l-Carnitine is a candidate therapeutic for the treatment of septic shock, a condition that carries a ≥40% mortality. Responsiveness to l-carnitine may hinge on unique metabolic profiles that are not evident from the clinical phenotype. To define these profiles, we performed an untargeted metabolomic analysis of serum from 21 male sepsis patients enrolled in a placebo-controlled l-carnitine clinical trial. Although treatment with l-carnitine is known to induce changes in the sepsis metabolome, we found a distinct set of metabolites that differentiated 1-year survivors from nonsurvivors. Following feature alignment, we employed a new and innovative data reduction strategy followed by false discovery correction, and identified 63 metabolites that differentiated carnitine-treated 1-year survivors versus nonsurvivors. Following identification by MS/MS and database search, several metabolite markers of vascular inflammation were determined to be prominently elevated in the carnitine-treated nonsurvivor cohort, including fibrinopeptide A, allysine, and histamine. While preliminary, these results corroborate that metabolic profiles may be useful to differentiate l-carnitine treatment responsiveness. Furthermore, these data show that the metabolic signature of l-carnitine-treated nonsurvivors is associated with a severity of illness (e.g., vascular inflammation) that is not routinely clinically detected.
Bibliographical noteFunding Information:
This work was supported by a metabolomics supplement to a grant from the National Institute of General Medical Sciences (NIGMS; R01GM103799 to A.E.J.), R01GM111400 to K.A.S., K23GM113041 to M.A.P. and R03CA211817 and U01CA235487 to A.K. Research reported in this publication was supported by Core Services supported by the National Institutes of Health (NIH) under Award No. U24 DK097153 (MRC2), U2CES026553 (MCHEAR), U24DK112342 (MiCAS), and U2CES030164 (MCIDC). The clinical trial was supported by a grant from the American Heart Association (10POST3560001) and the Cannon Foundation (SRG10-004). The content is solely the responsibility of the authors and does not necessarily present the official views of the NIGMS, NIDDK, the National Institute of Environmental Health Sciences, or the National Institutes of Health.
- liquid chromatography-mass spectroscopy
- vascular inflammation