Chronic kidney disease (CKD) affects 50% of patients with heart failure. The pathophysiology of CKD in heart failure is proposed to be driven by macrocirculatory hemodynamic changes, including reduced cardiac output and elevated central venous pressure. However, our understanding of renal microcirculation in heart failure and CKD remains limited. This is largely due to the lack of noninvasive techniques to assess renal microcirculation in patients. Moreover, there is a lack of clinically relevant animal models of heart failure and CKD to advance our understanding of the timing and magnitude of renal microcirculatory dysfunction. Patients with heart failure and CKD commonly require cardiac surgery with cardiopulmonary bypass (CPB) to improve their prognosis. However, acute kidney injury (AKI) is a frequent unresolved clinical complication in these patients. There is emerging evidence that renal microcirculatory dysfunction, characterized by renal medullary hypoperfusion and hypoxia, plays a critical role in the pathogenesis of cardiac surgery-associated AKI. In this review, we consolidate the preclinical and clinical evidence of renal macro- and microcirculatory perturbations in heart failure and cardiac surgery requiring CPB. We also examine emerging biomarkers and therapies that may improve health outcomes for this vulnerable patient population by targeting the renal microcirculation.

As a novel drug-drug cocrystal, sacubitril allisartan calcium (S086) has demonstrated significant efficacy in the treatment of hypertension and heart failure. S086 has two crystalline forms (α and ξ) with the same molecular composition, but only the crystal structure of the latter has been disclosed. Using the carboxylic group (COO-) and the amide group (CONH) as structural probes, the core structures and local dynamics of the Ca2+ coordination complex in the unit cell of the two cocrystals were examined by ultrafast two-dimensional infrared (2D IR) spectroscopy. A notable variation in the molar ratio of bidentate to bridging binding types of COO- groups that bind to Ca2+ was first identified between the two crystal forms by linear IR spectroscopy. This variation is accompanied by greater local structural rigidity of the α-crystal compared to that of the ξ-crystal, as evidenced by a greater residual amplitude in the spectral diffusion dynamics extracted from the time-dependent 2D IR spectroscopy. Vibrational energy transfer between the bidentate and tridentate COO- groups in the α-crystal was found to be faster than that in the ξ-crystal, suggesting shorter intermolecular distances between EXP3174 and sacubitril in the former. These findings provide dynamical structural parameters that help to understand the stability and releasing mechanisms of the drug molecules.

Sacubitril/valsartan (SAV) is crucial for managing heart failure (HF). Randomized clinical trials have shown SAV's superiority over angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs) in reducing N-terminal pro-B-type natriuretic peptide levels. However, results for cardiovascular (CV) mortality, HF rehospitalization, and all-cause mortality have been mixed.

This study aimed to determine hard endpoints among the population with HF treated with SAV vs ACEI/ARBs and conduct a comprehensive risk-benefit analysis of the safety profile for SAV vs ACEI/ARB.

We queried PubMed, EMBASE, Scopus, and the Cochrane Central Register of Controlled Trials for randomized clinical trials from inception to November 2023. We included studies that compared SAV to ACEI or ARBs and reported hard endpoints, including all-cause mortality, CV mortality, and HF rehospitalizations. Random effect model was used, and categorical values were analyzed using risk ratios (RRs) and 95% CI. The I2 test was used to assess between-study heterogeneity. Publication bias was assessed via funnel plots and the Egger test. This study was registered in PROSPERO (CRD42024497661).

The study included a total of 14 trials (n = 25,167). SAV reduced all-cause mortality in the population with an ejection fraction (EF) ≤40% (RR: 0.88; 95% CI: 0.81-0.94; P = 0.0006), but not in those with EF >40% (RR: 0.97; 95% 0.85-1.11; P = 0.67). There was no difference in CV mortality across EF spectrums (RR: 0.9; 95% CI: 0.79-1.03; P = 0.13). HF readmission was lower in the SAV-treated group regardless of EF (RR: 0.85; 95% CI: 0.79-0.91; P = 0.00001).

The SAV-treated group, across all EF spectrum, was less likely to be rehospitalized than the ACEI/ARB-treated group. However, all-cause mortality reduction was only noted in the SAV group with EF <40%. No reduction in CV-related mortality was observed across the EF spectrum.

Heart failure (HF) represents a significant global health challenge, characterized by high morbidity and mortality rates, decreased quality of life and a significant financial and economic burden. The prevalence of HF continues to rise, driven by an ageing population and an increasing burden of comorbidities such as hypertension, diabetes and obesity. Understanding the complex pathophysiology and developing effective treatments are critical for improving patient outcomes, yet the range of effective, life-prolonging medication classes has remained mostly constant in the last few decades. The introduction of angiotensin receptor neprilysin inhibitors (ARNI) was a major breakthrough in HF management, for the first time targeting the natriuretic peptide system in addition to the renin-angiotensin-aldosterone pathway to potentiate the effects of older drug classes. ARNI shows superiority in clinical outcomes compared to previous guideline-directed therapies, especially in patients with reduced ejection fraction (EF). It has now been implemented into international guidelines, endorsing its use in patients with HF and reduced ejection fraction (HFrEF) and HF with mildly reduced ejection fraction (HFmrEF). This review summarises the mechanism of action of Sac/Val, presents key clinical trials in a range of patient populations and HF aetiologies and outlines gaps in knowledge and potential novel uses of Sac/Val.

