Potential biomarker of acute anthracycline-induced cardiotoxicity among children with acute lymphoblastic leukemia: cardiac adriamycin-responsive protein

Abstract

This study aimed to investigate whether serum cardiac adriamycin-responsive protein (CARP) can serve as a sensitive and specific biomarker of Anthracyclines (ANT)-induced cardiotoxicity. Fifty-five children with acute lymphoblastic leukemia (ALL) were recruited. Before and after the administration of ANT, serum levels of CARP, high-sensitivity troponin T (TNT-HS), Creatine Kinase-MB (CK-MB), and electrocardiogram were measured. post-chemotherapeutic clinical manifestations of cardiotoxicity were also investigated. Adverse cardiac events (ACEs) were graded according to the Common Terminology Criteria for Adverse Events(CTC AE) 4.0. Then, the CARP expression was statistically analyzed among different groups. The receiver operating characteristic (ROC) curve was used to evaluate the efficacy of CARP in predicting acute ANT-induced cardiotoxicity. After ANT chemotherapy, the serum CARP concentration increased in the NACEs (Non-ACEs) group but decreased in the ACEs group (P<0.05). In addition, Not only the serum CARP levels (△CARP) was negatively correlated with the grade of ACEs (R=-0.754, P<0.0001) but also the extent of QTc prolongation (△QTc; R=-0.5592, P<0.01). The area under the ROC curve of CARP was 90.94% (P<0.0001), and the sensitivity and specificity were 88.64% and 91.67%, respectively, all of which are superior to △TNT-HS, △CK-MB, and △QTc. In conclusion, Serum CARP could serve as a novel sensitive and specific biomarker of acute ANT-induced cardiotoxicity, which is negatively associated with ACE grade.

Anthracyclines and cardiotoxicity: Is CARP a forgotten biomarker?

“…Having summarized the main findings reported by Li et al, 1 what are their strengths and weaknesses? We believe that the most remarkable strength of this work actually coincides with its most disappointing limitation.…”

“…In this issue of the Journal of Cardiovascular Pharmacology , Li et al 1 show that cardiac adriamycin-responsive protein (CARP) might serve as an informative biomarker of cardiotoxicity in patients treated with daunorubicin, member of the anthracycline family that has been used for some 40 years now to treat a broad spectrum of human tumors.…”

“…To illuminate strengths and weaknesses of the work by Li et al, 1 two questions must first be answered: what is CARP and in which clinical settings was its role characterized? CARP is the acronym of cardiac adriamycin (doxorubicin)-responsive protein but one may also read it as the acronym of cardiac ankyrin repeat protein.…”

“…Given the role of ankyrin-repeat proteins in assisting the attachment of integral membrane proteins to cytoskeletal proteins, and considering also the abundance of regulatory and nuclear translocation domains, the new CARP was considered as a regulator of cardiomyocyte structure and gene expression, and its downregulation by adriamycin was intuitively reconciled with earlier evidence for a broad effect of anthracyclines in disregulating cardiac-specific gene expression programs. 7,8 As to the second question, Li et al 1 focused on the circulating levels of CARP in children diagnosed with acute lymphoblastic leukemia (ALL) and treated with daunorubicin, a cogener of adriamycin. This was a good setting to explore, given that long-term survivors of childhood ALL and other cancers are plagued with an increased incidence of HF.…”

“…Li et al 1 monitored 55 children, of whom as many as 43 were diagnosed with daunorubicin-attributable adverse events (AE), usually in the form of grade ≤2 palpitation, chest tightness, or QTc prolongation. Only 4 children experienced grade ≥3 AE.…”