University of Connecticut Health Center Farmington United States
Heart failure with preserved ejection fraction HFPEF is a disorder with high morbidity and mortality. Unique among cardiovascular conditions, HFPEF affects women predominately more than men, but mechanisms for this sex dimorphism in HFPEF prevalence are incompletely understood. Sex-based dimorphisms have been studied mostly in non-human model systems, but are limited by incomplete recapitulation of human sex-based gene regulation and gene-environment interactions. Thus, there is a critical unmet need to develop in vitro human model systems to interrogate how sex regulates HFPEF pathogenesis and cardiac function broadly. The overarching goal of this project is to apply a cardiac microtissue assay to study sex dimorphisms in cardiac function. In Aim 1, we have generated cardiac microtissues from male and female induced cardiomyocytes iCMs differentiated from induced pluripotent stem cells iPSCs to study sex-based regulation of cardiac function. We quantified contractile function and gene expression analyses in these models. In Aim 2, we have produced the first FHL1 knockout iPS model using CRISPRCas9. We characterized the role of FHL1 in cardiomyocyte and cardiac tissue function using single cell and cardiac microtissues assays. Insights from this study have illuminated potential sex-dependent genetic mechanisms of HFPEF.