The acute response to therapeutic afterload reduction differs between heart failure with preserved (HFpEF) versus reduced ejection fraction (HFrEF), with larger left ventricular (LV) stroke work augmentation in HFrEF compared with HFpEF. This may (partially) explain the neutral effect of HFrEF-medication in HFpEF. It is unclear whether such differences in hemodynamic response persist and/or differentially trigger reverse remodeling in the case of long-term afterload reduction. A systematic search was performed, identifying 21 clinical trials investigating renin-angiotensin-aldosterone system (RAAS) inhibitors, β-blockers, and sodium-glucose cotransport 2 inhibitors that report data on afterload reduction, stroke volume, and reverse remodeling in HFpEF and/or HFrEF. In both HFpEF and HFrEF, meta-analyses revealed limited long-term change in systolic/diastolic blood pressure (-5.6/-3.2 and -4.6/-1.4 mmHg, respectively) and LV afterload reduction (arterial elastance: -0.039 and -0.055 mmHg/mL, respectively). Long-term treatment did not result in an increase in stroke volume, with the exception of β-blockers in HFrEF. Indexed LV mass decreased slightly in both HFpEF and HFrEF (-2.8 and -2.3 g/m2, respectively). In HFrEF, treatment reduced LV end-diastolic and end-systolic volume (-8 and -6 mL, respectively), whereas in HFpEF there was no relevant change. Contrary to acute heart failure studies, long-term afterload reduction had little effect on blood pressure and stroke volume augmentation in both HFpEF and HFrEF. However, reverse remodeling was clearly present in HFrEF but was essentially absent in HFpEF.

Patients suffering from heart failure with preserved ejection fraction (HFpEF) often exhibit a sedentary lifestyle, contributing to the worsening of their condition. Although there is an inverse relationship between physical activity (PA) and adverse cardiovascular outcomes, the implementation of Class Ia PA guidelines is hindered by low participation in supervised and structured programmes, which are not suitable for a diverse population of HFpEF patients. The MyoMobile study has been designed to assess the effect of a 12-week, app-based coaching programme on promoting PA in patients with HFpEF.

The MyoMobile study was a single-centre, randomized, controlled three-armed parallel group clinical trial with prospective data collection to investigate the effect of a personalized mobile app health intervention compared with usual care on PA levels in patients with HFpEF. Major inclusion criteria were age ≥ 45 years, a diagnosis of HFpEF, LVEF > 40%, and current HF symptoms (NYHA Class I-III). Major exclusion criteria included acute decompensated HF, non-ambulatory status, recent acute coronary syndrome or cardiac surgery, alternative diagnoses for HF symptoms, active cancer treatment, and physical or medical conditions affecting mobility. Participants were recruited from hospitals, general practices, and practices specialized in internal medicine and cardiology in the Rhine-Main area, Germany. Participants underwent an objective 7-day PA measurement with a 3D accelerometer (Dynaport, McRoberts) at screening and after the 12-week intervention period. Following the screening, eligible participants were randomized into one of three groups: standard care (PA consulting), the intervention arm with app-based PA tracking and coaching, or the intervention arm with tracking but without coaching. The primary efficacy endpoint was the change in average daily step count between the average step count at baseline and at the end of the intervention, comparing standard care to a 12-week app-based PA coaching intervention.

Exercise intolerance is a primary symptom in HFpEF patients, leading to poor quality of life and HF-related adverse outcomes due to physical inactivity. The MyoMobile study was designed to investigate the use of app-based coaching to improve PA in patients with HFpEF with a personalized, home-based intervention, focusing on simple step counts for flexibility and ease of integration into daily routines.

URL: https://clinicaltrials.gov/ct2/show/NCT04940312.

NCT04940312.

Despite favorable hemodynamic and neurohormonal effects, endothelin receptor antagonists have not improved outcomes in patients with heart failure (HF), possibly because they cause fluid retention.

In this randomized, double-blind, multicenter trial (SERENADE [Macitentan in Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease]), we evaluated the effects of an endothelin receptor antagonist, macitentan, in patients with HF, left ventricular ejection fraction ≥40%, and pulmonary vascular disease. After a 4-week placebo run-in (to ensure clinical stability), followed by a 5-week single-blind macitentan run-in, patients who did not exhibit fluid retention were randomized to macitentan or placebo. The primary end point was change in NT-proBNP (N-terminal pro-B-type natriuretic peptide; baseline to 24 weeks); secondary end points included change in KCCQ (Kansas City Cardiomyopathy Questionnaire) clinical summary score (baseline to 24 weeks) and time to worsening HF by 52 weeks.

Of 230 patients enrolled, 28 were excluded during the placebo run-in, 60 excluded during the macitentan run-in, and 142 were randomized. Macitentan had no effect on change in NT-proBNP (geometric mean ratio [macitentan/placebo], 1.02 [90% CI, 0.88-1.19]; P=0.79) or on secondary end points (placebo-corrected change in KCCQ clinical summary score, -3.5 [90% CI, -8.2 to +1.2]; P=0.22). Worsening HF occurred in 20 (28%) patients assigned to macitentan and 13 (18%) assigned to placebo (hazard ratio, 1.48 [90% CI, 0.83-2.67]; P=0.24). More macitentan-treated patients developed fluid retention (16 [23%] versus 10 [14%]) and cardiac adverse events (33 [46%] versus 22 [31%]) versus placebo.

