Tracking circulating neprilysin may aid risk stratification

There was a survival difference of about 40% between groups of patients with heart failure (HF) stratified by concentrations of soluble neprilysin plus concentrations of soluble corin in terms of the occurrence of cardiovascular (CV) death and HF hospitalization, European researchers reported.

After correction for baseline differences in age and sex, a significant association with survival was demonstrated with highest survival in a low soluble neprilysin (sNEP)/low soluble corin (sCOR) group and lowest in a high sNEP/high sCOR group for an adjusted hazard ratio (HR) of 1.56 (P=0.003), according to D.H. Frank Gommans, MD, PhD, of Radboud University Medical Centre in Nijmegen, the Netherlands, and co-authors.

The finding remained statistically significant after comprehensive multivariable analysis (adjusted HR1.41, P=0.03), they wrote in JACC: Heart Failure.

The authors also reported that during a median follow-up period of 4.5 years, 511 of 1,009 patients died; of these, 54% died from CV causes while 41% died from non-CV causes (5% unknown causes). Among known CV causes of death, refractory HF accounted for 52%, followed by sudden death (25%) and acute myocardial infarction (6%).

“During follow-up, 331 patients were admitted for HF and 449 patients fulfilled the primary endpoint of CV death or HF hospitalization,” they wrote.

“In this report we demonstrate for the first time that patients with HF can be stratified into different groups based on circulating concentrations of sNEP and sCOR with different baseline characteristics,” Gomman’s group explained. “After correction for age and sex, we demonstrated that these patients have different clinical outcomes in terms of CV death and HF hospitalization during long-term follow-up… These results suggest that the combination of sNEP and sCOR concentrations may hypothetically be an attractive approach to characterize patients with HF, which might ultimately inspire future studies on personalized HF therapies targeting the NP [natriuretic peptide] pathway.”

In an editorial comment accompanying the study, Scott D. Solomon, MD, of Brigham and Women’s Hospital in Boston, and co-authors offered some historical context for the findings.

“After the discovery of NPs, pioneering studies established that circulating levels were elevated in HF and higher concentrations correlated with symptom severity, left ventricular dysfunction, and elevated intracardiac filling pressures,” they wrote. “As such, measurement of NPs in at-risk individuals (for diagnosis) and among those with known HF (for prognosis) quickly became well established as a central part of HF clinical practice. With recognition of the cardiovascular effects of NPs, interest in therapeutic modulation of the NP system grew.”

The study by Gomman’s group showed that “one-third of patients had unmeasurable concentrations (<0.249 ng/ml)” of NP, which calls attention to the “heterogeneity in sNEP among chronic HF patients,” the editorialists noted.

They added that, although the authors’ reporting of a “trend toward lower N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the group with highs NEP and highs COR,” and the lack of correlation between “sNEP and sCOR,” as well as the fact that “younger age was the only predictor of higher concentrations of both peptides… may suggest that these enzymes are regulated entirely independently of one another, a number of other considerations make interpretation of these data challenging.”

As with NPs, the enzymes evaluated in the current study may be influenced by demographics, comorbidities, and biology, and “soluble levels may not reflect their biological activity or the proportion of membrane-bound forms of these enzymes. These factors are compounded by potential analytic uncertainties stemming from prolonged storage, sample handling, and assay cross-reactivity,” they wrote.

The editorialists called for “Well-controlled mechanistic studies with careful simultaneous measurement of multiple peptides and their processing enzymes among patients receiving contemporary pharmacotherapy,” while acknowledging that the current findings “move us closer to understanding the complex biology underlying this essential peptide system in HF.”

The NP pathway has become a noteworthy biotarget for HF based on results from the PARADIGM-HF and PARAGON-HF trials (Solomon served as an investigator on the latter), Gomman’s group noted.

“The main mechanism of action is probably an increase in NP concentration (with beneficiary natriuresis and vasodilation) through inhibition of NP degradation by… NEP,” the authors explained. “The observation that chronic HF patients with low…sNEP concentrations fare better than those with high sNEP concentrations corroborates these findings… In addition… corin also plays a pivotal role in NP processing in response to increased myocardial wall stretch and may contribute to the capacity to increase or maintain NP concentrations.”

