Clinical and Experimental Pediatrics

대한소아청소년과학회 (The Korean Pediatric Society)
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한국인 소아암 환자에서 anthracycline 유발 심독성에 대한 지표로서 BNP 혈장농도의 유용성

Plasma B-type natriuretic peptide (BNP): a useful marker for anthracycline-induced cardiotoxicity in Korean children with cancer

  • 이현동 (영남대학교 의과대학 소아과학교실) ;
  • 이재민 (영남대학교 의과대학 소아과학교실) ;
  • 이용직 (영남대학교 의과대학 소아과학교실) ;
  • 이영환 (영남대학교 의과대학 소아과학교실) ;
  • 하정옥 (영남대학교 의과대학 소아과학교실)
  • Lee, Hyun Dong (Department of Pediatrics, College of Medicine, Yeungnam University) ;
  • Lee, Jae Min (Department of Pediatrics, College of Medicine, Yeungnam University) ;
  • Lee, Yong Jik (Department of Pediatrics, College of Medicine, Yeungnam University) ;
  • Lee, Young Hwan (Department of Pediatrics, College of Medicine, Yeungnam University) ;
  • Hah, Jeong Ok (Department of Pediatrics, College of Medicine, Yeungnam University)
  • 투고 : 2007.05.03
  • 심사 : 2007.06.14
  • 발행 : 2007.08.15
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초록

목 적 : Anthracycline(AC) 계 약물은 소아암에 널리 쓰이지만 심독성으로 인하여 사용에 제한을 받게 된다. 이에 소아암 환자에서 AC 유발 심독성에 대한 지표로서 혈장 B-type natriuretic peptide(BNP)의 유용성을 심초음파와 비교하여 알아보고자 본 연구를 시도하였다. 방 법 : 2005년 5월 1일부터 2006년 12월 31까지 영남대학교병원 소아과에서 소아암으로 진단 받고 치료받은 환자 중에서 AC 계 약물을 투여 받은 환자 55명을 대상으로 AC 축적량과 임상증상을 조사하고, 심초음파 검사 중 좌심실 구획 단축률(left ventricular fractional shortening, LVFS)과 좌심실 박출 계수(left ventricular ejection fraction, LVEF) 결과와 BNP 혈장농도를 비교하였다. 결 과 : 환자 55명에서 BNP 혈장농도를 115회 측정하였고, 심초음파를 64회 시행하였다. AC 축적량의 중앙값은 $325mg/m^2$(범위 120-600; 평균 345)이었고, BNP 혈장농도의 중앙값은 10 pg/mL(범위 5-950; 평균 31)이었다. AC 축적량은 BNP 혈장농도와 좋은 상관관계를 나타내었다(P=0.002). 그리고 BNP 혈장농도는 LVFS(P=0.018), LVEF(P=0.025)와 역시 좋은 상관관계를 나타내었다. 확장형심근병증이 발생한 경우는 3명이었다. 급성기의 확장형심근병증 환자와 검사 시행 당시 급성호흡곤란 증상이 있었던 만성기의 확장형심근병증 환자에서는 LVFS과 LVEF이 비정상적으로 감소하면서 BNP 혈장농도가 비정상적으로 증가하였고, 증상이 없는 만성기의 확장형심근병증 환자에서는 LVFS, LVEF, BNP 혈장농도가 모두 정상이었다. 결 론 : 본 연구에서 한국인 소아암 환자의 AC 유발 심독성에 대한 지표로서 BNP 혈장농도는 심초음파 검사와 좋은 상관관계를 나타내어, AC로 치료받은 소아암 환자에서 심초음파를 시행할 수 없는 경우나 정기적인 추적관찰을 하기 위하여 유용한 검사로 생각된다.

Purpose : The anthracyclines (AC) are widely used chemotherapeutic agents for pediatric cancers. However, the therapeutic use of these agents is limited by their cardiotoxicity. The aim of the present study was to investigate the usefulness of plasma B-type natriuretic peptide (BNP) levels as a marker for AC-induced cardiotoxicity compared to echocardiography in Korean children with cancer. Methods : Fifty-five pediatric cancer patients who had received chemotherapy including AC were enrolled. The cumulative AC doses, clinical symptoms, and two echocardiography parameters, left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF), were studied and compared with plasma BNP levels. Results : In 55 patients, plasma BNP levels were measured 115 times and echocardiographies were performed 64 times. The median cumulative dose of AC was $325mg/m^2$ (range 120-600; mean 345) and the median plasma BNP level was 10 pg/mL (range 5-950; mean 31). The cumulative AC doses correlated significantly with the plasma BNP levels (P=0.002). The plasma BNP levels correlated significantly with LVFS (P=0.018) and LVEF (P=0.025). Dilated cardiomyopathies were identified in three patients. LVFS and LVEF decreased and plasma BNP levels increased in a patient with acute dilated cardiomyopathy and in that with symptomatic chronic dilated cardiomyopathy. However, LVFS, LVEF and plasma BNP levels were normal in a patient with asymptomatic chronic dilated cardiomyopathy. Conclusion : The results of this study demonstrated that plasma BNP levels could be used as a marker for AC-induced cardiotoxicity; they showed good correlation with echocardiography findings in pediatric cancer patients. Plasma BNP levels may be used for the detection and management of AC-induced cardiotoxicity in Korean children with cancer.

