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Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), is becoming more common in the treatment of heart failure and hypertension. Neprilysin is highly expressed in the renal tubules, and reports have shown increases in urinary C-peptide reactivity (CPR) levels after administration of ARNI. However, the effect of ARNI on serum CPR levels, a critical marker of insulin secretion in diabetes, remains underexplored. We evaluated the effect of ARNI on serum CPR levels in patients with type 2 diabetes and its impact on the assessment of endogenous insulin secretion. We retrospectively investigated the medical records of patients with type 2 diabetes at two hospitals, where fasting plasma glucose and serum CPR levels were measured before and after administration of ARNI. All eleven patients (five males, six females) who met the criteria showed an increase in median fasting serum CPR levels following ARNI administration. The levels rose from a median of 1.78 ng/mL (IQR: 1.26–2.02) to 3.19 ng/mL (IQR: 2.71–5.12), accompanied by significant increases in the C-peptide index. Immunoreactive insulin levels barely changed after ARNI administration, but the ratio of immunoreactive insulin to CPR decreased significantly, from 3.3 (IQR: 2.5–3.9) to 1.6 (IQR: 1.3–1.9). The increase in serum CPR levels is attributed to inhibition of CPR degradation rather than an increase in endogenous insulin secretion, as fasting blood glucose levels remained unchanged. These findings suggest the need for caution when using serum CPR levels to evaluate endogenous insulin secretion in patients treated with an ARNI, which are increasingly being prescribed for heart failure and hypertension. [ABSTRACT FROM AUTHOR]

Insect pests and fungal pathogens are estimated to cause 20–40% yield reduction to crops annually, causing $290 billion of economic loss every season worldwide. Pest and pathogen impacts are a persistent and ever-increasing problem for global food production, especially due to climate change and growing populations. Frequent use of chemical pesticides has resulted in increased resistance among pests and pathogens due to the strong selection pressure that the pesticides exert, resulting in the rapid accumulation of mutations that confer behavioural, mechanical and/or biochemical resistance within the pest populations. Due to rising resistance and increasing interest in control measures with low environmental impact, there is an immediate need to find alternative pest and pathogen management strategies. RNA interference (RNAi) has been developed as a control strategy by exploiting inherent cellular defence processes, providing a species-specific biological approach to crop management. Delivery of double-stranded RNA (dsRNA) can be accomplished non-transgenically by spray-induced gene silencing (SIGS), virus-mediated host-induced gene silencing (VmHIGS) or transgenically through host-induced gene silencing (HIGS), specifically targeting pest and pathogen messenger RNAs with sequence homology. Accomplishing effective RNAi strategies requires consideration into how SIGS, VmHIGS, and HIGS approaches intersect with the crop species and pest or pathogen being targeted. Additional technical advancements for the delivery and uptake of dsRNAs, messenger RNA target identification and the possibility of insect or fungal dsRNA resistance are currently being explored. These considerations will enhance the utility, ease of use and implementation of both spray-based and transgenic applications of RNAi technology for improved food security. [ABSTRACT FROM AUTHOR]

BackgroundWomen with heart failure with reduced ejection fraction (HFrEF) often experience worse clinical outcomes compared to men, including higher rates of mortality, hospitalization, and congestion. However, the effects of sacubitril/valsartan on these outcomes, as well as on ventricular tachyarrhythmias, have not been well studied in women with HFrEF.MethodsThis study included consecutive series of patients treated with sacubitril/valsartan at University Hospital Mannheim from 2016 to 2020. Baseline and follow-up data were compared between women and men. The endpoints included all-cause mortality, ventricular tachyarrhythmias, all-cause hospitalization, and congestion.ResultsA total of 246 patients were analyzed, comprising 50 (20.3%) women and 196 (79.7%) men. The study population consisted of 34.3% ambulatory patients and 65.7% hospitalized patients admitted for acute decompensated or symptomatic HF. The sex distribution was as follows: among women, 48.6% were ambulatory and 51.4% were hospitalized, while among men, 30.6% were ambulatory and 69.4% were hospitalized. Ischemic cardiomyopathy (ICM) was less common as a cause of heart failure (HF) in women than in men (32% vs. 57.7%, p = 0.001). During the 12-month follow-up, left ventricular ejection fraction (LVEF) improved more significantly in women than in men, increasing from 29.0% (10.0–45.0) to 40.0% (15.0–59.0) in women (p = 0.009) compared to an increase from 28.0% (3.0–65.0) to 33.0% (13.0–60.0) in men. There were no significant differences in all-cause mortality at 12-month between women and men (4% vs. 6.7%; p = 0.742). The results indicated no significant differences between the sexes in the incidence of ventricular tachyarrhythmias [ventricular fibrillation [VF] and sustained ventricular tachycardia [VT]] (4.5% vs. 0.6%; p = 0.121) (2.3% vs. 3.9%; p = 1.00), hospitalizations (70.2% vs. 67.8%; p = 0.769), congestion at 12-month follow-up (11.4% vs. 10.1%; p = 0.762). Female sex was not identified as a predictor for the occurrence of ventricular tachyarrhythmias or mortality rate at 12 months [hazard ratio (HR), 0.586; 95%-confidence interval (CI) 0.17–2.016; p = 0.397] (HR, 1.898; 95%-CI 0.381–9.464; p = 0.434).ConclusionWomen with HFrEF treated with sacubitril/valsartan showed a greater improvement in LVEF compared to men, though clinical outcomes were similar across sexes. Female sex was not a predictor of ventricular tachyarrhythmias or mortality at 12 months.

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.

