Abstract 564: Gender Dependent Protective Effects of Melusin Overexpression on Post Myocardial Infarction Remodelling and Survival in Mice
This study is part of the EU funded EUGeneHeart consortium aiming at the identification of differential pathways leading from a compensated challenged heart to either beneficial or maladaptive hypertrophic signaling. A model for adaptive hypertrophy (swimming) was compared to two models of maladaptive hypertrophy (transverse aortic constriction, TAC and myocardial infarction, MI) in wildtype (WT) and melusin overexpressing (OE) mice with special attention towards gender differences. Melusin, a muscle specific β1 integrin interacting protein, was shown to favorably influence heart failure after TAC. To achieve the highest possible standardization and homogeneity the interventions were carried out at a single center (1423 mice) and the harvested samples were distributed among the consortium members for in-depth analyses of signaling pathways, energy metabolism as well as characterization of the extracellular matrix. Swimming (n=391) and TAC (n=426) lead to comparable and significant degrees of hypertrophy (heart weight/body weight ratio +13.3% and +9.7%, respectively). While TAC caused a concentric hypertrophy (LVEDD −8.2%) swimming significantly increased LVEDD by 9.3%. At this compensated stage there were no significant morphometric or echocardiographic differences between WT and melusin OE mice. However, following MI (n=606), melusin OE mice showed reduced dilatation (LVEDD +49.8% wt vs. +29.0% melusin OE, n=136) and wall thinning (septum thickness −40.5% WT vs. −21.4% melusin OE). Gender separated analysis revealed a significant reduction in LVEDD only in the melusin OE males. A significantly improved survival rate was found for the melusin OE males (59% vs. 37%) whereas there was no significant effect on survival in females (82% vs. 76%). Analysis of shortening and calcium transients indicated a still compensated myocyte function on the single cell level for all three models, as intended. This is the first study that shows a prognostic effect of melusin overexpression in the setting of MI. Reduced mortality is associated with more favorable remodeling. Most interestingly, the effect is gender dependent. The present findings may be of future clinical relevance. Examinations of signaling pathways are currently being performed.