Abstract 14654: Clinical Relevance of Matrix Metalloproteinases and Tissue Inhibitor of Metalloproteinase in Pulmonary Arterial Hypertension
Background: Extracellular matrix remodeling from increased production/secretion of matrix metalloproteinases (MMP) characterizes the pulmonary vascular changes in pulmonary arterial hypertension (PAH) patients (pts). Though, plasma MMP-2, MMP-9 and tissue inhibitor of metalloproteinase (TIMP-1) levels are reported to be increased in PAH, their clinical relevance is unknown.
Methods: 38 chronic, stable, ambulatory PAH pts on oral and/or inhaled therapies with mean age 52±16 yrs (idiopathic, n=20; connective tissue disorders, n=12; congenital shunt, n=6) and 20 gender matched controls(C) with mean age 39±11 yrs had plasma MMP-2, MMP-9 and TIMP-1 levels measured (R & D Systems). PAH pts had concurrent assessment of NYHA class, and 6 minute walk distance (6MWD). Clinical worsening (death, requirement of intravenous prostacyclin therapy, and PAH related hospitalization) over the subsequent 1 year follow-up was evaluated. Group comparisons were done using Group comparisons were done using Wilcoxon-Mann-Whitney test.
Results: MMP-2, 9 and TIMP-1 levels were elevated in PAH pts compared to controls (PAH vs C: MMP-2: 294 ±78 vs 185 ±50 ng/ml, p=0.00001; MMP-9: 74 ±126 vs 4 ±16 ng/ml, p= 0.0001; TIMP-1: 248 ±139 vs 108 ±110 ng/ml, p= 0.02). MMP-2 and TIMP-1 levels were significantly higher in PAH pts with 6MWD < 400 meters (MMP-2: 286±64 vs 218±82 ng/ml, p=0.03; TIMP-1: 257±137 vs 158±89 ng/ml, p=0.03). NYHA class III or IV PAH pts also had significantly higher MMP-2 and TIMP-1 levels compared to NYHA class II pts (MMP-2: 301±73 vs 208±79 ng/ml, p=0.02; TIMP-1: 274±146 vs 181±129 ng/ml, p=0.049). PAH pts who developed clinical worsening (n=11) during follow-up trended to have higher MMP-9 levels, but this was not statistically significant.
Conclusions: Expression of MMP-2 and TIMP-1 is increased in PAH pts and correlates with severe symptoms and greater functional limitation. These pilot findings suggest that markers of extracellular matrix remodeling may have potential clinical application as biomarkers in PAH. Further confirmatory trials are required to validate these observations.
- © 2010 by American Heart Association, Inc.