Original Article
Association of Carotid Artery Atherosclerosis With Circulating Biomarkers of Extracellular Matrix Remodeling: The Framingham Offspring Study

https://doi.org/10.1016/j.jstrokecerebrovasdis.2008.06.002Get rights and content

Objective

We sought to relate circulating biomarkers of extracellular matrix turnover to site-specific measures of carotid artery atherosclerosis on duplex ultrasound.

Background

Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) regulate extracellular matrix remodeling, a key feature of atherosclerosis, and their circulating concentrations can be assayed. MMP-9, TIMP-1, and protocollagen-III n-terminal propeptide (PIIINP) may relate differentially to the severity of atherosclerosis at different carotid artery sites. However, data examining this premise are sparse.

Methods

We related circulating MMP-9, TIMP-1, and/or PIIINP concentrations to carotid atherosclerosis on duplex ultrasound in 1006 Framingham offspring (mean age 58 years, 56% women) who attended a routine examination from 1995 to 1998. We used multivariable regression to relate MMP-9 (detectable v undetectable), TIMP-1, and PIIINP (age- and sex-specific quartiles) to internal carotid artery (IC) stenosis (>25%) and log-transformed common carotid artery and IC intima-media thickness (IMT).

Results

Detectable MMP-9 was associated with carotid stenosis (odds ratio [OR] 1.71, P = .032) but not with IMT. Higher TIMP-1 was associated with carotid stenosis (OR for Quartiles (Q)4 v Q1-3, 1.63, P = .022) and a higher IC IMT (β 0.057 ± 0.025, Q4 v Q1-3, P = .023). Higher PIIINP (Q4 v Q1-3) showed a borderline association with carotid stenosis (OR 1.45 for Q4 v Q1-3, P = .095) but not with IMT. TIMP-1 was not associated with common carotid artery IMT.

Conclusions

In our community-based sample of middle-aged to older adults, higher circulating biomarkers of matrix remodeling were associated with a greater prevalence of carotid stenosis and subclinical atherosclerosis in the IC. Our findings are consistent with regional differences in matrix remodeling in the carotid artery.

Section snippets

Study Cohort

The Framingham offspring cohort was recruited in 1971, and includes individuals who are either children or the spouses of the children of the participants in the original Framingham Heart Study. The members of the offspring cohort have been examined approximately every 4 to 8 years since 1971. At the sixth examination cycle, 3377 attendees underwent carotid duplex ultrasound. Participants with available carotid ultrasound measurements and plasma biomarkers of ECM turnover (MMP-9, TIMP-1, and/or

Results

Clinical characteristics for the study participants are shown in Table 1. Carotid artery stenosis greater than 25% was observed in 168 participants (17%).

MMP-9 was detectable in 680 participants (20%). The median plasma concentration was 31 ng/dL in men and 34 ng/mL in women (range 20-248 ng/mL).

Principal Findings

This study demonstrates site-specific relations of circulating biomarkers of ECM remodeling and the carotid artery atherosclerosis measures assessed using duplex ultrasound. First, we noted significant associations of higher levels of TIMP-1 with IC IMT, but not with CC IMT. The associations with IC IMT remained statistically significant after adjustment for traditional vascular risk factors. Second, higher concentrations of TIMP-1 and detectable MMP-9 were associated with IC stenosis, with a

Conclusions

Higher circulating concentrations of ECM turnover markers, TIMP-1, MMP-9, and PIIINP are associated with measures of carotid artery atherosclerosis after adjusting for standard risk factors in a community-based sample of middle-aged adults, free of clinical stroke and dementia. Our findings are consistent with site-specific carotid artery ECM remodeling and support a pathophysiologic role for the MMP/TIMP pathway in atherosclerosis of the carotid artery.

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    Supported by the National Heart, Lung, and Blood Institute (NHBLI) Framingham Heart Study (National Institutes of Health/NHLBI Contract #N01-HC-25195); grants from the National Institute of Neurological Disorders and Stroke NS17950 (Dr. Wolf); the National Institute of Aging AG08122, AG16495 (Dr. Wolf); and NHBLI HL67288 and 2K24HL04334 (Dr Vasan).

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