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. This 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 hour and 15 minutes before surgery, respectively. Heart failure was induced using rapid ventricular pacing. Under general anesthesia with isoflurane, an IR model was created by coronary artery ligation for 30 minutes, followed by reperfusion for 15 minutes. Plasma NO end product 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 enhancing endothelial NO-synthase and phosphorylated enhancing endothelial NO-synthase proteins in the Rosuvastatin group. Furthermore, SERCA2a, phosphorylated connexin43, and phosphorylated phospholamban were downregulated 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.

Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia–Reperfusion Injury

“…Rapid right ventricular pacing was used to induce heart failure as described previously ( Chou et al, 2020b ). Briefly, the rabbits were premedicated with intramuscular injections of zoletil (10 mg/kg) and xylazine (5 mg/kg).…”

“…An IR model was created as described previously ( Chou et al, 2020b ). Briefly, the rabbits were premedicated with intramuscular injections of zoletil (10 mg/kg) and xylazine (5 mg/kg), intubated, and anesthetized with isoflurane.…”

“…The effective refractory period (ERP) was measured by giving a premature stimulus after 8 beats at a 400 ms pacing cycle length (PCL). Action potential duration (APD) and Ca i alternans were induced by a dynamic pacing protocol reported previously ( Chou et al, 2020b ). VF inducibility was defined as the ability to provoke VF by a dynamic pacing protocol or extrastimulus pacing protocol (up to S 5 ) ( Chang et al, 2019 ).…”

“…Cardiac tissues were sampled from the non-IR and IR zones at the end of the mapping studies for protein quantification as previously described ( n = 6 per group) ( Chou et al, 2020b ). Briefly, 50 μg of protein was loaded to each well in the SDS–PAGE gel for electrophoresis.…”

“…However, Akar et al (2007) reported that gap junction reserve is significantly reduced by the increase in non-phosphorylated Cx43 (NP-Cx43) and lateralization of phosphorylated Cx43 in a pacing-induced heart failure rabbit model. We previously reported that CV in the IR zone (CV IR ) is significantly slower than CV in the non-IR zone (CV non–IR ), which is associated with the upregulation of NP-Cx43 in the IR zone in failing rabbit hearts ( Chou et al, 2020b ). On the basis of these findings, we hypothesized that rotigaptide plays an antiarrhythmic role in failing rabbit hearts with acute IR injury undergoing TH.…”