Abstract 18024: Physiologic and Molecular Characterization of a Murine Model of Pulmonary Insufficiency
Introduction: Pulmonary insufficiency (PI) is a common long-term outcome after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and eventual RV failure. We characterize the first murine model of PI, developed to evaluate the physiologic and molecular characteristics of the volume-loaded RV and its transition to heart failure.
Methods: PI was created by entrapping the pulmonary valve leaflets with 10-0 sutures placed across the valve annulus. Severe PI was defined by reverse Doppler flow into the branch pulmonary arteries and RV dilation. Echocardiography, ECG, exercise testing and catheterization were performed and compared to sham controls. RNA from the RV of PI, sham and pulmonary artery constriction (PS) mice was hybridized to Agilent whole-genome oligonucleotide microarrays to evaluate gene expression.
Results: Median time to RV dilation was 7 d (range 5-13 d). All PI mice had right bundle branch block (RBBB) on ECG. HR (523±39 vs. 458±60 bpm), RV weight (35±3 vs. 26±4 gm), RV stroke volume (0.45±0.14 vs. 0.29±0.03 ml), RVEDP (8±1.7 vs. 3±0.3 mmHg) and dP/dt (1063±164 vs. 632±107 mmHg/sec) were all increased in PI vs. sham. Furthermore, exercise capacity was decreased (25±2 vs. 28±0.5 min) despite normal LV function (FS 39±3 vs. 41±3%). 177 genes were differentially regulated in PI vs. sham (79 up- and 98 down-regulated, p<0.01, fold change >2). Ontologic analysis identified categories including extracellular matrix (ECM), stress fibers, anion transport and cell cycling. In contrast, only 41 genes (related to ECM, Wnt and Jun signaling) were common to both volume overload (PI) and pressure overload (PS) models.
Conclusion: We describe a novel murine model of PI demonstrating RV dilation, RBBB, increased RV stroke volume and RVEDP, and changes in exercise capacity prior to the development of overt heart failure. Altered gene expression was dominated by ECM pathways, a likely precursor to fibrosis and RV diastolic dysfunction. While pressure and volume overload-induced RV remodeling share many common pathways, the majority are distinct to PI and may represent novel therapeutic targets for RV failure in patients with congenital heart disease.
- © 2010 by American Heart Association, Inc.