UNASSIGNED: Chronic kidney disease (CKD) patients are at high risk of heart failure (HF) and both share similar risk factors, including diabetes and elevated blood Pressure (B.P). Aim of this study was to determine the impact of sacubitril/valsartan on the quality of life (QOL) and ejection fraction (EF) of patients with HF with and without CKD.
UNASSIGNED: Single center (Doctors Hospital Lahore), observational study with longitudinal follow up, on 104 HF patients from July 2019 to July 2020. HF was diagnosed on both clinical and echo parameters. New York Heart Association Class II-IV, EF less than or equal to 40% HF with reduced EF and stage three CKD patients were included. Sacubitril/Valsartan was prescribed at a starting daily dose of 50mg and then up titrated to 400mg. Patients were followed up with clinical evaluation, QOL assessment, echocardiography and biochemical profile at one, four, eight and 12 months.
UNASSIGNED: Gender, age, and diabetes mellitus between CKD and non-CKD patients were noted to be statistically different, defined as p<0.05. CKD patients\' QOL increased from 45.15 to 57.57 from baseline to 12 months (p-value<0.01). Non-CKD patients\' QOL increased from 48.07 to 56.25. In CKD patients, EF increased from 27.87% to 29.29% from baseline to 12 months (p-value 0.03) whereas in non-CKD patients EF improved from 29.42% to 31.43%.
UNASSIGNED: Sacubitril/ valsartan improves QOL in patients of HF with reduced EF both with and without CKD. Clinical improvement was independent of Left Ventricular EF as measured by QOL. Thus, QOL is a useful tool to assess the drug\'s beneficial effect.

暂无摘要。

BACKGROUND: Sacubitril/valsartan is a foundational therapy for patients with heart failure. Although current U.S. Food and Drug Administration labeling does not provide guidance regarding initiation or continuation of sacubitril/valsartan in patients with worsening kidney function, guidelines identify estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 as a contraindication to therapy.
OBJECTIVE: This study aims to assess the safety and efficacy of continuing sacubitril/valsartan in patients with deterioration of kidney function below an eGFR of 30 mL/min/1.73 m2.
METHODS: The association between a deterioration in eGFR <30 mL/min/1.73 m2, efficacy and safety outcomes, and treatment with sacubitril/valsartan vs renin-angiotensin system inhibitor were evaluated using time updated Cox models in a post hoc parallel trial analyses of PARADIGM-HF and PARAGON-HF.
RESULTS: Among 8,346 randomized patients in PARADIGM-HF and 4,746 in PARAGON-HF, 691 (8.3%) and 613 (12.9%), respectively, had an eGFR <30 mL/min/1.73 m2 at least once in follow-up. Patients experiencing such deterioration were at higher risk of the primary outcome in both PARADIGM-HF and PARAGON-HF. However, the incidence of the primary outcome remained lower with sacubitril/valsartan vs renin-angiotensin system inhibitor, regardless of deterioration in kidney function in both PARADIGM-HF (Pinteraction = 0.50) and PARAGON-HF (Pinteraction = 0.64). Rates of key safety outcomes were higher among patients experiencing eGFR deterioration; however, rates were similar between treatment groups including among those who remained on treatment.
CONCLUSIONS: Patients experiencing deterioration of kidney function to a value below eGFR 30 mL/min/1.73 m2 faced high risk of cardiovascular and kidney disease outcomes. Continuation of sacubitril/valsartan was associated with persistent clinical benefit and no incremental safety risk. These data support continuation of sacubitril/valsartan for heart failure treatment even when eGFR declines below this threshold (PARADIGM-HF [Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure], NCT01035255; and PARAGON-HF [Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction], NCT01920711).

C-type natriuretic peptide (CNP) plays a crucial role in enhancing endochondral bone growth and holds promise as a therapeutic agent for impaired skeletal growth. To overcome CNP\'s short half-life, we explored the potential of dampening its clearance system. Neprilysin (NEP) is an endopeptidase responsible for catalyzing the degradation of CNP. Thus, we investigated the effects of NEP inhibition on skeletal growth by administering sacubitril, a NEP inhibitor, to C57BL/6 mice. Remarkably, we observed a dose-dependent skeletal overgrowth phenotype in mice treated with sacubitril. Histological analysis of the growth plate revealed a thickening of the hypertrophic and proliferative zones, mirroring the changes induced by CNP administration. The promotion of skeletal growth observed in wild-type mice treated with sacubitril was nullified by the knockout of cartilage-specific natriuretic peptide receptor B (NPR-B). Notably, sacubitril promoted skeletal growth in mice only at 3 to 4 weeks of age, a period when endogenous CNP and NEP expression was higher in the lumbar vertebrae. Additionally, sacubitril facilitated endochondral bone growth in organ culture experiments using tibial explants from fetal mice. These findings suggest that NEP inhibition significantly promotes skeletal growth via the CNP/NPR-B pathway, warranting further investigations for potential applications in people with short stature.

