Michael Hauser á Neil Wilson

Anthracycline induced cardiomyopathy:successful treatment with angiotensinconverting enzyme inhibitors

Received: 19 August 1999 /Accepted: 25 November 1999

The use of anthracyclines in paediatric oncology is limited by theirdose-related cardiotoxicity. Timely intervention with angiotensinconverting enzyme inhibitors in asymptomatic children with myo-cardial damage following anthracycline therapy may be bene®cial.

Many children have received anthracyclines in the therapy ofpaediatric oncological disorders. The usefulness of these agents islimited by dose related cardiotoxicity, with congestive heart failuredeveloping in up to 20% of patients [4]. Late mortality due tocardiac toxicity has thus become increasingly important. Symptomssuch as left ventricular dysfunction, elevated ®lling pressure andreduced cardiac output are common. We report successful treat-ment of severe daunorubicin-induced cardiomyopathy with angio-tensin converting enzyme (ACE) inhibitors in ®ve children withacute myeloic and in two with acute lymphoblastic leukaemia whohad received chemotherapy within the last 10 years. The medianage at diagnosis of leukaemia was 5.6 years (range 3.8±7.5 years).All children were in remission and developed cardiomyopathy afterrepeated administration of daunorubicin. Clinical signs of conges-tive heart failure appeared within a median of 3.8 years (range 1.2±7.0 years) after completion of chemotherapy. The median cumu-lative dosage of daunorubicin was 232 mg/m2 (range 147.0±270.0 mg/m2). In all patients echocardiographic measurements offractional shortening (FS) and ejection fraction (EF) as indicatorsof left ventricular function were markedly decreased (<3rdpercentile). The median FS was 13.4 % (range 10.1±18.6 %),median EF was 0.24 (range 0.22±0.29). Left ventricular dimensionswere increased (>95th percentile) and signi®cant mitral regurgi-tation was apparent on colour ¯ow Doppler in all patients.Myocardial biopsy was performed in two patients to exclude virus-associated myocarditis; histology revealed cytoplasmatic vacuoli-sation, widespread damage with necrosis of myocytes, disarray ofmyocardial ®bres and marked interstitial ®brosis, a consistent®nding in anthracycline-damaged myocardium. In addition toconventional heart failure treatment (digoxin, frusemide), captoprilwas administered at a dose of 2±5 mg/kg per day. In all patients,clinical signs improved within a matter of weeks after startingtherapy. FS and EF returned to normal in six patients within amedian period of 7.9 months (range 6.2±12.4 months) after startingtherapy. The remaining patient, whose therapy was started 4months ago, has improved clinically, albeit subnormal ventricularfunction with a FS of 23% and EF of 0.54, compared with 15%and 0.29 respectively before treatment. In four patients therapy wasstopped in median period of 10.4 months (range 8.1±14.7 months)after captopril administration; in these patients ventricular functionis still normal 1 year after treatment with ACE inhibitors.

At least 50% of recipients of anthracyclines have an abnormalelevation of afterload and this seems to progress with time [3].Increased ventricular wall stress implies increased myocardialoxygen consumption and there is some evidence that prolongedelevation of left ventricular wall stress is one factor contributing tothe myocardial deterioration. Concomitantly the renin-angioten-

sin-aldosterone axis is stimulated leading to neurohumoral activa-tion of vasoconstrictive hormones [2]. The noradrenaline releasefrom the synaptic nerve endings by activation of presynapticb-adrenoceptors is reduced due to downregulation of presynapticb-adrenoceptors caused by elevated noradrenaline levels in the faceof cardiac failure. Besides well known bene®cial haemodynamice�ects in congestive heart failure, ACE inhibitors also alter theunderlying neurohumoral events that exaggerate the severity ofheart failure. It also seems likely that there is a speci®c cellulare�ect of ACE inhibitors in remodelling ®brotic material in a�ectedhearts, since ACE inhibitors could function to decrease or preventthe ®brogenic e�ect of angiotensin II [1]. Angiotensin II stimulatescollagen synthesis from cardiac ®broblasts, whereas prostaglandinE2 inhibits this process. ACE inhibition could decrease levels ofboth circulating and tissue angiotensin II and increase myocardialprostaglandin E2 [1], which together may ameliorate myocardial®brosis. ACE inhibitors which contain a sulphhydryl group(captopril) possess radical scavanger properties that could be ofbene®t, especially in anthracycline-induced cardiomyopathy whichis almost certainly mediated by free radical damage [5]. The heartseems to be susceptible to this damage because of its high contentof mitochondria where free radicals are generated; low levels ofantioxidant enzymes may intensify this e�ect. Although the exactmechanism of the bene®cial e�ect of ACE inhibitors remainshypothetical, their use in anthracycline-induced cardiomyopathyhas logical prerequisites. We have been encouraged by the clinicalimprovement in our patients. Although well out of the scope of thisreport, it is possible that timely intervention with ACE inhibitors inasymptomatic children with myocardial damage following anth-racycline treatment may have bene®cial e�ect on myocardialfunction.

References

1. Davison G, Hall CS, Miller JG, Scott M, Wickline SA (1994)Cellular mechanism of captopril induced matrix remodelling inSyrian hamster cardiomyopathy. Circulation 90: 1334±1342

2. Erdman E (1994) Treatment of chronic heart failure with ACE-inhibitors. Z Kardiol 83[Suppl 4]: 75±79

3. Hausdorf G, Morf G, Beron G (1988) Long term doxorubicincardiotoxicity in childhood: noninvasive evaluation of thecontractile state and diastolic ®lling. Br Heart J 60: 309±315

4. Kantrowitz NE, Bristow MR (1984) Cardiotoxicity of antitu-mor agents. Prog Cardiovasc Dis 27: 195±199

5. Weglicki WB, Bloom S, Cassidy MM, Freddman AM (1992)Antioxidants and the cardiomyopathy of MF-de®ciency. Am JCardiovasc Pathol 4: 210±15

M. Hauser (&)Department of Paediatric Cardiology,German Heart Centre, Lazarettstra�e 36,80636 Munich, Germanye-mail: hauser@dhm.mhn.deTel.: +49-89-1218-2305; Fax: +49-89-1218-2303

N. WilsonRoyal Hospital for Sick Children, Yorkhill,Glasgow, Scotland, UK

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