In 2019, Schiattarella et al introduced a new mouse model mimicking heart failure with preserved ejection fraction (HFpEF). In this model, diastolic dysfunction is induced by a high fat diet (HFD) regimen together with L-NAME treatment. Even though small vessel disease is currently proposed to be responsible for HFpEF, the phenotype of the cardiac microvasculature has not been described in this model.

To characterize the phenotype of the cardiac microvasculature in this model.

Ovariectomized C57Bl6/J female mice were fed with HFD (60% kCal from fat) from 8 weeks of age. Discontinuous L-NAME (1g/L in the drinking water, 4 days a week) treatment was initiated 2 week later. Cardiac function was assessed via echocardiography and left ventricle (LV) catheterization at 20 weeks of age. Immediately after, mice were sacrificed for histological and gene expression analyses.

Consistently with Schiattarella et al data, HDF+L-NAME treated mice displayed increased end diastolic pressure [12.8±0,9mmHg vs. 4.0±0,6 in control mice (P<0,001)] with a preserved LV ejection fraction. Diastolic dysfunction was associated with cardiac hypertrophy and fibrosis. In these mice, capillary density was identical to that of control mice. However, capillaries display clear signs of endothelial dysfunction with an increased permeability to albumin and an increased expression of ICAM1 (172±16% of control mice, P<0.01) and E-selectin (295±71% of control mice, P<0.05). Endothelial cell activation was associated with an increased infiltration of CD45+ leucocytes especially, CD68+ macrophages, B220+B-lymphocytes and CD3+ T-Lymphocytes. Mural cell coverage was not modified.

Diastolic dysfunction observed in HFD+L-NAME treated mice is associated with endothelial dysfunction supporting that small vessel disease especially increased endothelial permeability and or activation could play a central role in the pathophysiology of HFpEF.