Abstract Body: Human cardiomyopathies exhibit a wide range of phenotypic trajectories and outcomes. This complexity limits both mechanistic insight and clinical management. Over the last decade it has become clear that genetic modifiers may explain this heterogeneity, however, identifying specific modifiers remains challenging. For instance, in the pediatric cancer population, considerable variation in the incidence of cardiotoxicity persists across chemotherapeutic dosing regimens and clinical risk factors have proven insufficient to predict risk. Previous studies on childhood cancer survivors who later developed cardiomyopathies identified a susceptibility genotype postulated to alter the splicing pattern of TNNT2, the gene encoding cardiac troponin T (cTnT), increasing expression of its fetal isoform. Thus, we propose that fetal-cTnT can act as a genetic modifier, altering anthracycline induced cardiomyopathic progression. Using Time Resolved Fluorescence we identified four common anthracyclines (Mitoxantrone, Doxorubicin, Daunorubicin, and Epirubicin) that alter the lifetime decay of labeled cardiac thin filaments, suggestive of direct binding. Isothermal Titration Calorimetry confirmed that Mitoxantrone and Doxorubicin have higher binding affinities for complexes containing fetal-cTnT. 2D echocardiography of fetal-cTnT mice treated with 3 mg/kg/week Doxorubicin to a cumulative dose of 21 mg/kg showed prolonged loss of contractile function, diastolic dysfunction, and progressive ventricular remodeling compared to treated non-transgenic (NT) mice. Consistent with the clinical risk factors, Doxorubicin treated female mice had accelerated loss of function and delayed recovery after treatment cessation as compared to male mice. To explore the earliest molecular pathways associated with these functional changes we performed transcriptional analysis. We observed a 2- to 7-fold increase in interferon signaling, known to be associated with cardiotoxicity and altered cardiomyocyte metabolism, beyond that elicited by Doxorubicin in NT mice. These data suggest that expression of fetal-cTnT may increase binding of anthracyclines at the myofilament, accelerating cardiac dysfunction, representing a unique, targetable genetic risk factor for anthracycline cardiotoxicity.