Abstract
Aim
To compare cardiac autonomic modulation in early- versus advanced-stage breast cancer patients before any type of cancer treatment and investigate associated factors.
Methods and results
This cross-sectional study included women (30–69 years old) with primary diagnosis of breast cancer and women with benign breast tumors. We evaluated cardiac modulation by heart rate variability and assessed factors of anxiety, depression, physical activity, and other relevant medical variables. Patients were divided into three groups based on TNM staging of cancer severity: early-stage cancer (n = 42), advanced-stage cancer (n = 37), or benign breast tumors to serve as a control (n = 37). We analyzed heart rate variability in time and frequency domains. The advanced-stage cancer group had lower vagal modulation than early-stage and benign groups; also, the advance-stage group had lower overall heart rate variability when compared to benign conditions. Heart rate variability was influenced by age, menopausal status, and BMI.
Conclusions
Heart rate variability seems to be a promising, non-invasive tool for early diagnosis of autonomic dysfunction in breast cancer and detection of cardiovascular impairments at cancer diagnosis. Cardiac autonomic modulation is inversely associated with breast cancer staging.
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References
Ferlay J, Héry C, Autier P, Sankaranarayanan R (2010) Global burden of breast cancer. In: Breast cancer epidemiology. Springer, New York, pp 1–19. https://doi.org/10.1007/978-1-4419-0685-4_1
Ginsburg O, Bray F, Coleman MP, Vanderpuye V, Eniu A, Kotha SR, Sarker M, Huong TT, Allemani C, Dvaladze A (2017) The global burden of women’s cancers: a grand challenge in global health. Lancet 389:846–860. https://doi.org/10.1016/S0140-6736(16)31392-7
Tilemann LM, Heckmann MB, Katus HA, Lehmann LH, Müller OJ (2018) Cardio-oncology: conflicting priorities of anticancer treatment and cardiovascular outcome. Clin Res Cardiol 1–10 https://doi.org/10.1007/s00392-018-1202-x
Lakoski SG, Jones LW, Krone RJ, Stein PK, Scott JM (2015) Autonomic dysfunction in early breast cancer: incidence, clinical importance, and underlying mechanisms. Am Heart J 170:231–241. https://doi.org/10.1016/j.ahj.2015.05.014
Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K (2011) Beta blockers and breast cancer mortality: a population-based study. J Clin Oncol 29:2635–2644. https://doi.org/10.1200/JCO.2010.33.5422
Melhem-Bertrandt A, Chavez-MacGregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, Gonzalez-Angulo A-M (2011) Beta-blocker use is associated with improved relapse-free survival in patients with triple-negative breast cancer. J Clin Oncol 29:2645–2652. https://doi.org/10.1200/JCO.2010.33.4441
Vigo C, Gatzemeier W, Sala R, Malacarne M, Santoro A, Pagani M, Lucini D (2015) Evidence of altered autonomic cardiac regulation in breast cancer survivors. J Cancer Surv 9:699–706. https://doi.org/10.1007/s11764-015-0445-z
Colzani E, Liljegren A, Johansson AL, Adolfsson J, Hellborg H, Hall PF, Czene K (2011) Prognosis of patients with breast cancer: causes of death and effects of time since diagnosis, age, and tumor characteristics. J Clin Oncol 29:4014–4021. https://doi.org/10.1200/JCO.2010.32.6462
Eick C, Duckheim M, Groga-Bada P, Klumpp N, Mannes S, Zuern CS, Gawaz M, Rizas KD, Bauer A (2017) Point-of-care testing of cardiac autonomic function for risk assessment in patients with suspected acute coronary syndromes. Clin Res Cardiol 106(9):686–694. https://doi.org/10.1007/s00392-017-1104-3
