Abstract
BackgroundDickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke.MethodsWe measured serum Dkk-3 levels in 3344 ischemic stroke patients from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of death and vascular events within 3 months after ischemic stroke.ResultsDuring 3 months of follow-up, the cumulative incidence rates of primary outcome among ischemic stroke patients in five quintiles of serum Dkk-3 (from low to high) were 4.49%, 3.74%, 2.54%, 5.23%, and 6.73%, respectively (log-rank p = 0.004). Multivariable Cox proportional hazards regression analyses showed that compared with the third quintile of serum Dkk-3, the adjusted hazard ratios (95% confidence intervals) associated with the first and fifth quintile were 3.49 (1.46–8.34) and 4.23 (1.86–9.64) for primary outcome, 3.47 (1.06–11.36) and 5.30 (1.81–15.51) for death, and 2.66 (1.01–7.01) and 3.35 (1.33–8.40) for vascular events, respectively. Multivariable-adjusted Cox proportional hazards regression model with restricted cubic splines showed a U-shaped association between serum Dkk-3 and the risk of primary outcome (p for nonlinearity = 0.030). Moreover, adding serum Dkk-3 to conventional risk factors could improve the predictive power for primary outcome (net reclassification improvement 28.44%, p < 0.001; integrated discrimination improvement 0.48%, p = 0.001).ConclusionsBoth low and high serum Dkk-3 levels are associated with increased risks of death and vascular events within 3 months after ischemic stroke, indicating that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke. We also found that serum Dkk-3 might be a prognostic biomarker for ischemic stroke. Further studies are needed to replicate our findings and to determine the optimal levels of serum Dkk-3.
Highlights
Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis
To our knowledge, this is the first study to investigate the association of serum Dkk-3 with death and vascular events after ischemic stroke. In this large-sample multicenter study of ischemic stroke patients, we found a Ushaped association between serum Dkk-3 and the risk of death and vascular events after adjustment for potential confounders. Both low and high serum Dkk-3 levels at baseline were associated with increased risk of poor prognosis, with minimum risk observed in the third quintile of serum Dkk-3
The addition of serum Dkk-3 to conventional prognostic factors could significantly improve the risk prediction for death and vascular events after ischemic stroke, as evidenced by Net reclassification improvement (NRI) and integrated discrimination improvement (IDI). These findings indicate that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke, that is, both too low and too high serum Dkk-3 levels are harmful to the prognosis of ischemic stroke
Summary
Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke. Stroke is the second most common cause of death and the leading cause of long-term disability worldwide [1]. Dickkopf-3 (Dkk-3) is a secreted protein of Dkk family involving in regulating Wnt pathway and determining cell fate during embryonic development [6, 7]. Some studies showed that Dkk-3 could play important roles in the development and progression of atherosclerosis [8, 9]. As an important regulator of cell fate determination [10, 11], Dkk was reported to have certain protective roles against atherosclerosis. Plasma Dkk-3 concentration was inversely related to carotid artery intima-media thickness, and Dkk could promote re-endothelialization after atherosclerosis or artery injury [9]
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