P6449Circulating long noncoding RNA expression signature as a novel biomarker for myocardial fibrosis

Abstract

Abstract Background Cardiac fibrosis (CF) plays a critical role in the pathogenesis of heart failure (HF), predisposing to contractile dysfunction, myocardial stiffness and life-threatening arrhythmias. Early detection and intervention of myocardial fibrosis, therefore, can delay or prevent the progression of HF. Current diagnostic and treatment options for CF, however, are very limited. Purpose To test the hypothesis that circulating lncRNA expression signature can be a sensitive biomarker to diagnose and correlate with the extent of CF in human heart. Methods Plasma RNA samples from healthy control (n=23) and from patients with diffuse myocardial fibrosis documented by cardiac magnetic resonance (T1 mapping technique, n=16) were analyzed by RNA sequencing (RNASeq), followed by differential expression, gene ontology/pathway and receiver operating characteristic (ROC) curve analyses. Results RNASeq revealed that 439 mRNAs were differentially expressed in the plasma from patients with CF, compared to that from controls. Gene ontology analyses showed significant enrichment of these CF-linked genes in cytoskeleton organization, innate immune response, and MAPK-Erk signaling, cellular processes known to contribute to the development of CF. Further analyses showed that 84 plasma lncRNAs were dysregulated in patients with CF; 5 of the lncRNAs (ENSGehz746.10420265401.1, ENSGehz746.10420229124.6, ENSGehz746.10420281376.1, ENSGehz746.10420273275.1 and ENSGehz746.10420179818.13) showed concordant changes with their cis-mRNA (UBB, VIM, BCL2L1, PPP3R1 and PCBP1). Hierarchical clustering analyses demonstrated that the expression signature of plasma lncRNAs could distinguish patients with CF from control patients (classification accuracy 87%). The expression levels of plasma lncRNAs ENSGehz746.10420258017.1 and ENSGehz746.10420265401.1, in particular, were markedly downregulated in patients with myocardial fibrosis. ROC curve analyses showed that low expression levels of ENSGehz746.10420258017.1 and ENSGehz746.10420265401.1 were highly sensitive and specific to detect the presence of CF in human heart (AUC 0.9 for both lncRNAs, Figure). LncRNA Predicts Cardiac Fibrosis Conclusions The present study revealed a circulating transcriptome signature that reflects the pathogenesis of CF. The expression profiles of circulating lncRNAs discriminated between patients with and without interstitial myocardial fibrosis. LncRNAs ENSGehz746.10420258017.1 and ENSGehz746.10420265401.1, in particular, are novel biomarkers with potential to facilitate clinical diagnosis of myocardial fibrosis.