Propranolol Normalizes Metabolomic Signatures Thereby Improving Outcomes After Burn

Abstract

Objective and Background: Propranolol, a nonselective beta-receptor blocker, improves outcomes of severely burned patients. While the clinical and physiological benefits of beta-blockade are well characterized, the underlying metabolic mechanisms are less well defined. We hypothesized that propranolol improves outcomes after burn injury by profoundly modulating metabolic pathways. Methods: In this phase II randomized controlled trial, patients with burns ≥20% of total body surface area were randomly assigned to control or propranolol (dose given to decrease heart rate <100 bpm). Outcomes included clinical markers, inflammatory and lipidomic profiles, untargeted metabolomics, and molecular pathways. Results: Fifty-two severely burned patients were enrolled in this trial (propranolol, n=23 and controls, n=29). There were no significant differences in demographics or injury severity between groups. Metabolomic pathway analyses of the adipose tissue showed that propranolol substantially alters several essential metabolic pathways involved in energy and nucleotide metabolism, as well as catecholamine degradation (P<0.05). Lipidomic analysis revealed that propranolol-treated patients had lower levels of proinflammatory palmitic acid (P<0.05) and saturated fatty acids (P<0.05) with an increased ratio of polyunsaturated fatty acids (P<0.05), thus shifting the lipidomic profile towards an anti-inflammatory phenotype after burn (P<0.05). These metabolic effects were mediated by decreased activation of hormone-sensitive lipase at serine 660 (P<0.05) and significantly reduced endoplasmic reticulum stress by decreasing phospho-JNK (P<0.05). Conclusion: Propranolol’s ability to mitigate pathophysiological changes to essential metabolic pathways results in significantly improved stress responses.