Abstract 16062: Circulating Matrix Metalloproteinases Mark Pathologic Right Ventricular Remodeling in Tetralogy of Fallot
Background: Right ventricular (RV) remodeling in tetralogy of Fallot (TOF) is associated with sudden arrhythmic death and congestive heart failure. Plasma matrix metalloproteinases (MMPs) can reflect cardiac fibrosis, which is linked to these same outcomes. We hypothesized RV remodeling could be assessed in plasma using multiple biomarkers associated with the MMP pathway.
Methods: Indices of RV remodeling, including QRS duration (ECG) and cardiac MRI-quantified RV end-diastolic volume(RVEDV), RV mass, and ejection fraction(RVEF) were measured in TOF patients (median age 28[25%-75% range 23-46 yrs]) who had undergone transannular patch repair alone (TAP, N=40) or following pulmonary valve replacement (PVR, N=12). Plasma collected at the time of CMRI was measured for multiple MMP, TIMP (tissue inhibitor of MMP), and related proteins with individual or multiplexed ELISA. Differences between TAP and PVR were assessed non-parametrically. Multivariable linear regression was used to show the relations between RV remodeling indices and plasma MMP/fibrosis, adjusted for multiple comparisons, and significant MMPs were added to clinical predictor models. Analytes are reported in ng/mL and standardized regression estimates are given.
Results: TAP patients had higher MMP2 (TAP median 172[25%-75% range 144-213] vs PVR 138[117-153], P=0.002) and MMP9 (TAP 29[24-43] vs PVR 22[21-28], P=0.03), but lower MMP3 (TAP 10[7-12] vs PVR 15[14-17], P=0.02). Increasing QRS duration was significantly related to decreasing MMP9 (b -0.32, P=0.005) independent of RVEDV, RV mass, and LV mass. Lower angiostatin (produced from plasminogen by MMP9), was also associated with QRS duration (b -0.30, P=0.01). Increasing RV mass was directly associated with higher with MMP3 concentrations (b 0.24, P=0.02), independent of body surface area, RVEDV, or RVEF.
Conclusions: Plasma concentrations of specific MMPs are independent markers of and implicate abnormal matrix turnover in the progression of pathologic TOF RV remodeling. Future work is needed to determine the ability of these indices to quantify matrix turnover and RV fibrosis, and whether specific interventions (e.g. PVR or drugs that alter remodeling) alter the MMP axis and thereby change outcome in TOF.
- © 2010 by American Heart Association, Inc.