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

Yen Bin Liu, Yuan Teh Lee, Hui Nam Pak, Shien Fong Lin, Michael C. Fishbein, Lan S. Chen, C. Noel Bairey Merz, Peng Sheng Chen

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18 Citations (Scopus)

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 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.

Original languageEnglish
Pages (from-to)69-75
Number of pages7
JournalHeart Rhythm
Volume6
Issue number1
DOIs
Publication statusPublished - 2009 Jan

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Liu, Y. B., Lee, Y. T., Pak, H. N., Lin, S. F., Fishbein, M. C., Chen, L. S., Merz, C. N. B., & Chen, P. S. (2009). Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia. Heart Rhythm, 6(1), 69-75. https://doi.org/10.1016/j.hrthm.2008.10.004