Published online before print October 9, 2006, doi: 10.1161/CIRCULATIONAHA.105.593483
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(Circulation. 2006;114:1847-1854.)
© 2006 American Heart Association, Inc.
Vascular Medicine |
Elevated Matrix Metalloproteinase-9 Associated With Stroke or Cardiovascular Death in Patients With Carotid Stenosis
From the Department of Vascular Surgery, Rigshospitalet, Copenhagen University Hospital (N.E., M.-L.M.G., H.S.) and Department of Clinical Biochemistry, Herlev University Hospital, University of Copenhagen (N.E., B.G.N.), Copenhagen, Denmark.
Correspondence to Professor Børge G. Nordestgaard, Department of Clinical Biochemistry, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark. E-mail brno{at}herlevhosp.kbhamt.dk
Received October 7, 2005; revision received August 4, 2006; accepted August 29, 2006.
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Abstract |
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Background— Matrix metalloproteinase-9 could exhibit an important role in the destabilization of atherosclerotic carotid plaques. We hypothesized that in patients with carotid stenosis, elevated levels of plasma matrix metalloproteinase-9 are associated with ipsilateral stroke or cardiovascular death.
Methods and Results— We followed up 207 patients with 
50% carotid stenosis initially for a mean of 4.4 years, during which time 53 patients developed ipsilateral stroke or died of cardiovascular causes. The cumulative incidence of ipsilateral stroke or cardiovascular death was higher in those with matrix metalloproteinase-9 above versus below the median of 41.9 ng/mL (log-rank P=0.002). Matrix metalloproteinase-9 above versus below the median had a hazard ratio for ipsilateral stroke or cardiovascular death of 1.9 (95% confidence interval [CI], 1.1 to 3.5); during extended follow-up, this remained significant until 10 years. The absolute risk of ipsilateral stroke or cardiovascular death at 4.4 years was 34% and 17% in those with matrix metalloproteinase-9 above and below the median, respectively. Elevated matrix metalloproteinase-9 and an echolucent plaque on B-mode ultrasound versus a low matrix metalloproteinase-9 and an echorich plaque had a hazard ratio for ipsilateral stroke or cardiovascular death of 4.4 (95% CI, 1.8 to 11.1) and for ipsilateral stroke of 3.3 (95% CI, 1.1 to 9.7).
Conclusions— Elevated levels of matrix metalloproteinase-9 in patients with 50% carotid stenosis were associated with a 2-fold risk of ipsilateral stroke or cardiovascular death. Combining elevated matrix metalloproteinase-9 and plaque echolucency was associated with a 4-fold risk for ipsilateral stroke or cardiovascular death and a 3-fold risk for ipsilateral stroke.
Key Words: atherosclerosis • carotid artery diseases • matrix metalloproteinases
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Introduction |
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Ruptured and ulcerated carotid plaques with superimposed thrombus are substrate for transient ischemic attack and stroke in 44% to 100% of patients with symptomatic carotid stenosis.1,2 The pathogenesis leading to plaque rupture is still not completely understood, but evidence is accumulating that matrix metalloproteinases exhibit an important role in vascular remodeling3 and destabilization of atherosclerotic plaques.4,5 Matrix metalloproteinase-9 has been shown to degenerate structural components of plaque matrix such as connective tissue collagens IV, V, VII, X, and XII and elastin, leading to destabilization of plaques.6 In patients with stable and unstable angina pectoris, levels of matrix metalloproteinase-9 in the fourth quartile compared with the first quartile were associated with a hazard ratio for cardiovascular mortality of 2.7 (95% confidence interval [CI], 1.4 to 5.0).7
It is therefore possible that individuals with elevated plasma levels of matrix metalloproteinase-9 have unstable atherosclerotic plaques, leading to a continuous escape of matrix metalloproteinase-9 from plaques to plasma. In other words, elevated plasma matrix metalloproteinase-9 could be a risk marker of unstable plaques and therefore could predict individuals at high risk of future cardiovascular events. It has never been investigated, however, whether plasma levels of matrix metalloproteinase-9 are associated with ischemic stroke or cardiovascular death in patients with carotid stenosis.
