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BACKGROUND Optimal antihypertensive medication for chronic type B aortic dissection (AD) remains undecided. This study compared the efficacy and safety of sacubitril/valsartan with valsartan to determine suitable antihypertensive drug combinations. METHODS In this single-center, open-label, randomized, controlled trial, patients with chronic Stanford type B AD and mild hypertension were randomized to receive sacubitril/valsartan 100/200 mg or valsartan 80/160 mg. The primary endpoint was the reduction in mean sitting systolic blood pressure (msSBP) at week 8 in patients with sacubitril/valsartan vs. valsartan. Key secondary endpoints included changes in (i) mean sitting diastolic blood pressure (msDBP); (ii) pulse pressure (PP); and (iii) mean ambulatory blood pressure (BP) for 24-hour, daytime, and nighttime. Safety assessments included adverse events (AEs) and serious AEs. This trial was registered with the Chinese Clinical Trial Registry, identifier: ChiCTR2300073399. RESULTS A total of 315 patients completed the study. Sacubitril/valsartan provided a significantly greater reduction in msSBP than valsartan at week 8 (between‐treatment difference: −5.1 mm Hg [95% confidence interval −5.8 to −4.5], P  < 0.001). Reductions in msSBP, msDBP, and PP as well as the mean ambulatory BP for 24-hour, daytime, and nighttime, were significantly greater in sacubitril/valsartan compared with valsartan (all P  < 0.001). No excessive episodes of AEs occurred in the sacubitril/valsartan group. CONCLUSIONS Sacubitril/valsartan and valsartan reduced BP compared with baseline values. However, sacubitril/valsartan improved BP control to a greater extent than valsartan. It may offer a new treatment option for patients with mild hypertension and chronic type B AD. [ABSTRACT FROM AUTHOR]

Objectives: Intestinal ischemia reperfusion (IIR) is a critical emergency situation that needs immediate intervention. Small intestine is one of the most sensitive tissues to IR injury and it remains a highly morbid condition, with reported mortality rates ranging from 30% to 90%. Thus, we aimed to evaluate the suspected protective role of sacubitril/valsartan (SAC/VAL) on IIR injury. Methods: Thirty-two adult male Wistar rats were used in our model and divided into four groups: sham group, SAC/VAL treated group without IIR, IIR group, and SAC/VAL treated group with IIR. SAC/VAL in a dose of 30 mg/kg was administered orally just before induction of IIR. Key findings: SAC/VAL significantly ameliorated IIR-induced changes as it decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), angiotensin II (ANG II), interleukin 6 (IL 6), active caspase 3, and signal transducer- and activator-of transcription (STAT1). However, SAC/VAL administration significantly increased antioxidant parameters such as total antioxidant capacity (TAC), superoxide dismutase (SOD), and reduced glutathione (GSH). Moreover, alteration of the histological structure was observed in IIR group that was improved by SAC/VAL. Conclusions: SAC/VAL prevents IIR-induced damage via modulation of renin angiotensin aldosterone system, antioxidant, anti-apoptotic, anti-inflammatory properties, and regulation of IL6/STAT1 pathway. Graphical Abstract [ABSTRACT FROM AUTHOR]

Aortic dissection (AD) is a serious condition that affects a significant number of individuals each year. Chronic type B aortic dissections (TBAD) have high mortality rates and managing this condition is crucial for improving patient outcomes. Hypertension is a key risk factor for AD, and reducing blood pressure is a primary goal in managing chronic TBAD. A recent clinical trial published in the American Journal of Hypertension explored the use of sacubitril/valsartan, a type of medication, in reducing blood pressure in individuals with chronic TBAD. The trial found that sacubitril/valsartan was more effective than valsartan in reducing blood pressure, and both medications were found to be safe. However, further research is needed to determine the efficacy of sacubitril/valsartan compared to other types of antihypertensive medications and in more diverse populations. Overall, this study provides important evidence for the medical management of hypertension in individuals with chronic TBAD. [Extracted from the article]

