scholarly journals Detection of Neprilysin-Derived BNP Fragments in the Circulation: Possible Insights for Targeted Neprilysin Inhibition Therapy for Heart Failure

2019 ◽  
Vol 65 (10) ◽  
pp. 1239-1247 ◽  
Author(s):  
Evgeniya E Feygina ◽  
Marina M Artemieva ◽  
Alexander B Postnikov ◽  
Natalia N Tamm ◽  
Marina N Bloshchitsyna ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ring Opening ◽  
Active Form ◽  
Cross Reactivity ◽  
Plasma Samples ◽  
Time Points ◽  
Positive Effects ◽  
Edta Plasma ◽  
Neprilysin Inhibition ◽  
Nep Inhibition

Abstract BACKGROUND Entresto™ is a new heart failure (HF) therapy that includes the neprilysin (NEP) inhibitor sacubitril. One of the NEP substrates is B-type natriuretic peptide (BNP); its augmentation by NEP inhibition is considered as a possible mechanism for the positive effects of Entresto. We hypothesized that the circulating products of BNP proteolysis by NEP might reflect NEP impact on the metabolism of active BNP. We suggest that NEP-based BNP cleavage at position 17–18 results in BNP ring opening and formation of a novel epitope with C-terminal Arg-17 (BNP-neo17 form). In this study, we use a specific immunoassay to explore BNP-neo17 in a rat model and HF patient plasma. METHODS We injected BNP into rats, with or without NEP inhibition with sacubitril. BNP-neo17 in plasma samples at different time points was measured with a specific immunoassay with neglectable cross-reactivity to intact forms. BNP-neo17 and total BNP were measured in EDTA plasma samples of HF patients. RESULTS BNP-neo17 generation in rat circulation was prevented by NEP inhibition. The maximum 13.2-fold difference in BNP-neo17 concentrations with and without sacubitril was observed at 2 min after injection. BNP-neo17 concentrations in 32 HF patient EDTA plasma samples ranged from 0 to 37 pg/mL (median, 5.4; interquartile range, 0–9.1). BNP-neo17/total BNP had no correlation with total BNP concentration (with r = −0.175, P = 0.680) and showed variability among individuals. CONCLUSIONS BNP-neo17 formation is NEP dependent. Considering that BNP-neo17 is generated from the active form of BNP by NEP, we speculate that BNP-neo17 may reflect both the NEP activity and natriuretic potential and serve for HF therapy guidance.

scholarly journals Immunoradiometric Assay for Intact Human Osteocalcin(1–49) without Cross-Reactivity to Breakdown Products

1999 ◽  
Vol 45 (4) ◽  
pp. 526-531 ◽  
Author(s):  
John W Colford ◽  
Bruce A Lueddecke ◽  
Michael Salvati ◽  
Dave Hanna ◽  
Dawn Sailer ◽  
...  
Keyword(s):  
Renal Failure ◽  
Solid Phase ◽  
Reference Interval ◽  
Serum Marker ◽  
Cross Reactivity ◽  
Plasma Samples ◽  
Serum Samples ◽  
Calcium Chelation ◽  
Heparin Plasma ◽  
Edta Plasma

Abstract Background: Osteocalcin (Oc), a serum marker of bone turnover, circulates in several forms. We developed an assay for intact human Oc and investigated its clinical features. Methods: We generated goat antibodies and N- and C-terminal Oc. The former was used on solid phase (polystyrene beads), and the latter was used as the tracer in an IRMA. Results: The assay was linear with no cross-reactivity to Oc(1–43), total imprecision (CV) of <10%, and recovery of 100% ± 10%. Assay values for intact Oc in EDTA plasma samples were unchanged at 18–25 °C for 6 h. Values for intact Oc in serum, EDTA plasma, and heparin plasma samples did not change after storage on ice for 8 h. Serum samples from patients with various conditions were stored at −70 or −135 °C for up to 5 years and yielded z-scores comparable to an Oc(1-43) IRMA for all conditions except for renal failure. In renal failure, the Oc(1–43) assay values were increased, whereas the intact assay values were in the reference interval. Conclusion: Decreases in Oc assay values are inhibited by calcium chelation, and slowed by reduced temperatures. The described assay for intact Oc allows improved specificity for bone compared with an assay for Oc(1–43).

Biological and In silico Studies on Synthetic Analogues of Tyrosine Betaine as Inhibitors of Neprilysin - A Drug Target for the Treatment of Heart Failure

2018 ◽  
Vol 24 (17) ◽  
pp. 1899-1904
Author(s):  
Daniel Fabio Kawano ◽  
Marcelo Rodrigues de Carvalho ◽  
Mauricio Ferreira Marcondes Machado ◽  
Adriana Karaoglanovic Carmona ◽  
Gilberto Ubida Leite Braga ◽  
...  
Keyword(s):  
Heart Failure ◽  
Secondary Metabolites ◽  
Structural Similarity ◽  
Structural Features ◽  
Major Constituent ◽  
Binding Modes ◽  
Starting Point ◽  
In Silico Studies ◽  
Nep Inhibition

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 spp., 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. Results: In spite of the similar binding modes with other NEP inhibitors, these compounds only displayed moderate inhibitory activities (IC50 ranging from 170.0 to 52.9 µM). However, they enclose structural features required to hinder passive blood brain barrier permeation (BBB). Conclusions: Tyrosine betaine remains as a starting point for the development of NEP inhibitors because of the low probability of BBB permeation and, consequently, of NEP inhibition at the Central Nervous System, which is associated to an increment in the Aβ levels and, accordingly, with a higher risk for the onset of Alzheimer's disease.

scholarly journals Predictors of diuresis response to levosimendan administration in patients with acute heart failure

