Proenkephalin and the risk of new‐onset heart failure: data from prevention of renal and vascular end‐stage disease

BACKGROUND: Enkephalins of the opioid system exert several cardiorenal effects. Proenkephalin (PENK), a stable surrogate, is associated with heart failure (HF) development after myocardial infarction and worse cardiorenal function and prognosis in patients with HF. The association between plasma PENK concentrations and new‐onset HF in the general population remains to be established. HYPOTHESIS: We hypothesized that plasma PENK concentrations are associated with new‐onset HF in the general population. METHODS: We included 6677 participants from the prevention of renal and vascular end‐stage disease study and investigated determinants of PENK concentrations and their association with new‐onset HF (both reduced [HFrEF] and preserved ejection fraction [HFpEF]). RESULTS: Median PENK concentrations were 52.7 (45.1–61.9) pmol/L. Higher PENK concentrations were associated with poorer renal function and higher NT‐proBNP concentrations. The main determinants of higher PENK concentrations were lower estimated glomerular filtration rate (eGFR), lower urinary creatinine excretion, and lower body mass index (all p < .001). After a median 8.3 (7.8–8.8) years follow‐up, 221 participants developed HF; 127 HFrEF and 94 HFpEF. PENK concentrations were higher in subjects who developed HF compared with those who did not, 56.2 (45.2–67.6) versus 52.7 (45.1–61.6) pmol/L, respectively (p = .003). In competing‐risk analyses, higher PENK concentrations were associated with higher risk of new‐onset HF (hazard ratio [HR] = 2.09[1.47–2.97], p < .001), including both HFrEF (HR = 2.31[1.48–3.61], p < .001) and HFpEF (HR = 1.74[1.02–2.96], p = .042). These associations were, however, lost after adjustment for eGFR. CONCLUSIONS: In the general population, higher PENK concentrations were associated with lower eGFR and higher NT‐proBNP concentrations. Higher PENK concentrations were not independently associated with new‐onset HFrEF and HFpEF and mainly confounded by eGFR.