Burden of cardiometabolic risk factors and vascular health

Abstract

Background: Cardiometabolic risk factors diabetes, obesity, and hypertension are highly prevalent and contribute to increased cardiovascular disease (CVD). Endothelial dysfunction precedes CVD development. The current study aimed to investigate the EC transcriptome among individuals with varying degree of cardiometabolic risk.

Methods: Adult participants without CVD and various degrees of cardiometabolic risk factor burden (hypertension, diabetes, obesity) were included. Participants underwent brachial vein EC harvesting followed by RNA sequencing. To evaluate the association between cardiometabolic comorbidity burden and outcome transcripts we performed linear regression with multivariable models, adjusting for age, sex, and race/ethnicity.

Results: A total of 18 individuals were included in the present analysis (mean age 47 ± 14, 44% female, and 61% White adults). Endothelial cell RNA sequencing revealed 588 differentially expressed transcripts (p-adj <0.05) with excellent discrimination in unsupervised hierarchical clustering analysis. Gene ontology enrichment analysis revealed upregulated pathways associated with T-cell activation (NES = 2.22, p<0.001), leukocyte differentiation (NES= 2.16, p<0.001), leukocyte migration (NES= 2.12, p<0.001), regulation of cell-cell adhesion (NES= 1.91, p=0.006). Downregulated pathways of interest included endothelial cell proliferation (NES= -1.68, p=0.03) and response to interleukin-1 (NES= -1.61, p=0.04). Upregulated genes included VCAM1, CEACAM1, ADAM 17, and CD99L2, all with a log-2-fold change >3 and p-adj <0.05. These genes demonstrated a graded increase in mean normalized counts with increasing number of risk factors.

Conclusions: We demonstrate a proinflammatory and pro-adhesive EC transcriptome associated with increased cardiometabolic risk factor burden offering insight into a potential mechanism linking these risk factors with the development of CVD.

Figure 1.

Endothelial cell Transcriptome Among Individuals with Varying Degree of Cardiometabolic Risk. (a) volcano plot (p-adjusted <0.05), (b) heatmap of log2 normalized counts of 193 top differentially expressed genes (p-adjusted <0.01), (c) top differentially enriched pathways via gene ontology pathway analysis, (d) mean log normalized counts for differentially expressed genes categorized by number of risk factors, including VCAM1 (p-trend=0.013), CEACAM1 (p-trend 0.089), ADAM17 (p-trend 0.005) and CD99L2 (p-trend 0.03). Risk factors categorized as 0, 1, 2, or 3 based on presence or absence of hypertension, diabetes mellitus, and obesity.