Plasma Concentrations and Genetic Variation of Matrix Metalloproteinase 9 and Prognosis of Patients With Cardiovascular Disease

Abstract

for the AtheroGene InvestigatorsBackground-Matrix metalloproteinase (MMP)-9 secretion by macrophages and other inflammatory cells accelerates atherosclerotic progression and destabilizes vulnerable plaque in animal models. However, epidemiological data evaluating the prognostic impact of circulating concentrations and functional genetic variations of MMP-9 are lacking. Methods and Results-In a prospective study of 1127 patients with documented coronary artery disease, we measured baseline plasma MMP-9 levels and determined the MMP-9/C-1562T and MMP-9/R279Q genotypes. During the follow-up period (mean of 4.1 years), 97 patients died from cardiovascular (CV) causes. Median concentrations of MMP-9 were significantly higher among patients who experienced a fatal CV event than among those who did not (62.2 versus 47.8 ng/mL; PϽ0.0001). The crude hazard risk ratio of CV death associated with increasing quartiles of MMP-9 was 1.4 (95% CI, 1.2 to 1.8; PϽ0.0001), and after adjustment for clinical and therapeutic confounders, it was 1.3 (95% CI, 1.1 to 1.6; Pϭ0.005). Additional adjustment for highly sensitive CRP, interleukin-6, fibrinogen, and interleukin-18 revealed a hazard risk ratio to 1.2 (95% CI, 0.9 to 1.6; Pϭ0.15). The T allele of the C-1562T polymorphism was associated with increased MMP-9 levels in a fairly codominant fashion (Pϭ0.004). Although none of the polymorphisms was significantly related with future CV death, there was a significant association (Pϭ0.02) between the R279Q polymorphism and CV events in patients with stable angina. Conclusions-Plasma MMP-9 concentration was identified as a novel predictor of CV mortality in patients with coronary artery disease. Whether it provides independent prognostic information compared with other inflammatory markers will have to be additionally assessed.

Endothelial dysfunction is associated with increased levels of biomarkers in essential hypertension

“…The role of metalloproteinases and their tissue inhibitor are still a matter of discussion in hypertension and cardiovascular disease. Although in atherosclerotic lesions and in patients with coronary artery disease, increased levels of metalloproteinases, in particular matrix metalloproteinases type 9, are associated with plaque vulnerability and rupture, 23 in hypertension most studies have found increased levels of TIMP-1 whereas metalloproteinases were normal or reduced. 15,25 In the process of vascular remodelling that takes place in hypertensives, a reduction in the ratio of metalloproteinases and TIMP-1 could be responsible for an increased extracellular matrix deposition.…”

“…19,20 Moreover, in patients with coronary heart disease some of these serum markers have prognostic implications. [21][22][23] The aim of this study was to evaluate the correlation between the degree of endothelial dys-function, as measured by the maximal acetylcholine-induced forearm vasodilation, and the serum level of biochemical markers of inflammation, remodeling and oxidative stress, in a group of newly diagnosed, never-treated, essential hypertensive patients.…”

Matrix metalloproteinases in cardiovascular disease

“…Recently, Blankenburg et al (16) conducted a study in patients with existing coronary artery disease. They found that soluble MMP-9 measured in the blood provided the most efficient prognostic information beyond that offered by traditional prognostic markers such as cholesterol or other inflammatory markers.…”

A randomized, controlled trial of the effects of rosiglitazone on adipokines, and inflammatory and fibrinolytic markers in diabetic patients: Study design and protocol

“…It has been implicated in the remodelling processes associated with atherogenesis and plaque rupture (21,22). A strong association between baseline MMP-9 levels and future risk of cardiovascular mortality has been demonstrated in patients with documented coronary artery disease (23), suggesting that MMP-9 might constitute a novel biomarker for characterizing individuals at higher cardiovascular risk.…”