Early Application of Sacubitril Valsartan Sodium After Acute Myocardial Infarction and its Influence on Ventricular Remodeling and TGF-ß1/Smad3 Signaling Pathway.

Objective: The objective of this study was to investigate the early application of sacubitril valsartan sodium (LCZ696) following acute myocardial infarction (AMI) and its impact on ventricular remodeling and the TGF-ß1/Smad3 signaling pathway in patients. Methods: The clinical data of 73 patients with AMI admitted to the hospital from June 2021 to September 2022 were retrospectively analyzed, and the patients were grouped according to the treatment methods, including 36 cases in the control group (conventional drug treatment) and 37 cases in the observation group (conventional drug + LCZ696 treatment). The clinical efficacy, cardiac function parameters [left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter (LVEDD), stroke volume (SV)], cardiac function biochemical indicators [N-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin 3 (Gal-3), amino-terminal peptide of type III procollagen (PIIINP)], ventricular remodeling indicators [left ventricular posterior wall end-diastolic thickness (PWD), posterior wall end-systolic thickness (PWS), ventricular septal end-systolic thickness (IVSS)], ventricular hydrodynamic parameters [left ventricular flow rate in peak ejection (FRPE), flow reversal rate (FRR), flow reversal interval (FRI)], TGF-ß 1/Smad3 signaling pathway-related indicators (TGF-ß1, Smad3), quality of life score (SF-36 Quality of Life Scale) and occurrence of adverse reactions were compared between the two groups. Results: The main findings of the study are as follows: The observation group was significantly better than the control group in many aspects such as overall clinical effectiveness, cardiac function parameters, biochemical indicators, ventricular structure and function, TGF-ß1/Smad3 signaling pathway, and quality of life. Specifically, the observation group showed more significant positive effects in terms of improvement of cardiac function, adjustment of biochemical status, and adjustment of ventricular structure and fluid dynamics parameters. These results provide strong support for the application of new therapeutic approaches in the management of cardiovascular disease. After treatment, the total clinical effective rate in the observation group (89.19%) was significantly higher than that in the control group (69.44%) (P < .05). LVEF and SV in the two groups were significantly increased (P < .05), while LVEDD was significantly decreased (P < .05), and there were statistically significant differences in parameters between the two groups (P < .05). The levels of NT-proBNP, Gal-3 and PIIINP in both groups were significantly reduced (P < .05), and the levels in the observation group were significantly lower than those in the control group (P < .05). The PWD, PWS and IVSS in both groups significantly declined (P < .05), and the indicators in the observation group were significantly lower than those in the control group (P < .05). The FRPE and FRR in the two groups were significantly enhanced (P < .05), while the FRI was significantly reduced (P < .05), and the differences in the above parameters between the two groups were statistically significant (P < .05). The levels of TGF-ß1 and Smad3 in the two groups were significantly declined (P < .05), and the levels in the observation group were significantly lower than those in the control group (P < .05). During the period from before treatment to 6 months of treatment, the quality of life score in the two groups showed a significant downward trend (P < .05), and the score in the observation group after 3 months to 6 months of treatment was significantly lower than that in the control group (P < .05). During treatment, there was no statistical significance in the total incidence rate of adverse reactions between the two groups (P > .05). Conclusion: Early application of LCZ696 after AMI has a significant efficacy, and it can effectively improve the ventricular remodeling, regulate the expression levels of TGF-ß1 and Smad3, inhibit the TGF-ß1/Smad3 signaling pathway, promote the improvements of cardiac function and quality of life, and it has good safety and is worthy of clinical promotion and application. The study's key findings have important clinical implications for understanding and managing acute myocardial infarction (AMI). The observation group showed significant improvements in overall clinical efficacy, cardiac function, biochemical status, ventricular structure and function, etc., providing strong evidence for comprehensive treatment of AMI patients. This treatment method is expected to become an important part of the care and treatment strategy for AMI patients, help reduce cardiovascular risk, improve quality of life, and provide new research directions for future AMI treatment.

Glutamate decarboxylase-1 is essential for efficient acclimation of Arabidopsis thaliana to nutritional phosphorus deprivation.

