Diagnostic and prognostic significance of miRNA-15a-5p, 16-5p, and 92a-3p in arrhythmogenic right ventricular cardiomyopathy

Shaylyn Joseph; Vivian Nogueira Silbiger; Meena Fatah; Diptendu Chatterjee; Antonia Pereira Rosa Neta; Luciana Sacilotto; Gabrielle D'Arezzo Pessente; Francisco Carlos da Costa Darrieux; Maurício Ibrahim Scanavacca; José Eduardo Krieger; Karolina Borowiec; Olgierd Woźniak; Elżbieta Katarzyna Biernacka; Corinna B Brunckhorst; Fu Guan; Firat Duru; Ardan M Saguner; Andre D Luchessi; Robert M Hamilton

doi:10.1016/j.hrthm.2025.04.014

Diagnostic and prognostic significance of miRNA-15a-5p, 16-5p, and 92a-3p in arrhythmogenic right ventricular cardiomyopathy

Heart Rhythm. 2025 Apr 11:S1547-5271(25)02321-5. doi: 10.1016/j.hrthm.2025.04.014. Online ahead of print.

Authors

Shaylyn Joseph¹, Vivian Nogueira Silbiger², Meena Fatah¹, Diptendu Chatterjee³, Antonia Pereira Rosa Neta⁴, Luciana Sacilotto⁵, Gabrielle D'Arezzo Pessente⁵, Francisco Carlos da Costa Darrieux⁵, Maurício Ibrahim Scanavacca⁵, José Eduardo Krieger⁶, Karolina Borowiec⁷, Olgierd Woźniak⁷, Elżbieta Katarzyna Biernacka⁷, Corinna B Brunckhorst⁸, Fu Guan⁸, Firat Duru⁹, Ardan M Saguner⁹, Andre D Luchessi⁴, Robert M Hamilton¹⁰

Affiliations

¹ Department of Pediatrics, The Labatt Family Heart Centre and Translational Medicine, The Hospital for Sick Children & Research Institute, The University of Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, ON, Canada.
² Department of Pediatrics, The Labatt Family Heart Centre and Translational Medicine, The Hospital for Sick Children & Research Institute, The University of Toronto, ON, Canada; Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, Brazil.
³ Department of Pediatrics, The Labatt Family Heart Centre and Translational Medicine, The Hospital for Sick Children & Research Institute, The University of Toronto, ON, Canada.
⁴ Department of Clinical Analysis and Toxicology, Federal University of Rio Grande do Norte, Natal, Brazil.
⁵ Arrhythmia Unit, Heart Institute (Institute Coração), University of São Paulo Medical School, São Paulo, Brazil.
⁶ Arrhythmia Unit, Heart Institute (Institute Coração), University of São Paulo Medical School, São Paulo, Brazil; Laboratory of Genetics and Molecular Cardiology (LGMC), Heart Institute (Institute Coração), University of São Paulo Medical School, São Paulo, Brazil.
⁷ Department of Congenital Heart Diseases, National Institute of Cardiology, Warsaw, Poland.
⁸ Department of Cardiology, University Heart Centre, University Hospital Zurich, Zurich, Switzerland.
⁹ Department of Cardiology, University Heart Centre, University Hospital Zurich, Zurich, Switzerland; Center for Translational and Experimental Cardiology (CTEC), Department of Cardiology, University Heart Centre, University Hospital Zurich, Zurich, Switzerland.
¹⁰ Department of Pediatrics, The Labatt Family Heart Centre and Translational Medicine, The Hospital for Sick Children & Research Institute, The University of Toronto, ON, Canada; Institute of Medical Sciences, University of Toronto, ON, Canada. Electronic address: robert.hamilton@sickkids.ca.

PMID: 40222719
DOI: 10.1016/j.hrthm.2025.04.014

Abstract

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) presents diagnostic challenges and significant clinical burden because of life-threatening ventricular arrhythmias, compounded by the limited ability to predict patient prognosis using current clinical parameters. MicroRNAs (miRNAs) offer potential as markers in cardiac diseases, including ARVC, providing insights into disease pathogenesis, identification, and prognosis. However, current diagnostic criteria lack sensitivity and specificity, highlighting the need for novel markers such as miRNAs to better understand ARVC's complex pathophysiologic mechanisms.

Objective: This multisite study assessed circulating miRNA expression in ARVC patients, stratified by 5-year event-free survival risk, to explore their potential as a marker for improving ARVC diagnosis and prognosis.

Methods: Blood samples from 102 ARVC patients, 24 Brugada syndrome (BrS) patients, and 22 healthy controls were analyzed for the expression of 20 miRNAs using TaqMan quantitative real-time polymerase chain reaction (PCR), ARVC patients were stratified by 5-year event-free survival risk. Six candidate miRNAs were selected for further analysis, and machine learning algorithms were applied for classification and risk stratification based on miRNA profiles. Additionally, genotyping and functional annotation of miRNA targets were performed.

Results: Six miRNAs exhibited differential expression between high- and low-risk ARVC patients. MiR-15a-5p, miR-16-5p, and miR-92a-3p demonstrated the best performance in risk stratification. MiR-15a-5p also displayed higher expression in patients with adverse cardiac events. Comparative analysis with BrS patients and healthy controls consistently demonstrated increased expression of these miRNAs in ARVC.

Conclusion: This study highlights miRNAs' potential to enhance the diagnosis, disease progression, and clinical outcomes of ARVC, supporting further research to improve patient care.

Keywords: ARVC risk calculator; Arrhythmogenic right ventricular cardiomyopathy; Biomarker; Ventricular arrythmia; miRNA expression.