Contributor: Nicole Smith

Is the opioid system responsible for deteriorating renal function in heart failure?

In a large chronic HF study population, Emmens and colleagues demonstrated higher levels of the opioid surrogate proenkephalin (PENK) are associated with worse HF and deterioration of kidney function. Could PENK be the next renal biomarker in heart failure?

PENK level was measured in 2180 HF patients from BIOSTAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). This large multicenter, multinational European cohort included chronic HF patients, on suboptimal HF therapy, after presentation with either new onset or worsening heart failure, defined as LVEF ≤ 40% and/or BNP > 400 pg/mL or NT-proBNP > 2000 pg/mL.

PENK was elevated in 57% of patients. Higher levels of PENK were associated with more advanced HF, renal dysfunction, and both glomerular and tubular dysfunction. Doubling of 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]; P=0.038; and increased mortality (hazard ratio, 1.23 [1.07–1.43]; P=0.004).  PENK was not associated with heart failure hospitalization following multivariable analysis.

Analyses in a separate validation cohort of 1703 patients with chronic HF yielded comparable findings.

No study is perfect. This cohort mainly included HFrEF patients, with different degrees of systolic dysfunction  between the index and validation cohort (mean LVEF 31% vs. 41%). Of note, this study was conducted prior to sacubitril/valsartan incorporation in HF therapy.  PENK levels could be different in this setting as enkephalins are a substrate of neprilysin. Most importantly, while the study demonstrated many associations, it failed to demonstrate causality.

In a heartbeat… Higher NT-proBNP is a better predictor of poor outcomes, particularly hospitalization, in HFpEF patients without AF compared to AF patients. Improved understanding of the relationship between NT-proBNP levels and outcomes in patients with AF is needed

Study Link: Proenkephalin, an Opioid System Surrogate, as a Novel Comprehensive Renal Marker in Heart Failure