Early detection of doxorubicin-induced cardiotoxicity and its prevention by carvedilol
Keywords:
Cardiac troponin I, Doxorubicin, Carvedilol, Lactate dehydrogenase, Creatine kinase-MB, Group, Body weightAbstract
Background: The objective was to detect doxorubicin (Dox) - induced myocardial injury at early stage by quantitative estimation of cardio specific protein, cardiac troponin I (cTnI) and to explore the cardioprotective effects of carvedilol.
Methods: The study design was lab-based randomized controlled in-vivo in rabbits conducted from January to August 2012. Cardiotoxicity was produced by single intravenous injection of 12 mg/kg body weight (BW) of Dox in a group of rabbits, control group was treated with normal saline only and the rabbits of third group were pre-treated with carvedilol 30 mg/kg of BW for 10 days before injecting Dox.
Results: Dox induced cardiotoxicity was depicted by markedly raised serum levels of cTnI, creatine kinase-MB, lactate dehydrogenase, and Grade 3 necrosis of the heart tissue in rabbits. The pre-treatment with carvedilol resulted in improved serum levels of these biomarkers and the histological picture of heart tissue.
Conclusions: Quantitative serum estimation of cTnI detects the presence of cardiotoxicity much before cardiac dysfunctions can be revealed by any other diagnostic technique. It can lead to significant economic impact in the management of cancer patients because the troponin-negative subjects can be excluded from long-term cardiac monitoring programs that involve high costs imaging techniques. The outcome of Dox chemotherapy can be made successful with the concurrent use of carvedilol.
References
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, et al. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440-6.
Mulrooney DA, Yeazel MW, Kawashima T, Mertens AC, Mitby P, Stovall M, et al. Cardiac outcomes in a cohort of adult survivors of childhood and adolescent cancer: retrospective analysis of the Childhood Cancer Survivor Study cohort. BMJ. 2009;339:b4606.
Chatterjee K, Zhang J, Honbo N, Karliner JS. Doxorubicin cardiomyopathy. Cardiology. 2010;115(2):155-62.
Kociol RD, Pang PS, Gheorghiade M, Fonarow GC, O’Connor CM, Felker GM. Troponin elevation in heart failure prevalence, mechanisms, and clinical implications. J Am Coll Cardiol. 2010;56(14):1071-8.
Weinstein DM, Mihm MJ, Bauer JA. Cardiac peroxynitrite formation and left ventricular dysfunction following doxorubicin treatment in mice. J Pharmacol Exp Ther. 2000;294(1):396-401.
Simunek T, Stérba M, Popelová O, Adamcová M, Hrdina R, Gersl V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacol Rep. 2009;61(1):154-71.
Sawyer DB, Zuppinger C, Miller TA, Eppenberger HM, Suter TM. Modulation of anthracycline-induced myofibrillar disarray in rat ventricular myocytes by neuregulin-1beta and anti-erbB2: potential mechanism for trastuzumab-induced cardiotoxicity. Circulation. 2002;105(13):
-4.
Ladenson JH. A personal history of markers of myocyte injury [myocardial infarction]. Clin Chim Acta. 2007;381:3 8.
Cardinale D, Sandri MT. Role of biomarkers in chemotherapy-induced cardiotoxicity. Prog Cardiovasc Dis. 2010;53(2):121-9.
O’Brien PJ. Cardiac troponin is the most effective translational safety biomarker for myocardial injury in cardiotoxicity. Toxicology. 2008;245(3):206-18.
Jaffe AS, Apple FS, Lindahl B, Mueller C, Katus HA. Why all the struggle about CK-MB and PCI? Eur Heart J. 2012;33(9):1046-8.
Lipshultz SE, Miller TL, Scully RE, Lipsitz SR, Rifai N, Silverman LB, et al. 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. 2012;30(10):1042-9.
