Published online before print August 12, 2004, doi: 10.1161/01.STR.0000141705.79393.e2
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(Stroke. 2004;35:2239.)
© 2004 American Heart Association, Inc.
Letters to the Editor |
The Unifying Role of Matrix Metalloproteinases in Atheroma and Vascular Stroke
City Hospital, Birmingham, UK
To the Editor:
Two recent articles published in Stroke, 1 by Morgan et al1 and the other by Alvarez-Sabin et al,2 highlight the role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the pathogenesis of vascular disease. Cerebrovascular disease whether thrombotic, embolic or hemorrhagic is associated with abnormal vascular structure. Morgan et al show higher levels of collagenase transcripts in plaques in keeping with the hypothesis that these are physically unstable and prone to rupture. Plaque rupture in the cerebral circulation can be associated with in situ thrombosis and ischemic stroke or alternatively vascular rupture producing hemorrhagic stroke. Equally, in the carotid circulation a subtotal plaque rupture may initiate mural thrombus and subsequent distal embolism resulting in embolic stroke associated with carotid atherosclerosis.
Given such a linkage, the findings by Alvarez-Sabin et al of higher levels of circulating MMPs and TIMPs in patients who experience hemorrhagic stroke is understandable. The strong associations with circulating markers of extracellular matrix turnover and hemorrhagic events in the studies of Alvarez-Sabin et al suggest that the MMP/TIMP system has a significant role in mediating vascular rupture. The association between perihematomal edema with higher levels of MMP-9, and lower levels of TIMP-1, strengthens the hypothesis that an interaction between enzyme and inhibitor is very important. Their data are consistent with an earlier study showing that circulating concentrations of MMP-9 are raised after spontaneous intracerebral hemorrhage.3
There are obvious connections between vascular pathology in the coronary and cerebral circulations, sharing similar population risk factors. Although the arterial process is similar, cerebral and coronary arteries are exposed to different pressures, ie, vascular wall stress and control factors. Notwithstanding these important differences, similar changes in circulating MMPs and TIMPs are in coronary arterial plaque.4 Extending the general role of MMP/TIMP in occlusive vascular events, recent work from our group on patients with diabetes and hypertension has suggested abnormal circulating levels of MMPs and TIMPs in hypertension5 and diabetes.6 We have found that MMP-9 may have prognostic value in predicting vascular events in hypertension and that there may be a possible link between cardiac stiffness and TIMP-1,7 as well as an increase in circulating neutrophil MMP-9 levels in stable coronary artery disease.8
In summary, the data of both Morgan et al and Alvarez-Sabin et al support a more general linking hypothesis that changes in MMPs and TIMPs are common to many different expressions of vascular disease. Although these processes remain distinct, they are linked at the basic level of vascular structural change. We would suggest that this process is, in large part, mediated by change in MMPs and TIMPs activies. It may be that in cerebrovascular states, as we have found in cardiovascular disease, that circulating levels may be a valid noninvasive assessment of vascular extracellular matrix turnover and propensity to vascular occlusion (whether ischemic, hemorrhagic or embolic). It is likely that changes in plaque turnover, suggesting instability, may provide a better functional assessment than imaging assessments of atheroma severity (angiographic or ultrasonic) and provide more accurate prognostic information to guide complex interventions such as carotid stenting or aneurysm surgery.
References
- Morgan A, Rerkasem K, Gallagher P, Zhang B, Morris G, Calder P, et al. Differences in matrix metalloproteinase-1 and matrix metalloproteinase-12 transcript levels among carotid atherosclerotic plaques with different histopathological characteristics. Stroke. 2004; 35: 1310–1315.
[Abstract/Free Full Text] - Alvarez-Sabin J, Delgaro P, Abilleira S, Molina C, Arenillas J, Ribo M, et al. Temporal profile of matrix metalloproteinases and their inhibitors after spontaneous intracerebral hemorrhage: relationship to clinical and radiological outcome. Stroke. 2004; 35: 1316–1322.
[Abstract/Free Full Text] - Abilleira S, Montaner J, Molina C, Monasterio J, Castillo J, Alvarez-Sabin J. Matrix metalloproteinase-9 concentration after spontaneous intracerebral haemorrhage. J Neurosurg. 2003; 99: 65–70.[Medline] [Order article via Infotrieve]
- Brown D, Hibbs M, Kearney M, Loushin C, Isner J. Identification of 92-KD gelatinase in human coronary atherosclerotic lesions: association of active enzyme synthesis with unstable angina. Circulation. 1995; 91: 2125–2131.
[Abstract/Free Full Text] - Tayebjee M, Nadar S, Blann A, Beevers D, MacFadyen R, Lip GYH. Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension: relationship to cardiovascular risk and treatment a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Am J Hypertens. 2004; In press.
- Tayebjee M, Lim HS, MacFadyen R, Lip GYH. Matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and -2 in type 2 diabetes mellitus: effect of 1 year’s cardiovascular risk reduction therapy. Diabetes Care. 2004; 27: 2049–2051.
[Free Full Text] - Tayebjee M, Nadar S, MacFadyen R, Lip GYH. Circulating tissue inhibitor of metalloproteinase-1 elevation correlates with impaired diastolic relaxation in hypertension: implications for diastolic heart failure. J Am Coll Cardiol. 2004; 43 (suppl A): 513.
[Abstract/Free Full Text] - Tayebjee M, Tan K, Lip GYH, MacFadyen R. Circulating neutrophil matrix metalloproteinase-9 is elevated in stable coronary artery disease and ischaemic cardiomyopathy [Abstract]. Atheroscler Suppl. 2004; 5: 19.[Medline] [Order article via Infotrieve]
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