Despite a novel enrichment trial design to target pulmonary vascular disease and exclude treatment-related fluid retention in patients with HF and preserved/mildly reduced left ventricular ejection fraction, macitentan neither lowered NT-proBNP nor improved HF outcomes.

URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03153111 and NCT03714815.

Acute myocardial infarction (AMI) significantly contributes to the progression of heart failure (HF). Standard treatment for HF has long been angiotensin-converting enzyme inhibitors (ACEIs), targeting the renin-angiotensin-aldosterone system (RAAS). Recent developments in HF management introduced sacubitril/valsartan (S/V), a novel angiotensin receptor-neprilysin inhibitor (ARNI), showing promising results in global trials. This study aimed to assess the efficacy of early S/V application compared to angiotensin-converting enzyme inhibitors (ACEIs) in reducing NT-proBNP levels and improving clinical outcomes, specifically focusing on dyspnea symptomatology, in Chinese patients with AMI complicated by HF.

This single-center, mixed methods study was conducted at Tangshan Gongren Hospital from January to December 2021, including 88 patients diagnosed with AMI and HF. Patients were divided into two groups: 31 received S/V, while 57 were treated with ACEIs. Data collection encompassed baseline demographic, clinical, and biochemical variables, NT-proBNP levels, blood pressure measurements, and dyspnea symptom severity. Follow-up assessments were conducted 1 year post-discharge to evaluate NT-proBNP levels, and symptom progression. Statistical analyses, including t-tests, Wilcoxon rank-sum tests, and chi-square tests, were performed to compare outcomes between the two groups.

At baseline, no significant differences were observed between the two groups in terms of demographic, lifestyle, and medical history. Although patients in the S/V group presented with more severe baseline renal impairment and cardiac dysfunction, there was no significant difference in NT-proBNP levels from admission to discharge. 1-year follow-up showed a trend towards reduced NT-proBNP levels in the S/V group, though this difference did not reach statistical significance. All patients in both groups reported improvements in dyspnea at discharge and at follow-up, with no significant inter-group difference. Notably, the S/V group demonstrated a more significant reduction in both systolic and diastolic blood pressure from admission to discharge compared to the ACEIs group.

This study found that S/V had similar effects to ACEIs in reducing NT-proBNP levels among Chinese patients with AMI complicated by HF, though S/V was associated with greater reductions in blood pressure. These findings suggest that while S/V may offer additional benefits in blood pressure management, its impact on cardiac biomarkers in acute settings may not significantly differ from ACEIs. Given the study's limitations, including its single-center design, small sample size, and baseline differences. Further multi-center, randomized controlled trials are warranted to validate these findings and explore tailored treatment strategies for AMI patients with concurrent HF.

Heart failure with preserved ejection fraction (HFpEF) represents a major clinical challenge with rising global prevalence. Women have a nearly double lifetime risk of developing HFpEF compared to heart failure with reduced ejection fraction (HFrEF). In HFpEF, sex differences emerge both in how traditional cardiovascular risk factors (such as hypertension, obesity, and diabetes) affect cardiac function and through distinct pathophysiological mechanisms triggered by sex-specific events like menopause and adverse pregnancy outcomes. These patterns influence not only disease development, but also therapeutic responses, necessitating sex-specific approaches to treatment. This review aims to synthesize existing knowledge regarding HFpEF in women including traditional and sex-specific risk factors, pathophysiology, presentation, and therapies, while outlining important knowledge gaps that warrant further investigation. The impact of HFpEF spans a woman's entire lifespan, requiring prevention and management strategies tailored to different life stages. While understanding of sex-based differences in HFpEF has improved, significant knowledge gaps persist. Through examination of current evidence and challenges, this review highlights promising opportunities for innovative research, therapeutic development, and clinical care approaches that could transform the management of HFpEF in women.

Treatment of heart failure and reduced ejection fraction (HFrEF) using angiotensin receptor-neprilysin inhibitor demonstrates beneficial effects on cardiac remodeling (CR). We assessed the impact of sacubitril/valsartan on the concentrations of HF biomarkers in relation to parameters of CR using imaging techniques in patients with HFrEF. In a prospective single-center open-label study, 68 patients with symptomatic HFrEF were treated with sacubitril/valsartan and followed-up every three months for 12 months. Soluble suppression of tumorigenicity 2 (sST2), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin I (hs-cTnI) were measured in blood samples. Additionally, echocardiography and cardiac magnetic resonance imaging (cMRI) were performed to assess heart structural and functional changes. Following treatment initiation, follow-up visits revealed an improved NYHA functional class in these patients, alongside significant decreases in all circulating biomarkers, increases in left ventricular ejection fraction (LVEF), and reductions in volume- and diameter-related LV parameters. Sustained gradual decreases in sST2 concentrations over time correlated with NT-proBNP concentrations (rho=+0.26, P < 0.001). Both biomarkers were inversely correlated with LVEF, and positively correlated with volume- and diameter-related LV parameters from echocardiography and cMRI. However, NT-proBNP concentrations exhibited stronger correlations with these LV parameters and were associated with the number of LV segments showing fibrosis, unlike sST2. Sacubitril/valsartan treatment in HFrEF leads to reduced sST2 and NT-proBNP concentrations with distinct decreasing curves, which are linked to reverse CR through LV-related parameters. In contrast to sST2, NT-proBNP is also associated with fibrosis, suggesting that both biomarkers unveil distinct mechanisms during CR in patients treated with sacubitril/valsartan.

