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Comparative Analysis of Circulating Noncoding RNAs Versus Protein Biomarkers in the Detection of Myocardial Injury

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Christian Schulte, Temo Barwari, Abhishek Joshi, Konstantinos Theofilatos, Anna Zampetaki, Javier Barallobre-Barreiro, Bhawana Singh, Nils A Sörensen, Johannes T. Neumann, Tanja Zeller, Dirk Westermann, Stefan Blankenberg, Michael Stephen Marber, Christoph Liebetrau, Manuel Mayr

Original languageEnglish
Article number10.1161
Pages (from-to)328-340
Number of pages13
JournalCirculation Research
Volume125
Issue number3
Early online date4 Jun 2019
DOIs
Publication statusPublished - 19 Jul 2019

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Abstract

Rationale:
Noncoding RNAs (ncRNAs), including microRNAs (miRNAs), circular RNAs (circRNAs), and long noncoding RNAs (lncRNAs), are proposed novel biomarkers of myocardial injury. Their release kinetics have not been explored without confounding by heparin nor has their relationship to myocardial protein biomarkers.

Objective:
To compare ncRNA types in heparinase-treated samples with established and emerging protein biomarkers for myocardial injury.

Methods and Results:
Screening of 158 circRNAs and 21 lncRNAs in human cardiac tissue identified 12 circRNAs and 11 lncRNAs as potential biomarkers with cardiac origin. Eleven miRNAs were included. At low spike-in concentrations of myocardial tissue, significantly higher regression coefficients were observed across ncRNA types compared with cardiac troponins and cMyBP-C (cardiac myosin-binding protein C). Heparinase treatment of serial plasma and serum samples of patients undergoing transcoronary ablation of septal hypertrophy removed spurious correlations between miRNAs in non-heparinase-treated samples. After transcoronary ablation of septal hypertrophy, muscle-enriched miRNAs (miR-1 and miR-133a) showed a steeper and earlier increase than cardiac-enriched miRNAs (miR-499 and miR-208b). Putative cardiac lncRNAs, including LIPCAR (long intergenic noncoding RNA predicting cardiac remodeling and survival), did not rise, refuting a predominant cardiac origin. Cardiac circRNAs remained largely undetectable. In a validation cohort of acute myocardial infarction, receiver operating characteristic curve analysis revealed noninferiority of cardiac-enriched miRNAs, but miRNAs failed to identify cases presenting with low troponin values. cMyBP-C was validated as a biomarker with highly sensitive properties, and the combination of muscle-enriched miRNAs with high-sensitive cardiac troponin T and cMyBP-C returned the highest area under the curve values.

Conclusions:
In a comparative assessment of ncRNAs and protein biomarkers for myocardial injury, cMyBP-C showed properties as the most sensitive cardiac biomarker while miRNAs emerged as promising candidates to integrate ncRNAs with protein biomarkers. Sensitivity of current miRNA detection is inferior to cardiac proteins but a multibiomarker combination of muscle-enriched miRNAs with cMyBP-C and cardiac troponins could open a new path of integrating complementary characteristics of different biomarker types.

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