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Arterioscler Thromb Vasc Biol. 2019 Feb;39(2):294-302. doi: 10.1161/ATVBAHA.118.311042.

Admission Levels of DKK1 (Dickkopf-1) Are Associated With Future Cardiovascular Death in Patients With Acute Coronary Syndromes.

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From the Research Institute of Internal Medicine, National Hospital (T.U., A.E.M., P.A.), University of Oslo, Norway.
K.G. Jebsen Inflammatory Research Center (T.U., P.A.), University of Oslo, Norway.
K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Norway (T.U., P.A.).
Division of Cardiology, Department of Medical Sciences (A.Å, S.K.J., L.W.), Uppsala University, Sweden.
Uppsala Clinical Research Center (A.Å, T.G., M.B., S.K.J., A.S., L.W.), Uppsala University, Sweden.
Division of Cardiovascular Health and Disease, Heart, Lung and Vascular Institute, University of Cincinnati College of Medicine, OH (R.C.B.).
AstraZeneca Research and Development, Gothenburg, Sweden (A.H.).
Department of Medical Sciences, Clinical Chemistry (A.S.), Uppsala University, Sweden.
Department of Infection, Immunity, and Cardiovascular Disease, University of Sheffield, United Kingdom (R.F.S.).
Department of Cardiology, Stavanger University Hospital, Norway (F.K.).
Drammen Heart Center, Norway (F.K.).
Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway (P.A.).


Objective- The Wnt/wingless signaling antagonist DKK1 (dickkopf-1) regulates platelet-mediated inflammation and may contribute to plaque destabilization. We hypothesized that DKK1 would be associated with cardiovascular outcomes. Approach and Results- We determined DKK1 levels in serum samples obtained before randomization, at discharge, and 1 and 6 months in a subset of 5165 patients with acute coronary syndromes in the PLATO trial (Platelet Inhibition and Patient Outcomes; NCT00391872). The median (interquartile range) DKK1 concentrations were 0.61 (0.20-1.27) ng/mL at baseline and increased during follow-up. The hazard ratio (95% CIs) for the composite end point (cardiovascular death, nonprocedural spontaneous myocardial infarction, or stroke) during 1 year of follow-up, per 50% increase in baseline DKK1 concentration, was 1.06 (1.02-1.10), P=0.0011, and remained significant in fully adjusted analysis with 14 conventional clinical and demographic and 6 biochemical variables, including NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-TnT (high-sensitivity troponin T), and GDF-15 (growth differentiation factor 15; 1.05 [1.00-1.09]; P=0.028). This association was mainly driven by the association with cardiovascular death, where a gradual increase in event rates was observed with increasing quartiles of DKK1 (2.7%, 3.0%, 4.3%, and 5.0%) and remained significant and unmodified in fully adjusted analysis (hazard ratio, 1.10 [1.04-1.17]; P=0.002). Change in DKK1 and levels at 1 month were unrelated to outcomes. A modifying effect of ticagrelor on DKK1 discharge levels was observed but not associated with prognosis. Conclusions- In patients with acute coronary syndromes treated with dual antiplatelet treatment, admission DKK1 levels were independently associated with a composite of cardiovascular death, myocardial infarction, or stroke and with cardiovascular death alone.


acute coronary syndrome; blood platelets; follow-up studies; humans; myocardial infarction


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