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Stephen Moss, Vasanta Subramanian, K Ravi Acharya
Neprilysin is a transmembrane M13 zinc metalloprotease responsible for the degradation of several biologically active peptides including insulin, enkephalin, substance P, bradykinin, endothelin-1, neurotensin and amyloid-β. The protein has received attention for its role in modulating blood pressure responses with its inhibition producing an antihypertensive response. To date, several inhibitor bound crystal structures of the human neprilysin extracellular domain have been determined, but, a structure free of bound inhibitor or substrate has yet to be reported...
June 12, 2018: Journal of Structural Biology
Merlin C Thomas
Heart failure is a leading cause for hospitalisation and for readmission, especially in patients over the age of 65. Diabetes is an increasingly common companion to heart failure. The presence of diabetes and its associated comorbidity increases the risk of adverse outcomes and premature mortality in patients with heart failure. In particular, patients with diabetes are more likely to be readmitted to hospital soon after discharge. This may partly reflect the greater severity of heart disease in these patients...
2018: Clinical Medicine Insights. Cardiology
Nancy Luo, Nicholas G Ballew, Emily C O'Brien, Melissa A Greiner, Pamela N Peterson, Bradley G Hammill, N Chantelle Hardy, Warren K Laskey, Paul A Heidenreich, Chun-Lan Chang, Adrian F Hernandez, Lesley H Curtis, Robert J Mentz, Gregg C Fonarow
BACKGROUND: On May 20, 2016, US professional organizations in cardiology published joint treatment guidelines recommending the use of angiotensin-receptor neprilysin inhibitor (ARNI) for eligible patients with heart failure with reduced ejection fraction (HFrEF). Using data from the Get With The Guidelines-Heart Failure registry, we evaluated the early impact of this update on temporal trends in ARNI prescription. METHODS: We analyzed patients with HFrEF who were eligible for ARNI prescription (EF ≤40%, no contraindications) and hospitalized from February 20, 2016, through August 19, 2016-allowing for 13weeks before and after guideline publication...
June 2018: American Heart Journal
Adam D DeVore, Xiaojuan Mi, Laine Thomas, Puza P Sharma, Nancy M Albert, Javed Butler, Adrian F Hernandez, J Herbert Patterson, John A Spertus, Fredonia B Williams, Carol I Duffy, Kevin McCague, Gregg C Fonarow
BACKGROUND: The US Food and Drug Administration approved sacubitril/valsartan for patients with chronic heart failure (HF) with reduced ejection fraction in 2015 on the basis of the results of the PARADIGM-HF (Prospective Comparison of ARNI [Angiotensin Receptor Neprilysin Inhibitor] With ACEI [Angiotensin-Converting Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. There are limited data assessing the generalizability of PARADIGM-HF trial participants to a broader population of patients with HF with reduced ejection fraction routinely encountered in outpatient clinical practice...
June 12, 2018: Journal of the American Heart Association
S A Galochkin, O I Lukina, I A Meraĭ, S V Villevalde, Z D Kobalava
The article discusses management of a female patient with chronic heart failure with reduced left ventricular ejection fraction after an episode of acute decompensation. Replacing an angiotensin-converting enzyme inhibitor with a representative of a new angiotensin receptor-neprilysin inhibitor class, sacubitril/valsartan, in the combination therapy allowed fast achievement and maintenance of the compensation state. The treatment was well tolerated and was not associated with clinically significant adverse effects...
2018: Kardiologiia
Kieran F Docherty, John J V McMurray
Despite significant advances in the last 30 years in reducing morbidity and mortality from heart failure with reduced ejection fraction (HFrEF) with pharmacological and device-based therapies, patients remain at a high risk of adverse cardiovascular outcomes. Sacubitril/valsartan, a first-in-class angiotensin receptor-neprilysin inhibitors (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalisation and improve symptoms in patients with chronic, ambulatory, symptomatic HFrEF in a large, phase 3, multicentre, international, randomised controlled trial, PARADIGM-HF, when compared to the gold-standard angiotensin converting enzyme inhibitor, enalapril...
June 2, 2018: International Journal of Cardiology
Giampaolo Scorcu, Annarita Pilleri
With improved health care and with population aging, heart failure (HF) has become a common disease among the elderly and is one of the principal causes of mortality in elderly age. But the pharmacological management of HF in the elderly has still not yet been defined, as the clinical context is complicated by comorbidities, and differs from that of younger adults. In general, elderly patients with HF should be treated according to current guideline recommendations, for which ACE-I, beta-blockers and anti-aldosterones constitute the cornerstone of therapy...
