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

TY - JOUR

T1 - Activation of Neutrophil Extracellular Trap Formation in Patients with Heart Failure and a Preserved Ejection Fraction

AU - VAN ESSEN, BART J.

AU - TROMP, JASPER

AU - GEVAERT, ANDREAS B.

AU - De Jong, TRISTAN V.

AU - OUWERKERK, WOUTER

AU - KOEKEMOER, ANDREA

AU - DJORDJEVIC, DJORDJE

AU - BAUMHOVE, LUKAS

AU - THARSHANA, GANASH N.

AU - CONDE-KNAPE, KARIN

AU - NATH, MINTU

AU - LANG, CHIM C.

AU - SAMANI, NILESH J.

AU - MICHAELSEN, NATASHA B.M.

AU - VOORS, ADRIAAN A.

N1 - Publisher Copyright: © 2025 The Authors

PY - 2026/3

Y1 - 2026/3

N2 - 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.

AB - 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.

KW - heart failure

KW - neutrophil extracellular trap

KW - pathway analysis

KW - Transcriptomics

UR - https://www.scopus.com/pages/publications/105002791900

U2 - 10.1016/j.cardfail.2025.02.015

DO - 10.1016/j.cardfail.2025.02.015

M3 - Article

C2 - 40081731

AN - SCOPUS:105002791900

SN - 1071-9164

VL - 32

SP - 596

EP - 604

JO - Journal of Cardiac Failure

JF - Journal of Cardiac Failure

IS - 3

ER -