Abstract 19945: Pathways of Myocardial Remodeling and Fibrosis in Duchenne Muscular Dystrophy: Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases
Background: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Biomarkers such as troponin and brain natriuretic peptide do not reliably assess disease severity. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate collagen turnover in the myocardial extracellular matrix (ECM) and may serve as novel cardiac biomarkers of remodeling and fibrosis or surrogate targets for drug therapy.
Hypothesis: We hypothesized that MMPs and TIMPs would be increased in DMD compared with control and would correlate with severity of DMD cardiomyopathy.
Methods: DMD subjects (n=48) were prospectively enrolled. Cardiac MRI with contrast determined chamber size, left and right ventricular ejection fraction (LVEF and RVEF), and late gadolinium enhancement (LGE) in DMD. Control samples (n=15) were collected for comparison. Serum was analyzed for MMP1, 3, 9, and 10 and TIMP 1 and 2; samples with coefficient of variation > 25% were not included in analysis. Wilcoxon Rank Sum, Kruskal-Wallis, and Spearman correlation used for statistical analysis.
Results: DMD and control subjects had similar ages (14.3 vs 13.7, p=0.98). Mean LVEF in DMD was 54% ± 10 and 30/43 (68%) had at least one segment with LGE. Mean MMP1 and MMP3 were higher in DMD than control (5800 pg/ml ± 6300 vs 2600 pg/ml ± 1900, p=0.011 and 27500 pg/ml ± 49400 vs 4700 pg/ml ± 2800, p=0.037, respectively). DMD subjects with LVEF<55% had increased MMP1 and MMP1/TIMP1 ratio compared with DMD subjects with LVEF≥55% and controls (Fig1). MMP1 and MMP1/TIMP ratio were also higher in DMD subjects with LGE compared to both DMD subjects without LGE and controls (Fig1). MMP9 correlated inversely with indexed LV mass (r=-0.37, p=0.017).
Conclusions: MMPs and TIMPs are involved in the progression of cardiac dysfunction in patients with DMD, likely through myocardial remodeling and fibrosis. MMP1 and the MMP1/TIMP1 ratio have potential as cardiac markers of DMD cardiomyopathy.
Author Disclosures: J.H. Soslow: None. K. Crum: None. W.B. Burnette: None. Y. Su: None. K. Tomasek: None. B.M. Damon: None. L.W. Markham: None.
- © 2016 by American Heart Association, Inc.