Heart failure with preserved ejection fraction (HFpEF) is associated with elevated rates of readmission and mortality. Accurate prediction of readmission risk is essential for optimizing healthcare resources and enhancing patient outcomes.

We conducted a retrospective cohort study utilizing HFpEF patient data from two institutions: the First Affiliated Hospital Zhejiang University School of Medicine for model development and internal validation, and the Affiliated Hospital of Xuzhou Medical University for external validation. A machine learning (ML) model was developed and validated using 53 variables to predict the risk of readmission within one year. The model's performance was assessed using several metrics, including the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, F1 score, model training time, model prediction time and brier score. SHAP (SHapley Additive exPlanations) analysis was employed to enhance model interpretability, and a dynamic nomogram was constructed to visualize the predictive model.

Among the 766 HFpEF patients included in the study, 203 (26.5%) were readmitted within one year. The LightGBM model exhibited the highest predictive performance, with an AUC of 0.88 (95% confidence interval (CI):0.84-0.91), an accuracy of 0.79, a sensitivity of 0.81, and a specificity of 0.78. Key predictors included the E/e' ratio, NYHA classification, LVEF, age, BNP levels, MLR, history of atrial fibrillation (AF), use of ACEI/ARB/ARNI, and history of myocardial infarction (MI). External validation also demonstrated strong predictive performance, with an AUC of 0.87 (95%CI:0.83-0.91).

The LightGBM model exhibited robust performance in predicting one-year readmission risk among HFpEF patients, providing a valuable tool for clinicians to identify high-risk individuals and implement timely interventions.

Sacubitril/valsartan, an angiotensin receptor neprilysin inhibitor (ARNI), shows promising result in treating resistant hypertension (RH) but lacks comprehensive evaluation. We performed a systematic review to assess and compare the efficacy of ARNI in managing RH.

We conducted a systematic search on multiple databases such as Cochrane, ProQuest, PubMed, and Google Scholar. Studies comparing the effects of ARNI on blood pressure in adult RH patients were included in the review. Data extraction and synthesis followed PRISMA guidelines, and the risk of bias was assessed using Cochrane tools. The primary outcome is to determine the effect of ARNI on blood pressure in RH patients, and the secondary outcome was to assess the safety of ARNI in RH patients.

Four studies involving 915 RH patients were included in the systematic review. The sacubitril/valsartan dose used ranged between 100 and 400 mg/day. All studies reported a statistically significant reduction in blood pressure, with 24-h blood pressure reduction ranging from 15.8/6.5 to 16.6/9.3 mmHg and office systolic blood pressure reduction ranging from 24.7 to 10.3 mmHg. Additionally, two studies reported improvements in cardiac remodeling and left ventricular function associated with sacubitril/valsartan. The most common adverse events were hypotension and elevated serum potassium levels, though these were minimal and did not require discontinuation of ARNI therapy.

Sacubitril/valsartan is a promising alternative to ARB or ACEi in managing RH, offering superior blood pressure reductions and potential benefits in reversing cardiac remodeling, while maintaining a favorable safety profile with minimal risk of serious adverse events.

Renin-angiotensin-aldosterone system (RAAS) is crucial in cardiovascular homeostasis. Any disruption in this homeostasis often leads to numerous cardiovascular diseases (CVDs) and non-cardiovascular diseases. Small molecules that show ability toward mechanically modulating RAAS components have been developed to address this problem, thus providing opportunities for innovative drug discovery and development. This review is put forth to provide a comprehensive understanding not only on the signaling mechanisms of RAAS that lead to cardiovascular events but also on the use of small molecules targeting the modulation of RAAS components. Further, the detailed descriptions of the drugs affecting the RAAS and their pharmacodynamics, kinetics, and metabolism profiles are provided. This article also covers the limitations of the present therapeutic armory, followed by their mechanistic insights. A brief discussion is offered on the analysis of the chemical space parameters of the drugs affecting RAAS compared to other cardiovascular and renal categories of medications approved by the US FDA. This review provides structural insights and emphasizes the importance of integrating the current therapeutic regimen with pharmacological tactics to accelerate the development of new therapeutics targeting the RAAS components for improved and efficacious cardiovascular outcomes. Finally, chemical spacing parameters of RAAS modulators are provided, which will help in understanding their peculiarities in modulating the RAAS signaling through structural and functional analyses. Furthermore, this review will assist medicinal chemists working in this field in developing better drug regimens with improved selectivity and efficacy.

Cardiorenal syndrome (CRS) refers to the bidirectional interactions between the acutely or chronically dysfunctioning heart and kidney that lead to poor outcomes. Due to the evolving literature on renal impairment and heart failure with preserved ejection fraction (HFpEF), this review aimed to highlight the pathophysiological pathways, diagnosis using imaging and biomarkers, and management of CRS in patients with HFpEF.

