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Aims: Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH)., Methods and Results: Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodelling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68 mg/kg/day for 2 weeks, per os) and bosentan (100 mg/kg/day for 2 weeks, per os) started 7 days after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodelling, and RV hypertrophy and fibrosis in rats. Consistent with these observations, co-treatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30 mg/kg/day for 3 weeks, per os) and bosentan (100 mg/kg/day for 3 weeks, per os) started 5 weeks after Sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (cGMP) are higher in rats co-treated with LCZ 696 (30 mg/kg/day) and bosentan (100 mg/kg/day) than in MCT and SuHx rats treated with vehicle., Conclusion: Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodelling and severity of experimental PH., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: Entresto (sacubitril/valsartan) is used to treat symptomatic chronic heart failure with reduced ejection fraction. Given its high potential budget impact, the Health Services Executive introduced a reimbursement application system (RAS) to ensure its appropriate use. The aim of this study was to evaluate the utilisation of Entresto in Ireland and compare patient characteristics to those of the pivotal PARADIGM-HF trial., Methods: We used dispensed claims data from the Primary Care Reimbursement Services, clinical data obtained from the RAS, and data from published studies of Entresto utilisation. Differences in the baseline characteristics in the study populations vs the Entresto arm of the PARADIGM-HF trial were analysed. We also investigated cardiovascular medication use in the 6 months pre- and post-Entresto initiation., Results: In 2018, there were 1043 individuals receiving Entresto, corresponding to an expenditure of €1.2 million. Patients prescribed Entresto in Ireland were older, had lower left ventricular ejection fraction and were more symptomatic than those in the PARADIGM-HF trial. Irish patient characteristics were reflective of Entresto-treated populations in other real-world studies. More than 63% of patients were commenced on the lowest Entresto dose. Entresto initiation was associated with a reduction in the use of other medications for heart failure., Conclusion: The utilisation of Entresto has been steadily increasing in Ireland since its reimbursement approval. The expenditure in the first year was substantially lower than predicted, and the RAS is an example of how health technology management can facilitate appropriate and cost-effective use of medicines., (© 2020 The British Pharmacological Society.)

Aim: Sacubitril valsartan (SV) has revolutionized disease history in patients with heart failure and reduced ejection fraction (HFrEF). Our study assessed SV impact on clinical and echocardiographic parameters in HFrEF outpatients previously treated with optimized therapy., Methods: Forty-nine HFrEF outpatients were retrospectively included in the study. We collected data from transthoracic echocardiography and clinical assessment at baseline and after 3 ± 1 and 12 ± 1 months of treatment with SV. Results were also stratified by sex to analyse possible sex-based differences in reverse remodelling response to SV., Results: After 3 months of treatment we observed a significative improvement of both systolic and diastolic function with a reduction of left ventricular mass and relative wall thickness (RWT). At 12 months we observed a further improvement of all previous parameters, plus systolic pulmonary artery pressure (PAP) and left atrial (LA) diameter. In women, most of the echocardiographic parameters improved after SV initiation, but did not reach the statistical significance, except for left ventricular ejection fraction (LVEF), PAP and LA diameter. As for clinical parameters, SV improved New York Heart Association (NYHA) Class, systolic blood pressure and loop diuretic dosage with a mild but significative increase in serum creatinine and potassium., Conclusion: Our study showed significative reverse remodelling properties of SV with an improvement of LV volumes, mass and systo-diastolic function. NYHA Class, systolic blood pressure and loop diuretic dosage also improved with only mild increase in serum creatinine and potassium. Women showed a lesser extent of reverse remodelling compared with men., Competing Interests: The authors report no relationships that could be construed as a conflict of interest., (© 2020 The Author(s).)

