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neprilysin - Top 30 Publications

Clinical features and prognosis in CD10(-) pre-B acute lymphoblastic leukemia.

Objective: To analyze the clinical features and prognosis of acute lymphoblastic leukemia patients with immunophenotype of CD10(-)pre-B (CD10(-) pre B-ALL) . Methods: 6 adult cases with CD10(-) pre B-ALL immunophenotypes were analyzed retrospectively, related literatures were reviewed to clarify these kind of patients' clinical features and prognosis. Results: CD10(-) pre B-ALL occurred in 1.5% of ALL, 1.8% of B-ALL and 11.5% of pre B-ALL respectively. All the 6 patients were male with the median age as 33.5 years old, the median white blood cells was 101.78×10(9)/L, MLL-AF4 fusion transcripts were evident in all cases. Complete remission (CR) was achieved in 5 patients after first induction chemotherapy, 1 patient failed to respond to induction therapy, and got CR after 3 courses of chemotherapy. 2 patients underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in CR(1), 1 patient relapsed in the short term and underwent allo-HSCT in CR(2). 1 patient was still waiting for allo-HSCT. Of the 2 patients who didn't receive transplantation, 1 died following a relapse, the other remained to be in CR. Conclusions: CD10(-) pre B-ALL was a rare but distinct subtype in adult ALL characterized by male dominance, high onset white blood cells and MLL rearrangement rate. Conventional chemotherapy produced a high response rate but more likely relapse, allo-HSCT may have the potential to improve the prognosis of these patients.

Protective effect of valproic acid in streptozotocin-induced sporadic Alzheimer's disease mouse model: possible involvement of the cholinergic system.

Sporadic Alzheimer's disease (SAD) is a slowly progressive neurological disorder that is the most common form of dementia. Cholinergic system dysfunction and amyloid beta formation are the two main underlying pathological mechanisms for the disease development. In recent studies, insulin receptor desensitization and disturbances in the downstream effects of insulin receptor signaling were observed in the brains of Alzheimer's patients. Currently, intracereberoventricular (ICV) injection of streptozotocin (STZ) is found to induce behavioral, neurochemical, and structural alterations in animals resembling those found in SAD patients. Valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was recently shown to regulate the transcription of several genes in both in vivo and in vitro models of Alzheimer's disease. The aim of the current study is to investigate the potential effect of different doses of valproic acid, in an ICV-STZ-induced animal model of SAD. Streptozotocin-injected mice showed cognitive and spatial memory dysfunction in the Y-maze, object recognition test, and Morris water maze (MWM) neurobehavioral tests. The mice also exhibited a decrease in acetylcholine (ACh) and neprilysin (NEP) levels accompanied by an increase in acetylcholinesterase (AChE) activity. For the first time to our knowledge, our findings have shown that VPA is capable of restoring ACh levels in ICV-STZ-injected mice, as well as normalizing both NEP levels and AChE activity. Via this mechanism, an enhancement of cognitive functions is observed. Thus, VPA is suggested to be a promising therapeutic approach against SAD.

Epigenetic regulation of HDAC1 SUMOylation as an endogenous neuroprotection against Aβ toxicity in a mouse model of Alzheimer's disease.

Amyloid-β (Aβ) produces neurotoxicity in the brain and causes neuronal death, but the endogenous defense mechanism that is activated on Aβ insult is less well known. Here we found that acute Aβ increases the expression of PIAS1 and Mcl-1 via activation of MAPK/ERK, and Aβ induction of PIAS1 enhances HDAC1 SUMOylation in rat hippocampus. Knockdown of PIAS1 decreases endogenous HDAC1 SUMOylation and blocks Aβ induction of Mcl-1. Sumoylated HDAC1 reduces it association with CREB, increases CREB binding to the Mcl-1 promoter and mediates Aβ induction of Mcl-1 expression. Transduction of SUMO-modified lenti-HDAC1 vector to the hippocampus of APP/PS1 mice rescues spatial learning and memory deficit and long-term potentiation impairment in APP/PS1 mice. It also reduces the amount of amyloid plaque and the number of apoptotic cells in CA1 area of APP/PS1 mice. Meanwhile, HDAC1 SUMOylation decreases HDAC1 binding to the neprilysin promoter. These results together reveal an important role of HDAC1 SUMOylation as a naturally occurring defense mechanism protecting against Aβ toxicity and provide an alternative therapeutic strategy against AD.Cell Death and Differentiation advance online publication, 10 February 2017; doi:10.1038/cdd.2016.161.

