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Background: Large cardiovascular outcomes trials in individuals with heart failure, with and without diabetes, have demonstrated a significant risk reduction in the composite outcome of cardiovascular death or hospitalizations for heart failure with SGLT2 inhibitor therapy. These positive outcomes have led to the recommendation that SGLT2 inhibitors serve as backbone therapy in patients with heart failure reduced ejection fraction (HFrEF). To date, there has not been enough participants in clinical trials on concomitant SGLT2 inhibitor and angiotensin receptor-neprilysin inhibitor therapy to evaluate the benefits and risks of combination therapy with these two agents outside of smaller subgroup analyses. Case Summary: This case describes a Black female with diabetes meeting her glycemic targets and concomitant stable NYHA FC II HFrEF on guideline-directed medical therapy (GDMT) with sacubitril/valsartan, spironolactone and metoprolol succinate who developed severe hypotension and dehydration requiring hospitalization after initiation of SGLT2 inhibitor therapy. Practice Implications: This case report raises the question of whether those with type 2 diabetes, and/or those on background angiotensin receptor-neprilysin inhibitor therapy, who are euvolemic or sensitive to diuretic therapy should be started on lower dose dapagliflozin and titrated to 10 mg daily based on response. It also raises awareness to the potential increased diuretic effect produced with concomitant use of sacubitril/valsartan and dapagliflozin. Caution and education to mitigate the risk for volume depletion should be provided to those patients who are euvolemic and initiated on a SGLT2 inhibitor, regardless of their background diuretic and GDMT. Conclusion: Future research should focus on the benefits and safety considerations and provide education on how to best initiate and adjust SGLT2 inhibitors in the setting of sacubitril/valsartan use in diverse heart failure patient populations., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Dr. Christine Schumacher is on the Speakers Bureau for Abbott and participated on an Advisory Board for Dexcom.

Background: Contemporary use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi) in patients with atrial fibrillation (AF) and heart failure (HF) has not been described., Methods and Results: We analyzed the MarketScan databases for the period January 1, 2021 to July 30, 2022. Validated algorithms were used to identify patients with AF and HF, and to classify patients into HF with reduced ejection fraction (HFrEF) or HF with preserved ejection fraction (HFpEF). We assessed the prevalence of SGLT2i and ARNi use overall and by HF type. Additionally, we explored correlates of lower use, including demographics and comorbidities. The study population included 60 927 patients (mean age, 75 years; 43% women) diagnosed with AF and HF (85% with HFpEF, 15% with HFrEF). Prevalence of ARNi use was 11% overall (30% in HFrEF, 8% in HFpEF), whereas the corresponding figure was 6% for SGLT2i (13% in HFrEF, 5% in HFpEF). Use of both medications increased over the study period: ARNi from 9% to 12% (22%-29% in HFrEF, 6%-8% in HFpEF), and SGLT2i from 3% to 9% (6%-16% in HFrEF, 2%-7% in HFpEF). Female sex, older age, and specific comorbidities were associated with lower use of these 2 medication types overall and by HF type., Conclusions: Use of ARNi and SGLT2i in patients with AF and HF is suboptimal, particularly among women and older individuals, though use is increasing. These results underscore the need for understanding reasons for these disparities and developing interventions to improve adoption of evidence-based therapies among patients with comorbid AF and HF.

Objective: This study aimed to determine the evolution of sacubitril-valsartan research and analyze the publications quantitatively and qualitatively., Materials and Methods: We used the bibliometric method and a combination of CiteSpace_6.1.6 and VOSviewer_1.6.18 to identify top authors, countries, institutions, co-cited articles, co-cited journals, keywords, and trends. This study prioritized key aspects in the existing global research on Entresto (Sacubitril/Valsartan) to assess our depth of knowledge in this field and identify potential insights. The objective was to generate a reference for the utilization of the "angiotensin receptor-neprilysin inhibitor" (ARNI)., Results: From 2008 to 2022, citations of sacubitril-valsartan showed an upward trend. VOSviewer keyword analysis of 3,408 publications identified 624 keywords and divided them into seven different clusters. The clustered network was constructed based on 1,191 references cited by 3,408 publications that met the terms, where the clustered network of sacubitril-valsartan was presented. These publications can be regarded as fundamental to Entresto's research. Analysis of co-cited reference clusters showed that other than Entresto's novel application in other diseases, the new combination with other medication or mechanical assistance therapies against heart failure was Entresto's latest focus. Analysis of citation bursts showed that the rank of the top 25 keywords, according to the chronological sequence, marked Entresto's research entering a new era of exploring the extended application in other diseases and novel combinations with other diverse therapies., Conclusions: We found that emerging new mechanisms in sacubitril-valsartan therapy intended for more targets in the pathogenesis of specific diseases will be the focus of further studies.

Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor aims at prompt improvement and prevention of readmission in patients hospitalized for heart failure with reduced ejection fraction. However, titration of quadruple therapy is time consuming. Lengthy up-titration of quadruple therapy may negate the benefit of early initiation. Quadruple therapy should start with a sodium glucose cotransporter 2 inhibition and a mineralocorticoid antagonist, as both enable safe decongestion and require minimal or no titration. Depending on the level of decongestion and clinical characteristics, patients receive an angiotensin receptor-neprilysin inhibitor or a beta-adrenergic receptor blocker to be titrated after hospital discharge. Outpatient addition of an angiotensin receptor-neprilysin inhibitor to a beta-adrenergic receptor blocker or vice versa completes the quadruple therapy scheme. By focusing on decongestion and matching intervention to patients' profile, the present therapeutic sequence allows rapid implementation of quadruple therapy at fully recommended doses., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The effect of sacubitril/valsartan on patients with heart failure (HF) with preserved ejection fraction (HFpEF) is a topic of ongoing debate., Methods: Medline was queried from inception through the last week of May 2023 for randomized studies assessing the effects of sacubitril/valsartan in patients with HFpEF. For continuous outcomes, we pooled either the geometric mean ratios (gMR) or weighted mean difference (WMD) with 95% confidence intervals (CI). For dichotomous outcomes, we pooled Risk ratios (RR) with 95% CI., Results: Four trials were included (N=8,129). Compared to the control, sacubitril/valsartan was associated with a reduction in NT-proBNP levels (gMR: 0.84, 95% CI 0.80, 0.88) and improvement in KCCQ score (WMD: 0.85, 95% CI: 0.02, 1.67). We observed no differences for HF hospitalization (RR: 0.90, 95% CI: 0.79, 1.01), cardiovascular mortality (RR: 0.83, 95% CI: 0.52, 1.32), all-cause mortality (RR: 0.99, 95% CI: 0.86-1.13) and improvement (RR: 1.15, 95% CI: 0.93, 1.42) or worsening (RR: 0.92, 95% CI: 0.78, 1.09) of NYHA class between the sacubitril/valsartan and comparator group. Sacubitril/valsartan was generally safe, and patients were less likely to have a ≥50% decline in eGFR compared to control (RR: 0.60, 95% CI: 0.39, 0.92)., Conclusion: Pooled analysis suggests that sacubitril/valsartan reduces natriuretic peptide levels and improves the quality of life in patients with HFpEF, which may translate into better clinical outcomes as observed by a numerical trend towards improvement in major HF outcomes with sacubitril/valsartan therapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Angiotensin receptor-neprilysin inhibitors (ARNIs) have been approved as antihypertensive agents in Japan, and thiazide diuretics (TZDs) are widely used concomitantly with renin-angiotensin system inhibitors (RASIs) for hypertension. This retrospective study included patients with hypertension who switched from RASI to ARNI therapy (ARNI group) and those who were prescribed TZDs with RASIs (TZD/RASI group). Drug-related changes in the estimated glomerular filtration rate (eGFR), blood pressure (BP), body weight (BW), serum electrolytes, uric acid (UA), and triglyceride levels were compared between the two groups. Overall, 70 participants (31 and 39 in the ARNI and TZD/RASI groups, respectively) were enrolled and observed for a median of 2 months. According to linear mixed models, compared with the TZD/RASI group, the ARNI group exhibited a significant change in mean eGFR of 3.71 mL/min/1.73 m 2 [95% confidence interval (CI), 0.57-6.84; P = 0.02] from the time of switching drug to the next outpatient visit. Further, compared with the TZD/RASI group, the ARNI group exhibited significant changes in mean serum UA (-1.27; 95% CI, -1.66 to -0.88), sodium (1.22; 95% CI, 0.12 to -2.32), chloride (2.14; 95% CI, 0.75-3.52), and triglyceride (-52.1; 95% CI, -100.9 to -3.29) levels. Conversely, serum potassium levels, BW, and systolic and diastolic BP did not differ significantly between the two groups (P = 0.69, 0.44, 0.49, and 0.66, respectively). Compared with the combination therapy of TZD and RASI, ARNI therapy causes less renal dysfunction, hyperuricemia, and hypertriglyceridemia with fewer electrolyte abnormalities and no significant difference in antihypertensive effects., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Importance: The US Food and Drug Administration expanded labeling of sacubitril-valsartan from the treatment of patients with chronic heart failure (HF) with reduced ejection fraction (EF) to all patients with HF, noting the greatest benefits in those with below-normal EF. However, the upper bound of below normal is not clearly defined, and value determinations across a broader EF range are unknown., Objective: To estimate the cost-effectiveness of sacubitril-valsartan vs renin-angiotensin system inhibitors (RASis) across various upper-level cutoffs of EF., Design, Setting, and Participants: This economic evaluation included participant-level data from the PARADIGM-HF (Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) and the PARAGON-HF (Prospective Comparison of ARNi with ARB Global Outcomes in HF With Preserved Ejection Fraction) trials. PARADIGM-HF was conducted between 2009 and 2014, PARAGON-HF was conducted between 2014 and 2019, and this analysis was conducted between 2021 and 2023., Main Outcomes and Measures: A 5-state Markov model used risk reductions for all-cause mortality and HF hospitalization from PARADIGM-HF and PARAGON-HF. Quality-of-life differences were estimated from EuroQol-5D scores. Hospitalization and medication costs were obtained from published national sources; the wholesale acquisition cost of sacubitril-valsartan was $7092 per year. Risk estimates and treatment effects were generated in consecutive 5% EF increments up to 60% and applied to an EF distribution of US patients with HF from the Get With the Guidelines-Heart Failure registry. The base case included a lifetime horizon from a health care sector perspective. Incremental cost-effectiveness ratios (ICERs) were estimated at EFs of 60% or less (base case) and at various upper-level EF cutoffs., Results: Among 13 264 total patients whose data were analyzed, for those with EFs of 60% or less, sacubitril-valsartan was projected to add 0.53 quality-adjusted life-years (QALYs) at an incremental lifetime cost of $40 892 compared with RASi, yielding an ICER of $76 852 per QALY. In a probabilistic sensitivity analysis, 95% of the values of the ICER occurred between $71 516 and $82 970 per QALY. Among patients with chronic HF and an EF of 60% or less, treatment with sacubitril-valsartan vs RASis would be at least of economic intermediate value (ICER <$180 000 per QALY) at a sacubitril-valsartan cost of $10 242 or less per year, of high economic value (ICER <$60 000 per QALY) at a cost of $3673 or less per year, and cost-saving at a cost of $338 or less per year. The ICERs were $67 331 per QALY, $59 614 per QALY, and $56 786 per QALY at EFs of 55% or less, 50% or less, and 45% or less, respectively. Treatment with sacubitril-valsartan in only those with EFs of 45% or greater (up to ≤60%) yielded an ICER of $127 172 per QALY gained; treatment was more cost-effective in those at the lower end of this range (ICER of $100 388 per QALY gained for those with EFs of 45%-55%; ICER of $84 291 per QALY gained for those with EFs of 45%-50%)., Conclusions and Relevance: Cost-effectiveness modeling provided an ICER for treatment with sacubitril-valsartan vs RASis consistent with high economic value for patients with reduced and mildly reduced EFs (≤50%) and at least intermediate value at the current undiscounted wholesale acquisition cost price at an EF of 60% or less. Treatment was more cost-effective at lower EF ranges. These findings may have implications for coverage decisions and value assessments in contemporary clinical practice guidelines.

