Open AccessSecreted W nt Modulators in Symptomatic Aortic Stenosis
Author(s) -
Askevold Erik Tandberg,
Gullestad Lars,
Aakhus Svend,
Ranheim Trine,
Tønnessen Theis,
Solberg Ole G.,
Aukrust Pål,
Ueland Thor
Publication year - 2012
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.112.002261
Subject(s) - wnt signaling pathway , medicine , wnt3a , calcification , inflammation , cardiology , etanercept , stenosis , lrp5 , endocrinology , pathology , signal transduction , microbiology and biotechnology , tumor necrosis factor alpha , biology
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.