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Myocardial high-energy phosphate metabolism is altered after treatment with anthracycline in childhood

Published online by Cambridge University Press:  19 August 2008

Andrea B. Eidenschink ,
Gerrit Schröter ,
Stefan Müller-Weihrich  and
Heiko Stern
Andrea B. Eidenschink*
Affiliation:
Department of Pediatrics
Gerrit Schröter
Affiliation:
Department of Nuclear Medicine, Technical University of Municb
Stefan Müller-Weihrich
Affiliation:
Department of Pediatrics
Heiko Stern
Affiliation:
Department of Pediatric Cardiology, University of Hamburg Eppendorf, Germany
*
Andrea B Eidenschink, MD, Children's Hospital, Technical University of Munch, Kolner Platz 1, 80804 Munch, Germany, Tel +49 8930682286, Fax +49 89 30683811, E-mail: Andrea@Eidenschinks de
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Abstract

Objectives

We aimed to investigate whether changes in high-energy phosphate metabolism after treatment of children and young adults with anthracycline can be demonstrated non-invasively by 31P magnetic resonance spectroscopy.

Background

Abnormal myocardial energy metabolism has been suggested as a mechanism for anthracycline-induced cardiotoxicity. Deterioration in such has been shown in animal studies by resonance spectroscopy.

Methods

We studied 62 patients, with a mean age of 13.5 ±5 years,3.7±4.3 years after a cumulative anthracycline dose of 270±137 mg/m2. Normal echocardiographic findings had been elicited in 54 patients. The control group consisted of 28 healthy subjects aged 20±7 years. Resonance spectrums of the anterior left ventricular myocardium were obtained at 1.5 Tesla using an image-selected in vivo spectroscopy localization technique.

Results

The ratio of phosphocreatine to adenosine triphosphate after blood correction was 1.09±0.43 for the patients, and 1.36±0.36 (mean±SD)for controls (p = 0.005), with a significantly reducedmean ratio even in the subgroup of patients with normal echocardiographic results ( l.11 ± 0. 44 versus1.36±0.36, p=0.01). The ratio did not correlate with the cumulative dose of anthracycline. The ratio of phosphodiester to adenosine triphosphate was similar in patients and controls (0.90±0.56 versus 0.88±0.62).

Conclusions

In patients treated with anthracyclines in childhood, myocardial high-energy phosphate metabolism may be impaired even in the absence of cardiomyopathy. Our data support the concept that anthracycline-induced cardiotoxicity is not clearly dose dependent.

Keywords

Magnetic resonance spectroscopy, high-energy phosphatesmetabolismanthracyclinescardiotoxicity
Type
Original Articles
Information
Cardiology in the Young , Volume 10 , Issue 6 , November 2000 , pp. 610 - 617
Copyright
Copyright © Cambridge University Press 2000

