Species-selective plasma metabolism drives lysophosphatidylcholine depletion after cardiac arrest.

Lysophosphatidylcholine (LPC) is an essential mammalian phospholipid that serves multiple physiological functions. We have previously shown that plasma LPC levels are rapidly reduced after cardiac arrest (CA) in humans and in rodent models, where exogenous supplementation improves survival and neurologic outcomes. However, the specific mechanisms driving this depletion remain undefined, precluding rational design of targeted therapies to preserve LPC levels and limiting clinical translation. Here, we provide the first pharmacokinetic analysis of acute LPC reduction through a novel stable-isotope tracer approach. Our findings demonstrate that saturation status of the fatty acyl chain in LPC species determines the degree of reduction after CA, with polyunsaturated species showing the greatest declines. Further, we found that in situ metabolism, not decreased hepatic production nor increased tissue distribution, underlies the observed depletion in plasma LPC after cardiac arrest. Polyunsaturated LPC species showed correlated changes with lysophosphatidic acid and choline-containing metabolites. These correlations likely reflect shared vulnerability to post-CA pathological stress rather than direct metabolic conversion, as conventional metabolic pathways could not account for the temporal patterns and magnitude of LPC reduction, suggesting a broader, systemic dysregulation of plasma lipid metabolism. These findings indicate that therapeutic strategies must focus on either identifying and targeting the novel metabolic mechanisms responsible for species-selective elimination or implementing LPC supplementation protocols designed to overcome accelerated plasma elimination.