Background: Heart failure (HF) is a highly prevalent syndrome in elderly subjects. Currently, multiple drugs have shown clinical benefits in patients with HF and reduced ejection fraction (HFrEF). However, evidence is scarce in elderly patients (beyond 75 years old), even more so for the latest drugs, such as angiotensin receptor-neprilysin inhibitors (ARNIs). This study aims to evaluate the use and benefits of ARNIs in elderly patients with HFrEF. Methods: A prospective observational cohort study was designed. Patients with left ventricular systolic dysfunction (defined by left ventricular ejection fraction [LVEF] < 40%) and age ≥ 75 years from January 2016 to December 2020 were prospectively included. Patients with an indication for ARNIs at inclusion or throughout follow-up were selected. Clinical, electrocardiographic and echocardiographic variables were collected. Results: A total of 616 patients were included, 34.4% of them female, with a mean age of 83.3 years, mean LVEF of 28.5% and ischemic etiology in 53.9% of patients. Only 14.3% of patients were taking ARNIs. After a mean follow-up of 34 months, 50.2% of patients died, and 62.2% had a cardiac event (total mortality or hospital admission due to HF). Multivariate Cox regression analysis showed that the use of ARNIs was independently and significantly associated with lower rates of mortality [HR 0.36 (95% CI 0.21–0.61)], with similar results in relation to all-cause mortality in a propensity-score-matched analysis [HR 0.33 (95% CI 0.19–0.57)]. Conclusions: We observed an important underuse of ARNIs in a cohort of elderly HFrEF patients, in which treatment with ARNIs was associated with a significant reduction in mortality. Greater implementation of clinical practice guidelines in this group of patients could improve their prognosis. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a progressive clinical syndrome characterized by the inability of the heart to efficiently perform its circulatory function. The burden of HF has been increasing globally, including in India, leading to higher mortality rates, hospitalizations, and diminished quality of life. The incidence of HF in India is expected to rise due to factors such as an aging population, increased cardiovascular risk factors, and the persistence of diseases like rheumatic heart disease. Despite advances in medical therapy, HF continues to impose a significant healthcare and economic burden. To understand the underlying substrate of hypertension leading to HF, a group of 20 experts from various regions of India participated in a national-level expert panel meeting. The experts reviewed scientific literature and discussed the management of hypertension, dyslipidemia, and HF in the Indian context. Consensus statements were developed based on the discussions and approved by all participating experts. Key findings include early onset of end-organ damage and microalbuminuria in Indian hypertensive patients, elevated sympathetic overactivity in certain subgroups, and the efficacy of combination therapies and calcium channel blockers. The management of dyslipidemias was found to be suboptimal, with physician inertia and concerns about side effects being barriers to guideline-directed therapy. Recommendations were made to improve physician education and patient awareness. In HF management, challenges were identified, and strategies were proposed to optimize guideline-directed medical therapy and implement newer therapies such as angiotensin receptor-neprilysin inhibitors (ARNIs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors. This consensus document provides valuable insights and recommendations for managing hypertension, dyslipidemia, and HF in the Indian population, with the potential to improve patient outcomes and reduce the burden of HF. [ABSTRACT FROM AUTHOR]

Background: Myocardial ischemia-reperfusion injury (I/R) has been improved with drugs and effective reperfusion, but it still cannot be prevented. Methods: To investigate whether renal denervation (RDN) reduces cardiomyocyte apoptosis by ameliorating endoplasmic reticulum stress, 60 male specific pathogen-free (SPF) Wistar rats were randomly divided into 6 groups (n = 6). We established the I/R rat model by ligating the left anterior descending artery. The I/R+ angiotensin receptor neprilysin inhibitors (ARNI) group received ARNIs for 2 weeks until euthanasia. Results: The I/R+RDN and I/R+ARNI groups have signifiantly ameliorated left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS) and reversed expansion of the left ventricular end-systolic diameter (LVSD) and left ventricular end diastolic diameter (LVDD) compared to the I/R group. The levels of norepinephrine (NE), angiotensin II, and aldosterone (ALD) increased signifiantly in the I/R group, but decreased signifiantly after RDN and ARNI intervention. In the I/R+RDN and I/R+ARNI groups, the myocardial tissue edema was alleviated. The infarct size was smaller in the I/R+RDN and I/R+ARNI groups compared to the I/R group. Apoptosis of cardiomyocytes and fib oblasts in myocardial tissue increased signifiantly in the I/R group, which was greatly diminished by RDN and ARNI. The expression of Bax, caspase-3, CHOP, PERK, and ATF4 protein was signifiantly increased in the I/R group, which compared to other groups, and the level of CHOP, PERK, and ATF4 gene expression increased. After RDN intervention, these expression levels recovered to varying degrees. Conclusion: The effect of RDN may be associated with regulating the endoplasmic reticulum stress PERK/ATF4 signaling pathway. [ABSTRACT FROM AUTHOR]

Aims: The effects of initiating sacubitril/valsartan in patients with stable heart failure with reduced ejection fraction (HFrEF) on response to fluid and sodium expansion are unknown. Methods and results: We have explored changes in natriuresis, diuresis, and congestion in response to the administration of intravenous fluid/sodium load in patients with HFrEF before as compared to after the initiation of sacubitril/valsartan. At baseline (before sacubitril/valsartan initiation) and 2 and 3 months after the initiation, patients underwent an evaluation that consisted of three phases of 3 h: the rest phase (0–3 h), the load phase (3–6 h) in which 1 L of intravenous Ringer solution was administered, and the diuretic phase (6–9 h) at the beginning of which furosemide was administered. Overall, 216 patients completed the study. In comparison to baseline values, at 2 and 3 months after sacubitril/valsartan initiation, patients' diuresis and natriuresis in response to Ringer administration significantly increased (mean difference: 38.8 [17.38] ml, p = 0.0040, and 9.6 [2.02] mmol, p < 0.0001, respectively). Symptoms and signs of congestion after the fluid/sodium challenge were significantly decreased at months 2 and 3 compared to baseline. Compared to baseline, there was also an increment of natriuresis after furosemide administration on sacubitril/valsartan (9.8 [5.13] mmol, p = 0.0167). There was a significant decrease in body weight in subsequent visits when compared to baseline values (−0.50 [−12.7, 7.4] kg at 2 months, and −0.75 [−15.9, 7.5] kg at 3 months; both p < 0.0001). Conclusions: The initiation of sacubitril/valsartan in HFrEF patients was associated with improvements in natriuresis, diuresis, and weight loss and better clinical adaptation to potentially decongestive stressors. [ABSTRACT FROM AUTHOR]

Cardiovascular Diseases (CVD) have claimed millions of lives, despite the efforts of medical professionals. There are several treatment methods for blocking a few neurohormonal cascades; however, it is debatable because there are few hypotheses, which claim that in Heart Failure (HF), these systems tend to activate potential counter-regulatory mechanisms. Angiotensin Receptor Neprilysin Inhibitors (ARNI) are developed to modulate both Renin-Angiotensi n-Aldosterone-System and Natriuretic Peptide, regulating neurohormonal cascade in HF. LCZ696 (Sacubitril/Valsartan) is the first-in-class ARNI, approved for managing HF. Initially, ARNI was developed to manage Hypertension, later the FDA regulatory label was expanded for the management of HF. Dapagliflozin belongs to the class of SGLT2 inhibitors that have shown potentially beneficial effects in HF. Would the two medications, which have distinct mechanisms of action but a similar effect-a decrease in the risk of HF-show additive or synergistic effects when taken together? India, known as "The Chronic Heart Disease Capital of the World", is accounting sharp rise in sudden cardiac death with young adults being the worst sufferers. This review inference that, using ARNI and Dapagliflozin together may have a larger positive effect on HF patients' quality of life by lowering their need for hospitalization due to HF deterioration. [ABSTRACT FROM AUTHOR]