Neprilysin Inhibitors in Cardiovascular Disease.

Mortality from heart failure remains high despite advances in medical therapy over the last three decades. Angiotensin receptor-neprilysin inhibitor (ARNI) combinations are the latest addition to the heart failure medical armamentarium, which is built on the cornerstone regimen of beta blockers, angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers, and aldosterone antagonists. Recent trial data have shown a significant mortality benefit from ARNIs, which, as of May 2016, have now received a class I recommendation for use in patients with heart failure and reduced ejection fraction from the major American and European cardiology societies.

Resolution of Cheyne-Stokes Respiration after Treatment of Heart Failure with Sacubitril/Valsartan: A First Case Report.

Sleep-disordered breathing (SDB) is highly prevalent in patients with heart failure (HF), and is known to be associated with a worse prognosis. The severity of central sleep apnea is thought to mirror cardiac dysfunction. The novel angiotensin receptor-neprilysin inhibitor (ARNi) sacubitril has been shown to improve HF, but a relationship between treatment with ARNi and the severity of SDB has not yet been investigated. We report the case of a 71-year-old male with HF and SDB. Treatment with sacubitril/valsartan was associated with improved cardiac function, as shown by a reduction in the level of N-terminal prohormone of brain natriuretic peptide from 3,249 to 1,720 pg/mL, and an improvement in left-ventricular ejection fraction from 30 to 35%. This was accompanied by a marked reduction in the apnea-hypopnea index (from 41 to 19/h). To the best of our knowledge, this is the first case to document parallel improvements in HF and SDB after the initiation of ARNi treatment.

Novel drugs for hypertension and heart failure: struggling for a place under the sun.

Current drug therapy for the management of arterial hypertension and heart failure has provided substantial benefits but has also some limitations. LCZ696, a dual inhibitor of angiotensin receptor blockers and neprilysin, and finerenone, a non-steroidal mineralocorticoid receptor antagonist, are two recently developed novel agents for the management of these conditions.

Correction.

There was an error in our CPD article Chronic heart failure part 2: treatment and management (11 January). On page 55, the first sentence in the angiotensin receptor neprilysin inhibitor section should read: Valsartan with sacubitril is an angiotensin receptor neprilysin inhibitor that has recently been approved for use as a replacement for ACE inhibitors, to further reduce the risk of hospitalisation and death in ambulatory patients with heart failure and an ejection fraction ≤35% who remain symptomatic despite optimal treatment with an ACE inhibitor, a beta-blocker and an aldersterone antagonist (Ponikowski et al 2016).

Changing the treatment of heart failure with reduced ejection fraction: clinical use of sacubitril-valsartan combination.

Despite significant therapeutic advances, patients with chronic heart failure (HF) remain at high risk of morbidity and mortality. Sacubitril valsartan (previously known as LCZ696) is a new oral agent approved for the treatment of symptomatic chronic heart failure in adults with reduced ejection fraction. It is described as the first in class angiotensin receptor neprilysin inhibitor (ARNI) since it incorporates the neprilysin inhibitor, sacubitril and the angiotensin II receptor antagonist, valsartan. Neprilysin is an endopeptidase that breaks down several vasoactive peptides including natriuretic peptides (NPs), bradykinin, endothelin and angiotensin II (Ang-II). Therefore, a natural consequence of its inhibition is an increase of plasmatic levels of both, NPs and Ang-II (with opposite biological actions). So, a combined inhibition of these both systems (Sacubitril / valsartan) may enhance the benefits of NPs effects in HF (natriuresis, diuresis, etc) while Ang-II receptor is inhibited (reducing vasoconstriction and aldosterone release). In a large clinical trial (PARADIGM-HF with 8442 patients), this new agent was found to significantly reduce cardiovascular and all cause mortality as well as hospitalizations due to HF (compared to enalapril). This manuscript reviews clinical evidence for sacubitril valsartan, dosing and cautions, future directions and its considered place in the therapy of HF with reduced ejection fraction.