Glutamate decarboxylase (GAD) is a Ca2+ -calmodulin-activated, cytosolic enzyme that produces γ-aminobutyrate (GABA) as the committed step of the GABA shunt. This pathway bypasses the 2-oxoglutarate to succinate reactions of the tricarboxylic acid (TCA) cycle. GABA also accumulates during many plant stresses. We tested the hypothesis that AtGAD1 (At5G17330) facilitates Arabidopsis acclimation to Pi deprivation. Quantitative RT-PCR and immunoblotting revealed that AtGAD1 transcript and protein expression is primarily root-specific, but inducible at lower levels in shoots of Pi-deprived (-Pi) plants. Pi deprivation reduced levels of the 2-oxoglutarate dehydrogenase (2-OGDH) cofactor thiamine diphosphate (ThDP) in shoots and roots by > 50%. Growth of -Pi atgad1 T-DNA mutants was significantly attenuated relative to wild-type plants. This was accompanied by: (i) an > 60% increase in shoot and root GABA levels of -Pi wild-type, but not atgad1 plants, and (ii) markedly elevated anthocyanin and reduced free and total Pi levels in leaves of -Pi atgad1 plants. Treatment with 10 mM GABA reversed the deleterious development of -Pi atgad1 plants. Our results indicate that AtGAD1 mediates GABA shunt upregulation during Pi deprivation. This bypass is hypothesized to circumvent ThDP-limited 2-OGDH activity to facilitate TCA cycle flux and respiration by -Pi Arabidopsis.

Effects of sacubitril/valsartan on exercise capacity: a prognostic improvement that starts during uptitration.

PURPOSE: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses. METHODS: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose. RESULTS: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003. CONCLUSIONS: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Pharmacotherapy of heart failure A.D. 2023. Expert opinion of Working Group on Cardiovascular Pharmacotherapy, Polish Cardiac Society.

Heart failure (HF) remains one of the most common causes of hospitalization and mortality among Polish patients. The position of the Section of Cardiovascular Pharmacotherapy presents the currently applicable options for pharmacological treatment of HF based on the latest European and American guidelines from 2021-2022 in relation to Polish healthcare conditions. Treatment of HF varies depending on its clinical presentation (acute/chronic) or left ventricular ejection fraction. Initial treatment of symptomatic patients with features of volume overload is based on diuretics, especially loop drugs. Treatment aimed at reducing mortality and hospitalization should include drugs blocking the renin-angiotensin-aldosterone system, preferably angiotensin receptor antagonist/neprilysin inhibitor, i.e. sacubitril/valsartan, selected beta-blockers (no class effect - options include bisoprolol, metoprolol succinate, or vasodilatory beta-blockers - carvedilol and nebivolol), mineralocorticoid receptor antagonist, and sodium-glucose cotransporter type 2 inhibitor (flozin), constituting the 4 pillars of pharmacotherapy. Their effectiveness has been confirmed in numerous prospective randomized trials. The current HF treatment strategy is based on the fastest possible implementation of all four mentioned classes of drugs due to their independent additive action. It is also important to individualize therapy according to comorbidities, blood pressure, resting heart rate, or the presence of arrhythmias. This article emphasizes the cardio- and nephroprotective role of flozins in HF therapy, regardless of ejection fraction value. We propose practical guidelines for the use of medicines, profile of adverse reactions, drug interactions, as well as pharmacoeconomic aspects. The principles of treatment with ivabradine, digoxin, vericiguat, iron supplementation, or antiplatelet and anticoagulant therapy are also discussed, along with recent novel drugs including omecamtiv mecarbil, tolvaptan, or coenzyme Q10 as well as progress in the prevention and treatment of hyperkalemia. Based on the latest recommendations, treatment regimens for different types of HF are discussed.

Real-world use patterns of angiotensin receptor-neprilysin inhibitor (sacubitril/valsartan) among patients with heart failure within a large integrated health system.

BACKGROUND: Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor (ARNI) that is now preferred in guidelines over angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for patients with heart failure with reduced ejection fraction (HFrEF). However, it has not been broadly adopted in clinical practice. OBJECTIVE: To characterize ARNI use within a large diverse real-world population and assess for any racial disparities. METHODS: We conducted a cross-sectional study within Kaiser Permanente Southern California. Adult patients with HFrEF who received ARNIs, ACEIs, or ARBs between January 1, 2014, and November 30, 2020, were identified. The prevalence of ARNI use among the cohort and patient characteristics by ARNIs vs ACEIs/ARBs use were described. Multivariable regression was performed to estimate odds ratios and 95% CIs of receiving ARNI by race and ethnicity. RESULTS: Among 12,250 patients with HFrEF receiving ACEIs, ARBs, or ARNIs, 556 (4.54%) patients received ARNIs. ARNI use among this cohort increased from 0.02% in 2015 to 7.48% in 2020. Patients receiving ARNIs were younger (aged 62 vs 69 years) and had a lower median ejection fraction (27% vs 32%) compared with patients receiving ACEIs/ARBs. They also had higher use of mineralocorticoid antagonists (24.1% vs 19.8%) and automatic implantable cardioverterdefibrillators (17.4% vs 13.3%). There were no significant differences in rate of ARNI use by race and ethnicity. CONCLUSIONS: Within a large diverse integrated health system in Southern California, the rate of ARNI use has risen over time. Patients given ARNIs were younger with fewer comorbidities, while having worse ejection fraction. Racial minorities were no less likely to receive ARNIs compared with White patients. DISCLOSURES: Dr Huang had stock ownership in Gilead and Pfizer. Dr Liang received support for article processing and medical writing.

Novel antihypertensive agents for resistant hypertension: what does the future hold?

Finding complementary compelling novel therapeutic agents for better control of blood pressure in people with resistant hypertension is moving into unchartered territory. The latest therapeutic developments explore approaches in the clinical arena that were either not examined or could only be examined in animal models two decades ago. Four main mechanisms have now been explored and operationalized in drug development: (a) mineralocorticoid receptor blockade using a nonsteroidal structure with many fewer side effects, (b) an aminopeptidase A inhibitor that has central effects on vasopressin, (c) a combined endothelin A and B receptor blocker and (d) an aldosterone synthase inhibitor devoid of glucocorticoid activity. All these agents are either completing Phase II development and starting Phase III or are involved in the ongoing recruitment of Phase III trials. Additionally, novel agents use antisense inhibition to block angiotensinogen development in the liver. These agents are discussed only for completeness, as they are still in Phase II trial development. Last, another agent that was initially being developed as an antihypertensive and once the data were reviewed by the company clearly showed efficacy as a heart failure agent was sacubitril/valsartan, which was ultimately approved. However, there are some discussions about reinvigorating the quest for an indication for hypertension, although no such steps have been formally initiated.

The glutamate/GABA system in the retina of male rats: effects of aging, neurodegeneration, and supplementation with melatonin and antioxidant SkQ1.

Glutamate and -aminobutyric acid (GABA) are the most abundant amino acids in the retina. An imbalance of the glutamate/GABA system is involved in the pathogenesis of various neurodegenerative disorders. Here we for the first time analyzed alterations of expression of glutamate- and GABA-synthesizing enzymes, transporters, and relevant receptors in the retina with age in Wistar rats and in senescence-accelerated OXYS rats who develop AMD-like retinopathy. We noted consistent age-dependent expression changes of GABAergic-system proteins (GAD67, GABA-T, and GAT1) in OXYS and Wistar rats: upregulation by age 3 months and downregulation at age 18 months. At a late stage of AMD-like retinopathy in OXYS rats (18 months), there was significant upregulation of glutaminase and downregulation of glutamine synthetase, possibly indicating an increasing level of glutamate in the retina. AMD-like-retinopathy development in the OXYS strain was accompanied by underexpression of glutamate transporter GLAST. Prolonged supplementation with both melatonin and SkQ1 (separately) suppressed the progression of the AMD-like pathology in OXYS rats without affecting the glutamate/GABA system but worsened the condition of the Wistar rat's retina during normal aging. We observed decreasing protein levels of glutamine synthetase, GLAST, and GABAAR1 and an increasing level of glutaminase in Wistar rats. In summary, both melatonin and mitochondrial antioxidant SkQ1 had different effect on the retinal glutamate / GABA in healthy Wistar and senescence-accelerated OXYS rats.

Clinical Effect of Qili Qiangxin Capsule Combined with Sacubitril-Valsartan in Patients with Chronic Heart Failure.

The clinical effect of Qili Qiangxin capsule combined with sacubitril-valsartan on patients with chronic heart failure was studied. We selected 108 patients with chronic heart failure in our hospital from March 2016 to January 2020 and divided them into a control group and a study group according to the random table method, with 54 cases in each. The control group took sacubitril and valsartan orally, and the study group took Qili Qiangxin pill on the basis of sacubitril and valsartan. The course of the treatment for 2 groups is 4 weeks. We compared the total effective rate of the treatment of the 2 groups for 4 weeks, cardiac function (left ventricular end-systolic volume (LVESV), left ventricular end-diastolic volume (LVEDV), and left ventricular ejection fraction (LVEF)) before and after 4 weeks of treatment, 6 min walking distance (6MWT), changes in cTnI and NT-proBNP levels, and adverse reactions. The total effective rate in the study group (90.74%) is higher than that in the control group (72.22%) (P＜0.05). After 4 weeks of treatment, the study group LVESV (45.23 ± 2.98 mm) and LVEDV (43.38 ± 4.01 mm) are lower than those of the control group ((49.98 ± 2.56 mm) and (50.75 ± 3.49 mm), respectively), while LVEF (47.38 ± 2.78%) is higher than that in the control group (42.08 ± 3.24%) (P ＜ 0.05). After 4 weeks of treatment, the study group 6MWT (476.58 ± 31.25 m) of patients with chronic heart failure is higher than that of the control group (396.52 ± 24.52 m) (P ＜0.05). After 4 weeks of treatment, the study group serum cTnI (0.36 ± 0.12 µg/L) and NT-proBNP (276.91 ± 30.12 pg/ml) of patients with chronic heart failure are lower than those in the control group (0.87 ± 0.25 µg/L) and (367.48 ± 48.57 pg/ml) (P＜0.05). There is no significant difference between the adverse reactions in the two groups (P ＞ 0.05). Conclusion: Xinbao pills combined with sacubitril and valsartan have a good effect on patients with chronic heart failure, which can improve the heart function and exercise endurance and reduce serum cTnI and NT-proBNP levels.

Sacubitril/Valsartan: A New Dawn has Begun! A Revisited Review.

Heart Failure (HF) is among the major causes of global morbidity as well as mortality. Increased prevalence, frequent and prolonged hospitalization, rehospitalization, long-term consumption of healthcare resources, absenteeism, and death upsurge the economic burden linked to HF. For decades, Angiotensin-Converting Enzyme Inhibitors (ACEIs), Angiotensin II Receptor Blockers (ARBs), Beta-Blockers (BBs), and mineralocorticoid receptor antagonists (MRA), have remained the mainstay of the standard of care for HF management. Despite their proven efficacy and cost-effectiveness, HF remains a global pandemic and is still increasing in prevalence. Sacubitril/ Valsartan (SAC/VAL) is an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) that proved out to be a game-changer drug in HF treatment. Recent data indicated that SAC/VAL is more efficient and can improve the overall quality of life of HF patients with reduced ejection fraction (HFrEF) with fewer side effects. It is now incorporated in the guidelines as an alternative to ACEIs or ARBs to lower morbidity in addition to mortality in HFrEF patients. This review article will discuss the current guidelines-approved indications and highlight the potential emerging indications, in addition to the currently ongoing clinical trials that will expand the use of SAC/VAL.

Establishment of a HPLC-MS/MS Detection Method for Glyphosate, Glufosinate-Ammonium, and Aminomethyl Phosphoric Acid in Tea and Its Use for Risk Exposure Assessment.

The tea shrub is grown in long-standing orchards, an environment that is suitable for persistent weed growth, which is increasingly controlled by herbicides. Therefore, there is increasing concern that tea consumers may be exposed to herbicide residues. In this study, the levels of glufosinate-ammonium (GLU), glyphosate [N-(phosphonomethyl) glycine; PMG], and its metabolite aminomethyl phosphoric acid (AMPA) were determined in tea samples by HPLC-MS/MS using several current purification methods and a new method that we developed herein. The matrix effect of our proposed method was between -27.3 and 27.7%, which was lower than that in other methods, indicating that this method effectively reduced the interference of tea matrix in the mass spectrometry process. This method was used to determine the levels of PMG, GLU, and AMPA in 780 samples, including six traditional Chinese teas (green tea, black tea, oolong tea, dark tea, white tea, and yellow tea) and a floral tea, from 14 provinces of China. Probability estimates showed that the 95th percentile risk entropy values of the three pesticide residues were far below the acceptable risk level. The risk assessment results showed that exposure to PMG, GLU, and AMPA caused by drinking tea beverages poses no significant risk to human health.

Renal protection in chronic heart failure: focus on sacubitril/valsartan.

Chronic kidney disease (CKD) is highly prevalent in patients with chronic heart failure (CHF) and increases the risk of overall and cardiovascular (CV) mortality. Despite evidence supporting the effectiveness of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers, and mineralocorticoid receptor antagonists in decreasing mortality in patients with CHF, CKD hampers the optimization of standard pharmacologic therapy for heart failure. Therefore, other treatment options are needed to optimize treatment outcomes in CHF patients with CKD. The first-in-class angiotensin receptor-neprilysin inhibitor, sacubitril/valsartan, has a complementary activity that counteracts the potential unwanted long-term effects of over-activation of the renin-angiotensin-aldosterone system. Sacubitril/valsartan reduced the risk of CV mortality compared to standard therapy with an ACE-I in patients with heart failure with reduced ejection fraction (HFrEF) in the PARADIGM-HF trial and has been shown to be safe and effective in a broad range of HFrEF patients. However, data on the efficacy and tolerability of sacubitril/valsartan in patients with more advanced CKD are limited. This review discusses the evidence for the role of sacubitril/valsartan in providing additional renal benefit in patients with HFrEF. Data from clinical trials and real-world experience in patients with HFrEF and advanced CKD support the benefits of dual angiotensin/neprilysin inhibition across the breadth of kidney disease stages, including patients with significant renal impairment that was not reported in the pivotal PARADIGM-HF trial, and suggests a central role for the cardiac benefits of sacubitril/valsartan in nephroprotection.

Cardiac and Noncardiac Disease Burden and Treatment Effect of Sacubitril/Valsartan: Insights From a Combined PARAGON-HF and PARADIGM-HF Analysis.

BACKGROUND: The net clinical benefit of cardiac disease-modifying drugs might be influenced by the interaction of different domains of disease burden. We assessed the relative contribution of cardiac, comorbid, and demographic factors in heart failure (HF) and how their interplay might influence HF prognosis and efficacy of sacubitril/valsartan across the spectrum of left ventricular ejection fraction. METHODS: We combined data from 2 global trials that evaluated the efficacy of sacubitril/valsartan compared with a renin-angiotensin antagonist in symptomatic HF patients (PARADIGM-HF [Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure; n=8399] and PARAGON-HF [Prospective Comparison of Angiotensin-Converting Enzyme Inhibitor With Angiotensin Receptors Blockers Global Outcomes in Heart Failure With Preserved Ejection Fraction; n=4796]). We decomposed the previously validated Meta-Analysis Global Group in Chronic Heart Failure risk score into cardiac (left ventricular ejection fraction, New York Heart Association class, blood pressure, time since HF diagnosis, HF medications), noncardiac comorbid (body mass index, creatinine, diabetes, chronic obstructive pulmonary disease, smoking), and demographic (age, gender) categories. Based on these domains, an index representing the balance of cardiac to noncardiac comorbid burden was created (cardiac-comorbid index). Clinical outcomes were time to first HF hospitalization or cardiovascular deaths and all-cause mortality. RESULTS: Higher scores of the cardiac domain were observed in PARADIGM-HF (10 [7-13] versus 5 [3-6], P<0.001) and higher scores of the demographic domain in PARAGON-HF (10 [8-13] versus 5 [2-9], P<0.001). In PARADIGM-HF, the contribution of the cardiac domain to clinical outcomes was greater than the noncardiac domain (P<0.001), while in PARAGON-HF the attributable risk of the comorbid and demographic categories predominated. Individual scores from each sub-domain were linearly associated with the risk of clinical outcomes (P<0.001). Beneficial effects of sacubitril/valsartan were observed in patients with preponderance of cardiac over noncardiac comorbid burden (cardiac-comorbid index >5 points), suggesting a significant treatment effect modification (interaction P<0.05 for both outcomes). CONCLUSIONS: Domains of disease burden are clinically relevant features that influence the prognosis and treatment of patients with HF. The therapeutic benefits of sacubitril/valsartan vary according to the balance of components of disease burden, across different ranges of left ventricular ejection fraction.