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 Ca 2+ cycling remain elusive., Methods and Results: Confocal microscopy (Fluo-4 AM) was used to investigate pro-arrhythmogenic sarcoplasmic reticulum (SR) Ca 2+ 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 Ca 2+ release, SR Ca 2+ load, and Ca 2+ -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 Ca 2+ -spark frequency (CaSpF) nor pro-arrhythmogenic SR Ca 2 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 Ca 2+ leak by 45 ± 9% in CMs put under catecholaminergic stress (isoproterenol 30 nmol/L, n = 81/7 vs. 62/7, P < 0.001 each). This could be attributed to Sac, as sole Sac treatment also reduced both parameters by similar degrees (reduction of CaSpF by 57 ± 7% and SR Ca 2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca 2+ release, SR Ca 2+ load, and Ca 2+ -transient kinetics including SERCA activity (k SERCA ) were not compromised by Sac in isolated murine CMs (n = 41/6 vs. 39/6). Importantly, the combination of Sac/Val and Sac alone also reduced diastolic CaSpF and SR Ca 2+ leak (reduction by 74 ± 7%) in human left ventricular CMs from patients with end-stage HF (n = 71/8 vs. 78/8, P < 0.05 each). Myocardial contractility of human ventricular trabeculae was not acutely affected by Sac treatment as the developed force remained unchanged over a time course of 30 min (n trabeculae/hearts = 3/3 vs. 4/3)., Conclusion: This study demonstrates that neprilysin inhibitor Sac directly improves Ca 2+ homeostasis in human end-stage HF by reducing pro-arrhythmogenic SR Ca 2+ leak without acutely affecting systolic Ca 2+ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM-HF trial., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Sacubitril/valsartan decreased the risk of sudden cardiac death (SCD) in patients suffering from heart failure with reduced ejection fraction (HFrEF). However, long-term data are sparse. Objective: The aim of the present study was to compare the incidence of life-threatening arrhythmias consisting of ventricular tachycardia and/or ventricular fibrillation before and after initiation of sacubitril/valsartan treatment. Methods: Out of 12,000 patients with HFrEF from 2016–2018, 148 patients were newly prescribed sacubitril/valsartan, but the long-term data of only 127 patients were available and included in this study. Results: Patients with an average age of 66.8 ± 12.1 had a median left ventricular ejection fraction (LVEF) of 25% (interquartile range (IQR) 5.00–45.00) and 30% (IQR 10.00–55.00, p < 0.0005) before and after sacubitril/valsartan treatment, respectively. Systolic blood pressure decreased from 127.93 ± 22.01 to 118.36 ± 20.55 mmHg (p = 0.0035) at 6 months of follow-up. However, in 59 patients with a long-term outcome of 12 months, ventricular arrhythmias persistently increased (ventricular fibrillation from 27.6 to 29.3%, ventricular tachycardia (VT) from 12% to 13.8%, and nonsustained VT from 26.6 to 33.3%). Conclusions: Sacubitril/valsartan does not reduce the risk of ventricular tachyarrhythmias in chronic HFrEF patients over 12 months of follow-up. [ABSTRACT FROM AUTHOR]

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 < 0.001). Microscopically, fibrosis area and intensity of oxidative stress (i.e. , DCFDA stain) in kidney/heart tissues exhibited a pattern identical to that of creatinine level among all groups (all p < 0.0001). Kidney injury score and protein expressions of autophagy (i.e. , beclin-1/Atg-5/protein ratio of LC3-BII/LC3-BI), fibrosis (Smad3/TGF-ß), apoptosis (mitochondrial-Bax/capase2/3/9), oxidative-stress (NOX-4/oxidized protein/xanthine-oxidase/catalase), membranous p47phox phosphorylation and mitochondrial-damage biomarker (cytosolic-cytochrome-C) were higher in Group 2 than those in Groups 1 and 3, and significantly higher in Group 3 than in Group 1, while protein expressions of anti-apoptosis (Bcl-2/Bcl-XL) and mitochondrial integrity (mitochondrial-cytochrome-C) markers displayed an opposite pattern among all groups in kidney tissues (all p < 0.0001). Conclusion: Oral administration of entresto was safe and could offer protection against CRS-induced heart and kidney damage. [ABSTRACT FROM AUTHOR]

Rhabdomyolysis is caused by extensive damage to skeletal muscles resulting in elevated creatine phosphokinase (CPK), Lactate dehydrogenase (LDH), and aspartate aminotransferase (AST), leading to life-threatening consequences like acute renal failure, cardiac arrhythmias, and hyperthermia. A variety of causes for muscle damage are known, and one of the most common is drug-induced. Statins and many other agents are known to induce muscle damage, but here we report Entresto™ (Sacubitril/Valsartan) induced rhabdomyolysis which has not been previously reported as solely responsible in the literature. [ABSTRACT FROM AUTHOR]

This study tested the hypothesis that entresto therapy effectively protected heart and lung against cardiopulmonary syndrome (CPS) caused by transverse aortic constriction (TAC) in rat. Adult-Male SD rats (n = 36) were equally categorized into group 1 [sham-operated control (SC)], group 2 [SC + enalapril (7 mg/kg/day) since day-28 after TAC induction], group 3 [SC + entresto (30 mg/kg/day) since day-14 after TAC induction], group 4 (TAC only), group 5 (TAC + enalapril) and group 6 (TAC + entresto) and euthanized at day 60 after TAC induction. By day 60, the left-ventricular (LV) ejection fraction was significantly lower in group 4 than in other groups and significantly lower in groups 5 and 6 than in groups 1 to 3, whereas the ratios of heart and lung weights to tibial-length as well as the right-ventricular-systolic blood pressure exhibited an opposite pattern among the groups (all P<0.001). The sarcomere-length (SL), LV fibrotic area, cardiomyocyte size, and lung injury score were highest in group 4, lowest in groups 1 to 3 and significantly lower in group 6 than in group 5 (all P<0.0001). The protein expressions of fibrotic (Smad3/TGF-β), apoptotic (mitochondrial-Bax/cleaved-caspase3/PARP) and DNA-damaged (γ-H2AX) markers in lung and LV myocardium as well as oxidative (NOX-1/NOX2/oxidized protein) in LV myocardium exhibited an identical pattern of SL (all P<0.0001). The protein expressions of pressure/volume overload (BNP/MHC-β) mitochondrial-damaged (cytosolic cytochrome-C) of LV myocardium exhibited an identical pattern of SL (all P<0.001). In conclusion, Entresto is non-inferior to enalapril for protecting the heart-lung against CPS., Competing Interests: None.

