Cardioprotective Effects of Pravastatin Against Lethal Ventricular Arrhythmias Induced by Reperfusion in the Rat Heart

Abstract

Background: Statins are reported to reduce mortality in patients with coronary artery disease and that mortality benefit might be related to the drugs' antiarrhythmic properties. Methods and Results: Male rats were fed with or without pravastatin (0.1mg·kg^-1·day^-1) for 7 days, and thereafter subjected to 10min of ischemia by coronary artery ligation followed by 20min reperfusion. Treatment with pravastatin reduced the frequency and duration of ventricular tachycardia and fibrillation (VT/VF) and improved the arrhythmia score after reperfusion. To investigate the rapid effects of pravastatin, isolated perfused rat hearts were subjected to 20min of global ischemia followed by 30 or 60min of reperfusion. Treatment with pravastatin (10nmol/L) from 10min before ischemia shortened the total duration of reperfusion-induced VT/VF. Interestingly, pravastatin administered from the beginning of reperfusion also exerted antiarrhythmic effects. These results indicate that pravastatin exerts antiarrhythmic effects not only with daily oral intake but also when administered just before ischemia or even after ischemia. Intracellular calcium ([Ca²⁺]_i) overload and collapse of mitochondrial inner membrane potential (Δψ_m) are associated with the arrhythmogenesis during ischemia-reperfusion. In cultured cardiomyocytes, pretreatment with pravastatin (10nmol/L) suppressed [Ca²⁺]_i overload and prevented Δψ_m loss induced by H₂O₂. Conclusions: Pravastatin attenuated reperfusion-induced lethal ventricular arrhythmias. Inhibition of [Ca²⁺]_i overload and preserving Δψ_m may be the mechanisms of the observed antiarrhythmic effects of pravastatin. (Circ J 2011; 75: 1601-1608)