Abstract 15911: Myocardial Matrix Dysregulation Occurs Early in Infant Right Ventricular Pressure Ovleroad
Background: Right ventricular failure due to abnormal hemodynamic load is a frequent occurrence and critical determinant of long-term outcome in many forms of congenital heart disease and pulmonary hypertension. These experiments examined the potential contribution of changes in extracellular matrix (ECM) regulation to the development of RV contractile abnormalities.
Methods: Newborn rabbits (n = 6-10/group, 10 d.o.) underwent pulmonary artery banding (or sham surgery), serial echocardiography, and RV pressure-volume (P-V) analyses. RV myocardium was processed for qRT-PCR, immunoblotting, enzyme activity,, HPLC, and microscopy at 3, 4, and 8 weeks after banding (corresponding to early RVH, established RVH, and clinical RV failure, respectively).
Results: Despite development of RVH, RV dilation, and peripheral edema, load-independent, volume-adjusted P-V indices of RV systolic function were largely preserved until >8 weeks. In contrast, RV volume progressively increased (3-4 fold, P=0.03) along with significantly increased RV chamber capacitance (P=0.02); active RV diastolic relaxation (tau) was reduced at 8 weeks (P=0.009). Progression of RV dilation occurred in conjunction with increased expression and activation of multiple matrix metalloproteinases (MMPs–3, 7, 9, and 13: all 2-4 fold, P<0.04). RV angiostatin (MMP product and angiogenesis inhibitor) also increased while capillary density (quantitative lectin staining) was progressively reduced. Although total RV collagen increased modestly during RVH and dilation, the organization of RV collagen was markedly disrupted and fragmented (picrosirius red polarized microscopy). RV ATP and PCr concentrations were also significantly reduced at 8 weeks.
Conclusion: Early diastolic and delayed systolic RV dysfunction are characteristic of several forms of congenital heart disease associated with RV overload. This study for the first time indicates that dysregulation of RV ECM homeostasis resulting from increased MMP expression and collagen degradation is likely to play a prominent role in the initiation of adverse non-compensatory remodeling, RV dilation, abnormal chamber compliance, vascular rarefaction, and the development and progression of RV contractile dysfunction.
- © 2011 by American Heart Association, Inc.