Association of cardiometabolic microRNAs with COVID-19 severity and mortality

Aims Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28-day intensive care unit (ICU) mortality. Methods and results We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18) and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT-qPCR) in a separate cohort of mild (n = 6), moderate (n = 39) and severe (n = 16) patients. Candidates were then measured by RT-qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). 60 miRNAs, including platelet-, endothelial-, hepatocyte- and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28-day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. Conclusion Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28-day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response. Translational perspective Adding biomarkers to conventional scores for illness severity and mortality could improve prognostic performance in COVID-19 patients. Circulating miRNAs are emerging as promising biomarkers with tissue specific origins but have only sparsely been investigated in COVID-19. We quantified circulating miRNAs of different tissue origin in COVID-19 patients, identifying several miRNAs of the cardiometabolic system to be associated with severity. Myocyte-derived miR-133a and liver-derived miR-122 also associated with mortality. Through longitudinal proteomics measurements, we related myomiR miR-133a release to neutrophil activation and miR-122 release to the hepatic acute phase response. Our findings highlight key pathophysiological changes and provide first evidence on the performance of miRNA biomarkers in COVID-19.