Romanov A, Minin S, Breault C, Pokushalov E (2017) Visualization and ablation of the autonomic nervous system corresponding to ganglionated plexi guided by D-SPECT 123 I-mIBG imaging in patient with paroxysmal atrial fibrillation. Clin Res Cardiol 106:76–78. https://doi.org/10.1007/s00392-016-1045-2
Camm AJ, Malik M, Bigger JT, Breithardt G, Cerutti S, Cohen RJ, Coumel P, Fallen EL, Kennedy HL, Kleiger RE, Lombardi F (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 93:1043–1065
Tsuji H, Venditti FJ, Manders ES, Evans JC, Larson MG, Feldman CL, Levy D (1994) Reduced heart rate variability and mortality risk in an elderly cohort. Framingham Heart Study Circ 90:878–883
Dekker JM, Crow RS, Folsom AR, Hannan PJ, Liao D, Swenne CA, Schouten EG (2000) Low heart rate variability in a 2-minute rhythm strip predicts risk of coronary heart disease and mortality from several causes. Circulation 102:1239–1244. https://doi.org/10.1161/01.CIR.102.11.1239
Camm AJ, Pratt CM, Schwartz PJ, Al-Khalidi HR, Spyt MJ, Holroyde MJ, Karam R, Sonnenblick EH, Brum JM (2004) Mortality in patients after a recent myocardial infarction. Circulation 109:990–996. https://doi.org/10.1161/01.CIR.0000117090.01718.2A
Nolan J, Batin PD, Andrews R, Lindsay SJ, Brooksby P, Mullen M, Baig W, Flapan AD, Cowley A, Prescott RJ (1998) Prospective study of heart rate variability and mortality in chronic heart failure. Circulation 98:1510–1516. https://doi.org/10.1161/01.CIR.98.15.1510
La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, Ferrari R, Franchini M, Gnemmi M, Opasich C (2003) Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation 107:565–570. https://doi.org/10.1161/01.CIR.0000047275.25795.17
Hillebrand S, Gast KB, Mutsert R, Swenne CA, Jukema JW, Middeldorp S, Rosendaal FR, Dekkers OM (2013) Heart rate variability and first cardiovascular event in populations without known cardiovascular disease: meta-analysis and dose–response meta-regression. Europace 15:742–749. https://doi.org/10.1093/europace/eus341
Bleiziffer S, Bosmans J, Brecker S, Gerckens U, Wenaweser P, Tamburino C, Linke A (2017) Insights on mid-term TAVR performance: 3-year clinical and echocardiographic results from the CoreValve ADVANCE study. Clin Res Cardiol 106:784–795. https://doi.org/10.1007/s00392-017-1120-3
Palma MR, Vanderlei LCM, Ribeiro FE, Mantovani AM, Christofaro DGD, Fregonesi CEPT. (2016) The relationship between post-operative time and cardiac autonomic modulation in breast cancer survivors. Intern J Cardiol 224:360–365. https://doi.org/10.1016/j.ijcard.2016.09.053
Hansen MV, Rosenberg J, Gögenur I (2013) Lack of circadian variation and reduction of heart rate variability in women with breast cancer undergoing lumpectomy: a descriptive study. Breast Cancer Res Treat 140:317–322. https://doi.org/10.1007/s10549-013-2631-x
Tjeerdsma G, Meinardi M, Van der Graaf W, van Den Berg M, Mulder N, Crijns H, De Vries E, Van Veldhuisen D (1999) Early detection of anthracycline induced cardiotoxicity in asymptomatic patients with normal left ventricular systolic function: autonomic versus echocardiographic variables. Heart 81:419–423
Poręba M, Poręba R, Gać P, Usnarska-Zubkiewicz L, Pilecki W, Piotrowicz E, Piotrowicz R, Rusiecki L, Kuliczkowski K, Mazur G (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 19:157–165. https://doi.org/10.1111/anec.12108
