Abstract 335: Murine Model of Chronic Right Ventricular Diastolic Heart Failure Is Associated with Energetic Alterations and Extracellular Matrix Remodeling
Introduction: Pulmonary insufficiency (PI) is a common long-term complication after repair of congenital heart diseases such as tetralogy of Fallot, causing progressive right ventricular (RV) dilation and eventual RV failure. We characterize the physiologic and molecular characteristics of the first murine model of RV volume overload
Methods: PI was created by entrapping the pulmonary valve leaflets with 2 sutures. Echo, MRI, catheterization and exercise testing were compared to sham controls at 1, 3 and 6 mos. RNA from RV free wall was hybridized to Agilent whole-genome microarrays.
Results: Data is presented as sham vs. PI at 1, 3 and 6 mos (*p<0.05). PI resulted in increased RV end-diastolic volume (5.6±1.4 vs. 8.7±2.5, 9.8±1.3, 10.5±1.1μ l*) and diastolic heart failure: early reversal of E/A ratio followed by pseudonormalization (1.04±0.07 vs. 0.87±0.15, 0.82±0.17 and 0.96±0.16*), elevated RV end-diastolic pressure (2.7±0.5 vs. 7.6±1.3, 6.9±1.6 and 7±1mmHg*) and decreased exercise capacity (30±2.3 vs. 26±0.8, 26±2 and 22±2.6min*). Systolic function (RV outflow tract shortening) was relatively preserved (49±6 vs. 39±4, 44±3 and 41±3%, p=NS). At 1 mo, 372 genes were downregulated, with metabolic pathways, including Complex I, III and V, and G protein-coupled receptor signaling being the most enriched. At 3 mos, 434 genes were upregulated featuring numerous collagen genes, while 307 were downregulated, including fatty acid transport and Ca2+ signaling. During this time course, pathways involving TGFβ signaling, extracellular matrix and p53 signaling transitioned from down- to up-regulated. Key hubs in upregulated gene networks were TGFβ1, thrombospondin1, VEGFa, TNFα and GSK3β while NFκB1 was a downregulated hub. RV Fibrosis increased over time (0 vs. 0.6±0.5, 5.9±2.9, 3.92±0.2%*).
Conclusion: We describe a novel murine model of chronic RV volume overload which recapitulates many aspects of clinical disease including RV dilation, impaired relaxation and decreased exercise capacity but preserved RV systolic function. Gene expression changes suggest mitochondrial bioenergetic dysfunction, ECM remodeling, enhanced TGF-β signaling and apoptosis. Many of these processes of RV diastolic heart failure are also known mechanisms of LV failure.
- © 2012 by American Heart Association, Inc.