[Decompensation of Heart Failure in "Fragile" Patients: Clinical Features and Approaches to Therapy].

AIM: To evaluate the impact of frailty syndrome (FS) on the course of acute decompensated heart failure (ADHF) and the quality of drug therapy before discharge from the hospital in patients with reduced and moderately reduced left ventricular ejection fraction (LVEF). MATERIAL AND METHODS: This open prospective study included 101 patients older than 75 years with reduced and mid-range LVEF hospitalized for decompensated chronic heart failure (CHF). FS was detected during the outpatient follow-up and identified using the Age is Not a Hindrance questionnaire, the chair rise test, and the One Leg Test. The "fragile" group consisted of 54 patients and the group without FS included 47 patients. Clinical characteristics of patients were compared, and the prescribing rate of the main drugs for the treatment of CHF was assessed upon admission to the hospital. The sacubitril/valsartan or dapagliflozin therapy was initiated in the hospital; prescribing rate of the quadruple therapy was assessed upon discharge from the hospital. Patients with reduced LVEF were followed up for 30 days, and LVEF was re-evaluated to reveal possible improvement due to optimization of therapy during hospitalization. Statistical analysis was performed with the SPSS 23.0 software. RESULTS: The main causes for decompensation did not differ in patients of the compared groups. According to the correlation analysis, FS was associated with anemia (r=0.154; p=0.035), heart rate ≥90 bpm (r=0.185; p=0.020), shortness of breath at rest (r =0.224; p=0.002), moist rales in the lungs (r=0.153; p=0.036), ascites (r=0.223; p=0.002), increased levels of the N-terminal pro-brain natriuretic peptide (NT-proBNP) (r= 0.316; p<0.001), hemoglobin concentration <120 g / l (r=0.183; p=0.012), and total protein <65 g / l (r=0.153; p=0.035) as measured by lab blood tests. Among patients with LVEF ≤40 % in the FS group (n=33) and without FS (n=33), the quadruple therapy was a part of the treatment regimen at discharge from the hospital in 27.3 and 3.0 % of patients, respectively (p=0.006). According to the 30-day follow-up data, improvement of LVEF was detected in 18.2% of patients with LVEF ≤40% in the FS group and 12.1% of patients with LVEF ≤40% in the FS-free group (p=0.020). In patients with LVEF 41-49 % in the FS (n=21) and FS-free (n=14) groups, the prescribing rate of the optimal therapy, including sacubitril/valsartan, sodium-glucose cotransporter 2 inhibitors, beta-blockers, and mineralocorticoid receptor antagonists, no statistically significant differences were detected (14.3 and 7.1 %, respectively; p=0.515) at discharge from the hospital. CONCLUSION: Patients with ADHF and FS showed more pronounced clinical manifestations of decompensation, anemia, heart rate ≥90 beats/min, and higher levels of NT-proBNP upon admission. The inpatient therapy with sacubitril/valsartan or dapagliflozin was more intensively initiated in FS patients with reduced LVEF. An individualized approach contributed to achieving a prescribing rate of sacubitril/valsartan of 39.4%, dapagliflozin of 39.4%, and quadruple therapy of 27.3% upon discharge from the hospital.

Real-World evidence revelations: The potential of patient support programmes to provide data on medication usage.

Patient Support Programmes (PSPs) are used by the pharmaceutical industry to provide education and support to consumers to overcome the challenges they face managing their condition and treatment. Whilst there is an increasing number of PSPs, limited information is available on whether these programmes contribute to safety signals. PSPs do not have a scientific hypothesis, nor are they governed by a protocol. However, by their nature, PSPs inevitably generate adverse event (AE) reports. The main goal of the research was to gather all Novartis-initiated PSPs for sacubitril/valsartan, followed by research in the company safety database to identify all AE reports emanating from these PSPs. Core data sheets (CDS) were reviewed to assess if these PSPs contributed to any new, regulatory-authority approved, validated signals. Overall, AEs entered into the safety database from PSPs confirmed no contribution to CDS updates. Detailed review of real-world data revealed tablet splitting or taking one higher dose tablet a day instead of twice daily. This research, and subsequent analyses, revealed that PSPs did not impact safety label changes for sacubitril/valsartan. It revealed an important finding concerning drug utilisation i.e. splitting of sacubitril/valsartan tablets to reduce cost. This finding suggests that PSPs may contribute important real-world data on patterns of medication usage. There remains a paucity of literature available on this topic, hence further research is required to assess if it would be worth designing PSPs for collecting data on drug utilisation and (lack of) efficacy. Such information from PSPs could be important for all stakeholders.

Comparative efficacy of vericiguat to sacubitril/valsartan for patients with heart failure reduced ejection fraction: Systematic review and network meta-analysis.

BACKGROUND: Despite the established efficacy of vericiguat compared to placebo, uncertainties remain regarding its comparative efficacy to sacubitril/valsartan for patients with heart failure reduced ejection fraction (HFrEF). This study aimed to assess the relative efficacy of vericiguat and sacubitril/valsartan through a systematic review, network meta-analysis, and non-inferiority tests. METHODS: A systematic review was conducted to identify the randomized phase 3 clinical trials involving vericiguat and sacubitril/valsartan. The hazard ratios (HRs) with 95% confidence intervals (CI) for cardiovascular death (CVD) and hospitalization due to HF (hHF) were extracted from these trials and synthesized via network meta-analysis. Non-inferiority testing of vericiguat was performed using a fixed-margin method with a predefined non-inferiority margin (1.24). Sensitivity analyses explored the impact of the time from hHF to screening. RESULTS: Among the 1366 studies, two trials (VICTORIA and PARADIGM-HF) met the inclusion criteria. Network meta-analysis demonstrated that the HR for CVD or hHF with vericiguat did not significantly differ from that for sacubitril/valsartan (HR: 0.88, 95% CI:0.62-1.23). The upper limit of the 95% CI was less than the predefined margin of 1.24, confirming vericiguat's non-inferiority to sacubitril/valsartan. Sensitivity analyses affirmed the robustness of the base-case results. CONCLUSION: Vericiguat exhibited a comparable risk of CVD or hHF when contrasted with sacubitril/valsartan. Importantly, in patients with HFrEF, vericiguat's efficacy was not statistically inferior to that of sacubitril/valsartan. These findings reinforce the potential of vericiguat as a viable treatment option for this patient population.

Pulmonary pressure-flow responses to exercise in heart failure treated with angiotensin receptor neprilysin inhibitor.

BACKGROUND: The role of the angiotensin receptor neprilysin inhibitor (ARNI) in cardiac function, particularly its impact on pulmonary circulation, remains underexplored. Recent studies have described abnormal mean pulmonary artery pressure (mPAP)-cardiac output (CO) responses as having the potential to assess the disease state. The aim of this study was to assess the effects of ARNI on pulmonary circulation in heart failure. We measured echocardiographic parameters post 6-min walk (6 MW) and compared the changes with baseline and follow-up. Our hypothesis was that pulmonary pressure-flow relationship of the pulmonary circulation obtained by 6 MW stress echocardiography would be improved with treatment. METHODS: We prospectively enrolled 39 heart failure patients and conducted the 6 MW test indoors. Post-6 MW echocardiography measured echocardiographic variables, and CO was derived from electric cardiometry. Individualized ARNI doses were optimized, with follow-up echocardiographic evaluations after 1 year. RESULTS: Left ventricular (LV) volume were significantly reduced (160.7 ± 49.6 mL vs 136.0 ± 54.3 mL, P < 0.001), and LV ejection fraction was significantly improved (37.6 ± 11.3% vs 44.9 ± 11.5%, P < 0.001). Among the 31 patients who underwent 6 MW stress echocardiographic study at baseline and 1 year later, 6 MW distance increased after treatment (380 m vs 430 m, P = 0.003). The ΔmPAP/ΔCO by 6 MW stress decreased with treatment (6.9 mmHg/L/min vs 2.8 mmHg/L/min, P = 0.002). The left atrial volume index was associated with the response group receiving ARNI treatment for pulmonary circulation. CONCLUSIONS: Initiation of ARNI was associated with improvement of left ventricular size and LVEF. Additionally, the 6 MW distance increased and the ΔmPAP/ΔCO was improved to within normal range with treatment.

