Abstract
Background: We previous showed statins could prevent or reverse cardiac nerve sprouting and sympathetic hyperinnervation induced by hypercholesterolemia (HC) in rabbit models. The significance and mechanisms are unclear. Methods and Results: We studied heart rate variability (HRV) and baroreflex sensitivity (BRS) in 23 rabbits with HC chow, standard chow (Control), or HC chow and atorvastatin. Myocardial content of nitrotyrosine, foam cell formation (RAM 11-positive cell) and serum high-sensitivity C reactive protein (hs-CRP) were measured in 56 rabbits fed with standard chow, HC chow or HC chow and atorvastatin. The status of Rac1 was also examined. The HRV and BRS were significantly reduced in HC rabbits (Control vs. HC; SDNN: 11.7±3.8 vs. 6.0±4.1 ms, p <0.01; RMSSD: 14.6±7.5 vs. 2.8±1.2 ms, p<0.001; LF/HF: 0.29±0.18 vs. 2.0±2.15, p <0.04; BRS: 8.5±4.6 vs. 2.2±2.2 ms/mmHg, p <0.01). Atorvastatin treatment prevented the decreases in HRV and BRS of HC rabbits (Statin, vs. HC; SDNN: 12.0±8.4 ms, p <0.1; RMSSD: 18.2±17.3 ms, p<0.02; LF/HF: 0.39±0.36, p=0.09; BRS: 11.2±4.8 ms/mmHg, p <0.01). Myocardial levels of nitrotyrosine were progressively increased while increasing the dietary cholesterol (Control: 0.34±0.01 nM; 0.25% HC: 0.68±0.04 nM; 0.5% HC: 1.15±0.25 nM; p<0.001). Following statin treatment, levels of nitrotyrosine were significantly reduced (p<0.001), and there was a dose-response relationship between the dosage of atorvastatin and myocardial nitrotyrosine levels. Myocardial RAM 11-positive cells and serum hs-CRP levels were increased in HC (Control vs. HC; RAM 11: 2.3±1.7 vs. 13.1±6.7 /microscopic field, p<0.01; hs-CRP: 1.6±1.0 vs. 7.7±5.2 mg/dl, p<0.01). Atorvastatin significantly reduced the levels of these inflammatory markers (p<0.05). In addition, atorvastatin administration significantly decreased the accentuated myocardial Rac1 expression in HC rabbits. Conclusion: HC rabbits have increased cardiac inflammation and heightened sympathetic tone. Atorvastatin significantly decreased the myocardial inflammation and reduced the cardiac sympathetic tone in HC rabbits. A reduction in myocardial Rac1 by atorvastatin may serve as a molecular mechanism for this reversing cardiac neural remodeling.
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