BACKGROUND Sacubitril/valsartan (LCZ696) is a widely used drug for hypertension in Asia, popular for its efficacy and safety. However, there has been no comprehensive literature review comparing it with olmesartan. This meta-analysis compared the antihypertensive and adverse effects of sacubitril/valsartan and olmesartan. METHODS We conducted a comprehensive search of Pubmed, Web of Science, Embase, Cochrane Library, and ClinicalTrials.gov databases to identify eligible randomized controlled trials (RCTs). The data were then analyzed and processed using Revman 5.4 and Stata SE14 software. RESULTS Six RCTs with 4,127 patients were identified, showing that LCZ696 had better blood pressure control than olmesartan; mean sitting systolic and diastolic blood pressure, sitting pulse pressure, 24-hour ambulatory systolic blood pressure, and 24-hour ambulatory diastolic blood pressure were significantly decreased with LCZ696 compared with olmesartan. No significant difference between LCZ696 and olmesartan was observed in the occurrence of the majority of adverse events, with a decreased probability of headache in patients with sacubitril/valsartan compared with olmesartan. The subgroup analysis showed treatment with 400 mg/d LCZ696 was better than olmesartan in reducing serious adverse events. CONCLUSIONS Sacubitril/valsartan was better than olmesartan in controlling blood pressure in patients with hypertension, with relatively higher safety. [ABSTRACT FROM AUTHOR]

Aims: Angiotensin receptor-neprilysin inhibitor (ARNI) is an established treatment for heart failure. However, whether ARNI has renoprotective effects beyond renin-angiotensin system inhibitors alone in cardiorenal syndrome (CRS) has not been fully elucidated. Here, we examined the effects of ARNI on the heart and kidneys of CRS model mice with overt albuminuria and identified the mechanisms underlying ARNI-induced kidney protection. Methods and results: C57BL6 mice were subjected to chronic angiotensin II infusion, nephrectomy, and salt loading (ANS); they developed CRS phenotypes and were divided into the vehicle treatment (ANS-vehicle), sacubitril/valsartan treatment (ANS-ARNI), and two different doses of valsartan treatment (ANS-VAL M, ANS-VAL H) groups. Four weeks after treatment, the hearts and kidneys of each group were evaluated. The ANS-vehicle group showed cardiac fibrosis, cardiac dysfunction, overt albuminuria, and kidney fibrosis. The ANS-ARNI group showed a reduction in cardiac fibrosis and cardiac dysfunction compared with the valsartan treatment groups. However, regarding the renoprotective effects characterized by albuminuria and fibrosis, ARNI was less effective than valsartan. Kidney transcriptomic analysis showed that the ANS-ARNI group exhibited a significant enhancement in the phosphoinositide 3-kinase (PI3K)-AKT signalling pathway compared with the ANS-VAL M group. Adding PI3K inhibitor treatment to ARNI ameliorated kidney injury to levels comparable with those of ANS-VAL M while preserving the superior cardioprotective effect of ARNI. Conclusion: PI3K pathway activation has been identified as a key mechanism affecting remnant kidney injury under ARNI treatment in CRS pathology, and blockading the PI3K pathway with simultaneous ARNI treatment is a potential therapeutic strategy for treating CRS with overt albuminuria. Graphical abstract [ABSTRACT FROM AUTHOR]

Objectives: Drug-induced cardiac injury is a potentially preventable cause of heart failure. Cisplatin (CIS) is a widely used chemotherapeutic agent complicated with cardiotoxicity that limits its clinical application so we aimed to evaluate the suspected cardioprotective effect of sacubitril/valsartan (Sac/Val) against CIS cardiotoxic injury. Methods: Forty male rats of Wistar albino species were divided into four groups. group I received the vehicle; group II was given the vehicle plus CIS (10 mg/kg) single i.p. on fifth day; group III was given Sac/Val (30 mg/kg/d) orally for 7 days plus CIS (10 mg/kg) single i.p. on fif5th day; group IV was given the same as group III plus nitro-ω-L-arginine (L-NNA) (25 mg/kg/d) orally for 7 days. Key findings: CIS-induced cardiotoxicity and L-NNA co-administered group showed significant increases in cardiac enzymes, toxic histopathological features, elevated heart weights, angiotensin II (Ang II), neprilysin, malondialdehyde (MDA), inflammatory mediators, blood pressure (BP) and caspase 3 expressions, but there are significant decreases in the antioxidant parameters, vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS). However, the co-administration of Sac/Val could ameliorate these changes of CIS. Conclusion: Sac/Val has an important cardioprotective effect against CIS cardiotoxicity with the involvement of eNOS. Graphical Abstract [ABSTRACT FROM AUTHOR]

