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.