Postoperative Stress Accelerates Atherosclerosis Through Inflammatory Remodeling of the HDL Proteome and Impaired Reverse Cholesterol Transport.

Abstract

Over 10 million patients undergoing non-cardiac surgery each year face major cardiovascular complications within 30 days, many due to destabilized atherosclerotic plaques. Reverse cholesterol transport (RCT), driven by HDL and Apoa1, protects against plaque progression, but the effects of surgical inflammation on this pathway remain unclear. Using an abdominal laparotomy model in ApoEmice on a Western diet, we isolated the impact of surgical inflammation without confounding blood loss. Surgery acutely impaired RCT and cholesterol efflux, with inflammatory remodeling of HDL marked by elevated SAA1/2 and reduced Apoa1. Plaques exhibited higher intracellular lipids, PLIN2 expression, and cleaved caspase-3, indicating lipid-driven apoptosis. Both leukocytic and non-leukocytic foam cells showed increased PLIN2, with apoptosis concentrated in PLIN2cells. Using a novel dual-label, dual-cell-type in vivo RCT model, we found that surgery significantly impaired macrophage RCT while VSMC RCT remained largely unaffected, highlighting foam cell subtype-specific vulnerability to surgical inflammation. These findings were mirrored in general surgery patients, whose postoperative plasma exhibited markedly reduced cholesterol efflux capacity. In mice, rh-APOA1 treatment partially restored RCT and reduced plaque lipid accumulation. Surgical inflammation rapidly disrupts HDL function and RCT, promoting foam cell apoptosis and plaque destabilization. Timely Apoa1 restoration may help reduce postoperative cardiovascular risk.