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Levels of Circulating miR-133a Are Elevated in Sepsis and Predict Mortality in Critically Ill Patients

Tacke, Frank MD, PhD1; Roderburg, Christoph MD1; Benz, Fabian MD1; Cardenas, David Vargas BSc1; Luedde, Mark MD2; Hippe, Hans-Joerg MD2; Frey, Norbert MD2; Vucur, Mihael MSc1; Gautheron, Jeremie PhD1; Koch, Alexander MD1; Trautwein, Christian MD1; Luedde, Tom MD, PhD1

doi: 10.1097/CCM.0000000000000131
Clinical Investigations

Objective: Serum levels of microRNA have been proposed as biomarkers in various inflammatory diseases. However, up to now, their clinical relevance in critical illness and sepsis is unclear.

Design: Single-center clinical study.

Setting: Fourteen-bed medical ICU of the University Hospital Aachen, university laboratory research unit.

Subjects and Patients: Experimental sepsis model in C57Bl/6 mice; 223 critically ill patients in comparison with 76 healthy volunteers.

Interventions: We used the model of cecal pole ligation and puncture for induction of polymicrobial sepsis in mice and measured alterations in serum levels of six different microRNAs with a known function in inflammatory diseases upon induction of septic disease. These results from mice were translated into a large and well-characterized cohort of critically ill patients admitted to the medical ICU.

Measurements and Main Results: Serum miR-133a was then measured in 223 critically ill patients (138 with sepsis and 85 without sepsis) and 76 controls and associated with disease severity, organ failure, and prognosis. Significant alterations of miR-133a, miR-150, miR-155, and miR-193b* were found in mice after cecal pole ligation and puncture–induced sepsis. Among all regulated microRNAs, miR-133a displayed the most prominent and concordant up-regulation in sepsis, and this microRNA was therefore chosen for further investigation in the human. Here, significantly elevated miR-133a levels were found in critically ill patients at ICU admission, when compared with healthy controls, especially in patients with sepsis. Correlation analyses revealed significant correlations of miR-133a with disease severity, classical markers of inflammation and bacterial infection, and organ failure. Strikingly, high miR-133a levels were predictive for an unfavorable prognosis and represented a strong independent predictor for both ICU and long-term mortality in critically ill patients.

Conclusions: miR-133a serum levels were significantly elevated in critical illness and sepsis. High miR-133a levels were associated with the severity of disease and predicted an unfavorable outcome of critically ill patients.

1Department of Medicine III, University Hospital RWTH Aachen, Aachen, Germany.

2Department of Cardiology and Angiology, University of Kiel, Kiel, Germany.

This work was performed at the Department of Medicine III, University Hospital RWTH Aachen.

Dr. Tacke, Dr. Roderburg, and Dr. Benz contributed equally to this work. Dr. Tacke, Dr. Roderburg, Dr. Benz, Dr. Mark Luedde, Dr. Hippe, Dr. Frey, Dr. Koch, Dr. Trautwein, and Dr. Tom Luedde designed the study, analyzed data, and wrote the article. Dr. Benz, Mr. Cardenas, Dr. Gautheron, and Mr. Vucur performed miR-133a measurements. Dr. Tacke, Dr. Roderburg, Dr. Benz, Dr. Koch, and Dr. Tom Luedde performed statistical analyses. Dr. Tacke and Dr. Koch collected data and organized patient recruitment.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (http://journals.lww.com/ccmjournal).

Dr. Tacke’s institution received grant support from the German-Research-Foundation (SFB-TRR57, Ta434/2-1). Dr. Tom Luedde’s institution received grant support from the European Research Council within the FP 7 (ERC-2007-Stg/208237-Luedde-Med3-Aachen), from the German-Research-Foundation (SFB-TRR 57, P06), from the German Cancer Aid (Deutsche Krebshilfe Grant 110043), EMBO Young Investigator Program, and the Ernst-Jung-Foundation Hamburg, a grant from the Medical Faculty Aachen and from the Interdisciplinary Center of Clinical Research, Aachen. The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: tluedde@ukaachen.de

© 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins