Abstract 6164: Plasma Profiles of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Patients with Pulmonary Hypertension
Regulation of matrix metalloproteinases (MMP) and tissue inhibitors of MMP (TIMP) have been implicated in the pathogenesis of pulmonary hypertension (PH) in animal models. Whether plasma profiles of MMP and TIMP are altered in PH patients (pts) is unknown. Plasma expression of MMP-2, 9 and TIMP-1 in PH pts were compared to healthy controls. 32 PH pts; NYHA class II-IV; age 53 ± 15 yrs; 93% female and 15 controls; age 38 ± 10 yrs; 60% female were enrolled in the study. Etiology of PH included idiopathic pulmonary arterial hypertension (PAH) in 56% (18/32), systemic sclerosis PAH in 22% (7/32), congenital shunt associated PAH in 13% (4/32), and left heart disease associated PH in 9% (3/32) of pts. Clinical data, and 6 minute walk distance (6MWD) were collected and plasma MMP- 2, 9 and TIMP-1 levels were measured in all pts and controls using ELISA kits. One way ANOVA was used for group comparisons and correlations used the Pearson’s method. Control subjects were younger (p=0.003) than PH pts. Plasma MMP-2 (251±83 vs. 172 ± 42 ng/ml), MMP-9 (70 ± 10 vs. 11 ± 16 ng/ml), TIMP-1 (220 ± 78 vs. 102 ± 16 ng/ml) levels, and MMP-9/TIMP-1 ratio (0.32 vs. 0.10) were increased (p= 0.001) in PH pts compared to controls. There were no differences in MMP and TIMP levels in the different PH subgroups based either on etiology or type of PH therapy (phophodiesterase- 5 inhibitor, endothelin receptor antagonist, prostanoids) or number of therapies. Plasma MMP-2 levels in PH pts were higher in NYHA class III/IV compared to class II (267± 83 vs. 185± 60 ng/ml, p= 0.03), and those with 6 minute walk distance < 300m compared to ≥ 300m (282± 73 vs. 229± 66 ng/ml, p= 0.07). There was a strong negative correlation between plasma MMP-2 level and 6MWD (r=−0.6, p =0.002). Plasma MMP-9 and TIMP-1 levels did not discriminate these groups. Plasma MMP-2, 9 and TIMP-1 levels are increased in all PH pts compared to healthy controls and the expression of MMP-2 in particular is greater in PH pts with more severe symptoms and functional limitation. This finding confirms that regulation of MMP and TIMP is important in the pathogenesis and progression of disease in PH pts.