OBJECTIVE: Sacubitril/valsartan (SV), a novel pharmacological class of angiotensin receptor neprilysin inhibitors, is effective in treating heart failure (HF) by inhibiting the degradation of natriuretic peptides and the renin-angiotensin-aldosterone system. However, no studies have observed the long-term effects of SV on patients with HF and preserved left ventricular ejection fraction (LVEF) undergoing hemodialysis (HD) over a long period.
METHODS: This single-center retrospective study of 21 months duration involved consecutive patients with HF and preserved LVEF undergoing HD, who received 50-200 mg/day. All patients were followed up regularly, and clinical, biochemical, and echocardiographic parameters were recorded at baseline and during follow-up. The efficacy and safety of SV were also analyzed.
RESULTS: This longitudinal study included nine patients, with a median age of 76 years. The median HD duration was 7 years. At baseline, the mean brain natriuretic peptide (BNP) was 133±73.6 pg/ml and that of LVEF was 66%±9%. After SV therapy, the systolic blood pressure, diastolic blood pressure, and heart rate decreased, albeit without statistical significance. BNP levels, LVEF, left atrial anteroposterior dimension, and left ventricular mass index did not change, compared to baseline values. No adverse effects were observed in any of the patients.
CONCLUSIONS: SV tended to decrease blood pressure and heart rate in patients with HF and preserved LVEF undergoing HD but did not alter cardiac function assessments, such as BNP or echocardiography.

UNASSIGNED: Sacubitril/valsartan (Sac/Val) is superior to angiotensin-converting enzyme inhibitors in reducing the risk of heart failure hospitalization and cardiovascular death, but its mechanistic data on myocardial scar after myocardial infarction (MI) are lacking. The objective of this work was to assess the effects of Sac/Val on inflammation, fibrosis, electrophysiological properties, and ventricular tachycardia inducibility in post-MI scar remodeling in swine.
UNASSIGNED: After MI, 22 pigs were randomized to receive β-blocker (BB; control, n=8) or BB+Sac/Val (Sac/Val, n=9). The systemic immune response was monitored. Cardiac magnetic resonance data were acquired at 2-day and 29-day post MI to assess ventricular remodeling. Programmed electrical stimulation and high-density mapping were performed at 30-day post MI to assess ventricular tachycardia inducibility. Myocardial samples were collected for histological analysis.
UNASSIGNED: Compared with BB, BB+Sac/Val reduced acute circulating leukocytes (P=0.009) and interleukin-12 levels (P=0.024) at 2-day post MI, decreased C-C chemokine receptor type 2 expression in monocytes (P=0.047) at 15-day post MI, and reduced scar mass (P=0.046) and border zone mass (P=0.043). It also lowered the number and mass of border zone corridors (P=0.009 and P=0.026, respectively), scar collagen I content (P=0.049), and collagen I/III ratio (P=0.040). Sac/Val reduced ventricular tachycardia inducibility (P=0.034) and the number of deceleration zones (P=0.016).
UNASSIGNED: After MI, compared with BB, BB+Sac/Val was associated with reduced acute systemic inflammatory markers, reduced total scar and border zone mass on late gadolinium-enhanced magnetic resonance imaging, and lower ventricular tachycardia inducibility.

OBJECTIVE: The PIONEER-HF and PARAGLIDE-HF trials aimed to determine the efficacy and safety of the in-hospital initiation of sacubitril/valsartan in patients hospitalized for AHF. However, whether the inclusion and exclusion criteria of the trials apply to patients encountered in real-world routine care is unclear. This study aimed to investigate the applicability of the PIONEER-HF and PARAGLIDE-HF trials to real-world AHF patients.
RESULTS: We identified 28 293 AHF hospitalized patients between August 2008 to August 2017 from the Chang Gung Research Database and classified them into four groups based on left ventricular ejection fraction (LVEF) and trial criteria. Cox proportional hazards models were used to compare the risk of HF hospitalization and cardiovascular (CV) death. We defined PIONEER-HF eligible (n = 3683) and non-eligible (n = 3502) patients with an LVEF ≤40%, and PARAGLIDE-HF eligible (n = 5191) and non-eligible (n = 5832) patients with an LVEF >40%. Over a mean follow-up of 3.5 years, the PIONEER-HF non-eligible and eligible groups exhibited similar rates of HF hospitalization and CV death (41.1% vs. 41.8%, adjusted hazard ratio [aHR]: 0.95; 95% CI: 0.88-1.04). No significant difference was found in the composite outcome between PARAGLIDE-HF non-eligible and eligible groups (36.7% vs. 38.6%; aHR: 0.97; 95% CI: 0.90-1.04).
CONCLUSIONS: Using trial criteria, only 31.3% of AHF patients were eligible for sacubitril-valsartan. Yet, non-eligible patients demonstrated similar outcomes to eligible patients, indicating a need for further evaluation of sacubitril-valsartan benefits in non-eligible AHF patients.