June 7, 2018: Monaldi Archives for Chest Disease, Archivio Monaldi Per le Malattie del Torace
J Wintrich, I Kindermann, M Böhm
Heart failure is one of the leading diseases in internal medicine worldwide. Because of the increase in population aging, the incidence and prevalence of heart insufficiency is rising annually and is now the most frequent individual diagnosis among hospitalized patients in Germany. The mortality rate has recently been reduced, since new pharmacological options, especially the inhibition of neprilysin, have been developed; however, heart failure is still associated with a high mortality and morbidity rate. Thus, guideline-conform treatment is of crucial importance...
June 5, 2018: Herz
Jie Feng, Jingxue Wang, Yehong Du, Ying Liu, Wei Zhang, Jingfei Chen, Yuanjie Liu, Min Zheng, Kejian Wang, Guiqiong He
BACKGROUND: Activated microglia-mediated inflammation plays a key role in the pathogenesis of Alzheimer's disease (AD). In addition, chronic activation of NLRP3 inflammasomes triggered by amyloid β peptide (Aβ) in microglia contributes to persistent neuroinflammation. Here, the primary goal was to assess whether Dihydromyricetin (DHM), a plant flavonoid compound, is effective therapies for AD; it is crucial to know whether DHM will affect microglial activation and neuroinflammation in APP/PS1 transgenic mice...
June 4, 2018: CNS Neuroscience & Therapeutics
H A Rawal, A G Kocheril
Sacubitril/valsartan is a combination drug described as a new class of dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) for heart failure. We present a case of a patient with NYHA class IV systolic heart failure who was refractory to all other classes of heart failure medications and was started on this new medication. On sacubitril/valsartan, he developed cardiogenic shock. This led us to reevaluate the use and risks of this medication in the class IV heart failure population.
2018: Case Reports in Cardiology
Rex C Liu
The clinical syndrome of heart failure (HF) can be described as the reduced capacity of the heart to deliver blood throughout the body. To compensate for inadequate tissue perfusion, the renin-angiotensin aldosterone system (RAAS) and the sympathetic nervous system (SNS) become activated, resulting in increased blood pressure, heart rate, and blood volume. Consequent activation of the natriuretic peptide system (NPS) typically balances these effects; however, the NPS is unable to sustain compensation for excessive neurohormonal activation over time...
May 31, 2018: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
Zhihao Xu, Wenbin Nan, Xiaoyue Zhang, Yuliang Sun, Jichao Yang, Kecheng Lu, Yalin Liu, Yaoxin Gao, Fen Yang, Wenchao Mao, Xuekun Xing, Jiang Du, Han Li, Yonghai Li, Huigen Feng, Zhiqing Yuan, Juntang Lin
Mesenchymal stem cell (MSC) therapy is a promising prospect for the treatment of Alzheimer's disease (AD); however, the underlying mechanisms by which MSCs mediate positive effects are still unclear. We speculated that MSCs mediate microglial autophagy and enhance the clearance of Aβ. To test this hypothesis, we cultured BV2 microglial cells with umbilical cord mesenchymal stem cells conditioned medium (ucMSCs-CM) in the presence or absence of Aβ25-35 oligomers. We investigated BV2 cell proliferation, cell death, and Aβ25-35 phagocytosis as well as protein expression levels of LC3, Beclin-1, p62, insulin-degrading enzyme (IDE), and neprilysin (Nep) with western blotting...
May 29, 2018: Journal of Molecular Neuroscience: MN
Michel Komajda, Michael Böhm, Jeffrey S Borer, Ian Ford, Luigi Tavazzi, Matthieu Pannaux, Karl Swedberg
AIMS: A network meta-analysis (NMA) of all recommended drug groups for the treatment of heart failure with reduced ejection fraction (HFrEF), including their combinations, was performed to assess the relative efficacy and incremental benefit. METHODS AND RESULTS: A search was made in biomedical databases for randomised controlled trials published between 1987 and 2017 on angiotensin-converting enzyme inhibitors (ACEI), beta-blockers (BB), angiotensin-II receptor blockers (ARB), mineralocorticoid receptor antagonists (MRAs), ivabradine (IVA) or angiotensin receptor/neprilysin inhibitors (ARNI)...
May 27, 2018: European Journal of Heart Failure
Jaesuk Yun, In Jun Yeo, Chul Ju Hwang, Dong-Young Choi, Hyung-Sik Im, Ji Youg Kim, Won Rak Choi, Myung Hee Jung, Sang-Bae Han, Jin Tae Hong
Estrogen is well known to have a preventative effect in Alzheimer's disease (AD) pathology. Several studies have demonstrated that nuclear factor kappa-B (NF-ĸB) can contribute to the effects of estrogen on the development of AD. We investigated whether NF-ĸB affects amyloid-beta (Aβ)-induced memory impairment in an estrogen-lacking condition. In the present study, nine-week-old Institute cancer research (ICR) mice were ovariectomized to block estrogen stimulation. Ten weeks after the ovariectomization, mice were administered with Aβ (300 pmol) via intracerebroventricular (ICV) infusion for 2 weeks...