Clinical Characteristics and Outcomes of Patients With Heart Failure With Reduced Ejection Fraction and Chronic Obstructive Pulmonary Disease: Insights From PARADIGM-HF.

Background Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM-HF (Prospective Comparison of Angiotensin Receptor Blocker-Neprilysin Inhibitor With Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non-COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT-proBNP (N-terminal pro-B-type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta-blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13-1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05-1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94-1.30), or all-cause mortality (HR, 1.14; 95% CI, 0.99-1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05-1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29-1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions In PARADIGM-HF, COPD was associated with lower use of beta-blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high-risk subgroup. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255.

Discovery and Biosynthetic Investigation of a New Antibacterial Dehydrated Non-Ribosomal Tripeptide.

Dehydroalanine (Dha) and dehydrobutyrine (Dhb) display considerable flexibility in a variety of chemical and biological reactions. Natural products containing Dha and/or Dhb residues are often found to display diverse biological activities. While the (Z) geometry is predominant in nature, only a handful of metabolites containing (E)-Dhb have been found thus far. Here we report discovery of a new antimicrobial peptide, albopeptide, through NMR analysis and chemical synthesis, which contains two contiguous unsaturated residues, Dha-(E)-Dhb. It displays narrow-spectrum activity against vancomycin-resistant Enterococcus faecium. In-vitro biochemical assays show that albopeptide originates from a noncanonical NRPS pathway featuring dehydration processes and catalysed by unusual condensation domains. Finally, we provide evidence of the occurrence of a previously untapped group of short unsaturated peptides in the bacterial kingdom, suggesting an important biological function in bacteria.

Improving exercise capacity and quality of life using non-invasive heart failure treatments: evidence from clinical trials.

Endpoints of large-scale trials in chronic heart failure have mostly been defined to evaluate treatments with regard to hospitalizations and mortality. However, patients with heart failure are also affected by very severe reductions in exercise capacity and quality of life. We aimed to evaluate the effects of heart failure treatments on these endpoints using available evidence from randomized trials. Interventions with evidence for improvements in exercise capacity include physical exercise, intravenous iron supplementation in patients with iron deficiency, and - with less certainty - testosterone in highly selected patients. Erythropoiesis-stimulating agents have been reported to improve exercise capacity in anaemic patients with heart failure. Sinus rhythm may have some advantage when compared with atrial fibrillation, particularly in patients undergoing pulmonary vein isolation. Studies assessing treatments for heart failure co-morbidities such as sleep-disordered breathing, diabetes mellitus, chronic kidney disease and depression have reported improvements of exercise capacity and quality of life; however, the available data are limited and not always consistent. The available evidence for positive effects of pharmacologic interventions using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, and mineralocorticoid receptor antagonists on exercise capacity and quality of life is limited. Studies with ivabradine and with sacubitril/valsartan suggest beneficial effects at improving quality of life; however, the evidence base is limited in particular for exercise capacity. The data for heart failure with preserved ejection fraction are even less positive, only sacubitril/valsartan and spironolactone have shown some effectiveness at improving quality of life. In conclusion, the evidence for state-of-the-art heart failure treatments with regard to exercise capacity and quality of life is limited and appears not robust enough to permit recommendations for heart failure. The treatment of co-morbidities may be important for these patient-related outcomes. Additional studies on functional capacity and quality of life in heart failure are required.