Advances in the pharmacotherapy of chronic heart failure with preserved ejection fraction: an ideal opportunity for precision medicine.

Heart failure with preserved ejection fraction (HFpEF), which comprises approximately 50% of all heart failure patients, is a challenging and complex clinical syndrome that is often thought to lack effective treatments. Areas covered: Despite the common mantra that HFpEF has no effective treatments, closer inspection of HFpEF clinical trials reveals that several of the drugs tested are associated with benefits in exercise capacity and quality of life, and reduction in heart failure hospitalization. Here we review major randomized controlled trials in HFpEF, focusing on renin-angiotensin-aldosterone system antagonists, organic nitrates, digoxin, beta-blockers, and phosphodiesterase-5 inhibitors. In addition, we review several classes of drugs currently in development for HFpEF such as neprilysin inhibitors, inorganic nitrates (nitrites), and soluble guanylate cyclase stimulators. Expert opinion: HFpEF should not be viewed as lacking effective treatments. While there have been no breakthrough clinical trials, several existing medications are likely to benefit specific subgroups of HFpEF patients. HFpEF is now well known to be a heterogeneous syndrome; thus, the clinical management of HFpEF patients and future HFpEF clinical trials will both likely require a nuanced, phenotype-specific approach instead of a one-size-fits-all tactic. Drug development for HFpEF therefore represents an exciting opportunity for personalized medicine.

Dynamic alteration of neprilysin and endothelin-converting enzyme in age-dependent APPswe/PS1dE9 mouse model of Alzheimer's disease.

Imbalance of Aβ production and Aβ removal leads to Aβ accumulation. Aβ degrading enzyme (including neprilysin-NEP, endothelin converting enzyme-ECE) as a therapeutic strategy for lowering brain Aβ deposition has attracted increasing attention. In this study, we investigated alteration of age and region-dependent in APP/PS1 double transgenic mice (3, 6, 9, 12 months) and their age-matched wild type mice including the ability of spatial memory, Aβ deposits, the protein expression, location and activity of NEP and ECE. Our data demonstrated that, as compared with wild type mice, APP/PS1 mice displayed significant cognitive deficit at 9 month revealed by obviously longer in the latency and distance to find the platform and shorter in time spent and swimming distance in the target quadrant. Aβ40 and Aβ42 levels exhibited a significant increase with age in the cerebral cortex and hippocampus of APP/PS1 mice after 6 month, compared with their age-matched wild type mice. And Aβ42 levels were significantly higher than Aβ40 levels in the same age of APP/PS1 mice. Furthermore, NEP protein and activity displayed a marked decrease with age in the cerebral cortex and hippocampus of APP/PS1 mice older than 6 month. Slightly different from NEP, ECE protein was up-regulated with age, while ECE activity showed a significantly decrease with age in cortex and hippocampus of APP/PS1 mice older than 6 month. Double immunofluorescence staining also demonstrated that ECE and NEP highly colocalized in cytoplasmic and membrane, and ECE immunoreactivity tended to increase with age in APP/PS1 mice, especially 12 month APP/PS1 mice. Correlation analysis showed the negative correlation between enzyme (NEP or ECE) activity and Aβ levels in the cerebral cortex and hippocampus of APP/PS1 mice, which was correlated with Aβ accumulation. These results indicate NEP rather than ECE plays more important role in resisting Aβ accumulation. The compensatory upregulation of NEP and ECE could balance Aβ metabolism and protect neuronal functions in infant and juvenile mice. These evidence might provide some clues for the treatment of Alzheimer's disease.

Paramount Importance of Angiotensin Receptor Neprilysin Inhibitor in Heart Failure Management.

Identification of Small Peptides in Human Cerebrospinal Fluid upon Amyloid-β Degradation.

Amyloid-β (Aβ) degradation in brains of Alzheimer disease patients is a crucial focus for the clarification of disease pathogenesis. Nevertheless, the mechanisms underlying Aβ degradation in the human brain remain unclear.

Effects of Sacubitril/Valsartan Versus Olmesartan on Central Hemodynamics in the Elderly With Systolic Hypertension: The PARAMETER Study.