UNASSIGNED: The objective was to assess the effect of ongoing angiotensin receptor-neprilysin inhibitor(ARNI) on the effect of the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin on left ventricular (LV) size and function in patients with heart failure and reduced ejection fraction(HFrEF).
UNASSIGNED: Post hoc analysis of the Empire HF trial, an investigator-initiated, double-blind, randomized controlled trial.
UNASSIGNED: 190 patients with HFrEF with New York Heart association class I-III symptoms with an ejection fraction of 40 % or below. Patients were stratified according to ongoing ARNI treatment at baseline.
UNASSIGNED: Empagliflozin 10 mg daily or placebo for 12 weeks. Echocardiography at baseline and follow-up.
UNASSIGNED: Left ventricular end-systolic volume index (LVESVI), end-diastolic volume index (LVEDVI), left atrial volume index (LAVI), left ventricular ejection fraction (LVEF).
UNASSIGNED: A total of 58 patients (31 %) received ARNI at baseline. Compared to with placebo, empagliflozin reduced the LVESVI ([-6.2 (-14.1 to 1.6); p = 0.12] and [-3.3 (-8.2 to 1.6); p = 0.19], interaction P = 0.49), LVEDVI ([-11.2 (-21.2 to -1.2); p = 0.03] and [-2.9 (-8.7 to 2.9); p = 0.32], interaction P = 0.13), and LAVI ([-3.9 (-9.1 to 1.2); p = 0.14] and. [-1.8 (-4.4 to 0.7); p = 0.16], respectively, interaction P = 0.9) in patients treated with and without ARNI at baseline, respectively. No treatment-by-ARNI subgroup interaction were found. Unaffected by baseline ARNI treatment, empagliflozin did not improve LVEF.
UNASSIGNED: The effect of empagliflozin on cardiac structure and function compared to placebo was not affected by background treatment with ARNI.

In addition to their usual use in the treatment of cardiovascular disease, weak evidence is available for the potential of combined use of neprilysin inhibitor (sacubitril) and AT1 receptor antagonist (valsartan) to promote browning of white adipose tissue (WAT) in rats with metabolic syndrome (MetS). This study involved 32 male Wistar albino rats divided into four groups: CTRL-healthy control rats; ENT-healthy rats treated with sacubitril/valsartan; MS-rats with MetS; MS + ENT-rats with MetS treated with sacubitril/valsartan. After finishing the experimental protocol, different WAT depots were isolated for further analysis of molecular pathways. Molecular docking and molecular dynamics studies were used for in silico assessment of the binding affinity of sacubitril and valsartan towards subunits of mechanistic target of rapamycin complex 1 (mTORC1). Sacubitril/valsartan treatment markedly diminished morphological changes in adipose tissue, resulting in smaller lipid size and multilocular lipid droplet structure in WAT. We showed significantly higher protein expression of uncoupling protein-1 (UCP-1) and mTORC1 in WAT of MS + ENT rats, correlating with increased relative gene expression of browning-related markers in tissue of rats treated with sacubitril/valsartan compared with MS group of rats. In silico analysis showed that sacubitrilat and valsartan exhibited the highest binding affinity against mTOR and mLST8, forming stable complexes with these mTORC1 subunits. The observed results confirmed strong potential of combined sacubitril/valsartan treatment to increase browning markers expression in different WAT depots in MetS condition and to form permanent complexes with mTOR and mLST8 subunits over the time.

UNASSIGNED: Sacubitril/valsartan has been shown to reduce hospital admissions and even mortality for heart failure. In heart failure and acute coronary syndrome, the effects of sacubitril/valsartan have been studied, but the effect on coronary artery flow is not known.
UNASSIGNED: We aimed to understand the effect of sacubitril/valsartan on coronary artery flow by using echocardiographic coronary flow reserve (CFR).
UNASSIGNED: Thirty-six patients (17 ischemic and 19 non-ischemic) with heart failure with reduced ejection fraction (EF of < 40%) eligible for sacubitril/valsartan treatment and 21 normal controls were recruited. The study group and controls were similar with regard to gender, smoking status, and age distribution (p = 0.874, p = 0.709, and p = 0.765, respectively). Blood pressure, heart rate, 6-minute walk test (6MWT), N terminal pro B type natriuretic peptide (NT-pro-BNP) level, standard echocardiography, from where left anterior descending mid-distal flow was seen, baseline peak diastolic flow rate and 2 minutes after dipyridamole infusion, and hyperemic peak diastolic flow rate were measured, and CFR with echocardiography was assessed prior to and at 6 months after sacubitril/valsartan initiation.
UNASSIGNED: Baseline peak diastolic flow rate did not exhibit a significant difference at 6 months (p = 0.143), but hyperemic peak diastolic flow rate, CFR, EF (%), and 6MWD values were significantly increased (all p < 0.001), and New York Heart Association Functional Class, NT-pro-BNP (pg/mL), left ventricule end diastolic diameter (mm), and left ventricule end systolic diameter (mm) values were significantly decreased (all p < 0.001) after sacubitril/valsartan treatment.
UNASSIGNED: Sacubitril/valsartan significantly alters coronary blood flow, especially its dynamic features, in patients with heart failure with reduced ejection fraction.