Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers

Kemal Marc Akat, D'Vesharronne Moore-McGriff, Pavel Morozov, Miguel Brown, Tasos Gogakos, Joel Correa Da Rosa, Aleksandra Mihailovic, Markus Sauer, Ruiping Ji, Aarthi Ramarathnam, Hana Totary-Jain, Zev Williams, Thomas Tuschl, P. Christian Schulze

Research output: Contribution to journalArticle

119 Scopus citations

Abstract

Heart failure (HF) is associated with high morbidity and mortality and its incidence is increasing worldwide. MicroRNAs (miRNAs) are potential markers and targets for diagnostic and therapeutic applications, respectively. We determined myocardial and circulating miRNA abundance and its changes in patients with stable and end-stage HF before and at different time points after mechanical unloading by a left ventricular assist device (LVAD) by small RNA sequencing. miRNA changes in failing heart tissues partially resembled that of fetal myocardium. Consistent with prototypical miRNA-target-mRNA interactions, target mRNA levels were negatively correlated with changes in abundance for highly expressed miRNAs in HF and fetal hearts. The circulating small RNA profile was dominated by miRNAs, and fragments of tRNAs and small cytoplasmic RNAs. Heart- and muscle-specific circulating miRNAs (myomirs) increased up to 140-fold in advanced HF, which coincided with a similar increase in cardiac troponin I (cTnI) protein, the established marker for heart injury. These extracellular changes nearly completely reversed 3 mo following initiation of LVAD support. In stable HF, circulating miRNAs showed less than fivefold differences compared with normal, and myomir and cTnI levels were only captured near the detection limit. These findings provide the underpinning for miRNA-based therapies and emphasize the usefulness of circulating miRNAs as biomarkers for heart injury performing similar to established diagnostic protein biomarkers.

Original languageEnglish (US)
Pages (from-to)11151-11156
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number30
DOIs
StatePublished - Jan 1 2014

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Keywords

  • Body fluids
  • Cardiovascular disease
  • Development
  • exRNA
  • miRNA-mRNA regulation

ASJC Scopus subject areas

  • General

Cite this

Akat, K. M., Moore-McGriff, DV., Morozov, P., Brown, M., Gogakos, T., Da Rosa, J. C., Mihailovic, A., Sauer, M., Ji, R., Ramarathnam, A., Totary-Jain, H., Williams, Z., Tuschl, T., & Schulze, P. C. (2014). Comparative RNA-sequencing analysis of myocardial and circulating small RNAs in human heart failure and their utility as biomarkers. Proceedings of the National Academy of Sciences of the United States of America, 111(30), 11151-11156. https://doi.org/10.1073/pnas.1401724111