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Acute decompensated heart failure (ADHF) is one of the conditions associated with high rates of mortality and morbidity, in addition to its economic burden. Sacubitril/valsartan, the emerging drug in the field of heart failure, has been showing favorable outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, its efficacy in patients with acute decompensated heart failure remains obscure. This systematic review aims to offer more clarity to this established gap of knowledge. PubMed, ScienceDirect, and ScienceOpen were explored to gain access to studies on this topic. We conducted a systematic review to evaluate the safety and efficacy of using sacubitril/valsartan in the acute setting. Five clinical trials, 10 observational studies, including two abstracts, in addition to seven case reports and one editorial, were obtained and analyzed. Key outcomes of interest were safety and tolerability, efficacy reflected by N-terminal proB-type natriuretic peptide (NT-proBNP), and other serum and echocardiographic parameters. Additionally, target dose attainment, rehospitalization rates, and hemodynamics effect were also outcomes of interest. Based on our findings, the use of sacubitril/valsartan in patients with ADHF and cardiogenic shock is an effective measure. Although most of the results pointed to its safety, some of them showed the outcome of serious adverse events recommending its cautious use.

This study tested the hypothesis that Entresto (En) therapy protected the cardiomyocytes and heart function in cardiorenal syndrome (CRS) rats fed with high-protein diet (HPD) through regulating the oxidative-stress and Mfn2-mediated mitochondrial functional integrity. En (12.5 μM for the in-vitro study) protected the H9C2-cells against H2O2-induced cell apoptosis, whereas stepwise-increased H2O2 concentrations induced a significant increase in protein expressions of Mfn2/phosphorylated (p)-DRP1/mitochondrial-Bax in H9C2-cells. En downregulated H2O2-induced mitochondrial fission/upregulated mitochondrial fusion and deletion of Mfn2 gene (i.e., shMfn2) to significantly reduce H2O2-induced ROS production. En significantly suppressed and shMfn2 further significantly suppressed both H2O2-reduced mitochondrial-membrane potential and H2O2-induced ROS production/cell apoptosis/mitochondrial damage/mitochondrial-Bax released from mitochondria in H9C2 cells. En significantly reduced protein expressions of Mfn2 and p-DRP1. Additionally, En significantly suppressed and shMfn2 further significantly suppressed the protein expressions of mitochondrial-damaged (DRP1)/oxidative-stress (NOX-1/NOX-2)/apoptosis (mitochondrial-Bax/caspase-3/PARP)/autophagic (LC3B-II/LC3B-I) biomarkers (all p

Background: This study tested the hypothesis that early administration of SS31 and entresto (En) was superior to either one alone on preserving the heart function in setting of dilated cardiomyopathy (DCM) induced by doxorubicin (Dox) [accumulated dosage of 12.5 mg/kg/administered by intraperitoneal (IP) at 4 separated time points within 20 days] in rat. Methods and results: Adult-male SD rats (n = 40) were equally categorized into groups 1 (sham-control), 2 (DCM), 3 (DCM + SS31/0.7 mg/kg/day/IP, since day-14 after DCM induction to day-60), 4 [DCM + En (30 mg/kg/day/orally since day-14 after DCM induction to day-60)] and 5 (DCM + combined SS31-En), and animals were euthanized by day 60. By day 60, left-ventricular ejection-fraction (LVEF) was highest in group 1, lowest in group 2 and significantly higher in group 5 than in groups 3 and 4 (all p

Heart failure (HF) is one of the leading causes of morbidity, mortality, and health care expenditures in the US and worldwide. For three decades, the pillars of treatment of HF with reduced ejection fraction (HFrEF) were medications that targeted the sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS). Prior attempts to augment the natriuretic peptide system (NPS) for the management of HF failed either due to lack of significant clinical benefit or due to the unacceptable side effect profile. This review article will discuss the NPS, the failure of early drugs which targeted the NPS as therapies for HF, and the sequence of events which led to the development of sacubitril plus valsartan (Entresto; LCZ696; Novartis). LCZ696 has been shown to be superior to the standard of care available for treatment of HFrEF in several substantial hard endpoints including heart failure hospitalizations, cardiovascular mortality, and all-cause mortality.

