Atrial natriuretic peptide stimulates autophagy/mitophagy and improves mitochondrial function in chronic heart failure.

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.

Sacubitril/valsartan ameliorates renal tubulointerstitial injury through increasing renal plasma flow in a mouse model of type 2 diabetes with aldosterone excess.

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.

Diuretic and renal effects of angiotensin receptor-neprilysin inhibitor in patients hospitalized for acute heart failure.

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.

Effect of sacubitril/valsartan on natriuretic peptide in patients with compensated heart failure.

The time-dependent changes in the natriuretic peptide families during sacubitril/valsartan (S/V) treatment remain obscure in the Asian heart failure (HF) cohort. Eighty-one outpatients with compensated HF were analyzed. The patients were divided into two groups based on the administration of S/V (n = 42) or angiotensin converting enzyme inhibitor (ACE-I; n = 39). Changes to the natriuretic peptide families and the daily dose of loop diuretics were evaluated 3 and 6 months after the intervention. The atrial natriuretic peptide (ANP) level was significantly increased (102 [63-160] pg/mL to 283 [171-614] pg/mL [3 months]; 409 [210-726] pg/mL [6 months]) in the S/V group but not in the ACE-I group. The dose of furosemide was significantly decreased during the six-month follow-up period in the S/V group (40 [20-40] mg to 20 [10-20] mg) but not in the ACE-I group. A multivariate logistic regression model showed that the presence of persistent atrial fibrillation (AF) and HF with a preserved left ventricular ejection fraction (HFpEF) was independently associated with a high delta-ANP ratio (≥ 4.5 ANP value on the start date/ANP value at 6 months; the mean value was used as the cutoff value) (odds ratio [OR]: 4.649, 95% CI 1.032-20.952 and OR: 7.558, 95% CI 1.427-40.042). The plasma level of ANP was increased, and the loop diuretic dose was decreased by the addition of neprilysin inhibitor therapy in patients with compensated HF. In patients with HFpEF and complicated persistent AF, neprilysin inhibitor therapy was associated with an increase in ANP.

Effects of sacubitril-valsartan on central and obstructive apneas in heart failure patients with reduced ejection fraction.

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.

Chronic Kidney Disease as a Comorbidity in Heart Failure.

Heart failure (HF) is one of the greatest problems in healthcare and it often coexists with declining renal function. The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration. It is also associated with difficulties in the treatment of aggravating HF and chronic kidney disease (CKD) and, as a consequence, recurrent hospitalizations and death. As the worsening of renal function has an undeniably negative impact on the outcomes in patients with HF, searching for new treatment strategies and identification of biomarkers is necessary. This review is focused on the pathomechanisms in chronic kidney disease in patients with HF and therapeutic strategies for co-existing CKD and HF.

Sacubitril/valsartan: An antiarrhythmic drug?

INTRODUCTION: Heart failure (HF) is a major cause of morbidity and mortality, with nearly half of all HF-related deaths resulting from sudden cardiac death (SCD), most often from an arrhythmic event. The pathophysiologic changes that occur in response to the hemodynamic stress of HF may lead to increased arrhythmogenesis. Theoretically, medications that block these arrhythmogenic substrates would decrease the risk of SCD. The combined angiotensin receptor and neprilysin inhibitor (ARNi; tradename Entresto) is the newest commercially available medication for the treatment of heart failure. METHODS AND RESULTS: We reviewed and synthesized the available literature regarding sacubitril/valsartan and its effects on cardiac rhythm. ARNi has been shown to decrease cardiovascular mortality and hospitalization in patients with HF with reduced ejection fraction (HFrEF). Emerging evidence suggests that ARNi also may play a role in reducing arrhythmogenesis and thereby SCD. CONCLUSION: This review summarizes the current data regarding this ARNi and its potential antiarrhythmic effects.

Low- vs high-dose ARNI effects on clinical status, exercise performance and cardiac function in real-life HFrEF patients.