The main stay pharmacotherapy for heart failure (HF) is targeted towards rennin-angiotensin-aldosterone (RAAS) and neprilysin pathways (NP). Both therapeutic strategies decreases morbidity and mortality but also carry considerable adverse effects. This review of the literature highlights the new generation of HF drug, sacubitril-valsartan (SV), trade name Entresto (researched as LCZ696, Novartis) which simultaneously blocks RAAS and NP. This dual action of angiotensin receptors blocker and neprilysin inhibitor (NPi) has improved HF prognosis and it is an evolution in the management of HF. Although the initial follow-up of patients treated with SV has yielded promising results, there are concerns regarding potential side effects especially an increase in the risk of Alzheimer's disease (AD) and young onset of AD. NPi interferes with the breakdown and clearing of beta-amyloid peptides, the plaques seen in AD, raising concern for AD in SV patients. On the other hand, hypertension and cardiovascular diseases are established risk factors for AD which can be decreased by SV therapy. It is therefore essential that SV treated patients are followed up over an extended period of time to detect any adverse cognitive changes., Competing Interests: Conflict-of-interest statement: None.

Background: Heart failure with preserved ejection fraction (HFpEF) makes up half of diagnosed heart failure (HF) cases and has similar outcomes compared to heart failure with reduced ejection fraction (HFrEF) but a discrepancy in knowledge and approach to treatment. HFpEF is diagnosed using the following criteria: symptoms, preserved ejection fraction (greater than 50%), and evidence of abnormal left ventricular filling or relaxation, or diastolic distensibility or stiffness. Studies conducted to examine the efficacy of angiotensin receptor blockers (ARB) (irbesartan and candesartan), thiazide diuretics (chlorthalidone), and angiotensin converting enzyme inhibitors (ACEI) (perindopril) in the treatment of HFpEF, showed moderate efficacy but no clear benefit. Recently, the FDA has approved a novel drug, which combines an angiotensin receptor neprilysin inhibitor and ARB (valsartan) named LCZ696 (entresto) for possible treatment of HFrEF., Conclusion: In this article, we will discuss the failure of previous treatment modalities and the promise that LCZ696 (entresto) may hold for treating patients with HFpEF., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Cardiovascular (CV) diseases in general and heart failure (HF) in particular are major contributors to death and morbidity and are also recognized as important drivers of health care expenditure. The PARADIGM-HF trial was a pivotal trial designed to compare the long-term effects of LCZ696 with enalapril in patients with symptomatic HF with reduced ejection fraction (HFrEF). This review article presents an in-depth view of the PARADIGM-HF trial and the implications of the results in the management of patients with HF and is based on peer reviewed manuscripts, editorials, perspectives and opinions written about the PARADIGM-HF trial. The article presents the key safety and efficacy results of the trial with specific emphasis on the clinical implications of these findings. The review highlights the highly statistically significant, 20% reduction in the primary composite endpoint of cardiovascular death or HF hospitalization, and a 16% reduction in the risk of death from any cause. It also provides an overview of the design, clinical findings, limitations and special areas of clinical interest. The review discusses the future of LCZ696 and additional trials that seek to answer questions in other sub-populations of patients with HF. The article reiterates what has been concluded by many experts in the field of HF- the introduction of LCZ696 into routine clinical care, while dependent on the regulatory approvals in various countries as well as acceptance by physicians, payers and patients, will change the treatment landscape for patients with HFrEF.

Objective: To evaluate the efficacy, safety, and clinical significance of sacubitril/valsartan (Entresto) in patients with heart failure with a reduced ejection fraction (HFrEF). Data Sources: An extensive search was conducted on Ovid MEDLINE using keywords and medical subject headings LCZ696, sacubitril/valsartan, angiotensin-receptor neprilysin inhibitor, and Entresto . Study Selection and Data Extraction: The search was conducted to retrieve clinical trials comparing sacubitril/valsartan to current guideline-directed therapy for HF. Articles using the limits of clinical trials "all" (phase I to IV), in English, and published within the past 5 years were reviewed. Supplemental sources included the Entresto package insert via the manufacturer's website. Primary end points included all-cause mortality and time to first hospitalization. Safety end points included incidence and severity of angioedema, cough, hyperkalemia, increased serum creatinine, and hypotension. Data Synthesis: This review critiques both clinical and statistical significance of the "Prospective Comparison of ARNi with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure" or PARADIGM-HF and other phase II to III clinical trials. Sacubitril/valsartan showed a 20% reduction in cardiovascular death and first hospitalization from HF compared with enalapril. Despite an overall reduction in adverse events, sacubitril/valsartan had increased occurrences of hypotension and nonserious angioedema. Conclusion: Sacubitril/valsartan is a viable option for newly diagnosed New York Heart Association (NYHA) class II to III and is an alternative to patients who are currently being treated with the maximum doses of current gold standard treatment. Clinicians initiating sacubitril/valsartan must monitor patients closely for signs, symptoms, and history of hypotension and angioedema., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2015.)