Molecular pathogenetic mechanisms and new therapeutic perspectives in anthracycline-induced cardiomyopathy
© Distefano; licensee BioMed Central Ltd. 2009
Received: 1 September 2009
Accepted: 20 November 2009
Published: 20 November 2009
Anthracyclines are among the most powerful drugs for the treatment of oncologic diseases both in childhood and in adulthood. Nevertheless, their major antineoplastic efficacy can be seriously impaired by collateral toxic cardiac effects causing cardiomyopathy with chronic heart failure that is refractory to conventional medical therapy.
This article reports possible subcellular molecular alterations of anthracycline-induced cardiomyopathy (reactive oxygen species formation, apoptosis, inflammatory signalling, altered expression of cardiomyocytes specific genes, etc) and indicates some new therapeutic perspectives resulting from a better understanding of the molecular pathogenetic mechanisms.
Today anthracyclines are among the most powerful drugs used for the treatment of oncologic diseases both in childhood and adulthood. Nevertheless their major antineoplastic efficacy can be seriously impaired by collateral toxic effects causing profound alterations in cardiac muscle. These effects can be associated to acute clinical manifestations, occurring within 24 hours from the beginning of treatment, such as hyperkinetic arrhythmias and/or reversible heart failure (myocarditis-pericarditis syndrome); subacute manifestations, occurring after weeks or months (up to 30 months), leading rapidly to progressive heart failure and 60% mortality; chronic manifestations, occurring 4-20 years after the treatment, with progressive irreversible cardiac insufficiency . The most interesting aspects are connected to late chronic cardiotoxicity that is particularly insidious. It has a long term asymptomatic course or presents slight electrocardiographic and/or echocardiographic anomalies that later evolve into chronic cardiomiopathy, dilated type in adulthood and restrictive-dilated in childhood, that is refractory to medical treatment . Another peculiar feature of chronic anthracycline cardiotoxicity is that it is strictly linked to drug cumulative dose. Indeed, the incidence of anthracycline - induced cardiomyopathy (AIC) and heart failure increases from 7% of cases for total doses of 550 mg/m2/bs, to 15% for 600 mg/m2/bs and 30-40% for 700 mg/m2/bs .
Pathological studies on experimental animal models and human endomyocardial biopsies have shown that AIC is characterized by histological alterations consisting in multiple areas of interstitial fibrosis associated with the presence of cardiomyocytes with vacuolar degeneration or compensatory hypertrophy. Necrotic cardiomyocytes with histiocytic infiltration, and stromal oedema with myocardial fibers dissociation can also be observed. Electron microscopy revealed that the damage caused by anthracyclines to cardiomyocytes appears as loss of myofibrils, distention of sarcoplasmic reticulum, mitochondrial swelling, increased lysosomal number and disorganization of nuclear chromatine [4–6].
In order to explain these alterations, numerous pathogenetic mechanisms have been proposed , and three seem to be the most important: free radical release secondary to the binding of anthracyclines to intracellular iron, interaction with nuclear and mitochondrial DNA, and gene activation with biochemical transduction signals inducing apoptosis [7, 8].
Prevention is particularly important in children, who, thanks to modern treatments, can survive leukemia and other tumoral diseases for several decades. The various approaches proposed are not always completely efficacious and include: cumulative dose under 450 mg/m2bs, use of anthracycline analogouses (epirubicin, idarubicin, mitoxantrone), alternative methods of administration (continuous slow infusion instead of rapid bolus, or liposome encapsulated anthracyclines) and, above all, use of antioxidants [3, 6]. Although classic molecules such as tocopherol, ascorbic acid and acetylcysteine have displayed encouraging results against acute anthracycline toxicity, they have not demonstrated clear clinical benefits in chronic cardiomyopathty . More recent studies reported that probucol, a lipid-lowering drug, that also exerts an antioxidant effect and promotes the activities of endogenous antioxidants, was effective in preventing anthracycline cardiomyopathty and heart failure in animal experiments, but further clinical trials are required . To date the most promising agent is dexrarozane, an iron-chelator capable of preventing the formation of extremely reactive hydroxyl radicals catalyzed by the anthracycline-iron complex . Clinical trials conducted in children have demonstrated that this drug has an effective cardioprotective action and reduces the cardiac side-effects of anthracyclines for up to 5 years after chemotherapy . Longer follow-up are required to determine the long-term cardioprotective effects of dexrazozane.