Novel doses of sacubitril/valsartan in patients unable to tolerate traditional therapy: Effects on N-terminal pro B-type natriuretic peptide levels.

BACKGROUND: Widespread use of angiotensin receptor blocker and neprilysin inhibitor (ARNI) remains low, and many patients are unable to tolerate the medication due to hypotension at the currently recommended starting dose. HYPOTHESIS: The aim of this study is to assess if lower than standard doses of ARNI, sacubitril/valsartan (S/V), significantly reduces NT-proBNP and leads to any change in diuretic dose, serum potassium, or creatinine. METHODS: In a retrospective study of 278 patients who were started on a low dose S/V at a single medical center, 45 patients were selected for the study cohort. Patients were subcategorized to Group 1 (n = 10): very low dose S/V (half a tab of 24/26 mg BID), Group 2 (n = 10): very low dose titrated to low dose S/V, and Group 3 (n = 25): low dose S/V (24/26 mg BID). NT-proBNP, diuretic dose, serum potassium, and creatinine were compared before and after initiation of S/V. RESULTS: Among all groups, there was a significant reduction in NT-proBNP level (Group 1: p < .01, Group 2: p < .01, and Group 3: p < .001). In addition, there was a significant reduction in diuretic dose across all groups combined (furosemide 53 mg/day vs. 73 mg/day; p = .03), with 17.8% (8/45) patients being able to discontinue their diuretic completely. There was no significant change in potassium or creatinine. CONCLUSIONS: Lower than standard dose of S/V significantly reduces NT-proBNP and diuretic requirement without change in potassium or creatinine, which provides hope that patients who cannot tolerate standard doses of S/V due to hypotension may be able to receive the benefits of S/V therapy.

Environmental risk assessment of glufosinate-resistant soybean by pollen-mediated gene flow under field conditions in the region of the genetic origin.

Pollen-mediated gene flow of genetically modified crops to their wild relatives can facilitate the spread of transgenes into the ecosystem and alter the fitness of the consequential progeny. A two-year field study was conducted to quantify the gene flow from glufosinate-ammonium resistant (GR) soybean (Glycinemax) to its wild relative, wild soybean (G. soja), and assess the potential weed risk of hybrids resulting from the gene flow during their entire life cycle under field conditions in Korea, where wild soybean is the natural inhabitant. Pollen-mediated gene flow from GR soybeans to wild soybeans ranged from 0.292% (mixed planting) to 0.027% at 8 m distance. The log-logistic model described the gene flow rate with increasing distance from GR soybean to wild soybean; the estimated effective isolation distance for 0.01% gene flow between GR and wild soybeans was 37.7 m. The F1 and F2 hybrids exhibited the intermediate characteristics of their parental soybeans in their vegetative and reproductive stages. Canopy height and stem length of hybrids were close to those of wild soybean, which shows an indeterminate growth; the numbers of flowers, pods, and seeds per hybrid plant were close to those of wild soybean and significantly higher than those of GR soybean. Seed longevity of F2 hybrid plants was also intermediate but significantly greater than that of GR soybean due to high seed dormancy. Our results suggest that transgenes of the GR soybean might disperse into wild populations and persist in the agroecosystem of the genetic origin regions due to the pollen-mediated gene flow and the relatively high fitness of the hybrid progeny.

Direct Analysis of Glyphosate, Glufosinate, and Their Metabolites in Palm Oil Using Liquid Chromatography with Tandem Mass Spectrometry.

