Effects Of Neprilysin Inhibition Research Articles

Relevance of Neutrophil Neprilysin in Heart Failure.

Significant expression of neprilysin (NEP) is found on neutrophils, which present the transmembrane integer form of the enzyme. This study aimed to investigate the relationship of neutrophil transmembrane neprilysin (mNEP) with disease severity, adverse remodeling, and outcome in HFrEF. In total, 228 HFrEF, 30 HFpEF patients, and 43 controls were enrolled. Neutrophil mNEP was measured by flow-cytometry. NEP activity in plasma and blood cells was determined for a subset of HFrEF patients using mass-spectrometry. Heart failure (HF) was characterized by reduced neutrophil mNEP compared to controls (p < 0.01). NEP activity on peripheral blood cells was almost 4-fold higher compared to plasma NEP activity (p = 0.031) and correlated with neutrophil mNEP (p = 0.006). Lower neutrophil mNEP was associated with increasing disease severity and markers of adverse remodeling. Higher neutrophil mNEP was associated with reduced risk for mortality, total cardiovascular hospitalizations, and the composite endpoint of both (p < 0.01 for all). This is the first report describing a significant role of neutrophil mNEP in HFrEF. The biological relevance of neutrophil mNEP and exact effects of angiotensin-converting-enzyme inhibitors (ARNi) at the neutrophil site have to be determined. However, the results may suggest early initiation of ARNi already in less severe HF disease, where effects of NEP inhibition may be more pronounced.

Correction to: Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

Correction to: Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

Circulating Neprilysin Level Predicts the Risk of Cardiovascular Events in Hemodialysis Patients.

Background: Neprilysin inhibition has demonstrated impressive benefits in heart failure treatment, and is the current focus of interest in cardiovascular (CV) and kidney diseases. However, the role of circulating neprilysin as a biomarker for CV events is unclear in hemodialysis (HD) patients.Methods: A total of 439 HD patients from the K-cohort were enrolled from June 2016 to April 2019. The plasma neprilysin level and echocardiographic findings at baseline were examined. The patients were prospectively followed up to assess the primary endpoint (composite of CV events and cardiac events).Results: Plasma neprilysin level was positively correlated with left ventricular (LV) mass index, LV end-systolic volume, and LV end-diastolic volume. Multivariate linear regression analysis revealed that neprilysin level was negatively correlated with LV ejection fraction (β = −2.14; p = 0.013). The cumulative event rate of the composite of CV events was significantly greater in neprilysin tertile 3 (p = 0.049). Neprilysin tertile 3 was also associated with an increased cumulative event rate of cardiac events (p = 0.016). In Cox regression analysis, neprilysin tertile 3 was associated with a 2.61-fold risk for the composite of CV events [95% confidence interval (CI), 1.37–4.97] and a 2.72-fold risk for cardiac events (95% CI, 1.33–5.56) after adjustment for multiple variables.Conclusions: Higher circulating neprilysin levels independently predicted the composite of CV events and cardiac events in HD patients. The results of this study suggest the importance of future studies on the effect of neprilysin inhibition in reducing CV events.

P0328 - The effect of neprilysin inhibition and the combination of neprilysin and renin inhibitions in renal ischemia-reperfusion injury

P0328 - The effect of neprilysin inhibition and the combination of neprilysin and renin inhibitions in renal ischemia-reperfusion injury

Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction.

Patients with left ventricular (LV) systolic dysfunction after myocardial infarction are at a high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system inhibition may result in greater attenuation of adverse LV remodeling as a result of increased levels of substrates for neprilysin with vasodilatory, antihypertrophic, antifibrotic, and sympatholytic effects. We performed a prospective, multicenter, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103 mg twice daily with valsartan 160 mg twice daily in patients ≥3 months after myocardial infarction with a LV ejection fraction ≤40% who were taking a renin angiotensin system inhibitor (equivalent dose of ramipril ≥2.5 mg twice daily) and a β-blocker unless contraindicated or intolerant. Patients in New York Heart Association class ≥II or with signs and symptoms of heart failure were excluded. The primary outcome was change from baseline to 52 weeks in LV end-systolic volume index measured using cardiac magnetic resonance imaging. Secondary outcomes included other magnetic resonance imaging measurements of LV remodeling, change in NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin I, and a patient global assessment of change questionnaire. From July 2018 to June 2019, we randomized 93 patients with the following characteristics: mean age, 60.7±10.4 years; median time from myocardial infarction, 3.6 years (interquartile range, 1.2-7.2); mean LV ejection fraction, 36.8%±7.1%; and median NT-proBNP, 230 pg/mL (interquartile range, 124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LV end-systolic volume index; adjusted between-group difference, -1.9 mL/m2 (95% CI, -4.9 to 1.0); P=0.19. There were no significant between-group differences in NT-proBNP, high-sensitivity cardiac troponin I, LV end-diastolic volume index, left atrial volume index, LV ejection fraction, LV mass index, or patient global assessment of change. In patients with asymptomatic LV systolic dysfunction late after myocardial infarction, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03552575.

