title: Secreted Wnt modulators in symptomatic aortic stenosis.
abstract: BACKGROUND
  Valve calcification and inflammation play key roles in the development of aortic stenosis (AS). The Wnt pathways have been linked to inflammation, bone metabolism, angiogenesis, and heart valve formation. We hypothesized that soluble Wnt modulators may be dysregulated in symptomatic AS.
  
  
  RESULTS
  We measured circulating levels (n=136) and aortic valve tissue expression (n=16) of the secreted Wnt modulators secreted frizzled related protein-3, dickkopf-1 (DKK-1), and Wnt 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 Wnt 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 Wnt modulators were markedly elevated in patients with symptomatic AS (mean increase 231% to 278%, P<0.001), (2) all Wnt 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 Wnt modulators, and DKK-1 in particular, predicted long-term mortality in these patients also after adjusting for conventional predictors including NT-proBNP.
  
  
  CONCLUSIONS
  Together, these in vivo data support the involvement of Wnt signaling in the development of AS and suggest that circulating Wnt modulators should be further investigated as risk markers in larger AS populations, including patients with asymptomatic disease.
authors: Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.
authors: Erik Tandberg
authors: ET
authors: Askevold
authors: Lars
authors: L
authors: Gullestad
authors: Svend
authors: S
authors: Aakhus
authors: Trine
authors: T
authors: Ranheim
authors: Theis
authors: T
authors: Tønnessen
authors: Ole G
authors: OG
authors: Solberg
authors: Pål
authors: P
authors: Aukrust
authors: Thor
authors: T
authors: Ueland
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000097:blood* / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D001021:Aortic Valve / Q000378:metabolism / Q000601:surgery; D001024:Aortic Valve Stenosis / Q000378:metabolism* / Q000401:mortality / Q000503:physiopathology / Q000601:surgery; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D015150:Echocardiography, Doppler; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000097:blood* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D011237:Predictive Value of Tests; D011379:Prognosis; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000097:blood* / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism* / Q000502:physiology; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; D012097:Repressor Proteins; D051153:Wnt Proteins; D000094742:Secreted Frizzled-Related Proteins; C501126:DKK1 protein, human; C485569:WIF1 protein, human
keywords: Wnt; aortic stenosis; mortality; prognosis