Joseph Shaylyn, Silbiger Vivian Nogueira, Fatah Meena, Chatterjee Diptendu, Rosa Neta Antonia Pereira, Sacilotto Luciana, D'Arezzo Pessente Gabrielle, Darrieux Francisco Carlos da Costa, Scanavacca Maurício Ibrahim, Krieger José Eduardo, Borowiec Karolina, Woźniak Olgierd, Biernacka Elżbieta Katarzyna, Brunckhorst Corinna B, Guan Fu, Duru Firat, Saguner Ardan M, Luchessi Andre D, Hamilton Robert M
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.
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.
Heart Rhythm. 2025 Apr 11. doi: 10.1016/j.hrthm.2025.04.014.
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.
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.
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.
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.
This study highlights miRNAs' potential to enhance the diagnosis, disease progression, and clinical outcomes of ARVC, supporting further research to improve patient care.
致心律失常性右室心肌病（ARVC）由于危及生命的室性心律失常而带来诊断挑战和巨大临床负担，而且利用当前临床参数预测患者预后的能力有限，这使情况更加复杂。微小RNA（miRNA）有望成为包括ARVC在内的心脏疾病的标志物，为疾病发病机制、诊断及预后提供线索。然而，目前的诊断标准缺乏敏感性和特异性，这凸显了需要诸如miRNA这样的新型标志物来更好地理解ARVC复杂的病理生理机制。
这项多中心研究评估了按5年无事件生存风险分层的ARVC患者循环miRNA的表达情况，以探索其作为改善ARVC诊断和预后标志物的潜力。
采用TaqMan定量实时聚合酶链反应（PCR）分析了102例ARVC患者、24例Brugada综合征（BrS）患者和22例健康对照者的血液样本中20种miRNA的表达情况。ARVC患者按5年无事件生存风险进行分层。选择6种候选miRNA进行进一步分析，并基于miRNA谱应用机器学习算法进行分类和风险分层。此外，还对miRNA靶标进行了基因分型和功能注释。
6种miRNA在高风险和低风险ARVC患者之间表现出差异表达。MiR-15a-5p、miR-16-5p和miR-92a-3p在风险分层中表现最佳。MiR-15a-5p在发生不良心脏事件的患者中也表现出较高的表达。与BrS患者和健康对照的比较分析一致显示，这些miRNA在ARVC患者中表达增加。
本研究突出了miRNA在增强ARVC诊断、疾病进展和临床结局方面的潜力，支持开展进一步研究以改善患者护理。