Ekholm EM, Salminen EK, Huikuri HV, Jalonen J, Antila KJ, Salmi TA, Rantanen VT (2000) Impairment of heart rate variability during paclitaxel therapy. Cancer 88:2149–2153. https://doi.org/10.1002/(SICI)1097-0142(20000501)88:9<2149::AID-CNCR22>3.0.CO;2-Z
Fadul N, Strasser F, Palmer JL, Yusuf SW, Guo Y, Li Z, Allo J, Bruera E (2010) The association between autonomic dysfunction and survival in male patients with advanced cancer: a preliminary report. J Pain Symptom Manage 39:283–290. https://doi.org/10.1016/j.jpainsymman.2009.06.014
Wang Y-M, Wu H-T, Huang E-Y, Kou YR, Hseu S-S (2013) Heart rate variability is associated with survival in patients with brain metastasis: a preliminary report. BioMed Res Int 2013:503421. https://doi.org/10.1155/2013/503421
Kim DH, Kim JA, Choi YS, Kim SH, Lee JY, Kim YE (2010) Heart rate variability and length of survival in hospice cancer patients. J Korean Med Sci 25:1140–1145. https://doi.org/10.3346/jkms.2010.25.8.1140
De Couck M, Maréchal R, Moorthamers S, Van Laethem J-L, Gidron Y (2016) Vagal nerve activity predicts overall survival in metastatic pancreatic cancer, mediated by inflammation. Cancer Epidemiol 40:47–51. https://doi.org/10.1016/j.canep.2015.11.007
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 32:516–520. https://doi.org/10.1097/WNP.0000000000000210
Giese-Davis J, Wilhelm FH, Tamagawa R, Palesh O, Neri E, Taylor CB, Kraemer HC, Spiegel D (2015) Higher vagal activity as related to survival in patients with advanced breast cancer: an analysis of autonomic dysregulation. Psychosom Med 77:346–355. https://doi.org/10.1097/PSY.0000000000000167
Arab C, Dias DPM, de Almeida Barbosa RT, de Carvalho TD, Valenti VE, Crocetta TB, Ferreira M, de Abreu LC, Ferreira C (2016) Heart rate variability measure in breast cancer patients and survivors: a systematic review. Psychoneuroendocrinology 68:57–68. https://doi.org/10.1016/j.psyneuen.2016.02.018
Lombardi F, Stein PK (2011) Origin of heart rate variability and turbulence: an appraisal of autonomic modulation of cardiovascular function. Front Physiol 2:1–7. https://doi.org/10.3389/fphys.2011.00095
Bettermann H, Kröz M, Girke M, Heckmann C (2001) Heart rate dynamics and cardiorespiratory coordination in diabetic and breast cancer patients. Clin Physiol 21:411–420. https://doi.org/10.1046/j.1365-2281.2001.00342.x
Edge SB, Compton CC (2010) The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol 17:1471–1474. https://doi.org/10.1245/s10434-010-0985-4
Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S, Cardoso F, ESMO Guidelines Working Group (2013) Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 24:vi7–vi23. https://doi.org/10.1093/annonc/mdt284
Gidron Y, Perry H, Glennie M (2005) Does the vagus nerve inform the brain about preclinical tumours and modulate them? Lancet Oncol 6:245–248. https://doi.org/10.1016/S1470-2045(05)70096-6
Entschladen F, Drell TL, Lang K, Joseph J, Zaenker KS (2004) Tumour-cell migration, invasion, and metastasis: navigation by neurotransmitters. Lancet Oncol 5:254–258. https://doi.org/10.1016/S1470-2045(04)01431-7
Carney RM, Blumenthal JA, Stein PK, Watkins L, Catellier D, Berkman LF, Czajkowski SM, O’connor C, Stone PH, Freedland KE (2001) Depression, heart rate variability, and acute myocardial infarction. Circulation 104:2024–2028. https://doi.org/10.1161/hc4201.097834
Almeida-Santos MA, Barreto-Filho JA, Oliveira JLM, Reis FP, da Cunha Oliveira CC, Sousa ACS (2016) Aging, heart rate variability and patterns of autonomic regulation of the heart. Arch Gerontol Geriatr 63:1–8. https://doi.org/10.1016/j.archger.2015.11.011