Background: Frail older adults may be less likely to receive guideline-directed medical therapy (GDMT)-renin-angiotensin blockers, beta-blockers, and mineralocorticoid receptor antagonists-for heart failure with reduced ejection fraction (HFrEF). We aimed to examine the uptake of angiotensin receptor neprilysin inhibitor (ARNI) and GDMT in frail older adults with HFrEF., Methods: Using 2015-2019 Medicare data, we estimated the proportion of beneficiaries with HFrEF receiving ARNI and GDMT each year by frailty status, defined by a claims-based frailty index. Logistic regression was used to identify clinical characteristics associated with ARNI initiation. Cox proportional hazards regression was used to examine the association of GDMT use in 2015 and death or heart failure hospitalization in 2016-2019., Results: Among 147,506-180,386 beneficiaries with HFrEF (mean age: 77 years; 27% women; 42.6-49.1% frail) in 2015-2019, the proportion of patients receiving ARNI increased in both non-frail (0.4%-16.4%) and frail (0.3%-13.7%) patients (p for yearly-trend-by-frailty = 0.970). Among those not receiving a renin-angiotensin system blocker, patients with age ≥ 85 years (odds ratio [95% CI], 0.89 [0.80-0.99]), dementia (0.88 [0.81-0.96]), and frailty (0.87 [0.81-0.94]) were less likely to initiate ARNI. The proportion of patients receiving all 3 GDMT classes increased in non-frail patients (22.0%-27.0%) but changed minimally in frail patients (19.6%-21.8%). Regardless of frailty status, treatment with at least 1 class of GDMT was associated with lower death or heart failure hospitalization than no GDMT medications (hazard ratio [95% CI], 0.94 [0.91-0.97], 0.92 [0.89-0.94], 0.94 [0.91-0.97] for 1, 2, and 3 classes, respectively)., Conclusions: Our results suggest an evidence-practice gap in the use of ARNI and GDMT in Medicare beneficiaries with HFrEF, particularly those with frailty. Efforts to narrow this gap are needed to reduce the burden of HFrEF in older adults., (© 2023 The American Geriatrics Society.)