Multiple medications for heart failure (HF) previously indicated only for patients with ejection fraction (EF) <= 40% offer clinical benefits to patients with EF above this cut-off. Graph: Graphical Abstract The totality of scientific evidence supports sacubitril/valsartan as reducing total worsening heart failure (HF) events and cardiovascular death compared with valsartan when tested in a broad population of patients with HF and EF > 40%. In both the primary pooled and overall pooled analyses, the benefit of sacubitril/valsartan was confined to the pre-specified subgroup of patients with EF <= 60%, with a statistically significant interaction I P i -value by EF group. [Extracted from the article]

Aims The PARAGLIDE-HF trial demonstrated reductions in natriuretic peptides with sacubitril/valsartan compared with valsartan in patients with heart failure (HF) with mildly reduced or preserved ejection fraction who had a recent worsening HF event, but was not adequately powered to examine clinical outcomes. PARAGON-HF included a subset of PARAGLIDE-HF-like patients who were recently hospitalized for HF. Participant-level data from PARAGLIDE-HF and PARAGON-HF were pooled to better estimate the efficacy and safety of sacubitril/valsartan in reducing cardiovascular and renal events in HF with mildly reduced or preserved ejection fraction. Methods and results Both PARAGLIDE-HF and PARAGON-HF were multicentre, double-blind, randomized, active-controlled trials of sacubitril/valsartan vs. valsartan in patients with HF with mildly reduced or preserved left ventricular ejection fraction (LVEF >40% in PARAGLIDE-HF and ≥45% in PARAGON-HF). In the pre-specified primary analysis, we pooled participants in PARAGLIDE-HF (all of whom were enrolled during or within 30 days of a worsening HF event) with a 'PARAGLIDE-like' subset of PARAGON-HF (those hospitalized for HF within 30 days). We also pooled the entire PARAGLIDE-HF and PARAGON-HF populations for a broader context. The primary endpoint for this analysis was the composite of total worsening HF events (including first and recurrent HF hospitalizations and urgent visits) and cardiovascular death. The secondary endpoint was the pre-specified renal composite endpoint for both studies (≥50% decline in estimated glomerular filtration rate from baseline, end-stage renal disease, or renal death). Compared with valsartan, sacubitril/valsartan significantly reduced total worsening HF events and cardiovascular death in both the primary pooled analysis of participants with recent worsening HF [ n = 1088; rate ratio (RR) 0.78; 95% confidence interval (CI) 0.61–0.99; P = 0.042] and in the pooled analysis of all participants (n = 5262; RR 0.86; 95% CI: 0.75–0.98; P = 0.027). In the pooled analysis of all participants, first nominal statistical significance was reached by Day 9 after randomization, and treatment benefits were larger in those with LVEF ≤60% (RR 0.78; 95% CI 0.66–0.91) compared with those with LVEF >60% (RR 1.09; 95% CI 0.86–1.40; P interaction = 0.021). Sacubitril/valsartan was also associated with lower rates of the renal composite endpoint in the primary pooled analysis [hazard ratio (HR) 0.67; 95% CI 0.43–1.05; P = 0.080] and the pooled analysis of all participants (HR 0.60; 95% CI 0.44–0.83; P = 0.002). Conclusion In pooled analyses of PARAGLIDE-HF and PARAGON-HF, sacubitril/valsartan reduced cardiovascular and renal events among patients with HF with mildly reduced or preserved ejection fraction. These data provide support for use of sacubitril/valsartan in patients with HF with mildly reduced or preserved ejection fraction, particularly among those with an LVEF below normal, regardless of care setting. [ABSTRACT FROM AUTHOR]

