Postdoctoral Fellow Northwestern Univ. Feinberg Sch. of Med. Chicago, Illinois, United States
Disclosure(s):
Bilal Khan Mohammed, MD: No financial relationships to disclose
Introduction/Rationale: Heart failure with preserved ejection fraction (HFpEF) is a major unmet need with no proven therapies and a striking female predominance. Chronic endothelial stress may activate type I interferon (IFN) pathways, priming neutrophils toward pro-inflammatory effector functions such as neutrophil extracellular trap (NET) formation. We hypothesized that IFN-primed neutrophils drive microvascular injury and diastolic dysfunction in HFpEF, revealing a novel immunologic target.
Methods: A female mouse model(n=15) of HFpEF was induced by combined metabolic and hypertensive stress. Cardiac neutrophil infiltration, IFN-stimulated gene (ISG) expression, and NETosis were assessed. Neutrophils were targeted by anti-Ly6G depletion or IFN-α/β receptor (IFNAR) knockout. Cardiac structure and function were evaluated by echocardiography, invasive hemodynamics, histology, and biomarkers. Translational relevance was tested by profiling neutrophil IFN signatures in women patients with pre-HFpEF(n=10).
Results: HFpEF mice showed a twofold increase in cardiac neutrophils (p=0.008), elevated ISGs, and increased NET burden, more pronounced in females (p=0.03 vs males). Neutrophil depletion reduced fibrosis (15±3% vs 27±4%, p=0.01) and improved diastolic indices (E/e′ 11.2±0.5 vs 15.0±0.7, p=0.002). IFNAR-deficient neutrophils lowered LVEDP (8.7±0.7 vs 12.5±0.8 mmHg, p=0.01), normalized BNP, and reduced cytokines (IL-6, TNF-α, p< 0.05). Women with pre-HFpEF displayed elevated IFN-driven neutrophil signatures.
Conclusion: Neutrophil-specific IFN signaling emerges as a key driver of HFpEF in females. The mechanistic link between immune activation and microvascular injury supports immune-guided therapies, including biomarker-based risk stratification and integration with device-based monitoring or targeted anti-inflammatory strategies.
