Retrospective studies suggest that statins might exert an antiarrhythmic effect on the heart. The mechanism of this effect is unclear. Parasympathetic stimulation of the heart has been shown to protect against ventricular arrhythmias. The goal of this study was to determine the effect of statins on ventricular arrhythmias and its correlation with changes in parasympathetic responsiveness and Gα i2 expression. Patients were randomized to pravastatin and simvastatin in a double-blind crossover design. Ventricular arrhythmias were determined by analysis of 24-hour Holter recordings. Spectral RR interval analysis of Holter studies determined peak high-frequency power fraction, which reflects parasympathetic modulation of heart rate. Expression of Gα i2 , a molecular component of the parasympathetic response pathway, was determined by Western blots of patients’ lymphocytes. Pravastatin treatment decreased the incidence of ventricular premature complexes by 22.5 ± 3.4% (n = 20, p <0.05), couplets, and runs of 3 to 6 beats of nonsustained ventricular tachycardia from 9.8 ± 2.67 to 3.9 ± 1.25 events/patient/24 hours (n = 12, p <0.05). Pravastatin increased peak high-frequency fraction by 29.8 ± 4.3% (n = 33, p <0.001), while Gα i2 expression increased by 51.3 ± 22.5% (n = 21, p <0.05). Effects of simvastatin on ventricular premature complexes and nonsustained ventricular tachycardia were not significant. Relative changes in couplets and nonsustained ventricular tachycardia in pravastatin-treated patients correlated negatively with changes in Gα i2 and high-frequency fraction (ρ = −0.588 and ρ = −0.763, respectively, n = 12, p <0.05). In conclusion, these data suggest that pravastatin might decrease cardiac irritability via an increase in parasympathetic responsiveness and that changes in Gα i2 expression might serve as a molecular marker for this effect, which might play a role in the molecular mechanism of the antiarrhythmic effect of statins.
Several retrospective studies have suggested that statins might exert an antiarrhythmic effect on the heart. The mechanism for this proposed antiarrhythmic effect of statins is unclear. Data from animal and clinical studies support the hypothesis that parasympathetic stimulation protects the heart from the development of ventricular arrhythmias. Recent studies have also demonstrated that an increase in expression of Gα i2 , a molecular component of the parasympathetic signaling pathway in the heart, resulted in reduced arrhythmogenicity of catecholamines in pacing-induced heart failure in dogs. Although ventricular irritability as demonstrated by the occurrence of spontaneous ventricular premature complexes (VPCs), couplets, and short runs of nonsustained ventricular tachycardia (NSVT) lacks prognostic significance in structurally normal hearts, it does reflect the level of excitability of the ventricle. We had previously suggested that treatment of patients with pravastatin resulted in an increase in the response of the heart to parasympathetic stimulation in association with an increase in the expression of Gα i2 in lymphocytes from these patients. However, the relevance of these observations to cardiac excitability could not be addressed because of the absence of any significant numbers of spontaneous VPCs or runs of NSVT in this homogenous Korean population. Given data supporting the protective effect of parasympathetic stimulation of the heart from the development of ventricular arrhythmias, the goal of the present study was to determine whether statins might decrease ventricular irritability in a heterogenous population of Americans who demonstrated significant levels of spontaneous VPCs and brief runs of NSVT during a period of 24 hours of Holter monitoring and whether this effect correlated with an increase in parasympathetic responsiveness and an increase in Gα i2 expression. Furthermore, because it had been suggested that hydrophobic and hydrophilic statins might exert differential effects, we determined the effect of simvastatin and pravastatin on the incidence of ventricular ectopic complexes.
Methods
The study was a double-blind, randomized crossover study of the effects of pravastatin and simvastatin on the incidence of VPCs and ventricular arrhythmias and its correlation with changes in parasympathetic response of the heart, in which each patient served as his or her own control ( Figure 1 ). The 2 drugs were reconstituted into identical capsules by the research pharmacy staff. Blinding was maintained throughout the analysis of the Holter data, including the analysis of arrhythmias and the Western blot analysis of Gα i2 in lymphocyte extracts. After giving informed consent, pretreatment baseline values were obtained ( Figure 1 ); blood was drawn for fasting baseline lipid profiles and liver enzymes. A baseline ambulatory 24-hour surface electrocardiogram was recorded using a Hi-Res Cassette Holter Performer Model 9900 (Applied Cardiac Systems, Laguna Hills, California). Total cholesterol, high-density lipoprotein, and triglycerides were determined enzymatically using a Beckman DXC automated analyzer (Beckman Coulter, Inc., Fullerton, California). Low-density lipoprotein (LDL) cholesterol was calculated as total cholesterol − (triglycerides/5 + high-density lipoprotein) for triglycerides <400 mg/dl. Patients were randomized to either pravastatin 40 mg or simvastatin 20 mg for 8 weeks, followed by crossover to the second drug for 10 weeks ( Figure 1 ). Lipid profiles, Holter recordings, and blood for lymphocytes were obtained at baseline, before crossover, and at the completion of the study. The study was approved by the institutional review board of each participating center and performed according to Good Clinical Practice standards and the principles of the Declaration of Helsinki and its subsequent amendments. Written informed consent was provided by all patients before enrollment in the study.