The mechanism of CRS in HFpEF can be hypothesized due to the interplay of elevated central venous pressure, renin-angiotensin-aldosterone system (RAAS) activation, oxidative stress, endothelial dysfunction, coronary microvascular dysfunction, and chronotropic incompetence. The correlation between HFpEF and worsening renal function seen in both long-term trials and observational data points to the evidence for these mechanisms. Upcoming biomarkers such as cystatin C, NGAL, NAG, KIM-1, ST-2, and galectin-3, along with conventional ones, are promising for early diagnosis, risk stratification, or response to therapy. Despite the lack of specific treatment for CRS in HFpEF, the management can be discussed with similar medications used in goal-directed medical therapy for heart failure with reduced ejection fraction (HFrEF). Additionally, there is increasing evidence for the role of vasodilators, inotropes, assist devices, and renal denervation, although long-term studies are necessary.

The management of CRS in HFpEF is an evolving field that currently shows promise for using diagnostic and prognostic biomarkers, conventional heart failure medications, and novel therapies such as renal denervation, interatrial shunt, and renal assist devices. Further studies are needed to understand the pathophysiological pathways, validate the use of novel biomarkers, especially for early diagnosis and prognostication, and institute new management strategies for CRS in patients with HFpEF.

Lower estimated glomerular filtration rate (eGFR) may be one of the major reasons for hesitation or failure to initiate potentially beneficial therapies in patients with heart failure (HF).

This study sought to assess if the effects of sacubitril/valsartan (vs valsartan) on cardiovascular outcomes differ according to baseline kidney function in patients with HF with preserved ejection fraction.

The PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction) trial was global clinical trial of 4,796 patients with chronic HF and left ventricular ejection fraction (LVEF) ≥45% randomly assigned to sacubitril/valsartan or valsartan. We examined the effect of treatment on cardiovascular outcomes using Cox regression models, stratified by region, and assessed for differential treatment effects according to the baseline eGFR and ejection fraction.

At randomization, mean eGFR was 67 ± 19 mL/min/1.73 m2; 1,955 (41%) participants had an eGFR <60 mL/min/1.73 m2. Compared with valsartan, sacubitril/valsartan reduced the primary cardiovascular outcome (cardiovascular death and total HF hospitalizations) to a greater extent among those with lower baseline eGFR (P interaction = 0.07 for continuous eGFR), and was most pronounced for those with eGFR ≤45 mL/min/1.73 m2 (RR: 0.69; 95% CI: 0.51-0.94). The influence of eGFR on the treatment effect for cardiovascular death was nonlinear, with the most pronounced treatment effect for those with baseline eGFR <45 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.97). In further subgroup analyses according to LVEF and eGFR, the treatment effect for the primary outcome was most pronounced among those with LVEF ≤57% and eGFR ≤45 mL/min/1.73 m2 (HR: 0.66; 95% CI: 0.45-0.97).

In the PARAGON-HF trial, the benefits of sacubitril/valsartan to reduce the frequency of HF hospitalizations and cardiovascular death were most apparent in patients with lower baseline eGFR and lower ejection fraction. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

In China, hypertension is the most common chronic non-communicable disease and the most significant risk factor for cardiovascular mortality among urban and rural residents. To standardize the clinical diagnosis and treatment of hypertension and to improve the prevention and control level of hypertension in China, Chinese Society of Cardiology, Chinese Medical Association; Hypertension Committee of Cross-Straits Medicine Exchange Association; Cardiovascular Disease Prevention and Rehabilitation Committee, Chinese Association of Rehabilitation Medicine, jointly collaborated to formulate the Clinical Practice Guideline for Hypertension Management in China. The Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to rate the quality of evidence and strength of recommendations, and the reporting items for practice guidelines in healthcare (RIGHT) were followed to establish the guideline. Detailed evidence-based recommendations for the diagnosis, evaluation, and treatment of 44 clinical questions in the field of hypertension, including essential and secondary hypertension, have been provided to guide clinical practice.

International Practice Guidelines Registry Platform, http://www.guidelines-registry.cn/ , No. IPGRP-2021CN346.

Cardiac contractility modulation (CCM) is non-excitatory electrical stimulation for improving cardiac function. This study aimed to evaluate the effects of CCM on autophagy and apoptosis of cardiac myocytes in a rabbit model of chronic heart failure (CHF) and explore its possible mechanism.

Thirty rabbits were randomised into the Sham, heart failure (HF) and CCM groups, and animals in all three groups were sacrificed after 16 weeks of ascending aortic constriction or sham surgery. The expression of autophagy associated protein LC3 was observed by immunofluorescence staining. With Western-blot measured the expression of Beclin1, P62, LC3B (II/I) and Bcl-2, ALDH2, Bax and Caspase-3 protein in myocardial tissue. The apoptosis rate and the apoptosis of myocardial cells was observed by flow cytometry and TUNEL method.

1) In comparison to the Sham group, the expression of LC3 and Beclin1 was significantly increased, and the expression of p62 protein was decreased in the heart tissues of rabbits in the HF group. Compared with HF group, after CCM intervention, the expression of Beclin1 and LC3B proteins decreased, while the P62 protein increased, and the LC3B(II/I) ratio decreased (P<0.05). 2) The expression of Bcl-2, ALDH2 protein and Bcl-2 mRNA decreased compared with the Sham group (P<0.05), while the expression of Bax, Caspase-3 protein and mRNA was significantly increased (P<0.05). However, the expression of ALDH2 mRNA in the CCM group was not statistically significant. The expression of Bcl-2, ALDH2 protein and mRNA increased after CCM intervention, and the expression of Bax, Caspase-3 protein and mRNA decreased (P<0.05). 3) The apoptosis situation in the Sham group was similar to that of normal myocardium, compared with the Sham group, the number of apoptotic bodies increased, and the apoptosis percentage of cardiomyocytes increased significantly (P<0.05). After CCM intervention, the number of apoptotic bodies and the percentage of apoptosis decreased compared with the HF group (P<0.05).

