Association of MME gene polymorphisms with susceptibility to Alzheimer's disease in an Iranian population.

Background: the MME gene encodes a membrane metalloendopeptidase, known as neprilysin (NEP). There are no reports on the potential implications of MME gene polymorphisms on the risk of Alzheimer's disease (AD) in the Iranian population. In this study, we studied the potential association of two single nucleotide polymorphisms (SNPs), rs6797911 and rs3736187, in the MME gene and the risk of developing AD in an Iranian population. Methods: This case-control study comprised 120 AD-diagnosed patients and 120 healthy individuals without any prior family history of AD. The patient and control groups were matched for major demographic and health characteristics. Genotyping was performed by amplification refractory mutation system-polymerase chain reaction (ARMS-PCR). Results: All patients included in this study were assessed by an experienced neurologist to exclude cases with other forms of dementia based on a brain computed tomography scan and other clinical findings. There were no significant differences in demographic and health characteristics including sex, diabetes, blood pressure, and cigarette smoking status between case and control groups (p > 0.05). However, the age difference appeared significant. Both SNPs were significantly associated with the risk of AD in our study population. The rs3736187 (T > C, 3:155168489) was strongly associated with AD risk under the log-additive model (OR = 1.67, CI = 1.18-2.37, p-value = 0.003). The rs6797911 (T > A, 3:155144601) also showed a significant association with AD risk under the dominant model (TT vs. TA and AA, OR = 3.37, CI = 1.86-6.1, p-value <0.001). Conclusion: There is a strong association between MME gene polymorphisms and susceptibility to AD in the Iranian population. Amyloid-ß (Aß) can serve as a substrate for the NEP metalloendopeptidase, the product of the MME gene. However, the mechanistic understanding of how these genetic variations affect NEP expression, function, and consequently susceptibility to AD, is poorly understood. Further research is required to fully understand the exact implication of MME gene variations on AD, particularly in a larger, ethnicity-diverse population.

Advances in pharmacotherapy for heart failure and reduced ejection fraction: what's new in 2024?

INTRODUCTION: The updated guidelines on the pillars for heart failure with reduced ejection fraction (HFrEF) and acute decompensation improved patient outcomes, but continuous efforts are made to uncover new evidence and develop novel treatments. This review aims to examine limitations of current therapies and the potential impact of emerging treatments. AREAS COVERED: The literature search was conducted focusing on studies that investigated drugs for treating patients with HFrEF. We examine recent clinical trials and emerging therapies to provide insights into potential treatments which may reshape the management of HFrEF. This review aims to highlight the strength of evidence, assess whether guideline updates are warranted, and explore how best to optimize and enhance patient outcomes. EXPERT OPINION: The treatment landscape for HFrEF is swiftly advancing, with notable progress in both well-established and novel therapies such as sodium/glucose cotransporter 1 and 2 inhibitors and sacubitril-valsartan. Despite the inherent challenges of managing acute decompensated heart failure, recent clinical trials highlight the potential of refining diuretic strategies and exploring anti-inflammatory treatments. These developments underscore a dynamic field committed to optimizing patient outcomes. While regulatory hurdles and safety concerns remain, ongoing research and comprehensive clinical trials are crucial for validating these emerging therapies and integrating them into standard practice.

Looking for the ideal medication for heart failure with reduced ejection fraction: a narrative review.

The main goals of the pharmacological treatment of Heart failure with reduced ejection fraction (HFrEF) are the reduction of mortality and the prevention of hospitalizations. However, other outcomes such as improvements in cardiac remodeling and clinical status, functional capacity and quality of life, should be taken into account. Also, given the significant inter-individual and intra-individual variability of HF, and the fact that patients usually present with comorbidities, an appropriate treatment for HFrEF should exert a clinical benefit in most patient profiles irrespective of their characteristics or the presence of comorbidities, while providing organ protection beyond the cardiovascular system. The aim of this narrative review is to determine which are the proven effects of the guideline-directed treatments for HFrEF on five key clinical outcomes: cardiovascular mortality and hospitalization due to HF, sudden death, reverse cardiac remodeling, renal protection and evidence in hospitalized patients. Publications that fulfilled the pre-established selection criteria were selected and reviewed. Renin-angiotensin system (RAS) inhibitors, namely angiotensin-converting enzyme inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers (BB), mineralocorticoid receptor antagonists (MRA), sodium-glucose co-transporter 2 inhibitors (SGLT2i) show a benefit in terms of mortality and hospitalization rates. ARNI, BB, and MRA have demonstrated a significant positive effect on the incidence of sudden death. ARB, ARNI, BB and SGLT2i have been associated with clear benefits in reverse cardiac remodeling. Additionally, there is consistent evidence of renal protection from ARB, ARNI, and SGLT2i in renal protection and of benefits for hospitalized patients from ARNI and SGLT2i. In conclusion, the combination of drugs that gather most beneficial effects in HFrEF, beyond cardiovascular mortality and hospitalization, would be ideally pursued.