This review article examines the mechanism of action of Angiotensin Receptor–Neprilysin Inhibitors (ARNIs) and Sodium–Glucose Co-Transporter 2 Inhibitors (SGLT2is) in managing chronic right ventricular (RV) dysfunction. Despite advancements in heart failure (HF) treatment, RV dysfunction remains a significant contributor to morbidity and mortality. This article explores the The article explores the impact of ARNIs and SGLT2is on RV function based on clinical and preclinical evidence, and the potential benefits of combined therapy. It highlights the need for further research to optimize patient outcomes and suggests that RV function should be considered in future clinical trials as part of risk stratification for HF therapies. This review underscores the importance of the early initiation of ARNIs and SGLT2is as per guideline-directed medical therapy for eligible HFrEF and HFpEF patients to improve co-existing RV dysfunction. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation is a constant phenomenon which accompanies the heart failure pathophysiology. In all phenotypes of heart failure, irrespective of the ejection fraction, there is a permanent low-grade activation and synthesis of proinflammatory cytokines. Many classes of anti-remodelling medication used in the treatment of chronic heart failure have been postulated to have an anti-inflammatory effect. Methods: This retrospective study enrolled 220 patients and focused on evaluating the effect of the most used active substances from these classes in reducing the level of inflammatory biomarkers (C reactive protein, erythrocyte sedimentation rate and fibrinogen) after initiation or up-titration. Our research is evaluating if this anti-inflammatory effect intensifies while raising the dose. The evaluation was performed at two visits with an interval between them of 6 months. Results: From the beta-blockers class, carvedilol showed a reduction in erythrocyte sedimentation rate (ESR), in low (6.25 mg, bi daily) and medium (12.5 mg, bi daily) doses. At the same time, sacubitril/valsartan showed a reduction in CRP levels. This effect was obtained only in the medium (49/51 mg, bi daily) and high (97/103 mg, bi daily) doses, with the maximum reduction being observed in the high dose. Conclusions: From the classes of medication evaluated, the study showed a significant reduction in ESR levels in the low and medium doses of carvedilol and a reduction in CRP values in the cases of medium and high doses of ARNI. [ABSTRACT FROM AUTHOR]

Background: In patients with heart failure with reduced ejection fraction (HFrEF), treatment with sacubitril–valsartan (S/V) may reverse left ventricular remodeling (rLVR). Whether this effect is superior to that induced by other renin–angiotensin system (RAS) inhibitors is not well known. Methods: HFrEF patients treated with S/V (n = 795) were compared, by propensity score matching, with a historical cohort of 831 HFrEF patients (non-S/V group) treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (RAS inhibitors). All patients were also treated with beta-blockers and shared the same protocol with repeat echocardiogram 8–12 months after starting therapy. The difference-in-difference (DiD) analysis was used to evaluate the impact of S/V on CR indices between the two groups. Results: After propensity score matching, compared to non-S/V group (n = 354), S/V group (n = 354) showed a relative greater reduction in end-diastolic and end-systolic volume index (ESVI), and greater increase in ejection fraction (DiD estimator = + 5.42 mL/m2, P = 0.0005; + 4.68 mL/m2, P = 0.0009, and + 1.76%, P = 0.002, respectively). Reverse LVR (reduction in ESVI ≥ 15% from baseline) was more prevalent in S/V than in non-S/V group (34% vs 26%, P = 0.017), while adverse LVR (aLVR, increase in ESVI at follow-up ≥ 15%) was more frequent in non-S/V than in S/V (16% vs 7%, P < 0.001). The beneficial effect of S/V on CR over other RAS inhibitors was appreciable across a wide range of patient's age and baseline end-diastolic volume index, but it tended to attenuate in more dilated left ventricles (P for interaction = NS for both). Conclusion: In HFrEF patients treated with beta-blockers, sacubitril/valsartan is associated with a relative greater benefit in LV reverse remodeling indices than other RAS inhibitors. [ABSTRACT FROM AUTHOR]

Background Optimal medical treatment can lead to improvement in left ventricular ejection fraction (LVEF) in patients with heart failure with reduced EF (HFrEF). We investigated the characteristics, predictors, and outcomes of HFrEF according to the 1‐year LVEF following angiotensin receptor–neprilysin inhibitors therapy (ARNI). Methods and Results Using the STRATS‐HF‐ARNI (Strain for Risk Assessment and Therapeutic Strategies in Patients With Heart Failure Treated With Angiotensin Receptor‐Neprilysin Inhibitor) registry, we identified 1074 patients with HFrEF who took ARNI and underwent baseline and 1‐year echocardiography. Patients were classified as HF with improved ejection fraction (HFimpEF) and persistent HFrEF (perHFrEF) (1‐year LVEF >40% and ≤40%). The primary and secondary outcomes were all‐cause and cardiac mortality from the 1‐year follow‐up. Among 1074 included patients, 498 (46.4%) had HFimpEF, and 576 (53.6%) had perHFrEF. Older age, male sex, and large LV end‐diastolic volumes were positive predictors of perHFrEF, whereas atrial fibrillation and high systolic blood pressure were identified as inverse predictors. Patients with HFimpEF showed lower all‐cause and cardiac mortality rates (both log‐rank P

Abstract Aims Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first‐line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. Methods and results A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10 years. The model included treatment specific all‐cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000–12 300 life years gained and 2600–4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112–195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. Conclusions Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first‐line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom.

Aims: Recent updates of international treatment guidelines for heart failure with reduced ejection fraction (HFrEF) differ regarding the use of angiotensin receptor neprilysin inhibitor (ARNI) as first‐line treatment. The American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) 2022 guidelines gives ARNI a Class IA recommendation for HFrEF patients while the European Society of Cardiology's guidelines are less clear when ARNI could be considered as first line treatment option in de novo patients. This study aimed to model the clinical and budgetary outcomes of implementing these guidelines, comparing conservative ARNI prescription patterns with less conservative in Sweden and in the United Kingdom. Methods and results: A health economic model was developed to compare different treatment patterns for HFrEF. Incident cohorts were included on an annual basis and followed over 10 years. The model included treatment specific all‐cause mortality and hospitalization rates, as well as drug acquisition, monitoring, and hospitalization costs. Increasing the use of ARNI could lead to about 7000–12 300 life years gained and 2600–4600 hospitalizations prevented in Sweden. These health benefits come with an additional cost of 112–195 million euros. Similar results were estimated for the United Kingdom, albeit on a larger population. Conclusions: Increasing the proportion of patients receiving ARNI instead of angiotensin converting enzyme inhibitors as first‐line treatment of HFrEF will lead to a considerable number of additional life years gained and prevented hospitalizations but with additional cost in terms of health care expenditure in Sweden and in the United Kingdom. [ABSTRACT FROM AUTHOR]

