Background: Anthracyclines are associated with left ventricular (LV) dysfunction in CCS with inevitable progression to congestive heart failure (CHF). Use of ejection fraction (EF) to identify LV dysfunction precludes intervention, because EF decline is a late event in the progression to CHF. Further, better understanding of pathogenesis at the cellular level could facilitate development of targeted interventions. Methods: Study design: Cross-sectional; Biomarkers: Echocardiographic (echo), and blood biomarkers in asymptomatic individuals exposed to anthracyclines ≥300mg/m² (high-risk [HR]: n=100) compared with: i) CCS exposed to <300 mg/m² (low-risk [LR]: n=50): and ii) matched healthy controls (Con: n=50). Pathogenesis: Metabolomic analyses (351 plasma metabolites; 64 pathways). Results: Time from dx to study was comparable for HR (12.0y) vs. LR (13.2y, p=0.8). All CCS had EF≥50%. Echo: HR had lower LV chamber thickness-dimension (T-D) ratio (Z-score: -0.62) compared with LR (-0.03) and Con (-0.02; P<0.01) as well as increased LV wall stress ([ESWS] HR: 66 g/cm², LR: 58 g/cm², Con: 55 g/cm², p<0.01) and higher myocardial performance index ([MPI] HR: 0.51, LR: 0.46, Con: 0.46; P<0.01). Blood biomarkers: HR had higher plasma NT-pro BNP (HR: 71 pg/dL, LR: 37 pg/dL, Con: 26 pg/dL; P<0.01); there were no differences in troponins, Galectin-3 or ST-2. Metabolomics:Individuals with LV dysfunction (>2 SD ESWS) had reduced plasma carnitine levels (relative ratio [RR]: 0.88, p<0.01) contributing to altered fatty acid β-oxidation and accumulation of cardiotoxic long-chain (docosadienoate [RR=1.26], adrenate [RR=1.29]; p<0.05) and essential fatty acid intermediates (dihomo-linolenate [RR=1.27], eicosapentaenoate [RR=1.23], docosapentaenoate [RR=1.46]; p<0.05). Conclusions: Comprehensive profiling of anthracycline-exposed CCS with preserved EF revealed dose-dependent echo (LV ESWS, T-D ratio, MPI) and blood (NT-ProBNP) abnormalities 10+years from dx; metabolomic studies demonstrated the role of carnitine in the pathogenesis of LV dysfunction. Taken together, these findings may facilitate early detection and targeted interventions in CCS at highest risk for CHF.