PURPOSE: Only a few studies are available on dose-related effects of sacubitril/valsartan (angiotensin receptor neprilysin inhibition (ARNI)) in real-life patients with heart failure and reduced ejection fraction (HFrEF). We sought to investigate clinical and functional effects in real-life HFrEF patients receiving ARNI at a different cumulative dose. METHODS: This was an observational study in consecutive outpatients admitted for HFrEF from October 2017 to June 2019. The PARADIGM criteria were needed for enrolment. ARNI was uptitrated according to blood pressure, drug tolerability, renal function and kaliemia. At least 10-month follow-up was required in each patient. Clinical assessment, Kansas City Cardiomyopathy Questionnaire (KCCQ) score, 6-min walk test and strain echocardiography were performed in each patient on a regular basis during the observational period. At the end of the study, patients were divided into two groups based on the median yearly dose of the ARNI medication. RESULTS: A total of 90 patients, 64 ± 11 years, 82% males, were enrolled. The cut-off dose was established in 75 mg BID, and the study population was divided into group A (≤ 75 mg), 52 patients (58%), and group B (> 75 mg), 38 patients (42%). The follow-up duration was 12 months (range 11-13). NYHA class, KCCQ score and 6MWT performance ameliorated in both groups, with a quicker time to benefit in group B. The proportion of patients walking > 350 m increased from 21 to 58% in group A (p < 0.001), and from 29 to 82% in group B (p < 0.001). A positive effect was also disclosed in the left ventricular remodelling, strain deformation and diastolic function. CONCLUSION: One-year ARNI treatment was effective in our real-life HFrEF patient population, leading to clinical and functional improvement in both study groups, slightly greater and with a shorter time to benefit in group B.

Acute Hemodynamic Effects of Sacubitril-Valsartan In Heart Failure Patients Receiving Intravenous Vasodilator and Inotropic Therapy.

BACKGROUND: Prior study has demonstrated that transitioning patients in acutely decompensated heart failure with a low cardiac output directly from intravenous (i.v.) vasoactive (ie, vasodilators or inotropes) drugs to sacubitril-valsartan (S/V) can be done safely with tolerance to the 1-month follow-up. Here, we further characterize the hemodynamic impact of S/V after patients have been optimized on vasoactive therapy. METHODS AND RESULTS: In a single-center, retrospective analysis, 25 patients with cardiac index of less than 2.2 L/min/m2 were admitted to the cardiac intensive care unit and newly initiated on angiotensin receptor-neprilysin inhibitor therapy with the guidance of invasive hemodynamic monitoring. Hemodynamic data were gathered and compared upon cardiac intensive care unit admission, after optimization with i.v. vasoactive therapy, and after S/V initiation and weaning off i.v. THERAPY: All patients who tolerated S/V (n = 20) were weaned off vasoactive medications before transfer out of cardiac intensive care unit. Patients maintained their significant improvement in cardiac index and reduction in SVR/PVR on transition from i.v. inotropic and vasodilator therapy to oral S/V. There was an increase in pulmonary artery pulsatility index with S/V therapy compared with the i.v. vasoactive phase of care. CONCLUSIONS: Patients in the cardiac intensive care unit can be successfully bridged from vasoactive i.v. therapy to oral S/V with sustained improvement in cardiac index garnered from vasoactive agents. We also observed improvement in the pulmonary artery pulsatility index and maintenance of left and right ventricular unloading with S/V. These encouraging findings merit further prospective study.

Safety of Contemporary Heart Failure Therapy in Patients with Continuous-Flow Left Ventricular Assist Devices.

BACKGROUND: Limited data are available concerning the safety, optimal administration and benefits of contemporary heart failure therapy in patients after left ventricular assist device (LVAD) implantation. METHODS: Between 2015 and 2019, 257 patients underwent LVAD implantation and were included in this observational study. Oral heart failure therapy was initiated and uptitrated during the further course. After propensity matching and excluding patients with immediate postoperative treatment in an affiliated center with different medical standards, hospitalization rates and mortality within 12 months after LVAD implantation were compared between 83 patients who received medical therapy including an angiotensin receptor neprilysin inhibitor (ARNI) and 83 patients who did not receive an ARNI. RESULTS: The overall use of heart-failure medications after 12 months was high: prescriptions: beta-blockers, 85%; angiotensin inhibiting drugs, 90% (angiotensin-converting-enzyme inhibitors 30%, angiotensin receptor blockers 23%, ARNI 37%); mineralocorticoid receptor antagonists, 80%. No serious drug-related adverse events occurred. The conditional 1-year survival in the group with ARNIs was 97% (95% CI: 94%-100%) compared to 88% in the group without an ARNI (95% CI: 80%-96%); P = 0.06. CONCLUSIONS: Contemporary heart failure therapy is safe in patients with LVADs. No increase in serious adverse events was seen in patients receiving ARNIs. No significant difference in the conditional 1-year survival was seen between the ARNI group and the nonARNI group.