Background There is little information on the pharmacokinetics and pharmacodynamics of sacubitril/valsartan (SV) in patients undergoing peritoneal dialysis (PD) complicated with hypertension or heart failure (HF). This study was designed to evaluate the pharmacokinetics and pharmacodynamics of SV in PD patients with complications of hypertension or HF. Methods This was an open-label and cross-sectional study investigating PD patients diagnosed with hypertension or New York Heart Association Class II–IV HF. The concentrations of valsartan, sacubitril and sacubitrilat (LBQ657) were measured by ultra-performance liquid chromatography tandem mass spectrometry in plasma, urine and peritoneal dialysate samples. Pharmacodynamics were evaluated by comparing changes in mean sitting systolic blood pressure (msSBP), mean sitting diastolic blood pressure (msDBP), mean sitting heart rate, N-terminal-pro B-type natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). Results Forty patients with PD were enrolled including 27 (67.5%) patients with hypertension, 4 (10%) patients with HF and 9 (22.5%) patients with both hypertension and HF. This study included three treatment cohorts: 50 mg twice daily (BID), 100 mg once daily and 100 mg BID. The plasma maximum drug concentrations in the 100 mg BID group were 1995 ± 1499 ng/mL for valsartan, 171 ± 148 ng/mL for sacubitril and 13 686 ± 7418 ng/mL for LBQ657. The 24-h recovery rate of LBQ657 was 3.77% in urine and 2.23% in peritoneal dialysate. After taking SV, msSBP and msDBP decreased by 19.25 ± 10.32 mmHg and 10.10 ± 8.00 mmHg from baseline, respectively. NT-proBNP decreased by 1436.50 (0.00–18 198.00) from baseline, while LVEF increased by 5.00 (–0.25 to 9.25) from baseline after SV treatment. Conclusions PD and residual renal function contributed only to a minor degree to the elimination of LBQ657. Additionally, a dose of 100 mg BID SV is safe and effective in patients with PD with complications of hypertension or HF. [ABSTRACT FROM AUTHOR]

Objectives: Sacubitril-valsartan, a recently approved treatment for heart failure, has shown some promise as a possible therapeutic option for diabetes mellitus. It is still not clear whether those beneficial effects are comparable to valsartan effects. In this work, we aimed at investigating Sacubitril-valsartan effect on metabolic changes in a model of high-fat high fructose diet-induced diabetes mellitus, in comparison to the metabolic changes induced by valsartan only. Methods: Rats were ad libitum fed with either standard chow plus tap water for drinking (controls) or 60% beef tallow and 10% fructose drinking water (diseased) for 11 weeks. Starting in week 9, each group was subdivided into four, namely vehicle, pioglitazone, Sacubitril-valsartan and valsartan. Treatments were administered from weeks 9 to 11, while rats were maintained in their respective diet groups. Key findings: Sacubitril-valsartan treatment significantly decreased daily food intake, body weight and epididymal white adipose weight, and normalized insulin and glycosylated haemoglobin in high-fat high fructose. Both valsartan and Sacubitril-valsartan only attenuated the elevated fasting blood glucose levels, glucose, insulin and pyruvate tolerance and increased protein kinase B phosphorylation in diseased rats. Conclusions: Sacubitril-valsartan may be an effective modulator of diabetes mellitus-associated metabolic aberration, superiorly compared to valsartan only. [ABSTRACT FROM AUTHOR]

Kidney surgery often includes organ ischaemia with a risk of acute kidney injury. The present study tested if treatment with the combined angiotensin II–angiotensin II receptor type 1 and neprilysin blocker Entresto (LCZ696, sacubitril/valsartan) protects filtration barrier and kidney function after ischaemia and partial nephrectomy (PN) in pigs. Single kidney glomerular filtration rate (GFR) by technetium-99m diethylene-triamine-pentaacetate clearance was validated (n  = 6). Next, four groups of pigs were followed for 15 days (n  = 24) after PN (one-third right kidney, 60 min ischaemia) + Entresto (49/51 mg/day; n  = 8), PN + vehicle (n  = 8), sham + Entresto (49/51 mg/day; n  = 4) and sham + vehicle (n  = 4). GFR, diuresis and urinary albumin were measured at baseline and from each kidney after 15 days. The sum of single-kidney GFR (right 25 ± 6 mL/min, left 31 ± 7 mL/min) accounted for the total GFR (56 ± 14 mL/min). Entresto had no effect on baseline blood pressure, p-creatinine, mid-regional pro-atrial natriuretic peptide (MR-proANP), heart rate and diuresis. After 15 days, Entresto increased GFR in the uninjured kidney (+23 ± 6 mL/min, P  < .05) and reduced albuminuria from both kidneys. In the sham group, plasma MR-proANP was not altered by Entresto; it increased to similar levels 2 h after surgery with and without Entresto. Fractional sodium excretion increased with Entresto. Kidney histology and kidney injury molecule-1 in cortex tissue were not different. In conclusion, Entresto protects the filtration barrier and increases the functional adaptive response of the uninjured kidney. [ABSTRACT FROM AUTHOR]

