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Genetic modifiers prevent left ventricular hypertrophy in the Epidermal Growth Factor Receptor (Egfr/ErbB1) waved‐2 mouse model for aortic stenosis
Author(s) -
Barrick Cordelia Johnson,
Rojas Mauricio,
Smyth Susan,
Threadgill David
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a638-a
Subject(s) - left ventricular hypertrophy , medicine , muscle hypertrophy , epidermal growth factor receptor , pressure overload , cardiology , stenosis , risk factor , endocrinology , blood pressure , receptor , cardiac hypertrophy
Left ventricular hypertrophy (LVH) is an independent risk factor for cardiovascular morbidity and mortality. LVH associated with aortic stenosis (AS) is initially a beneficial adaptation to pressure overload. However, variation exists in the geometric distribution of LVH and cardiac compensation in patients with similar AS. Moreover up to 10% of patients with severe AS do not develop LVH. Several clinical risk factors influence LVH in AS, yet few genetic markers have been identified. Mice homozygous for the hypomorphic Egfr waved2 ( wa2 ) allele were reported to have AS on a mixed genetic background. We created C57BL/6J (B6), 129S1SvEv (129S1) and B6.129 (F1) Egfr wa2/wa2 mice to investigate the effect of genetic modifiers on the cardiac response to chronic AS. At three months of age, all Egfr wa2/wa2 mice have evidence of AS associated with similar transvalvular gradients (B6 Egfr wa2/wa2 33 ± 25.5, F1 Egfr wa2/wa2 19.4, 129 Egfr wa2/wa2 26.5 ± 11.2 mmHg) yet only B6 Egfr wa2/wa2 mice have enlarged, fibrotic hearts, hypertrophied cardiomyocytes, and a reduced lifespan. These mice also have severely reduced systolic function (% FS: 26± 3.7 vs. 41±2.82 Egfr wa2/+ ) and altered expression of classic hypertrophy markers. Despite having equivalent AS, neither 129S1 nor F1‐ Egfr wa2/wa2 mice develop histologic, functional, or molecular evidence of LVH and maintain normal systolic function (% FS: F1 Egfr wa2/wa2 40 ± 3.0, 129 Egfr wa2/wa2 41.3 ± 6.5). These results confirm the usefulness of this model to study AS and LVH. Additionally, identification of 129S1 genetic modifiers may prove useful for treatment of LVH. Supported by NIH 5‐R01‐CA092479‐01