Kemp AH, Brunoni AR, Santos IS, Nunes MA, Dantas EM, Carvalho de Figueiredo R, Pereira AC, Ribeiro AL, Mill JG, Andreão RV (2014) Effects of depression, anxiety, comorbidity, and antidepressants on resting-state heart rate and its variability: an ELSA-Brasil cohort baseline study. Am J Psychiatry 171:1328–1334. https://doi.org/10.1176/appi.ajp.2014.13121605
O’Regan C, Kenny R, Cronin H, Finucane C, Kearney P (2015) Antidepressants strongly influence the relationship between depression and heart rate variability: findings from The Irish Longitudinal Study on Ageing (TILDA). Psychol Med 45:623–636. https://doi.org/10.1017/S0033291714001767
Matsudo S, Araújo T, Matsudo V, Andrade D, Andrade E, Oliveira LC, Braggion G (2012) Questionário Internacional De Atividade Física (Ipaq): Estupo De Validade E Reprodutibilidade No Brasil. Rev Bras Ativ Fís Saúde 6:5–18. https://doi.org/10.12820/RBAFS.V.6N2P5-18
Committee IR (2005) Guidelines for data processing and analysis of the International Physical Activity Questionnaire (IPAQ)—short and long forms. 1–15. http://www.ipaq.ki.se/dloads/IPAQ%20LS%20Scoring%20Protocols_Nov05.pdf. Accessed Dec 2015
Marcolino JÁM, Mathias L, Piccinini Filho L, Guaratini A, Suzuki FM, Alli LAC (2007) Escala hospitalar de ansiedade e depressão: estudo da validade de critério e da confiabilidade com pacientes no pré-operatório. Rev Bras Anestesiol 57:52–62. https://doi.org/10.1590/S0034-70942007000100006
Zigmond AS, Snaith RP (1983) The hospital anxiety and depression scale. Acta Psychiatr Scand 67:361–370
World Health Organization. Body mass index—BMI. http://www.euro.who.int/en/health-topics/disease-prevention/nutrition/a-healthy-lifestyle/body-mass-index-bmi. Accessed Mar 2016
Nunan D, Donovan G, Jakovljevic D, Hodges L, Sandercock G, Brodie D (2009) Validity and reliability of short-term heart-rate variability from the Polar S810. Med Sci Sports Exerc 41:243. https://doi.org/10.1249/MSS.0b013e318184a4b1
Gamelin FX, Berthoin S, Bosquet L (2006) Validity of the polar S810 heart rate monitor to measure RR intervals at rest. Med Sci Sports Exerc 38:887–893. https://doi.org/10.1249/01.mss.0000218135.79476.9c
Niskanen J-P, Tarvainen MP, Ranta-Aho PO, Karjalainen PA (2004) Software for advanced HRV analysis. Comput Methods Progr Biomed 76:73–81. https://doi.org/10.1016/j.cmpb.2004.03.004
Laboratorio deE. Estatística-Lee. São Paulo: Cálculo do tamanho amostral. http://www.lee.dante.br/pesquisa/amostragem/qua_2_medias Accessed Dec 2015
Mravec B, Gidron Y, Hulin I (2008) Neurobiology of cancer: interactions between nervous, endocrine and immune systems as a base for monitoring and modulating the tumorigenesis by the brain. Semin Cancer Biol 18:150–163. https://doi.org/10.1016/j.semcancer.2007.12.002
Ondicova K, Mravec B (2010) Role of nervous system in cancer aetiopathogenesis. Lancet Oncol 11:596–601. https://doi.org/10.1016/S1470-2045(09)70337-7
Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, Frenette PS (2013) Autonomic nerve development contributes to prostate cancer progression. Science 341:1236361. https://doi.org/10.1126/science.1236361
Cole SW, Nagaraja AS, Lutgendorf SK, Green PA, Sood AK (2015) Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer 15:563–572. https://doi.org/10.1038/nrc3978