The effect of neprilysin and renin inhibition on the renal dysfunction following ischemia-reperfusion injury in the rat.

The natriuretic peptide (NP) system counter‐regulates the renin‐angiotensin system (RAS), so enhancing the activity of natriuretic peptides (NPs) may be beneficial in conditions when RAS is activated such as ischemia‐reperfusion injury (IRI). Neprilysin is the key enzyme responsible for the degradation of NPs. The effects of neprilysin inhibition or the combination of neprilysin inhibition and RAS inhibition on renal IRI‐induced renal dysfunction have not been investigated yet. To investigate this, rats underwent sham surgery or bilateral IRI for 20 min. G‐Als, G‐Scb, and G‐Als+Scb underwent similar protocol but received aliskiren (renin inhibitor), sacubitril (neprilysin inhibitor) or a combination of both pre‐ and post‐IRI, respectively. IRI caused significant alterations in all renal functional parameters, markers of acute renal injury, pro‐inflammatory and pro‐fibrotic cytokines, and histological features. All these alterations were significantly attenuated in G‐Als, G‐Scb, and G‐Als+Scb. The attenuations in the alterations in serum creatinine, creatinine clearance, and histological features were larger in G‐Als+Scb compared to either G‐Als or G‐Scb. We conclude that RAS blockade by a renin inhibitor (aliskiren) or neprilysin inhibition by sacubitril separately led to significant attenuation in the renal IRI‐induced renal dysfunction. The combination of aliskiren and sacubitril was more effective than either one alone.

Renal protective effect of sacubitril/valsartan in patients with heart failure

Sacubitril/valsartan is a combined neprilysin inhibitor/angiotensin II receptor blocker designed for treatment of heart failure (HF). Nonetheless, its renal protective effect remained an issue of debate. This retrospective cohort study investigated the renal protective effect of sacubitril/valsartan in HF patients. HF patients on sacubitril/valsartan or valsartan for > 30 days were matched for gender, age, estimated glomerular filtration rate (eGFR), and left ventricular ejection fraction (LVEF) to be enrolled into analysis. The follow-up period was 18 months. The outcomes included end eGFR, renal function decline defined as 20% reduction of eGFR, mortality, and HF-related hospitalization. Each group had 137 patients after matching. The mean age was 72.7 years and 65.7% were male. Mean eGFR was 70.9 mL/min/1.73 m2 and LVEF was 54.0% at baseline. Overall, the eGFR of sacubitril/valsartan groups was significantly higher than valsartan group at the end (P < 0.01). Subgroup analysis showed that the difference in eGFR was significant in subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2. Multivariate Cox regression model showed that sacubitril/valsartan group had significantly reduced risk for renal function decline (hazard ratio: 0.5, 95% confidence interval: 0.3–0.9). Kaplan–Meier curve showed no difference in the risk for cardiovascular mortality, all-cause mortality or HF-related hospitalization. We showed renal protective effect of neprilysin inhibition in HF patients and specified that subgroups with LVEF ≥ 40% or eGFR ≥ 60 mL/min/1.73 m2 were sensitive to this effect, suggesting an optimal subgroup of this treatment.

A Randomized Trial Comparing The Effect Of Sacubitril/Valsartan To Valsartan On Left Ventricular Remodeling In Patients With Asymptomatic Left Ventricular Systolic Dysfunction After Myocardial Infarction

