Abstract 11375: Hyperlipidemia and Angiotensin-Mediated Hypertension Act Synergistically to Produce Aortic Valve Stenosis in Mice
Hypercholesterolemia (HC) increases risk for aortic stenosis (AS) in humans and mice. Hypertension (HT) increases risk for human AS, but its effects on aortic valve structure and function in mice have not been established.
Objective: to assess mechanisms of aortic valve remodeling and aortic valve dysfunction in HC and HT mice. We studied Control mice (total cholesterol [Chol] = 89 ± 13 mg/dl [mean ± SE], systolic blood pressure [SBP] = 114 ± 2 mmHg), HC Apoe-/- mice (Chol = 399 ± 19 mg/dl), HT mice (SBP = 148 ± 8 mmHg) due to overexpression of human renin + angiotensinogen, and mice with both HC and HT (HC/HT) (Chol = 357± 20 mg/dl, SBP = 151 ± 6 mmHg).
Results: At 9 mo. of age, calcification and fibrosis, assessed using quantitative histology, were similar in aortic valves of HC/HT, HC, and HT (p = NS). However, collagenous sites of cusp attachment to the valve annulus were selectively enlarged 2-fold (*p < 0.05) in HC/HT mice, compared to HC, HT, or control mice. There was greater intercusp raphe formation in HC/HT mice (histologic raphe length = 0.47 ± 0.04 mm* in HC/HT vs. 0.31 ± 0.01 in HC, 0.26 ± 0.01 in HT, and 0.21 ± 0.01 in Control). Cusp size was less symmetric in HC/HT mice than in HC, HT, and control mice. Right cusp/noncoronary cusp area ratio was 2.2 ± 0.5* in HC/HT vs. 1.0 ± 0.1 in all other mice. Disruption of valve annulus elastic fibers was greater in HC mice and HC/HT mice than in HT and Control mice (remodeling scores = 1.8 + 0.2*, 1.8 ± 0.2*, 0.1 ± 0.1, and 0.1 ± 0.1, respectively). Systolic aortic cusp separation (ACS, echocardiography) was 1.24 ± 0.03 mm in Control, 1.13 ± 0.03 in HC, 1.18 ± 0.06 in HT, vs. 0.84 ± 0.11* in HC/HT. Using a hemodynamically validated criterion (ACS ≤ 0.66 mm), prevalence of severe AS was 33%* in HC/HT mice, vs. 0% in all other groups. Significant aortic regurgitation was not present in any mice. Left ventricular mass was 242 ± 37* mg in HC/HT vs. 160 ±16 mg in HT mice, despite similar blood pressures, consistent with the presence of aortic stenosis in HC/HT mice.
Conclusions: Neither HC alone nor HT alone is sufficient to produce aortic stenosis by 9 mo. of age in mice. HC and HT combine synergistically to produce structural remodeling of the aortic valve annulus and cusp attachment loci, and aortic stenosis with cardiomyopathy, in HC/HT mice.
- © 2013 by American Heart Association, Inc.