The current study consecutively enrolled ambulatory patients treated at a multidisciplinary tertiary outpatient HF clinic between May 2006 and Feb. 2016 and narrowed them down to patients who had a remaining blood sample available for additional biomarker analysis. Patients’ median age was 67 for the total cohort and 70% were male. Left ventricle ejection fraction (LVEF) was 36% for the full cohort. The study primary outcome was the composite of CV death and HF hospitalization.

Gomman’s group reported that the median sNEP concentration was 0.493 ng/ml, and the median sCOR concentration was 1,613 pg/ml, which were not correlated (rank correlation coefficient: −0.04, P=0.21). Also, 33% of patients had sNEP concentrations that were below the limit of detection (<0.249 ng/ml), but none of the sCOR concentrations were below the limit of detection.

They found that age- and sex-adjusted sNEP concentrations were significantly tied to the composite primary endpoint (adjusted HR per standard deviation 1.13, 95% CI, 1.04 to 1.24, P=0.005), while sCOR concentrations were not (adjusted HR per SD 1.05, 95% CI 0.95 to 1.17, P=0.35). “As dichotomous variables relative to the median, both high sNEP and high sCOR were significantly associated with the primary endpoint,” they added (age- and sex-adjusted P=0.03 and P=0.047, respectively).

Finally, in 215 patients with ejection fraction ≥45%, the difference in survival for the composite primary endpoint was significant (adjusted HR 2.22, 95% CI 1.08 to 4.58, P=0.03). However, in the 794 patients with ejection fraction <45%, the observed difference did not reach statistical significance (adjusted HR 1.30, 95% CI 0.90 to 1.86, P=0.16), and in both groups, there was no interaction for sex (P>0.05).

Study limitations included the fact that the majority of White patients were treated at a multidisciplinary HF unit in a tertiary care hospital, and that the size of the study population was limited. Also, serum concentrations may not have reflected activity, the authors pointed out, and cautioned that “Prior to integration in daily clinical practice, it should be noted that methods of sCOR and sNEP assessment need to be improved and standardized (according to age and sex).”

While their data were “strictly observational… Our first-time observations may be an inspiration for future HF research,” Gomman and co-authors wrote.

  1. Stratification of patients with chronic heart failure (HF) based on circulating soluble neprilysin (sNEP) and soluble corin (sCOR) concentrations was associated with clinical outcomes with regard to cardiovascular death and HF hospitalization.

  2. A significant association with survival was demonstrated with highest survival in a low sNEP/low sCOR group and lowest in a high sNEP/high sCOR group after correction for baseline differences in age and sex.

Shalmali Pal, Contributing Writer, BreakingMED™

Gommans and two co-authors reported support from Novartis Pharma B.V. Two co-authors reported relationships with Critical Diagnostics.

Solomon reported support from, and/or relationships with, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lone Star Heart, Mesoblast, MyoKardia, the National Heart, Lung and, Blood Institute/NIH, NeuroTronik, Novartis, Respicardia, Sanofi Pasteur, Theracos, Akros, Arena, Cardior, Cardurion, Corvia, Daiichi-Sankyo, Gilead, Ironwood, Merck, MyoKardia, Novartis, Roche, Takeda, Theracos, Quantum Genetics, AOBiome, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, DiNAQOR, Tremeau, CellProthera, and Moderna. Co-authors reported support from, and/or relationships with, the South-Eastern Norway Regional Health Authority, Novartis, Novo Nordisk, Amgen, the Harvard Catalyst/The Harvard Clinical and Translational Science Center, Amgen, AstraZeneca, Baxter Healthcare, Bayer AG, Boehringer Ingelheim, Cytokinetics, Relypsa, Galmed, Novartis, and the NIH.

Cat ID: 3

Topic ID: 74,3,730,3,192,925