A doxo é administrada em pacientes com câncer e em nosso estudo os animais não apresentavam essa doença. Este fator pode ter influenciado os nossos resultados obtidos em animais previamente saudáveis. As interações de comorbidades podem levar a aspectos diferentes, mas, infelizmente, não podem ser reproduzidos em modelos experimentais. Apesar destas considerações é preciso entender que o objetivo do presente estudo foi atingido pois foi possível avaliar aspectos da cardiotoxicidade e do treinamento com o HIIT na função e na estrutura cardíaca.
Outro aspecto a se destacar é que o presente estudo não visou identificar possíveis vias de sinalização metabólica envolvidas na ação tóxica da doxo e do efeito favorável do treinamento intervalado de alta intensidade nestas mesmas vias, fato que impossibilita identificar os caminhos desta interação. Apesar desta limitação, os resultados obtidos abrem novas possibilidades de estudo e será interessante mapear as vias de síntese e degradação proteica envolvidas nestas duas condições abordadas.
O desenho do protocolo experimental não previu a realização de testes de tolerância ao esforço antes e após o treinamento que poderia permitir a verificação de melhora ou de piora individualizada após o uso de doxo. No entanto, a comparação feita entre grupos permite uma conclusão satisfatória quanto ao que verdadeiramente ocorreu ao final do experimento.
Infelizmente nosso modelo não permitiu a aferição do comportamento da pressão arterial e do débito cardíaco e os cálculos da resistência periférica, aspectos importantes para o melhor entendimento do comportamento hemodinâmico dos animais. Também não foi possível aferir-se a função do ventrículo direito e a capacidade de relaxamento ventricular do ventrículo esquerdo dificultando a interpretação exata dos achados.
CONCLUSÃO
O treinamento intervalado de alta intensidade realizado após a administração de doxo em ratos Wistar é capaz de reduzir a FC e preservar a estrutura de colágeno do coração.
O grupo DE apresentou menor peso corporal e maior razão PC/Pcorporal. O peso total do coração foi menor no grupo E.
A frequência cardíaca foi menor nos grupos que fizeram treinamento em relação ao controle e ao grupo D. A FC do grupo D foi menor em relação ao controle. A função do ventrículo esquerdo aferida pela FEVE e FS apresentou tendência à normalização com o HIIT.
O teor de colágeno aumentou no grupo D e foi normalizada pelo HIIT. O diâmetro transversal dos cardiomiócitos não apresentou modificação entre os grupos.
REFERÊNCIAS
ADAMOPOULOS, S.; PARISSIS, J. T.; KREMASTINOS, D. T. New aspects for the role of physical training in the management of patients with chronic heart failure. International journal of cardiology, v. 90, n. 1, p. 1-14, 2003.
https://doi.org/10.1016/S0167-5273(02)00504-1
ALBUQUERQUE, D. et al. I Registro Brasileiro de Insuficiência Cardíaca: aspectos clínicos, qualidade assistencial e desfechos hospitalares. Arq Bras Cardiol, v. 104, n. 6, p. 433-42, 2015.
ASCENSÃO, A. et al. Endurance training attenuates doxorubicin-induced cardiac oxidative damage in mice. International journal of cardiology, v. 100, n. 3, p. 451-460, 2005.
https://doi.org/10.1016/j.ijcard.2004.11.004
PMid:15837090
ASCENSÃO, A.; OLIVEIRA, P. J.; MAGALHÃES, J. Exercise as a beneficial adjunct therapy during Doxorubicin treatment—Role of mitochondria in cardioprotection. International journal of cardiology, v. 156, n. 1, p. 4-10, 2012.
https://doi.org/10.1016/j.ijcard.2011.05.060
PMid:21636148
BARRETTO, A. C. P.; RAMIRES, J. A. F. Insuficiência cardíaca. Arquivos brasileiros de cardiologia, v. 71, n. 4, p. 635-642, 1998.
https://doi.org/10.1590/S0066-782X1998001000014
PMid:10347943
BOCCHI, E. A. Heart failure in South America. Current cardiology reviews, v. 9, n. 2, p. 147-156, 2013.
