Alterations in adhesion junction precede gap junction remodelling during the development of heart failure in cardiomyopathic hamsters

Aims The intercalated disc (ID) contains two complexes, the adhesion junction (AJ) and the gap junction (GJ). We studied ID remodelling and its potential role in arrhythmogenesis and investigated the effects of olmesartan on ID remodelling during development of heart failure (HF) in UM-X7.1 cardiomyopathic hamsters. Methods and results The UM-X7.1 hamsters showed left ventricular (LV) hypertrophy by the age of 10-15 weeks and a moderate impairment in LV contractility at 20 weeks. At age 10-15 weeks, 10-20% of the hamsters died suddenly without HF, and ventricular tachycardia (VT)/ventricular fibrillation (VF) was induced in similar to 30% of hamsters. Electron microscopy showed that density linking cell-to-cell adhesion was irregular and unclearly defined, and filamentous structures attached to electron-dense components were arranged in disorder. Western blotting showed that the total cellular expression level of beta-catenin was decreased, and expression of nuclear beta-catenin, which functions as a T-cell factor/lymphocyte enhancer binding factor transcriptional activator, was also remarkably decreased. At age 20 weeks, LV connexin43 expression showed a remarkable decrease, and the VT/VF induction rate was similar to 90%. In UM-X7.1 hamsters, olmesartan improved abnormal ID ultrastructural changes, attenuated the decrease of total cellular and nuclear beta-catenin expression, decreased VT/VF induction, and improved survival rate. Conclusion These results suggest that changes in AJ protein precede connexin43 GJ alterations, and ID remodelling might contribute to arrhythmogenesis during the development of HF. Angiotensin receptor blockade might be a new therapy for lethal ventricular arrhythmia by modulating both AJ and GJ remodelling.