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CLINICAL RESEARCH: VULNERABLE PLAQUE

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

Giuseppe Sangiorgi, MD, FESC^_*,_*, Alessandro Mauriello, MD, Elena Bonanno, MD, Claus Oxvig, PhD^¶, Cheryl A. Conover, MD, Michael Christiansen, MD^#, Santi Trimarchi, MD, Vincenzo Rampoldi, MD, David R. Holmes, Jr, MD, FACC^||, Robert S. Schwartz, MD, FACC^_** and Luigi Giusto Spagnoli, MD

^_* Department of Cardiovascular Disease, Istituto Policlinico San Donato, San Donato Milanese, Milan, Italy
Department of Vascular Surgery, Istituto Policlinico San Donato, San Donato Milanese, Milan, Italy
Department of Pathology, University of Rome Tor Vergata, Rome, Italy
Endocrinology Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota
^|| Department of Cardiovascular Disease, Mayo Clinic and Foundation, Rochester, Minnesota
^¶ Department of Molecular and Structural Biology, University of Aarhus, Aarhus, Denmark
^# Department of Clinical Biochemestry, Staten Serum Institute, Copenhagen, Denmark
^_** Department of Cardiovascular Disease, Minneapolis Heart Foundation, Minneapolis, Minnesota

Manuscript received August 22, 2005; revised manuscript received September 27, 2005, accepted November 1, 2005.

^_* Reprint requests and correspondence: Dr. Giuseppe Sangiorgi, Emo Centro Cuore Columbus, Via Buonarroti 48, 20145 Milan, Italy. (Email: sangiorgi{at}emocolumbus.it).

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.

Abbreviations and Acronyms   CT = computed tomography   FITC = streptavidin-fluorescin conjugate   hsCRP = high-sensitivity C-reactive protein   ICM = immunofluorescence confocal microscopy   MMPs = serum matrix metalloproteinases   NASCET = North American Symptomatic Carotid Endarterectomy Trial   PAPP-A = pregnancy-associated protein-A   RT-PCR = quantitative real-time polymerase chain reaction   TIA = transient ischemic attack

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