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Plasma Proteolytic Profiles in Pediatric Dilated Cardiomyopathy
Tain-Yen Hsia, Jeremy M. Ringewald, Robert E. Stroud, Scott T. Reeves, Nidhi Kumar, Jeffrey A. Jones, *John S. Ikonomidis, Francis G. Spinale
Medical University of South Carolina, Charleston, SC
Objective: Dilated cardiomyopathy (DCM) is an important cause of heart failure and mortality in both children and adults. Furthermore, DCM is a more progressive disease process in children than in adults. However, the mechanistic explanation for this difference is unknown. In adult DCM, left ventricular remodeling is associated with changes in the myocardial levels of both matrix metalloproteinases (MMPs), and endogenous inhibitors of MMPs (TIMPs). Whether, and to what degree, changes in MMP/TIMP profiles exist in pediatric DCM has not been examined. Accordingly, the present study developed a low blood volume, high sensitivity assay to test the hypothesis that a unique and differential MMP/TIMP profile exists in pediatric DCM patients, which may serve as a biomarker signature for this disease process.
Methods: One ml of blood was obtained from pediatric patients with DCM (n=7, age 8±7 yrs), and 26 age-matched normal volunteers. Using a high throughput multiplex suspension immunoassay, plasma levels were quantified for the following MMP classes: gelatinases (MMP-2, -9), collagenases (MMP-8, -13), lysins (MMP-3, -7), and all 4 TIMPs. Ratios between the MMPs and TIMPs were calculated.
Results: Plasma MMP-2, -7, -8 and -9 levels were increased by >2-fold in DCM patients compared to normal controls (p<0.05; see Figure). DCM patients also had significantly higher levels of TIMP-1 and -4 (298% and 230% respectively; p<0.05). Furthermore, MMP-2/TIMP-2, MMP-7/TIMP-2, MMP-8/TIMP-2, MMP-9/TIMP-2, and MMP-9/TIMP-4 ratios in DCM patients were increased by 176-315% compared to normal controls (p<0.05).
Discussion: Pediatric DCM patients exhibit robust increases in plasma levels of a broad range of MMPs, having proteolytic activities against all components of the extracellular matrix. The increased MMP/TIMP ratios observed in pediatric DCM patients suggest a heightened proteolytic state, which could promote more progressive myocardial remodeling. Moreover, since TIMP-4 is cardiovascular specific, plasma MMP/TIMP-4 profiles could serve as a non-invasive biomarker for the degree of myocardial remodeling in pediatric DCM. These results demonstrate that MMP/TIMP profiling can be translated to pediatric patients, using a small volume-high sensitivity approach. MMP/TIMP profiling may provide a novel biomarker platform for screening, prognosis and treatment algorithms in pediatric DCM.  
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