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Spontaneous Aortic Regurgitation and Valvular Cardiomyopathy in Mice

Authors :
Robert M. Weiss
Kathy Zimmerman
Melissa K Davis
Robert M. Brooks
Donald D. Heistad
Gary L. Baumbach
Hardik Doshi
Donald D. Lund
Biyi Chen
Nathan D. Funk
Ramzi El Accaoui
Long-Sheng Song
Tariq Hameed
Georges P. Hajj
Yi Chu
Leslie A. Leinwand
Jason A. Magida
Source :
Arteriosclerosis, thrombosis, and vascular biology. 35(7)
Publication Year :
2014

Abstract

Objective— We studied the mechanistic links between fibrocalcific changes in the aortic valve and aortic valve function in mice homozygous for a hypomorphic epidermal growth factor receptor mutation (Wave mice). We also studied myocardial responses to aortic valve dysfunction in Wave mice. Approach and Results— At 1.5 months of age, before development of valve fibrosis and calcification, aortic regurgitation, but not aortic stenosis, was common in Wave mice. Aortic valve fibrosis, profibrotic signaling, calcification, osteogenic markers, lipid deposition, and apoptosis increased dramatically by 6 and 12 months of age in Wave mice. Aortic regurgitation remained prevalent, however, and aortic stenosis was rare, at all ages. Proteoglycan content was abnormally increased in aortic valves of Wave mice at all ages. Treatment with pioglitazone prevented abnormal valve calcification, but did not protect valve function. There was significant left ventricular volume overload, hypertrophy, and fetal gene expression, at all ages in Wave mice with aortic regurgitation. Left ventricular systolic function was normal until 6 months of age in Wave mice, but became impaired by 12 months of age. Myocardial transverse tubules were normal in the presence of left ventricular hypertrophy at 1.5 and 3 months of age, but became disrupted by 12 months of age. Conclusions— We present the first comprehensive phenotypic and molecular characterization of spontaneous aortic regurgitation and volume-overload cardiomyopathy in an experimental model. In Wave mice, fibrocalcific changes are not linked to valve dysfunction and are epiphenomena arising from structurally incompetent myxomatous valves.

Details

ISSN :
15244636
Volume :
35
Issue :
7
Database :
OpenAIRE
Journal :
Arteriosclerosis, thrombosis, and vascular biology
Accession number :
edsair.doi.dedup.....de78f145e78b7063dec6dc77a70a8a45