키워드

참고문헌

  1. Meinardi MT, Gietema JA, van Veldhuisen DJ, van der Graaf WT, Vries EG, Sleijfer DT. Long-term chemotherapyrelated cardiovascular morbidity. Cancer Treat Rev 2000;26: 429-47 https://doi.org/10.1053/ctrv.2000.0175
  2. von Hoff DD, Layard MW, Basa P, Davis HL Jr, von Hoff AL, Rozencweig M, et al. Risk factors for doxorubicin-in-duced congestive heart failure. Ann Intern Med 1979;91: 710-7 https://doi.org/10.7326/0003-4819-91-5-710
  3. Massin MM, Dresse MF, Schimitz V, Hoyoux C, Chantraine JM, Lepage P. Acute arrhythmogenicity of first-dose chemotherapeutic agents in children. Med Pediatr Oncol 2002; 39:93-8 https://doi.org/10.1002/mpo.10123
  4. Simbre VC, Duffy SA, Dadlani GH, Miller TL, Lipshultz SE. Cardiotoxicity of cancer chemotherapy: implications for children. Paediatr Drugs 2005;7:187-202 https://doi.org/10.2165/00148581-200507030-00005
  5. Shan K, Lincoff M, Young JB. Anthracycline induced cardiotoxicity. Ann Intern Med 1996;125:47-58 https://doi.org/10.7326/0003-4819-125-1-199607010-00008
  6. Steinherz LJ, Steinherz PG, Tan C. Cardiac failure and dysrhythmias 6-19 years after anthracycline therapy: a series of 15 patients. Med Pediatr Oncol 1995;24:352-61 https://doi.org/10.1002/mpo.2950240103
  7. Ganz WI, Sridhar KS, Ganz SS, Gonzalez R, Chakko S, Serafini A. Review of tests for monitoring doxorubicin-induced cardiomyopathy. Oncology 1996;53:461-70 https://doi.org/10.1159/000227621
  8. Villani F, Meazza R, Materazzo C. Non-invasive monitoring of cardiac hemodynamic parameters in doxorubicin-treated patients: comparison with echocardiography. Anticancer Res 2006;26:797-801
  9. Wilkins MR, Redondo J, Brown LA. The natriuretic-peptide family. Lancet 1997;349:1307-10 https://doi.org/10.1016/S0140-6736(96)07424-7
  10. Vanderheyden M, Bartunek J, Goethals M. Brain and other natriuretic peptides: molecular aspects. Eur J Heart Fail 2004;6:261-8 https://doi.org/10.1016/j.ejheart.2004.01.004
  11. Omland T, Aakvaag A, Bonarjee VV, Caidahl K, Lie RT, Nilsen DW, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Circulation 1996; 93:1963-9 https://doi.org/10.1161/01.CIR.93.11.1963
  12. McCullough PA, Omland T, Maisel AS. B-type natriuretic peptides: a diagnostic breakthrough for clinicians. Rev Cardiovasc Med 2003;4:72-80
  13. Kunii Y, Kamada M, Ohtsuki S, Araki T, Kataoka K, Kageyama M, et al. Plasma brain natriuretic peptide and the evaluation of volume overload in infants and children with congenital heart disease. Acta Med Okayama 2003;57:191-7
  14. Bernstein D. Heart failure. In: Behrman RE, Kliegman RM, Jenson HB, editors. Nelson textbook of pediatrics. 17th ed. Philadelphia: WB Saunders Co, 2004:1583-4
  15. Triage BNP Test Product Insert. San Diego CA: Biosite Diagnostics Inc. 2000
  16. Koch A, Singer H. Normal values of B type natriuretic peptide in infants, children, and adolescents. Heart 2003;89:875-8 https://doi.org/10.1136/heart.89.8.875
  17. Grenier MA, Lipshultz SE. Epidemiology of anthracycline cardiotoxicity in children and adults. Semin Oncol 1998;25 (Suppl 10):72-85
  18. Doroshow JH. Doxorubicin-induced cardiototoxicity. N Engl J Med 1991;324:843-5 https://doi.org/10.1056/NEJM199103213241210
  19. Doroshow JH, Locker GY, Myers CE. Enzymatic defenses of the mouse heart against reactive oxygen metabolites: alterations produced by doxorubicin. J Clin Invest 1980;65:128-35 https://doi.org/10.1172/JCI109642