Maki A, Kono H, Gupta M, Asakawa M, Suzuki T, Matsuda M, Fujii H, Rusyn I (2007) Predictive power of biomarkers of oxidative stress and inflammation in patients with hepatitis C virus-associated hepatocellular carcinoma. Ann Surg Oncol 14:1182–1190
Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature 454:436–444. https://doi.org/10.1038/nature07205
Voronov E, Shouval DS, Krelin Y, Cagnano E, Benharroch D, Iwakura Y, Dinarello CA, Apte RN (2003) IL-1 is required for tumor invasiveness and angiogenesis. Proc Natl Acad Sci USA 100:2645–2650
Ek M, Kurosawa M, Lundeberg T, Ericsson A (1998) Activation of vagal afferents after intravenous injection of interleukin-1β: role of endogenous prostaglandins. J Neurosci 18:9471–9479
Gidron Y, De Leeuw I, De Couck M, Blase K, Vanacker L (2017) The effects of heart rate variability biofeedback on levels of the tumor marker CEA in metastatic colon cancer: a pilot controlled pilot study. In: The international society for behavior medicine conference, Seville, Spain
Anker MS, Ebner N, Hildebrandt B, Springer J, Sinn M, Riess H, Anker SD, Landmesser U, Haverkamp W, von Haehling S (2016) Resting heart rate is an independent predictor of death in patients with colorectal, pancreatic, and non-small cell lung cancer: results of a prospective cardiovascular long-term study. Eur J Heart Fail 18:1524–1534. https://doi.org/10.1002/ejhf.670
Lee DH, Park S, Lim SM, Lee MK, Giovannucci EL, Kim JH, Kim SI, Jeon JY (2016) Resting heart rate as a prognostic factor for mortality in patients with breast cancer. Breast Cancer Res Treat 159:375–384. https://doi.org/10.1007/s10549-016-3938-1
Caro-Morán E, Fernández-Lao C, Galiano-Castillo N, Cantarero-Villanueva I, Arroyo-Morales M, Díaz-Rodríguez L (2016) Heart rate variability in breast cancer survivors after the first year of treatments a case-controlled study. Biol Res Nurs 18:43–49. https://doi.org/10.1177/1099800414568100
McCraty R, Shaffer F (2015) Heart rate variability: new perspectives on physiological mechanisms, assessment of self-regulatory capacity, and health risk. Glob Adv Health Med 4:46–61. https://doi.org/10.7453/gahmj.2014.073
Thayer JF, Åhs F, Fredrikson M, Sollers JJ, Wager TD (2012) A meta-analysis of heart rate variability and neuroimaging studies: implications for heart rate variability as a marker of stress and health. Neurosci Biobehav Rev 36:747–756. https://doi.org/10.1016/j.neubiorev.2011.11.009
Voss A, Schroeder R, Heitmann A, Peters A, Perz S (2015) Short-term heart rate variability—influence of gender and age in healthy subjects. PloS One 10:e0118308. https://doi.org/10.1371/journal.pone.0118308
Antelmi I, De Paula RS, Shinzato AR, Peres CA, Mansur AJ, Grupi CJ (2004) Influence of age, gender, body mass index, and functional capacity on heart rate variability in a cohort of subjects without heart disease. Am J Cardiol 93:381–385. https://doi.org/10.1016/j.amjcard.2003.09.065
Crosswell AD, Lockwood KG, Ganz PA, Bower JE (2014) Low heart rate variability and cancer-related fatigue in breast cancer survivors. Psychoneuroendocrinology 45:58–66. https://doi.org/10.1016/j.psyneuen.2014.03.011
Thayer JF, Yamamoto SS, Brosschot JF (2010) The relationship of autonomic imbalance, heart rate variability and cardiovascular disease risk factors. Int J Cardiol 141:122–131. https://doi.org/10.1016/j.ijcard.2009.09.543
Koenig J, Jarczok M, Warth M, Ellis R, Bach C, Hillecke T, Thayer JF (2014) Body mass index is related to autonomic nervous system activity as measured by heart rate variability—a replication using short term measurements. J Nutr Health Aging 18:300–302. https://doi.org/10.1007/s12603-014-0022-6
