Elevated circulating metalloproteinase 7 predicts recurrent cardiovascular events in patients with carotid stenosis: a prospective cohort study

Abstract

Background: Major adverse cardiovascular events are the main cause of morbidity and mortality over the long term in patients undergoing carotid endarterectomy. There are few reports assessing the prognostic value of markers of inflammation in relation to the risk of cardiovascular disease after carotid endarterectomy. Here, we aimed to determine whether matrix metalloproteinases (MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10), tissue inhibitor of MMPs (TIMP-1) and in vivo inflammation studied by 18 F-FDG-PET/CT predict recurrent cardiovascular events in patients with carotid stenosis who underwent endarterectomy. Methods: This prospective cohort study was carried out on 31 consecutive patients with symptomatic (23/31) or asymptomatic (8/31) severe (> 70%) carotid stenosis who were scheduled for carotid endarterectomy between July 2013 and March 2016. In addition, 26 healthy controls were included in the study. Plasma and serum samples were collected 2 days prior to surgery and tested for MMP-1, MMP-2, MMP-7, MMP-9, MMP-10, TIMP-1, high-density lipoprotein, low-density lipoprotein, high-sensitivity C-reactive protein and erythrocyte sedimentation rate. 18 F-FDG-PET/CT focusing on several territories' vascular wall metabolism was performed on 29 of the patients because of no presurgical availability in 2 symptomatic patients. Histological and immunohistochemical studies were performed with antibodies targeting MMP-10, MMP-9, TIMP-1 and CD68. Results: The patients with carotid stenosis had significantly more circulating MMP-1, MMP-7 and MMP-10 than the healthy controls. Intraplaque TIMP-1 was correlated with its plasma level (r = 0.42 P = .02) and with 18 F-FDG uptake (r = 0.38 P = .05). We did not find any correlation between circulating MMPs and in vivo carotid plaque metabolism assessed by 18 F-FDG-PET. After a median follow-up of 1077 days, 4 cerebrovascular, 7 cardiovascular and 11 peripheral vascular events requiring hospitalization were registered. Circulating MMP-7 was capable of predicting events over and above the traditional risk factors (HR = 1.15 P = .006). When the model was associated with the variables of interest, the risk predicted by 18 F-FDG-PET was not significant. Conclusions: Circulating MMP-7 may represent a novel marker for recurrent cardiovascular events in patients with moderate to severe carotid stenosis. MMP-7 may reflect the atherosclerotic burden but not plaque inflammation in this specific vascular territory.

Metalloproteinases and Their Inhibitors: Potential for the Development of New Therapeutics

“…MMP-13 expression, mediated by influenza a virus via p38 mitogen activated protein kinase, was found to destabilize the susceptible arterial plaques triggering cardiovascular events eventually [152]. In patients with carotid stenosis-a narrowing of the carotid arteries, caused by atherosclerosis-MMP-1, -7, and -10 proteins were seen to circulate at a much more significant level/frequency than the controls, providing more evidence and further confirming the hypothesized correlation of MMPs and atherosclerosis [153]. Interestingly, MMP-7 recently showed its promising role as a novel biomarker, in patients with severe carotid stenosis, for recurrent cardiovascular events [153].…”

“…In patients with carotid stenosis-a narrowing of the carotid arteries, caused by atherosclerosis-MMP-1, -7, and -10 proteins were seen to circulate at a much more significant level/frequency than the controls, providing more evidence and further confirming the hypothesized correlation of MMPs and atherosclerosis [153]. Interestingly, MMP-7 recently showed its promising role as a novel biomarker, in patients with severe carotid stenosis, for recurrent cardiovascular events [153]. The elevated protein expression of MMP-1 and -7 was selected as potential candidates for early death prediction in patients with heart failure [154].…”

“…Patients with severe periodontitis indicated a considerably higher level of proMMP-2 and MMP-2 than healthy individuals [157]. T2DM is also considered a risk for periodontitis as T2DM elevates inflammation in periodontal tissues in the presence of high levels of inflammatory mediators, i.e., IL-1β, TNFα, nitrites, and MMP activities [153]. Patients with severe periodontitis indicated a considerably higher level of salivary proMMP-2 and MMP-2 than healthy individuals [157].…”

Predictive Value of Matrix Metalloprotease 9 On Surgical Outcomes After Pericardiectomy

“…Abnormal expressions of MMPs and TIMPs are involved in a variety of pathological conditions, including in ammation and brosis [10]. In addition, the levels of MMPs have been reported to be associated with surgical outcomes and could be potential biomarkers predicting postoperative complications [11][12][13].…”

Importance of age and inflammation markers like the most important determinant of carotid artery disease in patients with aortic valve disease

“…These plaques have a thinner fibrous layer, and a large necrotic core or a highly inflammatory reaction within them [3]. The presence of matrix metalloproteinase and interleukins have been identified as markers of plaque instability and its association with clinical events, because they cause matrix degradation and induce an inflammatory response that leads to rupture and cerebrovascular events [4,5].…”