beraprost and Arrhythmias--Cardiac

Right ventricular (RV) dysfunction, caused by severe pulmonary hypertension (PH), is associated with high mortality because of RV failure. However, some patients can suffer from sudden cardiac death (SCD). We hypothesized that severe PH can cause RV arrhythmogenesis, leading to SCD. We sought to investigate arrhythmogenesis in PH. Optical mapping analysis (OMP) with an electrophysiological study (EPS) and pathological examination were performed in a monocrotaline (MCT)-induced rat PH model. Rats were injected with MCT (60 mg/kg), and OMP was performed in isolated Langendorff-perfused hearts. OMP revealed abnormal RV conduction delays and abnormal patterns, along with elevated RV pressure. In addition, impaired action potential duration dispersion (APDd), an index of myocardial repolarization instability, was observed only in the RVs with severe PH. The EPS demonstrated that lethal arrhythmias were induced by burst pacing to the RV when deteriorated APDd became evident. This arrhythmogenesis was inhibited by combination treatment with sildenafil and beraprost (SIL + BERA). RT-PCR showed an mRNA up-regulation of Type I collagen and down-regulation of connexin-43 in the RV at 5 weeks after MCT injection. Pathological examination revealed pulmonary vascular remodeling and RV hypertrophy with interstitial fibrosis, which was substantially reduced by SIL + BERA. Immunohistochemistry also revealed connexin-43 degradation in the RVs with severe PH. In contrast, connexin-43 was well preserved, and no lethal arrhythmias were induced by burst pacing to the RV in the absence of PH after SIL + BERA. In conclusion, RV electrical remodeling, including impaired APDd, causes arrhythmogenesis in severe PH, potentially associated with SCD attributable to PH.

Topics: Animals; Arrhythmias, Cardiac; Cardiotonic Agents; Collagen Type I; Connexin 43; Death, Sudden, Cardiac; Drug Therapy, Combination; Epoprostenol; Gene Expression Regulation; Heart; Humans; Hypertension, Pulmonary; Male; Monocrotaline; Organ Culture Techniques; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Sulfones; Ventricular Dysfunction, Right; Ventricular Remodeling; Voltage-Sensitive Dye Imaging

1. The effects of beraprost sodium (beraprost) on myocardial infarct size in an anesthetized open-chest canine model of regional myocardial ischemia and reperfusion were investigated. 2. Administration of beraprost (300 ng/kg/min, intravenously) to dogs 45 min after left circumflex coronary artery occlusion until 105 min after reperfusion resulted in a significant reduction in infarct size. 3. The values of control and beraprost treated infarct size expressed as a percentage of the total left ventricle were 15 +/- 3% and 4 +/- 2%, respectively. 4. Reperfusion arrhythmia, plasma creatine phosphokinase (CK) and lactate dehydrogenase (LDH) level were significantly suppressed by treatment with beraprost. 5. By histological examination, beraprost proved to reduce neutrophil migration in the ischemic myocardium after 5 h reperfusion. 6. Therefore, it is suggested that the cytoprotective effect of beraprost during myocardial ischemia and reperfusion may be the consequence of the inhibition of neutrophil migration.

Topics: Animals; Arrhythmias, Cardiac; Chemotaxis, Leukocyte; Disease Models, Animal; Dogs; Epoprostenol; Female; Hemodynamics; Leukocyte Count; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Neutrophils; Platelet Aggregation Inhibitors