Abstract Body: Background: Aortic stenosis is a progressive disease characterized by advancing aortic valve fibrosis and calcification. However, no pharmacological therapy has been established to slow disease progression. Although the sodium-glucose cotransporter 2 inhibitor empagliflozin has demonstrated significant cardiovascular benefits, its effects on aortic valve remodeling remain unclear.
Aims: This study aimed to determine whether empagliflozin suppresses the progression of aortic valve fibrosis and calcification and preserves valve function in a murine aortic valve wire injury (AVWI) model.
Methods: Male C57BL/6 mice aged 8–12 weeks were assigned to three groups (n=10 per group): sham, AVWI+vehicle, and AVWI+empagliflozin. AVWI was induced by inserting a guidewire via the right carotid artery to injure the aortic valve, and sham mice underwent the same surgery without valve injury. At week 2, AVWI mice with a peak aortic jet velocity (PeakV) >2.0 m/s were randomized to receive empagliflozin (3 mg/kg/day via osmotic pump) or vehicle. Echocardiography was performed at baseline and at weeks 2, 4, 8, and 12. At week 12, the aortic valves were harvested for histological and immunohistochemical analyses.
Results: PeakV increased by week 2, reaching 2.39±0.24 m/s in the empagliflozin group and 2.37±0.29 m/s in the vehicle group at week 2 (P = 0.91) (sham 1.17±0.12 m/s). After week 4 onward, PeakV remained stable in the empagliflozin group, but continued to rise in the vehicle group (P < 0.001 for group-by-time interaction). At week 12, PeakV was significantly lower in the empagliflozin group than in the vehicle group (2.00±0.41 m/s vs. 3.33±0.60 m/s, P < 0.001; sham 1.27±0.20 m/s). Empagliflozin also attenuated the increases in relative wall thickness (0.50±0.06 vs. 0.58±0.08, P = 0.021) and heart weight-to-body weight ratio (3.12±0.25 mg/g vs. 3.95±0.99 mg/g, P = 0.028). Histology showed that empagliflozin reduced AVWI-induced increases in valve area and leaflet thickness. Furthermore, empagliflozin attenuated fibrosis remodeling (Masson’s trichrome and Sirius Red) and calcification (von Kossa) while reducing the expression of RUNX2 and αSMA, compared with the vehicle group.
Conclusions: Empagliflozin suppresses aortic valve fibrosis and calcification, preventing the deterioration of valve function in a murine AVWI model. Empagliflozin may be a promising pharmacological strategy for attenuating the progression of fibrotic and calcific aortic valve disease.