Abstract 13577: Burden of Cardiometabolic Risk Factors and Vascular Health

Abstract

Introduction: Cardiometabolic risk factors (diabetes, obesity, and hypertension) are highly prevalent and contribute to cardiovascular disease (CVD). Endothelial dysfunction often precedes CVD development. Direct brachial vein endothelial cell (EC) harvesting enables the examination of vascular health via assessment of EC gene expression. Hypothesis: We hypothesized that individuals with greater cardiometabolic risk would demonstrate a more pro-inflammatory EC transcriptome. Methods: Adult participants without CVD underwent EC harvesting followed by RNA sequencing. We categorized individuals by number of risk factors (hypertension, diabetes, obesity) as 0 through 3. To evaluate the association between risk factor burden and outcome transcripts, we performed multivariable linear regression, adjusting for age, sex, and race/ethnicity. Results: Among 18 individuals (mean age 47 ± 14, 44% female, and 61% white), 17%, 44%, 28%, and 11% had 0,1,2, and 3 prevalent risk factors, respectively. EC RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with 585 upregulated, 3 downregulated, and excellent clustering ( Fig. a, b ). Gene ontology enrichment analysis demonstrated enriched and upregulated pathways of T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), and platelet aggregation (NES= 1.66, p=0.03) and downregulated pathways of endothelial cell proliferation (NES= -1.68, p=0.03). ( Fig. c ) Select upregulated genes (log 2FC >3, p-adj<0.05) included VCAM1, CEACAM1, ADAM 17, and CD99L2, with a graded increase in mean normalized counts with increasing number of risk factors. ( Fig. d ) Conclusions: We demonstrate a proinflammatory, pro-adhesive, and pro-coagulant EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into potential mechanisms linking cardiometabolic risk factors with the development of CVD.