A microRNA Expression Profile as Non-Invasive Biomarker in a Large Arrhythmogenic Cardiomyopathy Cohort

Abstract

Arrhythmogenic Cardiomyopathy (AC) is a clinically and genetically heterogeneous myocardial disease. Half of AC patients harbour private desmosomal gene variants. Although microRNAs (miRNAs) have emerged as key regulator molecules in cardiovascular diseases and their involvement, correlated to phenotypic variability or to non-invasive biomarkers, has been advanced also in AC, no data are available in larger disease cohorts. Here, we propose the largest AC cohort unbiased by technical and biological factors. MiRNA profiling on nine right ventricular tissue, nine blood samples of AC patients, and four controls highlighted 10 differentially expressed miRNAs in common. Six of these were validated in a 90-AC patient cohort independent from genetic status: miR-122-5p, miR-133a-3p, miR-133b, miR-142-3p, miR-182-5p, and miR-183-5p. This six-miRNA set showed high discriminatory diagnostic power in AC patients when compared to controls (AUC-0.995), non-affected family members of AC probands carrying a desmosomal pathogenic variant (AUC-0.825), and other cardiomyopathy groups (Hypertrophic Cardiomyopathy: AUC-0.804, Dilated Cardiomyopathy: AUC-0.917, Brugada Syndrome: AUC-0.981, myocarditis: AUC-0.978). AC-related signalling pathways were targeted by this set of miRNAs. A unique set of six-miRNAs was found both in heart-tissue and blood samples of AC probands, supporting its involvement in disease pathogenesis and its possible role as a non-invasive AC diagnostic biomarker.

Identifying Differentially Expressed MicroRNAs, Target Genes, and Key Pathways Deregulated in Patients with Liver Diseases

“…Miravirsen is a locked nucleic acid-modified DNA phosphorothioate antisense oligonucleotide that sequesters mature miR-122 in a highly stable heteroduplex, thereby inhibiting its function. Bueno Marinas et al [ 30 ] observed that miR-122-5p was underexpressed in tissue and overexpressed in the circulation, supporting the hypothesis that the high blood levels of miRNAs might be released from apoptotic or necrotic cardiomyocytes, indicating progression of tissue damage. They indicated that myocardial damage is reflected in the circulation and that these miRNAs can be used as noninvasive biomarkers of the disease, permitting differential diagnosis.…”

Circulating exosomal microRNA expression patterns distinguish cardiac sarcoidosis from myocardial ischemia

“…Of these, 11 miRNA transcripts were validated by qRT-PCR (Figs 5 and 6 ), and 8 of these 11 have been previously linked to human AMI {miR-1 [ 23 ]; miR-133 [ 23 , 24 ]; miR-146a [ 28 , 29 ]; miR-208b [ 23 ]; miR-335 [ 30 ]; miR-423 [ 24 ]; miR-483 [ 31 ] and miR-499 [ 27 ]}. In contrast, only 5 miRNAs showed a significantly increased concentration in CS when compared to AMI serum samples ( Table 3 ), of which 3 have been linked to myocardial disease {miR-144 (validated, Fig 6 ) [ 32 , 33 ], miR-624a and miR-624b [ 34 , 35 ]}.…”

The Role of MicroRNAs in Arrhythmogenic Cardiomyopathy: Biomarkers or Innocent Bystanders of Disease Progression?

“…Even though each group showed some of these miRNAs DE, only AC definite patients shared this unique 6-miRNA profile (AUC 0.995 AC definite vs. ctrl; >0.82 AC definite vs. validation cohorts) which support its role as non-invasive biomarker. In silico predictions showed a clear correlation of this 6-miRNA profile to AC-related signaling pathways but functional studies are needed to determine its role in disease pathogenesis [ 66 ].…”