Human epididymis protein 4 contributes to lower systolic function and poor prognosis in heart failure with reduced ejection fraction

Background Human epididymis protein 4 (HE4) is a novel fibrosis marker exclusively expressed in activated myofibroblast. We previously reported that HE4 serves as a useful biomarker for predicting future adverse cardiovascular events and for assessing left ventricular reverse remodeling (LVRR) in patients with dilated cardiomyopathy (DCM). However, it remains unclear whether these findings are applicable to general heart failure with reduced ejection fraction (HFrEF). Furthermore, the mechanisms underlying the prognostic impact of HE4 remain unknown. Purpose To evaluate the prognostic value, contribution to LVRR and underlying mechanisms of HE4 in HFrEF. Methods We measured serum HE4 levels in 140 patients with HFrEF (LVEF < 40%) and followed them for cardiovascular (CV) death and heart failure (HF) hospitalization over a 3-year period. LVRR was also assessed during a 1-year follow-up echocardiography, and we analyzed baseline measurements associated with HE4 levels. Serum HE4 levels were measured by CLIA method. Results Kaplan-Meier curve showed a higher rate of CV death or HF hospitalization in the high-HE4 group compared to the low HE4 group (log-rank test; p < 0.001) (Figure 1). Furthermore, when stratified into ischemic heart disease (IHD) and non-IHD groups, the high-HE4 group exhibited a significantly higher rate of future cardiovascular events(log-rank test; p = 0.025 and P = 0.006, respectively). Multivariate Cox hazard analysis identified serum HE4 (ln[HE4]) as an independent predictor of adverse outcomes (hazard ratio [HR]: 3.99; 95% CI: 2.05–7.75, p < 0.001). Receiver operator characteristic (ROC) analysis revealed that HE4 achieved an area under the curve (AUC) of 0.77 for predicting 3-year cardiovascular events (p < 0.001). However, logistic regression analyses revealed no significant relationship between HE4 levels and LVRR during the 1-year follow-up echocardiography. To investigate the mechanisms linking HE4 to prognosis, multivariate linear regression analysis was performed, demonstrating significant associations between HE4 levels and age, serum creatinine levels, plasma BNP levels, E/e', and GLS (β = −0.083; 95% CI: −0.111–−0.054; p < 0.001). Additionally, the Kaplan-Meier curve of the combination of HE4 and GLS showed a significant difference among the groups, and the high HE4/low GLS group had the most cardiovascular events (log-rank p < 0.001) (Figure 2). Conclusions Although HE4 was not associated with LVRR in HFrEF, it remains a potentially useful biomarker for assessing prognosis. Its significant association with GLS may reflect the mechanisms underlying poor outcomes and reduced cardiac function in HFrEF.Kaplan-Meier curve of HE4 and CV events. The combination of HE4 and GLS.