2005) Heart rate variability: measurement and clinical utility. Ann Noninvasive electrocardiol 10(1):88–101. https://doi.org/10.1111/j.1542-474X.2005.10101.x

    Article  PubMed  Google Scholar 

  30. Nunan D, Sandercock GR, Brodie DA (2010) A quantitative systematic review of normal values for short-term heart rate variability in healthy adults. Pacing Clin Electrophysiol PACE 33(11):1407–1417. https://doi.org/10.1111/j.1540-8159.2010.02841.x

    Article  PubMed  Google Scholar 

  31. Kamath MV, Fallen EL (1993) Power spectral analysis of heart rate variability: a noninvasive signature of cardiac autonomic function. Crit Rev Biomed Eng 21(3):245–311

    CAS  PubMed  Google Scholar 

  32. van Bilsen M, Patel HC, Bauersachs J, Bohm M, Borggrefe M, Brutsaert D, Coats AJS, de Boer RA, de Keulenaer GW, Filippatos GS, Floras J, Grassi G, Jankowska EA, Kornet L, Lunde IG, Maack C, Mahfoud F, Pollesello P, Ponikowski P, Ruschitzka F, Sabbah HN, Schultz HD, Seferovic P, Slart R, Taggart P, Tocchetti CG, Van Laake LW, Zannad F, Heymans S, Lyon AR (2017) The autonomic nervous system as a therapeutic target in heart failure: a scientific position statement from the Translational Research Committee of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 19(11):1361–1378. https://doi.org/10.1002/ejhf.921

    Article  PubMed  Google Scholar 

  33. Fradley MG, Viganego F, Kip K, Martin A, Patel AA, Ismail-Khan R, Chae S, Herweg B, Labovitz A (2017) Rates and risk of arrhythmias in cancer survivors with chemotherapy-induced cardiomyopathy compared with patients with other cardiomyopathies. Open Heart 4(2):e000701

    Article  PubMed  PubMed Central  Google Scholar 

  34. Shanafelt TD, Parikh SA, Noseworthy PA, Goede V, Chaffee KG, Bahlo J, Call TG, Schwager SM, Ding W, Eichhorst B, Fischer K, Leis JF, Chanan-Khan AA, Hallek M, Slager SL, Kay NE (2017) Atrial fibrillation in patients with chronic lymphocytic leukemia (CLL). Leukemia Lymphoma 58(7):1630–1639. https://doi.org/10.1080/10428194.2016.1257795

    Article  CAS  PubMed  Google Scholar 

  35. Heeringa J, van der Kuip DAM, Hofman A, Kors JA, van Herpen G, Stricker BHC, Stijnen T, Lip GYH, Witteman JCM (2006) Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 27(8):949–953. https://doi.org/10.1093/eurheartj/ehi825

    Article  PubMed  Google Scholar 

  36. Benjamin EJ, Levy D, Vaziri SM, D’agostino RB, Belanger AJ, Wolf PA (1994) Independent risk factors for atrial fibrillation in a population-based cohort: the Framingham Heart Study. Jama 271(11):840–844

    Article  CAS  PubMed  Google Scholar 

  37. Poreba M, Poreba R, Gac P, Usnarska-Zubkiewicz L, Pilecki W, Piotrowicz E, Piotrowicz R, Rusiecki L, Kuliczkowski K, Mazur G, Sobieszczanska M (2014) Heart rate variability and heart rate turbulence in patients with hematologic malignancies subjected to high-dose chemotherapy in the course of hematopoietic stem cell transplantation. Ann Noninvasive Electrocardiol 19(2):157–165. https://doi.org/10.1111/anec.12108

    Article  PubMed  Google Scholar 

  38. Christiansen JR, Massey R, Dalen H, Kanellopoulos A, Hamre H, Fossa SD, Ruud E, Kiserud CE, Aakhus S (2016) Utility of global longitudinal strain by echocardiography to detect left ventricular dysfunction in long-term adult survivors of childhood lymphoma and acute lymphoblastic leukemia. Am J Cardiol 118(3):446–452. https://doi.org/10.1016/j.amjcard.2016.05.021

    Article  PubMed  Google Scholar 

  39. Dos Santos MJ, da Rocha ET, Verberne HJ, da Silva ET, Aragon DC, Junior JS (2017) Assessment of late anthracycline-induced cardiotoxicity by (123)I-mIBG cardiac scintigraphy in patients treated during childhood and adolescence. J Nucl cardiol 24(1):256–264. https://doi.org/10.1007/s12350-015-0309-y

    Article  PubMed  Google Scholar 

  40. Floras JS, Ponikowski P (2015) The sympathetic/parasympathetic imbalance in heart failure with reduced ejection fraction. Eur Heart J 36(30):1974–1982b. https://doi.org/10.1093/eurheartj/ehv087

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Triposkiadis F, Karayannis G, Giamouzis G, Skoularigis J, Louridas G, Butler J (2009) The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications. J Am Coll Cardiol 54(19):1747–1762. https://doi.org/10.1016/j.jacc.2009.05.015

    Article  CAS  PubMed  Google Scholar 

  42. Faber J, Wingerter A, Neu MA, Henninger N, Eckerle S, Münzel T, Lackner KJ, Beutel ME, Blettner M, Rathmann W, Peters A, Meisinger C, Linkohr B, Neuhauser H, Kaatsch P, Spix C, Schneider A, Merzenich H, Panova-Noeva M, Prochaska JH, Wild PS (2018) Burden of cardiovascular risk factors and cardiovascular disease in childhood cancer survivors: data from the German CVSS-study. Eur Heart J 39(17):1555–1562. https://doi.org/10.1093/eurheartj/ehy026