Effective treatment of systolic hypertension in elderly patients remains a major therapeutic challenge. A multicenter, double-blind, randomized controlled trial with sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, was conducted to determine its effects versus olmesartan (angiotensin receptor blocker) on central aortic pressures, in elderly patients (aged ≥60 years) with systolic hypertension and pulse pressure >60 mm Hg, indicative of arterial stiffness. Patients (n=454; mean age, 67.7 years; mean seated systolic blood pressure, 158.6 mm Hg; mean seated pulse pressure, 69.7 mm Hg) were randomized to receive once-daily sacubitril/valsartan 200 mg or olmesartan 20 mg, force titrated to double the initial doses after 4 weeks, before primary assessment at 12 weeks. The study extended double-blind treatment for 12 to 52 weeks, during which amlodipine (2.5-5 mg) and subsequently hydrochlorothiazide (6.25-25 mg) were added-on for patients not achieving blood pressure target (<140/90). At week 12, sacubitril/valsartan reduced central aortic systolic pressure (primary assessment) greater than olmesartan by -3.7 mm Hg (P=0.010), further corroborated by secondary assessments at week 12 (central aortic pulse pressure, -2.4 mm Hg, P<0.012; mean 24-hour ambulatory brachial systolic blood pressure and central aortic systolic pressure, -4.1 mm Hg and -3.6 mm Hg, respectively, both P<0.001). Differences in 24-hour ambulatory pressures were pronounced during sleep. After 52 weeks, blood pressure parameters were similar between treatments (P<0.002); however, more patients required add-on antihypertensive therapy with olmesartan (47%) versus sacubitril/valsartan (32%; P<0.002). Both treatments were equally well tolerated. The PARAMETER study (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Measuring Arterial Stiffness in the Elderly), for the first time, demonstrated superiority of sacubitril/valsartan versus olmesartan in reducing clinic and ambulatory central aortic and brachial pressures in elderly patients with systolic hypertension and stiff arteries.

Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis.

Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction.

Molecular snapshot of an intracellular freezing event in an Antarctic nematode.

The Antarctic nematode, Panagrolaimus sp. DAW1 (formerly called Panagrolaimus davidi), is the best documented example of an organism able to survive intracellular ice formation in all of its compartments. Not only is it able to survive such extreme physiological disruption, but it is able to produce progeny once thawed from such a state. In addition, under slower rates, or less extreme degrees, of cooling, its body remains unfrozen and the vapour pressure difference between the supercooled body fluids and the surrounding ice leads to a process termed cryoprotective dehydration. In contrast to a fairly large body of work in building up our molecular understanding of cryoprotective dehydration, no comparable work has been undertaken on intracellular freezing. This paper describes an experiment subjecting cultures of Panagrolaimus sp. DAW1 to a range of temperatures including a rapid descent to -10 °C, in a medium just prior to, and after, freezing. Through deep sequencing of RNA libraries we have gained a snapshot of which genes are highly abundant when P. sp. DAW1 is undergoing an intracellular freezing event. The onset of freezing correlated with a high production of genes involved in cuticle formation and subsequently, after 24 h in a frozen state, protease production. In addition to the mapping of RNA sequencing, we have focused on a select set of genes arising both from the expression profiles, as well as implicated from other cold tolerance studies, to undertake qPCR. Among the most abundantly represented transcripts in the RNA mapping is the zinc-metalloenzyme, neprilysin, which also shows a particularly strong upregulated signal through qPCR once the nematodes have frozen.

Hyperbaric Oxygen Prevents Cognitive Impairments in Mice Induced by D-Galactose by Improving Cholinergic and Anti-apoptotic Functions.

