期刊
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
卷 304, 期 10, 页码 H1314-H1327出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpheart.00776.2012
关键词
ventricles; remodeling; congenital; heart failure; right ventricle
资金
- National Heart, Lung, and Blood Institute [HL-061535]
- Children's Heart Center Research Fund
- Lucile Packard Children's Hospital
- Stanford University
- Children's Heart Foundation
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 down-regulated. 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-alpha, transforming growth factor-beta(1) (TGF-beta(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-beta signaling, ECM remodeling, and apoptosis.
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