The effectiveness of conventional therapy of chronic heart failure traditionally based on the use of digitalis, vasodilators, diuretics and beta-blockers is debated. Even if these drugs can transitorily improve the hemodynamic status of subjects with AIC, they are not able to prevent cardiac insufficiency progressing toward more severe forms requiring cardiac transplantation .
On the basis of these considerations, it is likely that in the near future the better knowledge of the subtle biochemical mechanisms regulating the function and survival of cardiac cells and the emerging perspectives of a "molecular ventricular assistance" connected to the developing gene therapy of chronic heart failure may allow a more rational preventive and therapeutic approach to cardiac insufficiency associated to dilated cardiomyopathies and therefore revolutionize also the prognosis of AIC [30, 31].
The author would like to thank G. Vitaliti and N. Bonanno for their technical collaboration.
- Outomuro D, Grana DR, Azzato F, Milei J: Adriamycin-induced myocardial toxicity: new solutions for an old problem?. Int J Cardiol. 2007, 117: 6-15. 10.1016/j.ijcard.2006.05.005.View ArticlePubMedGoogle Scholar
- Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L: Antracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004, 56: 185-229. 10.1124/pr.56.2.6.View ArticlePubMedGoogle Scholar
- Iarussi D, Indorfi P, Casale F, Martino V, Di Tullio MT, Calabrò R: Anthracycline-induced cardiotoxicity in children with cancer. Strategies for prevention and management. Pediatr Drugs. 2005, 7: 67-76. 10.2165/00148581-200507020-00001.View ArticleGoogle Scholar
- Lushnikova EL, Klinnikova MG, Molodykh OP, Nepomnyashchikh LM: Morphological manifestations of heart remodelling in anthracycline-induced dilated cardiomyopathy. Bull Exp Biol Med. 2004, 138: 607-612. 10.1007/s10517-005-0138-0.View ArticlePubMedGoogle Scholar
- Menna P, Recalcati S, Cairo G, Minotti G: An introduction to the metabolic determinants of anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007, 7: 80-85. 10.1007/s12012-007-0011-7.View ArticlePubMedGoogle Scholar
- Takemura G, Fujiwara H: Doxorubicin-induced cardiomyopathy. From the cardiotoxic mechanisms to management. Progr Cardiovasc Dis. 2007, 49: 330-352. 10.1016/j.pcad.2006.10.002.View ArticleGoogle Scholar
- Kremer LC, Caron HN: Anthracycline cardiotoxicity in children. N Engl J Med. 2004, 351: 120-121. 10.1056/NEJMp048113.View ArticlePubMedGoogle Scholar
- Kalyanaraman B, Joseph J, Kalivendi S, Wang S, Konorev E, Kotamraju S: Doxorubicin-induced apoptosis: implications in cardiotoxicity. Mol Cell Biochem. 2002, 234/235: 119-124. 10.1023/A:1015976430790.View ArticleGoogle Scholar
- Rathe M, Carlsen NLT, Oxhoj H: Late cardiac effects of anthracycline containing therapy for childhood acute lymphoblastic leukemia. Pediatr Blood Cancer. 2007, 48: 663-667. 10.1002/pbc.20313.View ArticlePubMedGoogle Scholar
- Lebrecht D, Walker UA: Role of mtDNA lesions in anthracycline cardiotoxicity. Cardiovasc Toxicol. 2007, 7: 108-113. 10.1007/s12012-007-0009-1.View ArticlePubMedGoogle Scholar
- Wallace KB: Doxorubicin-induced cardiac mitochondrionopathy. Pharmacol Toxicol. 2003, 93: 105-115. 10.1034/j.1600-0773.2003.930301.x.View ArticlePubMedGoogle Scholar
- Lipshultz SE: Exposure to anthracyclines during childhood causes cardiac injury. Semin Oncol. 2006, 33: S8-S14. 10.1053/j.seminoncol.2006.04.019.View ArticlePubMedGoogle Scholar
- Creutzig U, Diekamp S, Zimmermann M, Reinhardt D: Longitudinal evaluation of early and late anthracycline cardiotoxicity in children with AML. Pediatr Blood Cancer. 2007, 48: 651-662. 10.1002/pbc.21105.View ArticlePubMedGoogle Scholar