Efficacy and safety of angiotensin receptor-neprilysin inhibition in heart failure patients with end-stage kidney disease on maintenance dialysis: A systematic review and meta-analysis.

AIMS: Angiotensin receptor-neprilysin inhibitor (ARNI) has played an increasingly important role in the management of heart failure (HF). However, the evidence on the benefits of ARNI in HF patients with end-stage kidney disease (ESKD) undergoing dialysis is limited. This study aimed to investigate the efficacy and safety of ARNI in patients with concomitant HF and ESKD on maintenance dialysis. METHODS AND RESULTS: We systematically searched the MEDLINE, Embase, Web of Science, Cochrane, and ClinicalTrials.gov databases for studies reporting outcomes after ARNI treatment in HF patients with ESKD on dialysis. All meta-analyses were performed using the random effects model. Twenty-six studies comprising 2494 patients with concomitant HF and ESKD undergoing dialysis were included. Our synthesis showed a significant improvement in left ventricular ejection fraction (LVEF) between before and after ARNI treatment (mean change: 8.05%; 95% confidence interval [CI] 5.57-10.54). Compared to the conventional group, the ARNI group showed a greater improvement in LVEF (mean difference: 4.03%; 95% CI 2.90-5.16). This effect was more pronounced in patients with HF with reduced ejection fraction (pinteraction < 0.0001). Patients treated with ARNI had a lower risk of all-cause mortality (risk ratio [RR] 0.64; 95% CI 0.45-0.92; p = 0.01) but had a similar rate of HF hospitalization (RR 0.71; 95% CI 0.43-1.18; p = 0.19). ARNI treatment showed benefits in the improvement of left ventricular end-systolic diameter, left ventricular mass index, left atrial diameter, and E/e' ratio (p < 0.05), while it did not significantly increase the risk of severe hyperkalaemia (p = 0.33) or symptomatic hypotension (p = 0.53). CONCLUSION: This meta-analysis provided insights into the benefits of ARNI in HF patients with ESKD undergoing dialysis by improving left ventricular function, reversing left ventricular remodelling, and reducing the risk of all-cause mortality, without increasing the risk of HF hospitalizations, severe hyperkalaemia, and symptomatic hypotension.

A Peptide Motif Covering Splice Site B in Neuroligin-1 Binds to Aß and Acts as a Neprilysin Inhibitor.

The most common cause of dementia among elderly people is Alzheimer's disease (AD). The typical symptom of AD is the decline of cognitive abilities, which is caused by loss of synaptic function. Amyloid-ß (Aß) oligomers play a significant role in the development of this synaptic dysfunction. Neuroligin-(NL)1 is a postsynaptic cell-adhesion molecule located in excitatory synapses and involved in the maintenance and modulation of synaptic contacts. A recent study has found that Aß interacts with the soluble N-terminal fragment of NL1. The present study aimed to elucidate the role of NL1 in Aß-induced neuropathology. Employing surface plasmon resonance and competitive ELISA, we confirmed the high-affinity binding of NL1 to the Aß peptide. We also identified a sequence motif representing the NL1-binding site for the Aß peptide and showed that a synthetic peptide modeled after this motif, termed neurolide, binds to the Aß peptide with high affinity, comparable to the NL1-Aß interaction. To assess the effect of neurolide in vivo, wild-type and 5XFAD mice were subcutaneously treated with this peptide for 10 weeks. We observed an increase in Aß plaque formation in the cortex of neurolide-treated 5XFAD mice. Furthermore, we showed that neurolide reduces the activity of neprilysin, the predominant Aß-degrading enzyme in the brain. Accordingly, we suggest that neurolide is the NL1-binding site for Aß peptide, and acts as an inhibitor of neprilysin activity. Based on these data, we confirm the involvement of NL1 in the development of AD and suggest a mechanism for NL1-induced Aß plaque formation.

Clinical and genetic features of CMT2T in Italian patients confirm the importance of MME pathogenic variants in idiopathic, late-onset axonal neuropathies.

BACKGROUND AND AIMS: Since 2016, biallelic mutations in the membrane metalloendopeptidase (MME) gene have been associated with late-onset recessive CMT2 (CMT2T). More recently, heterozygous mutations have also been identified in familial and sporadic patients with late-onset axonal neuropathy, ranging from subclinical to severe. This indicates that the heterozygous MME variants may not be fully penetrant, or alternatively, that they may be a potential risk factor for neuropathy. Here, we describe the clinical, neurophysiological, and genetic findings of 32 CM2T Italian patients. METHODS: The patients were recruited from four different Italian referral centers. Following a comprehensive battery of neurological, electrophysiological, and laboratory examinations, the patients' DNA was subjected to sequencing in order to identify any variants in the gene. Bioinformatic and modeling analyses were performed to evaluate the identified variants' effects. RESULTS: We observe a relatively mild axonal sensory-motor neuropathy with a greater impairment of the lower extremities. Biallelic and monoallelic patients exhibit comparable disease severity, with an earlier onset observed in those with biallelic variants. When considering a subgroup with more than 10 years of disease, it becomes evident that biallelic patients exhibit a more severe form of neuropathy. This suggests that they are more prone to quick progression. INTERPRETATION: CM2T has been definitively defined as a late-onset neuropathy, with a typical onset in the fifth to sixth decades of life and a more rapidly progressing worsening for biallelic patients. CMT2T can be included in the neuropathies of the elderly, particularly if MME variants heterozygous patients are included.

Plasma renin activity as a marker for predicting the antihypertensive effect of switching to sacubitril/valsartan in treated hypertensive patients: Usefulness in daily clinical practice.

The authors investigated the antihypertensive effect of sacubitril/valsartan (Sac/Val) when switching from other drugs and assessed whether brain natriuretic peptide (BNP) or plasma renin activity (PRA) before drug switching was a predictor of blood pressure lowering after switching to Sac/Val. In 92 patients with treated hypertension, clinic blood pressure, plasma BNP, and PRA were examined before and after switching to Sac/Val. Clinic systolic and diastolic blood pressures significantly decreased after drug switching to Sac/Val (p < .0001, respectively). The level before drug switching of BNP had no correlation with the change in systolic blood pressure (Δ-SBP) before and after switching to Sac/Val, but that of PRA was significantly correlated with Δ-SBP (r = .3807, p = .0002). A multiple regression analysis revealed that PRA before drug switching was an independent determinant of Δ-SBP. Our findings suggest that low PRA may become a useful marker to predict the antihypertensive effect of switching to Sac/Val in treated hypertensive patients.

Safety and efficacy of angiotensin receptor neprilysin inhibitor in improving cardiac function and blood pressure in dialysis patients.

Background: The efficacy of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (SV) in patients with chronic kidney disease (CKD) has been established. Two meta-analyses have demonstrated its significant role in enhancing ventricular remodeling. However, the effectiveness and safety of its use in patients with end-stage renal disease (ESRD) remain unclear. Methods and results: Up to October 2023, we searched the PubMed, Embase, and Web of Science databases for studies involving ESRD patients treated with ARNI. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Effect sizes were reported as mean differences (MD) with 95% confidence intervals (CIs). We included 10 studies, encompassing 649 patients. ARNI was associated with improvements in blood pressure and left ventricular (LV) function in ESRD patients, including systolic blood pressure (SBP) (MD -12.76 mmHg; 95% CI, -18.03 to -7.5 mmHg), diastolic blood pressure (DBP) (MD -6.41 mmHg; 95% CI, -8.10 to -4.72 mmHg), and left ventricular ejection fraction (LVEF) (MD, 4.61%; 95% CI, 1.78%-7.44%). Hemoglobin levels improved, but there were no significant statistical differences in other biomarkers for dialysis. Sacubitril/valsartan was generally well tolerated in ESRD patients. Improved indices of left ventricular function were noted at 6 months and were more pronounced at 12 months. A linear relationship between LVEF and left ventricular end-diastolic volume (LVEDV) was observed, as indicated by a high correlation coefficient (r-value). Conclusion: ARNI effectively reduces blood pressure and enhances left ventricular function in dialysis patients, with early treatment associated with greater benefits. ARNI also demonstrates a favorable safety profile in this population. Further prospective studies are required to fully understand the long-term efficacy and safety of sacubitril/valsartan in dialysis patients.

Pseudo-nephropathy and hyper-excretion of urinary C-peptide: an overlooked adverse effect of an angiotensin receptor-neprilysin inhibitor (ARNI).

Sacubitril/valsartan, which is a combined angiotensin receptor-neprilysin inhibitor (ARNI), is used for the treatment of chronic heart failure and hypertension. Substrates of neprilysin are numerous, and the systemic effects of an ARNI remain to be determined. Increased urinary C-peptide (UCPR) and urinary albumin (UAlb) excretion has been reported with the use of an ARNI, but the mechanism is still unknown. We report an 84-year-old man with type 2 diabetes and hypertension. His UAlb and UCPR excretion and (to a lesser degree) the estimated glomerular filtration rate were increased after ARNI administration. They returned to basal levels after discontinuing ARNI administration. There was little or no change in glycemic control. Therefore, increased glomerular permeability and filtration could partially explain how neprilysin inhibition led to an elevation in UCPR excretion, in addition to other mechanisms, such as impairment of the renal ability to degrade C-peptide. Physicians must be cautious when interpreting the insulin secretion capability by UCPR and nephropathy by UAlb in ARNI-treated patients with diabetes.

Post-acute CoVid-19 syndrome (PACS) linked cardiovascular symptoms.

Officials have marked the end of the CoVid-19 pandemic, yet we continue to learn more about the SARS-CoV2 virus itself and its lasting multidimensional effects after acute infection. Long COVID, or the post-acute CoViD-19 syndrome (PACS), manifests as a wide range of prolonged physical, mental, and emotional symptoms over at least 1 to 12 months after SARS-CoV2 infection. Here, we describe certain pervasive clinical consequences of PACS on the cardiovascular system, and insight on the potentially improved prognoses in heart failure patients.

Real-world experience of angiotensin receptor-neprilysin inhibitors in patients with heart failure and dialysis.

Introduction: Although angiotensin receptor-neprilysin inhibitor (ARNI) has shown promise in patients with heart failure and reduced ejection fraction (HFrEF), the treatment effect in HFrEF patients with end-stage renal disease (ESRD) undergoing dialysis is uncertain. This study aimed to examine the real-world effects of ARNI vs. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEI/ARB) in this subpopulation. Methods: This multi-institutional, retrospective study identified 349 HFrEF patients with ESRD on dialysis, who initiated either ARNI or ACEI/ARB therapy. Efficacy outcomes included rates of hospitalization for heart failure (HHF) and mortality, as well as changes in echocardiographic parameters. Safety outcomes encompassed hypotension and hyperkalemia. Treatment effects were assessed using Cox proportional hazards models, with additional sensitivity analyses for robustness. Results: Out of 349 patients screened, 89 were included in the final analysis (42 in the ARNI group and 47 in the ACEI/ARB group). After 1 year of treatment, echocardiographic measures between the two groups were comparable. The primary composite rate of HHF or mortality was 20.6 events per 100 patient-years in the ARNI group and 26.1 in the ACEI/ARB group; the adjusted hazard ratio was 0.98 (95% CI: 0.28-3.43, P = 0.97). Their safety outcomes did not differ significantly. Sensitivity analyses, including repetitive sampling, propensity score matching, and extended follow-up, corroborated these findings. Conclusion: ARNI has proven effective in treating HFrEF patients; however, significant benefits were not observed in these patients with ESRD undergoing dialysis compared with ACEI/ARB in this real-world cohort. Future research employing a more extended follow-up period, larger sample size, or randomized design is warranted to investigate the treatment effects in this subpopulation.

Association between treatment with sacubitril/valsartan and the risk of Alzheimer's disease: a clinical update.

Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition's benefits in heart failure, concerns about potential amyloid-beta (Aß) accumulation and Alzheimer's disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.

Trajectories of Sacubitril/Valsartan Adherence Among Medicare Beneficiaries With Heart Failure.

Background: Sacubitril/valsartan, an angiotensin receptor/neprilysin inhibitor (ARNi), improves heart failure (HF) outcomes, yet real-world adherence patterns are not well understood. Objectives: The purpose of this study was to analyze longitudinal patterns of adherence to ARNis in patients with HF and to identify factors associated with adherence patterns. Methods: Using Medicare beneficiaries from 2015 to 2018, we included patients diagnosed with HF who initiated an ARNi. A group-based trajectory model was constructed to identify adherence patterns during follow-up. We used multivariable logistic regression to investigate factors associated with membership in each adherence trajectory group. Results: Among 9,475 eligible beneficiaries (age 77 ± 7 years, 34% female), we identified 5 distinct ARNi adherence trajectories, characterized as: immediate discontinuers, who discontinued treatment within the first 3 months (12%); early discontinuers, who discontinued treatment in months 4 to 7 (10%); late discontinuers, who discontinued treatment in months 7 to 10 (12%); intermittently adherent patients (12%); and consistently adherent patients (54%). The first 4 groups were collectively categorized as nonconsistent adherents. Living in a socioeconomically disadvantaged area, ie, a county with the top 20% of Area Deprivation Index (adjusted OR [aOR]: 1.12 [95% CI: 1.00-1.24]) and Black race (aOR: 1.36, [95% CI: 1.18-1.56]) were associated with a higher likelihood of being nonconsistently adherent. Receiving prescriptions from a cardiologist (aOR: 0.64 [95% CI: 0.57-0.73]) was associated with a lower likelihood of suboptimal ARNi adherence. Conclusions: Half of ARNi users were not consistently adherent to the drug in the first year after treatment initiation. There exist significant racial and socioeconomic inequities in longitudinal adherence to ARNi.

Embracing an era of targeted combination therapy for heart failure with preserved ejection fraction.

The concept of quadruple therapy as a "one-size-fit-all" approach is effective among all eligible patients with heart failure with reduced ejection fraction, with consistent and significant clinical benefits including reduced mortality across various subgroups. However, with exception of sodium-glucose cotransporter 2 inhibitors, the consistency of benefit with therapies does not extend to patients with heart failure with preserved ejection fraction. The clinical benefits of other promising medical therapies, such as angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, and glucagon-like peptide-1 receptor agonists, have been demonstrated only in certain phenotypes of the highly heterogenous heart failure with preserved ejection fraction population. This variability can confuse frontline practicing cardiologists, potentially leading to the under-implementation of these medications. Therefore, we propose a simple approach: "targeted" combination therapy. This strategy aims to optimize evidence-based medications in heart failure with preserved ejection fraction by tailoring treatments to specific subgroups within the heart failure with preserved ejection fraction population where significant benefits are most evident.

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: real-life data from the Swedish Heart Failure Registry 2013-2020.

OBJECTIVES: This study is aimed to compare the effectiveness of modern therapy including angiotensin receptor-neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) with conventional heart failure treatment in the real world. BACKGROUND: Since ARNI and SGLT2i were introduced to treat heart failure (HF), its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). However, a comparison between conventional and modern treatment strategies with drugs in combination has not been performed. METHODS: This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n = 20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n = 709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. RESULTS: Modern HF therapy was associated with a significant 28% reduction in all-cause mortality (adjusted HR [aHR], 0.72 (0.54-0.96); p = 0.024) and a significant 62% reduction in CV mortality (aHR, 0.38 (0.21-0.68); p = 0.0013) compared to conventional HF treatment. Similar results emerged in a sensitivity analysis using propensity score matching. The interaction analyses did not reveal any trends for EF (< 40% and ≥ 40%), sex, age (< 70 and ≥ 70 years), eGFR (< 60 and ≥ 60 ml/min/1.73 m2), and etiology of HF subgroups. CONCLUSION: In this nationwide study, modern HF therapy was associated with significantly reduced all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF.

The contemporary role of sodium-glucose co-transporter 2 inhibitor (SGLT2i) and angiotensin receptor-neprilysin inhibitor (ARNI) in the management of heart failure: State-of-the-art review.

Novel therapies for heart failure with reduced ejection fraction (HFrEF) are angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose co-transporter 2 inhibitor (SGLT2i), etc. The purpose of this review is to determine the effects of ARNI and SGLT2i in heart failure (HF), compare the impact of SGLT2i with ARNI, and finally evaluate the current data regarding the combination of these two drugs in HF. Various trials on the respective medications have shown some significant reduction in all-cause mortality and cardiovascular (CV) death. The combination of these drugs has shown more CV benefits than monotherapy. There is emerging data about these two drugs in patients with heart failure with preserved ejection fraction (HFpEF). At present, there are less head-to-head comparison trials of these two drugs. This review provides insights on the current evidence, comparative efficacy, and combination therapy of ARNI and SGLT2i in managing HF, focussing on HFrEF and HFpEF.

Gut-specific Neprilysin Deletion Protects Against Fat-induced Insulin Secretory Dysfunction in Male Mice.