Background: Sacubitril/valsartan improves heart failure (HF) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, randomized controlled trials (RCTs) in patients with heart failure and mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) have shown inconsistent results. We conducted this meta-analysis to comprehensively evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan within this specific patient population. Methods: We searched the MEDLINE database and ClinicalTrials.gov and identified four RCTs that could be included in our analysis, with 3375 patients in the sacubitril/valsartan group and 3362 in the valsartan group. Results: Our study shows that, in patients with HFmrEF and HFpEF, sacubitril/valsartan was superior to valsartan in some of the key HF outcomes, such as the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), with a small but significant mean difference of 1.13 (95% confidence interval or CI of 0.15 to 2.11, p-value 0.024), an improvement in the New York Heart Association (NYHA) class (odds ratio or OR of 1.32, 95% CI 1.11 to 1.58, p-value 0.002), and the composite outcome of hospitalizations for HF and cardiovascular death, with a relative risk (RR) of 0.86 (95% CI 0.75 to 0.99, p-value 0.04). However, there was no additional benefit with sacubitril/valsartan compared to valsartan for the outcomes of cardiovascular death and all-cause mortality. In terms of side effects, sacubitril/valsartan was associated with a higher risk of hypotension when compared to valsartan (OR 1.67, 95% CI 1.27 to 2.19, p-value < 0.0001), but did not show an increased risk of hyperkalemia or worsening renal function. Conclusions: In individuals with HFmrEF or HFpEF, sacubitril/valsartan can result in improvements in the HF outcomes of the KCCQ CSS, the NYHA class, and the composite outcome of hospitalization for HF and cardiovascular death when compared to valsartan. While there was a higher risk of hypotension with sacubitril/valsartan compared to valsartan, there was no corresponding increase in the risk of hyperkalemia or worsening renal function. [ABSTRACT FROM AUTHOR]

Background Heart failure with reduced ejection fraction is associated with potentially deleterious imbalance of the cardiac autonomic nervous system. Sacubitril/valsartan (angiotensin receptor‐neprilysin inhibitor [ARNI]) reduces cardiovascular mortality and hospitalization for heart failure with reduced ejection fraction. Whether ARNI affects the cardiac autonomic nervous system has not been studied. Methods and Results This investigator‐initiated, prospective, single‐center cohort study compared heart rate (HR) variability, HR, deceleration capacity, and periodic repolarization dynamics as noninvasive measures of the cardiac autonomic nervous system before and after initiation of ARNI therapy. Patients underwent standardized 12‐lead Holter‐ECG, echocardiography and laboratory testing before and 3 months after start of therapy. End points were changes in HR variability (SD of normal‐to‐normal intervals, mean square of differences between consecutive R‐R intervals), HR, deceleration capacity, and periodic repolarization dynamics as well as ventricular function and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide). Of 63 patients with heart failure with reduced ejection fraction enrolled, 48 (76.2%) patients were still on ARNI at follow‐up. SD of normal‐to‐normal intervals increased from 25 to 36 milliseconds (P

Introduction and purpose: Heart failure is one of the most common cardiovascular diseases worldwide. It is an important factor leading to a reduced, health-related quality of life (HRQoL) not only because of its various symptoms but also due to loss of jobs or increase in medical expenses impairing the socioeconomic status of the sick. Nowadays scientists face this problem and are trying to invent specific pharmacotherapy that allows it to extend life and improve its quality. One of the elements of modern pharmacotherapy is the combination of sacubitril with valsartan. This work aims to evaluate the effect of this drug on the length and quality of life of patients with heart failure. Materials and methods: This article is a literature review based on publications from PubMed, Cochrane Library, ClinicalKey released since 2014, keywords included: sacubitril/valsartan; angiotensin receptor–neprilysin inhibitor; ARNI; heart failure. The state of knowledge: The use of sacubitril/valsartan drugs is an established agent used to reduce the risk of death from any cause in all patients with heart failure with reduced ejection fraction, death from cardiovascular causes and the rate of hospitalization due to exacerbation of symptoms. Some study analyses also indicate the utility of using sacubitril/valsartan in HFmrEF and HFpEF to reduce the rate of cardiovascular events and hospitalization because of heart failure. Conclusions: The use of sacubitril/valsartan is recognized to improve prognosis in patients with HFrEF. Evidence supporting its efficacy in the subgroup of patients with mid-range and preserved ejection fraction is still insufficient and requires further investigation.

Heart failure is a possible complication following ST-elevation myocardial infarction (STEMI) even after revascularization. Neuroendocrine activation in the process of ventricular remodeling can be regulated by angiotensin receptor-neprilysin inhibitor (ARNI) as well as angiotensin-converting enzyme (ACE) inhibitor. The use of ARNI in heart failure with reduced ejection fraction has been found to be superior to ACE inhibitor. The role of ARNI on cardiac function in STEMI has not been established. A clinician treating a patient with STEMI considered giving sacubitril/valsartan to reduce the risk of developing heart failure. Literature search was performed in three electronic databases: PubMed, Embase, and Cochrane. Keywords in the form of text words and MeSH terms were arranged using Boolean operator technique. Critical appraisal of selected articles was carried out according to the guideline from Oxford Centre for Evidence-Based Medicine. Four relevant randomized clinical trials were obtained. There was a reduced risk of heart failure events at 6 months following STEMI who underwent percutaneous coronary intervention (PCI) in the sacubitril/valsartan group compared to ACE inhibitor group, with a relative risk (RR) of 0.35 (95%CI 0.15 – 0.84; p=0.037); RR 0.5 (95%CI 0.31 – 0.82; p=0.004); and number needed to treat (NNT) of 6. Similar results were also found in STEMI patients complicated by cardiogenic shock: RR 0.47 (95%CI 0.24 – 0.94; p=0.044). Sacubitril/valsartan is more effective than ACE inhibitor in reducing the risk of heart failure at 6 months following STEMI post-PCI.

