Abstract 16165: Cardiac Overexpression of Membrane Type-1 Matrix Metalloproteinase Causes Left Ventricular Remodeling and Pump Dysfunction in Peripartum Cardiomyopathy
Introduction: Peripartum cardiomyopathy (PPCM) is a rare cause of heart failure (HF) in pregnancy. Like other forms of HF, left ventricular (LV) remodeling (LV dilation and LV pump dysfunction) occur with PPCM. The matrix metalloproteinases (MMPs) are implicated as a cause of adverse left ventricular (LV) remodeling and progression to HF. However, the role of MMPs in PPCM remains unclear. Within the class of membrane type MMPs, the subtype membrane type-1 MMP (MT1-MMP) is expressed in human myocardium and is known to be increased in HF. We tested the hypothesis that a causal relationship exists between myocardial overexpression of MT1-MMP and the development of PPCM.
Methods/Results: Pregnant transgenic mice designed to overexpress MT1-MMP (MT1OE; n=8) in cardiomyocytes and littermate wild-type (WT; n=8) and corresponding non-pregnant controls (n=6 each group) were used. MT1-MMP activity was higher in the non-pregnant MT1OE mice than in WT mice and further differentially increased with pregnancy (Fig, panel A). LV end-diastolic volume (LVEDV), LV ejection fraction (LVEF), and left atrial dimension (LAD) were measured (echo; Fig, panel B) at 7 day intervals throughout the peripartum period. Increased postpartum mortality (~25% by 2 weeks postpartum; Fig, panel C) in the MT1OE mice was accompanied by increased LVEDV and LAD, and reduction in LVEF. There was a significant correlation between MT1-MMP activity and LVEDV (r2= 0.45), LAD (r2=0.31) and a negative correlation to LVEF (r2=0.31; all p<0.01). In pregnant MT1OE mice administered an antibody against MT1-MMP (n=6), there was an attenuation of postpartum LV and LAD dilation with relative preservation of LVEF (Fig, panels B and C).
Conclusion: These unique findings suggest that increased MT1-MMP abundance and activity is a mechanism for LV dysfunction in the peripartum setting. These findings may present novel means for treatment of PPCM and may lead to new methods for patient screening and outcome prediction.
Author Disclosures: A.N. Franklin: None. S.L. Lieser: None. R.K. Patel: None. R.E. Stroud: None. J.A. Jones: Research Grant; Significant; VA Merit. A.W. Akerman: None. R. Mukherjee: None. J.S. Ikonomidis: Research Grant; Significant; NIH Grant.
- © 2014 by American Heart Association, Inc.