https://doi.org/10.2174/1573403X11309020007
PMid:23597301 PMCid:PMC3682398
CAMPOS, E. C. et al. Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy. The FASEB Journal, v. 26, n. 1 Supplement, p. 1036.1-1036.1, 2012.
https://doi.org/10.1016/j.ejphar.2011.09.021
PMid:21946105
CAMPOS, E. C. et al. Calpain-mediated dystrophin disruption may be a potential structural culprit behind chronic doxorubicin-induced cardiomyopathy. European journal of pharmacology, v. 670, n. 2, p. 541-553, 2011.
CHATTERJEE, K. et al. Doxorubicin cardiomyopathy. Cardiology, v. 115, n. 2, p. 155-162, 2010.
https://doi.org/10.1159/000265166
PMid:20016174 PMCid:PMC2848530
CHICCO, A. J. et al. Low-intensity exercise training during doxorubicin treatment protects against cardiotoxicity. Journal of Applied Physiology, v. 100, n. 2, p. 519-527, 2006.
https://doi.org/10.1152/japplphysiol.00148.2005
PMid:16210442
CHICCO, A. J.; SCHNEIDER, C. M.; HAYWARD, R. Exercise training attenuates acute doxorubicin-induced cardiac dysfunction. Journal of cardiovascular pharmacology, v. 47, n. 2, p. 182-189, 2006.
https://doi.org/10.1097/01.fjc.0000199682.43448.2d
PMid:16495754
CUMMINGS, J. et al. The molecular pharmacology of doxorubicin in vivo. European Journal of Cancer and Clinical Oncology, v. 27, n. 5, p. 532-535, 1991.
https://doi.org/10.1016/0277-5379(91)90209-V
DE ANGELIS, K. et al. Exercise training changes autonomic cardiovascular balance in mice. Journal of Applied Physiology, v. 96, n. 6, p. 2174-2178, 2004.
https://doi.org/10.1152/japplphysiol.00870.2003
PMid:14729725
DE BEER, E. L.; BOTTONE, A. E.; VOEST, E. E. Doxorubicin and mechanical performance of cardiac trabeculae after acute and chronic treatment: a review. European journal of pharmacology, v. 415, n. 1, p. 1-11, 2001.
https://doi.org/10.1016/S0014-2999(01)00765-8
DE BEER, E. L. et al. Doxorubicin interacts directly with skinned single skeletal muscle fibres. European journal of pharmacology, v. 214, n. 1, p. 97-100, 1992.
https://doi.org/10.1016/0014-2999(92)90103-B
DE OLIVEIRA BELMIRO, W.; NAVARRO, A. C. Os efeitos do treinamento intervalado de alta intensidade para o emagrecimento. RBONE-Revista Brasileira de Obesidade, Nutrição e Emagrecimento, v. 10, n. 59, p. 224- 230, 2016.
DHAKAL, B. P. et al. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction. Circulation: Heart Failure, p. CIRCHEARTFAILURE. 114.001825, 2014. DZAU, V.; BRAUNWALD, E. Resolved and unresolved issues in the prevention and treatment of coronary artery disease: a workshop consensus statement. American heart journal, v. 121, n. 4, p. 1244-1263, 1991.
ERTUNC, M.; SARA, Y.; ONUR, R. Differential contractile impairment of fast- and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure. Pharmacology, v. 84, n. 4, p. 240-248, 2009.
https://doi.org/10.1159/000241723
PMid:19776660
FACINA, T. Estimativa 2014–incidência de câncer no brasil. Rev Bras Cancerol, v. 60, n. 1, p. 63-64, 2014.
FIDALE, T. M. Efeitos da suplementação de leucina no coração de ratos tratados com doxorrubicina. 2017.
