Secreted Wnt Modulators in Symptomatic Aortic Stenosis

Abstract

Background Valve calcification and inflammation play key roles in the development of aortic stenosis ( AS ). The W nt pathways have been linked to inflammation, bone metabolism, angiogenesis, and heart valve formation. We hypothesized that soluble W nt modulators may be dysregulated in symptomatic AS . Methods and Results We measured circulating levels (n=136) and aortic valve tissue expression (n=16) of the secreted W nt modulators secreted frizzled related protein‐3, dickkopf‐1 ( DKK‐1 ), and W nt inhibitory factor‐1 ( WIF‐1 ) by enzyme immunoassay, immunostaining, and RT‐PCR in patients with symptomatic, severe AS and investigated associations with echocardiographic parameters of AS and cardiac function. Finally, we assessed the prognostic value of these W nt modulators in relation to all‐cause mortality (n=35) during long‐term follow‐up (median 4.6 years; survivors, 4.8 years; nonsurvivors, 1.9 years) in these patients. Our main findings were: (1) serum levels of all W nt modulators were markedly elevated in patients with symptomatic AS (mean increase 231% to 278%, P <0.001), (2) all W nt modulators were present in calcified aortic valves but correlated poorly with systemic levels or degree of AS , (3) some modulators (ie, WIF‐1 ) were associated with the degree of myocardial function and valvular calcification, (4) all W nt modulators, and DKK‐1 in particular, predicted long‐term mortality in these patients also after adjusting for conventional predictors including NT ‐pro BNP . Conclusions Together, these in vivo data support the involvement of W nt signaling in the development of AS and suggest that circulating W nt modulators should be further investigated as risk markers in larger AS populations, including patients with asymptomatic disease.