Elsevier

Heart Rhythm

Volume 4, Issue 5, May 2007, Pages 629-637
Heart Rhythm

Original-experimental
Lovastatin specifically prevents focal ischemic ventricular tachycardia due to triggered activity

https://doi.org/10.1016/j.hrthm.2006.12.051Get rights and content

Background

Use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor has been associated with reduced implantable defibrillator shocks in several multicenter trials, suggesting an antiarrhythmic effect.

Objective

The purpose of this study was to determine if lovastatin had an antiarrhythmic effect in a canine model of ischemic and inducible ventricular tachycardia (VT).

Methods

Forty-seven α-chloralose anesthetized dogs underwent left anterior descending coronary occlusion. Three-dimensional activation mapping identified the mechanism of reinducible VT and the response to lovastatin (0.5 mg/kg IV). The endocardium was excised from foci and studied using standard microelectrode techniques with Tyrode’s solution.

Results

Lovastatin blocked focal VT in 8 of 13 dogs (P <.01) compared with only 1 of 12 saline-treated dogs with focal VT. Lovastatin had no effect on reentrant VT. Lovastatin did not alter the effective refractory period, arterial pressure, or percentage of ischemic electrograms. Effective plasma concentration of lovastatin hydroxy acid ranged from 21–157 ng/mL (0.8–3.7 × 10−7 M). In vitro rapid pacing, mostly with isoproterenol (5 × 10−7 M) superfusion, produced delayed afterdepolarizations and triggered activity (9 ± 2 action potentials). Lovastatin (10−7 M) produced no change in action potentials or delayed afterdepolarizations. However, triggered activity was attenuated to 2 ± 1 action potentials with lovastatin (P <.05, n = 13) but not with vehicle alone. Triggered activity returned to control after lovastatin washout (20 minutes) as well as with co-superfusion with mevalonic acid (10−6 M, n = 5). 2,2,6,6-Tetramethylpiperidine-N-oxyl, an antioxidant that enters tissues (10−3 M, n = 8), prevented triggered activity in a fashion similar to lovastatin.

Conclusion

Lovastatin, in concentrations achievable in human plasma, specifically suppresses triggered activity and focal VT due to ischemia. A prenylated protein downstream from mevalonic acid may act as an antioxidant, producing the antiarrhythmic effect.

Introduction

Serum cholesterol levels and mortality from atherosclerotic heart disease have a direct relationship.1, 2, 3, 4 Studies of lipid-lowering agents—3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors—have demonstrated an overall reduction of 0.27 in the relative risk of all-cause mortality and a reduction of 0.28 in the relative risk of atherosclerotic heart disease mortality in association with a 20% reduction in total serum cholesterol levels and 23% reduction in serum LDL cholesterol levels.2, 3, 5 Two of these controlled trials showed a reduction in the relative risk of sudden death with HMG-CoA reductase inhibitor therapy,2, 3 which has led to the hypothesis that lipid-lowering drugs may have direct or indirect antiarrhythmic effects on ventricular tachyarrhythmias related to sudden death. De Sutter et al6 followed 78 patients with atherosclerotic heart disease and life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) who were treated with an implantable cardioverter-defibrillator (ICD) for 490 ± 319 days. Patients who received long-term lipid-lowering therapy had significantly fewer episodes of recurrent VT/VF than did patients who had not received lipid-lowering therapy. The AVID (Antiarrhythmics Versus Implantable Defibrillators) trial and MADIT (Multicenter Automatic Defibrillator Implantation Trial)-II also showed a reduction in ICD shocks.7, 8 Work in animals also suggests that statins reduce sympathetic outflow, providing a potential mechanism for the antiarrhythmic effect on VT.9 Thus, the purpose of the present study was to further evaluate the acute antiarrhythmic effect of the lipid-lowering agent lovastatin on VT induced in a dog model10, 11 with coronary artery occlusion, the most frequent etiology of human VT.

Section snippets

Animal preparation

Dogs (weight 16–25 kg) of either gender were used for this study. The protocol was approved by the Iowa City Veterans Administration Medical Center Animal Use and Care Committee and conformed to the guidelines of the American Physiological Society and the National Institutes of Health.

The animals were anesthetized with sodium thiopental 300 mg and α-chloralose 100–200 mg/kg intravenously as a bolus and continuous intravenous infusion. Animals were intubated and ventilated with a

In vivo experiments

Forty-three dogs with VT that was inducible after a 60-minute coronary artery occlusion were randomized to lovastatin (n = 20) or saline (n = 23). VT was reinduced from the same pacing site using a similar protocol in both groups before either lovastatin or saline was given (Table 1). In half of the experiments, VT accelerated to VF. An example of inducible VT of focal endocardial origin is shown in Figure 1. After the last of the drive pacing and two extrastimuli (downward arrows), a third

Discussion

The main observation of this study was that intravenous administration of the lipid-lowering drug lovastatin specifically blocked the induction of focal VT, whether from endocardium, Purkinje, or epicardium, during myocardial ischemia in a canine model. In tissues removed from endocardial sites of origin of VT, lovastatin superfusion for 20 minutes markedly reduced the frequency of triggered activity due to DADs, which was restored by mevalonic acid, suggesting the effect of a metabolite

Conclusion

Lovastatin, in concentrations achievable in human plasma, suppresses DADs and triggered activity, successfully suppressing ischemic focal VT.

Acknowledgment

We thank Ms. Linda Bang for excellent secretarial assistance.

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