Elsevier

Heart Rhythm

Volume 6, Issue 1, January 2009, Pages 69-75
Heart Rhythm

Original-experimental
Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia

https://doi.org/10.1016/j.hrthm.2008.10.004Get rights and content

Background

Significant cardiac neural and electrophysiologic remodeling occurs with hypercholesterolemia (HC). Whether simvastatin can reverse HC-induced remodeling is unclear.

Objective

The purpose of this study was to determine the mechanisms underlying the antiarrhythmic effects of statins.

Methods

Rabbits (N = 38) were fed HC chow (HC), standard chow (Control), HC chow followed by standard chow (Withdrawal), or HC chow and simvastatin (Statin) for 8 weeks. The hearts then were Langendorff-perfused for electrophysiologic studies. Nerves were identified by immunostaining of growth-associated protein-43 (GAP43) and tyrosine hydroxylase (TH). Action potential duration (APD) restitution in normal hearts with (N = 5) and without (N = 5) simvastatin therapy also was studied.

Results

Serum cholesterol levels (mg/dL) were 1,855 ± 533 in HC, 50 ± 21 in Control, 570 ± 115 in Withdrawal, and 873 ± 112 in Statin groups (P <.001). Compared with HC (16,700 ± 5,342; 12,200 ± 3,878 μm2/mm2), the Statin group had significantly reduced GAP43-positive (10,289 ± 3,393 μm2/mm2, P = .03) and TH-positive (7,685 ± 2,959 μm2/mm2, P = .04) nerve density, respectively. APD was longer in HC rabbits than in controls (192 ± 20 ms vs 174 ± 17 ms; P <.03). Withdrawal and Statin groups had less APD prolongation than HC group. Statin group has less repolarization heterogeneity than HC group (P <.01). Statin therapy flattened the slope of APD restitution in normal hearts. Ventricular fibrillation was either induced or occurred spontaneously in 79% of hearts in HC, 20% in Control, and 66% in Withdrawal groups. However, there was no VF in hearts of Statin group (P <.001).

Conclusion

Simvastatin significantly reduced vulnerability to ventricular fibrillation via the mechanism of reduction of HC-induced neural and electrophysiologic remodeling.

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.

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