Hypercholesterolemia and Angiotensin‐Mediated Hypertension Act Synergistically to Produce Aortic Stenosis in Middle‐Aged Mice

Hypercholesterolemia is a risk factor for aortic valve stenosis (AS) in humans and mice. Hypertension is a risk factor for AS in humans, but its effect on aortic valve function in mice is not known. Hypercholesterolemia and angiotensin‐mediated hypertension each induce oxidative stress, which is a putative mediator of aortic valve disease. We hypothesize that angiotensin‐mediated hypertension amplifies the effect of hypercholesterolemia on aortic valve function in mice. Four groups of mice (n=8–11 each) underwent assessment of aortic valve systolic dimension by echocardiography at age ~12 mo.: wild‐type (WT); apolipoprotein E null (apoE−/−, serum cholesterol ~500mg/dl); renin+angiotensinogen transgenic mice (R+A+, increased mean arterial pressure ~40mmHg); and apoE−/−R+A+. In WT mice, aortic valve systolic dimension was 1.05±0.04 mm, while in apoE−/− mice it was 0.97±0.06mm (p=NS). In R+A+ mice, aortic valve systolic dimension was 1.13±0.06 mm (p=NS vs. WT or apoE−/−). In apoE−/−R+A+, aortic valve systolic dimension was 0.69±0.05mm (p≤0.002 vs. WT, apoE−/− or R+A+). Using a criterion of aortic valve systolic dimension ≤0.66mm, which we have hemodynamically validated in mice, 6/11 hypercholesterolemic‐hypertensive mice developed severe AS vs . 0/24 mice in the other 3 groups; p<0.001. We conclude that at age 12 mo., when neither hypercholesterolemia nor angiotensin‐mediated hypertension alone produces hemodynamically significant aortic valve disease, the combination acts synergistically to produce severe AS in mice. These findings emphasize the importance of interactions between risk factors that result in the complex phenotype of aortic valve stenosis, in an experimental model with clinical relevance.