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1.  Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia 
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.
doi:10.1016/j.hrthm.2008.10.004
PMCID: PMC2757294  PMID: 19121803
Arrhythmia; Statin; Lipids; Nervous system; Pathology

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