Prognostic value of matrix metalloproteinases in patients with anthracycline-induced heart failure

Abstract

Highlights. Elevated levels of matrix metalloproteinases 2 and 9 are associated with the initiation and severity of CHF developed after breast cancer therapy with anthracyclines, which may contribute to cardiac remodeling and the progression of systolic dysfunction. Concentrations of matrix metalloproteinases-2 and -9 in blood serum serve as predictors of the unfavorable course of anthracycline-induced heart failure.Aim. To assess the role of matrix metalloproteinases-2 (MMP-2) and 9 (MMP-9) in the development and course of anthracycline-induced chronic heart failure (CHF) during 24 months of observation.Methods. The study included 114 women 12 months after completion of chemotherapy (CT) for breast cancer and developed CHF. The control group (n = 70) consisted of women (mean age 45.0 [42.0; 50.0] years old) who received doxorubicin as part of chemotherapy, but they did not develop CHF 12 months after completion of chemotherapy. The levels of biomarkers (MMP-2, MMP-9, NT-proBNP) in blood serum were determined using a sandwich immunoassay.Results. Patients with CHF had signs of cardiac remodeling and higher values of NT-proBNP, MMP-2 and MMP-9 (p<0.001) than women from the control group. After 24 months of observation, all patients with CHF were divided into 2 groups: group 1 – women with an unfavorable course of CHF (n = 54), group 2 – women with favorable course of pathology (n = 60). Criteria for the unfavorable course of CHF: the emergence of new or worsening of existing symptoms/signs of heart failure; and/or hospitalization due to HF decompensation; decrease in left ventricular ejection fraction by more than 10%; or an increase in the functional class of CHF by 1 or more. Baseline echocardiographic parameters and NT-proBNP values did not differ in groups 1 and 2. Levels of MMP-2 were higher by 8% (p = 0.017) and MMP-9 by 18.4% (p<0.001) in group 1. In 1 group the level of MMP-2 decreased after 24 months of observation. In group 2 the level of MMP-2 increased by the end of the observation period. MMP-2 levels ≥388.2 pg/ml (sensitivity 46%, specificity 80%; AUC = 0.64; p = 0.013) and MMP-9 ≥21.3 pg/ml (sensitivity 86%, specificity 84.4%; AUC = 0.9; p<0.001) were determined as predictors of an unfavorable course of CHF.Conclusion. Remodeling of the extracellular matrix may play an important role in the pathogenesis of CHF initiated by drugs of the anthracycline class. Elevated levels of MMP-2 and MMP-9 in the blood serum are associated with an unfavorable course of anthracycline-induced CHF and can be recommended when assessing the risk of an unfavorable course of pathology.