Left ventricular diastolic function after anthracycline chemotherapy in childhood: Relation with systolic function, symptoms, and pathophysiology

Abstract

Objectives: To examine left ventricular (LV) diastolic function in patients previoiusly 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 effect 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.