The intervention of CCM has been shown to enhance both myocardial systolic and diastolic function in rabbits with CHF. The mechanism may be related to the inhibition of cardiomyocyte autophagy by regulating the expression levels of Beclin1, P62, and LC3B(II/I) in cardiomyocytes, as well as the reversal of cardiomyocyte apoptosis by regulating the expression levels of Bcl-2, ALDH2, Bax, and Caspase-3 in cardiomyocytes.

Structurally knowing the active sites of a drug is important for understanding its therapeutic functions. S086 is a novel angiotensin receptor-neprilysin inhibitor that consists of the molecular moieties of EXP3174 (the active metabolite of the angiotensin receptor blocker losartan) and sacubitril (a neprilysin inhibitor prodrug) in a 1:1 molar ratio. There are two forms of cocrystals of S086, namely, ξ-crystal and α-crystal, which were formed both via intermolecular coordination bonding to calcium ions, with the aid of internal water. The binding state of multiple carboxyl anions (COO-) to Ca2+ of EXP3174 and sacubitril was examined in this study using infrared (IR) absorption spectroscopy, in which the asymmetric stretching (as) and symmetric stretching (ss) modes of the COO- groups were used as IR probes. Ultrafast two-dimensional (2D) IR spectroscopy was utilized for spectrally assigning the origin of multiple COO- groups by the presence or absence of interchromophore vibrational coupling. Key structural variation between the two crystal forms was found: in the unit cell of ξ-crystal, the ratio of "bridging" and "bidentate" types of COO- binding to Ca2+ for four EXP3174 molecules is 2:2, while the ratio is predicted to be 3:1 in the case of α-crystal. However, in both crystals, four sacubitril molecules are believed to similarly form a "trident" type of COO- binding to Ca2+. Our study demonstrates that linear and nonlinear IR spectroscopies can be used to characterize local crystal structures of drugs and reveal subtle difference between similar crystal structures.

In the past decade, our understanding of heart failure pathophysiology has advanced significantly, resulting in the development of new medications such as angiotensin-neprilysin inhibitors, sodium-glucose cotransporter-2 inhibitors and oral soluble guanylate cyclase stimulators. Backed by positive findings from large randomized controlled trials, recommendations for their use were recently included in the 2022 AHA/ACC/HFSA guidelines and 2023 ESC guidelines for management of heart failure. Promising drugs for future heart failure treatment include agents that modulate the neurohormonal system, vasodilators, anti-inflammatory drugs, mitotropes, which improve deranged energy metabolism of the failing heart, and myotropes, which increase cardiac contractility by affecting cardiac sarcomere function. Here, we discuss these new and future heart failure drugs. We explain their mechanisms of action, critically evaluate their performance in clinical trials and summarize the clinical scenarios in which the latest guidelines recommend their use. This Review aims to offer clinicians and researchers a comprehensive overview of novel therapeutic classes in heart failure treatment.

The promising results obtained in the PARADIGM-HF trial prompted the approval of sacubitril/valsartan (SAC/VAL) as a first-in-class treatment for heart failure with reduced ejection fraction (HFrEF) patients. The effect of SAC/VAL treatment was also studied in patients with heart failure with preserved ejection fraction (HFpEF) and, although improvements in New York Heart Association (NYHA) class, HF hospitalizations, and cardiovascular deaths were observed, these results were not so promising. However, the demand for HFpEF therapies led to the approval of SAC/VAL as an alternative treatment, although further studies are needed. We aimed to elucidate the effects of a 9-week SAC/VAL treatment in cardiac function and metabolism using a preclinical model of HFpEF, the Zucker Fatty and Spontaneously Hypertensive (ZSF1) rats. We found that SAC/VAL significantly improved diastolic function parameters and modulated respiratory quotient during exercise. Ex-vivo studies showed that SAC/VAL treatment significantly decreased heart, liver, spleen, and visceral fat weights; cardiac hypertrophy and percentage of fibrosis; lipid infiltration in liver and circulating levels of cholesterol and sodium. Moreover, SAC/VAL reduced glycerophospholipids, cholesterol, and cholesteryl esters while increasing triglyceride levels in cardiac tissue. In conclusion, SAC/VAL treatment improved diastolic and hepatic function, respiratory metabolism, reduced hypercholesterolemia and cardiac fibrosis and hypertrophy, and was able to modulate cardiac metabolic profile. Our findings might provide further insight into the therapeutic benefits of SAC/VAL treatment in obese patients with HFpEF.

