Br HeartJ7 1993;70:499-502

REVIEW

Anthracyclines and the heart

Walter Rhoden, Philip Hasleton, Nicholas Brooks

The anthracyclines are effective and widelyused antineoplastic agents. They are used totreat many types of malignancy includingacute lymphoblastic leukaemia.' Their intro-duction has considerably improved survival,especially in childhood cancers.

Signs of cardiac toxicity may develop dur-ing, soon after or many years after a course oftreatment. Early toxicity is dependent princi-pally on the cumulative anthracycline dose.Typically the patient presents with left ven-tricular or congestive heart failure and withclinical features of congestive cardiomyopa-thy. Less often an arrhythmia is the first man-ifestation of toxicity. The major differentialdiagnoses are malignant pericarditis, cardiacinjury from concomitant radiotherapy, andcoincidental heart muscle or coronary arterydisease.The two most widely used and studied

anthracyclines are daunorubicin and its C-14derivative, doxorubicin (adriamycin). Theyare glycoside antibiotics that owe their anti-neoplastic action to a complex effect thatresults in inhibition of nucleic acid synthesisby binding to both strands of the DNA helix,preventing the normal function of RNA andDNA polymerases.

Departments ofCardiology andPathology,WythenshaweHospital, ManchesterW RhodenP HasletonN BrooksCorrespondence to:Dr N Brooks, Departmnentof Cardiology, WythenshaweHospital, South Moor Road,Manchester M23 9LT

Pathogenesis ofmyocardial toxicityPossible mechanisms of the myocyte damageinclude a disturbance of calcium and sodiumexchange caused by an interaction with theinner mitochondrial membrane to form a

complex that inactivates the electron trans-port chain2 and the production of free oxygenradicals. Daunorubicin added to culturedmyocardial cells from neonatal rats at con-centrations similar to those used inchemotherapy is accompanied by rapid pro-duction of free radical derivatives.'4 An expla-nation for the myofibrillar loss is selectiveinhibition of gene expression in cardiac mus-cle cells. Doxorubicin causes a dose-depen-dent decrease in the concentrations ofmessenger RNA for a actin, troponin I,myosin light chain 2, and the M isoform ofcreatine kinase in rat cardiac muscle. Thesechanges in gene expression precede the clas-sic changes of anthracycline toxicity both inmyocyte cultures and cardiac muscle in vivo.5Doxorubicin induced automaticity in cul-tured chick heart aggregates by depolarisingthe cardiac membrane.6

Effects on ventricular functionDose-dependent myocardial toxicity is char-acterised by impairment of left ventriculardiastolic function which is followed byreduced systolic function7-9 with progressiveleft ventricular free wall thinning and dilata-tion.10 Dysfunction confined to the right ven-tricle has also been described.1' 12 An upperlimit to the cumulative dose of 450-550mg/M2 was recommended."134

Non-dose dependent electrocardiographicabnormalities including non-specific ST andT wave changes, low QRS voltage, and ven-tricular arrhythmias were described in areview of patients with evidence of early car-diotoxicity.15 Steinberg et al observed arrhyth-mias in 3% of patients during the first hour ofdoxorubicin administration, increasing to24% of subjects within the first 24 hours. Themost common abnormality was an increase inthe frequency of ventricular extrasystoles buta few patients developed non-sustained ven-tricular tachycardia. The appearance ofarrhythmias was not associated with anadverse outcome in this group of patients'6but sudden death has been reported by oth-ers.'7

Early congestive cardiac failure developedin about 30% of patients receiving more than550 mg/M2 doxorubicin but in only0 01-0 27% of patients receiving less than550 mg/m2.1'20 Smaller doses of anthracyclinecan lead to a reduction in myocardial func-tion that is demonstrable only on exercise.2122Cardiotoxicity can be enhanced when anthra-cyclines are used in combination with otheragents such as cyclophosphamide, bleomycin,cisplatin, methotrexate, and mitomycin C2324

as well as with thoracic irradiation.Cumulative anthracycline doses below the"safe upper limit" of 450-550 mg/M2 can befatal in these circumstances.

Heart failure late after anthracycline ther-apy is increasingly recognised.25-29

In a prospective study of 201 childrentreated with anthracyclines, Steinherz andcolleagues found that no patient assessed 4-6years after treatment had a fractional shorten-ing of less than 20%, whereas by 10 years onethird had values of less than 20% and overhalf of less than 25%.30 Limiting the dose ofanthracycline does not eliminate the risk oflong-term myocardial damage. Lipshultz et alidentified abnormalities of cardiac function in17% of patients who had received a singledose of only 45 mg/M2 of doxorubicin.3"

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Treatment of cardiotoxicityAnthracycline-induced heart failure should betreated with the conventional combination ofa diuretic and digoxin, and an angiotensinconverting enzyme inhibitor may be indicatedat an early stage.3233

Progressive heart failure unresponsive toconventional therapy has been successfullytreated by heart transplantation.3435

Prevention of cardiotoxicityDOSE REDUCTIONDose reduction reduces the incidence of earlymyocardial dysfunction but does not removethe risk of long-term problems. Low doseinfusion reduced cardiotoxicity in some stud-ies36-38 as did a weekly low dose schedule,39possibly by avoiding high peak concentra-tions. Continuous infusions can howevercause a progressive fall in resting left ventric-ular ejection fraction.40NEW ANTHRACYCLiNESAnthracycline analogues such as epirubicin,idarubicin, esorubicin and pirarubicin havebeen reported to cause less early cardio-toxicity than daunorubicin or doxorubicin4l43but their long-term effects cannot yet beassessed.

