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

Deanery of Clinical Sciences

Research output: Contribution to journal › Article › peer-review

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). A total of 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.

Original language	English
Pages (from-to)	461-474
Number of pages	14
Journal	Cardiovascular Research
Volume	118
Issue number	2
Early online date	10 Nov 2021
DOIs	https://doi.org/10.1093/cvr/cvab338
Publication status	Published - 29 Jan 2022

Keywords / Materials (for Non-textual outputs)

Adult
Aged
Biomarkers
COVID-19/complications
Cardiometabolic Risk Factors
Female
High-Throughput Nucleotide Sequencing
Humans
Intensive Care Units
Male
MicroRNAs/blood
Middle Aged
Patient Acuity
SARS-CoV-2

Access to Document

10.1093/cvr/cvab338

cvab338
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 2.81 MBLicence: Creative Commons: Attribution (CC-BY)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8689968/pdf/cvab338.pdf

Cite this

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. (2022). Association of cardiometabolic microRNAs with COVID-19 severity and mortality. Cardiovascular Research, 118(2), 461-474. https://doi.org/10.1093/cvr/cvab338

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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). A total of 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.",

keywords = "Adult, Aged, Biomarkers, COVID-19/complications, Cardiometabolic Risk Factors, Female, High-Throughput Nucleotide Sequencing, Humans, Intensive Care Units, Male, MicroRNAs/blood, Middle Aged, Patient Acuity, SARS-CoV-2",

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 = "2022",

month = jan,

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doi = "10.1093/cvr/cvab338",

language = "English",

volume = "118",

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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 2022, 'Association of cardiometabolic microRNAs with COVID-19 severity and mortality', Cardiovascular Research, vol. 118, no. 2, pp. 461-474. 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

N1 - © The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

PY - 2022/1/29

Y1 - 2022/1/29

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). A total of 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.

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). A total of 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.

KW - Adult

KW - Aged

KW - Biomarkers

KW - COVID-19/complications

KW - Cardiometabolic Risk Factors

KW - Female

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Intensive Care Units

KW - Male

KW - MicroRNAs/blood

KW - Middle Aged

KW - Patient Acuity

KW - SARS-CoV-2

U2 - 10.1093/cvr/cvab338

DO - 10.1093/cvr/cvab338

M3 - Article

C2 - 34755842

SN - 0008-6363

VL - 118

SP - 461

EP - 474

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 2

ER -

Association of cardiometabolic microRNAs with COVID-19 severity and mortality

Abstract

Keywords / Materials (for Non-textual outputs)

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