Association of ficolin-3 with severity and outcome of chronic heart failure

Abstract

Background: Inflammatory mechanisms involving complement activation has been shown to take part in the pathophysiology of congestive heart failure, but the initiating mechanisms are unknown. We hypothesized that the main initiator molecules of the lectin complement pathway mannose-binding lectin (MBL), ficolin-2 and ficolin-3 were related to disease severity and outcome in chronic heart failure.

Methods and results: MBL, ficolin-2 and ficolin-3 plasma concentrations were determined in two consecutive cohorts comprising 190 patients from Hungary and 183 patients from Norway as well as controls. Disease severity and clinical parameters were determined at baseline, and all-cause mortality was registered after 5-years follow-up. In univariate analysis a low level of ficolin-3, but not that of MBL or ficolin-2, was significantly associated with advanced heart failure (New York Heart Association Class IV, p<0.001 for both cohorts) and showed inverse correlation with B- type natriuretic peptide (BNP) levels (r = -0.609, p<0.001 and r = -0.467, p<0.001, respectively). In multivariable Cox regression analysis, adjusted for age, gender and BNP, decreased plasma ficolin-3 was a significant predictor of mortality (HR 1.368, 95% CI 1.052-6.210; and HR 1.426, 95% CI 1.013-2.008, respectively). Low ficolin-3 levels were associated with increased complement activation product C3a and correspondingly decreased concentrations of complement factor C3.

Conclusions: This study provides evidence for an association of low ficolin-3 levels with advanced heart failure. Concordant results from two cohorts show that low levels of ficolin-3 are associated with advanced heart failure and outcome. The decrease of ficolin-3 was associated with increased complement activation.

Figure 1. Association of MBL (panels A–B), ficolin-2 (C–D) and ficolin-3 (E–F) levels with severity of CHF.

P values of non-parametric Kruskall-Wallis test are indicated across NYHA class groups, stars indicate results of Dunnet’s post hoc test (*p<0.05, **p<0.01; as compared to NYHA I on panel E and NYHA II on panel F). Medians, 25 and 75 percentiles and ranges are indicated on logarithmic scales.

Figure 2. Univariate correlation of ficolin-3 levels with NT-proBNP (A and B) and complement C3 (C and D).

Pearson’s correlation coefficients and p values are indicated.

Figure 3. Kaplan-Meier plot of baseline ficolin-3 levels (<15.0 µg/ml, thick line and > = 15.0 µg/ml, thin line) and long term survival (all-cause mortality) in patients with CHF.

Log-rank test for the Hungarian cohort (panel A) and for the Norwegian cohort (panel B) is indicated.