Abstract 1250: Effects of Simvastatin on Neural and Electrophysiological Remodeling of Rabbits with Hypercholesterolemia
Significant cardiac neural and electrophysiological remodeling occurs in rabbits with hyper-cholesterolemia (HC). Whether or not simvastatin can reverse HC-induced proarrhythmic remodeling is unclear. We fed rabbits with (1) HC chow for 8 weeks (HC, N=15), (2) standard chow for 8 weeks (Control, N=10), (3) HC chow for 6 weeks followed by standard chow for 2 weeks (Withdrawal, N=6), and (4) HC chow and simvastatin 20mg/day for 8 weeks (Statin, N=7). The hearts were then Langendorff-perfused for electrophysiological studies.
Results: Serum cholesterol levels (mg/dl) were 1855±533 in HC, 50±21 in Control, 570±115 in Withdrawal and 873±112 in Statin groups (p<0.001 by ANNOVA). Densities of growth associated protein 43- (GAP43) and tyrosine hydroxylase- (TH) positive cardiac nerves, respectively, were significantly higher in Withdrawal (1.28±0.08 %; 0.74±0.09 %) and Statin (1.02±0.34 %; 0.77±0.3 %) groups than Control (0.49±0.15 %, p<0.02; 0.33±0.14 %, p<0.03). Compared with HC (1.67±0.53 %; 1.22±0.39%), Statin group had a significantly reduced GAP43-positive (p=0.03) and TH-positive (p=0.04) nerve density. The action potential duration (APD80) was significantly longer in HC rabbits than controls (192±20 vs. 174±17 ms; p<0.03). There is a 34% and 59% reduction in APD prolongation in Withdrawal and Statin groups, respectively, as compared with the HC group. Furthermore, heterogeneity of repolarization, represented as either the SD of APD at 100 points or the differences between the longest and shortest APD over the ventricular anterior wall, was significantly decreased in Statin group than that in HC group (SD: 4.4±1.1 vs. 8.3±3.1 ms, p<0.01; difference: 19.2±5.9 vs. 42.5±18.2 ms; p<0.01). Ventricular fibrillation (VF) 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<0.001).
Conclusion: In the rabbit model, simvastatin significantly reduced neural and electrophysiological remodeling induced by HC and reduced the vulnerability to VF. Because the Withdrawal group had lower cholesterol level than Statin group but continued to have inducible VF, the antiarrhythmic effects of simvastatin may not be attributed to cholesterol lowering alone.