Berridge BR, Pettit S, Walker DB, Jaffe AS, Schultze AE, Herman E, et al. A translational approach to detecting drug-induced cardiac injury with cardiac troponins: consensus and recommendations from the Cardiac Troponins Biomarker Working Group of the Health and Environmental Sciences Institute. Am Heart J. 2009;158(1):21-9.
Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56(2):185-229.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90.
Wouters KA, Kremer LC, Miller TL, Herman EH, Lipshultz SE. Protecting against anthracycline-induced myocardial damage: a review of the most promising strategies. Br J Haematol. 2005;131(5):561-78.
Zhou Q, Xiao J, Jiang D, Wang R, Vembaiyan K, Wang A, et al. Carvedilol and its new analogs suppress arrhythmogenic store overload-induced Ca2+ release. Nat Med. 2011;17(8):1003-9.
Watanabe K, Arozal W, Sari FR, Arumugam S, Thandavarayan AR, Suzuki K, et al. The role of carvedilol in the treatment of dilated and anthracyclines-induced cardiomyopathy. Kufa Med J. 2011;15(1):314.
Rehsia NS, Dhalla NS. Mechanisms of the beneficial effects of beta-adrenoceptor antagonists in congestive heart failure. Exp Clin Cardiol. 2010;15(4):e86-95.
Jasinska M, Owczarek J, Orszulak-Michalak D. The influence of simvastatin at high dose and diltiazem on myocardium in rabbits, the biochemical study. Acta Pol Pharm. 2006;63(5):386-90.
Cour M, Loufouat J, Paillard M, Augeul L, Goudable J, Ovize M, et al. Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study. Eur Heart J. 2011;32(2):226-35.
Billingham ME, Mason JW, Bristow MR, Daniels JR. Anthracycline cardiomyopathy monitored by morphologic changes. Cancer Treat Rep. 1978;62(6):865-72.
Che FF, Liu Y, Xu CG, Schisandrin B. Prevents doxorubicin-induced cardiotoxicity in rabbits. Int J Toxicol. 2011;00(0):1 9.
Gouri A, Dekaken A, Chefrour M, Bentorki AA, Yakhlef A. Hematologic malignancies therapy and cardiotoxicity: new biomarkers. J Hematol Thromb Dis. 2014;2:e110.
Hadi RN, Ali JS, Hinti N. Amelioration of doxorubicin induced cardiotoxicity. Qual Manage J. 2011;7(12):272 92.
Arozal W, Sari FR, Watanabe K, Arumugam S, Veeraveedu PT, Ma M, et al. Carvedilol-afforded protection against daunorubicin-induced cardiomyopathic rats in vivo: effects on Cardiac Fibrosis and Hypertrophy. ISRN Pharmacol. 2011;2011:430549.
Molenaar P, Christ T, Ravens U, Kaumann A. Carvedilol blocks beta2- more than beta1-adrenoceptors in human heart. Cardiovasc Res. 2006;69(1):128-39.
Spallarossa P, Garibaldi S, Altieri P, Fabbi P, Manca V, Nasti S, et al. Carvedilol prevents doxorubicin-induced free radical release and apoptosis in cardiomyocytes in vitro. J Mol Cell Cardiol. 2004;37(4):837-46.
Pereira GC, Silva AM, Diogo CV, Carvalho FS, Monteiro P, Oliveira PJ. Drug-induced cardiac mitochondrial toxicity and protection: from doxorubicin to carvedilol. Curr Pharm Des. 2011;17(20):2113-29.
Kalay N, Basar E, Ozdogru I, Er O, Cetinkaya Y, Dogan A, et al. Protective effects of carvedilol against anthracycline-induced cardiomyopathy. J Am Coll Cardiol. 2006;48(11):2258-62.
Hanif M, Zaidi P, Kamal S, Hameed A. Institution-based cancer incidence in a local population in Pakistan: nine year data analysis. Asian Pac J Cancer Prev. 2009;10(2):227-30.
