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Title: Proenkephalin and prognosis in heart failure with preserved ejection fraction: a GREAT network study.
Authors: Kanagala, P
Squire, IB
Jones, DJL
Cao, TH
Chan, DCS
McCann, G
Sandhu, JK
Quinn, PA
McAdam, J
Marsh, A-M
Davies, JE
Struck, J
Bergmann, A
Sabti, Z
Twerenbold, R
Herrmann, T
Kozhuharov, N
Mueller, C
Ng, LL
GREAT (Global REsearch on Acute Conditions Team) Network
First Published: 14-Feb-2019
Publisher: Springer (part of Springer Nature) for German Cardiac Society
Citation: Clinical Research in Cardiology, 2019, 108(8), pp 940–949.
Abstract: BACKGROUND: Proenkephalin (PENK), a stable endogenous opioid biomarker related to renal function, has prognostic utility in acute and chronic heart failure. We investigated the prognostic utility of PENK in heart failure with preserved ejection fraction (HFpEF), and its relationship to renal function, Body Mass Index (BMI), and imaging measures of diastolic dysfunction. METHODS: In this multicentre study, PENK was measured in 522 HFpEF patients (ejection fraction > 50%, 253 male, mean age 76.13 ± 10.73 years) and compared to 47 age and sex-matched controls. The primary endpoint was 2-years composite of all-cause mortality and/or heart failure rehospitalisation (HF). A subset (n = 163) received detailed imaging studies. RESULTS: PENK levels were raised in HFpEF (median [interquartile range] 88.9 [62.1-132.0]) compared to normal controls (56.3 [47.9-70.5]). PENK was correlated to urea, eGFR, Body Mass Index and E/e' (rs 0.635, - 0.741, - 0.275, 0.476, respectively, p < 0.0005). During 2 years follow-up 144 patients died and 220 had death/HF endpoints. Multivariable Cox regression models showed PENK independently predicted 2 year death/HF [hazard ratio (for 1 SD increment of log-transformed biomarker) HR 1.45 [95% CI 1.12-1.88, p = 0.005]], even after adjustment for troponin (HR 1.59 [1.14-2.20, p = 0.006]), and Body Mass Index (HR 1.63 [1.13-2.33, p = 0.009]). PENK showed no interaction with ejection fraction status for prediction of poor outcomes. Net reclassification analyses showed PENK significantly improved classification of death/HF outcomes for multivariable models containing natriuretic peptide, troponin and Body Mass Index (p < 0.05 for all). CONCLUSIONS: In HFpEF, PENK levels are related to BMI, and measures of diastolic dysfunction and are prognostic for all-cause mortality and heart failure rehospitalisation.
DOI Link: 10.1007/s00392-019-01424-y
eISSN: 1861-0692
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Copyright © the authors, 2019. This is an open-access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Description: The online version of this article ( contains supplementary material, which is available to authorized users.
Appears in Collections:Published Articles, Dept. of Cardiovascular Sciences

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