Matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 in hypertension and their relationship to cardiovascular risk and treatment: a substudy of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).
BACKGROUND
Hypertension results in structural changes to the cardiac and vascular extracellular matrix (ECM). Matrix metalloproteinases (MMP) and their inhibitors (TIMP) may play a central role in the modulation of this matrix. We hypothesized that both MMP-9 and TIMP-1 would be abnormal in hypertension, reflecting alterations in ECM turnover, and that their circulating levels should be linked to cardiovascular (CHD) and stroke (CVA) risk scores using the Framingham equation. Second, we hypothesized that treatment would result in changes in ECM indices.


METHODS
Plasma MMP-9 and TIMP-1 were measured before and after treatment (median 3 years) from 96 patients with uncontrolled hypertension participating in the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT). Pretreatment values were compared to circulating MMP-9 and TIMP-1 levels in 45 age- and sex-matched healthy controls.


RESULTS
Circulating pretreatment MMP-9 and TIMP-1 levels were significantly higher in patients with hypertension than in the normotensive controls (P =.0041 and P =.0166, respectively). Plasma MMP-9 levels decreased, and TIMP-1 levels increased after treatment (P =.035 and P =.005, respectively). Levels of MMP-9 correlated with CHD risk (r = 0.317, P =.007) and HDL cholesterol (r = -0.237, P =.022), but not CVA risk. There were no significant correlations between TIMP-1 and CVA or CHD scores.


CONCLUSIONS
Increased circulating MMP-9 and TIMP-1 at baseline in patients with hypertension could reflect an increased deposition and retention of type I collagen at the expense of other components of ECM within the cardiac and vascular ECM. After cardiovascular risk management, MMP-9 levels decreased and TIMP-1 levels increased. Elevated levels of MMP-9 also appeared to be associated with higher Framingham cardiovascular risk scores. Our observations suggest a possible role for these surrogate markers of tissue ECM composition and the prognosis of cardiovascular events in hypertension.
Tayebjee
Muzahir H
MH
Haemostasis Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Birmingham, United Kingdom.
Nadar
Sunil
S
Blann
Andrew D
AD
Gareth Beevers
D
D
MacFadyen
Robert J
RJ
Lip
Gregory Y H
GY
D000368:Aged; D000959:Antihypertensive Agents / Q000627:therapeutic use; D024042:Collagen Type I / Q000378:metabolism; D003430:Cross-Sectional Studies; D005109:Extracellular Matrix / Q000378:metabolism; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000453:epidemiology* / Q000378:metabolism*; D008137:Longitudinal Studies; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D008875:Middle Aged; D011379:Prognosis; D012307:Risk Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*; D016896:Treatment Outcome
D000959:Antihypertensive Agents; D024042:Collagen Type I; D019715:Tissue Inhibitor of Metalloproteinase-1; D020780:Matrix Metalloproteinase 9