The WAP Four-Disulfide Core Domain Protein HE4: A Novel Biomarker for Heart Failure

Study Questions:

What are the clinical determinants and prognostic value of HE4 as a biomarker in heart failure (HF)?


Plasma HE4 levels were determined in 567 participants of the COACH study (Coordinating study evaluating outcomes of Advising and Counseling in Heart failure). Patients had been hospitalized for HF and were followed for 18 months. The primary endpoint of this study was a composite of all-cause mortality and HF hospitalization.


HE4 showed a strong correlation with HF severity, according to New York Heart Association functional class and B-type natriuretic peptide (BNP) levels (p < 0.001). HE4 also showed a positive correlation with GDF15 (p < 0.001) and, in addition, correlated with kidney function (estimated glomerular filtration rate [eGFR], p < 0.001). Cox regression analysis revealed that a doubling of HE4 levels was associated with a hazard ratio (HR) of 1.73 (95% confidence interval [CI], 1.53-1.95) for the primary outcome (p < 0.001). After correction for age, gender, BNP, and eGFR, the HR was 1.46 (95% CI, 1.23-1.72; p < 0.001), and after additional adjustment for GDF15, the HR lowered to 1.30 (95% CI, 1.07-1.59; p = 0.009). The area under the curve in the receiver-operating characteristic curve analysis increased from 0.727 to 0.752 when HE4 was included in the clinical evaluation (p = 0.051). The integrated discrimination improvement and net reclassification index for reclassification showed significant improvements when HE4 was added to the clinical model, and this remained significant after BNP inclusion in the model.


The authors concluded that HE4 plasma levels are correlated with markers of HF severity, show prognostic value, and can improve risk assessment in HF.


This study suggested that HE4 was strongly associated with HF severity and outcome and that this association was independent of other established risk factors for poor outcome in HF including age, gender, BNP level, and renal function. Moreover, addition of HE4 to commonly used clinical parameters resulted in improved reclassification, as assessed by net reclassification index and integrated discrimination improvement. HE4 appears to improve risk classification, and may potentially improve disease management in HF. Whether HE4 also has value in monitoring response to HF therapy requires additional investigations.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: Biological Markers, Growth Differentiation Factor 15, Heart Failure, Disease Management, Glomerular Filtration Rate, Confidence Intervals, ROC Curve, Risk Assessment, New York, Hospitalization, Regression Analysis, Natriuretic Peptide, Brain

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