Shared Molecular Signatures across Heart Failure with Preserved and Reduced Ejection Fraction to Abdominal Aortic Aneurysm: An Integrative Transcriptomic Analysis

Abstract

Background: Heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) represent clinically distinct syndromes, yet both exhibit endothelial dysfunction and chronic inflammation. Abdominal aortic aneurysm (AAA) shares similar vascular remodeling mechanisms. The molecular commonalities among these three conditions remain poorly characterized.

Methods: Human transcriptomic datasets from the GEO repository GSE183464 (abdominal aortic aneurysm) and Zeedono4114617 (heart failure with preserved and reduced ejection fraction—right ventricular tissue) were analyzed using R for differential expression.Genes meeting |log₂FC| > 1 and adjusted p < 0.05 were considered significant. Overlapping upregulated and downregulated DEGs were identified. Functional enrichment was performed using Enrichr across six gene set libraries: Reactome, MSigDB, KEGG, and the three Gene Ontology categories (Biological Process, Cellular Component, and Molecular Function).Pathways were ranked by combined score and adjusted p-value.

Results: Shared pathways in upregulated genes included Leukocyte transendothelial migration, Extracellular matrix organization, MHC Class II antigen presentation, TNF-a signaling via NF-kB, hydrolysis of LPC, and TGF-β signaling pathway. This reflects a common pro-inflammatory and pro-fibrotic microenvironment that is common to all. Conversely, downregulated pathways highlighted Oxidative phosphorylation, Fatty acid β-oxidation, and Mitochondrial respiratory chain complex I assembly, Nuclear events Mediated by NFE2L2 (NRF2), and KEAP1-NRF2 pathways reflecting shared metabolic and mitochondrial impairment with decreased resistance to oxidative stress, possibly via the downregulation of NRF2 activity.

Conclusion: This cross-disease transcriptomic analysis reveals shared molecular biomarkers of endothelial inflammation and metabolic dysregulation linking HFpEF, HFrEF, and AAA. The overlap of inflammatory activation with metabolic suppression underscores a potential unified mechanism of vascular and myocardial remodeling, offering new molecular targets for future therapeutic exploration.