Background: U.S. guidelines recommend consideration of sacubitril/valsartan in chronic heart failure (HF) and mildly reduced or preserved ejection fraction (EF). Whether initiation is safe and effective in EF >40% after a worsening heart failure (WHF) event is unknown., Objectives: PARAGLIDE-HF (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF) assessed sacubitril/valsartan vs valsartan in EF >40% following a recent WHF event., Methods: PARAGLIDE-HF is a double-blind, randomized controlled trial of sacubitril/valsartan vs valsartan in patients with EF >40% enrolled within 30 days of a WHF event. The primary endpoint was time-averaged proportional change in amino terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline through Weeks 4 and 8. A secondary hierarchical outcome (win ratio) consisted of: 1) cardiovascular death; 2) HF hospitalizations; 3) urgent HF visits; and 4) change in NT-proBNP., Results: In 466 patients (233 sacubitril/valsartan; 233 valsartan), time-averaged reduction in the NT-proBNP was greater with sacubitril/valsartan (ratio of change: 0.85; 95% CI: 0.73-0.999; P = 0.049). The hierarchical outcome favored sacubitril/valsartan but was not significant (unmatched win ratio: 1.19; 95% CI: 0.93-1.52; P = 0.16). Sacubitril/valsartan reduced worsening renal function (OR: 0.61; 95% CI: 0.40-0.93) but increased symptomatic hypotension (OR: 1.73; 95% CI: 1.09-2.76). There was evidence of a larger treatment effect in the subgroup with EF ≤60% for NT-proBNP change (0.78; 95% CI: 0.61-0.98) and the hierarchical outcome (win ratio: 1.46; 95% CI: 1.09-1.95)., Conclusions: Among patients with EF >40% stabilized after WHF, sacubitril/valsartan led to greater reduction in plasma NT-proBNP levels and was associated with clinical benefit compared with valsartan alone, despite more symptomatic hypotension. (Prospective comparison of ARNI with ARB Given following stabiLization In DEcompensated HFpEF; NCT03988634)., Competing Interests: Funding Support and Author Disclosures PARAGLIDE-HF was funded by Novartis Pharmaceuticals Corporation. Dr Mentz has received research support and/or honoraria from Novartis, Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novo Nordisk, Pharmacosmos, Relypsa, Respicardia, Roche, Sanofi, Vifor, Windtree Therapeutics, and Zoll. Drs Ward, Sarwat, and Williamson are employees of Novartis. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Somologic, and Verily; and has served as a consultant for Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Merck, Novartis, and Novo Nordisk. Dr Morrow is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Abiomed, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, and Zora Biosciences; and has received consulting fees from Abbott Laboratories, ARCA Biopharma, Inflammatix, Merck and Co, Novartis, and Roche Diagnostics. Dr Sharma serves as an advisory board member and/or consultant to AstraZeneca, Alleviant, Bayer, Boehringer Ingelheim, Imbria, Novartis, Novo Nordisk, RIVUS, and ViCardia; and receives grant funding from Amgen and the American Heart Association. Dr Starling serves on the steering committee for the PARAGLIDE trial sponsored by Novartis. Dr Velazquez has received grants from Novartis, Amgen, Phillips, and the National Heart, Lung, and Blood Institute/National Institutes of Health. Dr Desai has received research grants (to BWH) from Abbott, Alnylam, AstraZeneca, Bayer, and Novartis; and has received personal consulting fees from Abbott, Alnylam, AstraZeneca, Avidity Biopharma, Axon Therapeutics, Bayer, Biofourmis, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Regeneron, River2Renal, Roche, Verily, and Veristat. Dr Zieroth has received research grant support, served on advisory boards for, or has had speaker engagements with Abbott, Akcea AstraZeneca, Amgen, Alnylam, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Servier and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer. Dr Solomon has received research grants from Alnylam, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Ionis, Lilly, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, Actelion, Amgen, Bellerophon, Celladon, Gilead, Mesoblast, Neurotronik, and US2; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Valo. Dr Braunwald has received grant support to his institution from Novartis for the conduct of the PIONEER-HF trial, for serving on the Executive Committee of the PARADISE-MI trial and the Steering Committee of the PARAGLIDE-HF trial, and for participation in an Advisory Board Meeting. Dr Lepage has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to determine the safety and feasibility of in-hospital sacubitril/valsartan initiation after clinical stabilization in patients with acute decompensated heart failure (ADHF) and reduced ejection fraction (EF)., Methods: This retrospective, multicenter observational study included patients admitted for ADHF in 2 Italian centers between February 2017 and January 2022. Feasibility was evaluated by assessing the proportion of patients discharged on sacubitril/valsartan. Key safety endpoints were the incidences of adverse events during hospitalization and during follow-up planned at 1 month, 3-6 months and 12-18 months after discharge., Results: One hundred and twenty-two patients were included. Median age was 71 (60-78) years, 78% male, 63% New York Heart Association (NYHA) Class III at admission with a median left ventricular ejection fraction (EF) of 25% (20-30). During hospitalization, 94 (77%) patients were treated with intravenous diuretics, 39 (32%) with inotrope/vasopressor, 51 (42%) with continuous positive airway pressure ventilation and 7 (6%) were assisted with an intra-aortic balloon pump. Median time from hospitalization to sacubitril/valsartan initiation was 4 (2-7) days. Sacubitril/valsartan was started at a dosage of 12/13 mg in 52 (43%) patients, 24/26 mg in 61 (50%) patients and 49/51 mg in 8 (7%) patients. Overall, 111 (91%) patients were discharged on sacubitril/valsartan. At 12-18-month follow-up, the vast majority of patients were still on sacubitril/valsartan therapy., Conclusions: In-hospital initiation of sacubitril/valsartan treatment in real-world ADHF patients may be a safe and feasible treatment option.

Background: Angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitor (SGLT2i) are emerging medical treatments for decompensated heart failure (HF) with reduced ejection fraction. In clinical practice, the combination of ARNI and SGLT2i cannot be administered owing to the poor hemodynamic status in patients with HF with reduced ejection fraction (HFrEF). This study aimed to compare different strategies of HF management for ARNI first or SGLT2i first in such a population., Methods: From January 2016 to December 2021, 165 patients were diagnosed with HFrEF and New York Heart Association functional class ≥II and already received optimal medical treatment. Ninety-five patients received the ARNI-first strategy, and 70 patients received the SGLT2i-first strategy according to the physician's choice. Age, sex, hemodynamic condition, etiologies of HF, comorbidities, serum creatinine, N-terminal pro-B-type natriuretic peptide (NT-ProBNP), echocardiographic parameters, and clinical outcomes were compared between the ARNI and SGLT2i-first strategy groups., Results: In the SGLT2i-first group, the median interval between the addition of the second medication was longer (ARNI-first vs. SGLT2i-first; 74 [49-100] days vs. 112 [86-138] days; p = 0.044). Improvement in left ventricular ejection fraction (LVEF), change in left atrial dimension, and change in left ventricular end-diastolic and end-systolic volume (LVESV) did not differ between the two groups. The incidence of HF hospitalization, cardiovascular mortality, and all-cause mortality did not differ between the two groups. A non-significant trend of lower NT-proBNP levels (ARNI-first vs. SGLT2i-first; 1383 [319-2507] pg/mL vs. 570 [206-1314] pg/mL; p = 0.055) and significantly higher discontinuation rate of diuretic agents (ARNI-first vs. SGLT2i- first; 6.8% vs. 17.5%; p = 0.039) were noted in the SGLT2i-first group. When early combination (≤14D) compared to late combination (>14D), better positive remodeling of LVESV presented significantly in early combination subgroups., Conclusions: In patients with symptomatic HFrEF, SGLT2i-first strategy may provide a higher possibility of discontinuing diuretic agents than the ARNI-first strategy. Changes in LV performance, progression of renal function, and clinical outcomes did not differ between the two groups. Early combination (≤14D) provided better LV remodeling., Competing Interests: The authors declare no conflict of interest., (© 2023 The Author(s). Published by IMR Press.)

The management of heart failure with preserved ejection fraction (HFpEF) is rapidly evolving. The pharmacologic treatment of patients with HFpEF includes symptom management with diuretics and optimization of comorbidities, including hypertension, obesity, diabetes mellitus, and atrial fibrillation. Specific therapies, including angiotensin II receptor blockers, mineralocorticoid receptor antagonists, angiotensin receptor-neprilysin inhibitors, and sodium-glucose cotransporter-2 inhibitors, are well tolerated and can reduce the risk of HF hospitalization, particularly in those on the lower end of the HFpEF left ventricular ejection fraction spectrum. Ongoing trials should continue to inform optimal therapy in this evolving field., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (© 2022 Wiley Periodicals LLC.)

This study aims to investigate the dosage pattern, efficacy, and safety of sacubitril/valsartan (Sac/Val) in Chinese heart failure with reduced ejection fraction (HFrEF) patients regarding real-world settings. Patients from 27 centers with a confirmed diagnosis of HFrEF and initiated Sac/Val treatment were enrolled. The primary objective was to evaluate the dosage pattern and change of heart failure status. In a final cohort of 983 patients, outpatient Sac/Val treatment demonstrated a similar beneficial effect in NT-proBNP and cardiac function. After initiating the treatment, overall and sub-population showed similar safety and efficacy. Patients who received a higher dose of Sac/Val (&gt; 200 mg/d) demonstrated better improvement in LV function and reduction of NT-proBNP regardless of adjustment. Among Chinese HFrEF patients, Sac/Val showed a comparable reduction in NT-proBNP and improvement in cardiac function. Data further support guideline recommendations of Sac/Val in Chinese population. Optimal up-titration might provide further benefits. Further long-term and prognostic studies are needed., (© 2022. The Author(s).)

Background: Despite the use of optimal medical therapy, heart failure and reduced left ventricular ejection fraction (HFrEF) remains a leading cause of morbidity, mortality and health care costs. The introduction of angiotensin receptor/neprilysin inhibitors (ARNIs) had a revolutionary impact on the treatment of patients with HFrEF. The aim of the study was to monitor over time the perceived quality of life, the physical performance, the trend of BNP and NT-ProBNP and the NYHA functional class in patients with HFrEF during treatment with sacubitril/valsartan., Methods: We enrolled 37 patients (63±10 years old, 76% men) who underwent a total of one-year follow-up. All patients underwent clinical evaluation, 6MWT, blood analysis (in particular, NT-pro-BNP and BNP, renal function test); Kansas City Cardiomyopathy Questionnaire (KCCQ) and the NYHA functional class assessment were also performed, at the beginning of the study and after 3, 6 and 12 months of therapy., Results: We observed at each follow-up a significant improvement of KCCQ score, 6MWT, NT-ProBNP, BNP and NYHA class. However, analyzing the ∆% of variation of each single parameter, the improvement was not uniform in time. We also observed that only 37% of patients tolerated the full recommended dose of sacubitril/valsartan (97/103 mg b.i.d.); of the remaining, 40% tolerated the intermediate dose (49/51 mg b.i.d.) and 23% the minimum (24/26 md b.i.d.)., Conclusions: Sacubitril/valsartan therapy improves significantly quality of life, physical effort resistance, BNP and NT-ProBNP and NYHA functional class in patients with HFrEF. Although not all the patients tolerated the maximum recommended dose, the beneficial effects were significant even at lower doses.