Hypertension, a key modifiable risk factor for cardiovascular diseases (CVD), significantly contributes to premature death and morbidity worldwide. Despite stabilization in age-adjusted global prevalence, the absolute number of hypertensive individuals doubled from 2000 to 2010, largely due to increases in low- and middle-income countries. In 2021, only 21% of hypertensive individuals globally had effective blood pressure (BP) control. In India, hypertension is the leading risk factor for death and disability, with prevalence rates of 24% in men and 21% in women, as reported by the 2019-2020 National Family Health Survey (NFHS-5). Alarmingly, just 25% of rural and 38% of urban hypertensive Indians are undergoing treatment, with only 10% and 20% achieving BP control, respectively. This highlights the hypertension paradox, where clinical inertia and hesitancy in intensifying BP-lowering therapy persist despite the availability of antihypertensive drugs. This expert opinion paper aims to provide a comprehensive evaluation of sacubitril/valsartan in hypertension management, leveraging insights from its approved use in heart failure and examining its benefits and challenges across diverse hypertensive populations. The formulation of this expert opinion involved employing evidence-based methodologies and utilizing all available data. The document underwent scrutiny by expert cardiologists, whose clinical experiences and examination of the evidence and guidelines informed the formation of the expert opinion. This expert opinion paper provides a thorough and informed evaluation of sacubitril/valsartan, highlighting its potential to address unmet needs in BP control, particularly in challenging cases such as resistant hypertension and chronic kidney disease.

The efficacy and safety of early sacubitril/valsartan (Sac/Val) initiation after acute heart failure (AHF) has not been demonstrated outside North America. The present study aimed to evaluate the effect of in-hospital Sac/Val therapy initiation after an AHF episode on N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in Japanese patients.

This was an investigator-initiated, multicentre, prospective, randomized, open-label, blinded-endpoint pragmatic trial. After haemodynamic stabilization within 7 days after hospitalization, eligible inpatients were allocated to switch from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to Sac/Val (Sac/Val group) or to continue angiotensin-converting enzyme inhibitor or angiotensin receptor blocker (control group). The primary efficacy endpoint was the 8-week proportional change in geometric means of NT-proBNP levels.

A total of 400 patients were equally randomized, and 376 (median age 75 years, 31.9% women, de novo heart failure rate 55.6%, and median left ventricular ejection fraction 37%) were analysed. The per cent changes in NT-proBNP level geometric means at Weeks 4/8 were -35%/-45% (Sac/Val group) and -18%/-32% (control group), and their group ratio (Sac/Val vs. control) was 0.80 (95% confidence interval 0.68-0.94; P = .008) at Week 4 and 0.81 (95% confidence interval 0.68-0.95; P = .012) at Week 8, respectively. In the pre-specified subgroup analyses, the effects of Sac/Val were confined to patients with a left ventricular ejection fraction < 40% and were more evident in those in sinus rhythm and taking mineralocorticoid receptor antagonists. No adverse safety signal was evident.

In-hospital Sac/Val therapy initiation in addition to contemporary recommended therapy triggered a greater NT-proBNP level reduction in Japanese patients hospitalized for AHF. These findings may expand the evidence on Sac/Val therapy in this clinical situation outside North America.

ClinicalTrial.gov (NCT05164653) and Japan Registry of Clinical Trials (jRCTs021210046).

Background and Objectives: Heart failure (HF) is one of the most common initial presentations of cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM). There are different cardiac biomarkers related to the pathophysiological mechanisms of HF in T2DM. The current research aims to identify additional biomarkers that could improve the diagnosis and prognosis of HFpEF, which is currently assessed using NT pro-BNP levels. NT pro-BNP is a valuable tool for diagnosing heart failure but may not always correlate with clinical symptom severity or can present normal levels in certain cases, such as obesity. Biomarkers like FGF-21 and galectin-3 could provide greater insight into heart failure severity, especially in diabetic patients. The main objective of the current study is to assess the performance of NT-proBNP, FGF21, Galectin-3 and Copeptin to discriminate between advanced and mild HF. Materials and Methods: A total of 117 patients were enrolled in this study and divided into two groups: 67 patients in NYHA functional class I-II (mild HF) and 50 patients in NYHA III-IV (advanced HF). NT-pro BNP, FGF21, Galectin 3 and Copeptin serum levels were determined with the ELISA method. Receiver operating characteristic (ROC) analysis and binomial logistic regression analysis were used to measure the ability of the studied biomarkers to distinguish between advanced and mild HF patients. Results: In patients with T2DM with advanced HF, serum FGF21 level was significantly positively correlated with eGFR (ρ = 0.35, p = 0.0125) and triglycerides (ρ = 0.28, p = 0.0465) and significantly negatively correlated with serum levels of HDL cholesterol (ρ = -0.29, p = 0.0386) and with RV-RA gradient (ρ = -0.30, p = 0.0358). In patients with mild HF, serum FGF21 level was significantly negatively correlated with NT-proBNP levels (ρ = -0.37, p = 0.0022), E/e' ratio (ρ = -0.29, p = 0.0182), TR velocity (ρ = -0.24, p = 0.0470) and RV-RA gradient (ρ = -0.24, p = 0.0472). FGF21 (AUC = 0.70, 95% CI: 0.60-0.79) and NT-proBNP (AUC = 0.73, 95% CI: 0.63-0.82) demonstrated significant predictive value to discriminate T2DM patients with advanced HF from those with mild HF. Elevated values for FGF21 (≥377.50 ng/mL) or NTproBNP (≥2379 pg/mL) were significantly associated with increased odds of advanced HF after adjusting for demographic and clinical covariates. Conclusions: NTpro-BNP and FGF21 have a similar ability to discriminate T2DM patients with advanced HF from those with mild HF. Univariable and multivariable logistic models showed that, FGF21 and NTproBNP were independent predictors for advanced HF in patients with preserved and mildly reduced ejection fraction and T2DM.