FIDALE, T. M. et al. Increased Dietary Leucine Reduces Doxorubicin- Associated Cardiac Dysfunction in Rats. Frontiers in physiology, v. 8, p. 1042, 2018.
https://doi.org/10.3389/fphys.2017.01042
PMid:29403386 PMCid:PMC5779071
GEWIRTZ, D. A critical evaluation of the mechanisms of action proposed for the antitumor effects of the anthracycline antibiotics adriamycin and daunorubicin. Biochemical pharmacology, v. 57, n. 7, p. 727-741, 1999.
https://doi.org/10.1016/S0006-2952(98)00307-4
GOLDSMITH, R. L. et al. Comparison of 24-hour parasympathetic activity in endurance-trained and untrained young men. Journal of the American College of Cardiology, v. 20, n. 3, p. 552-558, 1992.
https://doi.org/10.1016/0735-1097(92)90007-A
GOORMAGHTIGH, E.; RUYSSCHAERT, J. M. Anthracycline glycoside- membrane interactions. Biochimica et Biophysica Acta (BBA)-Reviews on Biomembranes, v. 779, n. 3, p. 271-288, 1984.
https://doi.org/10.1016/0304-4157(84)90013-3
GUIRAUD, T. et al. High-intensity interval training in cardiac rehabilitation. Sports Medicine, v. 42, n. 7, p. 587-605, 2012.
https://doi.org/10.2165/11631910-000000000-00000
PMid:22694349
HAYWARD, R.; HYDOCK, D. S. Doxorubicin cardiotoxicity in the rat: an in vivo characterization. Journal of the American Association for Laboratory Animal Science, v. 46, n. 4, p. 20-32, 2007.
HAYWARD, R. et al. Exercise training mitigates anthracycline‐induced chronic cardiotoxicity in a juvenile rat model. Pediatric blood & cancer, v. 59, n. 1, p. 149-154, 2012.
https://doi.org/10.1002/pbc.23392
HUANG, S.-C. et al. Modified high-intensity interval training increases peak cardiac power output in patients with heart failure. European journal of applied physiology, v. 114, n. 9, p. 1853-1862, 2014.
https://doi.org/10.1007/s00421-014-2913-y
PMid:24880226
HURST, J. W.; MORRIS, D. C.; ALEXANDER, R. W. The use of the New York Heart Association's classification of cardiovascular disease as part of the patient's complete Problem List. Clinical cardiology, v. 22, n. 6, p. 385-390, 1999.
https://doi.org/10.1002/clc.4960220604
PMid:10376176
HYDOCK, D. S. et al. Exercise preconditioning provides long-term protection against early chronic doxorubicin cardiotoxicity. Integrative cancer therapies, v. 10, n. 1, p. 47-57, 2011.
https://doi.org/10.1177/1534735410392577
PMid:21382960
HYDOCK, D. S. et al. Exercise preconditioning protects against doxorubicin- induced cardiac dysfunction. Medicine and science in sports and exercise, v. 40, n. 5, p. 808-817, 2008.
https://doi.org/10.1249/MSS.0b013e318163744a
PMid:18408619
JARRETT, C. L. et al. Effect of high intensity exercise preconditioning and training on antioxidant enzymes in cardiomyocytes during doxorubicin treatment. The FASEB Journal, v. 30, n. 1 Supplement, p. lb601-lb601, 2016. KITZMAN, D. W.; GROBAN, L. Exercise intolerance. Cardiol Clin, v. 29, n. 3, p. 461-77, Aug 2011.
https://doi.org/10.1016/j.ccl.2011.06.002
PMid:21803233 PMCid:PMC3694583
KITZMAN, D. W. et al. Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. Jama, v. 288, n. 17, p. 2144- 2150, 2002.
https://doi.org/10.1001/jama.288.17.2144
PMid:12413374
LA ROVERE, M. T. et al. Autonomic nervous system adaptations to short-term exercise training. CHEST Journal, v. 101, n. 5_Supplement, p. 299S-303S, 1992.
https://doi.org/10.1378/chest.101.5.299S
LILLY, L. S.; BRAUNWALD, E. Braunwald's heart disease: a textbook of cardiovascular medicine. Elsevier Health Sciences, 2012. ISBN 1455711470.
