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Review
. 2024 Feb 27;6(2):183-199.
doi: 10.1016/j.jaccao.2023.12.009. eCollection 2024 Apr.

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review

Hanne M Boen  1   2 , Martina Cherubin  3 , Constantijn Franssen  1   2 , Andreas B Gevaert  1   2 , Isabel Witvrouwen  1   2 , Matthias Bosman  4 , Pieter-Jan Guns  4 , Hein Heidbuchel  1   2 , Bart Loeys  3 , Maaike Alaerts  3 , Emeline M Van Craenenbroeck  1   2
Affiliations
Review

Circulating MicroRNA as Biomarkers of Anthracycline-Induced Cardiotoxicity: JACC: CardioOncology State-of-the-Art Review

Hanne M Boen et al. JACC CardioOncol. .

Abstract

Close monitoring for cardiotoxicity during anthracycline chemotherapy is crucial for early diagnosis and therapy guidance. Currently, monitoring relies on cardiac imaging and serial measurement of cardiac biomarkers like cardiac troponin and natriuretic peptides. However, these conventional biomarkers are nonspecific indicators of cardiac damage. Exploring new, more specific biomarkers with a clear link to the underlying pathomechanism of cardiotoxicity holds promise for increased specificity and sensitivity in detecting early anthracycline-induced cardiotoxicity. miRNAs (microRNAs), small single-stranded, noncoding RNA sequences involved in epigenetic regulation, influence various physiological and pathological processes by targeting expression and translation. Emerging as new biomarker candidates, circulating miRNAs exhibit resistance to degradation and offer a direct pathomechanistic link. This review comprehensively outlines their potential as early biomarkers for cardiotoxicity and their pathomechanistic link.

Keywords: cardiomyopathy; cardiotoxicity; chemotherapy; circulating biomarkers; epigenetics; heart failure.

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Conflict of interest statement

This work was supported by the Flanders Research Foundation - FWO (research grant G055821N, doctoral research grant 1192420N to Dr Boen and senior clinical investigator grant 1804320N to Dr Van Craenenbroeck) and by the Belgian Foundation against Cancer (research grant C/2020/1374 and clinical mandate grant to CF 2021/1594). Ms Cherubin was an Early Stage Researcher fellow on the INSPIRE project, which has received funding from the European Union's Horizon 2020 Research and Innovation Program (H2020-MSCA-ITN program, Grant Agreement: No858070), and has received a SEP-grant from the Research Council of the University of Antwerp. Mr Bosman was supported as a predoctoral fellow by the Fund for Scientific Research (FWO) Flanders (grant number: 1S33720N). Dr Loeys holds a consolidator grant from the European Research Council (Genomia – ERC-COG-2017-771945). Dr Gevaert has received institutional lecture/advisory board fees from Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, and Menarini outside the submitted work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Figures

None
Graphical abstract
Figure 1
Figure 1
Position of miRNAs in the Diagnostic Landscape and Mechanisms of CTRCD As cardiac damage develops over time, detection methods vary to detect the presence of cancer therapy–related cardiac dysfunction (CTRCD). Serum cardiac biomarkers such as (hs-)troponins I and T and natriuretic peptides are early, but nonspecific, markers. As cardiac damage progresses, cardiac dysfunction emerges, starting with a decrease in global longitudinal change (GLS) and followed by a more pronounced systolic dysfunction and reduction of left ventricular ejection fraction (LVEF). Patients will become symptomatic at a later stage. Circulating microRNAs (cmiRNAs) are epigenetic regulators and more specific for anthracycline-induced cardiotoxicity, mechanistically linked to the mode of action of anthracyclines, and are detectable before irreversible cardiac damage occurs (potentially reversible stage). Created with BioRender.com. CRP = C-reactive protein; GDF = growth differentiation factor; GPBB = glycogen phosphorylase BB; miRNA = micro-RNA; MPO = myeloperoxidase; NT-proBNP = N terminal pro–B-type natriuretic peptide; ST2 = soluble interleukin 1 receptor-like 1.
Central Illustration
Central Illustration
Circulating microRNA as Diagnostic Biomarkers of Anthracycline-Induced Cardiotoxicity This schematic representation highlights the need for new biomarkers, the dynamics of circulating microRNA (miRNA), and their pathomechanistic link, and explores future perspectives and remaining limitations for their routine use. HF = heart failure; ROS = reactive oxygen species.
Figure 2
Figure 2
Role of miRNAs and Apoptosis in Cardiotoxicity Schematic overview of the effects of various miRNAs on apoptosis in response to doxorubicin (DOX) treatment. An increase in reactive oxygen species (ROS) due to doxorubicin triggers the activation of the p53 pathway. Antiapoptotic miRNAs are displayed in green; proapoptotic miRNAs are displayed in red. Created with BioRender.com. Ac = acylated protein; BAX/BAK = Bcl-2-associated X protein; Bcl2 = B cell lymphoma 2; CCND1 = cyclin D1; CCND2 = cyclin D2; GATA4 = GATA binding protein 4; HIF = hypoxia inducible factor; miR = microRNA; MOMP = mitochondrial outer membrane permeabilization; p21 = cyclin-dependent kinase inhibitor 1; p53 = tumor protein p53; SIRT1 = sirtuin; TAF9B = TATA-binding protein associated factor 9b; TP53INP1 = tumor protein P53 inducible nuclear protein 1.
Figure 3
Figure 3
Role of miRNAs and Fibrosis in Cardiotoxicity Schematic overview of the effects of different miRNAs on fibrosis in response to DOX treatment. Doxorubicin activates the TGF-β pathway. Antifibrotic miRNAs are displayed in green; profibrotic miRNAs are displayed in red. Created with BioRender.com. BMP = bone morphogenetic protein; COL = collagen; HDAC4 = histone deacetylase 4; HMGB1 = high mobility group box 1; MMP = matrix metalloproteinase; SMAD = suppressor of mothers against decapentaplegic; TGF = transforming growth factor; other abbreviations as in Figures 1 and 2.
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