Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model

Aims Aortic stenosis (AS) is associated with significant morbidity and mortality. Recombinant apolipoprotein A-I Milano (rApoA-IM) induces atherosclerotic plaque regression. The Aims of this study were to determine the effects of rApoA-IM on experimental aortic valve degeneration and its mechanisms of action. Methods and results New Zealand White rabbits (n = 20) were fed an atherogenic diet for 9 months and then randomized to either placebo or rApoA-IM. Echocardiography was used to assess the effect of the treatments on AS. Porcine aortic valve myofibroblasts (PAVMF) treated with oxidized low-density lipoprotein served to define the effects of rApoA-IM on the expression of monocyte chemoattractant protein-1 (MCP-1), nuclear factor (NF)-B, and alkaline phosphatase (AP). Recombinant apolipoprotein A-I Milano increased aortic valve area (AVA) by 32 (0.25 ± 0.05 to 0.34 ± 0.07 cm², P < 0.01); whereas AVA remained unchanged in the placebo group (0.24 ± 0.05 to 0.26 ± 0.04 cm², P = 0.58). Histopathological examination of aortic valves in the rApoA-IM animals showed significantly less leaflet thickening, inflammation, and calcification vs. the placebo group. In vitro, rApoA-IM significantly inhibited MCP-1, AP, and NF-B and decreased intracellular cholesterol content in PAVMF. Conclusion Recombinant apolipoprotein A-I Milano treatment reverses AS in this experimental rabbit model. The beneficial effects seem to be mediated by enhanced cholesterol removal and by reduced inflammation and calcification.