Introduction In patients at high risk of heart failure (HF) following myocardial infarction (MI) as a result of residual left ventricular systolic dysfunction (LVSD), the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan may result in a greater attenuation of adverse LV remodeling than renin angiotensin aldosterone system inhibition alone, due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. In a randomized, double-blinded, active-comparator trial, we examined the effect of sacubitril/valsartan compared with the angiotensin receptor blocker (ARB), valsartan, on LV remodeling in patients with asymptomatic LVSD following MI using the gold-standard method of LV assessment, cardiac magnetic resonance imaging (MRI). Hypothesis In patients with LVSD and no evidence of HF following an MI, treatment with sacubitril/valsartan will result in a greater reduction in the degree of adverse remodeling than valsartan. Methods Key inclusion criteria were: 1) ≥3 months following MI, 2) LV ejection fraction ≤40% as measured by echocardiography, 3) tolerance of an ACE inhibitor or ARB at equivalent dose of ramipril ≥2.5mg twice daily, 4) taking a beta-blocker unless contraindicated or intolerant. Key exclusion criteria were: 1) Symptomatic HF (NYHA ≥II), 2) eGFR 5.2mmol/L, 4) symptomatic hypotension and/or systolic blood pressure Results From 7/19/2018 to 6/28/2019, 93 patients were randomized and the final study visit took place on 6/19/2020. Results from this trial will be available for presentation at the HFSA meeting. Conclusions This trial will investigate the effect of neprilysin inhibition on LV remodeling and the neurohumoral actions of sacubitril/valsartan in patients with asymptomatic LVSD following MI.

Increased concentrations of bioactive adrenomedullin subsequently to angiotensin-receptor/neprilysin-inhibitor treatment in chronic systolic heart failure.

AimsThe clinically investigated rationale for neprilysin (NEP)‐inhibition by angiotensinreceptor‐NEPinhibitor (ARNi) therapy is to induce elevations in endogenous natriuretic peptides. NEP, however, cleaves a broad spectrum of substrates, which partially hold significant implications in heart failure with reduced ejection fraction (HFrEF). The effect of NEP inhibition on these peptides has not been investigated thoroughly. This study explored the response of adrenomedullin (ADM) regulation to the initiation of ARNi.MethodsSeventy‐four patients with stable HFrEF and initiation of ARNi were prospectively enrolled, 67 patients on continuous angiotensin‐converting‐enzyme inhibitor(ACEi)/angiotensin‐receptor blocker (ARB) therapy served as control. Plasma bioactive‐ADM (bio‐ADM), mid‐regional‐pro‐ADM (MR‐proADM), B‐typenatriuretic peptide (BNP) and N‐terminal‐pro‐BNP (NT‐proBNP) were determined at baseline, short‐term, 1‐year and 2‐year follow up.ResultsFollowing ARNi initiation both bio‐ADM and MR‐proADM concentrations were significantly increased at early and long‐term follow up (bio‐ADM [pg/mL]: 26.0 [interquartile range {IQR}: 17.7–37.5] vs. 50.8 [IQR: 36.5–78.1] vs. 54.6 [IQR: 42.0–97.1] vs. 57.4 [IQR: 48.5–161.6]; MR‐proADM [nmol/L]: 0.87 [IQR: 0.64–1.12] vs. 1.25 [IQR: 0.93–1.79] vs. 1.42 [IQR: 0.95–1.90] vs. 1.60 [IQR: 1.12–2.46], P < .0001 for all). The ratios bio‐ADM/MR‐proADM and BNP/NT‐proBNP increased during ARNi‐therapy proving improved availability of bioactive peptides. The proportional increase of bio‐ADM markedly exceeded BNP increase. Patients converted to ARNi showed similar biomarker patterns irrespective of baseline renin–angiotensin system blocker therapy, i.e. ACEi or ARB (P > .05 for all), indicating that activation of the ADM‐axis arises particularly from NEPinhibition.ConclusionThe significant increase of MR‐proADM and bio‐ADM together with an elevated bioADM/MR‐proADM ratio suggest both enhanced formation and reduced breakdown of bioactive ADM following the initiation of ARNi. Activation of the ADM‐axis represents a so far unrecognized effect of ARNi.

P1620Association of granulocyte neprilysin (CD10) expression with prognosis in heart failure with reduced ejection fraction

