Author + information
- Received September 26, 2012
- Revision received November 14, 2012
- Accepted November 19, 2012
- Published online April 1, 2013.
- Rudolf A. de Boer, MD, PhD∗∗ (, )
- Qi Cao, MSc†,
- Douwe Postmus, PhD†,
- Kevin Damman, MD, PhD∗,
- Adriaan A. Voors, MD, PhD∗,
- Tiny Jaarsma, PhD∗,‡,
- Dirk J. van Veldhuisen, MD, PhD∗,
- William D. Arnold, PhD§,
- Hans L. Hillege, MD, PhD∗,† and
- Herman H.W. Silljé, PhD∗
- ↵∗Reprint requests and correspondence:
Dr. Rudolf A. de Boer, Department of Cardiology, University Medical Center Groningen, Internal Code AB43, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.
Objectives This study investigated clinical determinants and added prognostic value of HE4 as a biomarker not previously described in heart failure (HF).
Background Identification of plasma biomarkers that help to risk stratify HF patients may help to improve treatment.
Methods Plasma HE4 levels were determined in 567 participants of the COACH (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.
Results HE4 showed a strong correlation with HF severity, according to New York Heart Association functional class and brain 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 to 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 to 1.72; p < 0.001), and after additional adjustment for GDF15, the HR lowered to 1.30 (95% CI: 1.07 to 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.
Conclusions HE4 plasma levels are correlated with markers of HF severity, show prognostic value, and can improve risk assessment in HF.
Dr. de Boer is supported by the Netherlands Heart Foundation (grant 2007T046) and the Innovational Research Incentives Scheme program of the Netherlands Organization for Scientific Research (NWO VENI, grant 916.10.117). Dr. Arnold is currently employed by Alere. Dr. Voors has received research grants from Alere. All other authors have reported that they have no relationship relevant to the contents of this paper to disclose.
- Received September 26, 2012.
- Revision received November 14, 2012.
- Accepted November 19, 2012.
- American College of Cardiology Foundation