Biventricular adaptation to volume overload in mice with aortic regurgitation.
BACKGROUND
Aortic valve regurgitation is usually caused by impaired coaptation of the aortic valve cusps during diastole. Hypercholesterolemia produces aortic valve lipid deposition, fibrosis, and calcification in both mice and humans, which could impair coaptation of cusps. However, a link between hypercholesterolemia and aortic regurgitation has not been established in either species. The purpose of this study was to ascertain the prevalence of aortic regurgitation in hypercholesterolemic mice and to determine its impact on the left and right ventricles.


RESULTS
Eighty Ldlr-/-/Apob100/100/Mttpfl/fl/Mx1Cre+/+ ("Reversa") hypercholesterolemic mice and 40 control mice were screened for aortic regurgitation (AR) with magnetic resonance imaging at age 7.5 months. The prevalence of AR was 40% in Reversa mice, with moderate or severe regurgitation (AR+) in 19% of mice. In control mice, AR prevalence was 13% (p = 0.004 vs. Reversa), and was invariably trace or mild in severity. In-depth evaluation of cardiac response to volume overload was performed in 12 AR-positive and 12 AR-negative Reversa mice. Regurgitant fraction was 0.34 +/- 0.04 in AR-positive vs. 0.02 +/- 0.01 in AR-negative (mean +/- SE; p < 0.001). AR-positive mice had significantly increased left ventricular end-diastolic volume and mass and reduced ejection fraction in both ventricles. When left ventricular ejection fraction fell below 0.60 in AR-positive (n = 7) mice, remodeling occurred and right ventricular systolic function progressively worsened.


CONCLUSIONS
Hypercholesterolemia causes aortic valve regurgitation with moderate prevalence in mice. When present, aortic valve regurgitation causes volume overload and pathological remodeling of both ventricles.
Berry
Christopher J
CJ
University of Iowa Carver College of Medicine, Iowa City, USA. christipher-j-berry@uiowa.edu
Miller
Jordan D
JD
McGroary
KellyAnn
K
Thedens
Daniel R
DR
Young
Stephen G
SG
Heistad
Donald D
DD
Weiss
Robert M
RM
D000222:Adaptation, Physiological; D000818:Animals; D001022:Aortic Valve Insufficiency / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D053299:Apolipoprotein B-100 / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006937:Hypercholesterolemia / Q000150:complications* / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019028:Magnetic Resonance Imaging, Cine; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D012720:Severity of Illness Index; D013318:Stroke Volume; D016277:Ventricular Function, Left; D016278:Ventricular Function, Right; D020257:Ventricular Remodeling
D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D011973:Receptors, LDL; C106092:microsomal triglyceride transfer protein