Background: We have previously demonstrated in an in vitro model for lipid lowering, that lipoprotein depletion resulted in a marked increase in the negative chronotropic response to the acetylcholine analogue, carbamylcholine. Here we used heart rate variability analysis to determine the effect of lipid lowering by statins on the response of the heart to parasympathetic stimulation. In parallel, we examined whether changes in parasympathetic responsiveness correlated with changes in the expression of G慣i2, a molecular component of the parasympathetic signaling pathway in the heart. Methods and Results. Patients were randomized in a crossover study of pravastatin and simvastatin. R-R interval analysis of Holter monitor studies demonstrated that in patients treated initially with pravastatin the peak high frequency power fraction during sleep, which reflects parasympathetic modulation of heart rate, increased by 24.0짹5.02% (SEM, n=13, P<0.001) compared to the untreated control value. Simvastatin had no significant effect. Western blot analysis of lymphocytes from patients treated with pravastatin demonstrated a 90.1짹27.3% (n=10, P=0.009) increase in G慣i2 expression, while simvastatin had no effect. Relative changes in Gai2 correlated significantly with the changes in the fraction of high frequency power (��=0.574, P=0.016). Conclusions. These data are the first to suggest that cholesterol lowering by pravastatin might increase the response of the heart to parasympathetic stimulation and that changes in Gai2 expression might serve as a molecular marker for this effect.