We hypothesized that in patients with carotid stenosis, elevated plasma levels of matrix metalloproteinase-9 are associated with a higher risk of future stroke or cardiovascular death. For this purpose, we followed up 207 patients with 50% carotid stenosis initially for an average of 4.4 years, during which time 53 patients developed an ipsilateral ischemic stroke and/or died of cardiovascular causes; during extended follow-up to an average of 10 years, a total of 73 patients developed an ipsilateral ischemic stroke or died of cardiovascular causes. To examine the association between matrix metalloproteinase-9 and risk of ischemic stroke or cardiovascular death stratified for or combined with other risk factors, we also measured plaque echogenicity, degree of stenosis, symptomatic status at inclusion (symptomatic or asymptomatic), and the acute-phase reactants C-reactive protein and fibrinogen.
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Methods |
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Subjects
The present study included 207 patients recruited from 1556 consecutive patients referred for carotid ultrasound examination at Rigshospitalet, Copenhagen University Hospital (Denmark) from 1994 through 1996 (Figure 1). Patients were included if they had a carotid stenosis
50%. Of these, 119 previously had ipsilateral symptoms, and 88 were "asymptomatic" patients, implying that the previous symptoms were not related to the carotid plaque or that the carotid stenosis was found incidentally. The symptomatic patients with stenosis of 70% were included in the study if surgery was not indicated, ie, age 70 years (n=20), severe comorbidity (n=7), patient refusal (n=11), moderate to severe permanent neurological deficits (n=23), or neurological symptoms >6 months ago (n=24). Asymptomatic patients were duplex scanned for carotid bruit, for nonspecific nonhemispheric symptoms such as dizziness or vertigo (n=46), or because of symptomatic carotid stenosis of the contralateral side (n=42). The 1349 patients excluded from this prospective study were those with endarterectomy of the carotid artery, carotid stenosis <50%, total occlusion of internal carotid arteries, severe neurological deficits, severe dementia, cancer with a life expectancy <5 years, or lack of blood for biochemical tests (Figure 1).
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The medical ethics committee for Copenhagen and Frederiksberg approved the study. Patients gave written informed consent.
Laboratory Methods
Blood was drawn after the ultrasound examination of the carotid arteries and stored at –80°C. Plasma matrix metalloproteinase-9 was measured with a commercially available ELISA kit (Biotrak MMP-9 ELISA, RPN2614, Amersham Biosciences, Hilleroed, Denmark). Fibrinogen and high-sensitive C-reactive protein levels were measured with a colorimetric method (Boehringer Mannheim GmbH. Mannheim, Germany) and nephelometry (Dade Behring Diagnostica, Liederbach, Germany). Fibrinogen was measured immediately after blood sampling; matrix metalloproteinase-9 and high-sensitive C-reactive protein were measured after storage at –80°C. Lipids and lipoproteins were measured with standard hospital assays immediately after sampling.
Ultrasound Examination
At inclusion, all patients were examined with Doppler ultrasound, and degree of stenosis was determined to be 50% to 69% if peak systolic velocity was >120 cm/s or 70% to 99% if peak systolic velocity was >120 cm/s at the same time that peak diastolic velocity was >100 cm/s, according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET) criteria.8 These criteria define the degree of stenosis as follows: 1 minus the minimum diameter at the stenosis divided by the diameter of the distal internal carotid artery after the stenosis measured on a digital subtraction angiography.
All plaques were also recorded with high-resolution B-mode imaging (Interspec, ATL, Philips Medical Systems, Eindhoven, the Netherlands), and echogenicity of the plaque was determined according to the method described by Elatrozy et al.9 After calculation of the gray-scale median (GSM) value, the 207 patients were divided according to the median GSM value of 58: echorich (GSM 58) or echolucent (GSM <58).
End Points
Neurological and cardiac symptoms occurring during the initial mean 4.4-year (range, 3- to 6-year) observation period from 1994 through 1999 were noted at each 6-month visit or during a final telephone interview. Subsequently, neurological symptoms were further evaluated by a neurological consultant on the basis of collected copies of medical reports from hospitals and/or general practitioners. The consultant was not aware of results from the measurement of matrix metalloproteinase-9 or ultrasound examinations or any other covariate.
