Clinical Investigation
Clinical Correlates and Prognostic Value of Proenkephalin in Acute and Chronic Heart Failure

https://doi.org/10.1016/j.cardfail.2016.09.007Get rights and content

Highlights

  • Clinical and prognostic role of proenkephalin was tested in chronic and acute heart failure.

  • Proenkephalin was correlated with glomerular function but not with tubular dysfunction.

  • Proenkephalin did not show an additive prognostic information on top of preexisting renal markers in acute heart failure.

Abstract

Background

Proenkephalin (pro-ENK) has emerged as a novel biomarker associated with both renal function and cardiac function. However, its clinical and prognostic value have not been well evaluated in symptomatic patients with heart failure.

Methods and Results

The association between pro-ENK and markers of renal function was evaluated in 95 patients with chronic heart failure who underwent renal hemodynamic measurements, including renal blood flow (RBF) and glomerular filtration rate (GFR) with the use of 131I-Hippuran and 125I-iothalamate clearances, respectively. The association between pro-ENK and clinical outcome in acute heart failure was assessed in another 1589 patients. Pro-ENK was strongly correlated with both RBF (P < .001) and GFR (P < .001), but not with renal tubular markers. In the acute heart failure cohort, pro-ENK was a predictor of death through 180 days, heart failure rehospitalization through 60 days, and death or cardiovascular or renal rehospitalization through day 60 in univariable analyses, but its predictive value was lost in a multivariable model when other renal markers were entered in the model.

Conclusions

In patients with chronic and acute heart failure, pro-ENK is strongly associated with glomerular function, but not with tubular damage. Pro-ENK provides limited prognostic information in patients with acute heart failure on top of established renal markers.

Section snippets

Methods

This study was performed in 2 populations. First, a cardiorenal mechanistic cohort was used to investigate the association between pro-ENK and renal function, including hemodynamic parameters which were measured by means of radioactive tracers in patients with stable chronic heart failure.8, 9 Second, the PROTECT (Placebo-Controlled Randomized Study of the Selective A1 Adenosine Receptor Antagonist Rolofylline for Patients Hospitalized With Acute Decompensated Heart Failure and Volume Overload

Patient Characteristics

Baseline characteristics are presented in Table 1. The mean age was 60 ± 12 years, mean LVEF was 29 ± 10%, and 75 patients (79%) were male. The median value of pro-ENK was 62.2 (IQR 48.5 −92.5) pmol/L (Fig. 1), and 28 patients (29.5%) had pro-ENK levels above the 99th percentile upper reference limit of pro-ENK in healthy subjects. Higher pro-ENK tertiles were associated with higher age, female sex, lower blood pressure, higher New York Heart Association (NYHA) functional class, greater

Discussion

In acute and chronic heart failure, pro-ENK levels were higher in acute heart failure compared with chronic heart failure. Pro-ENK was clearly associated with RBF and GFR, but not with tubular function. In patients with heart failure, pro-ENK was associated with clinical outcome, but after adjustments for established prognostic predictors, including preexisting renal markers, the association was lost. Therefore, pro-ENK seems to be a renal marker but does not seem to have additive value on top

Conclusion

Pro-ENK levels were higher in acute heart failure compared with chronic heart failure. Pro-ENK levels were strongly associated with glomerular function and RBF, but not with tubular damage. Pro-ENK has limited additive prognostic predictive information on top of existing renal markers in this cohort of acute heart failure.

Disclosures

Y.M., J.M.t.M., and K.D., and have nothing to disclose. A.A.V. has received speaker/consultancy/research fees from Merck, Novacardia, Singulex, and Sphingotec. P.v.d.M. has received consulting fees from Novartis, Vifor Pharma, and ZS-Pharma. D.J.v.V. has received board membership fees from Amgen, BG Medicine, Biocontrol, Johnson and Johnson, Novartis, Sorbent, and Vifor. C.M.O'C. is a consultant to Merck. M.M. has received honoraria and reimbursements from Novacardia and Merck, that purchased

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    Funding: The PROTECT trial was supported by Novacardia, a subsidiary of Merck. Alere, Singulex, and Sphingotec kindly provided assays and performed biomarker measurements.

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