Aims Inhibition of neprilysin and angiotensin II receptor by sacubitril/valsartan (Val) (LCZ696) reduces mortality in heart failure (HF) patients compared with sole inhibition of renin–angiotensin system. Beneficial effects of increased natriuretic peptide levels upon neprilysin inhibition have been proposed, whereas direct effects of sacubitrilat (Sac) (LBQ657) on myocardial Ca2+ cycling remain elusive. Methods and results Confocal microscopy (Fluo‐4 AM) was used to investigate pro‐arrhythmogenic sarcoplasmic reticulum (SR) Ca2+ leak in freshly isolated murine and human ventricular cardiomyocytes (CMs) upon Sac (40 μmol/L)/Val (13 μmol/L) treatment. The concentrations of Sac and Val equalled plasma concentrations of LCZ696 treatment used in PARADIGM‐HF trial. Epifluorescence microscopy measurements (Fura‐2 AM) were performed to investigate effects on systolic Ca2+ release, SR Ca2+ load, and Ca2+‐transient kinetics in freshly isolated murine ventricular CMs. The impact of Sac on myocardial contractility was evaluated using in toto‐isolated, isometrically twitching ventricular trabeculae from human hearts with end‐stage HF. Under basal conditions, the combination of Sac/Val did not influence diastolic Ca2+‐spark frequency (CaSpF) nor pro‐arrhythmogenic SR Ca2 leak in isolated murine ventricular CMs (n CMs/hearts = 80/7 vs. 100/7, P = 0.91/0.99). In contrast, Sac/Val treatment reduced CaSpF by 35 ± 9% and SR Ca2+ leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P

Background: This study tested the hypothesis that Entresto could safely and effectively preserve heart and kidney function in rats with cardiorenal syndrome (CRS) induced by 5/6 nephrectomy and intra-peritoneal doxorubicin administration (accumulated dosage up to 7.5 mg/kg) together with daily high-protein-diet (HPD).Methods and Results: Adult male Sprague-Dawley rats (n = 24) were equally categorized into Group 1 (sham-operated control + HPD), Group 2 (CRS + HPD) and Group 3 [CRS + HPD + Entresto (100 mg/kg/day orally) since Day 14 after CRS induction] and euthanized by Day 63 after CRS induction. By Day 63, circulatory BUN and creatinine levels and ratios of urine protein to creatinine were significantly higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, whereas left-ventricular ejection fraction and kidney weight showed an opposite pattern among all groups (all p

Background: Peptide radioligands may serve as radionuclide carriers to tumor sites overexpressing their cognate receptor for diagnostic or therapeutic purposes. Treatment of mice with the neprilysin (NEP)-inhibitor phosphoramidon was previously shown to improve the metabolic stability and tumor uptake of biodegradable radiopeptides. Aiming to clinical translation of this methodology, we herein investigated the impact of the approved pill Entresto, releasing the potent NEP-inhibitor LBQ657 in vivo, on the stability and tumor uptake of two radiopeptides. Methods: The metabolic stability of [99mTc]Tc-DB4 (DB4, N4-Pro-Gln-Arg-Tyr-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Nle-NH2) and [111In]In-SG4 (SG4, DOTA-DGlu-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2) was tested in LBQ657/Entresto-treated mice vs. untreated controls. The uptake in gastrin-releasing peptide receptor (GRPR)-, or cholecystokinin subtype 2 receptor (CCK2R)-positive tumors respectively, was compared between LBQ657/Entresto-treated mice and untreated controls. Results: LBQ657/Entresto treatment induced marked stabilization of [99mTc] Tc-DB4 and [111In]In-SG4 in peripheral mice blood, resulting in equally enhanced tumor uptake at 4 h post-injection. Accordingly, the [99mTc]Tc-DB4 uptake of 7.13 &plusmn, 1.76%IA/g in PC-3 tumors increased to 16.17 &plusmn, 0.71/17.50 &plusmn, 3.70%IA/g (LBQ657/Entresto) and the [111In]In-SG4 uptake of 3.07 &plusmn, 0.87%IA/g in A431-CCK2R(+) tumors to 8.11 &plusmn, 1.45/9.61 &plusmn, 1.70%IA/g. Findings were visualized by SPECT/CT. Conclusions: This study has shown the efficacy of Entresto to notably improve the profile of [99mTc]Tc-DB4 and [111In]In-SG4 in mice, paving the way for clinical translation of this approach.

With an estimated prevalence of 5.8 million in the USA and over 23 million people worldwide, heart failure (HF) is growing in epidemic proportions. Despite the use of guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, beta-adrenergic blockers, angiotensin receptor blockers, and mineralocorticoid receptor antagonists for chronic systolic HF for almost two decades, HF remains a leading cause of morbidity, mortality, and health care expenditures. The Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial provided compelling evidence for the cardiovascular and mortality benefit of sacubitril/valsartan when compared to enalapril in patients with heart failure and reduced ejection fraction (HFrEF). Sacubitril/valsartan performed better than enalapril across various HFrEF patient characteristics and showed substantial benefit in patients with other common comorbidities. Following the trial, the US Food and Drug Administration approved this drug for the treatment of HF. Various international HF consensus guidelines endorse sacubitril/valsartan as a class I recommendation for the management of symptomatic HFrEF. Although this high-quality clinical study is the largest and the most globally represented trial in HFrEF patients, concerns have been raised regarding the generalizability of the trial results in real-world HF population. The gaps in US Food and Drug Administration labeling and guideline recommendations might lead to this medication being used in a larger population than it was studied in. In this review, we will discuss the current role of sacubitril/valsartan in the management of HF, concerns related to PARADIGM-HF and answers, shortcomings of this novel drug, effects on patient characteristics, real-world eligibility, and the role of ongoing and further investigations to clarify the profile of sacubitril/valsartan in the management of HF.

