Pulmonary hypertension induced right heart failure via upregulation of serum Dickkopf-1 expression

Pulmonary hypertension (PH)-induced right heart failure (RHF) is a progressive syndrome characterized by right ventricular (RV) enlargement and dysfunction. This study aimed to investigate factors associated with PH-induced RHF, with a focus on the role of Dickkopf-1 (DKK1).

Clinical data and serum samples were collected from healthy controls (n = 18), patients with PH (n = 29), and PH-RHF (n = 75). DKK1 expression was quantified in serum and RV tissue.

Serum DKK1 levels were significantly elevated in PH and PH-RHF patients compared to controls (1396.36 ± 413.40 vs. 2502.51 ± 962.81 vs. 3798.33 ± 1936.17 pg/mL, P < 0.001). Higher DKK1 levels were associated with impaired RV function, reflected by reduced TAPSE (P = 0.025), lower TAPSE/sPAP ratio (P = 0.024), and elevated sPAP (P = 0.017). DKK1 also correlated with invasive hemodynamic parameters, including RVP (P = 0.006), mPAP (P < 0.001), PVR (P = 0.014), SVR (P = 0.003), CO (P = 0.023), and CI (P = 0.002). Experimental models demonstrated marked DKK1 upregulation in hypoxia-stimulated cardiomyocytes and in serum and RV tissue of monocrotaline-treated and PAB rats.

Elevated DKK1 levels are associated with worsening RV dysfunction in PH, suggesting a potential pathogenic role in PH-induced RHF. DKK1 may serve as a complementary biomarker and a potential therapeutic target in PH-related RHF.