Abstract 15915: Integrated Plaque and Plasma Proteo-Lipidomics Reveal Novel Signatures of Coronary Atherosclerotic Plaque Disruption
Background: Clinical consequences of atherosclerotic plaque rupture vary between asymptomatic to acute arterial thrombosis, yet the mechanisms underpinning such differential biological response remain poorly understood. We investigated the upstream events that signify human coronary plaque rupture, and their relations to downstream effects.
METHOD: Plaque rupture was induced by percutaneous coronary intervention (PCI) with stenting (n=58); diagnostic angiography without stenting served as controls (n=16). Plaque morphology was characterised by optical coherence tomography before plaque rupture (n=36); Coronary plaque debris was collected by the Filterwire (n=2); Serial blood samples were collected after PCI. Targeted plasma analysis by enzyme immunoassay guided the selection of discovery cohorts (n=10/group) for untargeted omics analysis. Shotgun proteomics, lipidomics of plaque / plasma were performed by LC MSMS and MALDI TOF MS.
RESULTS: Proteomics revealed acute changes in plasma proteins within 5 minutes after plaque rupture, including release of cellular proteins identified in plaque debris. This was associated with changes in the plasma lipidomic profile. Ingenuity pathway analysis revealed activation of LXR/RXR and lipid synthesis pathways after plaque rupture, resulting in rapid release of Lipocalin-2 (P<0.05) and subsequently MMP9 (P<0.01), independent to the downstream myocardial injury (troponin) and inflammation response (CRP) from PCI. Further, rupture of lipid-rich plaques (n=28) resulted in earlier MMP9 release (<1hr, P<0.05) compared to the rest.
CONCLUSION: Plaque rupture resulted in rapid changes in plasma proteo-lipidomics profiles, followed by differential activation of the LXR/RXR pathway and systemic release of Lipocalin-2 and MMP9. Our novel insights confirm the central roles of lipid and extra cellular matrix metabolism in the biology of plaque rupture and highlight key targets for future investigations.
- © 2013 by American Heart Association, Inc.