Background: Angiotensin receptor/neprilysin inhibitor (ARNI) and sodiumglucose cotransporter 2 inhibitor (SGLT2i) have shown a significant protective role against cardiovascular diseases and type 2 diabetes mellitus (T2DM), and there is a growing proportion of patients who are undergoing combined therapy with the two drugs. However, the effect of this combination treatment on renal function has not yet been determined. Methods: This study included 539 patients who were diagnosed with cardiovascular disease combined with T2DM. According to the use of SGLT2i and ARNI, patients were divided into the combination treatment group, SGLT2i group, ARNI group and control group. Primary outcomes were serum creatinine (Scr) and estimated glomerular filtration rate (eGFR) changes in the 6th month and 12th month. Results: In the ARNI group, no significant changes in Scr or eGFR were observed during the follow-up period, while the above indicators showed a trend of deterioration in the other three groups. The univariate analysis results showed that at 6 months of follow-up, the renal function indicators of patients treated with ARNI (either alone or in combination) were better than those treated with SGLT2i alone. After 12 months of follow-up, the Scr results were the same as before, while the difference in eGFR between groups disappeared. After multivariate analysis, in terms of delaying the progression of Scr, the ARNI group was superior to the other groups at the end of follow-up. No significant difference in eGFR was observed between groups during follow-up. Conclusion: In patients with cardiovascular disease and T2DM, combination therapy with ARNI and SGLT2i did not show an advantage over monotherapy in delaying renal insufficiency progression, and renal function seems to be better preserved in patients treated with ARNI alone. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is a significant public health concern characterized by notable rates of morbidity and mortality. Multimorbidity, ranging from 43% to 98% among HF patients, significantly impacts prognosis and treatment response. HF management requires a holistic approach, including guideline-directed medical therapy. Sacubitril/valsartan (angiotensin receptor neprilysin inhibitor [ARNI]) is a cornerstone of HF treatment, supported by robust evidence from large-scale clinical trials across different levels of left ventricular ejection fraction. The recommendations presented in this paper have been developed by a group of cardiologists in India who convened in expert opinion meetings to discuss the utilization of ARNI in chronic HF patients with five different comorbid conditions like type 2 diabetes mellitus (T2DM), chronic kidney disease, myocardial infarction (MI), obesity, and hypertension. Key focus areas include initiation, dose titration, and management across different HF phenotypes and comorbidities. Emphasis is placed on the efficacy of ARNI irrespective of glycemic status in the T2DM population, its role in HF patients with obesity, and addressing challenges related to renal function decline and hyperkalemia. Additionally, the document highlights ARNI's potential benefits in hypertensive and post-MI HF patients, alongside observations on the obesity paradox in HF prognosis. Overall, these recommendations aim to optimize ARNI therapy in HF patient populations with different comorbidities, addressing specific challenges and considerations to improve outcomes and quality of life. Plain language summary: Angiotensin receptor neprilysin inhibitor (ARNI) in chronic heart failure and comorbidity management: Indian consensus statement Heart failure (HF) is a significant public health concern characterized by notable rates of morbidity and mortality. Multimorbidity, ranging from 43% to 98% among HF patients, significantly impacts prognosis and treatment response. HF management requires a holistic approach, including guideline-directed medical therapy (GDMT). Sacubitril/valsartan (ARNI) is a cornerstone of HF treatment, supported by robust evidence from large-scale clinical trials across different levels of left ventricular ejection fraction (LVEF). The recommendations presented in this paper have been developed by a group of cardiologists in India who convened in seven advisory board meetings to discuss the utilization of ARNI in chronic HF (CHF) patients with different comorbid conditions like Type 2 diabetes mellitus (T2DM), chronic kidney disease (CKD), myocardial infarction (MI), obesity, and hypertension. Key focus areas include initiation, dose titration, and management across different HF phenotypes and comorbidities. Emphasis is placed on the efficacy of ARNI irrespective of glycemic status in the T2DM population, its role in HF patients with obesity, and addressing challenges related to renal function decline and hyperkalemia. Additionally, the document highlights ARNI's potential benefits in hypertensive and post-MI HF patients, alongside observations on the "obesity paradox" in HF prognosis. The paper underscores the importance of accurate biomarkers and imaging in HF diagnosis and monitoring. Overall, these recommendations aim to optimize ARNI therapy in HF patient populations with different comorbidities, addressing specific challenges and considerations to improve outcomes and quality of life. [ABSTRACT FROM AUTHOR]

Purpose: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications. Methods: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy. Results: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure. Conclusion: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions. [ABSTRACT FROM AUTHOR]

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This review article examines the mechanism of action of Angiotensin Receptor–Neprilysin Inhibitors (ARNIs) and Sodium–Glucose Co-Transporter 2 Inhibitors (SGLT2is) in managing chronic right ventricular (RV) dysfunction. Despite advancements in heart failure (HF) treatment, RV dysfunction remains a significant contributor to morbidity and mortality. This article explores the The article explores the impact of ARNIs and SGLT2is on RV function based on clinical and preclinical evidence, and the potential benefits of combined therapy. It highlights the need for further research to optimize patient outcomes and suggests that RV function should be considered in future clinical trials as part of risk stratification for HF therapies. This review underscores the importance of the early initiation of ARNIs and SGLT2is as per guideline-directed medical therapy for eligible HFrEF and HFpEF patients to improve co-existing RV dysfunction.

Background Aldosterone has been assumed to be one of aggravating factors in diabetic kidney disease (DKD). Natriuretic peptides/guanylyl cyclase-A/cGMP signalling has been shown to ameliorate aldosterone-induced renal injury in mice. Sacubitril/valsartan (SAC/VAL) is used clinically for chronic heart failure and hypertension, in part by augmenting natriuretic peptide bioavailability. The effects of SAC/VAL on renal pathophysiology including in DKD, however, have remained unclarified. Methods Eight-week-old male db/db mice fed on a high-salt diet (HSD) were treated with vehicle or aldosterone (0.2 μg/kg/min), and divided into four groups: HSD control, ALDO (aldosterone), ALDO + VAL (valsartan), and ALDO + SAC/VAL group. After 4 weeks, they were analysed for plasma atrial natriuretic peptide (ANP) levels, renal histology, and haemodynamic parameters including glomerular filtration rate (GFR) by FITC-inulin and renal plasma flow (RPF) by para-amino hippuric acid. Results The ALDO + SAC/VAL group showed significantly increased plasma ANP concentration and creatinine clearance, and decreased tubulointerstitial fibrosis and neutrophil gelatinase-associated lipocalin expression compared to ALDO and ALDO + VAL groups. SAC/VAL treatment increased GFR and RPF, and suppressed expression of Tgfb1, Il1b, Ccl2 , and Lcn2 genes compared to the ALDO group. The percentage of tubulointerstitial fibrotic areas negatively correlated with the RPF and GFR. Conclusion In a mouse model of type 2 diabetes with aldosterone excess, SAC/VAL increased RPF and GFR, and ameliorated tubulointerstitial fibrosis. Furthermore, RPF negatively correlated well with tubulointerstitial injury, suggesting that the beneficial effects of SAC/VAL could be through increased renal plasma flow with enhanced natriuretic peptide bioavailability. [ABSTRACT FROM AUTHOR]

