Circulating long noncoding RNAs and risk of ischemic stroke or death in the elderly: insights from the VITA study

Abstract Introduction Long non-coding RNAs (lncRNAs) represent a superfamily of non-protein coding transcripts that regulate a variety of cellular processes and functions in health and disease. While our (patho-)physiological understanding of lncRNAs constantly evolves, their potential as cardiovascular biomarkers to predict adverse outcomes in the elderly remains poorly understood. Method A total of 361 healthy individuals aged 75, prospectively recruited in the Vienna Transdanube Aging (VITA) cohort, were included in the present analysis. A semi biased lncRNA screening strategy was employed: "Aging", ‘’stroke", "cardiac", "inflammation", and "neurodegenerative" served as keywords. The primary endpoint was a composite outcome of death and ischemic stroke. Death was assessed over a 14-year follow-up from public registries, and ischemic stroke was evaluated over a 90-month follow-up involving magnetic resonance imaging (MRI) based assessment. Expression of lncRNAs wasassessed using qRT-PCR (TaqMan Assays) with preamplification reaction, using 18S for normalization. Results The initial screening retrieved 24 lncRNAs, of which 6 showed a solid amplification signal. Over a median follow-up of 14 years, the incidence of the primary endpoint was 62.6%, with 53.5% deaths, 3.3% brain infarcts, and 12.7% lacunar strokes (which were studied during the 7.5 years). H19 predicted the incidence of the primary endpoint (HR 1.675, 95% C.I. 1.076-2.607, p= 0.023), which was mainly driven by its strong association with mortality, independent of potential confounders (adjusted HR 1.789, 95% C.I. 1.083-2.955, p= 0.023). In contrast, NKILA was found to predict the incidence of lacunar stroke beyond established risk factors (adjusted HR 0.259, 95% C.I. 0.087-0.768, p= 0.015) but was unexpectedly not associated with mortality risk. Conclusion In a prospective cohort of healthy elderly subjects, high levels of lncRNA H19 are associated with a high mortality risk, while low levels of lncRNA NKILA predict an increased risk of lacunar stroke.