title: Right ventricular electrical remodeling and arrhythmogenic substrate in rat pulmonary hypertension.
abstract: 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.
authors.affiliation: Division of Biomedical Engineering, National Defense Medical College Research Institute, Namiki 3-2, Tokorozawa, Saitama, Japan. yoshit@ndmc.ac.jp
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Tanaka
authors.forename: Bonpei
authors.initials: B
authors.lastname: Takase
authors.forename: Takashi
authors.initials: T
authors.lastname: Yao
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishihara
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000494:pharmacology; D024042:Collagen Type I / Q000235:genetics / Q000378:metabolism; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D004359:Drug Therapy, Combination; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D008297:Male; D016686:Monocrotaline; D009924:Organ Culture Techniques; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000494:pharmacology; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D020257:Ventricular Remodeling / Q000187:drug effects; D056969:Voltage-Sensitive Dye Imaging
chemical_list: D002316:Cardiotonic Agents; D024042:Collagen Type I; D018031:Connexin 43; D010879:Piperazines; D011687:Purines; D013450:Sulfones; C048081:beraprost; D016686:Monocrotaline; D000068677:Sildenafil Citrate; D011464:Epoprostenol