Background:

Aortic valve stenosis (AS) is the most common valve disease worldwide and is associated with a very high morbidity and mortality. Yet, no treatment options to prevent or positively modify the progression of AS are available. In the pathogenesis of AS, increased levels of free cholesterol accumulate in subendothelial layers of the aortic valve cusps and precipitate to cholesterol crystals (CC). Through the activation of the NLRP3 inflammasome, CC trigger a complex inflammatory response and aggravate the development of AS. 2-hydroxypropyl-β-cyclodextrin (CD) is a cyclic oligosaccharide that promotes the solubility of CCs, which results in a reduction of CC-load and therefore inhibits the pro-inflammatory immune response.

Methods:

AS was induced in 10 weeks old C57BL/6-J (WT) and Apolipoprotein-E-deficient (ApoE) mice. For this, a coronary spring wire was introduced into the left ventricle and was pushed and rotated over the aortic valve under echocardiographic guidance. ApoE mice were fed a cholesterol-rich western diet (WD) and concomitantly received daily injections of 2g/kg/d CD via subcutaneous injection. Cholesterol crystals were visualized with laser reflection confocal microscopy. Serum cholesterol analysis were performed via mass GC-MS-SIM.

Results: Compared to WT, ApoE mice that were fed a cholesterol-rich diet developed aggravated AS after wire injury, highlighting the negative effect of hypercholesterolemia on AS pathogenesis. Histological analysis revealed large CC-deposits in the aortic valves of ApoE mice. Interestingly, mice treated with CD displayed a significantly reduced peak blood velocity over the aortic valve while maintaining normal left ventricular function. In serum cholesterol analysis, CD treatment induces the synthesis of 27-hydroxycholesterol, an endogenous oxysterol of cholesterol metabolism, which reduces the potential for the conversion of free cholesterol into crystals. The endogenous regulation of cholesterol metabolism is not negatively affected, as the synthesis of cholesterol precursors and the concentration of phytosterols as the body's own absorption inhibitors are not altered.

Conclusion: These results underline the importance of CC as inflammatory triggers in the development of AS and demonstrate the increasing solubility of cholesterol through CD. Because the use of CD in humans is considered safe, it may be a clinically viable treatment option for aortic valve disease.