Abstract 372: Sexual Dimorphism of Myocardial Gene Expression in End-stage Human Heart Failure
Population-based studies have shown that men with nonischemic heart failure show more prominent left ventricular dilation and increased risk of death compared to women. However, the underlying molecular basis for this disparity remains unknown. The goal of this study was to test the hypothesis that the sex-based disparity in phenotype and increased risk of death with advanced idiopathic dilated cardiomyopathy may be linked to alterations in myocardial gene expression signatures. Gene expression data (HU133 gene chip, Affymetrix) was analyzed from left ventricular biopsies of 49 males with idiopathic end stage heart failure (42 +/− 10 yrs) and 20 females (45 +/− 10 yrs) harvested at the time of transplantation from 3 separate cohorts (Temple University, University of Minneapolis, University of Michigan). All subjects were < 55 yrs of age. Data was normalized using robust multiarray analysis (RMA) and analyzed in R. Expression levels of 54 genes were identified as significantly different, with a false discovery rate of 0.24%. Of these 54 genes, over half resided on either the X or Y chromosome. These genes included eukaryotic translation initiation factor 1A X-linked, eukaryotic initiation factor 1A Y-linked, and monoamine oxidase A. The remaining genes were located on the autosomes and included tropomyosin 3 and alpha myosin heavy chain 6, which were up-regulated 3.6 and 3.8 fold, respectively, in men compared to women. In conclusion, this is the first analysis of myocardial gene expression data from multiple cohorts comparing men and pre-menopausal aged women with idiopathic dilated cardiomyopathy. The 3.8 fold increase in expression of alpha myosin heavy chain is especially intriguing as a candidate to partially explain the sex-based difference in left ventricular dilation and increased risk of death in men, given recent genetic evidence suggesting that altered molecular function of this gene may initiate pathologic changes in contractile function.