Background: Although strategies for optimization of pharmacologic therapy in patients with heart failure with reduced ejection fraction (HFrEF) are scripted by guidelines, data from HF registries suggests that guideline-directed medical therapies (GDMT) are underutilized among eligible patients. Whether this discrepancy reflects medication intolerance, contraindications, or a quality of care issue remains unclear., Objective: The objective of this initiative was to identify reasons for underutilization and under-dosing of HFrEF therapy in patients at a large, academic medical center., Methods: Among 500 patients with HFrEF enrolled in a quality improvement project at a tertiary center, we evaluated usage and dosing of 4 categories of GDMT: ACE inhibitors/Angiotensin Receptor Blockers (ACE-i/ARB), Angiotensin Receptor-Neprilysin Inhibitors (ARNi), beta blockers, and Mineralocorticoid Receptor Antagonists (MRA). Reasons for nonprescription and usage of suboptimal doses were abstracted from notes in the chart and from telephone review of previous medication trials with the patient., Results: Of 500 patients identified, 472 subjects had complete data for analysis. Among eligible patients, ACE-i/ARB were prescribed in 81.4% (293 of 360) and beta blockers in 94.4% (442 of 468). Of these patients, 10.6% were prescribed target doses of ACE-i/ARB and 12.4% were prescribed target doses of beta blockers. Utilization of other categories of GDMT was lower, with 54% of eligible patients prescribed MRAs and 27% prescribed an ARNi. In most cases, the reasons for nonprescription or under-dosing of GDMT were not apparent on review of the health record or discussion with the patient., Conclusion: Clear rationale for nonprescription and under-dosing of GDMT often cannot be ascertained from detailed review and is only rarely related to documented medication intolerance or contraindications, suggesting an opportunity for quality improvement.

Importance: In recent years, significant progress has been made in the pharmacologic treatment of heart failure (HF) with reduced ejection fraction (HFrEF), but there is still insufficient evidence for drug therapy for HF with preserved ejection fraction (HFpEF) and mildly reduced ejection fraction (HFmrEF)., Objective: To compare the outcomes associated with different drug combinations for the treatment of HFpEF and HFmrEF., Data Sources: A search of the PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases was conducted for studies published from inception to October 9, 2021., Study Selection: Randomized clinical trials on the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), mineralocorticoid receptor antagonists (MRAs), β-blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors for patients with HFpEF or HFmrEF., Data Extraction and Synthesis: Data extraction and bias assessment were independently performed by 2 reviewers following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guideline. All data for 3 outcomes were pooled with a fixed-effect model., Main Outcomes and Measures: The main outcomes were first hospitalization for HF, all-cause mortality, and cardiovascular mortality. Hazard ratios (HRs) and 95% credible intervals (CrIs) were evaluated using a bayesian network meta-analysis model., Results: In this analysis, 19 randomized clinical trials, including 20 633 patients with HF and an ejection fraction of 40% or more, without a remarkable risk of bias were included. Compared with placebo, no treatments were associated with a significant reduction in the risk of all-cause death or cardiovascular death. SGLT2 inhibitors, ARNIs, and MRAs were associated with a significant decrease in the risk of HF hospitalization compared with placebo (SGLT2 inhibitors: HR, 0.71 [95% CrI, 0.60-0.83]; ARNIs: HR, 0.76 [95% CrI, 0.61-0.95]; MRAs: HR, 0.83 [95% CrI, 0.69-0.99]), and SGLT2 inhibitors were the optimal drug class in terms of reducing the risk for HF admission. Sensitivity analysis results demonstrated a progressive decrease in the risk of HF admission and an advance in mean rank associated with the increasing use of drug classes., Conclusions and Relevance: The findings of this study suggest that SGLT2 inhibitors were the optimal drug class for HFpEF and HFmrEF, consistent with the most recent guideline recommendation. The incremental use of combinations of SGLT2 inhibitors, ACE inhibitors or ARBs, and β-blockers may be associated with accumulative benefits in HF hospitalization rather than all-cause death among patients with HFpEF and HFmrEF.

Aims: Sub-analysis of a retrospective nation-wide observational analysis of heart failure (HF) epidemiology reported to the Czech National Registry of Reimbursed Health Services between 2012 and 2018 aimed at angiotensin-converting enzyme inhibitors (ACEI), angiotensin-II-receptor antagonists (ARB) and angiotensin receptor blocker/neprilysin inhibitor (ARNI) use., Methods and Results: ACEi and ARBs were generally used in 87.6% of all HF patients in 2012 (n=154 627); 84.5% in 2013 (n=170 861); 83.5% in 2014 (n=186 963); 81.6% in 2015 (n=198 844); 80.1% in 2016 (n=205 793); 78.0% in 2017 (n=212 152) and in 76.7% in 2018 (n=219 235). In a sub-analysis of patients with a medical procedure and/or examination using an I50.x ICD code accounted for in the given year, ACEi and ARBs were generally used in 99.3% in 2012 (n=63 250); 96% in 2013 (n=62 241); 95.2% in 2014 (n=64 414); 93.3% in 2015 (n=65 217); 91.8% in 2016 (n=65 236); 90.1% in 2017 (n=65 761) and in 88.6% in 2018 (n=66 332). In 2018, the majority of patients with HF were prescribed ramipril (n=49 909; 17.5%) and perindopril (n=44 332; 15.5%). The mostly prescribed ARBs in 2018 were telmisartan (n=18 669; 6.5%); losartan (n=13 935; 4.9%) and valsartan (n=4 849; 1.7%). In 24.5% of cases, ACEIs and ARBs were prescribed in a fixed combination with another drug. ARNI became gradually more prescribed from 2018 (n=9 659 in November 2020)., Conclusion: In an analysis of ACEIs, ARBs and ARNIs utilization in all patients treated for heart failure in the given year in the whole country, we found a comparable rate of drug prescription in comparison with specific heart failure registries. This indicates a good translation of current standard of care into common clinical practice. Ramipril and perindopril remained the mostly prescribed ACEIs and telmisartan became the mostly prescribed ARB. Since 2018, ARNIs began to be widely prescribed., Competing Interests: The authors report no conflicts of interest in this work.

Introduction: This consensus statement of Australian clinicians provides new recommendations for the pharmacological management of heart failure based on studies reported since the publication of the 2018 Australian heart failure guidelines., Main Recommendations: ▪Use of sodium-glucose cotransporter 2 (SGLT2) inhibitors to prevent hospitalisation for heart failure in type 2 diabetes mellitus can be extended to patients with multiple cardiovascular risk factors, albuminuric chronic kidney disease, or atherosclerotic cardiovascular disease. ▪New evidence supports the use of a mineralocorticoid receptor antagonist (finerenone) to prevent heart failure in type 2 diabetes mellitus associated with albuminuric chronic kidney disease. ▪In addition to renin angiotensin system inhibitors (angiotensin receptor neprilysin inhibitor preferred), beta blockers and mineralocorticoid receptor antagonists, an SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in all patients with heart failure with reduced left ventricular ejection fraction (LVEF ≤ 40%) (HFrEF). Lower quality evidence supports these therapies in patients with heart failure with mildly reduced LVEF (41-49%) (HFmrEF). ▪A soluble guanylate cyclase stimulator (vericiguat), selective cardiac myosin activator (omecamtiv mecarbil) and, if iron deficient, intravenous iron (ferric carboxymaltose) provide additional benefits in persistent HFrEF. ▪An SGLT2 inhibitor (empagliflozin) should be considered in patients with heart failure with preserved LVEF (≥ 50%) (HFpEF). Key changes in management from this statement: This document broadens the scope of angiotensin receptor neprilysin inhibitor use in patients with HFrEF and HFmrEF. SGLT2 inhibitor use expands to become a cornerstone therapy in HFrEF, with increasing evidence to support its use in HFmrEF and HFpEF., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

Renin-angiotensin-aldosterone system (RAAS) inhibition is a mainstay of the pharmacological treatment of heart failure with reduced ejection fraction (HFrEF). In the last years RAAS blockade has been improved by the introduction of the Angiotensin Receptor-Neprilysin Inhibitor (ARNI) sacubitril/valsartan, that combines RAAS inhibition with the block of neprilysin, boosting the positive effects of natriuretic peptides. The PARADIGM-HF trial demonstrated a significant advantage of sacubitril/valsartan over enalapril on the reduction of cardiovascular (CV) mortality and heart failure hospitalizations rates. Then, several randomized clinical trials and observational studies investigated its role in different clinical settings and its efficacy has been fully recognized in the most recent HFrEF European and USA guidelines. The effects of sacubitril/valsartan on major CV outcomes are associated with reduction of NT-proBNP levels and reverse cardiac remodeling and mitral regurgitation, recognized as one of the mechanistic effects of the drug explaining the favorable prognostic effects. A careful evaluation of patients' clinical profile is relevant to implement the use of ARNI in the clinical practice and to obtain the maximal treatment efficacy. The present Position Paper reports the opinion of the Italian Society of Cardiology on the optimal blockade of the RAAS system in HF patients with the aim of fostering widespread implementation of scientific evidence and practice guidelines in the medical community., (Copyright © 2022. Published by Elsevier B.V.)

