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Circulating neprilysin may predict CV death, HF hospitalization
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The identification of high levels of circulating soluble neprilysin in patients with HF may indicate increased risk for CV death and HF-related hospitalization, which supports the benefits of neprilysin inhibition as a therapeutic strategy in this patient population, researchers reported in a new study.
Researchers measured circulating soluble neprilysin levels in 1,069 consecutive ambulatory patients with HF who were treated from May 2006 to May 2013. The patients were followed for an average of 4 years, which included a minimum of quarterly visits with nurses, biannual visits with physicians and elective visits with specialists.
During follow-up, 449 patients died. Of those, 247 deaths were related to CVD (128, refractory HF; 53, sudden cardiac death; 23, acute MI). HF-related hospitalizations occurred in 231 patients. In total, the primary endpoint of CV death or HF hospitalization was met by 356 patients.
The median concentration of soluble neprilysin was 0.642 ng/mL. The researchers observed a weak but significant correlation between neprilysin concentration and age (P < .001), but no correlation with left ventricular ejection fraction (P = .35), estimated glomerular filtration rate (P = .1), NT-proBNP (P = .68), NYHA HF class (P = .72), BP (P = .7) or sex (P = .28). However, neprilysin levels were significantly higher in nonischemic patients compared with ischemic patients (0.69 ng/mL vs. 0.611 ng/mL; P = .002).
After adjustment for age, neprilysin concentration was significantly associated with CV death or HF hospitalization when assessed as a continuous variable (HR = 1.17; 95% CI, 1.06-1.29) and CV-related death alone (HR=1.19; 95% CI, 1.06-1.32). Both associations persisted on comprehensive multivariable analyses (HR = 1.18; 95% CI, 1.07-1.31 for the composite endpoint and HR = 1.18; 95% CI, 1.05-1.32 for CV-related death).
“The main objective of the present study was not to postulate neprilysin as a biomarker but rather to better understand soluble neprilysin pathobiology in HF and to put it into context of the results obtained in PARADIGM-HF,” the researchers wrote.
Previously reported results of the PARADIGM-HF study demonstrated that LCZ696, an angiotensin receptor-neprilysin inhibitor, was superior to ACE inhibition with enalapril for the reduction of death and HF hospitalization in patients with HF and reduced ejection fraction.
“We demonstrate for the first time that high levels of neprilysin are found in the circulation of patients with HF and that neprilysin concentrations are indicators of adverse outcomes for both CV mortality and morbidity,” the researchers concluded. “Neprilysin inhibition, provided by LCZ696, is necessary for targeting novel pathophysiological contributors to HF and is crucial for improving patient outcomes.”
Allan S. Jaffe
In a related editorial, Allan S. Jaffe, MD, noted that “the ability to add measurements of neprilysin concentrations to ongoing research efforts may enrich our understanding of these mechanisms and allow us to better leverage this approach to help patients with HF.
“The bigger hope is that future studies using serial samples will permit assessment of patient response to various treatments as part of efforts to improve our understanding of the basic mechanisms of neprilysin inhibition,” wrote Jaffe, from the division of core clinical laboratory service, department of laboratory medicine and pathology, Mayo Clinic College of Medicine, Rochester, Minnesota, and Cardiology Today Editorial Board member.
Disclosure: The researchers report no relevant financial disclosures. Jaffe reports consulting for Abbott Laboratories, Alere, Beckman Coulter, Critical Diagnostics, ET Healthcare, Radiometer, Roche Diagnostics USA, Siemens, Trinity and theheart.org.
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