Our previous study demonstrated that hyperbaric oxygen (HBO) improved cognitive impairments mainly by regulating oxidative stress, inflammatory responses and aging-related gene expression. However, a method for preventing cognitive dysfunction has yet to be developed. In the present study, we explored the protective effects of HBO on the cholinergic system and apoptosis in D-galactose (D-gal)-treated mice. A model of aging was established via systemic intraperitoneal injection of D-gal daily for 8 weeks. HBO was administered during the last 2 weeks of D-gal injection. Our results showed that HBO in D-gal-treated mice significantly improved behavioral performance on the open field test and passive avoidance task. Studies on the potential mechanisms of this effect showed that HBO significantly reduced oxidative stress and blocked the nuclear factor-κB pathway. Moreover, HBO significantly increased the levels of choline acetyltransferase and acetylcholine and decreased the activity of acetylcholinesterase in the hippocampus. Furthermore, HBO markedly increased expression of the anti-apoptosis protein Bcl-2 and glial fibrillary acidic protein meanwhile decreased expression of the pro-apoptosis proteins Bax and caspase-3. Importantly, there was a significant reduction in expression of Aβ-related genes, such as amyloid precursor protein, β-site amyloid cleaving enzyme-1 and cathepsin B mRNA. These decreases were accompanied by significant increases in expression of neprilysin and insulin-degrading enzyme mRNA. Moreover, compared with the Vitamin E group, HBO combined with Vitamin E exhibited significant difference in part of the above mention parameters. These findings suggest that HBO may act as a neuroprotective agent in preventing cognitive impairments.

Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure.

Inhibitors of the renin angiotensin system and neprilysin (RAS-/NEP-inhibitors) proved to be extraordinarily beneficial in systolic heart failure. Furthermore, compelling evidence exists that impaired mitochondrial pathways are causatively involved in progressive left ventricular (LV) dysfunction. Consequently, we aimed to assess whether RAS-/NEP-inhibition can attenuate mitochondrial adaptations in experimental heart failure (HF).

Heart Failure Due to Reduced Ejection Fraction: Medical Management.

Heart failure is an increasingly common condition resulting in high rates of morbidity and mortality. For patients who have heart failure and reduced ejection fraction, randomized clinical trials demonstrate consistent mortality benefit from angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, direct-acting vasodilators, beta blockers, and aldosterone antagonists. Additionally, some data show benefits from two new classes of drugs: angiotensin receptor blocker/neprilysin inhibitor and sinus node modulator. Diuretics and digoxin can be used as needed for symptom control. Statins are not recommended solely for treatment of heart failure. Implantable cardioverter-defibrillators and biventricular pacemakers improve mortality and function in selected patients. For patients who have been hospitalized for heart failure, disease management programs and telemonitoring can reduce hospitalizations and mortality.

Biochemistry, Therapeutics, and Biomarker Implications of Neprilysin in Cardiorenal Disease.

Neprilysin (NEP) is a membrane-bound neutral endopeptidase that degrades a variety of bioactive peptides. The substrates include natriuretic peptides (NPs), which are important regulating mediators for cardiovascular and renal biology. Inhibition of NEP activity and exogenous NP administration thus have emerged as potential therapeutic strategies for treating cardiorenal diseases. More recently, B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), 3'-5' cyclic guanosine monophosphate (cGMP), and soluble NEP as biomarkers have also been investigated in heart failure (HF) trials and their predictive value are beginning to be recognized.

The safety of sacubitril-valsartan for the treatment of chronic heart failure.

Sacubitril-valsartan is a combination drug that contains the neprilysin inhibitor sacubitril and angiotensin II receptor blocker valsartan. In 2015, the US Food and Drug Administration approved sacubitril-valsartan for treatment of heart failure patients with reduced ejection fraction and New York Heart Association class II-IV symptoms following a large, Phase III clinical trial (PARADIGM-HF) that demonstrated a 20% reduction in the combined primary end-point of death from cardiovascular cause or hospitalization for heart failure compared to enalapril. Areas covered: This review discusses the clinical efficacy and safety of angiotensin receptor neprilysin inhibitor sacubitril-valsartan in heart failure with reduced ejection fraction. Expert opinion: Based on the PARADIGM-HF trial, sacubitril-valsartan offers compelling reductions in meaningful clinical endpoints, independent of age or severity of disease. The rate of adverse events was comparable between the enalapril and sacubitril-valsartan groups, although the absolute rates are likely underestimated due to the entry criteria and run-in period. Future trials and post-market surveillance are critical to better understand the risk of angioedema in high risk populations, particularly African-Americans, as well as long-term theoretical risks including the potential for increased cerebral amyloid plaque deposition with possible development of neurocognitive disease. Current trials are underway to evaluate potential benefit in patients with heart failure with preserved ejection fraction.

