CARDIAC ANTHRACYCLINE ACCUMULATION AND B-TYPE NATRIURETIC PEPTIDE TO DEFINE RISK AND PREDICTORS OF CANCER TREATMENT RELATED EARLY DIASTOLIC DYSFUNCTION

Diastolic dysfunction (DD) was reported to precede heart failure (HF) in cancer patients treated with chemotherapy. We aimed at defining risk versus dose relationships and risk predictors in cancer patients treated mainly with anthracyclines. Data from 67 comorbid-free patients (60 treated with anthracyclines, 7 with nonanthracycline chemotherapy) were retrospectively incorporated in a mathematical function that correlated DD risk with experimental indices of anthracycline accumulation in human myocardium. Risk was calculated for all patients and for subgroups stratified by intertreatment levels of the endogenous cardiac relaxant agent, B-type natriuretic peptide (BNP). Grade I DD (impaired relaxation) occurred in 14/67 patients and 5% risk doses were much lower for DD than HF (mg of anthracycline/m2: 210 versus 470 or 190 versus 450 for all patients or anthracycline-treated patients in isolation, respectively, P=<0.01 for DD versus HF). Patients with transient BNP elevations showed the lowest 5% risk dose (150 mg/m2) while patients with persistent elevations showed the highest risk dose (280 mg/m2, P<0.05). Patients with or without DD were similar for systemic and cardiac exposure to anthracyclines; however, high risk patients with transient BNP elevations and DD were older and presented at baseline with lower indices of transmitral flow. In conclusion, DD risk develops after lower anthracycline doses than HF and intertreatment levels of BNP help to identify patients with high or low DD risk. These findings are of potential value to monitor or treat the cancer patient at risk of DD. Significance Statement Diastolic dysfunction (DD) is an early manifestation of cardiotoxicity from anthracyclines and nonanthracycline chemotherapeutics. We show that merging preclinical characterization of cardiac anthracycline accumulation with clinical data from patients treated primarily with anthracyclines identifies DD risk from very low anthracycline doses. DD risk is associated with older age, baseline diastolic indices toward the lower limit of normal, and transient intertreatment elevations of the endogenous cardiac relaxant agent, B-type natriuretic peptide. These findings have numerous pharmacological implications.