Genetic and In Vitro Inhibition of PCSK9 and Calcific Aortic Valve Stenosis

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Highlights • Aortic stenosis was less prevalent in carriers of the PCSK9 R46L variant. • Variation at the PCSK9 locus influences LDL-C levels, but not Lp(a). • PCSK9 is produced and secreted by aortic valves. • In vitro, PCSK9 inhibition might lower calcification in aortic valve cells. • PCSK9 inhibition could represent a therapeutic strategy for aortic stenosis.
Summary The authors investigated whether PCSK9 inhibition could represent a therapeutic strategy in calcific aortic valve stenosis (CAVS). A meta-analysis of 10 studies was performed to determine the impact of the PCSK9 R46L variant on CAVS, and the authors found that CAVS was less prevalent in carriers of this variant (odds ratio: 0.80 [95% confidence interval: 0.70 to 0.91]; p = 0.0011) compared with noncarriers. PCSK9 expression was higher in the aortic valves of patients CAVS compared with control patients. In human valve interstitials cells submitted to a pro-osteogenic medium, PCSK9 levels increased and a PCSK9 neutralizing antibody significantly reduced calcium accumulation.