Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2021 Dec;99(12):1711-1725.
doi: 10.1007/s00109-021-02119-6. Epub 2021 Sep 8.

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Marina C Costa  1 , Maria Calderon-Dominguez  2 , Alipio Mangas  3   4   5 , Oscar Campuzano  6   7   8 , Georgia Sarquella-Brugada  6   7   8 , Mónica Ramos  9 , Maribel Quezada-Feijoo  9 , José Manuel García Pinilla  10   11 , Ainhoa Robles-Mezcua  10   11 , Galan Del Aguila Pacheco-Cruz  3 , Thalia Belmonte  3 , Francisco J Enguita  1 , Rocío Toro  12   13
Affiliations
Multicenter Study

Circulating circRNA as biomarkers for dilated cardiomyopathy etiology

Marina C Costa et al. J Mol Med (Berl). 2021 Dec.

Abstract

Dilated cardiomyopathy (DCM) is the third most common cause of heart failure. The multidisciplinary nature of testing - involving genetics, imaging, or cardiovascular techniques - makes its diagnosis challenging. Novel and reliable biomarkers are needed for early identification and tailored personalized management. Peripheral circular RNAs (circRNAs), a leading research topic, remain mostly unexplored in DCM. We aimed to assess whether peripheral circRNAs are expressed differentially among etiology-based DCM. The study was based on a case-control multicentric study. We enrolled 130 subjects: healthy controls (n = 20), idiopathic DCM (n = 30), ischemic DCM (n = 20), and familial DCM patients which included pathogen variants of (i) LMNA gene (n = 30) and (ii) BCL2-associated athanogene 3 (BAG3) gene (n = 30). Differentially expressed circRNAs were analyzed in plasma samples by quantitative RT-PCR and correlated to relevant systolic and diastolic parameters. The pathophysiological implications were explored through bioinformatics tools. Four circRNAs were overexpressed compared to controls: hsa_circ_0003258, hsa_circ_0051238, and hsa_circ_0051239 in LMNA-related DCM and hsa_circ_0089762 in the ischemic DCM cohort. The obtained areas under the curve confirm the discriminative capacity of circRNAs. The circRNAs correlated with some diastolic and systolic echocardiographic parameters with notable diagnostic potential in DCM. Circulating circRNAs may be helpful for the etiology-based diagnosis of DCM as a non-invasive biomarker. KEY MESSAGES: The limitations of cardiac diagnostic imaging and the absence of a robust biomarker reveal the need for a diagnostic tool for dilated cardiomyopathy (DCM). The circular RNA (circRNA) expression pattern is paramount for categorizing the DCM etiologies. Our peripheral circRNAs fingerprint discriminates between various among etiology-based DCM and correlates with some echocardiographic parameters. We provide a potential non-invasive biomarker for the etiology-based diagnosis of LMNA-related DCM and ischemic DCM.

Keywords: Circulating circular RNA; Ischemic-dilated cardiomyopathy; Lamin A/C-dilated cardiomyopathy.

PubMed Disclaimer

Conflict of interest statement

We know of no conflicts of interest associated with this publication, and there has been no significant financial support for this work that could have influenced its outcome. The study protocol was approved by the Andalusian Biomedical Research Ethics committee. The study was performed in full compliance with the Declaration of Helsinki. Informed consent was obtained from all subjects involved in the study. Written informed consent has been obtained from the patients for paper publication.

Figures

Fig. 1
Fig. 1
Flowchart of the study design strategy. This figure illustrates the experimental workflow of the study including screening, validation, and peripheral circRNAs overexpressed for the LMNAPh−, LMNAPh+, and ischemic DCM cohort. Abbreviations: BAG3, BCL2-associated athanogene 3; DCM, dilated cardiomyopathy; lamin A/C; LMNAPh−, LMNA carrier of the pathogenic variant; LMNAPh+, LMNA carrier phenotype positive; LVEF, left ventricle ejection fraction
Fig. 2
Fig. 2
Boxplots of circRNA expression levels, normalized to MS2 RNA, in healthy subjects, BAG3-related DCM, idiopathic DCM, ischemic DCM, and LMNA-related DCM. The analysis was carried out using qRT-PCR. Data are present in log2. Data represent the mean ± SEM. *p < 0.05. Abbreviations: BAG3, BCL2-associated athanogene 3; CT, healthy cohort; circRNA, circular RNA; DCM, dilated cardiomyopathy; LMNA, lamin A/C; LMNAPh−, LMNA carrier of the pathogenic variant; LMNAPh+, LMNA carrier phenotype positive
Fig. 3
Fig. 3
Bivariate logistic regression analysis for LMNA-related DCM and ischemic DCM patients. A–F Logistic regression analysis for the LMNA-related DCM cohort. LVEF was independently negatively related with hsa_circ_0003258 (A), hsa_circ_0051238 (B), and hsa_circ_0051239 (C). D RV tricuspid annular plane systolic excursion (TAPSE) was negatively related to hsa_circ_0003258. E, F LV mitral annular plane systolic excursion (MAPSE) was negatively correlated with hsa_circ_0003258 and hsa_circ_0051238. G, H The levels of hsa_circ_0089762 were associated with A’s TDI (G) and RV (H). The odds ratio, 95% of CI, and p values are indicated for each logistic regression analysis. Abbreviations: A’s TDI, atrial septal mitral annular velocity; AUC, area under the curve; CT, healthy group; CI, confidence intervals; LMNA, lamin A/C gene; LVEF, left ventricle ejection fraction; MAPSE, mitral annular plane systolic excursion; OR, odd ratio; RV; right ventricle; TAPSE, tricuspid annular plane systolic excursion
Fig. 4
Fig. 4
CircRNA-centered regulatory network established among the selected circRNAs. The depicted interactions are based on data extracted from the circInteractome database and include miRNAs and RBPs. CircRNAs are represented as squares, RBPs as circles and miRNAs as triangles. The size of each symbol is proportional to the number of interactions established. The edge thickness is also proportional to the number of targets for each interacting partner as included in the circInteractome database. The regulatory network was prepared with Navigator software [14]. Abbreviations: DCM, dilated cardiomyopathy; LMNA, lamin A/C gene; miRNA, microRNA; RBP, RNA-binding protein
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Savarese G, Lund LH (2017) Global public health burden of heart failure. Card Fail Rev 03:7. 10.15420/cfr.2016:25:2 - PMC - PubMed
    1. McNally EM, Mestroni L. Dilated cardiomyopathy: genetic determinants and mechanisms. Circ Res. 2017;121:731–748. doi: 10.1161/CIRCRESAHA.116.309396. - DOI - PMC - PubMed
    1. Rosenbaum AN, Agre KE, Pereira NL. Genetics of dilated cardiomyopathy: practical implications for heart failure management. Nat Rev Cardiol. 2020;17:286–297. doi: 10.1038/s41569-019-0284-0. - DOI - PubMed
    1. Van Der Bijl P, Delgado V, Bootsma M, Bax JJ. Risk stratification of genetic, dilated cardiomyopathies associated with neuromuscular disorders. Circulation. 2018;137:2514–2527. doi: 10.1161/CIRCULATIONAHA.117.031110. - DOI - PubMed
    1. Domínguez F, Cuenca S, Bilińska Z, et al. Dilated cardiomyopathy due to BLC2- associated athanogene 3 (BAG3) mutations. J Am Coll Cardiol. 2018;72:2471–2481. doi: 10.1016/j.jacc.2018.08.2181. - DOI - PMC - PubMed

Publication types

Supplementary concepts