Epigenetic-sensitive liquid biomarkers and personalised therapy in advanced heart failure: a focus on cell-free DNA and microRNAs.

Dilated cardiomyopathy (DCM) represents a common genetic cause of mechanical and/or electrical dysfunction leading to heart failure (HF) onset for which truncating variants in titin (TTN) gene result in the most frequent mutations. Moreover, myocyte and endothelial cell apoptosis is a key endophenotype underlying cardiac remodelling. Therefore, a deeper knowledge about molecular networks leading to acute injury and apoptosis may reveal novel circulating biomarkers useful to better discriminate HF phenotypes, patients at risk of heart transplant as well as graft reject in order to improve personalised therapy. Remarkably, increased plasma levels of cell-free DNA (cfDNA) may reflect the extent of cellular damage, whereas circulating mitochondrial DNA (mtDNA) may be a promising biomarker of poor prognosis in patients with HF. Furthermore, some panels of circulating miRNAs may improve the stratification of natural history of disease. For example, a combination of miR-558, miR-122* and miR-520d-5p, as well as miR-125a-5p, miR-550a-5p, miR-638 and miR-190a, may aid to discriminate different phenotypes of HF ranging from preserved to reduced ejection fraction. We give update on the most relevant genetic determinants involved in DCM and discuss the putative role of non-invasive biomarkers to overcome current limitations of the reductionist approach in HF management.