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A Minimally Invasive Model of Aortic Stenosis in Swine

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Secreted Wnt modulators in symptomatic aortic stenosis.

Erik Tandberg Askevold¹, Lars Gullestad, Svend Aakhus

¹Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, Oslo, Norway.

Journal of the American Heart Association

|January 15, 2013

Summary

Circulating Wnt modulators are elevated in symptomatic aortic stenosis (AS) and predict mortality. These findings suggest Wnt signaling involvement in AS development and potential use as risk markers.

Keywords:

Wnt aortic stenosis mortality prognosis

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Area of Science:

Biochemistry
Cardiovascular Biology
Molecular Medicine

Background:

Aortic stenosis (AS) pathogenesis involves valve calcification and inflammation.
Wnt pathways are implicated in inflammation, bone metabolism, angiogenesis, and heart valve development.
Soluble Wnt modulators may be dysregulated in symptomatic AS.

Purpose of the Study:

To investigate circulating levels and aortic valve tissue expression of Wnt modulators in symptomatic severe AS.
To assess associations between Wnt modulators, AS echocardiographic parameters, and cardiac function.
To evaluate the prognostic value of Wnt modulators for long-term mortality in AS patients.

Main Methods:

Enzyme immunoassay, immunostaining, and RT-PCR were used to measure secreted frizzled related protein-3, dickkopf-1 (DKK-1), and Wnt inhibitory factor-1 (WIF-1).
Measurements were performed in serum (n=136) and aortic valve tissue (n=16) from symptomatic severe AS patients.
Prognostic value was assessed concerning all-cause mortality over a median follow-up of 4.6 years.

Main Results:

Serum levels of all Wnt modulators were significantly elevated in symptomatic AS patients (231%-278% increase).
Wnt modulators were present in aortic valves but showed poor correlation with systemic levels or AS severity.
WIF-1 correlated with myocardial function and valvular calcification; all modulators, especially DKK-1, predicted long-term mortality, even after adjusting for NT-proBNP.

Conclusions:

In vivo data support Wnt signaling's role in AS development.
Circulating Wnt modulators show potential as risk markers for AS.
Further investigation in larger AS cohorts, including asymptomatic patients, is warranted.