Hypercholesterolemia in minipigs impairs left ventricular response to stress: association with decreased coronary flow reserve and reduced capillary density.
BACKGROUND
Hypercholesterolemia induces functional and structural changes of the microvasculature and reduces coronary flow reserve in humans and experimental animals. The effect of hypercholesterolemia on left ventricular (LV) function in the absence of coronary stenosis is, however, unknown. Our objective was therefore to assess the effect of hypercholesterolemia and cholesterol withdrawal on LV function in the presence of advanced coronary plaques that do not cause stenosis.


RESULTS
Twenty-eight minipigs on cholesterol diet for 34 weeks and 16 control pigs were studied. Seven hypercholesterolemic pigs were withdrawn from the diet for 26 weeks. LV function was assessed with cine-MRI, myocardial blood flow with colored microspheres, and capillary density with immunohistochemistry, and microvascular endothelial cell apoptosis with terminal dUTP nick-end labeling staining. Hypercholesterolemia (17+/-8 versus 268+/-150 versus 12+/-10 mg/dL LDL cholesterol, control versus hypercholesterolemic versus cholesterol withdrawal; P<0.001) induced atherosclerosis but not stenosis in the left coronary artery. Baseline cardiac output, ejection fraction, and stroke volume were similar in control and hypercholesterolemic pigs. In dobutamine stress test, cardiac output (P<0.05) and stroke volume (P<0.01) were lower in hypercholesterolemic pigs compared with controls. The impaired response to dobutamine was reversible by dietary cholesterol withdrawal. Hypercholesterolemia reduced endomyocardial coronary flow reserve (P<0.01) and capillary density (P<0.05) and induced capillary endothelial cell apoptosis. Hypercholesterolemic pigs failed to reduce vascular resistance in response to increased LV workload and pharmacological vasodilation.


CONCLUSIONS
LDL hypercholesterolemia in minipigs impaired LV response to dobutamine stress in the absence of coronary stenosis.
Center for Molecular and Vascular Biology, Katholieke Universiteit Leuven, Leuven, Belgium.
Gregor
G
Theilmeier
Peter
P
Verhamme
Steven
S
Dymarkowski
Heike
H
Beck
Hilde
H
Bernar
Marleen
M
Lox
Stefan
S
Janssens
Marie-Christine
MC
Herregods
Erik
E
Verbeken
Désiré
D
Collen
Karl
K
Plate
Willem
W
Flameng
Paul
P
Holvoet
D000318:Adrenergic beta-Agonists; D000818:Animals; D017209:Apoptosis; D001161:Arteriosclerosis / Q000139:chemically induced / Q000473:pathology; D001783:Blood Flow Velocity; D001794:Blood Pressure / Q000187:drug effects; D002196:Capillaries / Q000473:pathology; D002452:Cell Count; D002791:Cholesterol, Dietary; D003326:Coronary Circulation; D004280:Dobutamine; D004730:Endothelium, Vascular / Q000473:pathology; D006937:Hypercholesterolemia / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D008055:Lipids / Q000097:blood; D019028:Magnetic Resonance Imaging, Cine; D008863:Microspheres; D013312:Stress, Physiological / Q000503:physiopathology*; D013556:Swine, Miniature; D014655:Vascular Resistance; D018487:Ventricular Dysfunction, Left / Q000150:complications / Q000175:diagnosis / Q000473:pathology / Q000503:physiopathology*
D000318:Adrenergic beta-Agonists; D002791:Cholesterol, Dietary; D008055:Lipids; D004280:Dobutamine