Circulating microRNAs in heart failure

In this thesis we addressed the identification of a circulating miRNA signature in patients with heart failure and placed these findings in perspective by investigating several hypotheses regarding their potential role and function. These miRNAs were found in the lowest levels in patients with the most acute state of heart failure and showed an increase towards stable forms of heart failure and healthy control subjects. A further in-hospital decrease was related to an increased risk of mortality. Several associations between miRNAs and other heart failure-related biomarkers were identified in patients with worsening heart failure, and target prediction complemented by pathway analyses resulted in potential mechanisms implicated in cardiac disease. Our results indicate that miRNAs and their correlation with biomarkers are dependent on timing of measurement and clinical disease status. It was additionally shown that changes in volume status were associated with changes in circulating miRNA levels, suggesting that fluid overload contributes to downregulated miRNA levels in acute heart failure. Furthermore, these miRNAs were associated to vascular dysfunction as reflected by the presence of atherosclerosis and related disease processes including inflammation, angiogenesis and endothelial dysfunction, and also have a predictive value for the risk of cardiovascular-related rehospitalization. In our attempt to identify a suitable heart failure animal model for mechanistic miRNA studies we were not able to replicate the previously found downregulated miRNA levels. These results place emphasis on the difficulty of translation between the human heart failure setting and animal data, and underline the complex biology of circulating miRNAs.