Background: Heart failure affects over 60 million people worldwide. A growing proportion of these cases is attributable to heart failure with preserved ejection fraction (HFpEF), which now accounts for over 50% of heart failure patients. HFpEF is associated with various predisposing factors, including coronary artery disease, renal dysfunction, hypertension, type II diabetes and obesity.
Study objective: Elucidate the role of immune cells, with a particular focus on neutrophils, and investigate potential sex-specific differences in the immune response during the development of HFpEF.
Methods: As a model of HFpEF, C57Bl/6N mice were subjected to combined metabolic and mechanical stress by feeding with high-fat diet (HFD) and inhibition of constitutive nitric oxide synthase using Nω-nitro-L-arginine methyl ester (L-NAME; PMID: 30971818). Changes in the composition of immune cells in the heart and blood were assessed after 5 weeks using flow cytometry.
Results: Treatment with HFD + L-NAME (HFpEF group) led to pronounced body weight gain (14±7% vs. 21±4%) and increase in E/E’ ratio (26±2 vs. 30±5) in male mice compared untreated controls. The proportion of myeloid cells, predominantly neutrophils, was increased in the blood (31±14% vs. 48±15% of CD45+) and hearts (16±8% vs. 22±9% of CD45+) of male HFpEF mice, whereas no changes were observed in the blood (13±3% vs. 15±4% of CD45+) and hearts (9±2% vs. 9±4% of CD45+) of female HFpEF mice compared to sex-matched controls. In particular, the proportion of immature neutrophils was significantly higher in hearts of male HFpEF mice compared to corresponding controls (69±8% vs. 87±3% of neutrophils; p=0,0001, two tailed Welch’s test). Furthermore, the E/E’ ratio correlated with the proportion of neutrophils in both the heart (r= 0,5214, p=0,0019) and blood (r = 0,4090, p = 0,0181).
Conclusion: These findings suggest that neutrophils are associated with the manifestation of HFpEF in male mice, while females are protected against neutrophil-driven cardiac inflammation in response to metabolic and mechanical stress. The causal role of neutrophils in this model and underlying mechanisms for sex-specific differences deserve further investigation.
(Data given as Mean ± Standard Deviation)
