Circulating microRNAs as potential biomarkers of hypertrophic cardiomyopathy phenotypic expression

Background Hypertrophic cardiomyopathy (HCM) is characterized by significant variability in clinical presentation among patients with similar genetic backgrounds. The role of microRNAs (miRNAs) as epigenetic regulators in HCM remains underexplored. This pilot study aims to identify and characterize circulating miRNAs associated with different HCM phenotypes. A cross-sectional study was conducted involving 28 participants: 10 with aggressive HCM, 10 with soft HCM, and 8 age- and sex-matched healthy controls. Circulating miRNAs were profiled using next-generation sequencing and quantitative real-time PCR. Differential expression analysis was performed to identify miRNAs associated with the aggressive phenotype. Results miR-16-5p, miR-17-5p, and let-7f-5p were identified as miRNAs significantly upregulated in the aggressive phenotype group compared to soft phenotypes and healthy controls. ROC analysis demonstrated statistically significant differences between aggressive HCM and softer forms with an area under the curve: miR-16-5p 0.833 (0.614 - 1), miR-17-5p 0.859 (0.648 – 1.00) and let-7f-5p 0.825 (0.62 – 1.00). After performing a target prediction analysis for the three miRNAs, the results were validated with three human transcriptomic datasets from control vs HCM patients. The analysis identified 34 quadruple coincidences across the four analyzed groups, and the enrichment analysis highlighted the hypoxia-inducible factor-1 (HIF-1) pathway. Conclusions miR-16-5p, miR-17-5p, and let-7f-5p appear to play a role in modulating the phenotypic expression of HCM. The potential use of these miRNAs as biomarkers for risk stratification and therapeutic targets to intervene in disease progression is promising. Validation in a wide clinical cohort is necessary to further elucidate the underlying mechanisms and therapeutic implications of miRNA dysregulation in HCM.