Arrhythmias and conduction disturbance
Differential Effects of Statins (Pravastatin or Simvastatin) on Ventricular Ectopic Complexes: Gαi2, a Possible Molecular Marker for Ventricular Irritability

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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 Gαi2 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 Gαi2, 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 Gαi2 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 Gαi2 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 Gαi2 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.

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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

Results

Forty-one patients were enrolled from a cohort of patients with risk-adjusted indications for the initiation of statin treatment who had never been treated with statins referred from outpatient general medical clinics: LDL ≥160 mg/dl with no risk factors or ≥130 mg/dl with 2 risk factors. All patients gave no history of cardiac symptoms and had normal results on physical examination and rest electrocardiography. Patients with myocardial infarctions within the past 4 months, diabetes mellitus,

Discussion

In the present study, we demonstrate that pravastatin treatment decreased the incidence of VPCs, couplets, and short runs of NSVT in a population of subjects with otherwise normal hearts, who had never been treated with statins before the study and were taking essentially no medications, but who demonstrated lipid profiles and risk factors that met the criteria for statin therapy. We further demonstrated that this decrease in spontaneous ventricular arrhythmias correlated with an increase in

Acknowledgment

We would like to acknowledge the invaluable assistance of Edward L. Decker, pharmacy clinical manager; Nassima Lamriben, pharmacy assistant; Terri Walsh for assistance in Holter studies; and Svati Shah for assistance in the recruitment of patients. We would like to acknowledge Eugene Braunwald for his insightful critique of this report.

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      The antiarrhythmic properties of statins appear to also extend to patients at high-risk for ventricular tachycardia and sudden cardiac death. In addition to their anti-ischemic effects, statins reduce ventricular irritability and increase myocardial parasympathetic responsiveness, which likely results in protection against ventricular arrhythmias in both ischemic and non-ischemic cardiomyopathy [41]. In a sub-study of the MADIT-II (Multicenter Automatic Defibrillator Implantation Trial II) trial [42], which included 654 patients with ischemic cardiomyopathy who underwent implantable cardioverter defibrillator placement, a Kaplan–Meier analysis revealed a 35% risk reduction for the combined endpoint of ventricular tachycardia, ventricular fibrillation, and/or sudden cardiac death in patients taking statins (p < 0.01).

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    This study was supported by an unrestricted grant from Bristol-Myers Squibb, New York, New York.

    Dr. Karas has received a research grant from AstraZeneca, Wilmington, Delaware, and is a member of the speakers bureau of Merck & Company, Whitehouse Station, New Jersey. Dr Estes: Tufts Medical Center has received educational grants from Boston Scientific Corporation, Natick, Massachusetts, Medtronic, Inc., Minneapolis, Minnesota and St. Jude Medical, Minneapolis, Minnesota, for EP fellowship funding. Dr. Estes serves on the Executive Committee of the MADIT-CRT and MADIT-RIT studies supported by Boston Scientific. No compensation. He has received honoraria for educational symposia from Boston Scientific.

    †

    Drs. Welzig and Park contributed equally to this work.

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