Abstract Body (Do not enter title and authors here): Background: Anthracyclines such as doxorubicin (Dox) are well recognized to induce dose-dependent cardiotoxicity. However, traditional imaging and blood biomarkers of myocardial injury are inadequate for early risk stratification. We aimed to identify novel plasma proteins that correlate with the development of anthracycline cardiotoxicity, with validation studies in preclinical models.
Methods: We used an aptamer-based proteomics platform to measure over 7000 proteins in plasma obtained from a prospectively enrolled cohort of patients with hematologic malignancies at baseline and 3 months after anthracycline chemotherapy (n=34). Transthoracic echocardiography was used to correlate change in left ventricular ejection fraction (ΔLVEF) with protein levels. Candidate biomarkers were validated in a second patient cohort treated with anthracyclines for hematologic malignancies (n=29), correlated with oncologic outcomes, and validated in a mouse model of delayed Dox cardiotoxicity.
Results: In both discovery and validation cohorts, baseline levels of carboxypeptidase vitellogenic-like protein (CPVL) and poly-immunoglobulin receptor (PIGR) measured in the plasma prior to anthracyclines correlated with a subsequent decline in LVEF. Findings were confirmed in human plasma samples using enzyme-linked immunosorbent assay (ELISA) or by western blot. PIGR was predictive of overall mortality but not of malignancy progression in both patient cohorts. A similar relationship between plasma CPVL and PIGR and cardiac function was observed in mice treated with Dox, and circulating levels of IgA⁺ B-cells correlated with the decline in LVEF, further supporting PIGR as a plasma biomarker of the systemic adaptive immune response to Dox.
Conclusions: Pre-anthracycline levels of the plasma immunologic proteins CPVL and PIGR were associated with a subsequent decline in cardiac function in both humans and mice treated with anthracyclines but not malignancy progression, representing potentially new inflammatory biomarkers of anthracycline cardiotoxicity.