    Article  CAS  PubMed  Google Scholar 

  43. Packer M (1998) Beta-adrenergic blockade in chronic heart failure: principles, progress, and practice. Progr Cardiovasc Dis 41(1 Suppl 1):39–52

    Article  CAS  Google Scholar 

  44. Hsu CY, Hsieh PL, Hsiao SF, Chien MY (2015) Effects of exercise training on autonomic function in chronic heart failure: systematic review. BioMed Res Int 2015:591708. https://doi.org/10.1155/2015/591708

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  45. Ricca-Mallada R, Migliaro ER, Silvera G, Chiappella L, Frattini R, Ferrando-Castagnetto F (2017) Functional outcome in chronic heart failure after exercise training: possible predictive value of heart rate variability. Ann Phys Rehabilit Med 60(2):87–94. https://doi.org/10.1016/j.rehab.2016.12.003

    Article  Google Scholar 

  46. Zhou W, Wan YH, Chen Q, Qiu YR, Luo XM (2017) Effects of Tai Chi exercise on cancer-related fatigue in patients with nasopharyngeal carcinoma undergoing chemoradiotherapy: a randomized controlled trial. J Pain Symptom Manag. https://doi.org/10.1016/j.jpainsymman.2017.10.021

    Article  Google Scholar 

  47. Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, Silverman LB, Colan SD, Neuberg DS, Dahlberg SE, Henkel JM, Asselin BL, Athale UH, Clavell LA, Laverdiere C, Michon B, Schorin MA, Sallan SE (2012) Changes in cardiac biomarkers during doxorubicin treatment of pediatric patients with high-risk acute lymphoblastic leukemia: associations with long-term echocardiographic outcomes. J Clin Oncol 30(10):1042–1049. https://doi.org/10.1200/jco.2010.30.3404

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bando S, Soeki T, Matsuura T, Tobiume T, Ise T, Kusunose K, Yamaguchi K, Yagi S, Fukuda D, Iwase T, Yamada H, Wakatsuki T, Shimabukuro M, Muguruma N, Takayama T, Kishimoto I, Kangawa K, Sata M (2017) Plasma brain natriuretic peptide levels are elevated in patients with cancer. PLoS One. https://doi.org/10.1371/journal.pone.0178607

    Article  PubMed  PubMed Central  Google Scholar 

  49. Dodos F, Halbsguth T, Erdmann E, Hoppe UC (2008) Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults. Clin Res Cardiol 97(5):318–326. https://doi.org/10.1007/s00392-007-0633-6

    Article  PubMed  Google Scholar 

  50. Riffel JH, Keller MG, Aurich M, Sander Y, Andre F, Giusca S, Aus dem Siepen F, Seitz S, Galuschky C, Korosoglou G, Mereles D, Katus HA, Buss SJ (2015) Assessment of global longitudinal strain using standardized myocardial deformation imaging: a modality independent software approach. Clin Res Cardiol 104(7):591–602. https://doi.org/10.1007/s00392-015-0822-7

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Institute of Cancer Research (ICR) of the Canadian Institutes of Health Research (CIHR), in collaboration with C17 Council, Canadian Cancer Society (CCS), Cancer Research Society (CRS), Garron Family Cancer Centre at the Hospital for Sick Children, Ontario Institute for Cancer Research (OICR) and Pediatric Oncology Group of Ontario (POGO) (grant number: TCF 118694). This research was also supported in part by PhD study grants from Cole Foundation, Fonds de Recherche du Québec—Santé (FRQS), Sainte-Justine University Hospital Center Foundation and Foundation of Stars. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. We appreciate the invaluable assistance of Ariane Levesque (McGill University) for her review of the article in the English language.

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Affiliations

  1. Laboratoire de Physiopathologie de l’EXercice (LPEX), Département de Kinésiologie, Université de Montréal, CEPSUM, 2100, boulevard Édouard Montpetit, H3C 3J7, Montreal, QC, Canada

    Maxime Caru, Denis Corbin, Valérie Lemay & Daniel Curnier

  2. Department of Psychology, University of Paris Nanterre, Nanterre, Ile-deFrance, France

    Maxime Caru

  3. Laboratoire EA 4430-Clinique Psychanalyse Developpement (CliPsyD), University of Paris Nanterre, Nanterre, Ile-de-France, France

    Maxime Caru

  4. Sainte-Justine University Health Center, Research Center, Montreal, QC, Canada

    Maxime Caru, Delphine Périé, Valérie Lemay, Jacques Delfrate, Simon Drouin, Laurence Bertout, Maja Krajinovic, Caroline Laverdière, Gregor Andelfinger, Daniel Sinnett & Daniel Curnier

  5. Department of Pediatrics, University of Montreal, Montreal, QC, Canada

    Maja Krajinovic, Caroline Laverdière, Gregor Andelfinger & Daniel Sinnett

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  1. Maxime Caru
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Caru, M., Corbin, D., Périé, D. et al. Doxorubicin treatments induce significant changes on the cardiac autonomic nervous system in childhood acute lymphoblastic leukemia long-term survivors. Clin Res Cardiol 108, 1000–1008 (2019). https://doi.org/10.1007/s00392-019-01427-9

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Keywords

  • Acute lymphoblastic leukemia
  • Cardiac autonomic nervous system
  • Heart rate variability
  • Doxorubicin treatments
  • Electrophysiology