The Role of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Duchenne Muscular Dystrophy Cardiomyopathy.

BACKGROUND: Cardiomyopathy is the leading cause of death in Duchenne muscular dystrophy (DMD). Standard cardiac biomarkers are poor indicators of DMD cardiovascular disease. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) regulate collagen turnover. Given the cardiac fibrosis seen in DMD, we hypothesized that MMPs and TIMPs correlate with severity of DMD cardiomyopathy.

METHODS AND RESULTS: Prospectively enrolled DMD subjects (n=42) underwent cardiac MRI for function and late gadolinium enhancement (LGE), including LGE severity from 0 (no LGE) to 4 (severe). Serum from DMD and healthy male controls (n=15) analyzed for MMP 1, 2, 3, 7, 9, 10 and TIMPs 1-4. MMP1, MMP7, and MMP10 were higher in DMD than control (median 5080pg/ml vs. 2120pg/ml, p=0.007; 2170pg/ml vs. 1420pg/ml, p<0.001; 216pg/ml vs. 140pg/ml, p=0.040); TIMP4 was lower in DMD (124pg/ml vs. 263pg/ml, p=0.046). Within DMD, MMP7 correlated inversely with left ventricular ejection fraction (r=-0.40, p=0.012) and directly with strain (r=0.54, p=0.001) and LGE severity (r=0.47, p=0.003). MMP7 was higher in DMD patients with LGE compared to those without LGE and controls (p<0.001).

CONCLUSIONS: Multiple MMPs are elevated in DMD compared with controls. MMP7 is related to DMD cardiac dysfunction and myocardial fibrosis, possibly through remodeling of the extracellular matrix.