LORELL, B. H.; CARABELLO, B. A. Left ventricular hypertrophy: pathogenesis, detection, and prognosis. Circulation, v. 102, n. 4, p. 470-479, 2000.
https://doi.org/10.1161/01.CIR.102.4.470
MARQUES-ALEIXO, I. et al. Physical exercise prior and during treatment reduces sub-chronic doxorubicin-induced mitochondrial toxicity and oxidative stress. Mitochondrion, v. 20, p. 22-33, 2015.
https://doi.org/10.1016/j.mito.2014.10.008
PMid:25446396
MEDEIROS, A. et al. Swimming training increases cardiac vagal activity and induces cardiac hypertrophy in rats. Brazilian Journal of Medical and Biological Research, v. 37, n. 12, p. 1909-1917, 2004.
https://doi.org/10.1590/S0100-879X2004001200018
PMid:15558199
MESQUITA, E. T. et al. Insuficiência cardíaca com função sistólica preservada. Arquivos Brasileiros de Cardiologia, v. 82, n. 5, p. 494-500, 2004.
https://doi.org/10.1590/S0066-782X2004000500014
PMid:15340682
MIJWEL, S. High-intensity interval training in combination with aerobic or resistance training for patients with breast cancer: a HIIT to counteract detrimental effects of chemotherapy. 2018.
MILL, J. G.; VASSALLO, D. V. Hipertrofia cardíaca. Rev Bras Hipertens, v. 8, n. 1, p. 18-29, 2001.
OCTAVIA, Y. et al. Doxorubicin-induced cardiomyopathy: from molecular mechanisms to therapeutic strategies. Journal of molecular and cellular cardiology, v. 52, n. 6, p. 1213-1225, 2012.
https://doi.org/10.1016/j.yjmcc.2012.03.006
PMid:22465037
OHHARA, H.; KANAIDE, H.; NAKAMURA, M. A protective effect of coenzyme Q 10 on the adriamycin-induced cardiotoxicity in the isolated perfused rat heart. Journal of molecular and cellular cardiology, v. 13, n. 8, p. 741-752, 1981. https://doi.org/10.1016/0022-2828(81)90256-X
OLIVEIRA, L. F. L. D. et al. Comparison between radionuclide ventriculography and echocardiography for quantification of left ventricular systolic function in rats exposed to doxorubicin. Arquivos brasileiros de cardiologia, v. 108, n. 1, p. 12-20, 2017.
https://doi.org/10.5935/abc.20160194
OLSON, R. D. et al. Doxorubicin cardiotoxicity may be caused by its metabolite, doxorubicinol. Proceedings of the National Academy of Sciences, v. 85, n. 10, p. 3585-3589, 1988.
https://doi.org/10.1073/pnas.85.10.3585
PFANNENSTIEL, K. B. Effects of resistance exercise training on doxorubicin-induced cardiotoxicity. University of Northern Colorado, 2015. ISBN 1339548844.
PIÑA, I. L. et al. Exercise and Heart Failure A Statement From the American Heart Association Committee on Exercise, Rehabilitation, and Prevention. Circulation, v. 107, n. 8, p. 1210-1225, 2003.
https://doi.org/10.1161/01.CIR.0000055013.92097.40
PMid:12615804
PONIKOWSKI, P. et al. Authors/Task Force Members. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J, v. 37, n. 27, p. 2129-200, 2016.
REDDI, B.; SHANMUGAM, N.; FLETCHER, N. Heart failure—pathophysiology and inpatient management. Bja Education, v. 17, n. 5, p. 151-160, 2017. https://doi.org/10.1093/bjaed/mkw067
ROCHETTE, L. et al. Anthracyclines/trastuzumab: new aspects of cardiotoxicity and molecular mechanisms. Trends in pharmacological sciences, v. 36, n. 6, p. 326-348, 2015.
https://doi.org/10.1016/j.tips.2015.03.005
PMid:25895646
SAÚDE, B. M. D. Protocolos Clínicos e Diretrizes Terapêuticas em Oncologia/Ministério da Saúde. Secretaria de Atenção à Saúde-Brasília: Ministério da Saúde, 2014.