The combined primary end point of the study was ischemic stroke developed ipsilateral to the relevant carotid stenosis or cardiovascular death defined as death resulting from cardiac disease (congestive heart failure, ischemic heart disease) or cerebrovascular disease. Ischemic strokes were defined as focal neurological symptoms lasting 24 hours (with or without persisting disabilities) for which computed tomography or magnetic resonance scans showed corresponding ischemic infarction and ruled out cerebral hemorrhage. Hemorrhagic strokes (n=4) were excluded as events, but these individuals were not censored at the event. Patients with bilateral hemispheric symptoms and those with known cardiac mural thrombus (as verified on echocardiography) were excluded from analysis because of suspected cardioembolic origin (n=5). Follow-up was 100%. This 100% follow-up rate was possible because all persons in Denmark are registered via a Central Person Registration number in all public databases, which are 100% complete. Thus, individuals who could not be reached by telephone were all found to have died in the meantime as registered in the public databases.
Follow-up from 1999 until September 2005 was gathered by searching the Danish National Register of Causes of Deaths for all deaths and the Danish National Hospital Register for hospitalizations for World Health Organization International Classification of Diseases, revision 10, codes I60 through I69 (cerebrovascular diseases); thus, the average follow-up was extended to 10 years. This search revealed 16 new ischemic strokes, of which 6 were ipsilateral to the carotid stenosis as confirmed by hospital discharge reports including a computed tonography or magnetic resonance scan. In Denmark, however, not all patients are hospitalized for minor stroke. Therefore, the register follow-up from the mean 4.4 years and beyond may not be as complete as the initial 4.4 years in which the patients were seen every 6 months. We have therefore chosen to use the initial mean 4.4 years of follow-up as the main data, whereas data for the extended 10-year follow-up are used to validate the finding of the initial follow-up.
Of the 40 patients who died during the initial mean 4.4 years of follow-up, 22 died of cardiovascular disease (stroke, myocardial infarction, or sudden death), and 18 died of other causes. Of the 97 patients who died during the 10 years of follow-up, 49 died of cardiovascular disease, and 48 died of other causes.
Statistical Analyses
Kaplan-Meier curves plotted cumulative incidence as a function of follow-up time, and a log-rank test was used to evaluate statistical significance between factors. Cox regression models were used to calculate hazard ratios adjusted for age or multifactorially for age and other risk factors. Interaction between matrix metalloproteinase-9 and other risk factors was tested for by introducing 2-factor interaction terms in Cox regression models including the 2 factors and age. Time from previous symptoms was assigned 1 for asymptomatic, 2 for the one third of patients with the longest time since symptoms, 3 for the one third of patients with symptoms around the mean time, and 4 for the one third of the patients with the most recent symptoms. A 2-sided value of P<0.05 was considered significant. All analysis was done with SPSS (version 12.0.2, SPSS Inc, Chicago, Ill).
The authors had full access to the data and take full responsibility for their integrity. All authors have read and agree to the manuscript as written.
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Results |
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Baseline characteristics of participants are shown in Table 1. The 207 patients were followed up initially for a mean of 4.4 years (range, 3 to 6 years), with extended follow-up for a mean of 10 years.
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Ipsilateral Stroke or Cardiovascular Death Associated With Elevated Matrix Metalloproteinase-9
Kaplan-Meier curves showed that a plasma concentration of matrix metalloproteinase-9 above versus below the median of 41.9 ng/mL was associated with an increased cumulative incidence of ipsilateral stroke or cardiovascular death (Figure 2, left; log-rank P=0.002). Similar results were observed when the end point of ipsilateral ischemic stroke was considered alone; this was not significant (Figure 2, right; log-rank P=0.08), however.
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Matrix metalloproteinase-9 above versus below the median had a hazard ratio for ipsilateral stroke or cardiovascular death of 2.4 (95% CI, 1.4 to 4.3) after adjustment for age (Table 2). The equivalent hazard ratio was 1.9 (95% CI, 1.1 to 3.5) after multifactorial adjustment for age, sex, smoking, hypertension, diabetes mellitus, atrial fibrillation, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, antiplatelet therapy, anticoagulation therapy, antihypertensive treatment, statin treatment, and symptomatic status. After adjustment for age and location of carotid territory ischemia (amaurosis fugax, transient ischemic attack, or stroke), severity of carotid stenosis, time since onset of previous symptom, and coronary artery disease (angina pectoris and myocardial infarction), these results were similar (data not shown). In a Cox regression model with age, prior symptoms (amaurosis fugax, transient ischemic attack, or ischemic stroke), and matrix metalloproteinase-9 in the prediction of ipsilateral stroke or cardiovascular death, only matrix metalloproteinase-9 above versus below the median was associated with future ipsilateral stroke or cardiovascular death (hazard ratio, 2.3; 95% CI, 1.3 to 4.1). The absolute risk of ipsilateral stroke or cardiovascular death after 4.4 years was 35% and 17% in those with matrix metalloproteinase-9 above and below the median, respectively (Table 2). Plaque echogenicity, degree of stenosis, symptomatic status, C-reactive protein, and fibrinogen, however, were not associated with an increased risk of ipsilateral stroke or cardiovascular death after age adjustment or after multifactorial adjustment (Table 2).