- Scully RE, Lipshultz SE: Anthracycline cardiotoxicity in long-term survivors of childhood cancer. Cardiovasc Toxicol. 2007, 7: 122-128. 10.1007/s12012-007-0006-4.View ArticlePubMedGoogle Scholar
- O'Laughlin PM: Congestive heart failure in children. Pediatr Clin North Am. 1999, 46: 263-273. 10.1016/S0031-3955(05)70117-6.View ArticlePubMedGoogle Scholar
- Shaddy RE, Tani LY, Gidding SS, Pahl E, Orsmond GS, Gilbert EM: Âeta-blocker treatment of dilated cardiomyopathy with congestive heart failure in children; a multi-institutional experience. J Heart Lung Transpl. 1999, 18: 269-274. 10.1016/S1053-2498(98)00030-8.View ArticleGoogle Scholar
- Bristow MR: Why does the myocardium fail? Insights from basic science. Lancet. 1998, 352: 8-14. 10.1016/S0140-6736(98)90311-7.View ArticleGoogle Scholar
- Colucci WS: Molecular and cellular mechanism of myocardial failure. Am J Cardiol. 1997, 80: 15L-25L. 10.1016/S0002-9149(97)00845-X.View ArticlePubMedGoogle Scholar
- Chien KR: Stress pathways and heart failure. Cell. 1999, 98: 555-558. 10.1016/S0092-8674(00)80043-4.View ArticlePubMedGoogle Scholar
- Izumo S, Nadal-Ginard B, Mahdavi V: Protooncogene induction and reprogramming of cardiac gene expression produced by pressure overload. Proc Natl Acad Sci USA. 1988, 85: 339-343. 10.1073/pnas.85.2.339.PubMed CentralView ArticlePubMedGoogle Scholar
- Cvetkovic RS, Scott LJ: Dexrazoxane: a review of its use for cardioprotection during anthracycline chemotherapy. Drugs. 2005, 65: 1005-1024. 10.2165/00003495-200565070-00008.View ArticlePubMedGoogle Scholar
- Kovács GT, Erlaky H, Tóth K, Horváth E, Szabolcs J, Csóka M, Jókúti L, Erdélyi D, Müller J: Subacute cardiotoxicity caused by anthracycline therapy in children: can dexrazoxane prevent this effect?. Eur J Pediatr. 2007, 166: 1187-1188. 10.1007/s00431-006-0370-2.View ArticlePubMedGoogle Scholar
- Barry E, Alvarez JA, Scully RE, Miller TL, Lipshultz SE: Anthracycline-induced cardiotoxicity: course, pathophysiology, prevention and management. Expert Opin Pharmacother. 2007, 8: 1039-1058. 10.1517/14656518.104.22.1689.View ArticlePubMedGoogle Scholar
- Distefano G: Myocardial remodelling and new therapeutic strategies in chronic heart failure. Italian J Pediatr. 2001, 27: 311-317.Google Scholar
- Bradham WS, Moe G, Wendt KA, Scott AA, Konig A, Romanova M, Naik G, Spinale FG: TNF-alpha and myocardial matrix metalloproteinases in heart failure: relationship to LV remodeling. Am J Physiol Heart Circ Physiol. 2002, 282: H1288-H1295.View ArticlePubMedGoogle Scholar
- Takemura G, Fujiwara H: Morphological aspects of apoptosis in heart diseases. J Cell Mol. 2006, 10: 56-75. 10.1111/j.1582-4934.2006.tb00291.x.View ArticleGoogle Scholar
- Krum H, Abraham WT: Heart Failure. Lancet. 2009, 373: 941-955. 10.1016/S0140-6736(09)60236-1.View ArticlePubMedGoogle Scholar
- Westermann D, Lettau O, Sobirey M, Riad A, Bader M, Schultheiss H-P, Tschope C: Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor. Biol Chem. 2008, 389: 713-718. 10.1515/BC.2008.070.View ArticlePubMedGoogle Scholar
- Kim K-H, Oudit GY, Backx PH: Erythropoietin protects against doxorubicin-induced cardiomyopathy via a phosphatidylinositol 3-kinase-dependent pathway. JPET. 2008, 324: 160-169. 10.1124/jpet.107.125773.View ArticleGoogle Scholar
- Isner JM: Myocardial gene therapy. Nature. 2002, 415: 234-239. 10.1038/415234a.View ArticlePubMedGoogle Scholar
- Vinge LE, Raake PW, Koch WJ: Gene therapy in heart failure. Circ Res. 2008, 102: 1458-1470. 10.1161/CIRCRESAHA.108.173195.PubMed CentralView ArticlePubMedGoogle Scholar
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