Original-experimentalEffects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia
Introduction
Hypercholesterolemia (HC) in rabbits produces significant cardiac proarrhythmic neural and electrical remodeling.1, 2, 3, 4 Dyslipidemia increases the incidence of ventricular tachycardia/ventricular fibrillation (VT/VF) after acute myocardial infarction.5 Lipid-lowering therapy using statins reduces VT/VF in patients with an implantable cardioverter-defibrillator (ICD).6, 7 Furthermore, statin use was associated with a significant reduction in sudden cardiac death in addition to preventing VT/VF.7, 8 Many other studies also found that statin use improved surrogate markers of arrhythmic risk in a population at certain risk for arrhythmic events.9, 10 These findings support the notion that statin use is antiarrhythmic. However, the mechanisms by which statins are antiarrhythmic remain unclear. Our previous study indicated that HC in rabbits can induce significant proarrhythmic neural and electrophysiologic remodeling.1 Therefore, we hypothesize that statin is antiarrhythmic because it reverses the proarrhythmic remodeling induced by HC. The purpose of the present study was to test this hypothesis.
Section snippets
Methods
All animal study protocols were approved by the Animal Care and Use Committee and conformed to the guidelines of the American Heart Association. Three-month-old female New Zealand white rabbits were used for the study. Total serum cholesterol and triglyceride levels were determined before the animals were sacrificed.
Results
Table 1 summarizes the serum cholesterol and triglyceride concentrations in the first four groups. Serum cholesterol levels were significantly higher in the HC group than in the Control group. Statin treatment resulted in a 53% reduction in serum cholesterol levels compared with the HC group (P <.001). The cholesterol levels in Statin group were significantly higher than in the Withdrawal group. There were no significant differences of serum triglyceride levels among the four groups.
Discussion
This study shows that simvastatin significantly reduced neural and electrophysiologic remodeling induced by HC and reduced vulnerability to VF. Because the Withdrawal group had a lower cholesterol level than the Statin group but continued to have inducible VF, these data suggest that the antiarrhythmic effects of simvastatin may not be attributed to cholesterol-lowering effects alone.
Acknowledgements
We thank Tsai-Tzu Wu, Nina Wang, and Elaine Lebowitz for assistance.
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This study was supported by National Science Foundation (Taiwan) Grant NSC 93-2314-B-002-204 and NSC 94-2314-B-002-204 to Dr. Liu; a Piansky endowment to Dr. Fishbein; an endowment from The Women's Guild of Cedars-Sinai Medical Center, Los Angeles, California, to Dr. Bairey Merz; a Pauline and Harold Price endowment to Dr. Chen; a grant from Merck Inc.; NIH Grants P50 HL52319, HL66389, and HL71140; and the Ralph M. Parsons Foundation, Los Angeles, California. Merck Inc. donated the simvastatin and provided a research grant that partially supported this study.