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Matrix metalloproteinase-9 above versus below the median had a hazard ratio for ipsilateral ischemic stroke of 1.8 (95% CI, 0.9 to 3.4) after age adjustment and 1.5 (95% CI, 0.7 to 3.0) after multifactorial adjustment (Table 2). After adjustment for age and location of carotid territory ischemia (amaurosis fugax, transient ischemic attack, or stroke), severity of carotid stenosis, time since onset of previous symptom, and coronary artery disease (angina pectoris and myocardial infarction), these results were similar (data not shown). The absolute risk of ipsilateral ischemic stroke at 4.4 years was 21% and 15% in those with matrix metalloproteinase-9 above and below the median, respectively. Echolucent versus echorich plaques were associated with a hazard ratio for ipsilateral ischemic stroke of 1.9 (95% CI, 1.0 to 3.8) after multifactorial adjustment. Degree of stenosis, symptomatic status, C-reactive protein, and fibrinogen were not associated with an increased risk of ipsilateral ischemic stroke (Table 2).
When follow-up was extended to a mean of 10 years, the elevated hazard ratio of ipsilateral stroke or cardiovascular death as a function of high versus low matrix metalloproteinase-9 levels was observed throughout the 10 years of follow-up (log-rank P=0.0003); this was also the case for the trend toward an elevated hazard ratio of ipsilateral stroke alone (P=0.22) (Figure 3).
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On a continuous scale, an increment of 1 SD (12.2 ng/mL) in matrix metalloproteinase-9 was associated with a hazard ratio for ipsilateral stroke or cardiovascular death of 1.6 (95% CI, 1.2 to 2.1) after adjustment for age and 1.4 (95% CI, 1.1 to 1.8) after multifactorial adjustment as shown in Table 2. The corresponding hazard ratios for ipsilateral stroke were 1.3 (95% CI, 0.9 to 1.8) after adjustment for age and 1.1 (95% CI, 0.8 to 1.6) after multifactorial adjustment.
On a continuous scale using receiver-operating characteristic curves, ipsilateral stroke or cardiovascular death, but not ipsilateral stroke, was predicted by matrix metalloproteinase-9 with an area under the curve of 0.62 (95% CI, 0.53 to 0.71; P=0.008) and 0.54 (0.43 to 0.65; P=0.46), respectively (Figure 4).
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Ipsilateral Stroke or Cardiovascular Death Associated With Matrix Metalloproteinase-9 After Stratification for Other Risk Factors
After stratification for plaque echogenicity, degree of stenosis, symptomatic status, C-reactive protein, and fibrinogen, the cumulative incidence of ipsilateral stroke or cardiovascular death in those with matrix metalloproteinase-9 above versus below the median was elevated in 7 of 10 strata with hazard ratios for ipsilateral stroke or cardiovascular death of 2.1 to 3.9 (Figure 5; log-rank P=0.002 to 0.05); however, we failed to show a statistically significant interaction between matrix metalloproteinase-9 with any of the risk factors stratified for in Figure 5 (echogenicity, P=0.30; degree of stenosis, P=0.57; previous symptoms, P=0.79; C-reactive protein, P=0.51; fibrinogen, P=0.17).
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Ipsilateral Stroke or Cardiovascular Death Associated With Matrix Metalloproteinase-9 Combined With Plaque Echogenicity or Degree of Stenosis
Patients with an echorich plaque and matrix metalloproteinase-9 above the median compared with those with an echorich plaque and a low matrix metalloproteinase-9 concentration had a hazard ratio for ipsilateral stroke or cardiovascular death of 3.7 (95% CI, 1.4 to 9.4) after age adjustment and 2.9 (95% CI, 1.1 to 7.7) after multifactorial adjustment (Table 3). There was no increase in risk for patients with an echolucent plaque and a low matrix metalloproteinase-9 concentration versus an echorich plaque and a low matrix metalloproteinase-9 concentration; however, an echolucent plaque and a high concentration of matrix metalloproteinase-9 versus an echorich plaque and a low matrix metalloproteinase-9 concentration had a hazard ratio for ipsilateral stroke or cardiovascular death of 4.4 (95% CI, 1.8 to 11.1) and 3.9 (95% CI, 1.5 to 10.0) after age and multifactorial adjustment. The risk of ipsilateral ischemic stroke in patients with an echolucent plaque and a high concentration of matrix metalloproteinase-9 versus an echorich plaque and a low matrix metalloproteinase-9 concentration was associated with a hazard ratio of 3.5 (95% CI, 1.3 to 9.8) and 3.3 (95% CI, 1.1 to 9.7) after age and multifactorial adjustment (Table 3).
