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.