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References

1. Boring, CC, Squires, TS, Tong, T, Mongomery, S.Cancer statistics, 1994. CA Cancer J Clin 1994; 44: 7–26CrossRefGoogle ScholarPubMed
2. Lipshultz, SE, Colan, SD, Gelber, RD, Perez-Atayde, AR, Sallan, SE, Sanders, SPLate cardiac effects ofdoxorubicin therapy for acute lymphoblastic leukemia in childhood. N Engl J Med 1991; 324: 808–815CrossRefGoogle Scholar
3. Steinherz, LJ, Steinherz, PG, Tan, C.Cardiac failure and dysrhythmias 6–19 years after anthracycline therapy: a series of 15 patients. Med Ped Oncol 1995; 24: 352–361CrossRefGoogle ScholarPubMed
4. Von Hoff, DD, Rozencweig, M, Piccart, M.The cardiotoxicity of anticanceragents. Semin Oncol, 1982; 9: 23–33Google Scholar
5. Olson, RD, Mushlin, PS.Doxorubicin cardiotoxicity: analysis of prevailing hypotheses. FASEB J 1990; 4: 3076–3086CrossRefGoogle ScholarPubMed
6. Keizer, HG, Pinedo, HM, Schuurhuis, GJ, Joenje, H.Doxorubicin (adriamycin): a critical review of free radical-dependent mechanisms of cytotoxicity. Pharmac Ther 1990; 47: 219–231CrossRefGoogle ScholarPubMed
7. Fu, LX, Waagstein, F, Hjaimarson, A.A new insight into adriamyin-induced cardiotoxicity. Intern J Cardiol 1990; 29: 15–20CrossRefGoogle ScholarPubMed
8. Goormaghtigh, E, Huart, P, Praet, M, Brasseur, R, Ruysschaert, JM.Structure of the adriamycin-cardiolipin complex- role in mitochondrial toxicity. BiophysChem 1990; 35: 247–257Google ScholarPubMed
9. Papadopoulou, LC, Tsitsoglou, AS.Mitochondrial cytochrome coxidase as a target site for daunomycinin k-562 cells and heart tissue. Cancer Res 1993; 53: 1972–1978Google Scholar
10. Bittner, YReeves, RC, Digerness, SB, Caulfield, JB, Pohost, GM.31P NMR spectroscopy in chronic adriamycin cardiotoxicity. Magn Res Med 1991; 17: 69–81CrossRefGoogle ScholarPubMed
11. Ng, TC, Daugherty, JP, Evanochko, WT, Digerness, SB, Durant, JR, Glickson, JD.Detection of antineoplastic agent induced cardiotoxicity by 31P NMR of perfused rat hearts. Biochem Biophys Res Comm 1983; 110: 339–347CrossRefGoogle ScholarPubMed
12. Nicolay, K, Aue, WP, Seelig, J, Echteld, van CJA, Ruigrok, TJC,Kruijff de, B.Effects of the anti-cancer drug adriamycin on the energy metabolism of rat heart as measured by in vivo 31PNMR and implications for adriamycin-induced cardiotoxicity. Biochim Biophys Acta 1987; 929: 5–13CrossRefGoogle ScholarPubMed
13. Steinherz, LJ, Graham, T, Hurwitz, R et al. , Guidelines for cardiac monitoring of children during and after anthracycline therapy: report of the cardiology committee of thechildrens cancer study group. Pediatrics 1992; 89: 942–949CrossRefGoogle ScholarPubMed
14. Colan, SD, Parness, I, Spevac, PJ, Sanders, SPDevelopmental modulation of myocardial mechanics: age-and growth-related alterations in afterload and contractility. J Am Coll Cardiol 1992; 19:619–629CrossRefGoogle ScholarPubMed
15. Ordidge, RJ, Connely, A, Lohman, JAB.Image-selected in vivo spectroscopy (ISIS): a new technique for spatially selective NMR spectroscopy. J Magn Reson 1985;66: 283–294Google Scholar
16. Neubauer, S, Krahe, T, Schindler, et al. 31P magnetic resonancespectroscopy in dilated cardiomyopathy and coronary artery disease. Circulation 1992; 86: 1810–1818CrossRefGoogle Scholar
17. Auffermann, W, Chew, WM, Wolfe, CL et al. , Normal and diffuselyabnormal myocardium in humans: functional and metabolic characterization with p-31 MR spectroscopy and cine MR imaging. Radiology 1991; 179: 253–259CrossRefGoogle ScholarPubMed
18. Jung, WI, Sieverding, L, Breuer, J et al. , 31P NMR spectroscopydetects metabolic abnormalities in asymptomatic patients with hypertrophic cardiomyopathy. Circulation 1998; 97: 2536–2542CrossRefGoogle ScholarPubMed
19. Yabe, T, Mitsumani, K, Inubushi, T, Kinoshita, M.Quantitiativemeasurements of cardiac phosphorus metabolites in coronary artery disease by 31P magnetic resonance spectroscopy. Circulation 1995;92: 15–23CrossRefGoogle ScholarPubMed