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Compared with patients with a low concentration of matrix metalloproteinase-9 and a 50% to 69% carotid stenosis, those with an elevated concentration of matrix metalloproteinase-9 and a 50% to 69% stenosis had a hazard ratio for ipsilateral stroke or cardiovascular death of 2.1 (95% CI, 1.0 to 4.5) and 1.7 (95% CI, 0.8 to 3.7) after age and multifactorial adjustment (Table 3). The equivalent hazard ratios for those with 70% to 99% stenosis instead of 50% to 69% stenosis were 0.9 (95% CI, 0.3 to 2.3) and 1.0 (95% CI, 0.4 to 2.6). A high concentration of matrix metalloproteinase-9 and 70% to 99% carotid stenosis versus a low concentration of matrix metalloproteinase-9 and 50% to 69% carotid stenosis had a hazard ratio for ischemic stroke of 2.6 (95% CI, 1.2 to 5.5) and 2.2 (95% CI, 1.0 to 4.7) after age and multifactorial adjustment (Table 3).
Matrix Metalloproteinase-9 and Coronary Disease
There was no association between new cardiac events during the initial mean 4.4 years of follow-up, defined as angina pectoris, acute myocardial infarction or cardiac revascularization, and metalloproteinase-9 above (14 events in 103 patients) versus below (15 events in 104 patients) the median (log-rank P=0.78).
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Discussion |
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Ipsilateral Stroke or Cardiovascular Death Associated With Matrix Metalloproteinase-9
In this cohort of patients with
50% carotid stenosis, elevated matrix metalloproteinase-9 above the median of 41.9 ng/mL was associated with a 2-fold risk of ipsilateral ischemic stroke or cardiovascular death. This is a novel observation. Carotid plaques in symptomatic versus asymptomatic patients have a higher content of macrophages and leukocytes,10 both cell types capable of secreting matrix metalloproteinase-9.3 In recently symptomatic patients, the level of matrix metalloproteinase-9 within the plaque is higher than in plaques from asymptomatic patients that caused symptoms >1 month ago.11 Thus, our results agree with histopathological findings of elevated matrix metalloproteinase-9 in recently ruptured carotid plaques.
Ipsilateral Stroke or Cardiovascular Death Associated With Matrix Metalloproteinase-9 After Stratification for Other Risk Factors
When we stratified for other risk factors, among patients with echolucent plaques, patients with high levels of C-reactive protein, and patients with a fibrinogen concentration below the median, matrix metalloproteinase-9 above versus below the median did not predict increased risk of ipsilateral stroke or cardiovascular death statistically significantly. However, because matrix metalloproteinase-9 did not interact with echogenicity, degree of stenosis, symptomatic status, C-reactive protein, or fibrinogen levels on risk of stroke or cardiovascular death, our data imply that matrix metalloproteinase-9 above versus below the median predicts risk of ipsilateral stroke or cardiovascular death regardless of levels of these 5 other risk factors.
Ipsilateral Stroke or Cardiovascular Death Associated With Matrix Metalloproteinase-9 Combined With Plaque Echogenicity or Degree of Stenosis
Another novel observation in the present study was the 4-fold risk of ipsilateral ischemic stroke or cardiovascular death and the 3-fold risk of ipsilateral ischemic stroke in those with both an echolucent plaque and levels of matrix metalloproteinase-9 above the median. This is in accordance with previous studies documenting that those with echolucent versus echorich plaques had higher risk of stroke.12 The present study thus suggests an additive effect of plaque echolucency and elevated matrix metalloproteinase-9 on stroke risk. Furthermore, for both 50% to 69% stenosis and 70% to 99% stenosis, a high level of matrix metalloproteinase-9 had a 2-fold risk for ipsilateral stroke or cardiovascular death; thus, there was no additive effect of degree of stenosis and metalloproteinase-9 on stroke risk.