Reverse Cardiac Remodeling and ARNI Therapy.

PURPOSE OF REVIEW: To review reverse cardiac remodeling and guideline-directed medical and device therapy (GDMT) within the context of recent data on combined angiotensin receptor/neprilysin inhibitor (ARNI) therapy. RECENT FINDINGS: Preliminary data suggested that ARNI therapy led to significant reversal of deleterious cardiac remodeling. More definitive data regarding impact of ARNI therapy on remodeling parameters are now available from two prospective trials, PROVE-HF (Prospective Study of Biomarkers, Symptom Improvement, and Ventricular Remodeling During Sacubitril/Valsartan Therapy for Heart Failure) and EVALUATE-HF (Study of Effects of Sacubitril/Valsartan vs. Enalapril on Aortic Stiffness in Patients With Mild to Moderate HF With Reduced Ejection Fraction). Both studies demonstrated marked improvements in biomarker and echocardiographic parameters of reverse cardiac remodeling in patients with heart failure with reduced ejection fraction (HFrEF). Much of the observed clinical benefit of sacubitril/valsartan therapy in patients with HFrEF is likely related to significant reverse cardiac remodeling. Ongoing trials will assess the role for ARNI therapy in patients with heart failure with preserved ejection fraction (HFpEF) and in the post-myocardial infarction setting. Future studies should comprehensively assess predictors of response to ARNI therapy.

Impact of Sacubitril/Valsartan on Right Heart Failure.

Sacubitril/valsartan improves mortality and morbidity in patients with heart failure with reduced ejection fraction. However, its impact on right heart failure remains unknown. We experienced a 70-year-old man who was started on sacubitril/valsartan to treat his right heart failure with moderate tricuspid regurgitation. Following the 3-month sacubitril/valsartan treatment, a functional and geological improvement was observed in the right heart as well as amelioration of his congestive symptoms. Sacubitril/valsartan might improve right heart failure in addition to conventionally-proven left heart failure. Further large-scale studies are warranted to validate our findings.

Impact of Sacubitril-Valsartan on Markers of Glomerular Function.

PURPOSE OF REVIEW: To provide pathophysiological and clinical insights into the effects of sacubitril/valsartan on glomerular function. RECENT FINDINGS: Heart failure and glomerular dysfunction are closely intertwined. In addition to reduced heart failure hospitalization and all-cause mortality, patients treated with sacubitril/valsartan have a slower deterioration of glomerular filtration rate over time compared with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. The effects of sacubitril/valsartan are probably mediated through enhancement of natriuretic peptides, reduction of glomerular inflammation and fibrosis, and relaxation of mesangial cells and podocytes. Further studies will elucidate underlying pathophysiological mechanisms of sacubitril/valsartan on glomerular function and their prognostic significance in subjects with and without heart failure.

Angiotensin Receptor-Neprilysin Inhibitors and the Natriuretic Peptide Axis.

PURPOSE OF THE REVIEW: The purpose of this review is to describe the effects of angiotensin receptor neprilysin inhibitor (ARNI) therapy on the natriuretic peptide axis (NPA), with a particular focus on B-type natriuretic peptide (BNP), atrial natriuretic peptide (ANP), and C-type natriuretic peptide (CNP) to better understand the biology behind the improved outcomes in patients with heart failure with reduced ejection fraction (HFrEF). RECENT FINDINGS: BNP, ANP, and CNP are the three main natriuretic peptides (NP); they share a common structure and ultimately mediate their actions by activating cyclic guanosine monophosphate (cGMP). ARNI therapy results in a decrease of N-terminal pro-BNP (NT-proBNP) and increase of BNP levels respectively. It is been questioned whether these changes may result from unique laboratory assays characteristics rather than actual biological implications. It appears to be that the prognostic accuracy of BNP for cardiovascular outcomes remains independent and comparable to that of NT-proBNP while on ARNI therapy. ANP levels also increase with ARNI therapy, but no consistent change has been described for CNP levels. There is evidence that the changes in BNP and NT-proBNP correlate with improvement in echocardiographic parameters of volume and function. The dual effect of neprilysin inhibition and angiotensin receptor blockade has substantial implications on the natriuretic peptide axis (NPA). The changes seen in BNP and NT-proBNP specifically have shown to correlate with improvement in echocardiographic parameters. Further results exploring the biologic effects of ARNI therapy on other NPs are still pending and likely will provide further insights in the mechanisms behind the improvement in cardiac function and clinical outcomes.

