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. 2015 Oct 22;10(10):e0141251.
doi: 10.1371/journal.pone.0141251. eCollection 2015.

Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness

Carmen Mikacenic  1 , William O Hahn  2 , Brenda L Price  3 , Susanna Harju-Baker  1 , Ronit Katz  4 , Kevin C Kain  5 , Jonathan Himmelfarb  4 , W Conrad Liles  2 , Mark M Wurfel  1
Affiliations

Biomarkers of Endothelial Activation Are Associated with Poor Outcome in Critical Illness

Carmen Mikacenic et al. PLoS One. .

Abstract

Background: Endothelial activation plays a role in organ dysfunction in the systemic inflammatory response syndrome (SIRS). Angiopoietin-1 (Ang-1) promotes vascular quiescence while angiopoietin-2 (Ang-2) mediates microvascular leak. Circulating levels of Ang-1 and Ang-2 in patients with SIRS could provide insight on risks for organ dysfunction and death distinct from inflammatory proteins. In this study, we determined if biomarkers of endothelial activation and inflammation exhibit independent associations with poor outcomes in SIRS.

Methods: We studied 943 critically ill patients with SIRS admitted to an Intensive Care Unit (ICU) of an academic medical center. We measured plasma levels of endothelial markers (Ang-1, Ang-2, soluble vascular cell adhesion molecule-1 (sVCAM-1)) and inflammatory markers (interleukin-6 (IL-6), interleukin-8 (IL-8), granulocyte-colony stimulating factor (G-CSF), soluble tumor necrosis factor receptor-1 (sTNFR-1)) within 24 hours of enrollment. We tested for associations between each marker and 28 day mortality, shock, and day 3 sequential organ failure assessment (SOFA) score. For 28 day mortality, we performed sensitivity analysis for those subjects with sepsis and those with sterile inflammation. We used multivariate models to adjust for clinical covariates and determine if associations identified with endothelial activation markers were independent of those observed with inflammatory markers.

Results: Higher levels of all biomarkers were associated with increased 28 day mortality except levels of Ang-1 which were associated with lower mortality. After adjustment for comorbidities and sTNFR-1 concentration, a doubling of Ang-1 concentration was associated with lower 28 day mortality (Odds ratio (OR) = 0.81; p<0.01), shock (OR = 0.82; p<0.001), and SOFA score (β = -0.50; p<0.001), while Ang-2 concentration was associated with increased mortality (OR = 1.55; p<0.001), shock (OR = 1.51; p<0.001), and SOFA score (β = +0.63; p<0.001). sVCAM-1 was not independently associated with SIRS outcomes.

Conclusions: In critically ill patients with SIRS, early measurements of Ang-1 and Ang-2 are associated with death and organ dysfunction independently of simultaneously-measured markers of inflammation.

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Conflict of interest statement

Competing Interests: Drs. Liles and Kain are co-inventors of patents regarding the use of endothelial biomarkers for risk prediction in critical illness: 1) Title: Biomarkers for early determination of a critical or life threatening response to illness and monitoring response to treatment thereof; Inventors: Kevin Kain, W. Conrad Liles, Laura Erdman, Andrea Conroy; CA2769433 A1 – 8/27/2013; WO20131270000 A1 – 9/6/2013). 2) Title: Angiopoietin-1 and -2 biomarkers for infectious diseases that compromise endothelial integrity; Inventors: Kevin C. Kain, W. Conrad Liles, Fiona E. Lovegrove; WO2009059404 A1 – 5/14/2009; US20110008804 A1 – 1/13/2011. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

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