Postoperative Atherosclerotic Plaque Destabilization: Mechanistic Insights and Therapeutic Opportunities

Abstract

Background: Myocardial Injury after Noncardiac Surgery (MINS) affects ~1 in 6 patients undergoing major noncardiac procedures. A subset of MINS cases is linked to atherosclerotic plaque disruption, but the mechanisms driving this postoperative instability remain poorly defined. Reverse Cholesterol Transport (RCT), the removal of peripheral cholesterol by HDL and ApoA-I, is critical for limiting plaque progression. Surgical inflammation is known to impair HDL function, but its impact on RCT and plaque stability is poorly understood.

Hypothesis: Postoperative inflammatory remodeling of the HDL proteome impairs RCT, promoting cholesterol accumulation and necrotic core expansion in atherosclerotic plaques, whereas perioperative rApoA-I prevents postoperative necrotic core expansion.

Results: ApoE⁻ᐟ⁻ mice on a Western diet underwent exploratory laparotomy or anesthesia only (control). LC-MS/MS of isolated mouse and human HDL revealed extensive inflammatory remodeling on postoperative day (POD) 1, marked by elevated serum amyloid A (SAA) and reduced ApoA-I, impairing multiple RCT-related pathways as identified by Gene Ontology analysis. In vitro, macrophage cholesterol efflux to postoperative plasma and HDL was substantially reduced, while vascular smooth muscle cell (VSMC) efflux showed modest reductions. Using a novel dual-label, dual-cell-type in vivo RCT assay - subcutaneously injecting ³H-cholesterol-labeled macrophages and ¹⁴C-cholesterol-labeled VSMCs - macrophage RCT was significantly impaired for >48h post-op, whereas VSMC RCT was largely preserved. In human noncardiac surgery patients (n=21), in vitro macrophage cholesterol efflux to postoperative plasma was similarly impaired.

Within atherosclerotic plaques, lipid accumulation (BODIPY) and perilipin-2 (PLIN2) expression increased in both macrophages and VSMCs on POD1. Apoptotic (cleaved caspase-3⁺) cells were enriched postoperatively, predominantly among PLIN2^hi populations. Neutrophil extracellular traps (H3Cit⁺MPO⁺) were also elevated. By POD3 and POD15, plaques exhibited reduced cellularity, fewer lipid-rich cells, and enlarged necrotic cores, suggesting acute lipid loading promotes cell death and plaque destabilization.

Therapeutically, a single rApoA-I dose (40 mg/kg i.p. at emergence) maintained supraphysiologic circulating ApoA-I levels through POD3, promoted redistribution of SAA from ApoB-containing lipoproteins toward HDL, enhanced serum cholesterol efflux capacity in vitro, and partially restored in vivo RCT. rApoA-I prevented the ~1.5-fold postoperative increase in BODIPY^hi myeloid cells within POD1 atherosclerotic plaques, and markedly attenuated the surge in apoptotic PLIN2^hi foam cells (3- vs 2-fold). rApoA-I additionally reduced neutrophil recruitment and postoperative NETosis within plaques on POD1. Importantly, a single dose of rApoA-I at emergence was sufficient to prevent necrotic core expansion on POD15. Delaying intervention till POD3 abolished protection against postoperative necrotic core enlargement, identifying a critical therapeutic window during the acute-phase response.

Conclusion: Our results implicate impaired lipid handling as a key driver of surgery-induced plaque destabilization. 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.