Anthracycline cardiotoxicity: a new paradigm for an old classic.

A nthracyclines are potent antineoplastic agents with proven efficacy in the treatment of many pediatric and adult hematologic and solid organ cancers. Dose-dependent anthracycline-induced cardiomyopathy is the most notorious and well-studied chemotherapy-induced cardiovascular toxicity that was first described in 1971 in 67 patients treated with Adriamycin for a variety of tumors. 1 The clinical significance of anthracycline cardiotoxicity is growing with increasing cancer survivorship and increasing use of anthracyclines in cohorts predisposed to adverse cardiac effects such as the elderly, those with cardiovascular comorbidities, and those receiving additional chemotherapies or thoracic irradiation. However, our current knowledge of anthracycline cardiotoxic-ity derives mainly from retrospective analyses of patients with cancer who have symptomatic heart failure during or after chemotherapy. This had led to wide variations in the estimated incidence and prognosis of anthracycline cardiotoxicity and has contributed to the lack of accepted guidelines for the surveillance and management of this potentially important complication of cancer therapy. For these reasons, the prospective study by Cardinale et al 2 in this issue of Circulation evaluating the incidence of cardiotoxicity, its timing of occurrence, and its clinical response to medical therapy in a large population of anthracycline-treated adults is an important step toward resolving these uncertainties. Cardinale et al 2 describe a 9% incidence of cardiotoxic-ity among 2625 anthracycline-treated patients who underwent periodic, scheduled surveillance of left ventricular (LV) function , before, during, and after chemotherapy, over a median follow-up of 5.2 years. In this cohort, cardiotoxicity, defined as a >10% decline in LV ejection fraction (LVEF) from baseline and a final LVEF of <50%, occurred almost exclusively (98% of cases) within the first year after completing anthracycline treatment. Late reductions in LVEF were observed in only 5 (2%) patients and occurred >5.5 years after chemotherapy. Full or partial recovery of LVEF was observed in 82% of cases after prompt initiation of enalapril, either alone or in conjunction with a β-blocker, with severity of postchemotherapy LV dysfunction and New York Heart Association functional class being the best predictors of recovery. The study findings suggest that anthracycline cardiotoxicity represents a continuum that begins with subclinical myocardial cell injury, followed by an early asymptomatic decline in LVEF that can progress to symptomatic heart failure, if left untreated (Figure). The few cases that presented late occurred in patients with confounding risks for the development of cardiomyopathy, raising questions about the involvement of anthracyclines or suggesting a double-hit phenomenon …