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Abstract Background and aims Clinical comparisons of angiotensin receptor–neprilysin inhibitors (ARNI) and sodium–glucose cotransporter 2 inhibitors (SGLT2i) treatment in patients with HFrEF and T2DM are limited. This study evaluated the clinical outcomes and treatment benefits of SGLT2i versus ARNI treatment in patients with HFrEF and T2DM in a large real-world data set. Methods We identified 1487 patients with HFrEF and T2DM who were undergoing ARNI or SGLT2i treatment for the first time (n = 647 and 840, respectively) between January 1, 2016, and December 31, 2021, and with clinical outcomes of CV death, hospitalization for heart failure (HHF), composite CV outcomes, or renal outcomes. Results The HHF risk reduction conferred by SGLT2i treatment was more significant than that conferred by ARNI treatment (37.7% vs. 30.4%; 95% confidence interval [CI] 1.06–1.41). SGLT2i use conferred significantly greater renal protection against the doubling of serum creatinine (13.1% vs. 9.3%; 95% CI 1.05–1.75), an estimated glomerular filtration rate decline of > 50% (24.9% vs. 20.0%; 95% CI 1.02–1.45), and progression to end-stage renal disease (3.1% vs. 1.5%; 95% CI 1.62–5.23). The improvements in echocardiographic parameters were comparable between the groups. Conclusions Compared with ARNI treatment, SGLT2i treatment was associated with a more significant HHF risk reduction and greater preservation of renal function in patients with HFrEF and T2DM. This study also supports the prioritization of SGLT2i use in these patients when patients' conditions or economic resources need to be considered.

One of the most relevant and differentiating aspects provided by the 2021 European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic heart failure is the retraction of the historical stepped and vertical pharmacological treatment scheme for heart failure with reduced ejection fraction (HFrEF). Subsequently, it was replaced by an updated algorithm that places four therapeutic families in the same initial horizontal step with an equally high degree of recommendation (class I). In this context, these four pillars, which have demonstrated a significant reduction in mortality and hospitalizations in patients with HFrEF, include (1) angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB)/angiotensin II receptor-neprilysin inhibitors (ARNi), (2) beta blockers, (3) mineralocorticoid receptor antagonists (MRA) and (4) sodium–glucose cotransporter 2 inhibitors (SGLT2is) as the main novelty. This manuscript reviews the current therapeutic algorithm with a special focus on the therapeutic value of adding an MRA (still underused in both clinical trials and real world), changing an ACEi/ARB for an ARNi and incorporating an SGLT2i in patients with HFrEF. This article is part of the Emerging concepts in heart failure management and treatment Special Issue: https://www.drugsincontext.com/special_issues/emerging-concepts-in-heart-failure-management-and-treatment

Abstract 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.

In patients hospitalized for acute decompensation of heart failure (HF), the impact of angiotensin receptor-neprilysin inhibitor (ARNI) on diuresis and renal function has not been fully investigated. Patients with HF and reduced ejection fraction who were hospitalized for acute decompensation and newly initiated ARNI after hemodynamic stabilization were enrolled. Changes in urine volume (UV), body weight, estimated glomerular filtration rate (eGFR), and urine N-acetyl-beta-d-glucosaminidase (uNAG) levels before and after ARNI initiation were investigated. Changes in the diuretic response [DR, calculated as urine volume/(intravenous furosemide volume/40 mg)], N-terminal pro-brain natriuretic peptide (NT-proBNP), hematocrit, and plasma volume (PV) were also evaluated. A total of 60 patients were enrolled. ARNI was initiated at a median of 6 [5, 7] days after hospitalization. After initiation of ARNI, body weight, NT-proBNP, and PV decreased. UV and DR increased only on the day of ARNI initiation (delta UV 400 ± 957 ml and delta DR 1100 ± 3107 ml/40 mg furosemide) and then decreased to baseline levels. In the multivariable linear regression analysis, younger age, higher BMI, and higher NT-proBNP levels were significantly associated with greater UV after ARNI initiation. eGFR and uNAG did not significantly change after the initiation of ARNI [delta eGFR -1.7 ± 12.0 mL/min/1.73 m2 and delta uNAG 2.0 (−5.6, 6.9) IU/L]. In patients hospitalized for HF, the initiation of ARNI was associated with a small and transient increase in UV and DR, and was not associated with worsening of renal function or tubular injury. [ABSTRACT FROM AUTHOR]

Background: Atrial septal defect(ASD) is a common congenital heart disease. Large ASDs result in increased pulmonary flow and pressures resulting in Eisenmenger syndrome(ES). Sacubitril/Valsartan is an angiotensin-receptor neprilysin inhibitor (ARNI), multiple Randomised control trials(RCT) have demonstrated its effectiveness in reducing heart failure(HF), rehospitalization, improving left ventricular ejection fraction (LVEF), LV reverse remodeling and lowering mortality in HF patients. Aim: The aim of this study is to evaluate right ventricular function in patients with large atrial septal defects with Eisenmenger syndrome initiated on ARNI. Methodology: In this single center prospective study, all ASD patients with ES and HF prescribed ARNI between August 2019 to August 2022 were identified. The NYHA functional class, 6MWT, TAPSE, LVEF, RVEF, PA pressures, NT-proBNP for each patient was established at baseline and at the end of 12 months. Results: The comparison of changes of the NYHA class, 6MWT, TAPSE, RVEF, PA pressures and NT-pro BNP from baseline to 12 months was statistically significant in our study. (p=0.001). Conclusion: ARNI treatment improves functional class, 6MWT, RVEF, PA pressures and decreases heart failure hospitalizations and NT-pro BNP in ASD-ES HF patients. [ABSTRACT FROM AUTHOR]

Despite the fact that cardiovascular disease (CVD) is the number 1 cause of death globally, investment in drug development and new drug approvals for CVD are precipitously declining. In contrast, the trajectory of both investment in development as well as new drug approvals for oncology have been increasing steadily over the same time frame. The factors that have spurred drug development in oncology may be applicable to new efforts to overcome barriers to drug development for CVD. Greater investment in basic research and application of expedited regulatory pathways have contributed to a lowering of development barriers in oncology. Barriers in implementation are also critical. More rapid adoption of guideline-based therapies and lower access barriers by payers have contributed to fewer implementation barriers for oncology therapeutics. There is substantially greater advocacy among patients and physicians for new oncology therapeutics, and such advocacy efforts are likely to have had a meaningful impact on lowering barriers to develop new oncology therapeutics. Broad support of patient and physician advocacy efforts directed towards CVD may help overcome existing development and implementation barriers to new drug development, thereby spurring more rapid progress in the fight to eradicate cardiovascular disease.

Abstract 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

BackgroundDiffuse interstitial myocardial fibrosis is a key common pathological manifestation in hypertensive heart disease (HHD) progressing to heart failure (HF). Angiotensin receptor–neprilysin inhibitors (ARNi), now a front-line treatment for HF, confer benefits independent of blood pressure, signifying a multifactorial mode of action beyond hemodynamic regulation. We aim to test the hypothesis that compared with angiotensin II receptor blockade (ARB) alone, ARNi is more effective in regressing diffuse interstitial myocardial fibrosis in HHD.MethodsRole of ARNi in Ventricular Remodeling in Hypertensive LVH (REVERSE-LVH) is a prospective, randomized, open-label, blinded endpoint (PROBE) clinical trial. Adults with hypertension and left ventricular hypertrophy (LVH) according to Asian sex- and age-specific thresholds on cardiovascular magnetic resonance (CMR) imaging are randomized to treatment with either sacubitril/valsartan (an ARNi) or valsartan (an ARB) in 1:1 ratio for a duration of 52 weeks, at the end of which a repeat CMR is performed to assess differential changes from baseline between the two groups. The primary endpoint is the change in CMR-derived diffuse interstitial fibrosis volume. Secondary endpoints include changes in CMR-derived left ventricular mass, volumes, and functional parameters. Serum samples are collected and stored to assess the effects of ARNi, compared with ARB, on circulating biomarkers of cardiac remodeling. The endpoints will be analyzed with reference to the corresponding baseline parameters to evaluate the therapeutic effect of sacubitril/valsartan vs. valsartan.DiscussionREVERSE-LVH will examine the anti-fibrotic potential of sacubitril/valsartan and will offer mechanistic insights into the clinical benefits of sacubitril/valsartan in hypertension in relation to cardiac remodeling. Advancing the knowledge of the pathophysiology of HHD will consolidate effective risk stratification and personalized treatment through a multimodal manner integrating complementary CMR and biomarkers into the conventional care approach.Clinical Trial Registration: ClinicalTrials.gov, identifier, NCT03553810.

(1) Background: Heart failure with reduced ejection fraction (HFrEF) remains a major health burden. Angiotensin-Receptor-Neprilysin-Inhibitors (ARNIs) are an established HFrEF therapy which increases natriuretic peptide levels by inhibiting neprilysin. Leptin is a lipid metabolism parameter, which is also involved in glucose metabolism and is suggested to correlate with HF burden. While the hormone also seems to interact with neprilysin, potential associations with ARNI therapy have not been investigated yet. (2) Methods: To study this issue, we measured levels of leptin and fructosamine in consecutive 72 HFrEF patients before initiation of ARNI therapy and 3–6 months after initiation of therapy in two European centers. Biomarker levels were correlated with clinical parameters including ejection fraction, LVEF, and NYHA class. (3) Results: During a follow-up of up to 6 months, clinical parameters improved significantly (LVEF: 30.2 ± 7.8% to 37.6 ± 10.0%, (p < 0.001) and a significant improvement of the mean NYHA class with initial 32 patients in NYHA III or IV and 8 patients in NYHA class III/IV during the follow up (p < 0.001). The initial NT-proBNP levels of 2251.5 ± 2566.8 pg/mL significantly improved to 1416.7 ± 2145 pg/mL, p = 0.008) during follow up. ARNI therapy was also associated with an increase in leptin levels (17.5 ± 23.4 µg/L to 22.9 ± 29.3, p < 0.001) and furthermore, affected glucose metabolism indicated by elevation of fructosamine values (333.9 ± 156.8 µmol/L to 454.8 ± 197.8 µmol/L, p = 0.013). (4) Conclusion: while in the early phase of therapy, ARNI promotes clinical improvement of HFrEF, and it also seems to affect fat and glucose parameters, indicating significant metabolic implications of this therapy regime. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction, causing increased reactive oxygen species (ROS) production, is a molecular feature of heart failure (HF). A defective antioxidant response and mitophagic flux were reported in circulating leucocytes of patients with chronic HF and reduced ejection fraction (HFrEF). Atrial natriuretic peptide (ANP) exerts many cardiac beneficial effects, including the ability to protect cardiomyocytes by promoting autophagy. We tested the impact of ANP on autophagy/mitophagy, altered mitochondrial structure and function and increased oxidative stress in HFrEF patients by both ex vivo and in vivo approaches. The ex vivo study included thirteen HFrEF patients whose peripheral blood mononuclear cells (PBMCs) were isolated and treated with αANP (10–11 M) for 4 h. The in vivo study included six HFrEF patients who received sacubitril/valsartan for two months. PBMCs were characterized before and after treatment. Both approaches analyzed mitochondrial structure and functionality. We found that levels of αANP increased upon sacubitril/valsartan, whereas levels of NT-proBNP decreased. Both the ex vivo direct exposure to αANP and the higher αANP level upon in vivo treatment with sacubitril/valsartan caused: (i) improvement of mitochondrial membrane potential; (ii) stimulation of the autophagic process; (iii) significant reduction of mitochondrial mass—index of mitophagy stimulation—and upregulation of mitophagy-related genes; (iv) reduction of mitochondrial damage with increased inner mitochondrial membrane (IMM)/outer mitochondrial membrane (OMM) index and reduced ROS generation. Herein we demonstrate that αANP stimulates both autophagy and mitophagy responses, counteracts mitochondrial dysfunction, and damages ultimately reducing mitochondrial oxidative stress generation in PBMCs from chronic HF patients. These properties were confirmed upon sacubitril/valsartan administration, a pivotal drug in HFrEF treatment. [ABSTRACT FROM AUTHOR]

Daphnia pulex is a natural food widely used in aquaculture, and S6K plays an important role in protein translation and ageing. To explore the function of S6K in the ageing process of D. pulex , we cloned and analysed the full-length cDNA of S6K. With the growth of D. pulex , the expression of S6K mRNA first increased, then peaked at 10 days, and then decreased. Western blot analysis showed that the S6K protein expression increased from 1 to 5 days of age, but did not change significantly from 5 to 25 days of age. RNAi knockdown of S6K, reduced the expression of S6K mRNA and S6K protein, and it causes changes in other genes associated with ageing in both sexes. S6K may be involved in reproductive transformation, affecting reproductive capacity, thus significantly affecting the ageing of D. pulex. miRNA with potential regulation of the S6K gene were screened by the bioinformatics method and validated using a dual luciferase reporter gene system. This study deepens our understanding of the mechanisms of ageing in D. pulex and expands our understanding of the role of S6K in the ageing process. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the effect of sacubitril-valsartan (SV) on central apneas (CA) and obstructive apneas (OA) in patients with heart failure with reduced ejection fraction (HFrEF). Methods: In patients with HFrEF, SV initiation was titrated to the highest tolerable dosage. Patients were evaluated with portable apnea monitoring, echocardiography, and cardiopulmonary exercise testing at baseline and 3 months later. Results: Of a total of 18 patients, 9 (50%) had OA, 7 (39%) had CA, and 2 (11%) had normal breathing. SV therapy was related to a reduction in NT-pro BNP and an improvement in LV function after 3 months. Portable apnea monitoring revealed a significant decrease of the respiratory event index (REI) after treatment with SV (20 ± 23 events/h to 7 ± 7 events/h, p = 0.003). When subgrouping according to type of apneas, REI, and time spent below 90% saturation (T90) decreased in patients with CA and OA (all p < 0.05). Conclusion: In this prospective study, SV treatment for 3 months in patients with CA and OA is associated with a significant decrease in REI. [ABSTRACT FROM AUTHOR]