May 18, 2018: Brain, Behavior, and Immunity
D Berliner, M Hallbaum, J Bauersachs
The prevalence of heart failure has been steadily increasing during the past few years, with a further increase predicted in the years to come. Without treatment, the syndrome of heart failure has a very poor prognosis. Advances in drug treatments and the consequent implementation of a guideline-recommended drug therapy have significantly improved the prognosis in heart failure with reduced ejection fraction (HFrEF). Besides angiotensin-converting enzyme (ACE) inhibitors (ACEi) or angiotensin receptor blockers, beta-blockers and diuretics treatment with mineralocorticoid receptor antagonists and ivabradine have become standard in the therapy of symptomatic patients with HFrEF...
May 18, 2018: Herz
Victor Shi, Michele Senni, Hendrik Streefkerk, Vikas Modgill, Wenchun Zhou, Allen Kaplan
BACKGROUND: PARADIGM-HF demonstrated significant clinical benefits for sacubitril/valsartan (LCZ696, an angiotensin receptor neprilysin inhibitor) versus the angiotensin-converting enzyme inhibitor (ACEI) enalapril in patients with heart failure with reduced ejection fraction. As inhibition of ACE, and co-inhibition of ACE and neprilysin, may increase the risk of angioedema, this was an adverse event of special interest. METHODS: Following sequential enalapril and sacubitril/valsartan run-ins, patients were randomized to twice-daily sacubitril/valsartan 200 mg or enalapril 10 mg...
August 1, 2018: International Journal of Cardiology
Mariusz Mital, Wojciech Bal, Tomasz Frączyk, Simon C Drew
Sporadic Alzheimer's disease (AD) is associated with an inefficient clearance of the β-amyloid (Aβ) peptide from the central nervous system. The protein levels and activity of the Zn2+ -dependent endopeptidase neprilysin (NEP) inversely correlate with brain Aβ levels during aging and in AD. The present study considered the ability of Cu2+ ions to inhibit human recombinant NEP and the role for NEP in generating N-truncated Aβ fragments with high-affinity Cu2+ binding motifs that can prevent this inhibition...
May 18, 2018: Inorganic Chemistry
Madoka Sakai, Sakiho Ueda, Takuji Daito, Megumi Asada-Utsugi, Yumiko Komatsu, Ayae Kinoshita, Takakuni Maki, Akira Kuzuya, Ryosuke Takahashi, Akiko Makino, Keizo Tomonaga
Accumulation of amyloid β (Aβ40 and Aβ42) in the brain is a characteristic of Alzheimer's disease (AD). Because neprilysin (NEP) is a major Aβ-degrading enzyme, NEP delivery in the brain is a promising gene therapy for AD. Borna disease virus (BoDV) vector enables long-term transduction of foreign genes in the central nerve system. Here, we evaluated the proteolytic ability of NEP transduced by the BoDV vector and found that the amounts of Aβ40 and Aβ42 significantly decreased, which suggests that NEP expressed from the BoDV vector is functional to degrade Aβ...
May 17, 2018: Microbiology and Immunology
Daniel Fabio Kawano, Marcelo Rodrigues de Carvalho, Mauricio Ferreira Marcondes Machado, Adriana Karaoglanovic Carmona, Gilberto Ubida Leite Braga, Ivone Carvalho
BACKGROUND: Fungal secondary metabolites are important sources for the discovery of new pharmaceuticals, as exemplified by penicillin, lovastatin and cyclosporine. Searching for secondary metabolites of the fungi Metarhizium ssp., we previously identified tyrosine betaine as a major constituent. METHODS: Because of the structural similarity with other inhibitors of neprilysin (NEP), an enzyme explored for the treatment of heart failure, we devised the synthesis of tyrosine betaine and three analogues to be subjected to in vitro NEP inhibition assays and to molecular modeling studies...
May 14, 2018: Current Pharmaceutical Design
Inder Anand
Primary care physicians play a significant role in managing heart failure (HF), with the goals of reducing mortality, avoiding hospitalization, and improving patients' quality of life. Most HF-related hospitalizations and deaths occur in patients with New York Heart Association functional class II or III, many of whom are perceived to have stable disease, which often progresses without clinical symptoms due to underlying deleterious effects of neurohormonal imbalance and endothelial dysfunction. Management includes lifestyle changes and stepped pharmacological therapy directed at the four stages of HF, with aggressive uptitration of therapies, including beta-blockers and inhibitors of the renin-angiotensin-aldosterone system...
May 14, 2018: American Journal of Cardiovascular Drugs: Drugs, Devices, and Other Interventions
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