Objectives: We evaluated whether Angiotensin receptor/Neprilysin inhibitors (ARNI) reduce heart failure (HF) hospitalizations and deaths in cardiac resynchronization therapy with defibrillator (CRTd) non-responders patients at 12 months of follow-up, modulating microRNAs (miRs) implied in adverse cardiac remodeling., Background: adverse cardiac remodeling characterized by left ventricle ejection fraction (LVEF) reduction, left ventricular end-systolic volume (LVESv) increase, and the 6-minute walking test (6MWT) reduction are relevant pathological mechanisms in CRTd non-responders and could be linked to changes in miRNAs (miRs), regulating cardiac fibrosis, apoptosis, and hypertrophy., Methods: miRs levels and clinical outcomes (LVEF, cardiac deaths, and 6MWT) were evaluated at baseline and one year of follow-up in CRTd non-responders divided into ARNI-users and Non-ARNI users., Results: At baseline, there were no differences in levels of inflammatory markers, miR-18, miR-145, and miR-181 (p > 0.05) between Non-ARNI users (n 106) and ARNI-users (n 312). At one year of follow-up, ARNI-users vs. Non-ARNI users showed lowest inflammatory markers (p < 0.01) and miR-181 levels (p < 0.01) and higher values of miR-18 (p < 0.01)and miR-145 (p < 0.01). At one year of follow-up, ARNI-users had a higher increase of LVEF (p < 0.01) and 6MWT (p < 0.01) along with a more significant reduction of LVESv (p < 0.01) compared to Non-ARNI users. Cox regression analysis evidenced that ARNI-based therapies increase the probability of anti-remodeling effects of CRTd. Based on symptomatic improvements, echocardiographic and functional classification improvements, 37 (34.9%) patients among ARNI-users became responders, while only twenty (6.4%) patients became responders among Non-ARNi-users., Conclusions: ARNI might influence epigenetic mechanisms modulating miRs implicated in the adverse cardiac remodeling responses to CRTd., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Collagen is a major component of the skin's support system, allowing for its firmness, elasticity, and mechanical strength. Skin collagen production decreases as we age and is associated with increased sagging, wrinkling, and thinning. The Renin-Angiotensin System (RAS) is a key hormonal system that changes with age and affects multiple organ systems. The primary health benefits of Angiotensin (Ang) receptor type1 (AT 1 R) blockers are believed to arise from systemic effects on blood pressure. However, there is also a skin-specific RAS, though this system has been less well characterized. There are eight FDA-approved angiotensin receptor blockers (ARBs) on the market, although the impact of topical ARBs on aging skin is unknown. Here, we evaluated the topical penetration of gel formulations of eight ARBs using human cadaver skin. Our results show that valsartan achieved the highest skin penetration compared to other ARBs. We then treated human skin fibroblasts from 2-year-old and 57-year-old individuals with valsartan alone or in combination with the neprilysin inhibitor sacubitril. Sacubitril works synergistically with valsartan by inhibiting the degradation of angiotensin II, thereby increasing its bioavailability. Treatment of young and older adult human skin cells with valsartan and sacubitril led to a five-fold increase in collagen type-1 production in the young cells and a four-fold increase in collagen type-1 in older adult cells. This study demonstrates a potential novel application for the widely prescribed drug combination sacubitril-valsartan as a topical agent in aged skin., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cardiac remodelling is an adverse phenomenon linked to heart failure progression and an important contributor to heart failure severity. Cardiac remodelling could represent the real therapeutic goal in the treatment of patients with heart failure with reduced ejection fraction, being potentially reversed through different pharmacotherapies. Currently, there are well-established drugs such as angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers and β-blockers with anti-remodelling effects; recently, angiotensin receptor neprilysin inhibitor effects on inhibiting cardiac remodelling (improving N-terminal pro-B-type natriuretic peptide levels, echocardiographic parameters of reverse cardiac remodelling and right ventricular function in patients with heart failure with reduced ejection fraction) were demonstrated. More recently, hemodynamic consequences of gliflozins, reduced cardiac hydrostatic pressure as a possible cause of ventricular remodelling and hypertrophy were proposed to explain potential anti-remodelling effects of gliflozins. Gliflozins exert their cardioprotective effects by attenuating myofibroblast activity and collagen-mediated remodelling. Another postulated mechanism is represented by the reduction in sympathetic activity, through the reduction in renal afferent nervous activity and the suppression of central reflex mechanisms. Benefits of gliflozins on left ventricular hypertrophy, dilation, and systolic and diastolic function were also described. In this review, we aimed to provide a wide overview on cardiac remodelling with a particular focus on possible anti-remodelling effects of angiotensin receptor neprilysin inhibitors and gliflozins., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Patients with adult congenital heart disease (ACHD) who have an anatomic right ventricle supporting the systemic circulation have increased mortality and morbidity from heart failure (HF). Angiotensin receptor-neprilysin inhibitors (ARNI) have emerged as a standard of therapy for adults with HF. However, the effects of this therapy have not been extensively studied in ACHD patients, especially those with systemic right ventricle (SRV)., Hypothesis: ARNIs are associated with subjective and objective improvement in SRV patients., Methods: Eighteen (18) SRV patients were prescribed ARNI at our institution in the last 5 years. Data before and during treatment, including demographics, medical history, New York Heart Association functional class (NYHA FC), labs, cardiac computed tomography (CT) or magnetic resonance imaging (MRI), echocardiographic measurements, cardiopulmonary stress test (CPET), and hospitalisation for HF were obtained by review of the electronic medical record. Statistical analysis was performed using paired t and Wilcoxon rank sum tests., Results: Eighteen (18) SRV patients (mean age 40 yrs, 72% male) were treated with ARNI (median duration 13 mo) in addition to other HF medications. All patients tolerated ARNI without symptomatic or asymptomatic hypotension or worsening kidney function. High ARNI dose (97/103 mg) was achieved in three (17%) patients, and moderate (49/51 mg) in three (17%). At baseline, nine patients were NYHA FC 2, seven FC 3, and two FC 4. Mean baseline cardiopulmonary exercise testing (CPET) and echocardiographic data were: oxygen uptake (VO 2 ) 18 mL/kg/min, minute ventilation/carbon dioxide (VE/VCO 2 ) 38, right ventricular ejection fraction (RVEF) 32%, fractional area change (FAC) 21%. Significant tricuspid regurgitation was present in 33% (28% moderate, and 5% severe) and mean tricuspid annular plane systolic excursion (TAPSE) was 9.4 mm. With treatment, there was no statistically significant difference in blood pressure, labs, testing, or imaging. There was a statistically significant improvement in median NYHA FC (2 vs 2.5, p=0.005). When compared to an equal pre-ARNI median timeframe, there was a noted decrease in cardiac hospitalisation (4 vs 9) that did not reach statistical significance (p=0.313)., Conclusion: In adult patients with failing systemic right ventricle, ARNI is safe and well tolerated. Their use is associated with improvement in functional status. Prospective studies on a larger group of patients are warranted to better understand the causes of this improvement., Competing Interests: Authors’ contributions All authors contributed to the written text and editing in final preparation of this manuscript. The authors read and approved the final manuscript. Declarations Competing Interests The authors declare that they have no competing interests. Availability of Data and Materials All data generated or analysed during this study are included in this published article. Acknowledgments None., (Copyright © 2022 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

The PARADISE-MI study compared standard treatment with an ACE inhibitor (ramipril) after an acute myocardial infarction with the newer sacubitril/ valsartan combination (so-called ARNI) medication in 5661 patients. Most patients had a reduced cardiac function (40% ejection fraction or less) and in about 50% of patients it was accompanied by complaints of congestion. The expected 15% reduction in primary endpoint cardiovascular death or rehospitalization or extra visits for heart failure was not met after 22 months. The study is characterized by an increased incidence of symptomatic hypotension of 28,3% in the group treated with the ARNI, compared to an incidence of 21,9% in the group treated with the ACE inhibitor. The interpretation of the trial is hampered by the mixed design of prevention and treatment trial for heart failure. A continuing careful approach is advised with ACE inhibitors as first choice in the first week(s) after myocardial infarction.

