A Synergistic Effect between Plasma Dickkopf-1 and Obstructive Coronary Artery Disease on the Prediction of Major Adverse Cardiac Events in Patients with Angina: An Observational Study

Abstract

The canonical β-catenin-dependent wingless (Wnt) pathway is associated with endothelial function. We examined the effect of plasma dickkopf-1 (DKK-1), an inhibitor of the Wnt pathway, on the prediction of major adverse cardiac events (MACEs). We enrolled patients who had undergone selective coronary angiography for angina. DKK-1 levels were determined using plasma collected at the outpatient visit after fasting. MACEs served as the primary endpoint. All 470 enrolled patients were divided into four groups according to their median plasma DKK-1 levels and the presence of obstructive coronary artery disease (CAD). Forty-eight patients reached the primary endpoint during a median follow-up time of 4.8 years. Kaplan-Meier survival analysis indicated that the group with high DKK-1 and obstructive CAD had a significantly higher mortality rate than the other three groups (log-rank test p = 0.001). Compared with the low plasma DKK-1 without significant coronary obstruction group, the high DKK-1 with obstructive CAD group had a hazard ratio of 10.640 (95% confidence interval: 1.350-83.874) for MACEs, as determined by multivariable Cox proportional hazard regression analysis. In conclusion, we observed a synergistic effect between high plasma DKK-1 and obstructive CAD on the prediction of MACEs in patients with angina.

Keywords: coronary artery disease; death; dickkopf-1; major adverse cardiac events; myocardial infarction; obstruction; stroke.

Figure 1

The comparison of the plasma concentrations of dickkopf-1 between patients without coronary artery disease (CAD) and those with CAD (614 ± 192 vs. 606 ± 187, p = 0.622).

Figure 2

Flow diagram of the enrollment of the study participants. Abbreviation: CAD = coronary artery disease, DKK-1 = dickkopf-1, and MACEs = major adverse cardiac events.

Figure 3

Kaplan–Meier curves showing the risk of major adverse cardiac events (MACEs) across the four groups, categorized using the median dickkopf-1 (DKK-1) value of 610 pg/mL and coronary artery disease (CAD) status (log-rank test: p = 0.001).

Figure 4

The Harrell’s concordance index (C index) for the prediction of major adverse cardiac events in the Framingham Risk Score (FRS)-alone model (model 1), in the FRS and coronary artery disease (CAD) model (model 2), and in the model adding dickkopf-1 (DKK-1) to FRS and CAD (model 3). Model 3 presents a significant improvement in predictive ability compared with model 2 (p = 0.027 according to integrated discrimination improvement and p = 0.033 according to continuous net reclassification improvement).