Mechanism
Inflammation is now recognized as an important part of the development, progression, and rupture of atherosclerotic plaques.13–17 Inflammatory activity in plaques is caused by monocyte-macrophages and T-lymphocytes, both of which are known to migrate into the plaque.13,18 These inflammatory cells tend to accumulate beneath the atheromatous core in relation to microvessels and in the shoulder regions of the plaque.18 There, they secrete matrix metalloproteinase-93 as part of the constant remodeling process in plaque matrix. Matrix metalloproteinase-9 degrades extracellular matrix components like collagen and elastin,19 which are the structural components of plaque matrix normally securing plaque stability.20 As plaque collagen and elastin become degraded as a result of matrix metalloproteinase-9 activity, their capability to withstand high shear stress at the plaque shoulder region probably becomes reduced, leading to rupture of the plaque cap.18 Therefore, it seems reasonable to assume that increased plasma levels of matrix metalloproteinase-9 reflect ongoing plaque remodeling, which potentially can lead to an unstable, rupture-prone plaque and consequently ipsilateral stroke or cardiovascular death.
Study Limitations
The present study was limited by the inclusion of only patients considered unfit for surgery or patients having <70% carotid stenosis. It would have been unethical, however, to withhold surgery in those patients eligible for this procedure in Denmark.
Selection bias is always a possible limitation in a study like this because of differential selection rates of subjects by disease and/or risk factor characteristics. However, in the present study, this is not very likely because the end points studied were collected prospectively after inclusion in the study and because matrix metalloproteinase-9 levels were measured in frozen samples after the end of follow-up, with researchers blinded to disease status.
In our study, male sex and diabetes mellitus were overrepresented among those reaching an end point. Therefore, diabetes and male sex could be independent or confounding risk factors. In a stepwise Cox regression model, diabetes, but not male sex, was associated with ipsilateral stroke or cardiovascular death with a hazard ratio of 2.0 (95% CI, 1.1 to 4.0); after adjustment for both diabetes mellitus and male sex, however, the association between matrix metalloproteinase-9 levels and ipsilateral stroke or cardiovascular death remained significant.
At first, it could seem contradictory that degree of stenosis and symptomatic status did not predict the combined end point of ipsilateral stroke or cardiovascular death, whereas it is well known from the literature that these 2 covariates predict risk of stroke.21 This could suggest unconsidered confounding factors, wrong measures of the degree of carotid stenosis, and/or wrong death-related diagnoses. However, in the present study, as for the combined end point, neither degree of stenosis or symptomatic status predicted risk of stroke alone statistically significantly. Therefore, the most likely explanation for the lack of association between degree of stenosis or symptomatic status and future ipsilateral stroke or cardiovascular death is limited statistical power in the present study. Another explanation for the lack of association between symptomatic status and future ipsilateral stroke or cardiovascular death can be the time from previous event to inclusion in the study. The mean time from previous event to inclusion into the study was >90 days, the same time as when the benefits of surgery start to cease22 and many initial events have already occurred. Thus, many of the initial events occurring shortly after the first event were not included in the present study. Interestingly, therefore, despite the fact that initial events were not included in the present study, elevated levels of matrix metalloproteinase-9 were still associated with increased risk of ipsilateral stroke or cardiovascular death.
We should consider whether the presence of other plaques elsewhere (in the peripheral vasculature for instance) could potentially bias our results. Certainly, peripheral artery plaques could play a role in plasma levels of matrix metalloproteinase-9. Therefore, a cautious interpretation of the present data would be that in patients with carotid stenosis, elevated plasma levels of matrix metalloproteinase-9, leaking from carotid or other atherosclerotic plaques, are a marker of increased risk of stroke or cardiovascular death.
Conclusions
Elevated plasma levels of matrix metalloproteinase-9 were associated with a 2-fold risk for ipsilateral stroke or cardiovascular death. Furthermore, combining elevated levels of matrix metalloproteinase-9 with an ultrasonic echolucent plaque was associated with a 4-fold risk of ipsilateral stroke or cardiovascular death and a 3-fold risk for ipsilateral ischemic stroke.
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Acknowledgments |
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Sources of Funding
This work was supported by the Danish Heart Foundation and the Danish Medical Research Council.
Disclosures
None.
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