  20. Larsen RL, Jakacki RI, Vetter VL, Meadows AT, Silber JH, Barber G. Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. Am J Cardiol 1992;70:73-7 https://doi.org/10.1016/0002-9149(92)91393-I
  21. Pai VB, Nahata MC. Cardiotoxicity of chemotherapeutic agents: incidence, treatment and prevention. Drug Safety 2000;22:263-302 https://doi.org/10.2165/00002018-200022040-00002
  22. Alderton PM, Gross J, Green MD. Comparative study of doxorubicin, mitoxantrone and epirubicin in combination with ICRF-187 (ADR-529) in a chronic cardiotoxicity animal model. Cancer Res 1992;52:194-201
  23. Cirillo R, Sacco G, Venturella S, Brightwell J, Giachetti A, Manzini S. Comparison of doxorubicin- and MEN 10755-induced long-term progressive cardiotoxicity in the rat. J Cardiovasc Pharmacol 2000;35:100-8 https://doi.org/10.1097/00005344-200001000-00013
  24. Steinherz LJ, Graham T, Hurwitz R, Sondheimer HM, Schwartz RG, Shaffer EM, et al. Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the Cardiology Committee of the Children Cancer Study Group. Pediatrics 1992;89:942-9
  25. Sparano JA, Brown DL, Wolff AC. Predicting cancer therapy- induced cardiotoxicity: the role of troponins and other markers. Drug Safety 2002;25:301-11 https://doi.org/10.2165/00002018-200225050-00001
  26. Lipshultz SE, Rifai N, Sallan SE, Lipsitz SR, Dalton V, Sacks DB, et al. Predictive value of cardiac troponin-T in pediatric patients at risk for myocardial injury. Circulation 1997;96:2641-8 https://doi.org/10.1161/01.CIR.96.8.2641
  27. Davidson NC, Naas AA, Hanson JK, Kennedy NS, Coutie WJ, Struthers AD. Comparison of atrial natriuretic peptide, B-type natriuretic peptide and N-terminal proatrial natriuretic peptide as indicators of left ventricular systolic dysfunction. Am J Cardiol 1996;77:828-31 https://doi.org/10.1016/S0002-9149(97)89176-X
  28. Cowie MR, Struthers AD, Wood DA, Coats AJ, Thompson SG, Poole-Wilson PA, et al. Value of natriuretic peptides in assessment of patients with possible new heart failure in primary care. Lancet 1997;350:1347-51
  29. Suzuki T, Hayashi D, Yamazaki T, Mizuno T, Kanda Y, Komuro I, et al. Elevated B-type natriuretic peptide levels after anthracycline administration. Am Heart J 1998;136:362-3 https://doi.org/10.1053/hj.1998.v136.89908
  30. Daugaard G, Lassen U, Bie P, Pedersen EB, Jensen KT, Abildgaard U, et al. Natriuretic peptides in the monitoring of anthracycline induced reduction in left ventricular ejection fraction. Eur J Heart Fail 2005;7:87-93 https://doi.org/10.1016/j.ejheart.2004.03.009
  31. Elbl L, Vasova I, Navratil M, Vorlicek J, Malaskova L, Spinar J. Comparison of plasmatic levels of B-natriuretic peptide with echocardiographic indicators of left ventricle function after doxorubicin therapy. Vnitr Lek 2006;52:563-70
  32. Pinarli FG, Oguz A, Tunaoglu FS, Karadeniz C, Gokcora N, Elbeg S. Late cardiac evaluation of children with solid tumors after anthracycline chemotherapy. Pediatr Blood Cancer 2005;44:370-7 https://doi.org/10.1002/pbc.20281
  33. Aggarwal S, Pettersen MD, Bhambhani K, Gurczynski J, Thomas R, L'ecuyer T. B-type natriuretic peptide as a marker for cardiac dysfunction in anthracycline-treated children. Pediatric Blood Cancer. Early View. Published Online: 2006 Dec
  34. Hayakawa H, Komada Y, Hirayama M, Hori H, Ito M, Sakurai M. Plasma levels of natriuretic peptides in relation to doxorubicin-induced cardiotoxicity and cardiac function in children with cancer. Med Pediatr Oncol 2001;37:4-9 https://doi.org/10.1002/mpo.1155