Galectin-3 Is Elevated and Associated With Adverse Outcomes in Patients With Single-Ventricle Fontan Circulation

Abstract

Background: Galectin-3 may play a role in cardiac and noncardiac fibrosis, and elevated circulating levels of this protein predict adverse outcomes in patients with heart failure who do not have congenital heart disease. We investigated galectin-3 in adults with single-ventricle Fontan circulation, patients who are prone to premature clinical deterioration in the context of extensive multiorgan fibrosis.

Methods and results: We measured plasma galectin-3 concentrations in 70 ambulatory adult Fontan patients and 21 age- and sex-matched control participants. Galectin-3 level was significantly higher in the Fontan group (11.85 ng/mL, interquartile range 9.9 to 15.0 ng/mL) versus the control group (9.4 ng/mL, interquartile range 8.2 to 10.8 ng/mL; P<0.001). Among Fontan patients, galectin-3 was positively correlated with age, uric acid, and high-sensitivity C-reactive protein and negatively correlated with estimated glomerular filtration rate. There was no significant relationship between galectin-3 and oxygen saturation, Fontan type, or ventricular morphology. Over a median follow-up of 461 days, 15 events occurred among the Fontan patients: 12 nonelective hospitalizations (with 2 subsequent deaths) and 3 deaths without prior hospitalization. Patients with elevated galectin-3 (n=19, defined as >2 SD above the control group mean value) had a higher risk of nonelective hospitalization or death (hazard ratio 6.0, 95% CI 2.1 to 16.8, P<0.001). This relationship persisted after individual adjustment for covariates including age, New York Heart Association functional class, C-reactive protein, and estimated glomerular filtration rate and after multivariable adjustment for independently predictive covariates (hazard ratio 9.2, 95% CI 2.4 to 35.2, P=0.001).

Conclusions: Galectin-3 concentrations are elevated among adults with a Fontan circulation, and elevated galectin-3 is associated with an increased risk of nonelective cardiovascular hospitalization or death.

Keywords: Fontan procedure; adult congenital heart disease; biomarker; congenital heart disease; galectin‐3.

Figure 1

Distribution of galectin‐3 values for Fontan participants and an age‐ and sex‐matched control group. A, Absolute galectin‐3 values for Fontan participants and the control group; the error bars represent the 25th to 75th percentiles. The dashed line designates 14.3 ng/mL, the cutoff used to define elevated galectin‐3 in this study. B, Cumulative distribution of galectin‐3 for control and Fontan participants, logarithmic scale. Numbers adjacent to respective curves designate the median value bounded by the first and third quartiles. The Wilcoxon rank sum test was used to compare galectin‐3 level between groups.

Figure 2

Associations between galectin‐3 and age (A), estimated glomerular filtration rate (B), and C‐reactive protein (C) among patients with a Fontan circulation. Galectin‐3 is plotted on a natural logarithmic scale, as is C‐reactive protein in (C). The horizontal dotted line signifies a galectin‐3 level of 14.3 ng/mL. eGFR indicates estimated glomerular filtration rate using the Chronic Kidney Disease Epidemiology Collaboration formula.27

Figure 3

Kaplan–Meier plot of event‐free survival stratified by galectin‐3 level ≤14.3 or >14.3 ng/mL. A Kaplan–Meier plot of risk in each group from time of blood draw is listed below the graph; hash marks designate censored observations. Event‐free survival refers to survival without nonelective cardiovascular or Fontan‐related hospitalization. Number of participants at risk in each group is listed below the x‐axis. A small subset of participants (3 of 51 and 2 of 19 in the normal and elevated galectin‐3 groups, respectively) had no follow‐up time.