Abstract
OBJECTIVE: Circulating microRNAs (miRNAs) have been implicated in both heart failure and atherosclerotic disease. The aim of this study was to examine associations between heart failure specific circulating miRNAs, atherosclerotic disease and cardiovascular-related outcome in patients with heart failure. METHODS: The levels of 11 heart failure-specific circulating miRNAs were compared in plasma of 114 heart failure patients with and without different manifestations of atherosclerotic disease. We then studied these miRNAs in relation to biomarkers associated to atherosclerosis and to cardiovascular-related rehospitalizations during 18 months of follow-up. RESULTS: At least one manifestation of atherosclerotic disease was found in 70 (61%) of the heart failure patients. A consistent trend was found between an increasing number of manifestations of atherosclerosis (peripheral arterial disease in specific), and lower levels of miR-18a-5p, miR-27a-3p, miR-199a-3p, miR-223-3p and miR-652-3p (all P < 0.05). Target prediction and network analyses identified several interactions between miRNA targets and biomarkers related to inflammation, angiogenesis and endothelial dysfunction. Lower miRNA levels were associated with higher levels of these atherosclerosis-related biomarkers. In addition, lower miRNA levels were significantly associated with rehospitalizations due to cardiovascular causes within 18 months, with let-7i-5p as strongest predictor [HR 2.06 (95% CI 1.29-3.28), C-index 0.70, P = 0.002]. CONCLUSIONS: A consistent pattern of lower levels of circulating miRNAs was found in heart failure patients with atherosclerotic disease, in particular peripheral arterial disease. In addition, lower levels of miRNAs were associated with higher levels of biomarkers involved in atherosclerosis and an increased risk of a cardiovascular-related rehospitalization.