Neprilysin is a ubiquitous peptidase that can modulate glucose homeostasis by cleaving insulinotropic peptides. While global deletion of neprilysin protects mice against high-fat diet (HFD)-induced insulin secretory dysfunction, strategies to ablate neprilysin in a tissue-specific manner are favored to limit off-target effects. Since insulinotropic peptides are produced in the gut, we sought to determine whether gut-specific neprilysin deletion confers beneficial effects on insulin secretion similar to that of global neprilysin deletion in mice fed a HFD. Mice with conditional deletion of neprilysin in enterocytes (NEPGut-/-) were generated by crossing Vil-Cre and floxed neprilysin mice. Neprilysin activity was almost abolished throughout the gut in NEPGut-/- mice, and was similar in plasma, pancreas, and kidney in NEPGut-/- vs control mice. An oral glucose tolerance test was performed at baseline and following 14 weeks of HFD feeding, during which glucose tolerance and glucose-stimulated insulin secretion (GSIS) were assessed. Despite similar body weight gain at 14 weeks, NEPGut-/- displayed lower fasting plasma glucose levels, improved glucose tolerance, and increased GSIS compared to control mice. In conclusion, gut-specific neprilysin deletion recapitulates the enhanced GSIS seen with global neprilysin deletion in HFD-fed mice. Thus, strategies to inhibit neprilysin specifically in the gut may protect against fat-induced glucose intolerance and beta-cell dysfunction.

Clinical Benefit of Sacubitril/Valsartan for Hypertensive Patients in Daily Practice and Predictors of Its Antihypertensive Effect.

Background: The blood pressure (BP)-lowering effect of sacubitril/valsartan (Sac/Val) is greater than that of angiotensin II receptor blockers (ARBs) but in in real-world clinical practice, Sac/Val is used in a variety of patterns other than switching from ARBs. In the present study we investigated the effects of Sac/Val on BP and biochemical parameters when switching from or adding it to various antihypertensive drugs and examined what factors could be predictors of the antihypertensive effect of Sac/Val. Methods and Results: In 108 hypertensive patients treated with antihypertensive agents (including 4 naïve cases), clinic BP and various biochemical parameters were assessed before and after switching to/adding Sac/Val (200 mg/day). Systolic and diastolic BPs significantly decreased after treatment with Sac/Val (P<0.0001, respectively). As for biochemical parameters, alanine aminotransferase, triglycerides, C-reactive protein, and uric acid significantly decreased after administration of Sac/Val, but renal function, B-type natriuretic peptide, and plasma renin activity (PRA) did not change before or after treatment with Sac/Val. Multiple regression analysis revealed that low PRA and high baseline systolic BP were independent determinants of systolic BP reduction after Sac/Val treatment. Conclusions: Sac/Val is beneficial for poorly controlled hypertension in daily clinical practice and low PRA may be a predictor of the antihypertensive effect of switching to/adding Sac/Val.

Status and timing of angiotensin receptor-neprilysin inhibitor implementation in patients with heart failure and reduced ejection fraction: Data from the Swedish Heart Failure Registry.

AIMS: We explored timing, settings and predictors of angiotensin receptor-neprilysin inhibitor (ARNI) initiation in a large, nationwide cohort of patients with heart failure (HF) with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Patients with HFrEF (ejection fraction <40%) registered in the Swedish HF Registry in 2017-2021 and naïve to ARNI were evaluated for timing and location of, and their characteristics at ARNI initiation. ARNI use increased from 8.3% in 2017 to 26.7% in 2021. Among 3892 hospitalized patients, 8% initiated ARNI in-hospital or ≤14 days after discharge, 4% between 15 and 90 days, and 88% >90 days after discharge or never initiated. Factors associated with earlier initiation included follow-up in specialized HF care, more severe HF, previous HF treatment use and higher income, whereas older age, higher comorbidity burden and living alone were associated with later/no initiation. Of 16 486 HFrEF patients, 8.1% inpatients and 5.9% outpatients initiated an ARNI at the index date. Factors associated with initiation in outpatients were overall consistent with those linked with an in-hospital/earlier ARNI initiation; 4.9% of 10 209 with HF duration <6 months and 9.1% of 5877 with HF duration ≥6 months initiated ARNI. Predictors of ARNI initiation in HF duration <6 months were inpatient status, lower ejection fraction, hypertension, whereas previous angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use was associated with less likely initiation. Discontinuation at 1 year ranged between 13% and 20% across the above-reported analyses. CONCLUSIONS: In-hospital and early initiation of ARNI are limited in real-world care but still slightly more likely than in outpatients. ARNI were more likely initiated in patients with more severe HF, which might suggest its use as a second-line treatment and only following worsening of clinical status. One-year discontinuation rates were consistent regardless of the timing/setting of ARNI initiation.