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

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' (r_s 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.

Keywords: B-type natriuretic peptide; Heart failure; Opioids; Preserved ejection fraction; Proenkephalin; Renal function.

Fig. 1

PENK relationship to the echocardiographic diastolic index E/e′. Correlation of PENK with echocardiographic index of diastolic dysfunction E/e′. The Spearman correlation coefficient was 0.453 (p < 0.0005)

Fig. 2

MRI-derived ventricular volumes according to PENK tertiles. Box and whisker plots of a LAEDVI and b LAESVI according to PENK tertiles. LAEDVI and LAESVI differed between PENK tertiles (ANOVA p = 0.024 and 0.01). Significant differences were seen between the second and first tertile of LAEDVI (p = 0.025) and between second and third tertiles of LAESVI and the first tertile (p = 0.016 and 0.042, respectively)

Fig. 3

Hazard ratios for PENK in Cox survival analysis for Death/HF or Death at 2 years in HFpEF and HFrEF. Forest plots showing hazard ratios and confidence intervals for PENK (as a univariable in A) following adjustment for a multivariable base model (B, containing the variables age, gender, NYHA class IV, past history of heart failure, ischemic heart disease, hypertension, diabetes, atrial fibrillation, systolic BP, heart rate, plasma urea, creatinine, sodium, haemoglobin, natriuretic peptide), base model with troponin (C), and base model with troponin and BMI (D). Hazard ratios for interaction of PENK with ejection fraction status are shown on the right of the figure

Fig. 4

Kaplan–Meier survival analysis for death/HF hospitalisation and all-cause mortality. Kaplan–Meier plots of a the composite endpoint of death and/or HF hospitalization and b all-cause mortality, according to PENK tertiles. Log rank tests showed differences between tertiles 1 and 3 (p < 0.0005 for both endpoints), and between tertiles 2 and 3 (p = 0.006 for death/HF and p < 0.0005 for death)