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), significantly reduces mortality and morbidity in patients with chronic heart failure with a reduced ejection fraction (HFrEF). However, a considerable number of patients treated with sacubitril/valsartan experience hypotension, oliguria, progressive azotemia, and renal failure as adverse events. These issues have been linked to significant gaps in the usage and dosing of guideline-directed medical therapy with ARNI in patients with HFrEF. We herein report a relevant case of pathologically proven acute tubular necrosis after the first dose of sacubitril/valsartan, highlighting the importance of optimizing the medical therapy in an outpatient with HFrEF.

Introduction: The knowledge on High-Output Cardiac Failure (HOCF) has greatly improved in the last two decades. One of the advances was the identification of a new phenotype of HOCF, characterized by the absence of ventricular dilation, already associated with liver disease, Arteriovenous Fistulas (AVF), lung disease, myelodysplastic syndromes, and obesity. However, it has been noted that any aetiology can present with one of the two phenotypes, depending on the evolution., Objective: The study aims to describe, through an integrative review, the physiopathology and aetiologies of HOCF and to discuss phenotypes associated with this condition., Methods: Revisions, guidelines, case-controls, cohort studies and clinical studies were searched in MEDLINE and LILACS, using the connectives in the "cardiac output, high" database (MeSH Terms) OR "high cardiac output" (All Fields)., Discussion: Two distinct phenotypes are currently described in the HOCF, regardless of the aetiology: 1) one with enlarged cardiac chambers; and 2) with normal heart chambers. The mechanisms related to HOCF are vasodilation, arteriovenous shunts that cause increased microvascular density, Reduced Systemic Vascular Resistance (RSVR), and high metabolism. These mechanisms lead to activation of the renin-angiotensin-aldosterone system, sodium and water retention, activation of neprilysin, of the sodium-glucose-2 transporter, which promote interstitial fibrosis, ventricular remodeling and a consequent increase in cardiac output >8L/min., Conclusion: Many aetiologies of HOCF have been described, and some of them are potentially curable. Prompt recognition of this condition and proper treatment may lead to better outcomes., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: This study used a real-world database to investigate the prescription patterns of sacubitril/valsartan (Sac/Val) among Taiwanese patients with heart failure with reduced ejection fraction (HFrEF)., Methods: The Treatment with Angiotensin Receptor neprilysin inhibitor fOr Taiwan Heart Failure patients (TAROT-HF) study is a principal investigator-initiated, multicenter, observational, retrospective study on Taiwanese HFrEF patients. A total of 1772 patients with HFrEF (mean age 62.5 years, 75.3% male, mean left ventricular ejection fraction [LVEF] 29.3%) who received Sac/Val at 10 hospitals between 2017 and 2018 were enrolled at the date of Sac/Val initiation. Among these patients, 585 (33%) initially received Sac/Val during acute decompensated heart failure (HF) hospitalization (TAROT-AHF arm), whereas 1187 (67%) initially received the same at the outpatient clinic (TAROT-CHF arm)., Results: A total of 1343 (75.8%) patients received an initial dose of 50 mg twice daily or fewer, whereas 422 (23.8%) received the standard initiation dose (100 mg twice daily). During outpatient Sac/Val initiation, the mean dosages were significantly higher than that following hospitalization (117 ± 55 mg vs 109 ± 57 mg; p = 0.014). Multivariate analysis identified younger age, higher systolic blood pressure, higher LVEF, prior use of renin-angiotensin system inhibitors, use of ivabradine, and a history of diabetes mellitus as independent factors for initiating a standard Sac/Val dose. Over a follow-up period of 18 months, incidences of cardiovascular death or first unplanned HF hospitalization were 18.69 and 33.11 per 100-person years for the TAROT-CHF and TAROT-AHF arms, respectively., Conclusion: The TAROT-HF study provided an opportunity to describe the clinical features of patients with HFrEF who received Sac/Val, assess the real-world utilization and efficacy of Sac/Val, and compare these patients with those included in prior registries., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2021, the Chinese Medical Association.)

Background: Heart failure with preserved ejection fraction (HFpEF) is a global public health problem with important regional differences. We investigated these differences in the PARAGON-HF trial (Prospective Comparison of Angiotensin Receptor Neprilysin Inhibitor With Angiotensin Receptor Blocker Global Outcomes in HFpEF), the largest and most inclusive global HFpEF trial., Methods: We studied differences in clinical characteristics, outcomes, and treatment effects of sacubitril/valsartan in 4796 patients with HFpEF from the PARAGON-HF trial, grouped according to geographic region., Results: Regional differences in patient characteristics and comorbidities were observed: patients from Western Europe were oldest (mean 75±7 years) with the highest prevalence of atrial fibrillation/flutter (36%); Central/Eastern European patients were youngest (mean 71±8 years) with the highest prevalence of coronary artery disease (50%); North American patients had the highest prevalence of obesity (65%) and diabetes (49%); Latin American patients were younger (73±9 years) and had a high prevalence of obesity (53%); and Asia-Pacific patients had a high prevalence of diabetes (44%), despite a low prevalence of obesity (26%). Rates of the primary composite end point of total hospitalizations for HF and death from cardiovascular causes were lower in patients from Central Europe (9 per 100 patient-years) and highest in patients from North America (28 per 100 patient-years), which was primarily driven by a greater number of total hospitalizations for HF. The effect of treatment with sacubitril-valsartan was not modified by region (interaction P >0.05)., Conclusions: Among patients with HFpEF recruited worldwide in PARAGON-HF, there were important regional differences in clinical characteristics and outcomes, which may have implications for the design of future clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

As the heart matures during embryogenesis from its foetal stages, several structural and functional modifications take place to form the adult heart. This process of maturation is in large part due to an increased volume and work load of the heart to maintain proper circulation throughout the growing body. In recent years, it has been observed that these changes are reversed to some extent as a result of cardiac disease. The process by which this occurs has been characterized as cardiac foetal reprogramming and is defined as the suppression of adult and re-activation of a foetal genes profile in the diseased myocardium. The reasons as to why this process occurs in the diseased myocardium are unknown; however, it has been suggested to be an adaptive process to counteract deleterious events taking place during cardiac remodelling. Although still in its infancy, several studies have demonstrated that targeting foetal reprogramming in heart failure can lead to substantial improvement in cardiac functionality. This is highlighted by a recent study which found that by modulating the expression of 5-oxoprolinase (OPLAH, a novel cardiac foetal gene), cardiac function can be significantly improved in mice exposed to cardiac injury. Additionally, the utilization of angiotensin receptor neprilysin inhibitors (ARNI) has demonstrated clear benefits, providing important clinical proof that drugs that increase natriuretic peptide levels (part of the foetal gene programme) indeed improve heart failure outcomes. In this review, we will highlight the most important aspects of cardiac foetal reprogramming and will discuss whether this process is a cause or consequence of heart failure. Based on this, we will also explain how a deeper understanding of this process may result in the development of novel therapeutic strategies in heart failure., (© 2020 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), has been shown to reduce the risk of cardiovascular death or heart failure hospitalization and improve symptoms among patients with chronic heart failure with reduced ejection fraction compared to enalapril, the gold standard angiotensin-converting enzyme inhibitor. In the 5 years since the publication of the results of PARADIGM-HF, further insight has been gained into integrating a neprilysin inhibitor into a comprehensive multidrug regimen, including a renin-angiotensin aldosterone system (RAS) blocker. This paper reviews the current understanding of the effects of sacubitril/valsartan and highlights expected developments over the next 5 years, including potential new indications for use. Additionally, a practical, evidence-based approach is provided to the clinical integration of sacubitril/valsartan among patients with heart failure with reduced ejection fraction., (Copyright © 2020. Published by Elsevier Inc.)

