Background AVID and MADIT-II trials showed that patients with coronary artery disease taking HMG-CoA reductase inhibitors have fewer ICD shocks suggesting anti-arrhythmic effects. Our aim was to analyze the effects of acutely administered lovastatin (LOVA): 1) on ICD defibrillation threshold (DFT) since antiarrhythmics can worsen DFT, and 2) on triggered activity (TA) recorded from ischemic endocardium excised from the anterior wall of anesthetized dogs with anterior descending coronary occlusion.
Methods and Results Dogs received LOVA dissolved in DMSO. DMSO alone produced no effect on DFT. LOVA 10 mg IV did not alter effective refractory period and tended to improve defibrillation success (from 20 ± 3 to 17 ± 3 J, P = 0.09 vs control). Ischemic endocardium was studied using standard microelectrode techniques with normal Tyrode's solution. There were no delayed afterdepolarizations (DADs) or TA at baseline in this depolarized tissue (-71 ± 4 mV). Isoproterenol (5 × 10-7 M) superfusion, produced sustained TA with DAD amplitudes of 4.2 ± 1 mV. LOVA (10-7 M) produced no change in resting membrane potential (-70 ± 4 mV), action potential duration at 90% (from 231 ± 11 to 229 ± 8 msec, ns), action potential duration at 50% (168 ± 7 to 166 ± 6 msec, ns), action potential amplitude (89 ± 5 to 85 ± 5 mV, ns), overshoot (11 ± 1 to 10 ± 1 mV) or DAD amplitude (4.0 ± 1 mV, ns). Interestingly, TA was attenuated to 1-5 complexes with LOVA (p<0.05) and not with DMSO alone. Reversibility to sustained TA also occurred after LOVA washout (20 min) as well as with co-superfusion with mevalonic acid (10-7 M, n = 4), which also did not change action potentials or DADs.
Conclusions These results are consistent with the possibility that a prenylated protein down-stream from the mevalonic acid pathway may underlie this effect. Thus LOVA in concentrations achievable in human plasma may be antiarrhythmic for TA without a deleterious effect on DFT.