Cost-Effectiveness of Switching Patients With Heart Failure and Reduced Ejection Fraction to Sacubitril/Valsartan: The Australian Perspective.

BACKGROUND: The cost-effectiveness, from the Australian health care perspective, of switching patients with heart failure and reduced ejection fraction (HFREF) stable on angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARBs) to the angiotensin receptor neprilysin inhibitor (ARNi) sacubitril/valsartan is unclear. We sought to assess the cost-effectiveness of sacubitril/valsartan versus enalapril in patients with HFREF in the contemporary Australian setting. METHODS: We developed a Markov model with two health states ('Alive' and 'Dead') to assess the cost-effectiveness of sacubitril/valsartan versus enalapril in patients with HFREF. Model subjects were 63 years of age at entry and had simulated follow-up over 20 years. Transition probabilities were derived from the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure (PARADIGM-HF) study. Costs and utility data were derived from published sources. All costs and effects were discounted at an annual rate of 5% and are presented in Australian dollars. Sensitivity analyses were undertaken to test variability in key data inputs. RESULTS: In the base-case analysis, sacubitril/valsartan was found to reduce non-fatal heart failure hospitalisations and cardiovascular deaths, with numbers-needed-to-treat over a 20-year period of 40 and 27, respectively. The use of sacubitril/valsartan led to an additional 6 months of life gained per patient, translating to A$27,954 per years of life saved (YoLS) and A$40,513 per quality-adjusted-life-years (QALY) gained. The results of the sensitivity analyses indicated that the results were robust. CONCLUSIONS: Our analysis supports switching HFREF patients on ACE inhibitor or ARB to sacubitril/valsartan.

Neprilysin Inhibitors: Emerging Therapy for Heart Failure.

Biologically active natriuretic peptides (NPs) are an integral part of cardiac homeostasis as they help to maintain sodium and fluid balance. When homeostasis is perturbed by neurohormonal activation in heart failure, levels of NPs rise in response. Neprilysin (NEP) is a naturally occuring enzyme that breaks down NPs. Scientists have recently discovered a novel pharmacologic agent that combines a NEP inhibitor and an angiotensin receptor blocker. In a large clinical trial, this new drug was found to reduce hospitalization and mortality in systolic heart failure. The challenges of implementing this therapy include patient selection, cost, and risk of side effects including angioedema and Alzheimer's disease.

Natriuretic Peptides in the Cardiovascular System: Multifaceted Roles in Physiology, Pathology and Therapeutics.

The natriuretic peptides (NPs) family includes a class of hormones and their receptors needed for the physiological control of cardiovascular functions. The discovery of NPs provided a fundamental contribution into our understanding of the physiological regulation of blood pressure, and of heart and kidney functions. NPs have also been implicated in the pathogenesis of several cardiovascular diseases (CVDs), including hypertension, atherosclerosis, heart failure, and stroke. A fine comprehension of the molecular mechanisms dependent from NPs and underlying the promotion of cardiovascular damage has contributed to improve our understanding of the molecular basis of all major CVDs. Finally, the opportunity to target NPs in order to develop new therapeutic tools for a better treatment of CVDs has been developed over the years. The current Special Issue of the Journal covers all major aspects of the molecular implications of NPs in physiology and pathology of the cardiovascular system, including NP-based therapeutic approaches.

Evolving Role of Natriuretic Peptides from Diagnostic Tool to Therapeutic Modality.

Natriuretic peptides (NP) are widely recognized as key regulators of blood pressure, water and salt homeostasis. In addition, they play a critical role in physiological cardiac growth and mediate a variety of biological effects including antiproliferative and anti-inflammatory effects in other organs and tissues. The cardiac release of NPs ANP and BNP represents an important compensatory mechanism during acute and chronic cardiac overload and during the pathogenesis of heart failure where their actions counteract the sustained activation of renin-angiotensin-aldosterone and other neurohormonal systems. Elevated circulating plasma NP levels correlate with the severity of heart failure and particularly BNP and the pro-peptide, NT-proBNP have been established as biomarkers for the diagnosis of heart failure as well as prognostic markers for cardiovascular risk. Despite activation of the NP system in heart failure it is inadequate to prevent progressive fluid and sodium retention and cardiac remodeling. Therapeutic approaches included administration of synthetic peptide analogs and the inhibition of NP-degrading enzyme neutral endopeptidase (NEP). Of all strategies only the combined NEP/ARB inhibition with sacubitril/valsartan had shown clinical success in reducing cardiovascular mortality and morbidity in patients with heart failure.

