Activation of Neutrophil Extracellular Trap Formation in Patients with Heart Failure and a Preserved Ejection Fraction

INTRODUCTION: Pathophysiological differences between heart failure (HF) with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) remain poorly understood. Therefore, we performed pathway analyses from whole-blood transcriptomics to distinguish HFpEF from HFrEF. METHODS AND RESULTS: Lexogen's QuantSeq was used to carry out whole-blood transcriptomics in 500 patients with HF (HFpEF n = 250, HFrEF n = 250). Differential gene expression analysis was performed on all protein-coding genes that met a predefined minimum expression level. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology over-representation analysis was utilized to identify upregulated and downregulated biological pathways. The findings were validated in an independent cohort of 727 patients with HF. Out of 7672 protein-coding transcripts, 217 were upregulated and 110 were downregulated in patients with HFpEF compared with HFrEF. The 3 most significantly upregulated genes were neutrophil-expressed elastase, defensin alpha 4, and pro-platelet basic protein. The 3 most significantly downregulated genes were lymphotoxin beta, bridging integrator 1, and V-set pre-B cell surrogate light chain 3. Translation of differentially expressed genes into biological pathways demonstrated that the most significantly activated KEGG pathway in HFpEF was neutrophil extracellular trap formation. DISCUSSION: Transcriptomics analyses suggest activation of neutrophil extracellular trap formation pathways in patients with HFpEF. This pathway is associated with endothelial and coronary microvascular dysfunction and might be a target for future drug development in patients with HFpEF.