SCOTT, J. M. et al. Modulation of anthracycline-induced cardiotoxicity by aerobic exercise in breast cancer. Circulation, v. 124, n. 5, p. 642-650, 2011. https://doi.org/10.1161/CIRCULATIONAHA.111.021774
PMid:21810673 PMCid:PMC3154075
SEIXAS-CAMBAO, M.; FEITE-MOREIRA, A. F. Fisiopatologia da insuficiência cardíaca crónica. Revista portuguesa de cardiologia, v. 28, n. 4, p. 439-471, 2009.
SOUZA, F. R. D. et al. Resposta Hipertrofica da Associacao de Hormonio Tireoidiano e de Exercicio Fisico no Coracao de Ratos. Arq Bras Cardiol, v. 102, n. 2, p. 187-191, 2014.
STEINHERZ, L. J. et al. Cardiac toxicity 4 to 20 years after completing anthracycline therapy. Jama, v. 266, n. 12, p. 1672-1677, 1991.
https://doi.org/10.1001/jama.266.12.1672
STURGEON, K. et al. Concomitant low-dose doxorubicin treatment and exercise. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, v. 307, n. 6, p. R685-R692, 2014.
https://doi.org/10.1152/ajpregu.00082.2014
PMid:25009215 PMCid:PMC4166763
SWAIN, S. M.; WHALEY, F. S.; EWER, M. S. Congestive heart failure in patients treated with doxorubicin. Cancer, v. 97, n. 11, p. 2869-2879, 2003. https://doi.org/10.1002/cncr.11407
PMid:12767102
TABATA, I. et al. Effects of moderate-intensity endurance and high-intensity intermittent training on anaerobic capacity and VO~ 2~ m~ a~ x. Medicine and science in sports and exercise, v. 28, p. 1327-1330, 1996.
https://doi.org/10.1097/00005768-199610000-00018
TEICHHOLZ, L. E. et al. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence or absence of asynergy. The American journal of cardiology, v. 37, n. 1, p. 7- 11, 1976.
https://doi.org/10.1016/0002-9149(76)90491-4
TERADA, S. et al. Effects of high‐intensity intermittent swimming on PGC‐1α protein expression in rat skeletal muscle. Acta physiologica scandinavica, v. 184, n. 1, p. 59-65, 2005.
https://doi.org/10.1111/j.1365-201X.2005.01423.x
PMid:15847644
TERADA, S. et al. Effects of high-intensity swimming training on GLUT-4 and glucose transport activity in rat skeletal muscle. Journal of Applied Physiology, v. 90, n. 6, p. 2019-2024, 2001.
https://doi.org/10.1152/jappl.2001.90.6.2019
PMid:11356760
WEISS, R. B. The anthracyclines: will we ever find a better doxorubicin? , Seminars in oncology, 1992. Elsevier. p.670-686.
WESTON, K. S.; WISLØFF, U.; COOMBES, J. S. High-intensity interval training in patients with lifestyle-induced cardiometabolic disease: a systematic review and meta-analysis. British journal of sports medicine, v. 48, n. 16, p. 1227- 1234, 2014.
https://doi.org/10.1136/bjsports-2013-092576
PMid:24144531
WISLØFF, U.; ELLINGSEN, Ø.; KEMI, O. J. High-intensity interval training to maximize cardiac benefits of exercise training? Exercise and sport sciences reviews, v. 37, n. 3, p. 139-146, 2009.
https://doi.org/10.1097/JES.0b013e3181aa65fc
WONDERS, K. Y. et al. Acute exercise protects against doxorubicin cardiotoxicity. Integrative Cancer Therapies, v. 7, n. 3, p. 147-154, 2008. https://doi.org/10.1177/1534735408322848
PMid:18815146
YANCY, C. W. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Journal of the American College of Cardiology, v. 62, n. 16, p. e147-e239, 2013.