Sex differences in gene expression in response to ischemia in the human myocardium

Abstract

Word Count: 7520 (intro-conclusion (4028) + 60 citations (1951 words)). Abstract: 254 words 2 Abstract and Keywords Background: Sex differences exist in the prevalence, presentation, and outcomes of ischemic heart disease. Females have higher risk of heart failure post myocardial infarction relative to males and the female sex is an independent risk factor for hospital and operative mortality after cardiac surgery. However, the mechanisms underlying this sexual dimorphism remain unclear.We examined sex differences in human myocardial gene expression in response to ischemia.Methods: Left ventricular biopsies from 68 male and 46 female patients undergoing aortic valve replacement surgery were obtained at baseline and after a median 74 minutes of cold cardioplegic arrest/ischemia and respective transcriptomes were quantified by RNA-Seq. Sexspecific responses to ischemia were quantified by differential gene expression, expression quantitative trait loci (eQTL) and pathway and functional analysis. Cell-type enrichment analysis. was used to obtain an estimate of the identity and relative proportions of different cell types present in each sample. Results:A sex-specific response to ischemia was observed for 271 genes. Functional annotation analysis revealed sex-specific modulation of the oxytocin signaling pathway and common pathway of fibrin clot formation. The eQTL analysis identified variant-by-sex interaction eQTLs at baseline and post-ischemia, indicative of sex differences in the genotypic effects on gene expression, and cell-type enrichment analysis showed sex-bias in proportion of specific cell types. Conclusion:In response to myocardial ischemia, the human left ventricle demonstrates changes in gene expression that differ between the sexes. These differences provide insight into the sexual dimorphism of ischemic heart disease and may aid in the development of sexspecific therapies that reduce myocardial injury.

Inter-species differences in response to hypoxia in iPSC-derived cardiomyocytes from humans and chimpanzees

“…As we observed depletion of eQTLs found in healthy individuals among the conserved response genes in our study, we next considered eQTLs found among CVD patients. To do so, we investigated the contribution of eQTLs identified in left ventricle heart tissue from patients undergoing aortic valve replacement surgery pre-and post-cardioplegic arrest and ischemia, to our hypoxia response categories (Stone et al 2018). Again, we observed a depletion of eGenes in the conserved response category for both pre-and post-ischemia eGenes (P = 0.03 and P =0.006 respectively; Figure S16A).…”

“…The gene sets belonging to each of the four response categories were investigated for common pathway enrichment using the KEGG database (Kanehisa et al 2017 For the overlap of our response categories with eQTLs identified pre-and post-ischemia, an RNAseq study of 114 patients undergoing aortic valve replacement surgery was used (Stone et al 2018). In this study, samples of heart left ventricle were obtained for each individual pre-and postcardioplegic arrest/ischemia.…”

Chemical and molecular tools to probe biological sex differences at multiple length scales

“…4 One such example is that females express genes associated with ischemic events which correlates with their higher risk of developing post-myocardial infarction relative to males. 5 Second, many neurological disorders also exhibit sex differences in incidence, severity, or response to treatment. For example, the hormone estrogen provides protective effects to the blood-brain barrier, making females less susceptible to neuroinflammatory disorders relative to males.…”