Background and objectives: The discovery and introduction of Neprilysin inhibitor in treating chronic heart failure (New York Heart Association class II–IV) with reduced ejection fraction (HFrEF) is a remarkable landmark in therapy. The clinical outcome of reducing the incidence of death from cardiovascular causes or first hospitalization for worsening heart failure was demonstrated at the large randomized, double blind, “Angiotensin-Neprilysin inhibition versus enalapril in heart failure (PARADIGM-HF trial).” We studied a total of 228 patients with HFrEF who was recently started on sacubitril/valsartan (EntrestoTM; previously known as LCZ696) testing the hypothesis of improving ejection fraction with sacubitril/valsartan, defined as an increase of ejection fraction from the baseline before treatment by 10–15%. Methods: This is a single-center, retrospective, descriptive study. The data was collected from the charts of patients followed up for a mean of 4.7 weeks after initiation of treatment with sacubitril/valsartan. A total of 228 patients with heart failure were prescribed 200 mg of sacubitril/valsartan twice daily, an improvement in ejection fraction by 10–15% was considered a successful response. Results: Out of the 228 patients, 51.3% showed a successful response. Most of the patients 97.9% and 58.0% were taking beta-blockers and aspirin respectively. The absolute number of black patients who improved was higher than others ethnic groups. However, the higher percentage of ejection fraction improvement 71% was reported among other ethnicities (not blacks or Caucasians). Patients without episodes of hospitalization showed better improvement than those with one or more episodes. Conclusion: In a predominantly black population with HFrEF, sacubitril/valsartan has shown improvement in ejection fraction effect. This finding was independent of other risk factors and concomitant heart failure treatment; however, further studies are recommended to validate this result. Ethics: Ethical approval of this study was obtained from the Research Committee, DMC/Wayne State University (IRB# 015618MP4X) on February 14, 2018.

Background: Hyperkalemia is a potential complication associated with the use of pharmacotherapies inhibiting the renin- angiotensin- aldosterone system (RAAS). Among patients with heart failure (HF) with reduced and preserved ejection fraction (HFrEF and HFpEF, respectively), dose up- titration of therapies inhibiting RAAS might be compromised due to fear of hyperkalemia. The use of RAAS inhibition is guideline-directed for reduction of mortality and morbidity in HFrEF, although no beneficial effects of these therapies on hard endpoints in HFpEF have been demonstrated. However, due to the high prevalence of hypertension in the HFpEF subgroup, the use of RAAS inhibitors in this population is common. Purpose: To determine whether the risk of hyperkalemia is reduced or enhanced by the use of sacubitril/valsartan (LCZ696), a drug that combines angiotensin receptor and neprilysin inhibitor in comparison with traditional RAAS inhibitors such as enalapril or valsartan among patients with HFrEF and HFpEF. Methods: MEDLINE and EMBASE databases were systematically searched to find randomized controlled clinical trials (RCTs) that examined the use of sacubitril/ valsartan vs. enalapril or valsartan or matching placebo in patients with HF. All included studies included data on hyperkalemia events during follow-up. Hyperkalemia was defined as serum potassium >5.5 mmol/L in a majority of studies. Random-effects meta- analysis with restricted maximum likelihood (REML) was performed with prespecified analysis according to HFrEF and HFpEF subgroups. Relative risk (RR) with 95% confidence intervals (95% CI) were reported as the main outcome measures. Heterogeneity across studies was inspected by I2 statistic. Results: A total of six RCTs encompassing 17.362 patients with pooled 2563 events of hyperkalemia (1250 in sacubitril/valsartan group and 1313 in RAAS inhibitor group). The crude average incidence of hyperkalemia was 16% in HFpEF and 14% in the HFpEF population. All included RCTs were multicentric and published in a period between 2012 and 2020 ; three trials included 9.744 patients with HFrEF while three trials enrolled 7.618 patients with HFpEF. Events of hyperkalemia were reported during the median follow-up period that ranged from 2 to 35 months.Low to moderate heterogeneity was detected across studies. The main finding (Figure 1) is that the use of sacubitril/valsartan was no different concerning the risk of hyperkalemia compared to RAAS inhibitors across the HF spectrum (RR 1.004, 95% CI 0.882-1.141), and for the main result, no significant heterogeneity was detected (p=0.120). This effect was consistent in both HFrEF (RR 1.048, 95% CI 0.838-1.310) and HFpEF subgroups (RR 1.015, 95% CI 0.799-1.289) with no significant heterogeneity detected across studies. Conclusion: In patients with HFrEF or HFpEF, treatment with sacubitril/valsartan is not associated with an increased risk of hyperkalemia compared to conventional RAAS inhibitor treatment.