Prognostic Significance of Interleukin-34 (IL-34) in Patients With Chronic Heart Failure With or Without Renal Insufficiency

Abstract

Background: Renal dysfunction, commonly associated with cardiac dysfunction, has predictive value for adverse long-term outcomes in heart failure (HF). We previously identified a novel renal biomarker, interleukin-34 (IL-34), elevated in HF patients and associated with kidney dysfunction and coronary artery disease during HF. However, the prognostic value of IL-34 in HF remains unclear, so that the present study aimed to determine it.

Methods and results: This prospective, observational study included 510 consecutive HF patients with their serum IL-34 as well as other variables measured at baseline, and they were followed up for 2 years. The primary end point was a composite of cardiovascular death or a first HF hospitalization, with cardiovascular death, HF hospitalization, and all-cause mortality as secondary outcomes. There was a significant and gradual increase in risk as IL-34 increased, determined by log-rank tests with Kaplan-Meier curves. Serum IL-34 was also a significant prognostic predictor of the primary end point (1.301 [1.115-1.518]; P=0.001), cardiovascular death (1.347 [1.096-1.655]; P=0.005), HF hospitalization (1.234 [1.018-1.494]; P=0.032), and all-cause mortality (1.343 [1.115-1.618]; P=0.002) in HF as per SD increase in the log IL-34 level after adjusting for age, sex, traditional risk factors, and N-terminal pro-brain natriuretic peptide. Especially, IL-34 had a more-significant prognostic value in HF patients with kidney impairment than those without.

Conclusions: IL-34 is a significant predictor of cardiovascular death, HF hospitalization, and all-cause mortality in chronic HF, especially when concomitant with renal dysfunction. Serum IL-34 measurement may provide new insights linking kidney impairment to poor HF outcomes beyond other renal markers.

Keywords: heart failure; interleukin‐34; prognosis; renal insufficiency.

Figure 1

Serum IL‐34 level can predict poor outcomes in heart failure. Kaplan–Meier curves for the primary end point (A) and the three secondary end points of cardiovascular death (B), HF hospitalization (C), and all‐cause mortality (D) according to the quartiles of serum IL‐34 levels. Differences among groups were evaluated with the log‐rank test. HF indicates heart failure; IL, interleukin.

Figure 2

Serum IL‐34 level predicted poor outcomes in heart failure, especially in those with renal dysfunction. A, Kaplan–Meier curves for the primary end point of 4 groups divided using the median IL‐34 level and an eGFR=60 mL/min per 1.73 m² as the cut‐off values: non‐CKD with IL‐34 below the median, non‐CKD with IL‐34 above the median, CKD with IL‐34 below the median, and CKD with IL‐34 above the median. Log‐rank tests were used to compare the impact of IL‐34 on patients with or without CKD. B, Kaplan–Meier curves for the primary end point according to 4 groups divided using the median IL‐34 and median cystatin C level as the cut‐off values, similar to that illustrated in (A). Log‐rank tests were also performed. CKD indicates chronic kidney disease; CysC, cystatin C; eGFR, estimated glomerular filtration rate; IL, interleukin.

Figure 3

Event rates and Kaplan–Meier curve analysis according to the estimated IL‐34 cut‐off value. A, Event rates of the primary end point, cardiovascular death, HF hospitalization, and all‐cause mortality for HF patients below and above the IL‐34 cut‐off value (110.4 pg/mL). The numbers above each bar indicate the corresponding hazard ratio using the IL‐34 level as a binary variable divided by the cut‐off value in Cox regression analyses. B, Kaplan–Meier curve for the primary end point dichotomized according to a clinical cut‐off value of 110.4 pg/mL for the serum IL‐34 level. *^* P<0.01; *^** P<0.001. HF indicates heart failure; IL, interleukin.

Figure 4

Risk stratification in patients with heart failure according to tertiles of serum IL‐34 and NT‐proBNP levels. The risk of the primary end point (cardiovascular death or HF hospitalization) significantly increases in patients with both biomarkers in the highest tertile compared with those with both biomarkers in the lowest tertile (P<0.001). HF indicates heart failure; IL, interleukin; NT‐proBNP, N‐terminal pro‐brain natriuretic peptide.