Background While it is well known that angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARBs) increase the risk of acute renal failure, the role of neprilysin inhibition (NEPi) is unclear and some physicians are reluctant to prescribe sacubitril/valsartan because of safety concerns. This meta-analysis aimed to examine the risk for renal events, progression of chronic kidney disease (CKD) or progression to dialysis on combined NEPi and ACEi/ARBs compared with ACEi or ARBs. Methods We performed a systematic meta-analysis including 17 randomized controlled trials (study drug sacubitril/valsartan or omapatrilat), involving a total of 23 569 patients, after searching PubMed, Cochrane, ClinicalTrials.org and Embase for eligible studies. From the included trials, all renal endpoints, including long- and short-term outcomes and hyperkalemia, were extracted. Pooled odds ratios (ORs) were calculated using the DerSimonian and Laird method. The study was registered at PROSPERO. Results Overall, treatment with sacubitril/valsartan or omapatrilat showed a slightly lower risk of any renal event [OR 0.82 (0.7–0.97)] compared with treatment with an ACEi or ARB alone. Also, there was a decreased risk of severe acute renal events [OR 0.8 (0.69–0.93)] and a decrease in estimated glomerular filtration rate decline [mean difference −0.58 mL/min (−0.83 to −0.33 mL/min)]. There was no difference in chronic renal events [OR 0.92 (0.8–1.05)] or hyperkalemia [OR 1.02 (0.84–1.23)]. Conclusion NEPi + ACEi/ARBs are safe in terms of renal adverse events. Longer trials focusing on CKD are needed to evaluate the effect of NEPi on decreasing progression of CKD. [ABSTRACT FROM AUTHOR]

Background Cancer therapy–related cardiac dysfunction (CTRCD) is a challenging and life-threatening complication of many chemotherapeutic regimens. CTRCD prevention, diagnosis, and therapy require both careful interdisciplinary assessment and management. For patients with CTRCD, current guidelines of the European Society of Cardiology (ESC) recommend an angiotensin-converting-enzyme inhibitor in combination with a beta-blocker. Recent studies indicate a beneficial effect of sacubitril/valsartan in this patient population. Case summary A 68-year-old female patient with a pleural epithelioid angiosarcoma developed heart failure with reduced ejection fraction and elevated serum biomarkers following doxorubicin treatment. After implementation of a recommended cardioprotective medical therapy including torasemide, ramipril, carvedilol, and spironolactone, the patient suffered two cardiac decompensations within 4 weeks after initiation of a paclitaxel regimen and pleural radiation therapy due to pain exacerbation. Despite a continuous application of the cardioprotective medical treatment regimen, no improvement of left-ventricular ejection fraction (LVEF) was detected in a 4-month follow up. Interestingly, after omitting ramipril and implementing low-dose sacubitril/valsartan (26/24 mg), we observed a decrease in serum biomarkers within 3 months as well as a significant improvement of LVEF within 6 months. After nearly 10 months of disease stabilization under paclitaxel, the patient suffered progressive cancer disease and deceased 1 week later after the initiation of a therapeutic attempt with pazopanib. Discussion This case report highlights the importance of interdisciplinary care in cancer patients as well as the promising role of (low-dose) sacubitril/valsartan in patients with CTRCD even in the setting of delayed initiation. [ABSTRACT FROM AUTHOR]

