Abstract Body: BACKGROUND: One in six patients undergoing major noncardiac surgery develops myocardial injury after noncardiac surgery (MINS). Untargeted metabolomics implicate disrupted cholesterol metabolism in MINS, but a direct mechanistic link to plaque rupture is unclear. We previously showed that exploratory laparotomy in ApoE^-/- mice acutely remodels HDL, reduces circulating apolipoprotein A-I (ApoA-I), and impairs reverse cholesterol transport (RCT) for ≥48 hrs. This results in rapid lipid accumulation, cell death, and NETosis within atherosclerotic plaques by 24 hrs after surgery, with necrotic core expansion by postoperative day (POD) 15. RCT can be augmented by a single intraperitoneal (IP) injection of recombinant ApoA-I (rApoA-I).
HYPOTHESIS: Perioperative rApoA-I prevents postoperative necrotic core expansion.
RESULTS: ApoE^-/- mice (8–11 weeks, both sexes) fed a Western diet for 8 weeks were randomized to anesthesia-only, surgery, or surgery plus rApoA-I (40 mg/kg IP at emergence; vehicle control). A single rApoA-I dose maintained supraphysiologic circulating ApoA-I levels for up to 72 hours and accelerated resolution of the acute-phase reactant serum amyloid A by POD2. Flow cytometry of aortic arch digests revealed that surgery induced an ~1.5-fold increase in neutral lipid-laden myeloid cells (BODIPY^hi) on POD1, which was completely abrogated by rApoA-I. This lipid accumulation was not due to impaired cellular cholesterol efflux, as expression of the cholesterol transporter ABCA1 increased postoperatively and was further augmented by rApoA-I (1.3- vs 1.8-fold). Immunofluorescence microscopy showed a 3-fold surge on POD1 in apoptotic (cleaved caspase-3⁺) leukocyte-derived (CD45⁺) and non–leukocyte-derived (CD45^-) foam cells (PLIN2^hi), consistent with lipotoxic cell death; this response was markedly attenuated by rApoA-I (3- vs 2-fold). rApoA-I also reduced postoperative NETosis and neutrophil recruitment to plaques on POD1. Notably, a single rApoA-I dose was sufficient to prevent necrotic core expansion on POD15, implicating impaired lipid handling as a key driver of surgery-induced plaque destabilization.
CONCLUSION: rApoA-I represents a clinically feasible strategy to mitigate postoperative cardiovascular risk by targeting an acute postoperative lipid–inflammatory axis. These findings identify a transient but critical window of vascular vulnerability after surgery and suggest that short-term intervention may suffice to confer durable benefit.