What Is New in Heart Failure Management in 2017? Update on ACC/AHA Heart Failure Guidelines.

PURPOSE OF REVIEW: The goal of this paper is to provide a summary of the new recommendations in the most recent 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. The intent is to provide the background and the supporting evidence for the recommendations and to provide practical guidance for management strategies in treatment of heart failure patients. RECENT FINDINGS: In the 2017 ACC/AHA/HFSA Focused Update of HF guidelines, important additions include new information on biomarkers, specifically on the topics of the diagnostic, prognostic role of natriuretic peptides in heart failure, and the role of natriuretic peptides in screening in patients high risk for HF and prevention of HF. There are important recommendations for treatment of patients with HF with reduced EF (HFrEF), including the beneficial role of angiotensin receptor blocker and neprilysin inhibition (ARNI) treatment in reducing outcomes including mortality, ivabradine in reducing heart failure hospitalizations in stable HFrEF patients with sinus rhythm and heart rate ≥ 70 bpm despite ß-blockers. In patients with HF with preserved EF (HFpEF), though there are no studies demonstrating survival benefit, potential benefit with aldosterone antagonism in reducing HF hospitalizations is noted. In treatment of comorbidities, optimization of blood pressure control to less than 130 mmHg is recommended in hypertensive patients to prevent HF or in patients with hypertension and HFrEF or HFpEF. In addition to recognition on the potential role of treatment of iron deficiency anemia to improve symptoms and functional capacity, caution against use of adaptive servo-ventilation in patients with HFrEF and central sleep apnea and against use of erythropoietin stimulating agents in patients with HFrEF is provided. There are new treatment strategies that are associated with significant improvements in mortality and other outcomes in patients with HF. Successful management of HF requires recognition of indications, contraindications, benefits, safety, and risk of these new therapies. In addition to incorporation of these new treatment strategies, it is critical to focus also on patient education, care coordination, identification of goals of care, monitoring, management of comorbidities, and individualization of therapies. New treatment modalities increase the choices for treatment and provide the opportunity to implement individualized treatment strategies for our patients.

The Sacubitril/Valsartan, a First-in-Class, Angiotensin Receptor Neprilysin Inhibitor (ARNI): Potential Uses in Hypertension, Heart Failure, and Beyond.

PURPOSE OF REVIEW: Sacubitril/valsartan (LCZ696) is a first-in-class, novel-acting, angiotensin receptor neprilysin inhibitor (ARNI) that provides inhibition of neprilysin and the angiotensin (AT1) receptor. A recent clinical trial PRARDIGM-HF demonstrated that this drug is superior to angiotensin-converting enzyme (ACE) inhibitors for improving the prognosis in the patients with heart failure, and this has resulted in the drug being included in clinical practice guidelines for the management of heart failure with reduced ejection fraction (EF). In addition, sacubitril/valsartan has been developed for the management of hypertension, because it has unique anti-aging properties. However, the clinical evidence of mechanism has not been well validated. RECENT FINDINGS: A recent mechanistic study PARAMETER demonstrated that sacubitril/valsartan (LCZ696) is superior to angiotensin receptor blocker (ARB) monotherapy for reducing central aortic systolic pressure (primary endpoint) as well as for central aortic pulse pressure (secondary endpoint) and nocturnal BP preferentially. Considering these results, sacubitril/valsartan may be an attractive therapeutic agent to treat the elderly with age-related hypertension phenotypes, such as drug-uncontrolled (resistant) hypertension characterized as systolic (central) hypertension (structural hypertension) and/or nocturnal hypertension (salt-sensitive hypertension). These are the high-risk hypertension phenotypes which are prone to develop heart failure with preserved EF and chronic kidney disease. Sacubitril/valsartan may be effective to suppress the age-related continuum from hypertension to heart failure, and it could be clinically useful not only for secondary prevention, but also as primary prevention of heart failure in uncontrolled elderly hypertensive patients.