2021 ◽  
Vol 10 (Supplement_1) ◽  
Author(s):  
J Plonka ◽  
J Bugajski ◽  
M Plonka ◽  
A Tycinska ◽  
M Gierlotka
Keyword(s):  
Heart Failure ◽  
High Risk ◽  
Acute Heart Failure ◽  
Clinical Status ◽  
Older Age ◽  
Analysis Model ◽  
Heart Failure Patients ◽  
Positive Effects ◽  
Pulmonary Hemodynamic ◽  
Recent Acute Myocardial Infarction

Abstract Funding Acknowledgements Type of funding sources: None. Levosimendan, a calcium sensitizer and potassium channel-opener, is appreciated  for its effects on systemic and pulmonary hemodynamic and for the relief of symptoms in acute heart failure (AHF). Positive effects of levosimendan on renal function have been also described. The aim of the present analysis was to assess the predictors of the diuresis response to levosimendan administration in high risk acute heart failure patients. Methods. We analysed 34 consecutive patients admitted with high risk AHF to one centre and treated in intensive cardiac care unit. Levosimendan was administered on top of other treatment as a 24-hour infusion of 12.5 mg total dose except for 7 patients (1 patient - terminated earlier due to intolerance, 5 patients – 48h infusion, 1 patient - 72h infusion). Decision of levosimendan administration was based on clinical status and left to attending physician. Diuresis and diuretic dosage before (24 hours) and after levosimendan infusion (48 hours) were taken into account for the present study. Results. The AHF was primary of cardiac origin in all patients. In 6 (18%) it was due to recent acute myocardial infarction. In-hospital mortality was 24%. Median length of hospitalization was 26 days (range 6 to 107 days). Mean age of the patients was 66 ± 12 years, 25 (74%) were men. Mean INTERMACS score was 3.4 ± 1.4 with wet-cold clinical profile present in 13 (38%) of patients. Mean left ventricle ejection fraction (LVEF) was 27 ± 13%, mean NTproBNP was 17176 ± 12464 pg/ml, and mean eGFR 48 ± 22 ml/min/1.73m2. At the time of levosimendan administration patients had background treatment with catecholamines (mean number per patient 1.4 ± 1.1, range 0-3) and with diuretics (mean dosage of furosemide 167 ± 102 mg/24h, range 20-500). 48-hours diuresis after levosimendan administration varies from 950 to 11300 ml (mean 4307 ± 2418 ml). It was significantly lower in patients with cold-wet profile (2646 ± 1335 vs. 5335 ± 2381 ml in other clinical profiles, p = 0.0002). Additionally, 48-hour diuresis was negatively correlated with age (r=-0.46, p = 0.0062) and the number of background catecholamines (r=-0.47, p = 0.0047), and not significantly with the furosemide dosage (r=-0.28, p = 0.10) – figure. No association with diuresis was found for LVEF, NTproBNP, and eGFR. In multiple regression analysis (model R2 = 0.63, p = 0.0085) both older age (p = 0.026) and cold-wet profile (p = 0.0074) were significant predictors of poor diuresis after levosimendan administration. Conclusion. Older age and cold-wet profile were significant predictors of poor diuresis response to levosimendan administration in high risk acute heart failure patients. Although concomitant catecholamines and high diuretic dosage use cloud also be markers of non-responders to levosimendan in terms of diuresis. Abstract Figure

scholarly journals P787Angiotensin-neprilysin inhibition further reverses cardiac remodeling as compared to angiotensin inhibition in reduced heart failure patients

EP Europace ◽  
2018 ◽  
Vol 20 (suppl_1) ◽  
pp. i139-i139 ◽  
Author(s):  
C De Diego ◽  
L Gonzalez-Torres ◽  
E R Centurion ◽  
G De Lara ◽  
M Macias
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Heart Failure Patients ◽  
Neprilysin Inhibition

scholarly journals Direct supplementation with Urolithin A overcomes limitations of dietary exposure and gut microbiome variability in healthy adults to achieve consistent levels across the population

2021 ◽  
Author(s):  
Anurag Singh ◽  
Davide D’Amico ◽  
Pénélope A. Andreux ◽  
Gillian Dunngalvin ◽  
Timo Kern ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Dietary Exposure ◽  
Food Product ◽  
Pomegranate Juice ◽  
Healthy Population ◽  
Plasma Samples ◽  
Time Points ◽  
Natural Exposure ◽  
Microbiome Diversity ◽  
Urolithin A

Abstract Background Urolithin A (UA) is produced by gut microflora from foods rich in ellagitannins. UA has been shown to improve mitochondrial health preclinically and in humans. Not everyone has a microbiome capable of producing UA, making supplementation with UA an appealing strategy. Objective This is the first detailed investigation of the prevalence of UA producers in a healthy population and the ability of direct UA supplementation to overcome both microbiome and dietary variability. Dietary intake of a glass of pomegranate juice (PJ) was used to assess UA producer status (n = 100 participants) and to characterize differences in gut microbiome between UA producers from non-producers. Methods Subjects were randomized (1:1) to either PJ or a food product containing UA (500 mg). Prevalence of UA producers and non-producers were determined in the PJ group. Diet questionnaires and fecal samples were collected to compare differences between UA producers and non-producers along with plasma samples at different time points to assess levels of UA and its conjugates between the interventions. Results Only 12% of subjects had detectable levels of UA at baseline. Following PJ intake ~40% of the subjects converted significantly the precursor compounds into UA. UA producers were distinguished by a significantly higher gut microbiome diversity and ratio of Firmicutes to Bacteroides. Direct supplementation with UA significantly increased plasma levels and provided a >6-fold exposure to UA vs. PJ (p < 0.0001). Conclusions Differences in gut microbiome and diet that dictate natural exposure to UA can be overcome via direct dietary UA supplementation.

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