GLP-1 receptor independent pathways: emerging beneficial effects of GLP-1 breakdown products.

The glucagon-like peptide-1 (GLP-1) axis has emerged as a major therapeutic target for the treatment of type 2 diabetes and, recently, of obesity. The insulinotropic activity of the native incretin hormone GLP-1(7-36)amide, which is mainly exerted through a unique G protein-coupled receptor (GLP-1R), is terminated via enzymatic cleavage by dipeptidyl peptidase-IV that generates a C-terminal GLP-1 metabolite GLP-1(9-36)amide, the major circulating form in plasma. GLP-1(28-36)amide and GLP-1(32-36)amide are further cleavage products derived from GLP-1(7-36)amide and GLP-1(9-36)amide by the action of a neutral endopeptidase known as neprilysin. Until recently, GLP-1-derived metabolites were generally considered metabolically inactive. However, emerging evidence indicates that GLP-1 byproducts have insulinomimetic activities that may contribute to the pleiotropic effects of GLP-1 independently of the canonical GLP-1R. The recent studies reporting the beneficial effects of the administration of these metabolites in vivo and in vitro are the focus of this review. Collectively, these results suggest that GLP-1 metabolites inhibit hepatic glucose production, exert antioxidant cardio- and neuroprotective actions, reduce oxidative stress in vasculature and have both anti-apoptotic and proliferative effects in pancreatic β-cells, putatively by the modulation of mitochondrial functions. These findings have implication in energy homeostasis, obesity and its associated metabolic and cardiovascular complications as well as incretin-based therapies for the treatment of diabetes and obesity.

Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy.

The objective of this study is to evaluate the efficacy and safety of sacubitril/valsartan (LCZ696, an angiotensin receptor and neprilysin inhibitor) add-on to amlodipine compared with amlodipine monotherapy in Asian patients with systolic hypertension uncontrolled with amlodipine.

Efficacy and safety of sacubitril/valsartan (LCZ696) in Japanese patients with chronic heart failure and reduced ejection fraction: Rationale for and design of the randomized, double-blind PARALLEL-HF study.

The prognosis of heart failure patients with reduced ejection fraction (HFrEF) in Japan remains poor, although there is growing evidence for increasing use of evidence-based pharmacotherapies in Japanese real-world HF registries. Sacubitril/valsartan (LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor shown to reduce mortality and morbidity in the recently completed largest outcome trial in patients with HFrEF (PARADIGM-HF trial). The prospectively designed phase III PARALLEL-HF (Prospective comparison of ARNI with ACE inhibitor to determine the noveL beneficiaL trEatment vaLue in Japanese Heart Failure patients) study aims to assess the clinical efficacy and safety of LCZ696 in Japanese HFrEF patients, and show similar improvements in clinical outcomes as the PARADIGM-HF study enabling the registration of LCZ696 in Japan.

Sacubitril/Valsartan (LCZ696) in Heart Failure.

It has been known since the 1990s that long-term morbidity and mortality is improved in patients with heart failure with reduced ejection fraction (HFrEF) by treatments that target the renin-angiotensin-aldosterone system (RAAS). It has also long been thought that enhancement of the activity of natriuretic peptides (NPs) could potentially benefit patients with HFrEF, but multiple attempts to realize this benefit had failed over the years - until 2014, when a large, phase III, randomized, controlled clinical trial (PARADIGM-HF) was completed comparing sacubitril/valsartan with enalapril, a well-established treatment for HFrEF. Sacubitril/valsartan (formerly known as LCZ696) is a first-in-class angiotensin receptor neprilysin inhibitor (ARNI) that simultaneously suppresses RAAS activation through blockade of angiotensin II type 1 receptors and enhances vasoactive peptides including NPs through inhibition of neprilysin, the enzyme responsible for their degradation. In PARADIGM-HF, patients with HFrEF treated with sacubitril/valsartan had 20% less risk for cardiovascular death or hospitalization for heart failure (the primary endpoint), 20% less risk for cardiovascular death, 21% less risk for first hospitalization for heart failure, and 16% less risk for death from any cause, compared with enalapril (all p < 0.001). Concerning tolerability, the sacubitril/valsartan group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough, compared with the enalapril group. The use of sacubitril/valsartan has been endorsed by the latest heart failure treatment guidelines in Europe and the USA. This chapter reviews the discoveries, scientific reasoning, and clinical evidence that led to the development of sacubitril/valsartan, the first novel therapy in a new drug class to improve survival in HFrEF in the last 15 years.

