Abstract Body: Background: Over 10 million patients undergoing non-cardiac surgery annually experience major cardiovascular complications within 30 days. Atherosclerosis is implicated in a significant number of cases, yet how plaque disruption is precipitated in the perioperative period remains unclear. Reverse cholesterol transport (RCT), which facilitates cholesterol removal via HDL and apoA-I, plays a key role in preventing plaque progression. Surgery-associated inflammation can impair HDL function, but its effects on RCT and plaque stability remain poorly understood.
Hypothesis: Inflammatory remodeling of the HDL proteome impairs reverse cholesterol transport, promoting cholesterol accumulation and necrotic core expansion in atherosclerotic plaques.
Results: ApoE^-/- mice fed a Western diet underwent exploratory abdominal surgery or anesthesia only (control). RCT was impaired for at least 48 hours postoperatively, paralleling reduced in vitro cholesterol efflux to plasma and isolated HDL. Proteomic analysis via LC-MS/MS revealed extensive postoperative inflammatory remodeling of the HDL proteome, with a marked increase in SAA protein abundance and a concurrent reduction in ApoA-I. This acute-phase HDL remodelling amounted to a reduction of several cholesterol transport-related biological pathways as defined by Gene Ontology (GO). Atherosclerotic plaques exhibited a 1.6-fold increase in intracellular lipids (BODIPY) and perilipin-2 at 24 hours post-surgery, with elevated cleaved-caspase-3 expression in lipid-rich cells. By day 15, lipid-rich cells fell below control levels, while plaque necrotic core area expanded by 1.5-fold, suggesting that acute lipid accumulation triggers cell death and necrotic core growth. Preliminary experiments intervening with rApoA-I postoperatively partially restored RCT, lessened acute cholesterol accumulation in plaques, and modulated postoperative inflammation, with ongoing studies assessing its ability to prevent necrotic core expansion.
Conclusion: Postoperative inflammation profoundly impairs RCT, driving acute lipid accumulation, cell death, and plaque destabilization. These findings highlight rapid lipid dynamics in plaques during surgical inflammation and underscore the need for targeted strategies to mitigate postoperative atherogenic mechanisms.