Aims: Heart failure with preserved ejection fraction (HFpEF) is characterized by diastolic dysfunction and cardiac hypertrophy. Leukocytes are an integral part of the healthy myocardium, which may have protective functions but also contribute to cardiac pathologies. This study aims to unravel phenotypic and genetic changes in cardiac immune cells during heart failure with preserved ejection fraction.

Methods and results: We implemented a model of nitrosative stress, in which mice were treated with a combination of high-fat diet with the administration N^ω-nitro-L-arginine methyl ester (L-NAME) for 11 weeks. Mice were analyzed with echocardiography and histology to verify the presence of HFpEF features. Inflammatory changes were assessed with flow cytometry and histology. Single Cell RNA sequencing was performed on sorted cardiac leukocytes in mice with HFpEF. The myocardium in HFpEF is characterized by changes in leukocyte composition and the emergence of Trem2-expressing macrophages, which might mediate both, tissue inflammation and the adaptive response to cardiac injury. Specifically, the fractalkine receptor CX3CR1 was upregulated in Trem2-expressing macrophages. Therefore, we tested the effect of the CX3CR1 inhibitor AZD8797 in HFpEF development. Here, we observed improvements in hemodynamic function (HFpEF-PBS E/e`= 39,29 vs. HFpEF-AZD8797= 32,51, p-value= 0,0326) and cardiac structure (HFpEF-PBS left atrium size= 4,482mm², HFpEF-AZD8797 left atrium size= 3.935 mm², p-value= 0,017) after five weeks of treatment.

Conclusion: CX3CR1 is expressed in a subset of TREM2 expressing macrophages, which substantially expand in a mouse model of HFpEF. CX3CR1 inhibition results in an improvement of cardiac function in mice with HFpEF. Further analysis of the effects instigated by TREM2 expressing macrophages is required, especially as anti-TREM2 therapies are tested in oncology trials and Alzheimers disease.