Association of cardiometabolic microRNAs with COVID-19 severity and mortality

Abstract

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.

Cardiovascular signatures of COVID-19 predict mortality and identify barrier stabilizing therapies

“… 96 , 97 While still investigational, given the extent of pre-clinical and clinical research on miRNAs, 68 it is reasonable to expect miRNA datasets will soon be amenable for clinical implementation. 94 , 95 As an example of the importance of a multi-omic approach that includes clinically relevant disease negative controls, miR-1 (which has been intensively studied as a cardiac enriched miRNA and associated with numerous cardiac etiologies 69 , 70 , 71 , 98 ) failed to show an association with in-hospital mortality in our study. If the promising miRNAs, miR-30b/c/e, -6080, -181a-5p, -199a-3p, and -339 identified here are validated in larger populations, they would represent new biomarkers that could be utilized for rapid in-hospital risk assessment.…”

“…In recent years, circulating miRNAs have emerged as exquisite biomarkers for complex pathological conditions, including influenza and sepsis, 92 , 93 and studies are beginning to emerge assessing select circulating miRNAs in COVID-19 cohorts. 94 , 95 The inherent stability of plasma miRNAs under harsh conditions and reproducible quantification makes them attractive candidates for use as noninvasive biomarkers. 50 Incorporating whole transcriptome miRNA sequencing as an added metric allowed for the effective differentiation between severities of COVID-19 and severe SARS-CoV-2 negative controls using samples gathered on admission.…”

Elevated expression of RGS2 may underlie reduced olfaction in COVID-19 patients

“…As a regulator of several G-protein coupled receptors, the elevated expression of RGS2 may drive further neurological symptoms observed in COVID-19 patients, sometimes lingering beyond negative SARS-CoV-2 PCR test findings (25). The highly correlated expression of RGS2 with CXCL8, PTGS2, NAMPT, ILB1 and further inflammatory genes in COVID-19 positive nasopharyngeal swabs ( Figures 1-5, Table 1 ) suggests the involvement of a common regulator, which might explain the distinct classes of COVID-19 symptoms.…”

MiRNA-SARS-CoV-2 dialogue and prospective anti-COVID-19 therapies

“…miR-29, which has been previously associated with kidney diseases, is reported to promote pathologic hypertrophy of cardiac myocytes and their serum expression analysis in hospitalized COVID-19 patients observes a reduced expression with an elevation of their mRNA targets correlating with the disease severity, possibly aiding in futuristic SARS-CoV-2 diagnostic targets [116] . In another study, analyzing the cardiometabolic miRNAs associations with SARS-CoV-2 severity, myocyte-derived (myomiR) miR-133a along with liver-derived miR-122 were reported to be associated with inflammation-induced myocyte damage and hepatic acute phase responses respectively, which upon further analysis reported to be possible markers of SARS-CoV-2 severity and mortality [117] .…”