Underuse of hydralazine/nitrate (HYD/NIT) in black patients with heart failure and reduced ejection fraction (HFrEF) has been previously described, but whether this important treatment gap persists in contemporary practice is unknown. Sacubitril/valsartan has become a part of guideline-directed medical therapy for HFrEF but data on utilization of this therapy in black patients is lacking. This study addressed these issues by assessing the frequency of HYD/NIT and sacubitril/valsartan use in black patients with HFrEF in the Change the Management of Patients with Heart Failure Registry, a multicenter cohort study. The association of race with utilization rates of these agents was also evaluated. Clinical and medication data at baseline and during 12 months of follow-up from black and nonblack registry patients without documented contraindications or intolerance to the medications of interest were analyzed. Data were available from December 2015 to October 2017, in 4,848 HFrEF patients, of whom 853 were black (18%) and 3995 were nonblack. Black patients were younger, more likely to be female, and had lower ejection fractions compared with nonblacks. Only 11% of black patients were receiving HYD/NIT therapy at baseline and 13% at 1 year. The percentage of black patients treated at baseline with sacubitril/valsartan was also low at 18% and remained unchanged at 1 year. After adjustment for covariates, race was independently associated with HYD/NIT use (odds ratio 8.32; 95% confidence interval 6.12 to 11.3; p < 0.0001), but not for sacubitril/valsartan. In conclusion, study findings demonstrate a marked persistent treatment gap for HYD/NIT and similar poor utilization of sacubitril/valsartan in black patients with HFrEF despite current guideline recommendations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Clinical symptoms of heart failure in older patients can be similar to those of other diseases in geriatrics. Therefore, the diagnosis should be confirmed by echocardiography. The treatment of older patients with heart failure with reduced left ventricular ejection fraction (HFrEF) should be carried out in accordance with the guidelines with regular control of volume status, renal function and serum electrolytes. Due to the lack of effective treatment of heart failure with preserved ejection faction (HFpEF) blood pressure control as a measure of prevention is important. Patients can benefit from the new treatment options for secondary mitral regurgitation if the patient selection is correct. For older and frail patients a special management would be desirable, with the aim of reducing functional loss through hospitalization. In order to reduce the rehospitalization rate of older patients, it is necessary to improve the collaboration between outpatient and inpatient care providers and nursing personnel should be better qualified.

Background: Heart failure is a highly prevalent disease with a global prevalence of 37 million, and the prevalence is increasing. Patients with heart failure are at an increased risk of death and morbidity. Traditionally, patients with heart failure have been treated with a beta-blocker in addition to an inhibitor of the renin-angiotensin-aldosterone system. However, new drugs are currently being added to the recommended guideline therapy. The latest drug to be added combines inhibition of the renin-angiotensin-aldosterone system pathway with inhibiting the neprilysin enzyme and is therefore classified as an ARNI. Our objective is to identify the beneficial and harmful effects of ARNIs in the treatment of patient with heart failure., Methods: This protocol for a systematic review was undertaken using the recommendations of the Cochrane, the Preferred Report Items of Systematic reviews with Meta-Analysis Protocols, and the eight-step assessment procedure suggested by Jakobsen and colleagues. We plan to include all relevant randomised clinical trials assessing the use of ARNIs in the treatment of patients with heart failure. We will search the Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Excerpta Medica database (EMBASE), Latin American and Caribbean Health Sciences Literature (LILACS), Science Citation Index Expanded on Web of Science, Chinese Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese Science Journal Database (VIP), and BIOSIS to identify relevant trials. We will also search for grey literature and unpublished trials. Extracted data will be analysed using Review Manager 5, STATA 5, and Trial Sequential Analysis. Our primary outcomes will be all-cause mortality and serious adverse events. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes, and we will assess the quality of evidence using the GRADE assessment., Discussion: The present systematic review will have the potential to aid clinicians in decision-making and thereby, benefit patients with heart failure., Systematic Review Registration: PROSPERO CRD42019129336.

Background: The combination drug sacubitril/valsartan was reported to be superior to enalapril in reducing all-cause death, cardiovascular mortality, and heart failure (HF) hospitalizations in patients with cardiac insufficiency and reduced left ventricular ejection fraction (HFREF) with NYHA class II-IV., Methods: Our retrospective cohort study aimed to assess the effects of sacubitril/valsartan in addition to a beta-blocker and mineral receptor antagonist (MRA) in a group of HFREF patients with NYHA class II-III HF vs. conventional therapy (ACE inhibitor or angiotensin II receptor blocker added to a beta-blocker plus an MRA) administered to a control group of HFREF patients with comparable clinical features. In both groups, treatment was supplemented by a loop diuretic, usually furosemide, at variable doses. The primary outcomes were all-cause death and HF hospitalizations. Safety outcomes were symptomatic hypotension, angioedema, hyperkalemia, and worsening renal function., Results: Mortality at 6 months was 6.8% in patients taking sacubitril/valsartan vs. 34% in those on conventional therapy (odds ratio [OR] = 0.14; 95% CI: 0.04-0.49). Moreover, there was a 4.5% rate of HF hospitalizations in the sacubitril/valsartan group vs. 59% in the control group (OR = 0.03; 95% CI: 0.01-0.14). Safety outcomes were comparable in the two groups, although hypotension (systolic blood pressure < 100 mm Hg) was found in 15.9% of patients in the sacubitril/valsartan group vs. 5.7% in the control group (OR = 3.14; 95% CI: 0.94-10.55)., Conclusion: Sacubitril/valsartan offered strong protection against all-cause death and HF hospitalizations at 6 months without any significant side effects. To validate this efficacious molecule, further postmarketing observational studies, focusing mainly on hypotension and angioedema are warranted.

Besides noticeable progress in device therapy during the past decade, more recent advances in the management of chronic heart failure have led to exciting new pharmacological options. Among these, the combined angiotensin II receptor/neprilysin inhibitor (ARNI) valsartan/sacubitril has already proven highly effective in heart failure with reduced ejection fraction (HFrEF), and convincing data are available regarding the cardioprotective effects of sodium-glucose-co-transporter 2 (SGLT2) inhibitors. These two treatments have earned a class I and a class II recommendation, respectively, in the European Society of Cardiology guidelines for the diagnosis and treatment of heart failure. Whereas progress with respect to heart failure with preserved ejection fraction (HFpEF) is still slow, both ARNIs and SGLT2 inhibitors hold great promise for this condition as well, and large clinical trials are currently ongoing. In addition, new diagnostic algorithms have recently been developed to improve the diagnostic accuracy for HFpEF, which will ultimately aid the search for effective therapies in future clinical trials. In this review article, these most recent advances in the diagnosis and pharmacological management of HFrEF and HFpEF are highlighted, and set-backs as well as opportunities for future developments (e.g., tafamidis for the treatment of transthyretin amyloid cardiomyopathy) are discussed.

Background The angiotensin-receptor/neprilysin inhibitor ( ARNI ) sacubitril/valsartan reduces hospitalization and mortality for patients with heart failure with reduced ejection fraction. However, adoption of ARNI into clinical practice has been slow. Factors influencing use of ARNI have not been fully elucidated. Using data from the Get With The Guidelines-Heart Failure registry, Hospital Compare, Dartmouth Atlas, and the American Hospital Association Survey, we sought to identify hospital characteristics associated with patient-level receipt of an ARNI prescription. Methods and Results We analyzed patients with heart failure with reduced ejection fraction who were eligible for ARNI prescription (ejection fraction≤40%, no contraindications) and hospitalized from October 1, 2015 through December 31, 2016. We used logistic regression to estimate the associations between hospital characteristics and patient ARNI prescription at hospital discharge, accounting for clustering of patients within hospitals using generalized estimating equation methods and adjusting for patient-level covariates. Of 16 674 eligible hospitalizations from 210 hospitals, 1020 patients (6.1%) were prescribed ARNI at discharge. The median hospital-level proportion of patients prescribed ARNI was 3.3% (Q1, Q3: 0%, 12.6%). After adjustment for patient-level covariates, for-profit hospitals had significantly higher odds of ARNI prescription compared with not-for-profit hospitals (odds ratio, 2.53; 95% CI , 1.05-6.10; P=0.04), and hospitals located in the Western United States had lower odds of ARNI prescription compared with those in the Northeast (odds ratio, 0.33; 95% CI , 0.13-0.84; P=0.02). Conclusions Relatively few hospital characteristics were associated with ARNI prescription at hospital discharge, in contrast to what has been observed in early adoption in other disease areas. Additional evaluation of barriers to implementing new evidence into heart failure practice is needed.

