Simvastatin preserves myocardial perfusion and coronary microvascular permeability in experimental hypercholesterolemia independent of lipid lowering.
OBJECTIVES; This study was designed to assess the lipid-independent effects of simvastatin on myocardial perfusion (MP) and coronary microvascular permeability index (PI) at baseline and during episodes of increased cardiac demand in experimental hypercholesterolemia.


BACKGROUND
Simvastatin preserves coronary endothelial function in experimental hypercholesterolemia independent of its lipid-lowering effect. However, the functional significance of this observation is unknown.


METHODS
Pigs were randomized to three groups: normal diet (N), high-cholesterol diet (HC) and HC diet plus simvastatin (HC+S) for 12 weeks. Subsequently, cardiac electron beam computed tomography was performed before and during intravenous infusion of adenosine and dobutamine, and MP and PI were calculated.


RESULTS
Total and low density lipoprotein cholesterol levels were similarly and significantly increased in HC and HC+S animals compared with N. Basal MP was similar in all groups. Myocardial perfusion significantly increased in response to either adenosine or dobutamine in N and HC+S animals. Dobutamine also significantly increased MP in HC animals. However, the changes of MP in response to either drug were significantly lower in the HC group compared with the other two groups (p < 0.01 for adenosine and p < 0.05 for dobutamine vs. N and HC+S). Basal PI was similar in all groups and was not altered by either drug in N and HC+S animals. In contrast, PI significantly increased in HC pigs during infusion of either adenosine (p < 0.001) or dobutamine (p < 0.05).


CONCLUSIONS
These findings demonstrate that chronic administration of simvastatin preserves myocardial perfusion response and coronary microvascular integrity during cardiac stress in experimental hypercholesterolemia independent of lipid lowering.
Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Piero O
PO
Bonetti
Stephanie H
SH
Wilson
Martin
M
Rodriguez-Porcel
David R
DR
Holmes
Lilach O
LO
Lerman
Amir
A
Lerman
D000818:Animals; D000924:Anticholesteremic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001835:Body Weight / Q000502:physiology; D002199:Capillary Permeability / Q000187:drug effects*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D003331:Coronary Vessels / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000000981:diagnostic imaging / Q000188:drug therapy*; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000517:prevention & control*; D011897:Random Allocation; D019821:Simvastatin / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013318:Stroke Volume / Q000502:physiology; D013552:Swine; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014463:Ultrasonography
D000924:Anticholesteremic Agents; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin