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Aims: 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. Methods and 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. [ABSTRACT FROM AUTHOR]

Aims: This study sought to assess the effect of treatment of sacubitril/valsartan (S/V) on improving cardiac function and reversing cardiac remodelling in patients with acute coronary syndrome (ACS) complicated with heart failure with reduced ejection fraction after percutaneous coronary intervention (PCI). Methods and results: We enrolled 275 ACS patients with reduced left ventricular ejection fraction after PCI. The patients were divided into the routine and S/V groups according to the treatment drugs. The symptoms, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) concentrations, echocardiographic parameters [left ventricular ejection fraction (LVEF), left ventricular mass index (LVMI), left ventricular end‐diastolic volume index (LVEDVI), and left ventricular end‐systolic volume index (LVESVI)], major adverse cardiac events (MACEs), and adverse reactions were recorded at baseline and 6 months after treatment when a clinical follow‐up was performed. The S/V group was further divided into prespecified subgroups including unstable angina (UA) group, non‐ST‐elevation myocardial infarction (NSTEMI) group, and ST‐elevation myocardial infarction (STEMI) group according to the type of ACS. We analysed the changes in LVEF, LVMI, LVEDVI, LVESVI, and NT‐proBNP in both groups and evaluated the correlation between the changes in the above variables (ΔLVEF, ΔLVMI, ΔLVEDVI, ΔLVESVI, and ΔNT‐proBNP). Cox regression model was used to assess the independent risk factors of MACE. Prespecified subgroup analyses were also conducted. Compared with baseline, LVEF increased significantly (P < 0.05), NT‐proBNP, LVMI, and LVESVI decreased significantly in both groups after 6 months (P < 0.05), and LVEDVI decreased significantly in the S/V group (P = 0.001). In the S/V group, ΔLVEF (t = −2.745, P = 0.006), ΔNT‐proBNP (P = 0.009), ΔLVEDVI (t = 4.203, P = 0.001), and ΔLVESVI (t = 3.907, P = 0.001) were significantly improved than those in the routine group. In the S/V group, ΔLVEF was negatively correlated with ΔNT‐proBNP (r = −0.244, P = 0.004), ΔLVMI (r = −0.190, P = 0.028), ΔLVEDVI (r = −0.173, P = 0.045), and ΔLVESVI (r = −0.261, P = 0.002). In Cox regression model analysis, ΔLVEF {hazard ratio [HR] = 0.87 [95% confidence interval (CI) 0.80–0.95], P = 0.003}, ΔLVEDVI [HR = 1.04 (95% CI 1.01–1.06), P = 0.013], and ΔLVESVI [HR = 1.04 (95% CI 1.01–1.08), P = 0.026] were independent risk factors for MACE. Subgroup analysis showed that ΔLVEF (t = 6.290, P = 0.001), ΔLVEDVI (t = 2.581, P = 0.011), and ΔNT‐proBNP (P = 0.019) in the NSTEMI group were significantly improved than those in the UA group, ΔLVEDVI in the NSTEMI group was significantly better than that in the STEMI group (t = −3.365, P = 0.001), and ΔLVEF in the STEMI group was significantly better than that in the UA group (t = −3.928, P = 0.001). There was a significant difference in the survival probability without MACE among the three groups in the analysis of the Kaplan–Meier curve (P = 0.042). The incidence of MACE in the UA group was significantly higher than that in the NSTEMI group (32.4% vs. 6.3%, P = 0.004). Conclusions: The cardiac function is improved and cardiac remodelling is reversed significantly after treatment of S/V in ACS patients with reduced left ventricular ejection fraction after PCI, and the improvement is more obvious than the routine group. There is a significant negative correlation between the change in LVEF and the changes in NT‐proBNP, LVMI, LVEDVI, and LVESVI. The increase of LVEF and the decrease of LVEDVI and LVESVI are protective factors to improve the prognosis. Patients with myocardial infarction and reduced left ventricular ejection fraction might benefit more from the initiation of S/V as first‐line heart failure treatment after PCI. [ABSTRACT FROM AUTHOR]

Aims: The current European Society of Cardiology (ESC) guidelines provide clear indications for the treatment of acute and chronic heart failure (HF). Nevertheless, there is a constant need for real‐world evidence regarding the effectiveness, adherence, and persistence of drug therapy. We investigated the use of sacubitril/valsartan for the treatment of HF with reduced ejection fraction in real‐world clinical practice in Italy. Methods and results: An observational, retrospective, non‐interventional cohort study based on electronic medical records from nine specialized hospital HF centres in Italy was carried out on patients with prescription of sacubitril/valsartan. Overall, 948 patients had a prescription of sacubitril/valsartan, with 924 characterized over 6 months and followed up for 12 months. Pharmacoutilization data at 1 year of follow‐up were available for 225 patients {mean age 69.7 years [standard deviation (SD) = 10.8], 81.8% male}. Of those, 398 (45.2%) reached the target dose of sacubitril/valsartan of 97/103 mg in a mean time of 6.9 (SD = 6.2) weeks. Blood pressure and hypotension in 61 patients (65%) and worsening of chronic kidney disease in 10 patients (10.6%) were the main reasons for not reaching the target dose. Approximatively 50% of patients had a change in sacubitril/valsartan dose during follow‐up, and 158 (70.2%) were persistent with the treatment during the last 3 months of follow‐up. A sensitivity analysis (persistence during the last 4 months of follow‐up) showed persistence for 162 patients (72.0%). Adherence data, available for 387 patients, showed full adherence for 205 (53%). Discontinuation (102/717 patients, 14.2%) was mainly due to hypotension and occurred after a mean time of 34.3 (SD = 28.7) weeks. During follow‐up, out of 606 patients with available data, 434 patients (71.6%) had an HF add‐on drug or drugs concomitant with sacubitril/valsartan. HF‐related hospitalization during follow‐up was numerically higher in non‐persistent (16/67 patients, 23.9%) vs. patients persistent to sacubitril/valsartan (30/158, 19%) (P = 0.405). Conclusions: Real‐world data on the use of sacubitril/valsartan in clinical practice in Italy show a rapid titration to the target dose, high therapeutic adherence enabling a good level of therapeutic management in line with ESC guidelines for patients with reduced ejection fraction. [ABSTRACT FROM AUTHOR]

Aims: Serial assessment of natriuretic peptides is widely utilized in heart failure clinics. Uncertainty exists regarding the value of multiple natriuretic peptide measurements and how they might be best interpreted. Methods and results: Six hundred thirty‐two patients with heart failure with reduced ejection fraction (<40%) and complete biomarker data were enrolled to receive sacubitril/valsartan. Patients underwent periodic study visits during 1‐year follow‐ups. Echocardiographic data and cardiac biomarkers, including N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were collected during study visits. Patients were categorized into three groups based on tertiles of baseline NT‐proBNP levels. The area under the curve (AUC) of NT‐proBNP measurements across study visits was calculated. Compared with patients with higher AUC (and thus higher concentrations over a longer period of time), those with lower AUC were younger, had a lower prevalence of chronic kidney disease, prior coronary artery bypass graft, atrial fibrillation, and higher body‐mass index. A significant interaction existed between baseline NT‐proBNP and subsequent AUC for predicting LVEF change across visits (P‐value < 0.001): among those with lower baseline NT‐proBNP, similar improvements in left ventricular (LV) volumes LV ejection fraction, and LV mass index were observed across subsequent AUC (P‐value > 0.1). However, among those with higher baseline NT‐proBNP, those with lower subsequent AUC had a greater improvement in cardiac remodelling indices (P‐value < 0.05). Conclusions: Serial NT‐proBNP monitoring (integrating the totality of measurements as an AUC) during treatment with sacubitril/valsartan informs unique information regarding the future changes in cardiac remodelling indices, especially among those with higher NT‐proBNP levels at baseline. [ABSTRACT FROM AUTHOR]

Aims: In recent years, survival in patients with breast cancer has increased. Despite the improvement in outcomes of those patients, the risk of treatment‐related cardiotoxicity remains high, and its presence has been associated with a higher risk of treatment termination and thus lower therapeutic efficacy. Prior trials demonstrated that a preventive initiation of heart failure drugs, including the renin–angiotensin–aldosterone inhibitors, might reduce the risk of treatment‐related cardiotoxicity. However, to date, no study investigated the efficacy of sacubitril/valsartan, a novel antineurohormonal drug shown to be superior to the previous therapies, in the prevention of cardiotoxicity in patients with early‐stage breast cancer, which is the aim of the trial. Methods and results: MAINSTREAM is a randomized, placebo‐controlled, double‐blind, multicentre, clinical trial. After the run‐in period, a total of 480 patients with early breast cancer undergoing treatment with anthracyclines and/or anti‐human epidermal growth factor receptor 2 drugs will be randomized to the highest tolerated dose of sacubitril/valsartan, being preferably 97/103 mg twice daily or placebo in 1:1 ratio. The patients will be monitored, including routine transthoracic echocardiography (TTE) and laboratory biomarker monitoring, for 24 months. The primary endpoint of the trial will be the occurrence of a decrease in left ventricular ejection fraction by ≥5% in TTE within 24 months. The key secondary endpoints will be the composite endpoint of death from any cause or hospitalization for heart failure, as well as other imaging, laboratory, and clinical outcomes, including the occurrence of the cancer therapy‐related cardiac dysfunction resulting in the necessity to initiate treatment. The first patients are expected to be recruited in the coming months, and the estimated completion of the study and publication of the results are expected in December 2027, pending recruitment. Conclusions: The MAINSTREAM trial will determine the efficacy and safety of treatment with sacubitril/valsartan as a prevention of cardiotoxicity in patients with early breast cancer (ClinicalTrials.gov number: NCT05465031). [ABSTRACT FROM AUTHOR]

Aims: A novel tool for the evaluation of left ventricular (LV) systo‐diastolic function through echo‐derived haemodynamic forces (HDFs) has been recently proposed. The present study aimed to assess the predictive value of HDFs on (i) 6 month treatment response to sacubitril/valsartan in heart failure with reduced ejection fraction (HFrEF) patients and (ii) cardiovascular events. Methods and results: Eighty‐nine consecutive HFrEF patients [70% males, 65 ± 9 years, LV ejection fraction (LVEF) 27 ± 7%] initiating sacubitril/valsartan underwent clinical, laboratory, ultrasound and cardiopulmonary exercise testing evaluations. Patients experiencing no adverse events and showing ≥50% reduction in plasma N‐terminal pro‐B‐type natriuretic peptide and/or ≥10% LVEF increase over 6 months were considered responders. Patients were followed up for the composite endpoint of HF‐related hospitalisation, atrial fibrillation and cardiovascular death. Forty‐five (51%) patients were responders. Among baseline variables, only HDF‐derived whole cardiac cycle LV strength (wLVS) was higher in responders (4.4 ± 1.3 vs. 3.6 ± 1.2; p = 0.01). wLVS was also the only independent predictor of sacubitril/valsartan response at multivariable logistic regression analysis [odds ratio 1.36; 95% confidence interval (CI) 1.10–1.67], with good accuracy at receiver operating characteristic (ROC) analysis [optimal cutpoint: ≥3.7%; area under the curve (AUC) = 0.736]. During a 33 month (23–41) median follow‐up, a wLVS increase after 6 months (ΔwLVS) showed a high discrimination ability at time‐dependent ROC analysis (optimal cut‐off: ≥0.5%; AUC = 0.811), stratified prognosis (log‐rank p < 0.0001) and remained an independent predictor for the composite endpoint (hazard ratio 0.76; 95% CI 0.61–0.95; p < 0.01), after adjusting for clinical and instrumental variables. Conclusions: HDF analysis predicts sacubitril/valsartan response and might optimise decision‐making in HFrEF patients. [ABSTRACT FROM AUTHOR]

Aims: The study aims to explore the real‐world titration patterns of sacubitril/valsartan in a chronic heart failure (HF) follow‐up management system and the effect on the recovery of ventricular remodelling and cardiac function in China. Methods and results: This is a single‐centre, observational study of 153 adult outpatients with HF and reduced ejection fraction who were managed in the chronic HF follow‐up management system and prescribed with sacubitril/valsartan from August 2017 to August 2021 in China. All patients tried to titrated sacubitril/valsartan to the tolerant dose during follow‐up. The primary outcome was the proportion of patients who reached and maintained the target dose of sacubitril/valsartan. The main secondary outcomes were the changes in left atrium diameter, left ventricular end‐diastolic diameter (LVEDD), and left ventricular ejection fraction (LVEF) from baseline to 12 months. Among the patients, 69.3% were male, with a median age of 49 years. The baseline systolic blood pressure (SBP) was 117.6 ± 18.3 mmHg before starting the treatment of sacubitril/valsartan. Benefiting from the management system, 117 (76.5%) patients achieved the target dose of sacubitril/valsartan, and the median time to reach the target dose was 3 (IQR 1–5) months. Advanced age and lower SBP may be predictors of failure to reach the target dose. Compared with baseline, standard treatment resulted in a pronounced improvement in left ventricular geometry and cardiac function. The patients showed a significant increase in LVEF [28 (IQR 21–34) % vs. 42 (IQR 37.0–54.3) %, P < 0.001], with a great reduction in left atrium diameter [45 (IQR 40.3–51.0) mm vs. 41 (IQR 37.0–45.3) mm, P < 0.001] and LVEDD [65 (IQR 60.0–70.3) mm vs. 55 (IQR 52–62) mm, P < 0.001] during 12 month follow‐up. Of patients, 36.5% had a LVEF ≥50%, 54.1% had LVEF >40%, and 81.1% experienced an increase in LVEF of ≥10%. After 12 month follow‐up, the proportion of patients with New York Heart Association classification I or II increased from 41.8% to 96.4%. Additionally, there was a significant improvement in N‐terminal pro‐B‐type natriuretic peptide (P < 0.001). At Month 12, 50% of patients achieved the target dose of beta‐blockers. No serious adverse events caused by sacubitril/valsartan were observed during the follow‐up. Conclusions: Optimising HF follow‐up management was essential and effective in a real‐world clinical setting; the majority could reach the target dose of sacubitril/valsartan within the management system and achieve a remarkable improvement in cardiac function and ventricular remodelling. [ABSTRACT FROM AUTHOR]

The amount of evidence for guideline‐directed new heart failure (HFrEF) disease‐modifying drugs in the context of chronic kidney disease (CKD) is relatively modest, especially in end‐stage CKD. We report a case of dramatic reverse remodelling and disease regression in a naïve HFrEF young woman on haemodialysis treated with sacubitril/valsartan and SGLT2i. At 10‐month follow‐up, the patient normalized left ventricle and atrial volumes and improved ejection fraction to the normal range, assessed both by echocardiography and cardiac magnetic resonance. Cardiac biomarkers and exercise performance improved consensually. The haemodialysis protocol and the loop diuretic dose were unchanged within the whole period. [ABSTRACT FROM AUTHOR]

Background: Guidelines classify sacubitril/valsartan as a significant part of medical treatment of heart failure with reduced ejection fraction (HFrEF). Data have shown that the HbA1c levels in patients with diabetes mellitus could be impacted by sacubitril/valsartan. A possible positive effect in diabetes patients treated with sacubitril/valsartan on outcome and echocardiography parameters is not well studied yet. Aims: The aim of the present study was to compare the impact of sacubitril/valsartan on life‐threatening arrhythmias, atrial fibrillation, different echocardiography parameters and congestion rate in patients suffering from HFrEF according to the diagnosis diabetes mellitus or no diabetes mellitus. Methods and results: Consecutive 240 patients with HFrEF from 2016 to 2020 were treated with sacubitril/valsartan and separated to concomitant diabetes mellitus (n = 87, median age 68 years interquartile range (IQR) [32–87]) or no diabetes mellitus (n = 153, median age 66 year IQR [34–89]). Different comorbidities and outcome data were evaluated over a follow‐up period of 24 months. Arterial hypertension (87% vs. 64%; P < 0.01) and coronary artery disease (74% vs. 60%; P = 0.03) were more often documented in patients with diabetes mellitus compared with patients without diabetes mellitus. Over the follow‐up of 24 months several changes were noted in both subgroups: Median left ventricular ejection fraction (EF) increased significantly in non‐diabetes (27% IQR [3–44] at baseline to 35% IQR [13–64]; P < 0.001), but not in diabetic patients (29% IQR [10–65] at baseline to 30% IQR [13–55]; P = 0.11). Accordingly, NT‐proBNP and troponin‐I levels decreased significantly in non‐diabetes patients (NT‐brain natriuretic peptide [NT‐proBNP] from median 1445 pg/mL IQR [12.6–74 676] to 491 pg/mL IQR [13–4571]; P < 0.001, troponin‐I levels from 0.099 ng/mL IQR [0.009–138.69] to 0.023 ng/mL IQR [0.006–0.635]; P < 0.001), but not in diabetic patients (NT‐proBNP from 1395 pg/mL IQR [100–29 924] to 885 pg/mL IQR [159–4331]; P = 0.06, troponin‐I levels from 0.05 ng/mL IQR [0.013–103.0] to 0.020 ng/mL IQR [0.015–0.514]; P = 0.27). No significant change of laboratory parameters e. g. glomerular filtration rate, potassium level and creatinine levels were found in diabetes or non‐diabetes patients. Comparing further echocardiography data, left atrial surface area, right atrial surface area, E/A ratio did not show a significant change either in the diabetes or non‐diabetes group. However, the tricuspid annular plane systolic excursion was significantly increased in non‐diabetes mellitus patients (from 17 mm IQR [3–31] to 18 mm [2.5–31]; P = 0.04), and not in diabetic s patients (17.5 mm IQR [8–30] to 18 mm IQR [14–31]; P = 0.70); the systolic pulmonary artery pressure remained unchanged in both groups. During follow‐up, a similar rate of ventricular tachyarrhythmias was observed in both groups. The congestion rate decreased significantly in both groups, in diabetes patients (44.4% before sacubitril/valsartan and 13.5% after 24 months treatment; P = 0.0009) and in non‐diabetic patients (28.4% before sacubitril/valsartan and 8.4% after 24 months treatment; P = 0.0004). The all‐cause mortality rate was higher in patients with diabetes mellitus as compared with those without diabetes (25% vs. 8.1%; P < 0.01). Conclusions: Sacubitril/valsartan reverses cardiac remodelling in non‐diabetes patients. However, it reduces the congestion rate in diabetes and non‐diabetes patients. The rates of ventricular tachyarrhythmias were similar in DM compared with non‐DM over follow‐up. The mortality rate remained to be over follow‐up higher in diabetes patients compared with non‐diabetes; however, it was lower compared with published data on diabetes and concomitant HFrEF not treated with sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

Aims: Sacubitril/valsartan has changed the treatment of heart failure with reduced ejection fraction (HFrEF), due to the positive effects on morbidity and mortality, partly mediated by left ventricular (LV) reverse remodelling (LVRR). The aim of this multicenter study was to identify echocardiographic predictors of LVRR after sacubitril/valsartan administration. Methods and results: Patients with HFrEF requiring therapy with sacubitril/valsartan from 13 Italian centres were included. Echocardiographic parameters including LV global longitudinal strain (GLS) and global peak atrial longitudinal strain by speckle tracking echocardiography were measured to find the predictors of LVRR [= LV end‐systolic volume reduction ≥10% and ejection fraction (LVEF) improvement ≥10% at follow‐up] at 6 month follow‐up as the primary endpoint. Changes in symptoms [New York Heart Association (NYHA) class] and neurohormonal activations [N‐terminal pro‐brain natriuretic peptide (NT‐proBNP)] were also evaluated as secondary endpoints; 341 patients (excluding patients with poor acoustic windows and missing data) were analysed (mean age: 65 ± 10 years; 18% female, median LVEF 30% [inter‐quartile range: 25−34]). At 6 month follow‐up, 82 (24%) patients showed early complete response (LVRR and LVEF ≥ 35%), 55 (16%) early incomplete response (LVRR and LVEF < 35%), and 204 (60%) no response (no LVRR and LVEF < 35%). Non‐ischaemic aetiology, a lower left atrial volume index, and a higher GLS were all independent predictors of LVRR at multivariable logistic analysis (all P < 0.01). A baseline GLS < −9.3% was significantly associated with early response (area under the curve 0.75, P < 0.0001). Left atrial strain was the best predictor of positive changes in NYHA class and NT‐proBNP (all P < 0.05). Conclusions: Speckle tracking echocardiography parameters at baseline could be useful to predict LVRR and clinical response to sacubitril–valsartan and could be used as a guide for treatment in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Abstract Aims This study aims to investigate the role of echocardiographically determined left ventricular output indices on sacubitril/valsartan titration in a cohort of outpatients with heart failure and reduced ejection fraction (HFrEF). Methods and results We analysed 106 HFrEF patients who underwent echocardiography examination up to 1 week before starting treatment with sacubitril/valsartan. For each patient, a comprehensive list of clinical and laboratory parameters was collected, and stroke volume index (SVi), cardiac index, and flow rate were calculated. The primary endpoint was the occurrence of complete titration of sacubitril/valsartan. The secondary endpoint was the incidence of adverse events (hypotension and renal adverse events). Univariate and multivariate logistic regression were used to identify variables associated with the primary and secondary endpoints. Mean age of patients was 73.7 ± 10.4 years, 72 patients (71.7%) had ischaemic aetiology of HF, and mean ejection fraction was 29.4 ± 5.9%. At multivariate analysis, SVi [odds ratio (OR) 1.43 per 5 mL/m2 increase, 95% confidence interval (CI) 1.03–1.97; P = 0.028], serum sodium (OR 1.18, 95% CI 1.02–1.37; P = 0.022), and haemoglobin (OR 1.73, 95% CI 1.25–2.40; P = 0.001) were found to be independent predictors of titration during follow‐up. Multivariate analysis for the secondary endpoint showed SVi (OR 0.63 per 5 mL/m2 increase, 95% CI 0.44–0.90; P = 0.012) and New York Heart Association Class III (OR 2.65, 95% CI 1.07–6.5; P = 0.034) to be associated with hypotension. Conclusions Stroke volume index is positively associated with complete titration of sacubitril/valsartan. Patients with low SVi are more prone to experience hypotension during titration

Aims: Acute viral myocarditis (AVMC) is the aetiology of heart failure (HF) with few specific treatments. The improvement of left ventricular ejection fraction (LVEF) is a critical predictor for the prognosis of AVMC. LCZ696 is a drug used in HF to improve LVEF, with a few research on AVMC. In this research, we evaluated the effects and mechanism of LCZ696 in improving LVEF in AVMC. Methods: Eighty 4‐week‐old male BALB/c mice were randomly divided into four groups of 20: Sham; Sham + LCZ696 (60 mg/kg/d); AVMC; AVMC + LCZ696. The above experiments were repeated by CVB3‐infected HL‐1 and Mdivi‐1 to down‐regulated dynamin‐related protein 1(Drp1). Adeno‐associated virus 9 (AAV9) with enhanced green fluorescent proteins (GFP) was injected to produce Drp1‐overexpression mice and set up four groups: AVMC group, AVMC + AAV group, AVMC + LCZ696 group, and AVMC + LCZ696 + AAV group (n = 20 in each group). LVEF was evaluated by echocardiography at a similar heart rate (HR) at d7, Drp1 (p‐Drp1), inflammation and apoptosis by histology and Western blot (WB), and mitochondrial by electron microscopy. Results: Cardiac function were injured in AVMC that LCZ696 reversed (LVEF, %: Sham: 68.99 ± 9.67; Sham + LCZ696: 71.96 ± 6.20; AVMC: 30.95 ± 6.40*; AVMC + LCZ696: 68.99 ± 9.67*#, *P < 0.05 vs. Sham, #P < 0.05 vs. AVMC). LCZ696 attenuated p‐Drp1 expression, inflammation, apoptosis, and mitochondrial fission (p‐Drp1/Drp1: Sham: 1; Sham + LCZ696: 1.37 ± 0.22; AVMC: 2.29 ± 0.36*; AVMC+LCZ696: 1.43 ± 0.08*#, *P < 0.05 vs. Sham, #P < 0.05 vs. AVMC). Some of the above results were repeated in CVB3‐infected HL‐1 cells and Mdivi‐1. AAV increased Drp1 expression and mitochondrial fission, inflammatory, and apoptosis. Compared with the AVMC + AAV group, the LVEF increased from 24.44 ± 0.03% to 32.33 ± 0.05% in the AVMC + LCZ696 + AAV group(P < 0.05), p‐Drp1/Drp1 decreased from 0.54 ± 0.12 to 0.42 ± 0.09*, and IL‐6, c‐IL‐1β, and c‐caspase‐3/caspase‐3 decreased from 1.07 ± 0.22 to 0.72 ± 0.08*, from 1.03 ± 0.14 to 0.79 ± 0.09*, and from 4.69 ± 0.29 to 0.92 ± 0.13*, respectively (*P < 0.05). Conclusions: LCZ696 has a protective effect on AVMC by improving LVEF and reducing inflammation and apoptosis, which may be due to the inhibition of Drp1‐mediated mitochondrial fission. [ABSTRACT FROM AUTHOR]

Aims: Inhibitors of SGLT2 (SGLT2i) have shown a positive impact in patients with chronic heart failure and reduced ejection fraction (HFrEF). Nonetheless, the direct effects of SGLT2i on cardiac cells and how their association with main drugs used for HFrEF affect the behaviour and signalling pathways of myocardial fibroblasts are still unknown. We aimed to determine the effects of dapagliflozin alone and in combination with sacubitril/valsartan (LCZ696) or spironolactone on the function of myocardial fibroblasts of patients with heart failure and reduced ejection fraction (HFrEF). Methods and results: Myocardial fibroblasts isolated from HFrEF patients (n = 5) were treated with dapagliflozin alone (1 nM–1 μM) or combined with LCZ696 (100 nM) or spironolactone (100 nM). The migratory rate was determined by wound‐healing scratch assay. Expression of heart failure (HF) markers and signalling pathways activation were analysed with multiplexed protein array. Commercially available cardiac fibroblasts from healthy donors were used as Control (n = 4). Fibroblasts from HFrEF show higher migratory rate compared with control (P = 0.0036), and increased expression of HF markers [fold‐change (Log2): COL1A1–1.3; IL‐1b–1.9; IL‐6–1.7; FN1–2.9 (P < 0.05)]. Dapagliflozin slowed the migration rate of HFrEF fibroblasts in a dose‐dependent manner and markedly decreased the expression of IL‐1β, IL‐6, MMP3, MMP9, GAL3, and FN1. SGLT2i had no effect on control fibroblasts. These effects were associated with decreased phosphorylation of AKT/GSK3 and PYK2 kinases and the signal transducer and activator of transcription (STAT). A combination of dapagliflozin + LCZ696 further decreased fibroblast migration, although it did not have a significant effect on the regulation of signalling pathways and the expression of biomarkers induced by SGLT2 inhibition alone. In contrast, the combination of dapagliflozin + spironolactone did not change the migration rate of fibroblast but significantly altered SGLT2i responses on MMP9, GAL3, and IL‐1b expression, in association with increased phosphorylation of the kinases AKT/GSK3 and ERK1/2. Conclusions: SGLT2i, LCZ696, and spironolactone modulate the function of isolated myocardial fibroblasts from HFrEF patients through the activation of different signalling pathways. The combination of SGLT2i + LCZ696 shows an additive effect on migration, while spironolactone modifies the signalling pathways activated by SGLT2i and its beneficial effects of biomarkers of heart failure. [ABSTRACT FROM AUTHOR]

Aims: Diabetes mellitus is associated with worse outcomes and lower attainment of disease‐modifying therapies in patients with heart failure with reduced ejection fraction (HFrEF). This post hoc analysis of TRANSITION compared the patterns of tolerability and uptitration of sacubitril/valsartan in patients with HFrEF stabilized after hospital admission due to acute decompensated HF depending on the presence or absence of diabetes as a co‐morbidity. Methods: TRANSITION, a randomized, open‐label study compared sacubitril/valsartan initiation pre‐discharge vs. post‐discharge (up to14 days) in 991 patients hospitalized for acutely decompensated HFrEF. The impact of diabetes status on tolerability and safety was studied at 10‐week and 26‐week post‐randomization. Results: Among the 991 patients analysed at baseline, 460 (46.4%) had diabetes and exhibited a higher risk profile. At 10 weeks, sacubitril/valsartan target dose (97/103 mg bid) was achieved in a similar proportion of patients in each subgroup, when initiated pre‐discharge or post‐discharge respectively [diabetes subgroup: 47% (n = 105/226) vs. 50% (n = 115/228); relative risk ratio (RRR), 0.923; P = 0.412; non‐diabetes subgroup: 45% (n = 119/267) vs. 51% (n = 133/261); RRR, 0.878; P = 0.155]. The proportions of patients achieving and maintaining either 49/51 mg or 97/103 mg bid [diabetes subgroup: 61.1% (n = 138/226) vs. 67.5% (n = 154/228); RRR, 0.909; P = 0.175; non‐diabetes subgroup: 62.9% [n = 168/267] vs 69.3% [n = 181/261]; RRR, 0.906; P = 0.118] or any dose for ≥2 weeks leading to Week 10 [diabetes subgroup: 85% (n = 192/226) vs. 88.2% (n = 201/228); RRR, 0.966; P = 0.356; non‐diabetes subgroup: 86.9% (n = 232/267) vs. 90.8% (n = 237/261); RRR, 0.963; P = 0.215] were also similar in each subgroup, when initiated pre‐discharge or post‐discharge, respectively. At 10 weeks, hypotension and renal dysfunction rates were similar, although hyperkalaemia was higher among patients with diabetes (15.9% vs. 9.5%). The rate of permanent discontinuation due to adverse events was similar in the diabetes and non‐diabetes subgroups at 10 weeks, respectively: pre‐discharge (7.5% vs. 7.1%) or post‐discharge (5.7% vs. 4.2%). Similar patterns of uptitration and tolerability were observed at 26 weeks. Cardiac biomarkers including NT‐proBNP (P < 0.005) and hs‐TnT (P < 0.005) reduced significantly from baseline levels in both subgroups at Weeks 4 and 10; however, the response was greater among patients without diabetes. Mortality (diabetes vs. non‐diabetes subgroups: 3.3% vs 4.0%; P = 0.438) and HF rehospitalization (diabetes vs. non‐diabetes subgroups: 36.3% vs. 33.0%; P = 0.295) did not differ between the groups at 26 weeks. Conclusions: Despite a higher risk profile among patients with diabetes, sacubitril/valsartan initiation either before or shortly after discharge in hospitalized patients with HFrEF resulted in comparable rates of dose up‐titration and tolerability as in those without diabetes. [ABSTRACT FROM AUTHOR]

Aims: Sacubitril/valsartan (SAC/VAL) has been used in patients with heart failure and reduced ejection fraction (HFrEF), and cardiac resynchronization therapy (CRT) could benefit the HFrEF patients with wide QRS durations. This study aimed to evaluate the clinical impacts of SAC/VAL on reverse cardiac remodelling in CRT‐eligible and CRT‐ineligible HFrEF patients with different QRS durations. Methods and results: The TAROT‐HF study was a multicentre, observational study enrolling patients who initiated SAC/VAL from 10 hospitals since 2017. Patients with baseline left ventricular ejection fraction (LVEF) ≤ 35% were classified into two groups: (i) Group 1: CRT‐eligible group, patients with left bundle branch block (LBBB) morphology plus QRS duration ≥130 ms or non‐LBBB morphology plus QRS duration ≥150 ms; and (ii) Group 2: CRT‐ineligible group. Propensity score matching was performed to adjust for confounders, and 1168 patients were analysed. Baseline characteristics were comparable between the two groups. The improvements in LVEF and left ventricular end‐systolic volume index (LVESVi) were more significant in Group 2 than in Group 1 after 1 year SAC/VAL treatment (LVEF: 8.4% ± 11.3% vs. 4.5% ± 8.1%, P < 0.001; change percentages in LVESVi: −14.4% ± 25.9% vs. −9.6% ± 23.1%, P = 0.004). LVEF improving to ≥50% in Groups 1 and 2 constituted 5.2% and 20.2% after 1 year SAC/VAL treatment (P < 0.001). Multivariate analyses showed that wide QRS durations were negatively associated with the reverse cardiac remodelling in these HFrEF patients with SAC/VAL treatment. Conclusion: Despite SAC/VAL treatment, wide QRS durations are associated with lower degrees of left ventricular improvement than narrow ones in the HFrEF patients. Optimal intervention timing for the CRT‐eligible patients requires further investigation. [ABSTRACT FROM AUTHOR]

Heart failure (HF) treatment has changed substantially over the last 30 years, leading to significant reductions in mortality and hospital admissions in patients with HF with reduced ejection fraction (HFrEF). Currently, the optimization of guideline‐directed chronic HF therapy remains the mainstay to further improve quality of life, mortality, and HF hospitalizations for patients with HFrEF. The angiotensin receptor‐neprilysin inhibitor sacubitril/valsartan (S/V) has an important role in the treatment of patients with HFrEF. The PARADIGM‐HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) randomized controlled trial has established solid evidence for the treatment of HFrEF in various subgroups. Apart from HFrEF, several studies have been conducted using S/V in various indications: patients hospitalized with acute decompensated HF, HF with preserved ejection fraction, acute myocardial infarction with reduced ejection fraction, uncontrolled and resistant hypertension, and chronic kidney disease. Data from the German Institute for Drug Use Evaluation reveal that implementation of S/V has increased steadily over time and, by the end of 2021, an estimated 266 000 patients were treated with S/V in Germany. The estimated cumulative real‐world patient exposure is >5.5 million patient‐treatment years worldwide. The number of patients treated with S/V largely exceeds the number of patients treated in clinical trials, and the current indication for S/V is larger than the strict inclusion/exclusion criteria of the randomized trials. Especially elderly patients, women, and patients with more and more severe comorbidities are underrepresented in the clinical trials. We therefore aimed to summarize the importance of S/V in HF in terms of efficacy and safety in clinical trials and daily clinical practice. [ABSTRACT FROM AUTHOR]

Aims: ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause‐specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods: ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office‐based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non‐S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. Results: At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non‐S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non‐S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient‐years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient‐years in the non‐S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non‐S/V, S/V, and rS/V groups, respectively. Conclusions: This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real‐world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment. [ABSTRACT FROM AUTHOR]

Aims: The angiotensin receptor‐neprilysin inhibitor (ARNI) sacubitril/valsartan (Sac/Val) demonstrated to be superior to enalapril in reducing hospitalizations, cardiovascular and all‐cause mortality in patients with ambulatory heart failure and reduced ejection fraction (HFrEF), in particular when it is maximally up‐titrated. Unfortunately, the target dose is achieved in less than 50% of HFrEF patients, thus undermining the beneficial effects on the outcomes. In this study, we aimed to evaluate the role of Sac/Val and its titration dose on reverse cardiac remodelling and determine which echocardiographic index best predicts the up‐titration success. Methods and results: From January 2020 to June 2021, we retrospectively identified 95 patients (65.6 [59.1–72.8] years; 15.8% females) with chronic HFrEF who were prescribed Sac/Val from the HF Clinics of 5 Italian University Hospitals and evaluated the tolerability of Sac/Val high dose (the ability of the patient to achieve and stably tolerate the maximum dose) as the primary endpoint in the cohort. We used a multivariable logistic regression analysis, with a stepwise backward selection method, to determine the independent predictors of Sac/Val maximum dose tolerability, using, as candidate predictors, only variables with a P‐value < 0.1 in the univariate analyses. Candidate predictors identified for the multivariable backward logistic regression analysis were age, sex, body mass index (BMI), chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), dyslipidaemia, atrial fibrillation, systolic blood pressure (SBP), baseline tolerability of ACEi/ARBs maximum dose, left ventricle global longitudinal strain (LVgLS), LV ejection fraction (EF), tricuspid annulus plane systolic excursion (TAPSE), right ventricle (RV) fractional area change (FAC), RV global and free wall longitudinal strain (RVgLS and RV‐FW‐LS). After the multivariable analysis, only one categorical (ACEi/ARBs maximum dose at baseline) and three continuous (younger age, higher SBP, and higher TAPSE), resulted significantly associated with the study outcome variable with a strong discriminatory capacity (area under the curve 0.874, 95% confidence interval (CI) (0.794–0.954) to predict maximum Sac/Val dose tolerability. Conclusions: Our study is the first to analyse the potential role of echocardiography and, in particular, of RV dysfunction, measured by TAPSE, in predicting Sac/Val maximum dose tolerability. Therefore, patients with RV dysfunction (baseline TAPSE <16 mm, in our cohort) might benefit from a different strategy to titrate Sac/Val, such as starting from the lowest dose and/or waiting for a more extended period of observation before attempting with the higher doses. [ABSTRACT FROM AUTHOR]

Aims: Prior studies have not fully characterized the haemodynamic effects of the angiotensin receptor‐neprilysin inhibitor (ARNI) sacubitril/valsartan in heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF–PH). The aim of the Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device (ARNIMEMS‐HFpEF) study is to assess pulmonary artery pressure (PAP) dynamics by means of implanted PAP monitors in patients with HFpEF–PH treated with sacubitril/valsartan. Methods and results: This single‐arm, investigator‐initiated, interventional study included 14 consecutive ambulatory symptomatic HFpEF–PH patients who underwent CardioMEMS implantation prior to enrolment [mean ejection fraction 60.4 ± 7.2%, baseline mean PAP (mPAP) 33.9 ± 7.6 mmHg]. Daily PAP values were examined during three periods: a 6 week period after CardioMEMS implantation and before sacubitril/valsartan treatment (pre‐ARNI), a 6 week period with sacubitril/valsartan treatment (ARNI ON), and a 6 week period of sacubitril/valsartan withdrawal (ARNI OFF). The primary endpoint was change in mPAP with and without sacubitril/valsartan. Secondary endpoints included changes in 6 min walking distance, B‐line sum in lung ultrasound, and quality of life (QoL). During the study period, 1717 mPAP measurements were recorded. Between pre‐ARNI vs. ARNI ON, mPAP significantly declined by −4.99 mmHg [95% confidence interval (CI) −5.55 to −4.43]. Between ARNI ON vs. ARNI OFF, mPAP significantly increased by +2.84 mmHg [95% CI +2.26 to +3.42]. Between pre‐ARNI vs. ARNI ON, we found an improvement in 6 min walking distance, B‐lines, and QoL. Mean loop diuretic management did not differ between periods. Conclusions: Sacubitril/valsartan significantly reduced mPAP in patients with HFpEF–PH, independent of loop diuretic management, together with improvement in functional capacity, lung congestion, and QoL. Sacubitril/valsartan may be a therapeutic alternative in HFpEF–PH. [ABSTRACT FROM AUTHOR]

Aims: We evaluated the clinical outcomes and trajectory of cardiac reverse remodelling according to the timing of sacubitril/valsartan (Sac/Val) use in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods and results: Patients with de novo HFrEF who used Sac/Val between June 2017 and October 2019 were retrospectively enrolled. Patients were grouped into the earlier use group (initiation of Sac/Val < 3 months after the first HFrEF diagnosis) and the later use group (initiation of Sac/Val ≥ 3 months after the first HFrEF diagnosis). Primary outcome was a composite of HF hospitalization and cardiac death. Secondary outcomes were HF hospitalization, cardiac death, all‐cause death, significant ventricular arrhythmia (ventricular tachycardia or ventricular fibrillation), and echocardiographic evidence of cardiac reverse remodelling including left ventricular ejection fraction (LVEF) change during follow‐up. Among 115 enrolled patients, 67 were classified in the earlier use group, and 48 were classified in the later use group. Mean period of HFrEF diagnosis to Sac/Val use was 52.1 ± 14.3 days in the earlier use group, and 201.8 ± 127.3 days in the later use group. During the median follow‐up of 721 days, primary outcome occurred in 21 patients (18.3%). The earlier use group experienced significantly fewer primary outcome than the later use group (10.4% vs. 29.2%, P = 0.010). The Kaplan–Meier survival curve showed better event‐free survival in the earlier use group than in the later use group (log rank = 0.017). There were no significant differences in cardiac death, all‐cause death, and ventricular arrhythmia between two groups (1.5% vs. 2.1%, P = 0.811; 1.5% vs. 4.2%, P = 0.375; 3.0% vs. 0%, P = 0.227, respectively). Despite a significantly lower baseline LVEF in the earlier use group (21.3 ± 6.4% vs. 24.8 ± 7.9%, P = 0.012), an early prominent increase of LVEF was noted before 6 months (35.2 ± 11.9% vs. 27.8 ± 8.8%, P = 0.007). A delayed improvement of LVEF in the later use group resulted in similar LVEF at last follow‐up in both groups (40.7 ± 13.4% vs. 39.4 ± 10.9%, P = 0.686). Although the trajectory of left ventricular remodelling showed similar pattern in two groups, left atrial (LA) reverse remodelling was less prominent in the later use group during the follow‐up period (final LA volume index: 43.6 ± 14.3 mL/m2 vs. 55.2 ± 17.1 mL/m2, P = 0.011). Conclusions: Earlier use of Sac/Val was related with better clinical outcome and earlier left ventricular reverse remodelling. Remodelling of LA was less prominent in the later use group implying delayed response in diastolic function. [ABSTRACT FROM AUTHOR]

Aims: Radiofrequency catheter ablation (RFCA) is now an established therapeutic option for patients with atrial fibrillation (AF), but the long‐term recurrence rate of AF is still high. Sacubitril/valsartan (Sac/Val) is superior to valsartan in attenuating ventricular remodelling and improving clinical outcomes in heart failure patients, but whether this additional benefit exists in reversing atrial remodelling and reducing AF recurrence of RFCA‐treated AF patients remains uncovered. Methods and results: Patients that had undergone RFCA were enrolled and randomly assigned 1:1 to valsartan (160 mg/day) or Sac/Val (200 mg/day) treatment group, in addition to other standard treatment of AF. Patients were followed up for 24 weeks. Echocardiography and ambulatory Holter monitoring for 24 h was performed at 24 weeks after RFCA. The primary end point was the change of atrial diameter from baseline to 24 weeks after RFCA. Second end points included the recurrence rate of AF, all‐cause hospitalization and all‐cause death. A total of 64 AF patients were enrolled, 32 of which received Sac/Val and 32 received valsartan treatment. There was no difference in the age (64.8 ± 9.8 vs. 63.7 ± 9.0, P = 0.634), gender (per cent of male: 59.4% vs. 50.0%, P = 0.616), heart rate (84.7 ± 4.1 b.p.m. vs. 80.9 ± 2.6 b.p.m., P = 0.428), systolic (127.5 ± 15.4 mmHg vs. 130.0 ± 17.8 mmHg, P = 0.549) or diastolic (81.7 ± 9.8 mmHg vs. 79.9 ± 12.6, P = 0.537) blood pressure upon admission between valsartan and Sac/Val treatment groups. The percentage of persistent AF was also comparable (43.8% vs. 53.1%, P = 0.617) in both treatment groups. Patients receiving Sac/Val treatment displayed significant decrease in the left atrial diameter (4.3 ± 0.5 cm to 3.8 ± 0.5 cm, P < 0.001), volume index (48.0 ± 6.4 mL/m2 to 41.7 ± 7.0 mL/m2, P < 0.001), and right atrial diameter (4.4 ± 0.8 cm to 3.9 ± 0.7 cm, P = 0.017) from baseline to 24 weeks after RFCA. This effect was not observed in valsartan treatment group. There was a numerical decrease in AF recurrence rate in the Sac/Val group compared with valsartan group (9.4% vs. 15.6%), although this difference did not reach a statistical significance (P = 0.708). No difference in all‐cause hospitalization rate (6.3% in each group) or all‐cause death rate (0% in each group) was observed. Conclusions: Our data indicate that Sac/Val is superior to valsartan in attenuating atrial structural remodelling in catheter ablation‐treated AF patients. [ABSTRACT FROM AUTHOR]

Aims This study aims to investigate the role of echocardiographically determined left ventricular output indices on sacubitril/valsartan titration in a cohort of outpatients with heart failure and reduced ejection fraction (HFrEF). Methods and results We analysed 106 HFrEF patients who underwent echocardiography examination up to 1 week before starting treatment with sacubitril/valsartan. For each patient, a comprehensive list of clinical and laboratory parameters was collected, and stroke volume index (SVi), cardiac index, and flow rate were calculated. The primary endpoint was the occurrence of complete titration of sacubitril/valsartan. The secondary endpoint was the incidence of adverse events (hypotension and renal adverse events). Univariate and multivariate logistic regression were used to identify variables associated with the primary and secondary endpoints. Mean age of patients was 73.7 ± 10.4 years, 72 patients (71.7%) had ischaemic aetiology of HF, and mean ejection fraction was 29.4 ± 5.9%. At multivariate analysis, SVi [odds ratio (OR) 1.43 per 5 mL/m2 increase, 95% confidence interval (CI) 1.03–1.97; P = 0.028], serum sodium (OR 1.18, 95% CI 1.02–1.37; P = 0.022), and haemoglobin (OR 1.73, 95% CI 1.25–2.40; P = 0.001) were found to be independent predictors of titration during follow-up. Multivariate analysis for the secondary endpoint showed SVi (OR 0.63 per 5 mL/m2 increase, 95% CI 0.44–0.90; P = 0.012) and New York Heart Association Class III (OR 2.65, 95% CI 1.07–6.5; P = 0.034) to be associated with hypotension. Conclusions Stroke volume index is positively associated with complete titration of sacubitril/valsartan. Patients with low SVi are more prone to experience hypotension during titration [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) is a systemic inflammatory disorder with infections being an important cause of morbidity and mortality. We asked if HF patients have a higher susceptibility to infections compared with the general population and if a subtle secondary immunodeficiency facilitates infectious complications. Methods and results: In a cohort of 92 patients with HF with reduced ejection fraction, we analysed recirculating lymphocyte subpopulations, serum immunoglobulin levels, and specific antibody titres against pneumococcal antigens. We quantified susceptibility to infections of the respiratory tract with a validated questionnaire and compared it to the general population. Susceptibility to infections of the respiratory tract was comparable in HF patients and the general population. Hypogammaglobulinaemia was present in 16% of HF patients, but anti‐pneumococcal titres showed no evidence of specific secondary antibody deficiency. Relative lymphopaenia in our HF cohort was due to B lymphocytopenia with a relative reduction in naive B‐cells and expansion of memory B‐cells while CD4+ and CD8+ T‐lymphocytes as well as NK‐cell counts were comparable between HF and healthy donors. The intake of the angiotensin receptor neprilysin (CD10) inhibitor (ARNI) sacubitril/valsartan was associated with increased B‐lymphocyte counts, possibly by an increased output of CD10+ transitional B lymphocytes from the bone marrow. Conclusion: Despite a reduction of B lymphocytes in HF and mild hypogammaglobulinaemia, patients showed no evidence of secondary immunodeficiency or increased susceptibility to infections. The relevance of B‐cell lymphopenia in HF patients and modulation of B‐cell counts under ARNI treatment remains to be investigated. [ABSTRACT FROM AUTHOR]

Aim: Echo‐derived haemodynamic classification, based on forward‐flow and left ventricular (LV) filling pressure (LVFP) correlates, has been proposed to phenotype patients with heart failure and reduced ejection fraction (HFrEF). To assess the prognostic relevance of baseline echocardiographically defined haemodynamic profile in ambulatory HFrEF patients before starting sacubitril/valsartan. Methods and results: In our multicentre, open‐label study, HFrEF outpatients were classified into 4 groups according to the combination of forward flow (cardiac index; CI:< or ≥2.0 L/min/m2) and early transmitral Doppler velocity/early diastolic annular velocity ratio (E/e′: ≥ or <15): Profile‐A: normal‐flow, normal‐pressure; Profile‐B: low‐flow, normal‐pressure; Profile‐C: normal‐flow, high‐pressure; Profile‐D: low‐flow, high‐pressure. Patients were started on sacubitril/valsartan and followed‐up for 12.3 months (median). Rates of the composite of death/HF‐hospitalization were assessed by multivariable Cox proportional‐hazards models. Twelve sites enrolled 727 patients (64 ± 12 year old; LVEF: 29.8 ± 6.2%). Profile‐D had more comorbidities and worse renal and LV function. Target dose of sacubitril/valsartan (97/103 mg BID) was more likely reached in Profile‐A (34%) than other profiles (B: 32%, C: 24%, D: 28%, P < 0.001). Event‐rate (per 100 patients per year) progressively increased from Profile‐A to Profile‐D (12.0%, 16.4%, 22.9%, and 35.2%, respectively, P < 0.0001). By covariate‐adjusted Cox model, profiles with low forward‐flow (B and D) remained associated with poor outcome (P < 0.01). Adding this categorization to MAGGIC‐score and natriuretic peptides, provided significant continuous net reclassification improvement (0.329; P < 0.001). Intermediate and high‐dose sacubitril/valsartan reduced the event's risk independently of haemodynamic profile. Conclusions: Echocardiographically‐derived haemodynamic classification identifies ambulatory HFrEF patients with different risk profiles. In real‐world HFrEF outpatients, sacubitril/valsartan is effective in improving outcome across different haemodynamic profiles. [ABSTRACT FROM AUTHOR]

Aims: The angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, has been shown to be effective in treatment of patients with heart failure (HF), but limited data are available in patients with advanced disease. This retrospective observational study assessed the effects of ARNI treatment in patients with advanced HF. Methods and results: We reviewed medical records of all advanced HF patients evaluated at our centre for unconventional therapies from September 2016 to January 2019. We studied 44 patients who started ARNI therapy and who had a haemodynamic assessment before beginning ARNI and after 6 ± 2 months. The primary endpoint was variation in pulmonary pressures and filling pressures at 6 months after starting ARNI therapy. Mean patient age was 51.6 ± 7.4 years; 84% were male. At 6 ± 2 months after starting ARNI, there was significant reduction of systolic pulmonary artery pressure [32 mmHg, interquartile range (IQR) 27–45 vs. 25 mmHg, IQR 22.3–36.5; P < 0.0001] and mean pulmonary artery pressure (20 mmHg, IQR 15.3–29.8 vs. 17 mmHg, IQR 13–24.8; P = 0.046). Five of 22 patients (23%) were deferred from the heart transplant list because of improvement, whereas four were listed de novo. After 23 ± 9 months, three patients were treated with a left ventricular assist device implantation, whereas six patients underwent heart transplantation (one in emergency conditions for refractory ventricular tachycardia). Conclusions: Sacubitril/valsartan is effective in reducing filling pressures and pulmonary pressures in patients with advanced HF. The absence of adverse events during follow‐up suggests that sacubitril/valsartan is safe and well‐tolerated in this cohort of patients. [ABSTRACT FROM AUTHOR]

Aims: In the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON‐HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios. Methods and results: Eligibility was assessed in the Karolinska‐Rennes study (acute HFpEF, LVEF ≥ 45%, and N‐terminal pro‐B‐type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (<54% in women and <52% in men); and (iv) LVEF below mean of normal range (<64% in women and <62% in men). Among 425 patients [age 78 (72–83) years, 57% women, 28% LVEF ≤ 57% (median in PARAGON‐HF), the trial scenario, identified 34% as eligible. Left atrial enlargement and/or left ventricular hypertrophy were present in 99%. Inclusion criteria not met were diuretic treatment and New York Heart Association class. Important exclusion criteria were estimated glomerular filtration rate <30 mL/min/1.73 m2, haemoglobin <10 g/day, and cancer. In the pragmatic scenario, 63% were eligible. In LVEF below lower limit of normal range, 5.4% were eligible, and in LVEF below mean of normal range, 41% were eligible. In patients with LVEF ≤ 57%, eligibility was 42%, 69%, 21%, and 91% according to the trial scenario, pragmatic scenario, LVEF below lower limit of normal range, and LVEF below mean of normal range, respectively. Conclusions: In real‐world HFpEF (LVEF ≥ 45%) with N‐terminal pro‐B‐type natriuretic peptide and cardiac structure/function assessed, eligibility for sacubitril/valsartan was according to PARAGON‐HF complete criteria 34%, pragmatic criteria 63%, LVEF below lower limit of normal range 5.4%, and LVEF below mean of normal range 41%. Cardiac structural impairment was almost ubiquitous. Ineligibility was more due to exclusion criteria than failing to meet inclusion criteria. [ABSTRACT FROM AUTHOR]

Aims: The angiotensin receptor–neprilysin inhibitor (ARNI), sacubitril/valsartan, confers additional protective effects compared with angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers (ACEIs/ARBs) in terms of reversed left ventricular (LV) remodelling and improves the prognosis of patients with heart failure (HF). However, few studies have examined the effects of ARNI on the left atrium. Accordingly, this study compared the effects of ARNI and ACEI/ARB on left atrial (LA) remodelling in heart failure with reduced ejection fraction (HFrEF). Methods and results: This was a single‐centre retrospective study of patients with HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University between 26 February 2016 and 8 July 2020. Patients were classified into ARNI and ACEI/ARB groups and further subgroups based on the left atrial volume index (LAVI): mildly abnormal (29 mL/m2 ≤ LAVI < 34 mL/m2), moderately abnormal (34 mL/m2 ≤ LAVI < 40 mL/m2), and severely abnormal (LAVI ≥ 40 mL/m2). The primary endpoint was changes in LA parameters by echocardiography. The secondary endpoint was all‐cause mortality. A total of 336 patients (mean age: 64.11 ± 12.86, 30.06% female) were included. Except those lost to follow‐up, 274 HFrEF patients remained, with 144 cases in the ARNI group and 130 cases in the ACEI/ARB group. Greater reductions from baseline were seen with ARNI in LA diameter (LAD) (P = 0.013, t‐test), superior and LA superior–inferior diameter (LASID) (P < 0.0001), LA transverse diameter (LATD) (P < 0.0001), LA volume (LAV) (P < 0.0001), LAVI (P < 0.0001), and LA sphericity index (LASI) (P < 0.0001). Over a mean follow‐up of 19.40 months, 97 patients (67.3%) in the ARNI group and 29 patients (22.3%) in the ACEI/ARB group showed LA reverse remodelling (LARR). Kaplan–Meier analysis showed significantly lower overall mortality in the ARNI group compared with the ACEI/ARB group (P = 0.048, log‐rank test). The mildly abnormal LAVI group of ARNI patients showed a reduction in mortality compared with ACEI/ARB patients (P = 0.044). However, no significant difference was observed for the moderately abnormal (P = 0.571) or severely abnormal LAVI groups (P = 0.609), suggesting that early initiation of ARNI was associated with a better prognosis. Conclusions: In this proof‐of‐concept study, ARNI use showed greater effects on LARR and was associated with a better prognosis compared with ACEI/ARB use in HFrEF. Early initiation of ARNI in the HF disease process may produce greater benefit, but this needs to be confirmed in future studies. [ABSTRACT FROM AUTHOR]

Aims: We aimed to investigate whether sacubitril–valsartan could further improve the prognosis, cardiac function, and left ventricular (LV) remodelling in patients following acute myocardial infarction (AMI). Methods and results: We searched the PubMed, Embase, Cochrane Library, and China National Knowledge Infrastructure (CNKI) from inception to 10 May 2021 to identify potential articles. Randomized controlled trials (RCTs) meeting the inclusion criteria were included and analysed. Thirteen RCTs, covering 1358 patients, were analysed. Compared with angiotensin‐converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB), sacubitril–valsartan did not significantly reduced the cardiovascular mortality [risk ratio (RR) 0.65, 95% confidence interval (CI) 0.22 to 1.93, P = 0.434] and the rate of myocardial reinfarction (RR 0.65, 95% CI 0.29 to 1.46, P = 0.295) of patients following AMI, but the rate of hospitalization for heart failure (HF) (RR 0.48, 95% CI 0.35 to 0.66, P < 0.001) and the change of LV ejection fraction (LVEF) [weighted mean difference (WMD) 5.49, 95% CI 3.62 to 7.36, P < 0.001] were obviously improved. The N‐terminal pro‐brain natriuretic peptide (NT‐ProBNP) level (WMD −310.23, 95% CI −385.89 to −234.57, P < 0.001) and the LV end‐diastolic dimension (LVEDD) (WMD −3.16, 95% CI −4.59 to −1.73, P < 0.001) were also significantly lower in sacubitril–valsartan group than in ACEI/ARB group. Regarding safety, sacubitril–valsartan did not increase the risk of hypotension, hyperkalaemia, angioedema, and cough. Conclusions: This meta‐analysis suggests that early administration of sacubitril–valsartan may be superior to conventional ACEI/ARB to decrease the risk of hospitalization for HF, improve the cardiac function, and reverse the LV remodelling in patients following AMI. [ABSTRACT FROM AUTHOR]

Abstract 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

Aims We systematically reviewed the European real-world evidence (RWE) about sacubitril-valsartan for heart failure with reduced ejection fraction. Methods and results Twenty-one articles, including 16 952 subjects, were identified until 31 October 2020. Taking as reference the PARADIGM-HF cohort, few baseline characteristics were presented in >80% of these studies, most often with high heterogeneity. In random-effects model meta-analysis, age was higher (mean difference +3.84, 95% CI 1.92–5.76), ischaemic aetiology (OR 0.76, 95% CI 0.64–0.91), hypertension (OR 0.55, 95% CI 0.37–0.82), and diabetes (OR 0.77, 95% CI 0.64–0.92) were less common, and the use of mineralocorticoid receptor antagonists was more frequent (OR 3.54, 95% CI 2.27–5.53) in real-life than in PARADIGM-HF. Other clinical and medical features were presented in 19–76% of the selected publications and suggested more severe heart failure with reduced ejection fraction. Sacubitril-valsartan was titrated to 97/103 mg b.i.d. in 35% (95% CI 23–47) and discontinued in 12.8% (95% CI 7.4–18.3) patients. When reported, the incidence of hyperkalaemia (six studies, no. 1076), all-cause mortality (five studies, no. 684), and any hospitalization (three studies, no. 390) was 12 (95% CI 5–19)/100 person-year, 8 (95% CI 4–12)/100 person-year, and 24 (95% CI 5–42)/100 person-year, respectively. Knowledge contribution, a metric measuring the proportion of RWE provided by each article based on the number of reported variables and the sample size, was 58.8% and 13.6% for the two biggest investigations (12 082 and 2037 patients), and <5% for all others (most with <100 subjects). Conclusions Limited-quality RWE indicates that there are important differences between European patients prescribed sacubitril-valsartan and the PARADIGM-HF population, including the frequency of target dose achievement. [ABSTRACT FROM AUTHOR]

Aims Takotsubo syndrome (TTS) is an acute potentially reversible cardiac syndrome characterized by variable regional myocardial akinesia that cannot be attributed to a culprit coronary artery occlusion. TTS is an important differential diagnosis of acute heart failure where brain natriuretic peptides are elevated. Sacubitril/valsartan is a novel and effective pharmacological agent for the treatment of patients with heart failure. Our aim was to explore whether treatment with sacubitril/valsartan could prevent isoprenaline-induced takotsubo-like phenotype in rats. Methods and results A total number of 186 Sprague–Dawley male rats were randomized to receive pretreatment with water (CONTROL, n = 62), valsartan (VAL, n = 62), or sacubitril/valsartan (SAC/VAL, n = 62) before receiving isoprenaline for induction of TTS. We recorded heart rate and blood pressure invasively. Cardiac morphology and function were evaluated by high-resolution echocardiography 90 min after the administration of isoprenaline. We documented the survival rate at the time of echocardiography. Compared with the CONTROL group, the SAC/VAL group had less pronounced TTS-like cardiac dysfunction and lower mortality rate, while the VAL group did not differ. Heart rate and blood pressure were not significantly different between the groups. Analysis of cardiac lipids was performed with mass spectrometry. The VAL and SAC/VAL groups had significantly higher levels of lysophosphatidylcholine (LPC), in particular LPC 18:1 and LPC 16:0. Conclusions Pretreatment with sacubitril/valsartan but not with valsartan reduces mortality and attenuates isoprenalineinduced apical akinesia in the TTS-like model in rats. Sacubitril/valsartan could be a potential treatment option in patients with TTS in humans. [ABSTRACT FROM AUTHOR]

Aims Sacubitril/valsartan significantly reduced heart failure (HF) hospitalization and cardiovascular mortality in a randomized controlled trial. However, little is known about real-world efficacy and safety of sacubitril/valsartan in Chinese patients with HF with reduced ejection fraction (HFrEF). We aimed to evaluate whether sacubitril/valsartan could improve cardiac function in Chinese patients with HFrEF in a tertiary hospital in China. Methods and results Patients with HFrEF receiving sacubitril/valsartan in our hospital between January 2018 and January 2020 were recruited in the present study. We retrospectively collected and analysed all clinical parameters at baseline and during follow-up. A total of 100 consecutive patients (73% male) with HFrEF were recruited in the present study. During a median follow-up period of 365 days [interquartile range (IQR), 346–378], a pronounced improvement of cardiac function was achieved. New York Heart Association classification was significantly improved (P < 0.001), and median N-terminal pro- B-type natriuretic peptides level significantly decreased from 3003 pg/mL (IQR, 1513–5404) to 2039 pg/mL (IQR, 921–3955) (P = 0.010). Mean left ventricular ejection fraction increased from 31 ± 6% to 38 ± 10% (P < 0.001) and median left ventricular end-diastolic diameter reduced from 63 mm (IQR, 59–67) to 60 mm (IQR, 55–68) (P = 0.001). Mean pulmonary arterial systolic pressure decreased significantly from 49 ± 13 mmHg to 44 ± 12 mmHg (P < 0.001) and median right ventricular end-diastolic diameter reduced from 23 mm (IQR, 21–26) to 22 mm (IQR, 20–25) (P = 0.030). After treatment with sacubitril/valsartan, mean estimated glomerular filtration rate significantly decreased (from 88.8 ± 22.4 mL/min to 71.8 ± 27.3 mL/min, P < 0.001). Median serum creatinine and median blood urea nitrogen levels significantly increased [from 0.9 mg/dL (IQR, 0.8–1.0) to 1.1 mg/dL (IQR, 0.9–1.3), P < 0.001, and from 6.8 mmol/L (IQR, 5.5–8.9) to 8.0 mmol/L (IQR, 6.6–10.3), P = 0.002, respectively]. The proportion of patients with chronic kidney disease Stage 3/4 increased significantly from 8% to 39% (P < 0.001). Conclusions In Chinese patients with HFrEF, sacubitril/valsartan treatment was associated with a pronounced improvement of cardiac function, but might be prone to a decrease in blood pressure and deterioration in renal function. [ABSTRACT FROM AUTHOR]

Aims: Optimizing medical cardiac treatment for sleep apnoea (SA) in patients with chronic heart failure and reduced ejection fraction (HFrEF) is an expert Grade C recommendation based on six studies encompassing a total of 67 patients only. Whether sacubitril–valsartan (SV), a cornerstone of HFrEF medical treatment, impacts SA is unknown and requires evaluation. Methods and results: The ENTRESTO‐SAS trial is a six‐centre, prospective, open‐label real‐life cohort study (NCT02916160). Ambulatory patients eligible for SV (i.e. HFrEF adults who remain symptomatic despite optimal treatment) were evaluated before and after 3 months of SV (including nocturnal ventilatory polygraphy); 118 patients were final analysed [median age was 66 (IQ25–75: 56–73) years, 81.4% male, 36.5% New York Heart Association III–IV, N‐terminal pro‐B‐type natriuretic peptide level of 1564 (701–3376) ng/L, left ventricular ejection fraction of 30 (25–34)%, 60.7% ischaemic HFrEF, 97.5% initially treated with angiotensin‐converting enzyme inhibitors or angiotensin II receptor blockers, 83.9% with beta‐blockers, 64.4% with mineralocorticoid receptor antagonists, and 74.6% with diuretics]. Three groups were defined according to initial central/obstructive apnoea–hypopnoea indices (AHIs): G1 (n = 49, AHIcentral ≥ 5/h and AHIobstructive < 15/h); G2 (n = 27, AHIobstructive ≥ 15/h); and G3 (n = 42, AHIcentral < 5/h and AHIobstructive < 15/h). At 3 months, the AHI (main predefined outcome) decreased significantly by −7.10/h (IQ25–75: −16.10 to 0.40; P < 0.001) in G1 + G2 without positive airway pressure treatment (45 patients, median initial AHI of 24.20 (IQ25–75: 16.40–43.50)/h). Of these, 24.4% presented an AHI decrease ≥50% and 37.78% had a final AHI < 15/h (tendency for improvement from an initial value of 20%: P = 0.0574). For G1 patients (n = 37), AHI significantly decreased from a median of 22.90 (16.00–43.50)/h to 19.20 (12.70–31.10)/h (P = 0.002). For G2 patients (n = 8), AHI decreased from a median of 30.10 (26.40–47.60)/h to 22.75 (14.60–36.90)/h (statistically non‐significant, P = 0.059). Conclusions: In this real‐life population, SV treatment for 3 months in SA patients is associated with a significant decrease in AHI. These results support the current guidelines that recommend first an optimization of the HFrEF treatment in patients with HFrEF and central SA. A potential positive airway pressure sparing effect merits further investigation. [ABSTRACT FROM AUTHOR]

Aims: Improving the health status (symptoms, function, and quality of life) of patients with heart failure with reduced ejection fraction (HFrEF) is a primary treatment goal. Angiotensin receptor neprilysin inhibitors (ARNI) improve short‐term health status in clinical practice, but the sustainability of these improvements is unknown. Methods and results: In CHAMP‐HF, a multicentre observational study of outpatients with HFrEF, patients initiated on ARNI were propensity score matched 1:2 to patients not using ARNI with Cox regression modelling time to ARNI initiation, adjusted for sociodemographic and clinical variables, medical history, medications, and baseline Kansas City Cardiomyopathy Questionnaire (KCCQ) scores. Repeated measures models for the overall KCCQ score and each domain compared the health status trajectories of patients initiated on ARNI vs. not. Among 3930 participants, 746 (19.0%) began ARNI, of whom 576 were matched to 1152 non‐ARNI patients. Prior to matching, participants initiated on ARNI were younger, non‐Hispanic, had lower EFs, more commonly had a history of ventricular arrhythmia, were less likely to be taking an ACEI/ARB, and more likely to be treated with beta‐blockers and mineralocorticoid receptor antagonists. There were no differences after matching. In the matched cohort, participants initiated on ARNI experienced improved health status by 3 months that persisted through 12 months [KCCQ Overall Summary Score (OSS) = 73.4 vs. 70.8; P < 0.001], with the largest benefit observed in the KCCQ Quality of Life domain (68.7 vs. 64.7; P < 0.001). Similar health status benefits were noted through 18 months (KCCQ‐OSS = 73.9 vs. 71.3; P < 0.001). A responder analysis showed that 12 patients would need to be initiated on ARNI for one to experience at least a large improvement (≥10 points) in health status benefit at 12 months. Conclusions: In outpatient practice, ARNI therapy was associated with improved health status by 3 months and continued to 18 months after initiating therapy. [ABSTRACT FROM AUTHOR]

Aims: We applied the restricted mean survival time (RMST) to analyse the survival data reported in the PARADIGM‐HT trial in which sacubitril + valsartan was studied in comparison with enalapril in patients with heart failure. The estimates of this parameter were compared with the published values of hazard ratio (HR). Methods: Two endpoints were evaluated: a composite of death or hospitalization and cardiovascular death. Our analyses were performed by considering the original follow‐up of 41.4 months and on the basis of a lifetime perspective. All statistical calculations were carried out using specific packages developed under the R‐platform. Results: According to our RMST analysis, the results for the composite endpoint in the comparison of sacubitril + valsartan vs. enalapril showed an improvement from 32.9 to 34.2 months (gain of 1.25 months). This result is based on a time horizon of 41.4 months. The results for the cardiovascular mortality endpoint showed a RMST of 37.2 months for sacubitril + valsartan vs. 36.2 for enalapril (gain of 0.96 months). In the two lifetime analyses, the improvements were much more relevant and yielded a gain of 25.8 months for the composite endpoint and 27.6 months for survival free from cardiovascular death. Conclusions: Using the data of the PARADIGM‐HT trial, our analysis confirmed that the RMST has documented advantages over the HR, particularly when the clinical study is characterized by a long follow‐up. The number needed to treat (NNT) has a more specific methodological role and cannot be replaced by the RMST. [ABSTRACT FROM AUTHOR]

Aims: Despite well‐established benefits of sacubitril/valsartan for cardiac reverse remodelling and the prognosis of patients with heart failure with reduced ejection fraction (HFrEF), there are some patients with limited therapeutic response, even with optimal therapy. We assessed the treatment response to sacubitril/valsartan in patients with HFrEF, focusing on the association between reverse remodelling and the prognosis. Methods and results: Using a retrospective cohort of consecutive patients with HFrEF treated with sacubitril/valsartan, we compared the time trajectory of cardiac function in 415 patients (1258 echocardiograms), according to the occurrence of cardiovascular death and hospitalization for HF during a median follow‐up of 19.1 (interquartile range, 10.9–27.6) months. A higher sacubitril/valsartan dose was associated with a better prognosis, whereas advanced age, diabetes, left ventricular (LV) hypertrophy, left atrial enlargement, and pulmonary hypertension were associated with a worse prognosis. Patients without an event (n = 337; 81.2%) showed LV reverse remodelling (LV ejection fraction ≥45% or LV end‐systolic volume reduction by 15% from baseline), which was typically observed within 6 months of sacubitril/valsartan treatment. Reverse remodelling achievement was significantly associated with a better prognosis. However, patients without reverse remodelling had a worse prognosis, as poor as that in patients with HFrEF not treated with sacubitril/valsartan. Conclusions: In patients with HFrEF treated with sacubitril/valsartan, LV reverse remodelling reflects the treatment response and predicts the prognosis, whereas a lack of reverse remodelling indicates the lack of treatment benefits. Prediction and assessment of reverse remodelling may facilitate the selection of patients with greater benefits by sacubitril/valsartan. [ABSTRACT FROM AUTHOR]

Aims: Sacubitril/valsartan combines renin–angiotensin–aldosterone system inhibition with amplification of natriuretic peptides. In addition to well‐described effects, natriuretic peptides exert direct effects on pulmonary vasculature. The effect of sacubitril/valsartan on pulmonary artery pressure (PAP) has not been fully defined. Methods and results: This was a retrospective case‐series of PAP changes following transition from angiotensin‐converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) to sacubitril/valsartan in patients with heart failure reduced ejection fraction and a previously implanted CardioMEMS™ sensor. Pre‐sacubitril/valsartan and post‐sacubitril/valsartan PAPs were compared for each patient by examining averaged consecutive daily pressure readings from 1 to 5 days before and after sacubitril/valsartan exposure. PAP changes were also compared between patients based on elevated trans‐pulmonary gradients (trans‐pulmonary gradient ≥ 12 mmHg) at time of CardioMEMS™ sensor implantation. The cohort included 18 patients, 72% male, mean age 60.1 ± 13.6 years. There was a significant decrease in PAPs associated with transition from ACEI/ARB to sacubitril/valsartan. The median (interquartile range) pre‐treatment and post‐treatment change in mean, systolic and diastolic PAPs were −3.6 (−9.8, −0.7) mmHg (P < 0.001), −6.5 (−15.0, −2.0) mmHg (P = 0.001), and −2.5 (−5.7, −0.7) (P = 0.001), respectively. The decrease in PAPs was independent of trans‐pulmonary gradient (F(1,16) = 0.49, P = 0.49). Conclusions: In this retrospective case series, transition from ACEI/ARB to sacubitril/valsartan was associated with an early and significant decrease in PAPs. [ABSTRACT FROM AUTHOR]

Aims: Ivabradine and sacubitril/valsartan are second‐line therapies for patients with heart failure and reduced ejection fraction (HFrEF) based on guideline recommendations. We aimed to evaluate the synergistic effects of these two medications. Methods and results: Patients' data were extracted from a multicentre database between 2016 and 2018. Patients were classified into (1) Simultaneous group: simultaneous prescription of ivabradine and sacubitril/valsartan within 6 weeks; (2A) Sequential group, ivabradine‐first: ivabradine was prescribed first, followed by sacubitril/valsartan; and (2B) Sequential group, sacubitril/valsartan‐first: sacubitril/valsartan was prescribed first, followed by ivabradine. A total of 464 patients with HFrEF were enrolled. Cardiovascular death and/or unplanned re‐hospitalizations for HF were less frequent (28.6% vs. 44.8%, P = 0.01), and the improvement of left ventricular ejection fraction (LVEF) was significantly greater in patients from the Simultaneous group than those from the Sequential group (∆LVEF 12.8 ± 12.9% vs. 9.3 ± 12.6%, P = 0.007). Among Sequential subgroups, the ivabradine‐first treatment decreased heart rate and increased systolic blood pressure (SBP) compared with sacubitril/valsartan‐first treatment (∆heart rate −9.1 ± 12.9 b.p.m. vs. 2.6 ± 16.0 b.p.m., P < 0.001; ∆SBP 4.6 ± 16.5 mmHg vs. −4.8 ± 17.2 mmHg, P < 0.001), whereas sacubitril/valsartan‐first treatment showed a higher degree of LVEF improvement (∆LVEF 3.6 ± 7.8% vs. 0.7 ± 7.7%, P = 0.002) than ivabradine‐first treatment. At the end of follow‐up, SBP, LVEF, and left ventricular volume were comparable between two Sequential subgroups. Conclusions: Among patients with HFrEF, simultaneous rather than sequential treatment with sacubitril/valsartan and ivabradine was a better strategy to reduce adverse events and achieve left ventricular reverse remodelling. Ivabradine treatment had a more significant benefit on improving haemodynamic stability, whereas sacubitril/valsartan treatment showed a more significant effect on improving LVEF. [ABSTRACT FROM AUTHOR]

Aims: Sacubitril/valsartan (sac/val) has shown superior effect compared with blockade of the renin–angiotensin–aldosterone system in heart failure with reduced ejection fraction. We aimed to investigate effects of sac/val compared with valsartan in a pressure overload model of heart failure with preserved ejection fraction (HFpEF). Methods and results: Sprague–Dawley rats underwent aortic banding or sham (n = 16) surgery and were randomized to sac/val (n = 28), valsartan (n = 29), or vehicle (n = 26) treatment for 8 weeks. Sac/val reduced left ventricular weight by 11% compared with vehicle (P = 0.01) and 9% compared with valsartan alone (P = 0.04). Only valsartan reduced blood pressure compared with sham (P = 0.02). Longitudinal early diastolic strain rate was preserved in sac/val compared with sham, while it was reduced by 23% in vehicle (P = 0.03) and 24% in valsartan (P = 0.02). Diastolic dysfunction, measured by E/e'SR, increased by 68% in vehicle (P < 0.01) and 80% in valsartan alone (P < 0.001), while sac/val showed no increase. Neither sac/val nor valsartan prevented interstitial fibrosis. Although ejection fraction was preserved, we observed mild systolic dysfunction, with vehicle showing a 28% decrease in longitudinal strain (P < 0.01). Neither sac/val nor valsartan treatment improved this dysfunction. Conclusions: In a model of HFpEF induced by cardiac pressure overload, sac/val reduced hypertrophy compared with valsartan alone and ameliorated diastolic dysfunction. These effects were independent of blood pressure. Early systolic dysfunction was not affected, supporting the notion that sac/val has the largest potential in conditions characterized by reduced ejection fraction. Observed anti‐hypertrophic effects in preserved ejection fraction implicate potential benefit of sac/val in the clinical setting of hypertrophic remodelling and impaired diastolic function. [ABSTRACT FROM AUTHOR]

Aims: Clinical trials and observational cohorts show that beneficial effects of sacubitril/valsartan are less strong in an appreciable proportion of patients with heart failure with reduced ejection fraction (HFrEF). Lower blood pressure and impaired renal function predict suboptimal sacubitril/valsartan titration and a less favourable response. Circulating renin encompasses neurohormonal activation, intravascular volume, and renal function. We hypothesized that renin may predict response to sacubitril/valsartan, assessed by changes in N‐terminal fraction of pro‐brain natriuretic peptide (NT‐proBNP). Methods and results: We performed a prospective, open‐label, real‐life cohort study. The study population consisted of 80 consecutive HFrEF patients (age 66 ± 10 years, 83% men) planned to initiate sacubitril/valsartan. Clinical and biohumoral assessment, including a full neurohormonal panel, was performed at baseline and at 1, 3, and 6 month follow‐up. Response to sacubitril/valsartan was defined as ≥30% reduction in NT‐proBNP levels from baseline to 6 months. Patients in the lower renin tertile had higher blood pressure and plasma sodium concentration (all P < 0.05). At follow‐up, 38 patients (48%) were classified as responders. Circulating renin was lower in the responder group compared with non‐responders (19.8 mU/L, IQR 3.7–78.0 mU/L vs. 55.0 mU/L, IQR 16.4–483.1 mU/L; P = 0.004). After adjustment for age, renal function, and blood pressure, renin was independently associated to response to sacubitril/valsartan (P = 0.018). Conclusions: In our preliminary study, we show that circulating renin predicts reduction in NT‐proBNP levels after sacubitril/valsartan initiation in HFrEF patients. Renin assessment might be useful to discriminate potential responders from the subgroup with a weaker expected benefit, thus needing a closer, tailored management strategy. [ABSTRACT FROM AUTHOR]

Aims: The aim of our study was to investigate heterogeneity of health status treatment response of sacubitril/valsartan in patients with heart failure with reduced ejection fraction (HFrEF). Methods and results: We leveraged data from CHAMP‐HF, an observational registry of 140 US clinics and 5026 outpatients with chronic HFrEF, where health status was serially assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ)‐12 Overall Summary Scale (range from 0 to 100; ≥20‐point improvement is a very large improvement). In 334 patients newly initiated on sacubitril/valsartan, we used hierarchical multivariable logistic regression (13 patient‐level characteristics as well as baseline KCCQ‐12 score) to calculate the odds ratio (OR) of any characteristic being associated with a very large health status improvement. A total of 104/334 (31.1%) of patients achieved the primary endpoint, where only worse baseline health status [KCCQ‐12 score of 0–60 points had an OR = 0.86/5‐point higher score (CI 0.79, 0.93)], and those with a KCCQ‐12 score of 60–80 points had an OR = 0.61/5‐point higher score (0.45–0.82), which was associated with a very large benefit. No other patient characteristic was associated with a very large health status improvement (P > 0.05). Conclusions: We found that, after initiation of sacubitril/valsartan, only worse baseline health status was associated with very large health status improvement. Accordingly, a trial of therapy—particularly in those with worse symptoms, function, and quality of life—and assessing treatment response are likely to be the best prospective strategy. [ABSTRACT FROM AUTHOR]

Aims: Hypertension is a significant risk for the development of left ventricular hypertrophy, diastolic dysfunction, followed by heart failure and sudden cardiac death. While therapy with sacubitril/valsartan (SV) reduces the risk of sudden cardiac death in patients with heart failure and systolic dysfunction, the effect on those with diastolic dysfunction remains unclear. We hypothesized that, in the animal model of hypertensive heart disease, treatment with SV reduces the susceptibility to ventricular arrhythmia. Methods and results: Young adult female spontaneous hypertensive rats (SHRs) were randomly separated into three groups, which were SHRs, SHRs treated with valsartan, and SHRs treated with SV. In addition, the age‐matched and weight‐matched Wistar Kyoto rats were considered as controls, and there were 12 rats in each group. In vivo ventricular tachyarrhythmia induction and in vitro optical mapping were used to measure the inducibility of ventricular arrhythmias and to characterize the dynamic properties of electrical propagation. The level of small‐conductance Ca2+‐activated potassium channel type 2 (KCNN2) was analysed in cardiac tissue. Compared with SHR with left ventricular hypertrophy, treatment with SV significantly improved cardiac geometry (relative wall thickness, 0.68 ± 0.11 vs. 0.76 ± 0.13, P < 0.05) and diastolic dysfunction (isovolumetric relaxation time, 59.4 ± 3.2 vs. 70.5 ± 4.2 ms, P < 0.05; deceleration time of mitral E wave, 46 ± 4.8 vs. 42 ± 3.8, P < 0.05). The incidence of induced ventricular arrhythmia was significantly reduced in SHR treated with SV compared with SHR (ventricular tachycardia, 1.14 ± 0.32 vs. 2.91 ± 0.5 episodes per 10 stimuli, P < 0.001; ventricular fibrillation, 1.72 ± 0.31 vs. 5.81 ± 0.42 episodes per 10 stimuli, P < 0.001). The prolonged action potential duration (APD) and increase of the maximum slope of APD restitution were observed in SHR, while the treatment of SV improved the arrhythmogeneity (APD, 37.12 ± 6.18 vs. 92.41 ± 10.71 ms at 250 ms pacing cycle length, P < 0.001; max slope 0.29 ± 0.01 vs. 1.48 ± 0.04, P < 0.001). These effects were strongly associated with down‐regulation of KCNN2 (0.38 ± 0.07 vs. 0.74 ± 0.12 ng/ml, P < 0.001). The treatment of SV also decreased the level of N‐terminal pro‐B‐type natriuretic peptide, cardiac bridging integrator‐1, and intramyocardial fibrosis of SHR. Conclusions: In conclusion, synergistic blockade of the neprilysin and the renin–angiotensin system by SV in SHRs results in KCNN2‐associated electrical remodelling in ventricle, which stabilizes electrical dynamics and attenuates arrhythmogenesis. [ABSTRACT FROM AUTHOR]

A worsening renal function is prevalent among patients with cardiovascular disease, especially heart failure (HF). Sacubitril/valsartan appears to prevent worsening of renal function and progression of chronic kidney disease (CKD) as compared with renin–angiotensin system (RAS) inhibitors alone in HF patients. It is unclear whether these advantages are present in HF patients only, or can be extended to other categories of patients, in which this drug was studied. We performed a systematic review and meta‐analysis to assess the consistency of effect size regarding renal outcome across randomized controlled trials (RCTs) that compared sacubitril/valsartan with RAS inhibitors in patients with or without HF. We searched Medline (PubMed), Scopus, and Thomson Reuters Web of Science databases until June 2020. We took into account RCTs that compared sacubitril/valsartan with a RAS inhibitor and reported data regarding renal function. We used random‐effects models to obtain summary odds ratio (OR) with 95% confidence interval (CI). We extracted hazard ratios for renal outcomes, glomerular filtration rate slopes or rates of renal adverse events. Sensitivity analyses were performed by moderator analysis and random‐effects meta‐regression. The search revealed 10 RCTs (published between 2012 and 2019) on 16 456 subjects. Sacubitril/valsartan resulted in a lower risk of renal dysfunction as compared with RAS inhibitors alone [k = 10; pooled OR = 0.70 (95% CI 0.57–0.85); P < 0.001], with a moderate inconsistency between studies [Q(9) = 15.18; P = 0.086; I2 = 40.73%]. A stronger association was found in studies including older patients (k = 10; β = −0.047730; P = 0.020) or HF patients with preserved ejection fraction [pooled OR = 0.53 (0.41–0.68) vs. 0.76 (0.57–1.01) for studies on HF patients with reduced ejection fraction; P for comparison = 0.065]. The effect size did not change with different comparators (angiotensin‐converting enzyme inhibitors vs. angiotensin II type 1 receptor blockers, P = 0.279). No significant association was found when the analysis was restricted to studies on non‐HF patients [k = 3; pooled OR = 0.86 (0.61–1.22); P = 0.403] and studies with high risk of bias [k = 3; pooled OR = 0.34 (0.08–1.44); P = 0.143]. Our findings support the role of sacubitril/valsartan on preservation of renal function, especially in older patients and HF patients with preserved ejection fraction. However, evidence is currently limited to HF patients, while the renal outcome of sacubitril/valsartan therapy outside the HF setting needs to be further investigated. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to evaluate the safety profile in terms of changes in renal function after co‐treatment with sacubitril/valsartan and empagliflozin in patients with type 2 diabetes (T2D) and heart failure with reduced ejection fraction (HFrEF). Methods and results: This multicentre observational analysis included 108 patients with T2D and HFrEF treated with both agents: baseline sacubitril/valsartan (Group A; n = 43), baseline empagliflozin (Group B; n = 42), or both agents initiated simultaneously (Group C; n = 23). The primary endpoint was estimated glomerular filtration rate (eGFR) dynamics across treatment groups. A binary characterization of worsening renal function (WRF)/improved renal function (IRF) was included in the primary endpoint. WRF and IRF were defined as an increase/decrease in serum creatinine ≥ 0.3 mg/dL or GFR ≥ 20%. Changes in quantitative variables were evaluated using joint modelling of survival and longitudinal data (JM). Rates and their treatment differences were determined by Poisson regression. The mean left ventricle ejection fraction and eGFR were 32 ± 6% and 70 ± 28 mL/min/1.73 m2, respectively. At a median follow‐up of 1.01 years (inter‐quartile range 0.71–1.50), 377 outpatient visits were recorded. Although there were differences in GFR trajectories over time within each treatment, they did not achieve statistical significance (omnibus P = 0.154). However, when these differences were contrasted among groups, there was a significant decrease in GFR in Group A as compared with Group B (P = 0.002). The contrast between Groups C and B was not significant (P = 0.430). These differences were also reflected when the rates for WRF and IRF were contrasted among treatments. Conclusions: The co‐administration of sacubitril/valsartan and empagliflozin in patients with HFrEF and concomitant T2D appears to be safe in terms of renal function. [ABSTRACT FROM AUTHOR]

Aims: Optimal medical therapy after cardiac resynchronization therapy (CRT) implantation is important in heart failure (HF) with reduced ejection fraction (HFrEF) patients. Although sacubitril/valsartan (SV) is a mainstay in the treatment of HFrEF, its efficacy in the management of CRT non‐responders has not been emphasized. We aimed to investigate the efficacy of SV in CRT non‐responders. Methods and results: We analysed 175 HFrEF patients who received CRT implantation between January 2010 and January 2019. CRT responder was defined as a decrease in left ventricular (LV) end‐systolic volume > 15% on echocardiography 6 months after implantation. Medical records were retrospectively reviewed. Patients underwent follow‐up for HF rehospitalization, heart transplantation (HT), implantation of a LV assistant device (LVAD), cardiac death, and all‐cause death. Among the study population, 164 patients were evaluated for CRT response; 54 (33%) were CRT non‐responders. Four patients (6%) who received SV before CRT implantation were excluded, leaving 50 patients for analysis. Twenty‐two non‐responders (44%) received SV. There was no significant difference in baseline characteristics between SV users and non‐users (n = 28). During follow‐up, SV users had significantly lower incidence of all‐cause death [1 (5%) vs. 10 (36%), P = 0.022] and tended to have lower HF rehospitalization [6 (27%) vs. 16 (57%), P = 0.068] and cardiac death (including HT and LVAD implant) [2 (9%) vs. 10 (36%), P = 0.064]. Kaplan–Meier survival analysis revealed that SV use was associated with a lower risk of cardiac death (including HT and LVAD implant) (log‐rank P = 0.029). Conclusions: SV treatment was related to a lower incidence of cardiac death including HT and LVAD implant in CRT non‐responders. The optimization of HF management, including SV, should be considered in CRT non‐responders. [ABSTRACT FROM AUTHOR]

Aims: Little is known about patient characteristics, outcomes, and the effect of treatment in relation to duration of heart failure (HF). We have investigated these questions in PARADIGM‐HF. The aim of the study was to compare patient characteristics, outcomes, and the effect of sacubitril/valsartan, compared with enalapril, in relation to time from HF diagnosis in PARADIGM‐HF. Methods and results: HF duration was categorized as 0–1, >1–2, >2–5, and >5 years. Outcomes were adjusted for prognostic variables, including N‐terminal pro‐brain natriuretic peptide (NT‐proBNP). The primary endpoint was the composite of HF hospitalization or cardiovascular death. The number of patients in each group was as follows: 0–1 year, 2523 (30%); >1–2 years, 1178 (14%); >2–5 years, 2054 (24.5%); and >5 years, 2644 (31.5%). Patients with longer‐duration HF were older, more often male, and had worse New York Heart Association class and quality of life, more co‐morbidity, and higher troponin‐T but similar NT‐proBNP levels. The primary outcome rate (per 100 person‐years) increased with HF duration: 0–1 year, 8.4 [95% confidence interval (CI) 7.6–9.2]; >1–2 years, 11.2 (10.0–12.7); >2–5 years, 13.4 (12.4–14.6); and >5 years, 14.2 (13.2–15.2); P < 0.001. The hazard ratio was 1.26 (95% CI 1.07–1.48), 1.52 (1.33–1.74), and 1.53 (1.33–1.75), respectively, for >1–2, >2–5, and >5 years, compared with 0–1 year. The benefit of sacubitril/valsartan was consistent across HF duration for all outcomes, with the primary endpoint hazard ratio 0.80 (95% CI 0.67–0.97) for 0–1 year and 0.73 (0.63–0.84) in the >5 year group. For the primary outcome, the number needed to treat for >5 years was 18, compared with 29 for 0–1 year. Conclusions: Patients with longer‐duration HF had more co‐morbidity, worse quality of life, and higher rates of HF hospitalization and death. The benefit of a neprilysin inhibitor was consistent, irrespective of HF duration. Switching to sacubitril/valsartan had substantial benefits, even in patients with long‐standing HF. [ABSTRACT FROM AUTHOR]

Aims: Sacubitril‐valsartan has been shown to have superior effects over angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in patients with heart failure (HF) and hypertension. The efficacy and safety of sacubitril‐valsartan in patients with HF are controversial. We performed a meta‐analysis of randomized controlled trials to assess and compare the effect and adverse events of sacubitril‐valsartan, valsartan, and enalapril in patients with HF. Methods and results: We conducted a systematic search using PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov. Randomized controlled trials involving the use of sacubitril‐valsartan in patients with HF were included. We assessed the pooled odds ratio (OR) of all‐cause mortality, cardiovascular mortality, and hospitalization for HF in fixed‐effects models and the pooled risk ratio (RR) of symptomatic hypotension, worsening renal function, and hyperkalaemia in fixed‐effects models. Of the 315 identified records, six studies involving 14 959 patients were eligible for inclusion. Sacubitril‐valsartan reduced the endpoints of all‐cause mortality and cardiovascular mortality in patients with HF with reduced ejection fraction (HFrEF) in three trials with pooled ORs of 0.83 (P = 0.0006) and 0.78 (P < 0.0001), respectively. Regarding the composite outcome of hospitalization for HF in five trials, the pooled OR was 0.79 (P < 0.00001). Compared with enalapril or valsartan, sacubitril‐valsartan was associated with a high risk of symptomatic hypotension (RR 1.47, P < 0.00001), low risk of worsening renal function (RR 0.81, P = 0.005), and low rate of serious hyperkalaemia (≥6.0 mmol/L) (RR 0.76, P = 0.0007) in all six trials. Conclusions: Compared with angiotensin‐converting enzyme inhibitors or angiotensin receptor blockers, sacubitril‐valsartan significantly decreased the risk of death from all causes or cardiovascular causes in HFrEF and hospitalization for HF in both patients with HFrEF and HF with preserved ejection fraction. Sacubitril‐valsartan reduced the risk of renal dysfunction and serious hyperkalaemia but was associated with more symptomatic hypotension. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study is to study the introduction of sacubitril/valsartan (sac/val) in Sweden with regards to regional differences, clinical characteristics, titration patterns, and determinants of use and discontinuation. Methods and results: A national cohort of heart failure was defined from the Swedish Prescribed Drug Register and National Patient Register. A subcohort with additional data from the Swedish Heart Failure Registry (SwedeHF) was also studied. Cohorts were subdivided as per sac/val prescription and registration in SwedeHF. Median sac/val prescription rate was 20 per 100 000 inhabitants. Between April 2016 and December 2017, we identified 2037 patients with ≥1 sac/val prescription, of which 1144 (56%) were registered in SwedeHF. Overall, patients prescribed with sac/val were younger, more frequently male, and had less prior cardiovascular disease than non‐sac/val patients. In SwedeHF subcohort, patients prescribed with sac/val had lower ejection fraction. Overall, younger age [hazard ratio 2.81 (95% confidence interval 2.45–3.22)], registration in SwedeHF [1.97 (1.83–2.12)], male gender [1.50 (1.37–1.64)], ischaemic heart disease [1.50 (1.39–1.62)], lower left ventricular ejection fraction [3.06 (2.18–4.31)], and New York Heart Association IV [1.50 (1.22–1.84)] were predictors for sac/val use. As initiation dose in the sac/val cohort, 38% received 24/26 mg, 54% 49/51 mg, and 9% 97/103 mg. Up‐titration to the target dose was achieved in 57% of the overall cohort over a median follow‐up of 6 months. The estimated treatment persistence for any dose at 360 days was 82%. Conclusions: Implementation of sac/val in Sweden was slow and varied five‐fold across different regions; younger age, male, SwedeHF registration, and ischaemic heart disease were among the independent predictors of receiving sac/val. Overall, treatment persistence and tolerability was high. [ABSTRACT FROM AUTHOR]

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 < 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 Ca2+ leak by 76 ± 5%; n = 101/4 vs. 108/4, P < 0.01 each), whereas sole Val treatment did not. Systolic Ca2+ release, SR Ca2+ load, and Ca2+‐transient kinetics including SERCA activity (kSERCA) 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 Ca2+ 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 Ca2+ homeostasis in human end‐stage HF by reducing pro‐arrhythmogenic SR Ca2+ leak without acutely affecting systolic Ca2+ release and inotropy. These effects might contribute to the mortality benefits observed in the PARADIGM‐HF trial. [ABSTRACT FROM AUTHOR]