Although not correlated with each other, increased levels of circulating according to prospective analysis involving 1,009 HF patients.
Dr. Peder L. Myhre
This implies that these enzymes might have value for individualizing care, including treatment of patients in heart failure with preserved ejection fraction (HFpEF), reported a team of investigators led by D.H. Frank Gommans, MD, PhD, department of cardiology, Radboud University Medical Center, Nijmegen, the Netherlands.
When followed for up to 7 years and after adjustment for differences in sex and age, the highest risk for the primary composite endpoint of cardiovascular (CV) death and heart failure hospitalization was observed in those with both high soluble neprilysin (sNEP) and high soluble corin (sCOR). The lowest risk was observed in the group with low levels of both enzymes.
The data suggest that monitoring these enzymes might provide “a step toward individualized CHF patient management,” Dr. Gommans reported in JACC Heart Failure, the adjusted hazard ratio for elevated sNEP and sCOR translated into a greater than 50% increase in the composite primary endpoint relative to low levels of both (HR, 1.56; P = .003). After a “comprehensive multivariable analysis,” the increased risk remained substantial and significant (HR, 1.41; P = .03).
In the natriuretic peptide pathway, which has long been recognized as a mediator of vasodilation, venous compliance, diuresis, and other processes dysregulated in heart failure, NEP and COR are “key mediators,” according to the investigators, who cited previously published studies. More attention has turned to these enzymes as potential biomarkers in the context of the PARADIGM trial, which associated an angiotensin-receptor neprilysin inhibitor (ARNI) with a survival benefit in CHF.
The observational study consisted of CHF patients attending a heart failure clinic and who were ARNI naive at inclusion. On the basis of circulating enzyme measurements undertaken from blood samples employing standard techniques, they were stratified into four groups. Those with low levels of both enzymes served as the reference. They were compared with those with low sNEP and high sCOR, those with high sNEP and low sCOR, and those with high levels of both enzymes.
Over the course of a median 4.5 years of follow-up, there were 511 deaths, of which 54% were from a CV cause. There were also 331 heart failure hospitalizations. In all, 449 patients reached the primary composite endpoint.
When compared with the group with low sNEP and low sCOR, an elevation in either enzyme was associated with a numerically but not significantly greater hazard ratio for the primary composite endpoint. The lack of correlation in the elevation of these two enzymes suggests each provides different prognostic information, although it appears that both must be considered together to predict outcomes.
Clinically, stratification of these enzymes might be most useful in HFpEF patients. Relative to the separation of event curves in the CHF patients with reduced ejection fraction (HFrEF), the divergence in the event curves for HFpEF were greater. In addition, event curves separated from the reference in HFpEF patients but not the HFrEF patients if either enzyme was elevated.
Asked if these data hold particular promise for monitoring and individualizing therapy in HFpEF patients, Dr. Gommans said yes. Although he cautioned that this was an observational study and that the differences between the HFpEF and HFrEF should be considered exploratory, he agreed that components of the natriuretic peptide pathway have particular potential to provide new prognostic information and individualize care in HFpEF, where therapeutic options remain limited.
Stratification of natriuretic peptide enzymes in this group might “present as an interesting alternative to ejection fraction” for prognosis and the consideration of treatment choices, he suggested.
Although further validation of the prognostic importance of sNEP and sCOR is needed, according to Dr. Gommans, he foresees the potential of therapeutic trials based on elevated levels of these enzymes. For example, he speculated that these levels might distinguish HFpEF patients who could benefit from a first-line ARNI.
In an accompanying editorial, significant doubts were expressed about simple measurements of sNEP and sCOR concentrations to predict clinical course or guide treatment decisions. The authors of the editorial agreed this is an important area of study but warned of its complexity.
“Concentrations of circulating neprilysin have been shown to correlate poorly with neprilysin activity. Thus the rate of natriuretic peptide degradation by neprilysin cannot be determined solely by measuring circulating levels,” cautioned Peder L. Myhre, MD, PhD, who is a cardiology fellow at Akershus University Hospital in Nordbyhagen, Norway, and postdoc researcher at the University of Oslo.
“Accordingly, concentrations of neprilysin and corin cannot alone be used to predict response to therapies interacting with these peptides,” he added. He agreed that neprilysin and corin might be appropriate biomarkers in CHF, but he thinks the focus must be on their enzymatic activity, not their circulating levels.
“Measuring the enzymatic activity may be a feasible strategy, but this remains to be seen,” he said.
Dr. Gommans reported a financial relationship with Novartis. Dr. Myhre reported financial relationships with Amgen, Novartis, and Novo Nordisk.