Impact of Treatment With Sacubitril/Valsartan on Erectile Dysfunction in Patients With Heart Failure With Reduced Ejection Fraction.

Sacubitril/valsartan (S/V), an angiotensin receptor-neprilysin inhibitor, has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and relieve symptoms in patients with chronic heart failure with reduced ejection fraction. The objective of this study was to assess the effects of S/V on erectile dysfunction in patients with heart failure with reduced ejection fraction (HFrEF). A prospective, open-label study was conducted with 59 male patients diagnosed with HFrEF and concomitant erectile dysfunction. Patients were treated with S/V for a duration of 1 month. The International Index of Erectile Function (IIEF) questionnaire was used to assess the severity of erectile dysfunction and sexual activities at baseline and follow-up visits. Other clinical parameters, including heart rate, were also monitored. After S/V treatment, a significant improvement was observed in sexual activities at the 1-month follow-up visit. The IIEF score showed a statistically significant increase, indicating a decrease in the severity of erectile dysfunction. However, it should be noted that the numerical increase in the IIEF score did not reach clinical significance. This study suggests that S/V treatment in patients with HFrEF may lead to improvements in sexual activities and a reduction in the severity of erectile dysfunction as measured by the IIEF score.

Reverse Remodeling Effects of Sacubitril-Valsartan: Structural and Functional Optimization in Stage C Heart Failure.

Sacubitril-valsartan, an angiotensin receptor-neprilysin inhibitor, reduces all-cause mortality and the rate of heart failure hospitalizations in patients with heart failure with reduced ejection fraction. This study aimed to elucidate the benefits of initiating sacubitril-valsartan on ventricular remodeling in patients previously optimized on guideline-directed medical therapy. In this prospective, single-arm longitudinal study, 40 patients with heart failure with reduced ejection fraction who were optimized on guideline-directed medical therapy were transitioned to sacubitril-valsartan. The primary end point was the change in left ventricular (LV) volume at 1 year as assessed by 3-dimensional transthoracic echocardiography. Other echocardiographic end points included change in LV-function and change in right ventricular (RV) size and function. The mean age was 55 ± 12 years, and 63% were male. At 1 year, LV end-diastolic volume decreased from 242 ± 71 to 157 ± 57 ml (p <0.001) with a corresponding increase in LV ejection fraction from 32 ± 7% to 44 ± 9% (p <0.001). RV end-diastolic volume decreased from 151 ± 51 to 105 ±45 ml (p <0.001). Although RV ejection fraction did not change (51 ± 8 vs 51 ± 10; p = 0.35), RV global longitudinal strain improved from -14.9 ± 3.4 % to -19.3 ± 4.3% (p <0.001). When added to standard medical therapy for heart failure, sacubitril-valsartan induces significant remodeling of both the right and left ventricles as assessed by 3-dimensional echocardiography.

Use of sacubitril/valsartan in patients with heart failure: evidence from the real world.

BACKGROUND: To characterize the use of sacubitril/valsartan in a group of patients with heart failure in Colombia. RESEARCH DESIGN AND METHODS: Follow-up study of patients with heart failure who started sacubitril/valsartan and were affiliated with the Colombian health system between 2019 and 2021. Sociodemographic, clinical, and pharmacological variables and adherence and persistence of use were identified. RESULTS: A total of 514 patients were identified, with a mean age of 65.7 years, 73.7% of whom started sacubitril/valsartan at low doses, and only 12.5% reached the maximum dose. Adherence was 78.2% and persistence was 56.8% at 1 year of follow-up. The increase in systolic blood pressure (odds ratio (OR): 1.01; 95% CI: 1.00-1.03) and the use of ß-blockers (OR: 2.63; 95% CI: 1.42-4.85) were correlated with a greater persistence, while receiving furosemide (OR: 0.59; 95% CI: 0.39-0.89) and not having received renin - angiotensin - aldosterone system inhibitors in the 3 months before starting sacubitril/valsartan (OR: 0.48; 95% CI: 0.31-0.76) were associated with lower persistence. CONCLUSIONS: The persistence of treatment 1 year after starting sacubitril/valsartan was not high, and a small proportion of patients reached the target dose of the drug. Nontitration of the drug dose was common.

The Clinical Evolution of Diffuse Myocardial Fibrosis in Patients With Arterial Hypertension and Heart Failure With Mildly Reduced Ejection Fraction Treated by Olmesartan or Sacubitril / Valsartan.

Aim      A 12-month evaluation of the potentialities of the angiotensin II receptor inhibitor olmesartan (Olme) and the angiotensin receptor and neprilysin inhibitor (ARNI) sacubitril/valsartan in patients with arterial hypertension (AH) and dyslipidemia in the dynamics of the following indicators of chronic heart failure (CHF): N-terminal pro-brain natriuretic peptide (NT-proBNP), left ventricular ejection fraction (LVEF), LV global longitudinal strain (LV GLS) in diffuse myocardial fibrosis (MF) previously diagnosed by magnetic resonance imaging (MRI).Material and methods  Olmesartan medoxomil (n=56) and sacubitril/valsartan (n=63) were used for 12 months in patients with hypertension, dyslipidemia and NYHA functional class II-III CHF with mid-range LVEF (CHFmrEF). MF was diagnosed by the following MRI criteria: late gadolinium enhancement and an increased proportion of extracellular matrix (33% or more). The frequency of persisting late gadolinium enhancement and the increased proportion of extracellular matrix (33% or more) was evaluated at 12 months; changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), NT-proBNP, and LV GLS were evaluated after 3, 6, and 12 months of follow-up.Results Baseline parameters did not differ between groups. The late gadolinium enhancement and increased proportion of extracellular matrix were present at baseline in all patients of both groups (100%; p=1.0). Already at 3 months, statistically significant decreases in SBP and DBP were observed in both groups. In addition, the LV GLS monitoring showed LV GLS significantly increased in both groups after 3 months and continued changing after 6 and 12 months. The NT-proBNP concentration significantly decreased in both groups already after 3 months and continued to decrease after 6 and 12 months. At 6 and 12 months, sacubitril/valsartan was superior to olmesartan in reducing SBP and NT-proBNP and in restoring LV GLS. At 12 months, the incidence of persisting, abnormal late gadolinium enhancement and increased proportion of extracellular matrix was significantly less in the ARNI group.Conclusion      Olmesartan was demonstrated effective in the multi-modality therapy of CHFmrEF and MF in patients with AH and dyslipidemia. ARNI was superior to olmesartan in this regard, but further research of this issue is required.

Sacubitril/valsartan attenuates myocardial inflammation, hypertrophy, and fibrosis in rats with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) represents a multifaceted syndrome related to complex pathologic mechanisms. Sacubitril/valsartan (Sac/val) has demonstrated therapeutic efficacy in HFpEF treatment. However, additional research is required to elucidate its pharmacological mechanisms. Accordingly, this study aimed to explore the potential therapeutic effects of Sac/val in HFpEF rats and the underlying molecular mechanisms. In this study, rats with HFpEF were induced by subjecting spontaneously hypertensive rats to a diet rich in fats, salts, and sugars, along with administering streptozotocin. Subsequently, they were administered Sac/val at a daily dosage of 18 mg/kg. Finally, cardiac structure and function were assessed using echocardiography; Hematoxylin and eosin staining and Masson's trichrome staining were employed to evaluate the pathological changes; Quantitative real-time polymerase chain reaction and Western blot analysis were conducted to determine the expression of pertinent mRNA and proteins. Sac/val treatment attenuated left ventricular (LV) remodeling and diastolic dysfunction in HFpEF rats, possibly related to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic efficacy. Mechanistically, Sac/val might inhibit inflammation by down-regulating cell adhesion molecule (intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial cell adhesion molecule-1 (VCAM-1)) expression. Additionally, it blocked the phosphorylation of glycogen synthase kinase 3ß (GSK-3ß) to prevent cardiomyocyte hypertrophy. Furthermore, it effectively suppressed myocardial fibrosis by inhibiting the transforming growth factor-beta1 (TGF-ß1)/Smads pathway. Our findings suggest that Sac/val improved LV remodeling and diastolic dysfunction, potentially attributed to its anti-inflammatory, anti-hypertrophic, and anti-fibrotic effects. These results provide a sound theoretical rationale for the clinical application of Sac/val in patients with HFpEF.

Effect on the Quality of Life of Patients with Heart Failure and Reduced/Preserved Ejection Fraction Using Sacubitril/Valsartan. / Efeito na Qualidade de Vida de Pacientes com Insuficiência Cardíaca e Fração de Ejeção Reduzida/Preservada em Uso de Sacubitril/Valsartan.

BACKGROUND: Heart failure (HF) management has markedly improved, but a clinically meaningful improvement in functional capacity and quality of life is perhaps more important for patients than living longer. OBJECTIVE: This study aimed to review the improvement in quality of life with sacubitril/valsartan in patients with HF and reduced/preserved ejection fraction (EF) from prospective clinical trials. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) and prospective cohort studies published from inception to July 2021. A total of 6 clinical trials and 16854 patients with HF were included. The primary outcome was the change from baseline in KCCQ clinical summary score. The secondary outcomes were scores in other domains of KCCQ, the occurrence of serious adverse events (AEs), and overall mortality. P-values <0.05 were considered statistically significant. RESULTS: Treatment of sacubitril/valsartan showed significantly higher KCCQ-CSS compared to the control (WMD=0.975, 95% CI: 0.885, 1.064, p<0.001; I2=94.8%, pheterogeneity<0.001). A significant decrease in the mortality rate was observed in the sacubitril/valsartan group compared to the control group (RR=0.895, 95%CI:0.831, 0.965, p=0.004; I2=43.6%, pheterogeneity=0.150). Nevertheless, no significant reduction in the occurrence of serious AEs was found among HF patients treated with sacubitril/valsartan compared to the control group (RR=0.950, 95%CI: 0.879, 1.027, p<0.001; I2=68.1%, pheterogeneity=0.024). CONCLUSIONS: Our study demonstrated that sacubitril/valsartan might significantly improve the HRQL compared to other treatments according to the results in KCCQ-CSS and some subdomains in the KCCQ index during the follow-up in patients with HF.

FUNDAMENTO: O manejo da insuficiência cardíaca (IC) tem melhorado acentuadamente, mas uma melhora clinicamente significativa na capacidade funcional e na qualidade de vida talvez seja mais importante para os pacientes do que viver mais. OBJETIVO: Este estudo teve como objetivo revisar a melhora na qualidade de vida com sacubitril/valsartan em pacientes com IC e fração de ejeção (FE) reduzida/preservada a partir de ensaios clínicos prospectivos. MÉTODOS: PubMed, Embase e Cochrane Library foram pesquisados em busca de ensaios clínicos randomizados (ECRs) e estudos de coorte prospectivos publicados desde o início até julho de 2021. Um total de 6 ensaios clínicos e 16.854 pacientes com IC foram incluídos. O desfecho primário foi a alteração da linha de base na pontuação do resumo clínico do KCCQ. Os desfechos secundários foram pontuações em outros domínios do KCCQ, ocorrência de eventos adversos graves (EAs) e mortalidade geral. Valores de p < 0,05 foram considerados estatisticamente significativos. RESULTADOS: O tratamento de sacubitril/valsartan mostrou KCCQ-CSS significativamente maior em comparação com o controle (DMP=0,975, IC 95%:0,885, 1,064, p<0,001; I2=94,8%, pheterogeneidade<0,001). Uma diminuição significativa na taxa de mortalidade foi observada no grupo sacubitril/valsartan em comparação com o grupo controle (RR=0,895, IC 95%: 0,831, 0,965, p=0,004; I2=43,6%, pheterogeneidade=0,150). No entanto, nenhuma redução significativa na ocorrência de EAs graves foi encontrada entre pacientes com IC tratados com sacubitril/valsartan em comparação com o grupo controle (RR=0,950, IC 95%: 0,879, 1,027, p<0,001; I2=68,1%, pheterogeneidade= 0,024). CONCLUSÕES: Nosso estudo demonstrou que o sacubitril/valsartan pode melhorar significativamente a QVRS em comparação com outros tratamentos de acordo com os resultados do KCCQ-CSS e alguns subdomínios do índice KCCQ durante o acompanhamento em pacientes com IC.

Neurohumoral Activation in Heart Failure.

In patients with heart failure (HF), the neuroendocrine systems of the sympathetic nervous system (SNS), the renin-angiotensin-aldosterone system (RAAS) and the arginine vasopressin (AVP) system, are activated to various degrees producing often-observed tachycardia and concomitant increased systemic vascular resistance. Furthermore, sustained neurohormonal activation plays a key role in the progression of HF and may be responsible for the pathogenetic mechanisms leading to the perpetuation of the pathophysiology and worsening of the HF signs and symptoms. There are biomarkers of activation of these neurohormonal pathways, such as the natriuretic peptides, catecholamine levels and neprilysin and various newer ones, which may be employed to better understand the mechanisms of HF drugs and also aid in defining the subgroups of patients who might benefit from specific therapies, irrespective of the degree of left ventricular dysfunction. These therapies are directed against these neurohumoral systems (neurohumoral antagonists) and classically comprise beta blockers, angiotensin-converting enzyme (ACE) inhibitors/angiotensin receptor blockers and vaptans. Recently, the RAAS blockade has been refined by the introduction of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan, which combines the RAAS inhibition and neprilysin blocking, enhancing the actions of natriuretic peptides. All these issues relating to the neurohumoral activation in HF are herein reviewed, and the underlying mechanisms are pictorially illustrated.

Comparative Outcomes of Sacubitril/Valsartan Use After Hospitalization for Heart Failure Among Medicare Beneficiaries Naïve to Renin-Angiotensin System Inhibitors.

Sacubitril/valsartan improves outcomes in patients with heart failure with reduced ejection fraction (HFrEF) compared with angiotensin-converting enzyme inhibitors (ACEis). However, data on postdischarge outcomes in renin-angiotensin system inhibitor (RASi)-naïve patients are limited. We included Medicare beneficiaries aged ≥65 years who were hospitalized for HFrEF in the Get With The Guidelines-Heart Failure registry between October 2015 and June 2019, had part D prescription coverage, and were not on RASi therapy during the 6 months before hospital admission. We examined the associations between sacubitril/valsartan prescription at hospital discharge and outcomes at 30 days and 1 year after discharge using overlap-weighted median regression and Cox proportional hazards models. The end points included "home time" (defined as days alive and out of any health care institution), mortality, and rehospitalization. Among 3,572 patients with HFrEF and who are naïve to RASi therapy, at discharge, 290 (8.1%) were prescribed sacubitril/valsartan and 1,390 (38.9%) were prescribed ACEis and angiotensin receptor blockers. After adjusting for baseline characteristics, patients prescribed sacubitril/valsartan had a longer median home time (parameter estimate 27.0 days, 95% confidence interval [CI] 12.40 to 41.6, p <0.001) and lower all-cause mortality (hazard ratio [HR] 0.74, 95% CI 0.61 to 0.91, p = 0.004) at 1 year than patients not prescribed sacubitril/valsartan. The prescription of sacubitril/valsartan was not significantly associated with all-cause rehospitalization (HR 0.87, 95% CI 0.74 to 1.03, p = 0.10) or heart failure rehospitalization (HR 0.87, 95% CI 0.70 to 1.07, p = 0.19). In a restricted comparison of patients discharged on sacubitril/valsartan versus ACEis and angiotensin receptor blockers, there were no significant differences in the outcomes. In conclusion, in this contemporary population of RASi-naïve patients with HFrEF from routine clinical practice, compared with not initiating, the initiation of sacubitril/valsartan at discharge was associated with longer home time and improvements in overall survival.

Sacubitril/valsartan mitigates cardiac remodeling, systolic dysfunction, and preserves mitochondrial quality in a rat model of mitral regurgitation.

Sacubitril/valsartan (SAC/VAL), an angiotensin receptor blocker-neprilysin inhibitor, has been widely used to treat several types of heart failure. Nevertheless, the effects of drugs in mitral regurgitation patients, from the molecular level to therapeutic effects, remain unclear. This study investigates the roles of SAC/VAL on cardiac function, mitochondrial quality, autophagy, mitophagy, and natriuretic peptides in a rat model of chronic mitral regurgitation. Male Sprague-Dawley rats underwent MR induction (n = 16) and sham surgeries (n = 8). Four weeks post-surgery confirmed MR rats were randomly divided into MR (n = 8) and SAC/VAL (n = 8) groups. The SAC/VAL group was administered SAC/VAL, whereas the MR and the sham rats received vehicle via oral gavage daily for 8 weeks. Cardiac geometry, function, and myocardial fibrosis were assessed by echocardiography and histopathology. Spectrophotometry and real-time PCR were performed to assess the pharmacological effects on mitochondrial quality, autophagy, mitophagy, and natriuretic peptides. MR rats demonstrated significant left heart dilation and left ventricular systolic dysfunction compared with the sham group, which could be significantly improved by SAC/VAL. In addition, SAC/VAL significantly reduced myocardial cardiac remodeling and fibrosis in MR rats. SAC/VAL improved the mitochondrial quality by attenuating mitochondrial reactive oxygen species production and mitochondrial depolarization compared with the MR group. Also, the upregulation of autophagy-related, mitophagy-related, and natriuretic peptide system gene expression in MR rats was attenuated by SAC/VAL treatment. In conclusion, this study demonstrated that SAC/VAL treatment could provide numerous beneficial effects in MR conditions, suggesting that this drug may be an effective treatment for MR.

Changes in mid-regional pro-adrenomedullin during treatment with sacubitril/valsartan.

AIMS: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. METHODS AND RESULTS: Mid-regional pro-adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with heart failure with preserved ejection fraction (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nmol/L in HFrEF and 0.88 (0.68-1.20) nmol/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status. CONCLUSIONS: MR-proAD concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of heart failure. CLINICAL TRIAL REGISTRATION: PROVE-HF ClinicalTrials.gov Identifier: NCT02887183, PARAMOUNT ClinicalTrials.gov Identifier: NCT00887588.

Prevalent and Incident Anemia in PARADIGM-HF and the Effect of Sacubitril/Valsartan.

BACKGROUND: Anemia is common in patients with heart failure with reduced ejection fraction and is associated with poor clinical outcomes. Renin-angiotensin system blockers lower hemoglobin and may induce anemia. OBJECTIVES: The authors investigated whether concomitant neprilysin inhibition might ameliorate this effect of renin-angiotensin system blockers in PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure). METHODS: Anemia was defined as hemoglobin <120 g/L in women and <130 g/L in men at screening. The authors investigated the effect of randomized treatment on clinical outcomes according to anemia status, change in hemoglobin from baseline, and the incidence of anemia. RESULTS: Of 8,239 participants with a baseline hemoglobin measurement, 1,677 (20.4%) were anemic. Patients with anemia had a more severe heart failure profile, worse kidney function, greater neurohormonal derangement, and worse clinical outcomes. Sacubitril/valsartan, compared with enalapril, decreased the risk of cardiovascular death or heart failure hospitalization similarly in patients with (HR: 0.84; 95% CI: 0.71-1.00) and without anemia (HR: 0.78 [95% CI: 0.71-0.87]; P value for interaction = 0.478). Between baseline and 12 months, hemoglobin decreased by 1.5 g/L (95% CI: 1.2-1.7 g/L) with sacubitril/valsartan compared with 2.3 g/L (95% CI: 2.0-2.6 g/L) with enalapril: mean difference 0.8 g/L (95% CI: 0.5-1.2 g/L; P < 0.001). Patients assigned to sacubitril/valsartan were less likely to develop anemia at 12 months (321 of 2,806 [11.4%]) compared with patients randomized to enalapril (440 of 2,824 [15.6%]) (OR: 0.70 [95% CI: 0.60-0.81]; P < 0.001). These findings were similar in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) (sacubitril/valsartan vs valsartan). There was biomarker evidence of increased iron utilization with sacubitril/valsartan. CONCLUSIONS: Irrespective of anemia status, sacubitril/valsartan compared with enalapril, decreased mortality and hospitalization. Hemoglobin decreased less with sacubitril/valsartan and the incidence of new anemia was lower with sacubitril/valsartan. (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure [PARADIGM-HF] trial; NCT01035255).