BACKGROUND: Glyphosate and glufosinate are broad-spectrum herbicides which are frequently used in palm oil plantations for weed control. Metabolites of these herbicides are known to have environmental and food safety implications. As there is no validated method for multiresidue testing of these herbicides and their metabolites in palm oil products, a new method was needed for the purpose of regulatory analysis. OBJECTIVE: In this study, we endeavored to develop a rapid method for multiresidue analysis of glyphosate (+aminomethylphosphonic acid) and glufosinate (+3-methylphosphinicopropionic acid and N-acetyl-glufosinate) in refined and crude palm oil matrices using liquid chromatography (LC) tandem mass spectrometry (MS/MS). METHOD: The optimized sample preparation workflow included extraction of refined or crude palm oil (10 g) with acidified water (0.1 M HCl), cleanup by phase separation with dichloromethane, and analysis by LC-MS/MS with multiple reaction monitoring. RESULTS: The use of a Torus-DEA LC column ensured simultaneous analysis of these compounds within a runtime of 10 min. The LOQ of these analytes was 0.01 mg/kg, except that of aminomethylphosphonic acid which was 0.02 mg/kg. The method sensitivity complied with the national maximum residue limits of Malaysia and the European Union. Also, the method selectivity, sensitivity, accuracy, and precision were aligned with the SANTE/12682/2019 guidelines of analytical quality control. CONCLUSIONS: The potentiality of the optimized method lies in a high throughput direct analysis of glyphosate and glufosinate with their metabolites in a single chromatographic run. The method is fit for purpose for regulatory testing of these residues in a broad range of palm oil matrices. HIGHLIGHTS: The study reports for the first time a validated method for simultaneous analysis of glyphosate, glufosinate, and their metabolites in a range of palm oil products. The method did not require a derivatization step and provided a high throughput analysis of these compounds with satisfactory selectivity, sensitivity, accuracy, and precision.

A comparison of PTI defense profiles induced in Solanum tuberosum by PAMP and non-PAMP elicitors shows distinct, elicitor-specific responses.

The induction of general plant defense responses following the perception of external elicitors is now regarded as the first level of the plant immune response. Depending on the involvement or not of these molecules in pathogenicity, this induction of defense is called either Pathogen-Associated Molecular Pattern (PAMP) Triggered Immunity or Pattern Triggered Immunity-both abbreviated to PTI. Because PTI is assumed to be a widespread and stable form of resistance to infection, understanding the mechanisms driving it becomes a major goal for the sustainable management of plant-pathogen interactions. However, the induction of PTI is complex. Our hypotheses are that (i) the recognition by the plant of PAMPs vs non-PAMP elicitors leads to specific defense profiles and (ii) the responses specifically induced by PAMPs target critical life history traits of the pathogen that produced them. We thus analyzed, using a metabolomic approach coupled with transcriptomic and hormonal analyses, the defense profiles induced in potato foliage treated with either a Concentrated Culture Filtrate (CCF) from Phytophthora infestans or two non-PAMP preparations, ß-aminobutyric acid (BABA) and an Ulva spp. Extract, used separately. Each elicitor induced specific defense profiles. CCF up-regulated sesquiterpenes but down-regulated sterols and phenols, notably α-chaconine, caffeoyl quinic acid and rutin, which decreased spore production of P. infestans in vitro. CCF thus induces both defense and counter-defense responses. By contrast, the Ulva extract triggered the synthesis of a large-spectrum of antimicrobial compounds through the phenylpropanoid/flavonoid pathways, while BABA targeted the primary metabolism. Hence, PTI can be regarded as a heterogeneous set of general and pathogen-specific responses triggered by the molecular signatures of each elicitor, rather than as a uniform, non-specific and broad-spectrum set of general defense reactions.

Three poisonous plants (Oenanthe, Cicuta and Anamirta) that antagonise the effect of γ-aminobutyric acid in human brain.

Although we are familiar with common British plants that are poisonous, such as Atropa belladonna (deadly nightshade) and Aconitum napellus (monkshood), the two most poisonous plants in the British Flora are Oenanthe crocata (dead man's fingers) and Cicuta virosa (cowbane). In recent years their poisons have been shown to be polyacetylenes (n-C2H2). The plants closely resemble two of the most common plants in the family Apiaceae (Umbelliferae), celery and parsley. Unwittingly, they are ingested by naive foragers and death occurs very rapidly. The third plant Anamirta derives from South-East Asia and contains a powerful convulsant, picrotoxin, which has been used from time immemorial to catch fish, and more recently to poison Birds of Paradise. All three poisons have been shown to block the γ-aminobutyric acid (GABA) system in the human brain that normally has a powerful inhibitory neuronal action. It has also been established that two groups of sedative drugs, barbiturates and benzodiazepines, exert their inhibitory action by stimulating the GABA system. These drugs are the treatments of choice for poisoning by the three vicious plants.