Abstract 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 Aims To assess the effect of angiotensin receptor blockers/neprilysin inhibitors (ARNI) on left ventricular (LV) ejection fraction (LVEF) and LV dimensions in a real‐life cohort of heart failure and reduced ejection fraction (HFrEF) patients, while analysing patient characteristics that may predict reverse LV remodelling. Methods and results The ARNI‐treated HFrEF patients followed at a single tertiary medical centre HF‐outpatient clinic were included in the study. Clinical and echocardiographic parameters were evaluated prior to ARNI initiation, and while on ARNI therapy, assessing patient characteristics associated with reverse LV remodelling. The cohort included 91 patients (mean age 60.5 years, 90% male) and 47 (52%) patients exhibited ARNI responsiveness, defined as an increase in LVEF during therapy. Overall, LVEF increased by 19% post‐ARNI (23.8 to 28.4%, P

Heart failure is a cardiovascular condition, leading to fatigue, breathlessness, and fluid retention. It affects around 56 million people globally and is a leading cause of hospitalization and mortality. Its prevalence is rising due to aging populations and lifestyle factors. Managing heart failure demands a multidisciplinary approach, encompassing medications, lifestyle modifications, and often medical devices or surgeries. The treatment burden is substantial, impacting patients’ daily lives and straining healthcare systems. Improving early detection, novel therapies, and patient education are crucial for alleviating the burden and enhancing the quality of life. There are notable advancements in the field of heart failure treatment and prevention. We will discuss significant pharmacological and device advances related to heart failure, including angiotensin receptor–neprilysin inhibitor, sodium–glucose co-transporter inhibition, glucagon-like peptide-1 agonist, cardiac resynchronization therapy, cardiac contractility modulation, mechanical circulatory support devices, and transcatheter valve interventions. We will also review novel therapies on the horizon, emerging technologies like CRISPR-based treatments for genetic anomalies, and the involvement of artificial intelligence in heart failure detection and management.

BackgroundEvidence regarding the mortality benefit of implantable cardioverter defibrillator (ICD) non-ischemic dilated cardiomyopathy (NIDCM) is inconsistent. The most recent randomized study, the DANISH trial, did not find improved outcomes with ICD. However, based on previous studies and meta-analyses, current guidelines still highly recommend ICD implantation in NIDCM patients. The introduction of novel medications for heart failure improved the clinical outcome dramatically. We aimed in this study to evaluate the effect of Angiotensin Receptor-Neprilysin Inhibitors (ARNi) and sodium-glucose transport protein 2 inhibitors (SGLT2i) on the mortality benefit of ICD in NIDCM.MethodsWe used a previous metanalysis algorithm and added an updated comprehensive literature search in PubMed for randomized control trials that examined the mortality benefit of ICD in NIDCM vs. optimal medical treatment. The primary outcome included death from any cause. We did a meta-regression analysis to search for a single independent factor affecting mortality. Using previous data, we evaluated the theoretical effect of ICD implementation on patients treated with SGLT2 inhibitors and ARNi.ResultsNo new articles were added to the results of the previous meta-analysis. 2,622 patients with NIDCM from 5 cohort studies published between 2002 and 2016 were included in the analysis. 50% of them underwent ICD implantation for primary prevention of sudden cardiac death, and 50% did not. ICD was associated with a significantly decreased risk for death from any cause compared to control (OR = 0.79, 95%CI: 0.66–0.95, p = 0.01, I2 = 0%). The theoretical addition of ARNi and the SGLT2 inhibitor dapagliflozin did not change the significant mortality effect of ICD (OR = 0.82, 95%CI: 0.7–0.9, p = 0.001, I2 = 0%) and (OR = 0.82, 95%CI: 0.7–0.9, p = 0.001, I2 = 0%). A meta-regression revealed no association between death from any cause and left bundle branch block (LBBB), use of amiodarone, use of angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers, year initiated enrollment, and the year ended enrollment (R2 = 0.0).ConclusionIn patients with NIDCM, the addition of ARNi and SGLT2i did not affect the mortality advantages of ICD for primary prevention.PROSPERO registry numberhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42023403210.

(1) Background: Previous studies showed left ventricular (LV) and left atrial (LA) improvement and reverse remodeling after therapy with Sacubitril/Valsartan (S/V) in patients affected by heart failure with reduced ejection fraction (HFrEF). Therefore, we sought to investigate predictors of LA structural and functional reverse remodeling (LARR) in this setting of patients after therapy with S/V, focusing on left atrial strain parameters, such as peak atrial longitudinal strain (PALS). (2) Methods: Patients with HFrEF underwent clinical and echocardiographic evaluation at baseline and after six months of therapy with S/V. Measures of LA structure (LA volume index, LAVi) and function (LA emptying fraction (LAEF), PALS, LA conduit strain and peak atrial contraction strain (PACS) were also analyzed. Patients were divided in two groups, those with a LARR (relative reduction in LAVi > 15%, LARR+) and those without (LARR−). (3) Results: A total of 47 consecutive patients (66 ± 8 years, 85% male, mean LVEF 28 ± 6%) were enrolled in the study and followed up. A significant increase of LAEF (46 ± 13 vs. 37 ± 11%, p < 0.001) and a significant reduction of LAVi (42 ± 15 vs. 45 ± 15 mL/m2, p = 0.008) were found after 6 months of S/V therapy; 47% of the population showed LA reverse remodeling. LA strain parameters, PALS (19 ± 8 vs. 15 ± 7 %, p < 0.001) and LA conduit (−9.7 ± 5.2% vs. −7.6 ± 4.1%, p = 0.007) significantly improved after 6 months of S/V therapy. At multivariable stepwise regression analysis, changes in LV End Diastolic Volume (LVEDV) and PALS were significantly proportional to changes in LAVi values. (4) Conclusions: Six months of treatment with S/V in patients with HFrEF was associated with an improvement in LA functional reverse remodeling in a real-world scenario. LARR was not significantly correlated to baseline echocardiographic variables, but was proportional to changes in LV volumes and LA strain parameters. Finally, after S/V therapy, a strict connection between LA and LV reverse remodeling and between LA anatomical and functional reverse remodeling seems to be outlined. [ABSTRACT FROM AUTHOR]