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Proenkephalin and prognosis in heart failure with preserved ejection fraction: a GREAT network study.

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posted on 2019-08-09, 14:13 authored by P Kanagala, IB Squire, DJL Jones, TH Cao, DCS Chan, G McCann, JK Sandhu, PA Quinn, J McAdam, A-M Marsh, JE Davies, J Struck, A Bergmann, Z Sabti, R Twerenbold, T Herrmann, N Kozhuharov, C Mueller, LL Ng, GREAT (Global REsearch on Acute Conditions Team) Network
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.


This work was supported by the John and Lucille Van Geest Foundation, British Heart Foundation (FS/15/10/31223) and the National Institute for Health Research Leicester Biomedical Research Centre. Sphingotec GmbH is a midsized company based in Hennigsdorf, Germany; it commercializes immunoassays, and has developed the Proenkephalin assay, for which it owns patent rights.



Clinical Research in Cardiology, 2019, 108(8), pp 940–949.

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Clinical Research in Cardiology


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