Long-term neprilysin inhibition - implications for ARNIs.

Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor-neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015. This approval was the first for chronic neprilysin inhibition. The many peptides metabolized by neprilysin suggest many potential consequences of chronic neprilysin inhibitor therapy, both beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema, bronchial reactivity, inflammation, and cancer, and might predispose to polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-β peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible adverse consequences of chronic neprilysin inhibition comes from studies in animal models, and the relevance of this evidence to humans is unknown. This Review summarizes current knowledge of neprilysin function and possible consequences of chronic neprilysin inhibition that indicate a need for vigilance in the use of neprilysin inhibitor therapy.

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants.

Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.

Heart failure - what's new and what's changed?

Physicians responsible for the care of patients with heart failure due to left ventricular systolic dysfunction have access to a broad range of evidence-based treatments that prolong life and reduce symptoms. In spite of the significant progress made over the last four decades, there is an ongoing need for novel therapies to treat a condition that is associated with stubbornly high morbidity and mortality. In this article, we discuss the findings of SERVE-HF, a randomised controlled trial of adaptive servo-ventilation in patients with left ventricular systolic dysfunction, as well as EMPA-REG, a study of the effects of a novel diabetic agent that may be of greater interest to heart failure specialists than diabetologists. We also examine further analyses of the groundbreaking PARADIGM-HF trial, which attempt to answer some of the unresolved questions from the original study of the first combined angiotensin-receptor blocker and neprilysin inhibitor, sacubitril valsartan. The recently published National Institute for Health and Care Excellence guidelines for the management of acute heart failure and plans to introduce best practice tariffs bring into focus the need for well-organised, multidisciplinary care. We discuss the challenges involved in developing and delivering a specialist service that meets the needs of a growing population of patients living with heart failure.

Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye.

Dysfunction of the renin-angiotensin system (RAS) contributes to pathogenesis of diabetic retinopathy (DR). Yet RAS blockers have only limited beneficial effects on progression of DR in clinical trials. The natriuretic peptide system offsets RAS, so that enhancing the activity of this system on top of RAS blockade might be beneficial. Neprilysin has an important role in the degradation of natriuretic peptides. Therefore, we hypothesize that dual angiotensin receptor-neprilysin inhibition (ARNI) may outperform angiotensin receptor blocker (ARB) in protection against DR. We tested this hypothesis in streptozotocin-induced diabetic transgenic (mRen2)27 rats.

Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels.

Neprilysin, a widely expressed peptidase, is upregulated in metabolically altered states such as obesity and type 2 diabetes. Like dipeptidyl peptidase-4 (DPP-4), neprilysin can degrade and inactivate the insulinotropic peptide glucagon-like peptide-1 (GLP-1). Thus, we investigated whether neprilysin deficiency enhances active GLP-1 levels and improves glycaemia in a mouse model of high fat feeding.

Importance of endogenous compensatory vasoactive peptides in broadening the effects of inhibitors of the renin-angiotensin system for the treatment of heart failure.

The magnitude of the clinical benefits produced by inhibitors of the renin-angiotensin system in heart failure has been modest, possibly because of the ability of renin-angiotensin activity to escape from suppression during long-term treatment. Efforts to intensify pharmacological blockade by use of dual inhibitors that interfere with the renin-angiotensin system at multiple sites have not yielded consistent incremental clinical benefits, but have been associated with serious adverse reactions. By contrast, potentiation of endogenous compensatory vasoactive peptides can act to enhance the survival effects of inhibitors of the renin-angiotensin system, as evidenced by trials that have compared angiotensin-converting enzyme inhibitors with drugs that inhibit both the renin-angiotensin system and neprilysin. Several endogenous vasoactive peptides act as adaptive mechanisms, and their augmentation could help to broaden the benefits of renin-angiotensin system inhibitors for patients with heart failure.