Abstract Body: Introduction: Heart failure (HF) is a leading cause of cardiovascular morbidity and mortality. HF with preserved ejection fraction (HFpEF) is a growing subset of HF without many proven efficacious therapies. Emerging evidence suggests that chronic inflammation, metabolic syndrome, and endothelial dysfunction play key roles in HFpEF pathogenesis and may present novel therapeutic targets. Emerging evidence also suggests that neutrophils and their response to interferons may play an essential role in the inflammatory response to ischemic cardiac injury.
Hypothesis: We hypothesized that disrupting interferon signaling in neutrophils would attenuate inflammation and mitigate the development of diastolic dysfunction in a murine model of HFpEF.
Goals: The primary goal of this study was to determine the role of interferon-responsive neutrophils in the development of HFpEF.
Methods: Male wild-type (WT) and neutrophil-specific interferon receptor knockout (KO) C57BL/6J mice (6-8 weeks old) were randomized to either a standard chow diet (control) or a high-fat diet (HFD) supplemented with N(ω)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 15 weeks to induce an HFpEF phenotype. Body weight and blood pressure were monitored weekly. Echocardiography (Echo) was performed at baseline and at 5, 10, and 15 weeks. At study completion, mice were euthanized, and heart tissue was collected for flow cytometry, biochemical analysis, and histology. Statistical significance was assessed using unpaired one-way ANOVA, with p < 0.05 considered significant.
Results: Echo analysis confirmed that HFD/L-NAME induced a similar level of diastolic dysfunction in both WT and KO mice. Preliminary data from flow cytometry indicate that KO of the interferon receptor affects the abundance of intracardiac inflammatory cells, predominantly neutrophils and macrophages, in response to HFD/L-NAME. Additionally, cardiac PCR analysis revealed that KO mice exhibited lower expression of pro-inflammatory markers such as TNFα and interferon-stimulated genes (ISGs) (Fold change: 1.8 ± 0.5 vs. 0.99 ± 0.1 and 1.7 ± 0.8 vs 0.26 ± 0.07, p< 0.05 respectively) compared to WT after exposure to HFD/L-NAME.
Conclusions: While deletion of the interferon receptor in neutrophils did not significantly alter cardiac function in this HFpEF model, it did modulate the inflammatory milieu. These findings warrant further investigation into immune-mediated mechanisms that contribute to the development of HFpEF.