CARDIOPROTECTIVE AGENTSThe ICRF187, given with an anthracycline,seems to reduce cardiotoxicity without lessen-ing its antineoplastic action.4A6 The mecha-nism of action of ICRF187 is unknown.Niacin and isocitrate have both been shownto reduce cardiotoxicity in mice.47

SURVEILLANCE FOR SIGNS OF TOXICITYSteinberg and Wasserman recommended thatduring treatment left ventricular functionshould be monitored by serial radionuclideventriculography, and that doxorubicinshould be stopped if the ejection fractionsdropped to <45% at rest or failed to increasewith exercise.48 The results of serial radionu-clide studies must, however, be interpretedwith caution to avoid labelling spontaneousvariations in the left ventricular ejection frac-tion as doxorubicin cardiotoxicity.49 M Modeechocardiography can also be used to identifypatients with asymptomatic ventricular dys-function. Both these approaches require theclinician to wait until ventricular systolicfunction has been affected before alteringtreatment. Assessment of left ventricular dias-tolic performance by measurement of isovolu-mic relaxation time50 and pulsed waveDoppler transmitral flow velocity5' can give

Electron micrograph of amyocardialfibre affected byanthracycline toxicityshowing a relativelynormal appearance on theleft and extensivemyofibrliar loss anddegenerative elongatedmitochondria on the right.(Original magnification,x 7000).

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Anthracyclines and the heart

an earlier indication of cardiotoxicity. Ideallymethods of identifying patients at risk of car-diotoxicity, or of identifying cardiotoxicitybefore it causes irreversible depression ofmyocardial function need to be developed.

Monoclonal antimyosin antibody imaginghas been proposed for the early diagnosis ofanthracycline cardiotoxicity5253 because anti-body uptake seems to predate other markersof myocardial damage. Evidence from 123I.Methoxy-isobutyl isonitrile (MIBI) scanningsuggests that doxorubicin-related cardiotoxic-ity involves myocardial adrenergic derange-ment,54 pointing to the possibility that thestudy of cardiac autonomic function could behelpful for patient monitoring. One studyshowed a reduction in respiratory sinusarrhythmia that preceded the onset of clinicalcongestive cardiac failure by several months55;however, another study that identified abnor-malities in cardiovascular responses to handgrip and standing found no correlation withventricular function.56The Cardiology Committee of the

Children's Cancer Study Group recommendsregular echocardiography and radionuclideventriculography during treatment.57 If initialinvestigations remain normal, long-termechocardiographic follow-up should be car-ried out three to six months, 12 months, andthen on alternate years after completion ofchemotherapy. Five-yearly radionuclide ven-triculography and Holter monitoring are alsorecommended. Abnormal results shouldprompt shortening of the follow up interval.

If anthracycline toxicity is suspected or iffurther treatment is required for a patientwho has already received a high dose of oneof the agents, endomyocardial biopsy shouldbe considered as a guide to the safety of fur-ther therapy.58

Ultrastructural changesLight microscopy is unreliable for the earlydiagnosis of anthracycline cardiotoxicity. Atleast three biopsy specimens of themyocardium should be obtained and exam-ined by electron microscopy. Two types ofmyocardial damage occur in anthracyclinetoxicity. One is sarcotubular dilatation whichmay progress to vacuolisation with the mito-

Morphological grading system for anthracyclinecardiotoxicity

Grade Morphology

0 Normal myocardial ultrastructure1 Isolated myocytes with distended sarcotubular

system and/or early myofibrillar loss; damageto <5% of all cells in 10 plastic blocks

1-5 As grade 1 but with 6-15% of all cellsaffected in 10 plastic blocks

2 Clusters of myocytes affected by myofibrillarloss and/or vacuolisation, with damage to 16-25% of cells in 10 plastic blocks

2-5 Many myocytes, <26%-35% of all cells in 10plastic blocks, affected by vacuolisationand/or myofibrillar loss

3 Severe and diffuse myocyte damage with >35% ofall cells in 10 plastic blocks showing vacuolisation and/or myofibrillar loss

From Billingham and Bristow."

chondria remaining intact. The second ismyofibrillar loss of actin and myosin, leavingan empty cell with small elongated mitochon-dria (figure) and peripheral Z-band remnants.For grading, both types of cell damage arecounted equally58 (table).

At grade 2-5 only one more dose of anthra-cycline should be administered without fur-ther evaluation. At grade 3*0 no moreanthracycline should be given.Some oncologists are reluctant to use

endomyocardial biopsy but the procedureprovides uniquely valuable information inplanning further therapy.

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