Molfino A, Fiorentini A, Tubani L, Martuscelli M, Fanelli FR, Laviano A (2009) Body mass index is related to autonomic nervous system activity as measured by heart rate variability. Eur J Clin Nutr 63:1263–1265. https://doi.org/10.1038/ejcn.2009.35
Zhao R, Li D, Zuo P, Bai R, Zhou Q, Fan J, Li C, Wang L, Yang X (2015) Influences of age, gender, and circadian rhythm on deceleration capacity in subjects without evident heart diseases. Ann Noninvasive Electrocardiol 20:158–166. https://doi.org/10.1111/anec.12189
Liu C, Kuo TB, Yang CC (2003) Effects of estrogen on gender-related autonomic differences in humans. Am J Physiol Heart Circ Physiol 285:H2188-H2193. https://doi.org/10.1152/ajpheart.00256.2003
Narod SA (2011) Hormone replacement therapy and the risk of breast cancer. Nat Rev Clin Oncol 8:669–676
Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 362:419–427 https://doi.org/10.1016/S0140-6736(03)14065-2
De P, Neutel CI, Olivotto I, Morrison H (2010) Breast cancer incidence and hormone replacement therapy in Canada. J Natl Cancer Inst 102:1489–1495. https://doi.org/10.1093/jnci/djq345
Dietel M (2010) Hormone replacement therapy (HRT), breast cancer and tumor pathology. Maturitas 65:183–189. https://doi.org/10.1016/j.maturitas.2009.11.005
Proietti M, Nobili A, Raparelli V, Napoleone L, Mannucci PM, Lip GY (2016) Adherence to antithrombotic therapy guidelines improves mortality among elderly patients with atrial fibrillation: insights from the REPOSI study. Clin Res Cardiol 105(11):912–920. https://doi.org/10.1007/s00392-016-0999-4
Tsai YS, Lai FC, Chen SR, Jeng C (2011) The influence of physical activity level on heart rate variability among asthmatic adults. J Clin Nurs 20:111–118. https://doi.org/10.1186/s12890-015-0118-8
Lai FC, Chang WL, Jeng C (2012) The relationship between physical activity and heart rate variability in orthotopic heart transplant recipients. J Clin Nurs 21:3235–3243. https://doi.org/10.1111/j.1365-2702.2012.04070.x
Reland S, Ville NS, Sara W, Senhadji L, Carré F (2004) Does the level of chronic physical activity alter heart rate variability in healthy older women? Clin Sci 107:29–35. https://doi.org/10.1089/jwh.2011.2932
Gonçalves TR, Farinatti PdTV, Gurgel JL, da Silva Soares PP (2015) Correlation between cardiac autonomic modulation in response to orthostatic stress and indicators of quality of life, physical capacity, and physical activity in healthy individuals. J Strength Cond Res 29:1415–1421. https://doi.org/10.1519/JSC.0000000000000769
Acknowledgements
We thank all medical doctors, nurses and receptionists of hospitals participants of the present study that collaborated on patient screening and evaluation; Professor Dr. Claudio Leone for assisting on statistical analysis; PhD Cand. Renata Thais de Almeida Barbosa for helping on data collection; PhD Cand. Fernando Rocha Oliveira for assisting on HRV analysis; and the Laboratorio de Escrita Cientifica of Faculdade de Medicina do ABC for supplying Polar RS800Cx wristwatch and WearLink Wind.
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Arab, C., Vanderlei, L.C.M., da Silva Paiva, L. et al. Cardiac autonomic modulation impairments in advanced breast cancer patients. Clin Res Cardiol 107, 924–936 (2018). https://doi.org/10.1007/s00392-018-1264-9
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DOI: https://doi.org/10.1007/s00392-018-1264-9