BACKGROUND: Modulation of sympathetic tone may contribute to statin-mediated reduction in sudden cardiac death. We examined the effect of simvastatin on heart rate variability (HRV) in patients with non-ischemic dilated cardiomyopathy to evaluate for an antisympathetic effect of statins independent of anti-ischemic properties. METHODS: The study was a prospective, open-label, self-controlled trial. Frequency domain analysis of HRV was assessed in 25 patients with non-ischemic dilated cardiomyopathy at baseline and after a 6-week course of simvastatin. The primary end point was the change in 5-minute sitting total spectral power (TSP) as a composite measurement of autonomic nervous system modulation. Secondary end points included the change in respiratory frequency area (RFa) with deep breathing (parasympathetic stress) and in low-frequency area (LFa) with Valsalva (sympathetic stress). RESULTS: Simvastatin had no effect on 5-minute sitting TSP (baseline 1932 +/- 1165 vs posttreatment 2570 +/- 1877 square milliseconds, P = .770), RFa with deep breathing (baseline 19 +/- 7 vs posttreatment 14 +/- 4 [beat/min]2, P = .31), or LFa with Valsalva (baseline 26 +/- 6 vs posttreatment 32 +/- 8 [beat/min]2, P = .342). Bivariate analysis demonstrated no correlation between low-density lipoprotein (LDL) change and change in TSP or RFa, but did demonstrate an inverse relationship between change in LDL and change in LFa with Valsalva stress (r = -0.45 and P = .041). CONCLUSION: Although simvastatin did not change baseline HRV, a modest relationship exists between the extent of LDL reduction and sympathetic responsiveness to stress.