20. Blackledge, MJ, Rajagopalan, B, Oberhaensli, RD, Bolas, NM,Styles, P, Radda, G.Quantitative studies of human cardiac metabolism by 31P rotating frame NMR. Proc Natl Acad Sci USA 1987 84: 4283–4287CrossRefGoogle ScholarPubMed
21. Sakuma, H, Takeda, K, Tagami, T et al. , 31P MR spectroscopy in hypertrophic cardiomyopathy: comparison withTI-201 myocardial perfusion imaging. Am Heart J 1993; 125: 1323–1328CrossRefGoogle ScholarPubMed
22. Conway, MA, Allis, J, Ouwerkerk, R, Niioka, T, Rajagopalan, B,Radda, GK.Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet 1991; 338:973–976CrossRefGoogle ScholarPubMed
23. Steinherz, LJ, Steinherz, PG, Tan, CT, Heller, G, Murphy, ML.Cardiac cardiotoxicity 4 to 20 years after completing anthracycline therapy. YAMA 1991; 266: 1672–1677CrossRefGoogle Scholar
24. Bu-Lock, FA, Mott, MG, Oakhill, A, Martin, RPLeft ventricular diastolic function after anthracycline chemotherapy in childhood: relation with systolic function, symptoms and pathophysiology. Br Heart J 1995; 73: 340–350CrossRefGoogle ScholarPubMed
25. Lipshultz, SE, Sanders, SP, Goorin, AM, Krischer, JP, Sallan, SE,Colan, SD.Monitoring for anthracycline cardiotoxicity. Pediatrics 1994; 93: 433–437CrossRefGoogle ScholarPubMed
26. Nysom, K, Holm, K, Lipsitz, SR et al. , Relationship between cumulative anthracycline dose and late cardiotoxicity in childhood acute lymphoblastic leukemia. J Clin Oncol 1998; 16: 545–550CrossRefGoogle ScholarPubMed
27. Krischer, JP, Epstein, S, Cuthbertson, DD, Goorin, AM, Epstein, ML, Lipshultz, SE.Clinical cardiotoxicity following anthracycline treatment for childhood cancer: The pediatric ancology group experience. J Clin Oncol 1997; 15: 1544–1552CrossRefGoogle ScholarPubMed
28. Sorensen, K, Levitt, G, Bull, C, Chessells, J, Sullivan, I.Anthracycline dose in childhood acute lymphoblastic leukemia: issue of early survival versus late cardiotoxicity. J Clin Oncol 1997; 15:61–68CrossRefGoogle ScholarPubMed
29. Lang, D, Hilger, F, Binswanger, J, Andelfinger, G, Hartmann, E.Late effects of anthracycline therapy in childhood in relation to the function of the heart at rest and under physical stress. Eur J Pediatr 1995; 154:340–345CrossRefGoogle Scholar
30. Sung, RYT, Huang, GY, Sing, MK et al. , Echocardiographic evaluation of cardiac function in paediatric oncology patients treated with or without anthracyclines. Int J Cardiol 1997; 60:239–248CrossRefGoogle ScholarPubMed
31. Billingham, ME, Mason, JVBristow, MR, Daniels, JR.Anthracycline cardiomyopathy monitored by morphological changes. Cancer Treat Rep 1978; 62: 865–872Google Scholar
32. Pihkala, J, Sariola, H, Saarinen, UM.Myocardial function and postmortem myocardial histology in children given anthracycline therapy for cancer. Ped Hematol Oncol 1994; 11: 259–269Google ScholarPubMed
33. Ali, MK, Ewer, MS, Gibbs, HR, Swafford, J, Graff, KL.Late doxorubicin-associated cardiotoxicity in children. Cancer 1994;74: 182–1883.0.CO;2-2>CrossRefGoogle ScholarPubMed
34. Bu-Lock, FA, Mott, MG, Oakhill, A, Martin, RP.Left ventriculardiastolic filling patterns associated with progressive anthracycline-induced myocardial damage: a prospective study. Pediatr Cardiol 1999; 252–263CrossRefGoogle Scholar
35. Goens, MB, Karr, SS, Seibel, N, Martin, GR.Ultrasound myocardial tissue caracterisation by integrated backscatter in children treated with anthracyclines. Pediatr Cardiol 1999; 20: 264–270CrossRefGoogle Scholar
36. Hashimoto, I, Fukiko, I, Miura, M et al. , Automatic border detection identifies subclinical cardiotoxicity in children with malignancy. Circulation 1999; 99: 2367–2370CrossRefGoogle ScholarPubMed
37. Carrio, I, Estorch, M, Lopez-Pousa, A.Assessing anthracycline cardiotoxicity in the 1990s. Eur J Nucl Med 1996; 23:359–364CrossRefGoogle ScholarPubMed