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The objective of this study was to examine changes in diastolic function associated with progressive myocardial damage and their implications. We used prospective sequential Doppler echocardiographic studies of left ventricular (LV) function. The study included 125 consecutive children (median age 6.3 years) receiving anthracyclines to cumulative doses between 45 and 1150 mg/m2 (median 270 mg/m2). We measured peak early (E) and atrial (A) phase filling velocities, EA ratio, deceleration and isovolumic relaxation times (EDecT and IVRT), heart rate, and fractional shortening (SF). Results were compared serially and with individually paired control data matched for body surface area. Progressive myocardial damage was evidenced by a mean SF decrease of 1 absolute %/100 mg/m2 of anthracycline. Six patients developed cardiac failure. After 1-100 mg/m2 of anthracyclines, the EA ratio decreased (mean 1.54-1.40, p = 0.02) and IVRT became prolonged (54 vs 52 msec in controls, p = 0.03). EA ratio increased again with the next dose, usually normalizing thereafter. Twelve patients ended treatment with an EA ratio <1 (1 cardiac death) and 17 with EA ratio >2 (2 cardiac deaths). Diastolic abnormalities were not strongly predictive of reduced SF. Modest changes in left ventricular diastolic filling patterns occur during anthracycline treatment of childhood malignancies. Although 20% of patients have significant abnormalities of diastolic filling by the end of treatment, considerable individual variability renders the pathophysiological and clinical implications of the early changes uncertain.

The number of survivors of childhood cancer affected by anthracycline cardiomyopathy is steadily increasing, despite efforts to limit cardiotoxicity by dose restriction. Cardiac function was evaluated prospectively in 125 children during treatment to attempt to identify individual susceptibilities to cardiotoxicity and hence any potential for treatment modification. Left ventricular shortening fraction was used as an index of cardiotoxicity. Shortening fraction declined as cumulative anthracycline dose increased, at an average rate of 1% per 100 mg/m2. Six patients (5%) developed heart failure. Twenty four patients (19%) had abnormal shortening fraction (< 30%) by the end of treatment, and their rate of fall of shortening fraction was significantly steeper throughout treatment than in patients finishing with normal function (shortening fraction > or = 30%). This differential susceptibility to cardiotoxicity was apparent from very early in treatment, interquartile ranges of the two shortening fraction groups separating at doses > 200 mg/m2. Patients at high risk of risk of important anthracycline cardiotoxicity may be identifiable early in treatment by regular and careful monitoring of shortening fraction. However, frequent assessment is required and this has significant resource implications.

Objectives: To examine left ventricular (LV) diastolic function in patients previously treated with anthracycline drugs for childhood malignancy. To consider clinical relevance, relations with systolic dysfunction, and the pathophysiology of anthracycline cardiotoxicity., Design: Cross sectional echocardiographic study of LV function., Setting: Supraregional centre for paediatric cardiology, principal centre for the treatment of childhood malignancy in southwest England., Patients: 226 of 236 patients surviving between 6.5 months and 17 (median 5.3) years from initial anthracycline treatment for childhood malignancy attended for clinical and echocardiographic examination. Cumulative anthracycline doses were between 50 and 750 (median 300) mg/m2. 22 patients had also received cardiac irradiation., Methods: Detailed assessment of transmitral diastolic pulsed wave Doppler flow patterns along with LV dimensions and systolic function measured by M mode echocardiography., Main Outcome Measures: Peak early (E) and atrial (A) phase filling velocities and EA ratio, time and acceleration and deceleration to and from peak E velocity, velocity integrals and ratio, isovolumic relaxation time (IVRT), and heart rate were measured. Results were examined in relation to LV cavity and posterior wall dimensions and shortening fraction (SF), and compared with paired control data matched for body surface area., Results: Eleven (5%) patients had abnormal effort tolerance. Fifty one (23%) had SF < 30% and SF was inversely correlated with cumulative dose and time from treatment. The relative risk of symptomatic cardiac failure was greatly increased by prior irradiation; > 60% of irradiated patients who received > 400 mg/m2 of anthracycline were symptomatic. Early diastolic filling was relatively normal or enhanced at low anthracycline doses or when SF was preserved, with a shorter IVRT and increased atrial phase filling. Early filling was reduced at higher doses or with reduced SF, with longer IVRT and a further increase in atrial phase filling. A more "restrictive" pattern of diastolic filling (with high E and low A velocities) was seen in some patients, particularly after cardiac irradiation., Conclusions: Significant abnormalities of diastolic function are associated with anthracycline induced cardiac damage. These are not linearly related to anthracycline dose but appear to reflect the underlying myocardial pathophysiology associated with anthracycline toxicity, which is not demonstrated by the standard M mode echocardiogram. Although the overall clinical significance of such diastolic dysfunction is uncertain, some individual abnormalities may have significant management and therapeutic implications.

Objective: A pilot study to assess the efficacy of ICRF187 as a protective agent against the cardiotoxic effects of anthracycline drugs used to treat childhood malignancies., Design: A study of cardiac function in children treated receiving ICRF187 ((s)-(+)-1,2 bis (3,5-dioxopiperazenyl) propane) in addition to anthracycline therapy compared with contemporary controls selected retrospectively on the basis of anthracycline dose matching., Patients: Five children in whom recurrence of malignant disease was re-treated with chemotherapy containing anthracycline drugs and additional ICRF187 (supplied on a compassionate-use basis) (cumulative anthracycline doses 550-1650 mg/m2). Five more children with recurrence of malignant disease were re-treated to similar cumulative anthracycline doses (600-1150 mg/m2) without ICRF187., Methods: Cardiac function was assessed clinically and echocardiographically throughout treatment. Clinical and echocardiographic state were compared before treatment and after completion of therapy within and between groups treated with and without ICRF187., Results: Two patients treated without ICRF187 developed symptomatic congestive cardiac failure from which one died. Another developed considerable but as yet asymptomatic left ventricular dysfunction. No patient receiving additional ICRF187 developed cardiac failure or left ventricular dysfunction. There were no significant differences in cumulative anthracycline dose, dose increase, type of anthracycline used, survival rate, or length of survival between groups. Left ventricular shortening fraction fell by a mean of 1.0% in patients receiving ICRF187 and by a mean of 11% in the patients treated without it (p = 0.04)., Conclusions: ICRF187 seems to have provided highly effective cardioprotection to this small group of children with end-stage malignancy. Severe cardiotoxicity was seen in a similar group treated with comparable anthracycline doses but without ICRF187.