Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure.

Johanna E Emmens,Nilesh J Samani,Joachim Struck,Dirk J Van Veldhuisen,Chim C Lang,Kenneth Dickstein,Adriaan A Voors,Rudolf A De Boer,Kevin Damman,Iziah E Sama,Andreas Bergmann,Stefan D Anker,Jozine M Ter Maaten,Koen W Streng,Leong L Ng,Marco Metra

doi:10.1161/circheartfailure.118.005544

Abstract

PENK (proenkephalin) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function. PENK has been associated with heart failure (HF) severity and renal dysfunction. We therefore hypothesized that PENK could be associated with deterioration of kidney function and could have a role as a novel renal marker in HF. In 2180 patients with HF of a large multicenter cohort (BIOSTAT-CHF [A Systems Biology Study to Tailored Treatment in Chronic Heart Failure]), the relationship between PENK and clinical variables, plasma and urinary biomarkers, and clinical end points was established. Data were validated in a separate cohort of 1703 patients with HF. PENK was elevated (>80 pmol/L, 99th percentile) in 1245 (57%) patients. Higher PENK was associated with more advanced HF and glomerular and tubular dysfunction. The strongest independent predictor of PENK was estimated glomerular filtration rate. Others were plasma NGAL (neutrophil gelatinase-associated lipocalin) and NT-proBNP (N-terminal pro-B-type natriuretic peptide; all P<0.001). Using correlation heatmaps and hierarchical cluster analyses, PENK clustered with estimated glomerular filtration rate, creatinine, NGAL, galectin-3, and urea. Higher PENK was independently associated with increased risk of deterioration of kidney function between baseline and 9 months (odds ratio, 1.29 [1.02-1.65] per PENK doubling; P=0.038; defined as >25% decrease in estimated glomerular filtration rate) and mortality (hazard ratio, 1.23 [1.07-1.43] per doubling; P=0.004). Analyses in the validation cohort yielded comparable findings. Higher PENK levels are associated with more severe HF, with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality. These findings suggest that the opioid system might be involved in deteriorating kidney function in HF.

Highlights

Enkephalins are endogenous opioid peptides that exert several cardiovascular effects by reducing myocardial contractility, blood pressure, and heart rate, while inhibiting norepinephrine release and sympathetic vasoconstriction. 1 Opioid peptides play a role in ischemic preconditioning and cardiac hypertrophy. 1 Besides cardiovascular effects, enkephalins exert renal effects predominantly by increasing renal blood flow and urinary output. 2 By their established effects on cardiac contractility, hemodynamics, and renal function, enkephalins might play a pathophysiological role in the development and progression of cardiorenal failure.endogenous enkephalins are unstable, and difficult to measure in plasma
Higher PENK levels are associated with more severe heart failure (HF), with glomerular and tubular renal dysfunction, with incidence of a deterioration of kidney function, and with mortality
These findings suggest that the opioid system might be involved in deteriorating kidney function in HF

Summary

Introduction

Enkephalins are endogenous opioid peptides that exert several cardiovascular effects by reducing myocardial contractility, blood pressure, and heart rate, while inhibiting norepinephrine release and sympathetic vasoconstriction. 1 Opioid peptides play a role in ischemic preconditioning and cardiac hypertrophy. 1 Besides cardiovascular effects, enkephalins exert renal effects predominantly by increasing renal blood flow and urinary output. 2 By their established effects on cardiac contractility, hemodynamics, and renal function, enkephalins might play a pathophysiological role in the development and progression of cardiorenal failure.endogenous enkephalins are unstable, and difficult to measure in plasma. Enkephalins are endogenous opioid peptides that exert several cardiovascular effects by reducing myocardial contractility, blood pressure, and heart rate, while inhibiting norepinephrine release and sympathetic vasoconstriction. 2 By their established effects on cardiac contractility, hemodynamics, and renal function, enkephalins might play a pathophysiological role in the development and progression of cardiorenal failure. Due to the profound cardiovascular and renal effects of enkephalins and previously reported associations of PENK with both disease severity and renal dysfunction in heart failure, we hypothesized that PENK, as a surrogate of the opioid system, could become a novel renal marker in heart failure, reflecting both cardiac, glomerular and tubular dysfunction. Proenkephalin (PENK) is a stable surrogate for enkephalins, endogenous opioid peptides, which exert cardiodepressive effects and improve renal function.

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