Novel Biomarkers of Heart Failure Prognosis – Investigating the Role of Circulating MicroRNAs and Leucocyte Telomere Length

<p dir="ltr">Background: Heart failure is a complex syndrome that encompasses a wide range of pathophysiological processes. Despite recent advances in treatment, predicting patients with poor prognosis remains challenging. Both circulating microRNA expression and leucocyte telomere length (LTL) have shown diagnostic promise but their potential role as novel biomarkers of heart failure prognosis remains unclear.</p><p dir="ltr">Methods and Results: Participants were selected from sub-cohorts of BIOSTAT-CHF, a multi-national cohort study of over 4,000 patients with chronic heart failure. Using the HTG EdgeSeq Whole Transcriptome Assay, 2,083 microRNAs were screened for differential expression in plasma samples from a small discovery cohort of extensively matched participants with early mortality (N = 43) or event-free survival (N = 41). Three candidate microRNAs were validated in age- and sex-matched participants with either cardiovascular mortality (N = 253) or event-free survival (N = 549) using reverse-transcription quantitative polymerase chain reaction (RT-qPCR). Using Cox proportional hazards analyses, miR-150-5p, miR-342-3p, and miR-29a-3p were each found to be univariate predictors of mortality – hazard ratios for those with the lowest expression (quartile 4) compared to the highest expression (quartile 1) were 3.35 (P = 1.48 x 10-9), 2.46 (P = 4.46 x 10-9), and 2.18 (P = 5.05 x 10-5), respectively. After correction for established risk factors using the validated BIOSTAT-CHF mortality risk score, only miR-150-5p was independently associated with mortality (Q4 vs. Q1 HR = 1.65 [1.08 – 2.50, P = .019]). Using LTL measured by qPCR in 3,673 participants, survival analyses showed that after correction for the BIOSTAT-CHF risk score, LTL was independently associated with all-cause mortality (meta-analysis HR [per SD decrease in LTL] = 1.12 [1.05 – 1.20]; P = 1.04 x 10-3) but not heart failure hospitalisation (HR = 0.99 [0.92 – 1.07]; P = .855).</p><p dir="ltr">Conclusions: In their largest prognostic studies to date, this thesis shows that circulating miR-150-5p and LTL are independent predictors of mortality amongst heart failure patients. Circulating miR-342-3p and miR-29-3p are strong univariate predictors of mortality. These findings provide further support for the key role of both microRNAs and telomere length in heart failure pathogenesis.</p>