Background
Calcific aortic valve disease (CAVD) is the most frequent valvular heart disease and remains without effective pharmacological therapy. Current treatment is limited to surgical or transcatheter valve replacement. Increasing evidence suggests that lipid accumulation, inflammation, and metabolic dysregulation contribute to disease progression. Recent work from our group indicates a key role of sphingolipids—particularly ceramides—in promoting inflammatory and calcifying processes within the aortic valve. Lipidomics of human CAVD samples demonstrated sphingolipid accumulation in calcified and fibrotic tissue. In a murine CAVD model inhibition of ceramide biosynthesis with Myriocin significantly reduced valve thickening and transvalvular gradients. Due to Myriocin’s toxicity in humans, the present project investigates the clinically approved sphingolipid modulator Fingolimod (FTY720) as a potential therapeutic approach. The study aims to further elucidate the role of sphingolipid metabolism in CAVD pathogenesis and to explore novel metabolic targets for pharmacological intervention.
Methods
A murine model of calcific aortic valve disease (CAVD) was established using ApoE-/- mice fed a high-cholesterol diet and further enhanced by adenoviral PCSK9 overexpression (PCSK9-AAV) to induce hyperlipidaemia. Mice received the sphingolipid pathway modulator Fingolimod (1.25 mg/kg/day, p.o.) for 21 weeks to assess the impact of sphingolipid accumulation, lipotoxicity, and inflammation on aortic valve calcification. After 21 weeks, hemodynamic assessment was performed by transthoracic echocardiography focusing on transvalvular jet velocity, pressure gradients, valve dynamics, and left ventricular dilation. Subsequently organs were harvested for histological and molecular analyses to evaluate calcification, metabolic alterations, and inflammatory responses.
Results
Fingolimod treatment significantly reduced transvalvular peak velocity (Vmax: 0.93 ± 0.23 cm/s vs. control 1.33 ± 0.23 cm/s, p < 0.05) and mean pressure gradient (dpmean: 2.17 ± 1.22 mmHg vs. 3.45 ± 1.17 mmHg, p < 0.05). Valve leaflet thickness was decreased by 38.9 % and histological analyses revealed reduced calcium deposition and macrophage infiltration.
Conclusion
Our data demonstrate that the myriocin analogue fingolimod exerts protective effects in a murine model of aortic valve stenosis and may therefore represent a promising novel therapeutic approach for the treatment of CAVD.