The common ultimate pathological feature for all cardiovascular diseases, congestive heart failure (CHF), is now considered as one of the main public health burdens that is associated with grave implications. Neurohormonal systems play a critical role in cardiovascular homeostasis, pathophysiology, and cardiovascular diseases. Hormone treatments such as the newly invented dual-acting drug valsartan/sacubitril are promising candidates for CHF, in addition to the conventional medications encompassing beta receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists. Clinical trials also indicate that in CHF patients with low insulin-like growth factor-1 or low thyroid hormone levels, supplemental treatment with growth hormone or thyroid hormone seems to be cardioprotective; and in CHF patients with volume overload the vasopressin antagonists can relieve the symptoms superior to loop diuretics. Furthermore, a combination of selective glucocorticoid receptor agonist and mineralocorticoid receptor antagonist may be used in patients with diuretic resistance. Finally, the potential cardiovascular efficacy and safety of incretin-based therapies, testosterone or estrogen supplementation needs to be prudently evaluated in large-scale clinical studies. In this review, we briefly discuss the therapeutic effects of several key hormones in CHF.

Levels of natriuretic peptides (NPs), such as B-type NP (BNP) and the N-terminal fragment of its prohormone (NT-proBNP), are well-established biomarkers for patients with heart failure (HF). Although these biomarkers have consistently demonstrated their value in the diagnosis and prognostication of HF, their ability to help clinicians in making treatment decisions remains debated. Moreover, some new HF drugs can affect concentrations of NPs, such as the prevention of BNP degradation by angiotensin receptor/neprilysin inhibitors (ARNIs), and may present a challenge in the interpretation of levels of BNP. Use of NT-proBNP measurement has been suggested in the context of ARNI therapy because its concentrations are not affected by neprilysin inhibition. As biomarkers are reconsidered in the context of ARNI therapy, cutoff levels and the effects of individual patient characteristics, such as renal function and age, on biomarker concentrations should be reassessed.

Heart failure is a disease with a high prevalence and incidence. New therapeutic approaches are needed to prevent the onset of heart failure and to reduce the high morbidity and mortality associated with this disease. An optimized therapy of arterial hypertension in patients with risk factors and the use of the SGLT2 inhibitor empagliflozin in type 2 diabetics are proven strategies to prevent heart failure. The therapeutic options in heart failure with preserved ejection fraction are still insufficient. In heart failure with reduced ejection fraction sacubitril/valsartan, the first approved angiotensin receptor-neprilysin inhibitor, is superior to an angiotensin converting enzyme (ACE) inhibitor. Whether digitalis affects the prognosis in heart failure remains unclear; however, serum concentration should be targeted at the lower therapeutic range. Iron supplementation in heart failure with reduced systolic function and iron deficiency improves symptoms and quality of life.

Purpose of Review: The aim of this paper is to discuss strategies for prevention and management of hyperkalemia in patients with heart failure, including the role of novel therapies., Recent Findings: Renin-angiotensin-aldosterone system (RAAS) antagonists, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and mineralocorticoid receptor antagonists (MRA) decrease mortality and morbidity in heart failure but increase the risk of hyperkalemia, especially when used in combination. Prevention of hyperkalemia and its associated complications requires careful patient selection, counseling regarding dietary potassium intake, awareness of drug interactions, and regular laboratory surveillance. Recent data suggests that the risk of hyperkalemia may be further moderated through the use of combined angiotensin-neprilysin inhibitors, novel MRAs, and novel potassium binding agents. Clinicians should be mindful of the risk of hyperkalemia when prescribing RAAS inhibitors to patients with heart failure. In patients at highest risk, such as those with diabetes, the elderly, and advanced chronic kidney disease, more intensive laboratory surveillance of potassium and creatinine may be required. Novel therapies hold promise for reducing the risk of hyperkalemia and enhancing the tolerability of RAAS antagonists.

The implementation into clinical practice of new therapeutic strategies that could improve the prognosis of patients with heart failure (HF) with reduced ejection fraction (HFrEF) remains relevant. Innovative approach is to restore imbalances of neurohumoral systems by inhibiting angiotensin II receptor and neprilysin. The review presents the role of the natriuretic peptides system in the HFrEF pathophysiology, historical approaches to neurohormonal modulation, clinical pharmacology of the first in the class of angiotensin receptor and neprilysin inhibitor sakubitril/valsartan. The results of the study PARADIGM-HF, in which sakubitril/valsartan therapy in patients with HFrEF compared with the recommended doses of enalapril was associated with the decrease of the of cardiovascular death and hospitalizations for HF by 20%, the risk of death from any cause by 16%, improvement of symptoms and exercise tolerance. Sakubitril/valsartan tolerated better than enalapril, rarely causes a cough, hyperkalemia or renal dysfunction. There was no increase in the risk of angioedema. Based on the results of the study PARADIGM-HF sakubitril/valsartan was included in the national and international guidelines for HF.

Backgound: Current drug therapy for the management of arterial hypertension and heart failure has provided substantial benefits but has also some limitations. LCZ696, a dual inhibitor of angiotensin receptor blockers and neprilysin, and finerenone, a non-steroidal mineralocorticoid receptor antagonist, are two recently developed novel agents for the management of these conditions., Methods: This review aims to present the pathophysiological basis for the use of these two novel drugs, critically discuss available clinical data, and provide future perspectives., Results: LCZ696 seems a very promising antihypertensive agent, that additionally generates clinically meaningful benefits in patients with heart failure with reduced injection fraction and raises expectations for the management of patients with heart failure with preserved ejection fraction. Finerenone aims to be safer than current aldosterone antagonists and has been so far tested in patients with heart failure and in patients with albuminuria. First available data are very promising for the efficacy of the drug, while it provides a better safety profile than current mineralocorticoid antagonists., Conclusion: LCZ696 and finerenone are two novel drugs for the management of arterial hypertension and heart failure. First available data point toward important clinical benefits from their use. Future large trials further investigating the cardiovascular profile of these agents will establish the use of these drugs., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Importance: Angiotensin receptor neprilysin inhibition (ARNI) therapy provided incremental survival benefit to patients with heart failure and reduced ejection fraction (HFrEF) in clinical trials. To date, estimation of the potential benefits that could be gained from optimal implementation of ARNI therapy at the population level have not been quantified., Objective: To quantify the projected gains for deaths prevented or postponed with comprehensive implementation of ARNI therapy for patients with HFrEF in the United States., Design, Setting, and Participants: Eligibility criteria for ARNI therapy, population-based estimates of patients with HFrEF in the United States, and numbers needed to treat to overt death were obtained from published sources. The potential numbers of deaths prevented or postponed as a result of ARNI were estimated along with multiple-way sensitivity analysis., Main Outcome and Measure: All-cause mortality., Results: Of 2 736 000 patients with HFrEF patients in the United States, 2 287 296 (84%) were projected to be candidates for ARNI therapy. Optimal implementation of ARNI therapy was empirically estimated to prevent 28 484 deaths a year (range, 18 230-41 017 deaths per year)., Conclusions and Relevance: A substantial number of deaths in the United States could potentially be prevented by optimal implementation of ARNI therapy. These data support implementation of evidence into practice in a timely manner because this may have a material impact on population health among patients with HFrEF.

Background: Heart failure with preserved ejection fraction (i.e. diastolic heart failure) accounts for about half of heart failure cases. The aim of this review is to reflect current knowledge regarding the epidemiology, pathophysiology and treatment., Results: Diastolic heart failure patients are principally elderly and predominantly female. Numerous pathophysiological alterations in this disease have been shown and recent therapeutic recommendations include control of cardiovascular risk factors and symptoms. New therapeutic options, such as inhibition of late sodium current, aldosterone receptor blockade, combined inhibition of AT1 receptor and the enzyme neprilysin, and phosphodiesterase 5 inhibition are discussed in this review and ongoing clinical trials are also briefly presented., Conclusion: Diastolic heart failure remains a cardiac disease which is difficult to treat; however, new study results allow a better definition of a population of patients who could benefit from specific therapies.

The angiotensin converting enzyme (ACE), endothelin (ET) converting enzyme (ECE) and neutral endopeptidase (NEP) are all zinc-metallopeptidases expressed in almost all the organs, such as heart, vessels and kidneys. While ACE and ECE are respectively involved in the transformation of angiotensin I and Big-ET into angiotensin II and ET-1 respectively, which possess vasoconstrictor and mitogenic properties, NEP is involved in the degradation of atrial natriuric factor (ANF), which possesses vasorelaxant, diuretic/natriuretic and antihypertrophic properties. These three systems are activated in heart failure and modulate the progression of heart failure. This article will discuss preliminary date concerning simultaneous inhibition of ACE, ECE and/or NEP and their therapeutic potential interest in the treatment of heart failure.