Pregnancy-associated plasma protein-a is markedly expressed by monocyte-macrophage cells in vulnerable and ruptured carotid atherosclerotic plaques: a link between inflammation and cerebrovascular events

OBJECTIVES: The study aim was to evaluate serologic expression of pregnancy-associated protein-A (PAPP-A) in patients affected by cerebrovascular accidents and to correlate it with histopathologic carotid plaque complexity. BACKGROUND: Little is known about PAPP-A expression in carotid atherosclerotic disease and whether this protein represents a marker of plaque vulnerability also in carotid district. METHODS: Seventy-two carotid plaques from patients submitted to surgical endarterectomy (19 who suffered a major stroke, 24 transient ischemic attack, and 29 asymptomatic) were evaluated. Serologic PAPP-A levels were determined by enzyme-linked immunoadsorbent assay. Plaques were divided in three groups based on histology: 1) stable (n= 38); 2) vulnerable (n= 13); 3) ruptured with thrombus (n= 14). Immunohistochemical staining for PAPP-A, smooth muscle cells, macrophages, and T-lymphocytes was performed in all cases. Real-time polymerase chain reaction assessed local PAPP-A production, and double immunofluorescence confocal microscopy (ICM) characterized cell type expressing PAPP-A. RESULTS: Pregnancy-associated protein-A (serologic values were 4.02 +/- 0.18 mIU/l in Group 1, 7.43 +/- 0.97 mIU/l in Group 2, and 6.97 +/- 0.75 mIU/l in Group 3 [1 vs. 3, p= 0.01; 1 vs. 2, p= 0.004; 2 vs. 3, p= 0.71, respectively]). Pregnancy-associated protein-A (expression showed a mean score value of 0.62 +/- 0.06 for stable plaques, 2.54 +/- 0.14 for vulnerable plaques, and 2.71 +/- 0.12 for ruptured plaques [1 vs. 2, p= 0.001; 1 vs. 3, p= 0.001; 2 vs. 3, p= 0.37, respectively]). Real-time polymerase chain reaction demonstrated local messenger ribonucleic acid PAPP-A production, and double ICM confirmed monocyte/macrophage expression of PAPP-A in Groups 2 and 3 but not Group 1. CONCLUSIONS: This study suggests that PAPP-A is a marker of carotid plaque destabilization and rupture. Further studies are necessary to determine if PAPP-A can represents a new target for stratifying the risk of cerebrovascular events.