The cardiotoxicity induced by arsenic trioxide (ATO) limits its clinical application in acute promyelocytic leukemia treatment. Sacubitril/valsartan (LCZ696) is an effective drug for the treatment of heart failure. In this study, we aimed to investigate the protective effect and mechanisms of LCZ696 against the ATO-induced cardiotoxicity in mice and H9c2 cells. We found that LCZ696 could alleviate the decrease of ejection fraction and fractional shortening induced by ATO, thereby improving mouse cardiac contractile function. LCZ696 could also reduce the myocardial enzyme, resist oxidative stress, mitigate myocardial fibrosis, and ameliorate myocardial structure, thereby alleviating myocardial damage caused by ATO. In addition, LCZ696 could significantly increase the cell viability and reduce the accumulation of reactive oxygen species in ATO-treated H9c2 cells. Besides, in vivo and in vitro studies have been found that LCZ696 could restore the expression of Bcl-2 and reduce Bax and Caspase-3 levels, inhibiting ATO-induced apoptosis. Meanwhile, LCZ696 decreased the levels of IL-1, IL-6, and TNF-α, alleviating the inflammatory injury caused by ATO. Furthermore, LCZ696 prevented NF-κB upregulation induced by ATO. Our findings revealed that LCZ696 has a considerable effect on preventing cardiotoxicity induced by ATO, which attributes to its capability to suppress oxidative stress, inflammation, and apoptosis. [ABSTRACT FROM AUTHOR]

Background: The mortality rate of patients suffering from choronic heart failure is still high despite advantages in diagnosis and treatment. A new therapeutic class of agents acting on the renin angiotensin aldosterone system (RAAS) and neutral endopeptidase system has been developed, known as angiotensin receptor neprilysin inhibitors (ARNI). Recently, promising data from its administration have demonstrated a decrease in the mortality rate as compared to angiotensin receptor blocker alone. Aim of the Work: The aim of this study is to asses effect of Sacubitril/Valsartan combination on abnormal ECG and ECHO parameters in patients with heart failure with reduced ejection fraction as a marker of reverse cardiac remodeling. Patients and Methods: Our study was conducted at Ain Shams university hospitals and our target population was heart failure patients with reduced ejection fraction planned to initiate Sacubitril \ Valsartan combination therapy. 100 patients were collected from February 2022 to August 2022. It was an interventional study to follow up the effects of the drug on ECG parameters besides ECHO parameters 6 months after drug initiation. Results: We found that in Sacubitril/Valsartan combination therapy there was significant decrease in HR, QRS width and QTc values which reflects the role of this combination to reduce ventricular arrhythmias and preventing SCD. There was significant increase in the EF which was correlated to the significant decrease in QRS width. There was significant improvement in diastolic dysfunction. There was significant decrease in the LA and LV dimensions giving an explanation of the role of the drug in reverse cardiac remodeling. There was significant improvement in NYHA class reflecting the role of the drug in improving quality of life. Conclusion: HR, QRS width and QTc were significantly decreased with Sacubitril/Valsartan combination therapy through the follow up period reflecting the effect of the drug on ECG. EF, LA dimension and LVID were improving with Sacubitril/Valsartan combination therapy through the follow up period which give an explanation of the combination therapy for its role in reverse cardiac remodeling. NYHA class of our patients was improving through follow up period which means this drug improves quality of life and reduces hospitalization. [ABSTRACT FROM AUTHOR]

Background Atorvastatin and sacubitril/valsartan (Entresto™) have been cornerstones in managing patients with coronary artery disease and heart failure (HF). We report a case of life-threatening rhabdomyolysis associated with the co-administration of atorvastatin and sacubitril/valsartan. Case summary A 58-year-old male with coronary heart disease and chronic HF treated with the optimal dose of atorvastatin and other cardiovascular medications was frequently admitted for acute decompensation of HF. We decided to optimize his condition by adding sacubitril/valsartan to his treatment regime. He presented to our outpatient clinic with worsening myalgia and oliguria 6 days later. He was readmitted with markedly elevated serum creatinine kinase (CK) (94 850 U/L; normal range 32–294 U/L), deranged liver function tests, and acute kidney injury. We withheld atorvastatin and sacubitril/valsartan and treated him with renal replacement therapy. Discussion Sacubitril inhibits the excretion of statins, thereby elevating serum statin concentration and increasing the likelihood of developing muscle-related toxicity. Co-administration of atorvastatin and sacubitril/valsartan should be monitored closely with laboratory investigations of CK and liver and renal function. The physician may consider starting low-dose atorvastatin at 20 mg daily in combination with sacubitril/valsartan 24 mg/26 mg twice daily and titrating accordingly to optimal doses. Rosuvastatin could be an alternative to atorvastatin, as it has less drug–drug interaction with sacubitril, thereby reducing the adverse effect. [ABSTRACT FROM AUTHOR]

