Abstract 8197: Serum Dickkopf-1 Level Predicts Cardiac Events in Chronic Heart Failure Patients

Background: The Wnt signaling pathway is an important regulator of adult tissue maintenance and homeostasis. Disorder in Wnt signaling pathway causes cancer, human degenerative disease, and aging-associated heart disorders such as diastolic dysfunction. Dickkopf-1 (DKK-1) is negative regulator protein of the Wnt signaling pathway and is associated with a variety of organic diseases. Chronic heart failure (CHF) is characterized by systemic abnormalities and the myocardium is continually exposed to various stressors such as anoxia, ischemia, inflammation, and free radicals. Increasing age had been reported to increase mortality of CHF patients. Under the hypothesis that DKK-1 as a regulator protein is involved in ventricular remodeling, ongoing myocardial damage, and aging-associated disorders, we aimed to examine the prognostic value of serum DKK-1 in patient with CHF. Methods and Results: Serum DKK-1 level was measured in 210 CHF patients and 62 control subjects by the competitive enzyme-linked immunosorbent assay. Patients were prospectively followed with endpoints of cardiac death or re-hospitalization for worsening CHF during a median follow-up period of 720 days. Serum DKK-1 level was higher in CHF patients than in control subjects and increased with advancing NYHA functional class (P < 0.0001). Furthermore, serum DKK-1 level was significantly increased with aging. There were 88 cardiac events during follow-up period (42%). Serum DKK-1 level was significantly higher in patients with cardiac events than those in event free patients. Kaplan-Meier analysis clearly demonstrated that the high DKK-1 group had a significantly higher incidence of cardiac events than the low DKK-1 group (P < 0.0001). Patients were divided into 3 groups based upon DKK-1 level, and the highest 3rd tertile was associated with the highest risk of cardiac events (8.68-fold compared to the 1st tertile). In the multivariate Cox analysis, DKK-1 level was an independent risk factor for cardiac events (hazard ratio 3.66, 95% confidence interval 1.49-4.76, P = 0.0015). Conclusion: Elevated serum DKK-1 level, a major antagonist of the Wnt signaling pathway, is associated to increased cardiac events and provides prognostic information in CHF patients.