A Single Bolus Rosuvastatin Accelerates Calcium Uptake and Attenuates Conduction Inhomogeneity in Failing Rabbit Hearts with Regional Ischemia-reperfusion Injury.

Abstract

Acute statin therapy reduces myocardial ischemia/reperfusion (IR) injury-induced ventricular fibrillation (VF), but the underlying electrophysiological mechanisms remain unclear. The present study sought to investigate the antiarrhythmic effects of a single bolus rosuvastatin injection in failing rabbit hearts with IR injury and to unveil the underlying molecular mechanisms. Rabbits were divided into Rosuvastatin, Rosuvastatin + L-NAME, control, and L-NAME groups. Intravenous bolus rosuvastatin (0.5 mg/kg) and/or L-NAME (10 mg/kg) injections were administered 1 h and 15 min before surgery, respectively. Heart failure was induced using rapid ventricular pacing. Under general anesthesia with isoflurane, IR model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min. Plasma NO end products levels were measured during IR. Then hearts were excised and Langendorff-perfused for optical mapping studies. Cardiac tissues were sampled for Western blot analysis. Rosuvastatin increased plasma NO levels during IR, which was abrogated by L-NAME. Spontaneous VF during IR was suppressed by rosuvastatin (P<0.001). Intracellular calcium (Cai) decay and conduction velocity were significantly slower in the IR zone. Rosuvastatin accelerated Cai decay, ameliorated conduction inhomogeneity, and reduced the inducibility of spatially discordant alternans and VF significantly. Western blots revealed significantly higher expression of eNOS and phosphorylated eNOS proteins in the Rosuvastatin group. Furthermore, SERCA2a, phosphorylated connexin43, and phosphorylated phospholamban were down-regulated in the IR zone, which was attenuated or reversed by rosuvastatin. Acute rosuvastatin therapy before ischemia reduced IR-induced VF by improving SERCA2a function and ameliorating conduction disturbance in the IR zone.