Background Sacubitril/valsartan is approved for the treatment of chronic heart failure with reduced left ventricular ejection fraction of ≤40% to decrease mortality and morbidity. Nasal pruritus is not a recognized adverse effect in the product information. In this case series, we encountered three patients who presented with nasal pruritus that improved after discontinuation of sacubitril/valsartan. Case summary Three patients aged 58–73 years-old presented with pruritus at the nasal septum post-initiation of sacubitril/valsartan. The pruritus did not subside despite the use of anti-histamines. Within 3–6 months, all individuals discontinued sacubitril/valsartan with complete resolution of their nasal pruritus. Discussion Many physicians may not aware of this unusual but reversible adverse effect of sacubitril/valsartan. Despite the positive prognostic value of sacubitril/valsartan, the constant nasal pruritus had impacted the quality of life of our patients, leading them to discontinue sacubitril/valsartan permanently. [ABSTRACT FROM AUTHOR]

Context Inhibitors of the protease neprilysin (NEP) are used for treating heart failure, but are also linked to improvements in metabolism. NEP may cleave proglucagon-derived peptides, including the glucose and amino acid (AA)-regulating hormone glucagon. Studies investigating NEP inhibition on glucagon metabolism are warranted. Objective This work aims to investigate whether NEP inhibition increases glucagon levels. Methods Plasma concentrations of glucagon and AAs were measured in eight healthy men during a mixed meal with and without a single dose of the NEP inhibitor/angiotensin II type 1 receptor antagonist, sacubitril/valsartan (194 mg/206 mg). Long-term effects of sacubitril/valsartan (8 weeks) were investigated in individuals with obesity (n = 7). Mass spectrometry was used to investigate NEP-induced glucagon degradation, and the derived glucagon fragments were tested pharmacologically in cells transfected with the glucagon receptor (GCGR). Genetic deletion or pharmacological inhibition of NEP with or without concomitant GCGR antagonism was tested in mice to evaluate effects on AA metabolism. Results In healthy men, a single dose of sacubitril/valsartan significantly increased postprandial concentrations of glucagon by 228%, concomitantly lowering concentrations of AAs including glucagonotropic AAs. Eight-week sacubitril/valsartan treatment increased fasting glucagon concentrations in individuals with obesity. NEP cleaved glucagon into 5 inactive fragments (in vitro). Pharmacological NEP inhibition protected both exogenous and endogenous glucagon in mice after an AA challenge, while NEP-deficient mice showed elevated fasting and AA-stimulated plasma concentrations of glucagon and urea compared to controls. Conclusion NEP cleaves glucagon, and inhibitors of NEP result in hyperglucagonemia and may increase postprandial AA catabolism without affecting glycemia. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims We evaluated the influence of sacubitril/valsartan on the effects of sodium-glucose cotransporter 2 (SGLT2) inhibition with empagliflozin in patients with heart failure and a reduced ejection fraction. Methods and results The EMPEROR-Reduced trial randomized 3730 patients with heart failure and an ejection fraction ≤40% to placebo or empagliflozin (10 mg/day), in addition to recommended treatment for heart failure, for a median of 16 months. A total of 727 patients (19.5%) received sacubitril/valsartan at baseline. Analysis of the effect of neprilysin inhibition was 1 of 12 pre-specified subgroups. Patients receiving a neprilysin inhibitor were particularly well-treated, as evidenced by lower systolic pressures, heart rates, N-terminal prohormone B-type natriuretic peptide, and greater use of cardiac devices (all P  < 0.001) when compared with those not receiving sacubitril/valsartan. Nevertheless, when compared with placebo, empagliflozin reduced the risk of cardiovascular death or hospitalization for heart failure in patients receiving or not receiving sacubitril/valsartan [hazard ratio 0.64 (95% CI 0.45–0.89), P  = 0.009 and hazard ratio 0.77 (95% CI 0.66–0.90), P  = 0.0008, respectively, interaction P  = 0.31]. Empagliflozin slowed the rate of decline in estimated glomerular filtration rate by 1.92 ± 0.80 mL/min/1.73 m2/year in patients taking a neprilysin inhibitor (P  = 0.016) and by 1.71 ± 0.35 mL/min/1.73 m2/year in patients not taking a neprilysin inhibitor (P  < 0.0001), interaction P  = 0.81. Combined inhibition of SGLT2 and neprilysin was well-tolerated. Conclusion The effects on empagliflozin to reduce the risk of heart failure and renal events are not diminished in intensively treated patients who are receiving sacubitril/valsartan. Combined treatment with both SGLT2 and neprilysin inhibitors can be expected to yield substantial additional benefits. [ABSTRACT FROM AUTHOR]

