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

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.