Biomarkers of inflammation, hypercoagulability and endothelial injury predict early asymptomatic doxorubicin-induced cardiotoxicity in breast cancer patients

Valentina K Todorova; Ping-Ching Hsu; Jeanne Y Wei; Angel Lopez-Candales; Jim Zhongning Chen; L Joseph Su; Issam Makhoul

Biomarkers of inflammation, hypercoagulability and endothelial injury predict early asymptomatic doxorubicin-induced cardiotoxicity in breast cancer patients

Am J Cancer Res. 2020 Sep 1;10(9):2933-2945. eCollection 2020.

Authors

Valentina K Todorova¹, Ping-Ching Hsu², Jeanne Y Wei³, Angel Lopez-Candales¹, Jim Zhongning Chen¹, L Joseph Su⁴, Issam Makhoul¹

Affiliations

¹ Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences Little Rock, Arkansas, United States of America.
² Department of Environmental and Occupational Health, College of Public Health, University of Arkansas for Medical Sciences Little Rock, Arkansas, United States of America.
³ Department of Geriatrics, University of Arkansas for Medical Sciences Little Rock, USA.
⁴ Department of Epidemiology, College of Public Health, University of Arkansas for Medical Sciences Little Rock, Arkansas, United States of America.

PMID: 33042627
PMCID: PMC7539772

Abstract

Doxorubicin (DOX)-induced cardiotoxicity is a major limitation to its clinical application. Cardiotoxicity of DOX is dose-dependent that begins with the first dose. Oxidative stress and inflammation are involved in DOX-related cardiotoxicity. This study aimed to determine whether multiple markers of inflammation, hypercoagulability and endothelial injury correlate with the risk of early DOX-induced cardiotoxicity in breast cancer patients. Blood samples of 51 breast cancer patients treated with DOX-based chemotherapy were collected before (baseline) and after the first cycle of chemotherapy. The risk of cardiotoxicity was defined as an asymptomatic reduction of cardiac left ventricle ejection fraction (LVEF) >10% at completion of chemotherapy versus baseline. Plasma samples were examined for multiple biomarkers of inflammation, hypercoagulability and endothelial dysfunction, including C-reactive protein (CRP), thrombomodulin (TM), thrombin-antithrombin complex (TAT), myeloperoxidase (MPO), von Willebrand factor (vWF) and P-selectin. Surrogate markers of neutrophil extracellular traps (NETs) nucleosomes and double stranded DNA (dsDNA) were also measured. Patients with abnormal decline of LVEF >10% (n=21) had significantly elevated levels of MPO and TM both at baseline, and after the first dose of DOX-based chemotherapy relative to patients with normal LVEF (n=30) after adjusting for race, age, BMI and type of breast cancer. The first dose of DOX also induced significantly higher circulating levels of TAT complex and nucleosomes in patients at risk of cardiotoxicity in comparison with patients without. The comparison between the means of the biomarkers in after-before DOX-based chemotherapy of the two groups of patients showed significant differences for MPO, TAT complex and CRP. The results from this study suggest that the risk of DOX-induced cardiotoxicity in breast cancer is associated with endothelial dysfunction, inflammation and prothrombotic state before and after the first dose of chemotherapy.

Keywords: Chemotherapy; biomarkers; cardiotoxicity; doxorubicin; endothelial dysfunction; inflammation; thrombosis.

Grants and funding

P30 AG028718/AG/NIA NIH HHS/United States