Abstract 12205: Cellular and Morphologic Changes Typical for Calcific Aortic Stenosis Produce Predominant Aortic Regurgitation in EgfrWa2/Wa2 Mice
Background: The epidermal growth factor receptor (EGFR) mediates cardiac semilunar valvulogenesis, and postnatal responses to cardiovascular stress. EgfrWa2/Wa2 mice have a 90% reduction in EGFR activity, aortic valve (AoV) cusp redundancy, and postnatal fibrocalcific changes, whereas EgfrWa2/+ mice are normal.
Hypothesis: Fibrocalcific AoV disease causes valvular heart disease in EgfrWa2/Wa2 mice.
Methods and Results: Moderate or severe AoV regurgitation (echo, MRI) was present in 80% of EgfrWa2/Wa2 mice (background strain: C57BL/6J) by age 6 months (N = 18; regurgitant fraction = 46 ± 12% [mean ± SE]) vs. 0%* of EgfrWa2/+ mice (N = 24) (*p < 0.05, EgfrWa2/Wa2 vs. EgfrWa2/+). Severe AoV stenosis (echo) was present in only 5% of EgfrWa2/Wa2 mice and 0% of EgfrWa2/+ mice. Peak LV/Ao systolic gradient (cath) was 27 ± 9 mmHg (range 3 - 65) in EgfrWa2/Wa2 mice vs. 2 ± 1* mmHg in EgfrWa2/+ mice. AoV systolic orifice dimension (echo) was similar for EgfrWa2/Wa2 and EgfrWa2/+ mice (1.1 ± 0.1 vs. 1.2 ± 0.1 mm, p = NS). LV/Ao systolic gradient > 20 mmHg, in the absence of reduction of systolic AoV orifice, occurred in 75%* of EgfrWa2/Wa2 mice vs. 0 EgfrWa2/+ mice. LV/Ao gradient correlated with AoV regurgitant fraction and LV stroke volume (LVSV) (r = 0.87* and 0.90*, respectively). We identified an LVSV threshold of 1.5 µL/mg BW, above which significant LV/Ao gradients arose. By age 12 months, EgfrWa2/Wa2 mice developed 2-fold increase in LV end-diastolic volume* and mass*, 28% decrease in LVEF*, and 25% increase in aortic root diameter*. EgfrWa2/Wa2 AoV demonstrated > 10-fold increase in osteogenic markers, osterix* and osteocalcin*, and > 25-fold increase in calcification*. Pro-fibrotic markers, TGF-β* and pSMAD2*, and valve collagen* were all increased > 3-fold in EgfrWa2/Wa2 AoV. Apoptosis was increased 11-fold* in EgfrWa2/Wa2 AoV.
Conclusions: Reduction of EGFR activity produces severe fibrocalcific AoV disease, and elevated transvalvular gradients in mice. Whereas those findings are frequently considered pathognomonic for AoV stenosis, the predominant functional phenotype is AoV regurgitation and volume-overload cardiomyopathy in EgfrWa2/Wa2 mice. These findings may have implications in clinical diseases where EGFR inhibition is a therapeutic target.
- © 2012 by American Heart Association, Inc.