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Effects of simvastatin on cardiac neural and electrophysiologic remodeling in rabbits with hypercholesterolemia
Yen-Bin Liu1, Yuan-Teh Lee, Hui-Nam Pak
1Department of Internal Medicine, Division of Cardiology, National Taiwan University Hospital and National Taiwan University School of Medicine, UCLA, Los Angeles, California, USA.
Insights
Simvastatin effectively reverses hypercholesterolemia-induced cardiac remodeling, significantly reducing ventricular fibrillation risk. This study reveals simvastatin
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Cardiac Electrophysiology
Background:
- Hypercholesterolemia (HC) causes significant cardiac neural and electrophysiologic remodeling.
- The potential of simvastatin to reverse HC-induced remodeling remains unclear.
Purpose of the Study:
- To investigate the mechanisms behind the antiarrhythmic effects of statins.
- To determine if simvastatin can reverse cardiac remodeling caused by hypercholesterolemia.
Main Methods:
- Rabbits were divided into four groups: hypercholesterolemia (HC), control, withdrawal from HC, and simvastatin treatment.
- Hearts underwent Langendorff-perfusion for electrophysiologic studies.
- Cardiac nerve density was assessed using immunostaining for GAP43 and TH.
Main Results:
- Simvastatin treatment significantly reduced serum cholesterol and cardiac nerve density (GAP43 and TH positive areas).
- Simvastatin therapy lessened action potential duration prolongation and repolarization heterogeneity in HC rabbits.
- No ventricular fibrillation (VF) occurred in the simvastatin group, compared to 79% in the HC group.
Conclusions:
- Simvastatin effectively reduces vulnerability to ventricular fibrillation.
- The antiarrhythmic effect is mediated by reducing HC-induced neural and electrophysiologic remodeling.
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).
Conclusion:
Simvastatin significantly reduced vulnerability to ventricular fibrillation via the mechanism of reduction of HC-induced neural and electrophysiologic remodeling.
