Abstract P025: Cite-seq And Predixcan Analyses Identify Galectin-1 As A Potential Novel Mediator Of Heart Failure With Preserved Ejection Fraction In Mice And Humans

Abstract

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome where patients, despite having a normal left ventricular systolic function, present with symptoms of volume overload. Recent data have shown that HFpEF is associated with elevation of inflammatory biomarkers. In a well-known rodent hypertensive model (DOCA-salt), we isolated CD45+ leukocytes from the heart and then performed CITE-Seq, a novel technique to obtain transcriptomic and surface marker expression on single cells, on a total of 4,359 and 7,600 cells from four sham and four DOCA-salt left ventricles, respectively. Analysis showed significant differential gene expression in the myeloid (macrophage/monocytic) population. We then took the top 20 genes that were differentially expressed between DOCA-salt vs sham treated myeloid cells and performed a genetic analysis called PrediXcan in Vanderbilt’s DNA databank, BioVU. Our analysis used gene expression prediction models built from the GTEx Project and tested its association with the HFpEF phenotype, which was derived on ICD-9 and 10 codes and natural language programming. From BioVU, 88,660 subjects were included in the association analysis. Of the 20 genes, 8 did not meet prediction model criteria for PrediXcan. In the remaining 12 genes, genetically predicted expression of only 2 ( Lgals1 and Ctsl ) are associated with a HFpEF phenotype. Of these, the gene encoding galectin 1, Lgals1 , had the lowest p-value (0.02) and highest beta coefficient (0.32) corresponding to an odds ratio for HFpEF of 1.38. Galectin-1 is a well known mediator of inflammation resolution in infection and tumor biology, however its role in heart failure is unknown. We are currently exploring the role of galectin-1 in the pathophysiology of HFpEF through Lgals1 -/- and LysM-Cre x Lgals1 fl/fl mice. In conclusion, using two different approaches in mice and humans, we identified galectin-1 as a new potential mediator in HFpEF development.