Abstract 10228: The Effects of Olmesartan on Intercalated Disc Remodeling During the Development of Heart Failure
Background: Heart failure is known to predispose to life-threatening ventricular tachyarrhythmias. The intercalated disc (ID) contains different junctional complexes, adhesion junction (AJ) and gap junction (GJ) that enable the myocardium to function as a syncytium. The AJ mediates normal mechanical coupling between cardiomyocytes and plays a key role in the formation and stability of GJ.
Purpose: We clarified the ID remodeling and its potential role in the pathogenesis of arrhythmias, and investigated the effects of Olmesartan on ID remodeling during development of heart failure in UM-X7.1 cardiomyopathic hamster (UMX).
Methods and Results: UMX developed left ventricular (LV) hypertrophy by age 15w, and showed a moderate reduction in LV contractility at age 20w. At age 15w with normal LV function, ∼20% of UMX died suddenly without heart failure, and VT/VF was inducible in ∼30% hamsters. Electron microscopy revealed that density linking cell-cell adhesion was irregular and unclearly defined, and filamentous structures attached to electron-dense components arranged in disorder. Immunohistochemistry revealed that expression of N-cadherin and β-catenin at ID was increased at 15w. Interestingly, western blotting showed the expression of β-catenin of total cellular fraction was decreased at 15w. Although there was no significant change in Cx43 expression, the expression of nuclear β-catenin, which functions as TCF/LEF transcriptional activator and Cx43 is known to be one of the TCF/LEF target genes, was remarkably decreased (∼40% decrease) at 15w compared with control. At age 20w (heart failure stage), LV Cx43 protein expression was significantly decreased (∼50% decrease). The lethal ventricular arrhythmias were inducible in ∼80% UMX at 20w. In UMX, Olmesartan improved survival rate, attenuated VT/VF induction (∼50% decrease), and inhibited the decrease of nuclear β-catenin expression.
Conclusion: These results suggest that alterations in AJ precede Cx43 GJ remodeling, and ID remodeling might contribute to arrhythmogenesis during development of heart failure. Olmesartan treatment might be a new upstream therapy for lethal arrhythmia by modulating/improving ID remodeling.
- © 2010 by American Heart Association, Inc.