Carotid Atherosclerotic Plaque Matrix Metalloproteinase‐12–Positive Macrophage Subpopulation Predicts Adverse Outcome After Endarterectomy

Abstract

Matrix metalloproteinase‐12 ( MMP ‐12) promotes atherosclerosis in animal models. MMP ‐12 is expressed in only a subset of foam‐cell macrophages ( FCM s) in human plaques. We investigated whether the prevalence of this MMP ‐12–expressing subpopulation is a prognostic indicator of adverse outcome in patients after carotid endarterectomy ( CEA ). Serial sections of culprit lesions from 236 patients who underwent CEA and had undergone 3 years of clinical follow‐up were stained immunocytochemically for MMP ‐12 and for CD 68, and the MMP ‐12/ CD 68 ratio was used to quantify the MMP ‐12–expressing subpopulation. A high MMP ‐12/ CD 68 ratio correlated with a high content of lipid and total macrophages and a low content of vascular smooth muscle cells, as well as with MMP ‐8 ( R =0.211, P =0.001), MMP ‐9 ( R =0.251, P R =0.142, P =0.036) activity measured in a neighboring segment. Dual immunohistochemical examination confirmed the location of MMP ‐12 in a subpopulation of MMP ‐8– and MMP ‐9–positive FCM s, whereas all apoptotic FCM s were MMP ‐12 positive. Patients who yielded plaques within the highest quartile compared with the lowest quartile of MMP ‐12/ CD 68 ratio had a 2.4‐fold (hazard ratio, 2.4; 95% CI, 1.1‐ to 5.1‐fold; adjusted P =0.027) increased risk of major adverse cardiovascular event and a 3.4‐fold (3.4; 1.2‐ to 9.6‐fold, P =0.024) increased risk for stroke. The prevalence of an MMP ‐12–positive subset of FCM s is a prognostic marker for adverse clinical outcome after CEA.