However, dialysis patients have usually been excluded from trials of HF therapies, including trials of treatments targeting the natriuretic peptide system. Twenty-six (65%) patients received SV 100 mg BD, 6 (15%) received SV 100 mg OD and 8 (20%) received SV 50 mg BD [[9]]. Patients with chronic kidney disease (CKD) are at increased risk of progression to kidney failure and cardiovascular events [[1]]. [Extracted from the article]

Valsartan (VAL) and sacubitril (SAC) are combined in a supramolecular complex, LCZ696, which is a newly approved remedy for heart failure. SAC-related substance (biphenyl methyl pyrrolidinone [BMP]) which also appears as an intermediate during SAC synthesis is considered to be a suspected impurity for SAC and/or LCZ696 tablets. The study investigates the analysis of VAL and SAC in their supramolecular complex along with SAC-related substance, BMP, using high performance thin-layer chromatography (HPTLC) and high performance liquid chromatography (HPLC) with two different detectors; fluorescence detector (FLD) and diode array detector (DAD). The work aimed at analyzing BMP at low levels in the presence of its parent drug, SAC. BMP was successfully analyzed at a level of 0.167, 1 and 3% of its parent drug, SAC upon using HPLC-FLD, HPLC-DAD and HPTLC, respectively. For HPLC-FLD, the detector was set at λex/λem (nm/nm): 0-4.5min at 255/374; 4.5-6min at 255/314, for achieving an adequate sensitivity of the method to monitor and quantify VAL and SAC in the presence of BMP. Low limits of detection (8.3, 3.3 and 1.7 ngmL-1) and limits of quantitation (25, 10 and 5 ngmL-1) values obtained for VAL, SAC and BMP, respectively, upon using FLD suggest that low level of baseline noise enables the detection and quantitation of low BMP concentration. [ABSTRACT FROM AUTHOR]

Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): Ministry for Education, University and Research Introduction The majority of elderly patients with heart failure has a preserved ejection fraction (HFpEF) that constitutes a syndrome characterized by frequent hospitalizations and high mortality. Despite the growing social burden of HFpEF, the comprehension of its pathophysiology is incomplete, and treatment remains largely undefined. Aging itself may contribute independently to deterioration of diastolic function. Methods 18-month old female Fischer 344 rats were treated with oral administration of either sacubitril/valsartan (60 mg/kg/die, 1:1 ratio) or valsartan alone (30 mg/kg/die) for 12 weeks. Tail-cuff method was used to monitor blood pressure weekly. Echocardiography and left ventricle catheterization were employed to assess systolic and diastolic function, at baseline, and before sacrifice. Cardiac tissue was used for molecular biology and histochemistry assays. Results Tail-cuff analysis indicated a comparable decrease in blood pressure between treatments. Hypertrophy also showed a significant reduction with both treatments. On the contrary, myocardial function analysis demonstrated that no treatment was efficacy on diastolic dysfunction. The lack of improvement of cardiac function could be attributed to the inability of the treatments to counteract the accumulation of fibrotic tissue in the left ventricle, which, in turn, is attributable to the failure to reduce the inflammatory process and oxidative stress, and to the inability to modulate angiotensin II pathway. Conclusion Our results evidenced that both sacubitril/valsartan or valsartan treatment was able to improve diastolic function and pro-fibrotic remodeling, partly due to a lack of effect on classical and non-classical pathways of angiotensin II. [ABSTRACT FROM AUTHOR]

These corrections do not affect the results or the conclusions of this manuscript. Corrigendum to "LCZ696, Angiotensin II Receptor-Neprilysin Inhibitor, Ameliorates High-Salt-Induced Hypertension and Cardiovascular Injury More Than Valsartan Alone" by Kusaka et al. [Extracted from the article]