Abstract Background The exact mechanism of action of neprilysin inhibition (NEPi) is still a subject of debate. The soluble form of the enzyme (sNEP), detectable in plasma, is discussed controversially as a potential biomarker in heart failure with reduced ejection fraction (HFrEF). NEP is present on solid tissues but identically to CD10, expressed on the surface of leukocytes under physiological conditions. The possible impact of NEP expression on peripheral leukocytes on prognosis and its association with sNEP levels have not been investigated yet. Methods 99 stable HFrEF patients were prospectively enrolled and clinically followed-up. Laboratory markers including NT-proBNP were assessed. NEP (CD10) expression on peripheral blood cells were measured by flow cytometry using a combination of six antibodies with fluorescence minus one samples as control [CD3 (#555339), CD19 (#555413), CD56 (#335826), CD16 (#561306), CD14 (#562692), +/−CD10 (#332777); BD Biosciences,USA]. sNEP levels were determined by a specific ELISA [SEB785Hu, USCN, China].Associations between NEP expression and heart failure severity, sNEP levels and all-cause mortality were determined. Results Median age was 65 years (IQR: 55–73), 75% were male. Median NT-proBNP level was 1700pg/ml (IQR: 794–4009).NEP was expressed on granulocytes with 94.8% (IQR: 90.5–97.4) of CD10+ cells and measurable on B-cells and monocytes with 8.5% (IQR: 5.3–13.5) and 0.8% (IQR: 0.4–1.5) of CD10+ cells of the respective leukocyte subtype. NEP expression on T-cells was not detectable. The mean fluorescence intensity (MFI) of CD10+ cells was 5461 (IQR: 4028–6904) for granulocytes, 640 (IQR: 535–740) for B-cells and 1589 (IQR: 1395–1975) for monocytes. Granulocyte NEP expression, but not NEP expression on B-cells or monocytes, correlated inversely with heart failure severity reflected by NT-proBNP level (r=−0.46, p&lt;0.001) and NYHA class (p=0.013) (Figure A). sNEP concentrations correlated weakly with NEP expression on granulocytes (r=0.22, p=0.030) as well as the MFI of CD10+ granulocytes (r=0.31, p=0.003). 15% of the patients died during a median FUP of 24 (IQR: 23–28) months. Increased NEP expression on granulocytes was indicative for better overall survival even after adjustment for age and kidney function [adj. HR per 1-IQR increase of MFI 0.41 (95% CI: 0.18–0.94), p=0.035]. Kaplan-Meier analysis illustrates the impact of granulocyte NEP expression on outcome graphically (Figure B). Figure 1 Conclusions Albeit beneficial effects of NEPi by ARNI therapy, NEP expression on granulocytes is inversely correlated with heart failure severity and mortality. The results support the inverse relationship between BNP and plasma NEP activity reported for a mixed population of heart failure patients. The positive correlation of granulocyte NEP expression and sNEP indicates a possible contribution of shed membrane NEP molecules to plasma NEP levels as a surrogate marker. The utility of granulocyte NEP expression or sNEP as biomarkers in HFrEF have to be further evaluated.

Combining angiotensin II receptor 1 antagonism and neprilysin inhibition for the treatment of heart failure

ABSTRACTSacubitril/valsartan is a novel, first-in-class drug, which combines a neprilysin inhibitor with an angiotensin receptor blocker. Sacubitril inhibits neprilysin endopeptidase, blocking the catabolism of natriuretic peptides (NP), thereby increasing their bioavailability. Valsartan counterbalances the increase of angiotensin II that results from neprilysin inhibition, exerting also the beneficial effects of angiotensin receptor blockers seen in previous HF trials. PARADIGM-HF trial has proved the superiority of sacubitril/valsartan (LCZ696) over ACE inhibitor enalapril to reduce mortality and morbidity of symptomatic HF patients with reduced ejection fraction (HFrEF), setting the grounds for the replacement of ACE inhibitors by sacubitril/valsartan in the management of HFrEF. Sacubitril/valsartan is currently being tested in a phase III trial (PARAGON-HF) in patients with HF with preserved EF. PARAGON-HF is also expected to provide further data regarding the long-term safety of sacubitril/valsartan, hopefully to alleviate concerns regarding the effects of neprilysin inhibition on cognitive function.

Will sacubitril-valsartan diminish the clinical utility of B-type natriuretic peptide testing in acute cardiac care?

Since the approval of sacubitril-valsartan for the treatment of chronic heart failure with reduced ejection fraction, a commonly raised suspicion is that a wider clinical use of this new drug may diminish the clinical utility of B-type natriuretic peptide testing as sacubitril may interfere with B-type natriuretic peptide clearance. In this education paper we critically assess this hypothesis based on the pathophysiology of the natriuretic peptide system and the limited published data on the effects of neprilysin inhibition on natriuretic peptide plasma concentrations in humans. As the main clinical application of B-type natriuretic peptide testing in acute cardiac care is and will be the rapid rule-out of suspected acute heart failure there is no significant impairment to be expected for B-type natriuretic peptide testing in the acute setting. However, monitoring of chronic heart failure patients on sacubitril-valsartan treatment with B-type natriuretic peptide testing may be impaired. In contrast to N-terminal-proBNP, the current concept that the lower the B-type natriuretic peptide result in chronic heart failure patients, the better the prognosis during treatment monitoring, may no longer be true.