title: Physiologic and molecular characterization of a murine model of right ventricular volume overload.
abstract: Pulmonary insufficiency (PI) is a common long-term sequel after repair of tetralogy of Fallot, causing progressive right ventricular (RV) dilation and failure. We describe the physiologic and molecular characteristics of the first murine model of RV volume overload. PI was created by entrapping the pulmonary valve leaflets with sutures. Imaging, catheterization, and exercise testing were performed at 1, 3, and 6 mo and compared with sham controls. RNA from the RV free wall was hybridized to Agilent whole genome oligonucleotide microarrays. Volume overload resulted in RV enlargement, decreased RV outflow tract shortening fraction at 1 mo followed by normalization at 3 and 6 mo (39 ± 2, 44 ± 2, and 41 ± 2 vs. 46 ± 3% in sham), early reversal of early and late diastolic filling velocities (E/A ratio) followed by pseudonormalization (0.87 ± 0.08, 0.82 ± 0.08, and 0.96 ± 0.08 vs. 1.04 ± 0.03; P < 0.05), elevated end-diastolic pressure (7.6 ± 0.7, 6.9 ± 0.8, and 7 ± 0.5 vs. 2.7 ± 0.2 mmHg; P < 0.05), and decreased exercise duration (26 ± 0.4, 26 ± 1, and 22 ± 1.3 vs. 30 ± 1.1 min; P < 0.05). Subendocardial RV fibrosis was evident by 1 mo. At 1 mo, 372 genes were significantly downregulated. Mitochondrial pathways and G protein-coupled receptor signaling were the most represented categories. At 3 mo, 434 genes were upregulated and 307 downregulated. While many of the same pathways continued to be downregulated, TNF-α, transforming growth factor-β(1) (TGF-β(1)), p53-signaling, and extracellular matrix (ECM) remodeling transitioned from down- to upregulated. We describe a novel murine model of chronic RV volume overload recapitulating aspects of the clinical disease with gene expression changes suggesting early mitochondrial bioenergetic dysfunction, enhanced TGF-β signaling, ECM remodeling, and apoptosis.
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA. sureddy@stanford.edu
authors.forename: Sushma
authors.initials: S
authors.lastname: Reddy
authors.forename: Mingming
authors.initials: M
authors.lastname: Zhao
authors.forename: Dong-Qing
authors.initials: DQ
authors.lastname: Hu
authors.forename: Giovanni
authors.initials: G
authors.lastname: Fajardo
authors.forename: Ethan
authors.initials: E
authors.lastname: Katznelson
authors.forename: Rajesh
authors.initials: R
authors.lastname: Punn
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Spin
authors.forename: Frandics P
authors.initials: FP
authors.lastname: Chan
authors.forename: Daniel
authors.initials: D
authors.lastname: Bernstein
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D006328:Cardiac Catheterization; D003251:Constriction, Pathologic / Q000503:physiopathology; D004452:Echocardiography; D004562:Electrocardiography; D005260:Female; D005333:Fetus / Q000378:metabolism; D005355:Fibrosis; D015870:Gene Expression / Q000502:physiology; D054144:Heart Failure, Diastolic / Q000000981:diagnostic imaging / Q000503:physiopathology; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D032342:Muscle Cells / Q000473:pathology; D009206:Myocardium / Q000473:pathology; D010807:Physical Endurance / Q000502:physiology; D005082:Physical Exertion / Q000502:physiology; D011247:Pregnancy; D011651:Pulmonary Artery / Q000502:physiology; D012313:RNA / Q000096:biosynthesis / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013318:Stroke Volume / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D018497:Ventricular Dysfunction, Right / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*
chemical_list: D016159:Tumor Suppressor Protein p53; D012313:RNA
keywords: congenital; heart failure; remodeling; right ventricle; ventricles