title: Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia.
abstract: 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 microm(2)/mm(2)), the Statin group had significantly reduced GAP43-positive (10,289 +/- 3,393 microm(2)/mm(2), P = .03) and TH-positive (7,685 +/- 2,959 microm(2)/mm(2), 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).
  
  
  CONCLUSIONS
  Simvastatin significantly reduced vulnerability to ventricular fibrillation via the mechanism of reduction of HC-induced neural and electrophysiologic remodeling.
authors.affiliation: Department of Internal Medicine, Division of Cardiology, National Taiwan University Hospital and National Taiwan University School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Yen-Bin
authors.initials: YB
authors.lastname: Liu
authors.forename: Yuan-Teh
authors.initials: YT
authors.lastname: Lee
authors.forename: Hui-Nam
authors.initials: HN
authors.lastname: Pak
authors.forename: Shien-Fong
authors.initials: SF
authors.lastname: Lin
authors.forename: Michael C
authors.initials: MC
authors.lastname: Fishbein
authors.forename: Lan S
authors.initials: LS
authors.lastname: Chen
authors.forename: C Noel Bairey
authors.initials: CN
authors.lastname: Merz
authors.forename: Peng-Sheng
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000097:blood*; D022062:Electrophysiologic Techniques, Cardiac; D005260:Female; D005500:Follow-Up Studies; D006329:Heart Conduction System / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D006352:Heart Ventricles / Q000187:drug effects / Q000294:innervation* / Q000503:physiopathology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D006937:Hypercholesterolemia / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D007150:Immunohistochemistry; D011817:Rabbits; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome; D014693:Ventricular Fibrillation / Q000503:physiopathology / Q000517:prevention & control; D020257:Ventricular Remodeling / Q000187:drug effects* / Q000502:physiology
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D019821:Simvastatin