Association of cardiometabolic microRNAs with COVID-19 severity and mortality

Clemens Gutmann; Kseniya Khamina; Konstantinos Theofilatos; Andreas B Diendorfer; Sean A Burnap; Adam Nabeebaccus; Matthew Fish; Mark J W McPhail; Kevin O'Gallagher; Lukas E Schmidt; Christian Cassel; Georg Auzinger; Salvatore Napoli; Salma F Mujib; Francesca Trovato; Barnaby Sanderson; Blair Merrick; Roman Roy; Jonathan D Edgeworth; Ajay M Shah; Adrian C Hayday; Ludwig Traby; Matthias Hackl; Sabine Eichinger; Manu Shankar-Hari; Manuel Mayr

doi:10.1093/cvr/cvab338

Association of cardiometabolic microRNAs with COVID-19 severity and mortality

Clemens Gutmann, Kseniya Khamina, Konstantinos Theofilatos, Andreas B Diendorfer, Sean A Burnap, Adam Nabeebaccus, Matthew Fish, Mark J W McPhail, Kevin O'Gallagher, Lukas E Schmidt, Christian Cassel, Georg Auzinger, Salvatore Napoli, Salma F Mujib, Francesca Trovato, Barnaby Sanderson, Blair Merrick, Roman Roy, Jonathan D Edgeworth, Ajay M ShahAdrian C Hayday, Ludwig Traby, Matthias Hackl, Sabine Eichinger, Manu Shankar-Hari, Manuel Mayr

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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.

Original language	English
Journal	Cardiovascular Research
DOIs	https://doi.org/10.1093/cvr/cvab338
Publication status	E-pub ahead of print - 10 Nov 2021

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Association of cardiometabolic microRNAs with COVID-19 severity and mortality - Cardiovascular Research 2021Final published version, 2.84 MBLicence: CC BY

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Gutmann, C., Khamina, K., Theofilatos, K., Diendorfer, A. B., Burnap, S. A., Nabeebaccus, A., Fish, M., McPhail, M. J. W., O'Gallagher, K., Schmidt, L. E., Cassel, C., Auzinger, G., Napoli, S., Mujib, S. F., Trovato, F., Sanderson, B., Merrick, B., Roy, R., Edgeworth, J. D., ... Mayr, M. (2021). Association of cardiometabolic microRNAs with COVID-19 severity and mortality. Cardiovascular Research. Advance online publication. https://doi.org/10.1093/cvr/cvab338

@article{432dc81afd2c4aa9865fa8fa25bbb873,

title = "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.",

author = "Clemens Gutmann and Kseniya Khamina and Konstantinos Theofilatos and Diendorfer, {Andreas B} and Burnap, {Sean A} and Adam Nabeebaccus and Matthew Fish and McPhail, {Mark J W} and Kevin O'Gallagher and Schmidt, {Lukas E} and Christian Cassel and Georg Auzinger and Salvatore Napoli and Mujib, {Salma F} and Francesca Trovato and Barnaby Sanderson and Blair Merrick and Roman Roy and Edgeworth, {Jonathan D} and Shah, {Ajay M} and Hayday, {Adrian C} and Ludwig Traby and Matthias Hackl and Sabine Eichinger and Manu Shankar-Hari and Manuel Mayr",

note = "{\textcopyright} The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.",

year = "2021",

month = nov,

day = "10",

doi = "10.1093/cvr/cvab338",

language = "English",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

}

Gutmann, C, Khamina, K, Theofilatos, K, Diendorfer, AB, Burnap, SA , Nabeebaccus, A , Fish, M , McPhail, MJW , O'Gallagher, K , Schmidt, LE, Cassel, C, Auzinger, G, Napoli, S, Mujib, SF, Trovato, F, Sanderson, B, Merrick, B, Roy, R, Edgeworth, JD , Shah, AM , Hayday, AC, Traby, L, Hackl, M, Eichinger, S, Shankar-Hari, M & Mayr, M 2021, 'Association of cardiometabolic microRNAs with COVID-19 severity and mortality', Cardiovascular Research. https://doi.org/10.1093/cvr/cvab338

TY - JOUR

T1 - Association of cardiometabolic microRNAs with COVID-19 severity and mortality

AU - Gutmann, Clemens

AU - Khamina, Kseniya

AU - Theofilatos, Konstantinos

AU - Diendorfer, Andreas B

AU - Burnap, Sean A

AU - Nabeebaccus, Adam

AU - Fish, Matthew

AU - McPhail, Mark J W

AU - O'Gallagher, Kevin

AU - Schmidt, Lukas E

AU - Cassel, Christian

AU - Auzinger, Georg

AU - Napoli, Salvatore

AU - Mujib, Salma F

AU - Trovato, Francesca

AU - Sanderson, Barnaby

AU - Merrick, Blair

AU - Roy, Roman

AU - Edgeworth, Jonathan D

AU - Shah, Ajay M

AU - Hayday, Adrian C

AU - Traby, Ludwig

AU - Hackl, Matthias

AU - Eichinger, Sabine

AU - Shankar-Hari, Manu

AU - Mayr, Manuel

PY - 2021/11/10

Y1 - 2021/11/10

N2 - 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.

AB - 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.

U2 - 10.1093/cvr/cvab338

DO - 10.1093/cvr/cvab338

M3 - Article

C2 - 34755842

SN - 0008-6363

JO - Cardiovascular Research

JF - Cardiovascular Research

ER -

Association of cardiometabolic microRNAs with COVID-19 severity and mortality

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