Martin Ingi Sigurdsson1,2, Hirotada Kobayashi3, Karin Amrein4, Kiichi Nakahira5,6, Angela J Rogers7, Mayra Pinilla-Vera8, Rebecca M Baron8, Laura E Fredenburgh8, Jessica A Lasky-Su9, Kenneth B Christopher10,11. 1. Anesthesiology and Critical Care Medicine, Landspitali University Hospital, University of Iceland, Hringbraut 101, 101, Reykjavík, Iceland. 2. Faculty of Medicine, University of Iceland, Vatnsmyrarvegur 16, 101, Reykjavik, Iceland. 3. Division of Renal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, USA. 4. Division of Endocrinology and Diabetology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria. 5. Nara Medical University, 840 Shijocho, Kashihara, Nara, 634-8521, Japan. 6. Weill Cornell Medicine, 1300 York Avenue, New York, 10065, USA. 7. Stanford University Medical Center, 300 Pasteur Dr. H3143, Stanford, 94305, USA. 8. Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, USA. 9. Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, 02115, USA. 10. Division of Renal Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, 02115, USA. kbchristopher@bwh.harvard.edu. 11. Channing Division of Network Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Boston, 02115, USA. kbchristopher@bwh.harvard.edu.
Abstract
BACKGROUND: Cell stress promotes degradation of mitochondria which release danger-associated molecular patterns that are catabolized to N-formylmethionine. We hypothesized that in critically ill adults, the response to N-formylmethionine is associated with increases in metabolomic shift-related metabolites and increases in 28-day mortality. METHODS: We performed metabolomics analyses on plasma from the 428-subject Correction of Vitamin D Deficiency in Critically Ill Patients trial (VITdAL-ICU) cohort and the 90-subject Brigham and Women's Hospital Registry of Critical Illness (RoCI) cohort. In the VITdAL-ICU cohort, we analyzed 983 metabolites at Intensive Care Unit (ICU) admission, day 3, and 7. In the RoCI cohort, we analyzed 411 metabolites at ICU admission. The association between N-formylmethionine and mortality was determined by adjusted logistic regression. The relationship between individual metabolites and N-formylmethionine abundance was assessed with false discovery rate correction via linear regression, linear mixed-effects, and Gaussian graphical models. RESULTS: Patients with the top quartile of N-formylmethionine abundance at ICU admission had a significantly higher adjusted odds of 28-day mortality in the VITdAL-ICU (OR, 2.4; 95%CI 1.5-4.0; P = 0.001) and RoCI cohorts (OR, 5.1; 95%CI 1.4-18.7; P = 0.015). Adjusted linear regression shows that with increases in N-formylmethionine abundance at ICU admission, 55 metabolites have significant differences common to both the VITdAL-ICU and RoCI cohorts. With increased N-formylmethionine abundance, both cohorts had elevations in individual short-chain acylcarnitine, branched chain amino acid, kynurenine pathway, and pentose phosphate pathway metabolites. CONCLUSIONS: The results indicate that circulating N-formylmethionine promotes a metabolic shift with heightened mortality that involves incomplete mitochondrial fatty acid oxidation, increased branched chain amino acid metabolism, and activation of the pentose phosphate pathway.
BACKGROUND: Cell stress promotes degradation of mitochondria which release danger-associated molecular patterns that are catabolized to N-formylmethionine. We hypothesized that in critically ill adults, the response to N-formylmethionine is associated with increases in metabolomic shift-related metabolites and increases in 28-day mortality. METHODS: We performed metabolomics analyses on plasma from the 428-subject Correction of Vitamin D Deficiency in Critically Ill Patients trial (VITdAL-ICU) cohort and the 90-subject Brigham and Women's Hospital Registry of Critical Illness (RoCI) cohort. In the VITdAL-ICU cohort, we analyzed 983 metabolites at Intensive Care Unit (ICU) admission, day 3, and 7. In the RoCI cohort, we analyzed 411 metabolites at ICU admission. The association between N-formylmethionine and mortality was determined by adjusted logistic regression. The relationship between individual metabolites and N-formylmethionine abundance was assessed with false discovery rate correction via linear regression, linear mixed-effects, and Gaussian graphical models. RESULTS: Patients with the top quartile of N-formylmethionine abundance at ICU admission had a significantly higher adjusted odds of 28-day mortality in the VITdAL-ICU (OR, 2.4; 95%CI 1.5-4.0; P = 0.001) and RoCI cohorts (OR, 5.1; 95%CI 1.4-18.7; P = 0.015). Adjusted linear regression shows that with increases in N-formylmethionine abundance at ICU admission, 55 metabolites have significant differences common to both the VITdAL-ICU and RoCI cohorts. With increased N-formylmethionine abundance, both cohorts had elevations in individual short-chain acylcarnitine, branched chain amino acid, kynurenine pathway, and pentose phosphate pathway metabolites. CONCLUSIONS: The results indicate that circulating N-formylmethionine promotes a metabolic shift with heightened mortality that involves incomplete mitochondrial fatty acid oxidation, increased branched chain amino acid metabolism, and activation of the pentose phosphate pathway.
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