Dilated cardiomyopathy (DCM) entails a broad group of diseases, acquired or genetic, which result in a similar phenotype. In the era of precision medicine, genotype-directed therapies have started to emerge. The understanding of gene-specific pathogenetic mechanisms and the unraveling of the functional effects of each variant should dictate different therapeutic strategies. MicroRNAs (miRNAs) are short sequences of non-coding RNA that play an important role in the regulation of gene expression. Over the last years, it has been shown that miRNAs are crucial in the development of several cardiovascular diseases (CVDs), including DCM. MiRNome and transcriptome of myocardial biopsies from 3 patients with ischemic DCM (ICM) and 4 with DCM caused by volume overload (VCM) were analyzed by next-generation sequencing. Analysis showed 5 miRNAs and 112 mRNAs dysregulated in ICM vs VCM, and unveiled 37 miRNA-mRNA interactions. Gene ontology (GO) analysis revealed extracellular matrix (ECM) organization, ECM structural constituent, and collagen-containing ECM among the most enriched GO terms in biological process, molecular functions, and cellular component, respectively. Kyoto City Encyclopaedia of Genes and Genomes (KEGG) pathway revealed NF-kappa B signaling and cardiac muscle contraction among the most enriched pathway. Finally, qRT-PCR validation in all collected ICM (n = 6) and VCM (n = 9) samples showed that miR-494-3p, 

miR-218-5p and miR-487b-3p are downregulated in myocardial tissue from patients with ICM as compared to those from VCM.