Plasma Proteins Associated With the Immune Response to Anthracycline Cardiotoxicity in Patients With Hematologic Malignancies

BACKGROUND: Anthracyclines such as doxorubicin 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 discover plasma proteins that correlate with the subsequent development of anthracycline-induced systolic dysfunction in patients, with validation studies in preclinical models. METHODS: We used an aptamer-based proteomics platform to measure over 7000 proteins in the plasma obtained at baseline (before anthracycline chemotherapy) in a prospectively enrolled cohort of patients with hematologic malignancies (n=34). The correlation between protein levels and change in left ventricular ejection fraction was assessed. Candidate biomarkers were validated in a second patient cohort treated with anthracyclines for hematologic malignancies (n=32), as well as in a mouse model of delayed doxorubicin cardiotoxicity. RESULTS: In both discovery and validation cohorts, baseline levels of CPVL (carboxypeptidase vitellogenic-like protein) and PIGR (poly immunoglobulin receptor) measured in the plasma before anthracycline treatment correlated with a subsequent decline in left ventricular ejection fraction (PIGR: R =−0.74; P =0.0022; CPVL: R =−0.74; P =0.0022). Findings were confirmed in human plasma samples using ELISA or Western blot, and similar changes in proteins were observed in mice treated with doxorubicin. In further support of PIGR as a biomarker representing the systemic adaptive immune response, doxorubicin treatment was associated with increased circulating levels of IgA + (immunoglobulin A) B cells in mice, which similarly correlated with the decline in left ventricular ejection fraction. The highest quartile of PIGR and CPVL levels was associated with decreased overall survival but not progression-free survival. CONCLUSIONS: Preanthracycline levels of the plasma immunologic proteins CPVL and PIGR were associated with a subsequent decline in cardiac function, representing potentially new inflammatory biomarkers of anthracycline cardiotoxicity.