Heart failure with preserved ejection fraction (HFpEF) is a cardiovascular disease characterized by telediastolic dysfunction. Main risks factors include advanced age (>67years old), sex (women being more susceptible to develop the disease), and several comorbidities, in particular obesity and diabetes. HFpEF has been shown to be associated with the rarefaction of the coronary small vessels.

The aim of our study was to characterize quantitatively the 3D topological reorganization of the coronary microvasculature of the capillary coronary network in a mouse model of HFpEF.

Experiments were done on 14-week old female C57BL/Ks Leprdb/db mice, accumulating risk factors of human HFpEF (n=7). Leprdb/db mice develop early obesity and type 2 diabetes, and C57BL/Ks mice have an increased risk of renal dysfunction. Eight-week old male C57BL/6J mice were used as normal control (n=7). 3D imaging was done by light-sheet microscopy on iDISCO+ optical cleared hearts after lectin-labeling of the capillaries. Image processing consisted of skeletonization and distance mapping of greyscale segmented images using ImageJ software. Capillary network in the left ventricle (LV), right ventricle (RV), and septum (S) was characterized by the volume network density, the fractal dimension, the average length, diameter, and tortuosity of the segments, and (normalized per mm³ of cardiac tissue) the numbers of segments and nodes and the total network length. Data are given as mean±SD. Differences were significant if P<0.05.

Compared to controls, Leprdb/db mice LV showed a significantly reduced volume density (40±6 vs. 49±9%), number of segments (402,000±68,000 vs. 518,000±110,000), number of nodes (220,000±39,000 vs. 280,000±60,000) and total length (55±1.2 vs. 54±1.7m). LV capillaries were significantly more tortuous than control ones. Leprdb/db mice RV showed a significantly reduced fractal dimension (2.4±0.03 vs. 2.4±0.02), number of segments (339,000±24,000 vs. 401,000±43,000), number of nodes (180,000±14,000 vs. 220,000±25,000) and total length (53±0.6 vs. 54±1.3m). RV capillaries were significantly larger than control ones. S capillary network was not different from control (Fig. 1).

Our study showed that LV capillary network presented signs of rarefaction and structural alterations that may contribute to LV dysfunction in HFpEF. It also evidenced alterations of the RV capillary network architecture, suggesting a possible impairment of RV function.