584 Circulating Matrix GLA Protein and Faster Progression Rate of Aortic Stenosis - a Substudy of the Astronomer Trial

Abstract

In a previous substudy of the ASTRONOMER trial, we reported that metabolic syndrome (MetS) is associated with faster progression of aortic stenosis (AS). Recent studies suggested that dysregulation of mineral metabolism or its modulators could play a role in the pathogenesis of AS. The carboxylated form of the Matrix Gla Protein (MGP) is an inhibitor of ectopic calcification. The objective of this study was to determine the association between circulating levels of the total (i.e. carboxylated and non carboxylated) MGP and AS progression rate. Among the 269 patients randomized in ASTRONOMER, mean follow-up time 3.4 ±1.3 years, 217 had baseline measurement of circulating level of total MGP. None of the patient had hypercholesterolemia, diabetes, or coronary artery disease at baseline. However, 29% had systemic hypertension and 28% had MetS. Hemodynamic progression rate of AS was measured with the use of the annualized increase in peak aortic jet velocity (Vpeak). In the whole cohort, baseline MGP level was significantly associated with AS progression rate in univariate analysis (r=0.15; p=0.03) but not in multivariate analysis (p=NS). There was a significant interaction (p=0.03) between MGP level and age with respect to its relationship with AS progression rate. In the subset of patients with age<57 years (median value), higher MGP level was significantly associated with faster AS progression rate (r=0.22; p=0.02) whereas no such relationship was observed in older patients. After adjustment for gender, hypertension, LDL-chol, creatinin, baseline valve calcification and Vpeak, and status of randomization (statin vs. placebo), higher MGP level (p=0.008) and MetS (p=0.001) were independent predictors of faster AS progression in younger patients. Baseline level of MGP was positively related to age (p=0.03), LDL-chol (p=0.02), oxidized-LDL (p=0.005), glycaemia (p=0.001), and HOMA-IR index (p=0.05). In multivariate analysis, oxidized-LDL (p=0.03) and glycaemia (p=0.01) were the only two factors independently associated with circulating MGP levels. This study reports an association between higher circulating levels of total MGP and faster progression of AS in the younger population. These findings suggest that valvular calcification may lead to increased MGP expression, perhaps in a feedback attempt to physiologically reduce bone-like formation of calcium deposits in the valve. Further studies with measures of both carboxylated and uncarboxylated forms of MGP in the blood as well as in the valvular tissues are needed to clarify the exact role of the MGP system in the pathogenesis of AS.