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

Abstract

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.

Effects of Metoprolol Succinate Combined with Entresto on Cardiac Function Indexes and Coagulation Function in Patients with Congestive Heart Failure

“…The relevant study implicates that the onset and development of CHF are closely related to various factors, and the key mechanism lies in the excessive activation of neuroendocrine system and cytokines, leading to gradual myocardial remodeling and continuous progress of CHF [ 14 ]. In the actual classification of CHF, the key to death in these patients depends on the relevant indicators of the left ventricle (LV) of CHF [ 15 ]. Patients with CHF can be treated with antiplatelet drugs, statins, diuretics, cardiotonic agents, and so on, among which metoprolol succinate is a commonly used drug in clinic [ 16 ].…”

A common gene signature of the right ventricle in failing rat and human hearts

“…Based on these and other observations in LHF, a common PENK-dependent inter-organ pathway was postulated that affects both the heart and the kidneys (Matsue et al, 2017;Ng et al, 2017). In this pathway, high PENK levels might be detrimental, reflect a counter-regulatory response of an over-activated opioid system, or might be both, initially protective and later on maladaptive (Bozkurt et al, 2021;Emmens et al, 2021;Ng et al, 2017;Siong Chan et al, 2018). Almost nothing is known about a (specific) role of Penk and the opioid system in RVH and RVF, but the highly consistent upregulation of Penk mRNA in RHF observed in our study strongly suggests that its mechanistic role and potential use as an early biomarker for RHF should be analyzed in future studies.…”

“…Higher PENK levels were also associated with more advanced LHF and glomerular and tubular dysfunction (Emmens et al, 2019). In the prevention of renal and vascular endstage disease (PREVEND) study, in > 6000 participants, PENK levels were associated with both reduced renal function and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, but were not independently associated with new-onset LHF, suggesting that PENK may serve primarily as a novel biomarker for renal glomerular dysfunction (Emmens et al, 2021). Based on these and other observations in LHF, a common PENK-dependent inter-organ pathway was postulated that affects both the heart and the kidneys (Matsue et al, 2017;Ng et al, 2017).…”