Reduced Fetuin-A Levels Are Associated With Exercise Intolerance and Predict the Risk of Adverse Outcomes in Patients With Heart Failure: The Role of Cardiac-Hepatic-Peripheral Interaction

Abstract

Background: Exercise intolerance in heart failure arises from multifactorial pathophysiological mechanisms. Hepatokines, liver-synthesized molecules, regulate systemic metabolisms in peripheral tissues. We previously identified the hepatokine fetuin-A as being linked to liver hypoperfusion in heart failure. Here, we investigated the role of fetuin-A in connecting cardiac-hepatic-peripheral interaction.

Methods and results: We conducted a prospective study involving 202 consecutive hospitalized patients (mean age, 56.8 years; 76.2% men) with heart failure who underwent cardiopulmonary exercise testing. We measured the serum concentration of fetuin-A by ELISA. Correlation analysis revealed a negative association between fetuin-A levels and the ratio of minimum minute ventilation to carbon dioxide production, its slope, and a tendency toward a positive correlation with peak oxygen uptake. Patients with impaired exercise tolerance exhibited lower fetuin-A levels. During a median follow-up of 1045 days, 18.3% experienced cardiac events, including 4 cardiac deaths and 33 cases of worsening heart failure. Classification and regression tree analysis identified a high-risk subgroup with lower fetuin-A (<24.3 mg/L) and impaired exercise tolerance (peak oxygen uptake<14.2 mL/kg per min). Kaplan-Meier analysis revealed that this subgroup had the highest risk of cardiac events. In a multivariable Cox proportional hazard model, the combination of lower fetuin-A and exercise intolerance was independently associated with increased risks of cardiac events.

Conclusions: Reduced circulating fetuin-A levels were associated with exercise intolerance in heart failure patients. Fetuin-A could emerge as a target implicated in exercise capacity connecting cardiac-hepatic-peripheral interaction and as a valuable biomarker for predicting prognosis when combined with peak oxygen uptake.

Keywords: biomarker; exercise intolerance; fetuin‐A; heart failure; hepatokine.

Figure 1. Classification and regression tree analysis to determine the cutoff values for predictors associated with cardiac events based on fetuin‐A levels and peak oxygen uptake (VO₂).

A and B, Classification and regression tree decision tree for fetuin‐A and peak Vo ₂ to derive predictors associated with cardiac events. Each node in these trees displays the corresponding value of fetuin‐A, along with the calculated Gini index. The number displayed on each node represents the patients included within that particular node. The lower section of the table shows the distribution of patient counts at each node. C, A table categorizes patients into 4 groups based on the parameters established in (A) and (B). ET indicates exercise tolerance; and Vo ₂, oxygen uptake.

Figure 2. Fetuin‐A levels between patients with impaired and preserved ET.

Serum fetuin‐A levels in heart failure patients with peak Vo ₂ <14.2 mL/kg per min (impaired exercise tolerance, n=88) and peak Vo ₂≥14.2 mL/kg per min (preserved exercise tolerance, n=114). The serum fetuin‐A concentrations were measured by ELISA. Comparisons of values between the 2 groups were performed by the Mann–Whitney U test. All data are presented as median (interquartile range). ET indicates exercise tolerance.

Figure 3. Kaplan–Meier analysis for cardiac events rates stratified by fetuin‐A levels and peak Vo ₂.

Patients were categorized into four groups based on serum fetuin‐A levels of 24.3 mg/L and peak Vo ₂ at 14.2 mL/kg per min, during the median follow‐up of 1045 days, 37 composite cardiac events occurred, including 4 cardiac deaths and 33 worsening heart failure. The log‐rank test was performed for the statistical comparison. ET indicates exercise tolerance; and Vo ₂, oxygen uptake.