Heart failure (HF) and renal dysfunction often coexist and interact in many complex and bidirectional pathways, leading to detrimental effects on patient outcomes. The treatment of HF patients with renal dysfunction presents a significant clinical challenge. Interestingly, sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), may have beneficial effects on cardiac and renal outcomes in patients with HF with reduced ejection fraction, particularly by slowing the rate of decrease in the estimated glomerular filtration rate compared to a single angiotensin-converting enzyme inhibitor. Recently, more reports have emphasized the renal protection of sacubitril/valsartan in patients with HF. In HF patients with renal dysfunction, however, there is no strong evidence supporting the use of sacubitril/valsartan to reduce the absolute risk of hyperkalemia and worsening renal function; therefore, the administration of ARNI requires a careful balance between the benefits and risks. Furthermore, the lack of evidence-based management highlights the importance of an individualized approach based on published experience and multidisciplinary collaborations, as well as underlines the need for in-depth studies investigating the underlying mechanisms in cardiorenal interactions with a focus on treatments.

Heart failure (HF) is a global health challenge that requires a multidisciplinary approach. Despite recent advances in pharmacological and interventional therapy, morbidity and mortality in these patients remain high. For this reason, and because of its interplay with other cardiovascular and non-cardiovascular diseases, HF represents a major area of research, with new trials being published every year and international guidelines constantly updated.

The authors review the current status and possible future developments in HF pharmacotherapy.

The treatment of HF has made significant advances in recent years, and the current recommendations are based on large outcome trials. This has led to significant reductions in both mortality and morbidity, but the death rate remains unacceptably high. In this context, a patient-centered approach that considers comorbidities and specific clinical scenarios when dosing HF medication is essential. Prevention of hospital admissions for cardiac decompensation is of utmost importance in patients with HF as is the enablement of activities of daily living, an endpoint which has only recently been incorporated into major HF trials.

Obesity is associated with adverse cardiac remodeling and is a key driver for the development and progression of heart failure (HF). Once-weekly semaglutide (2.4 mg) has been shown to improve HF-related symptoms and physical limitations, body weight, and exercise function in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), but the effects of semaglutide on cardiac structure and function in this population remain unknown.

In this echocardiography substudy of the STEP-HFpEF Program, we evaluated treatment effects of once-weekly semaglutide (2.4 mg) vs placebo on cardiac structure and function.

Echocardiography at randomization and 52 weeks was performed in 491 of 1,145 participants (43%) in the STEP-HFpEF Program (pooled STEP-HFpEF [Semaglutide Treatment Effect in People with Obesity and HFpEF] and STEP-HFpEF DM [Semaglutide Treatment Effect in People with Obesity, HFpEF, and Type 2 Diabetes] trials). The prespecified primary outcome was change in left atrial (LA) volume, with changes in other echocardiography parameters evaluated as secondary outcomes. Treatment effects of semaglutide vs placebo were assessed using analysis of covariance stratified by trial and body mass index, with adjustment for baseline parameter values.

Overall, baseline clinical and echocardiographic characteristics were balanced among those receiving semaglutide (n = 253) and placebo (n = 238). Between baseline and 52 weeks, semaglutide attenuated progression of LA remodeling (estimated mean difference [EMD] in LA volume, -6.13 mL; 95% CI: -9.85 to -2.41 mL; P = 0.0013) and right ventricular (RV) enlargement (EMD in RV end-diastolic area: -1.99 cm2; 95% CI: -3.60 to -0.38 cm2; P = 0.016; EMD in RV end-systolic area: -1.41 cm2; 95% CI: -2.42 to -0.40] cm2; P = 0.0064) compared with placebo. Semaglutide additionally improved E-wave velocity (EMD: -5.63 cm/s; 95% CI: -9.42 to -1.84 cm/s; P = 0.0037), E/A (early/late mitral inflow velocity) ratio (EMD: -0.14; 95% CI: -0.24 to -0.04; P = 0.0075), and E/e' (early mitral inflow velocity/early diastolic mitral annular velocity) average (EMD: -0.79; 95% CI: -1.60 to 0.01; P = 0.05). These associations were not modified by diabetes or atrial fibrillation status. Semaglutide did not significantly affect left ventricular dimensions, mass, or systolic function. Greater weight loss with semaglutide was associated with greater reduction in LA volume (Pinteraction = 0.033) but not with changes in E-wave velocity, E/e' average, or RV end-diastolic area.

In the STEP-HFpEF Program echocardiography substudy, semaglutide appeared to improve adverse cardiac remodeling compared with placebo, further suggesting that treatment with semaglutide may be disease modifying among patients with obesity-related HFpEF. (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity [STEP-HFpEF]; NCT04788511; Research Study to Look at How Well Semaglutide Works in People Living With Heart Failure, Obesity and Type 2 Diabetes [STEP-HFpEF DM]; NCT04916470).

Heart failure (HF) is a debilitating clinical syndrome affecting 64.3 million patients worldwide. More than 50% of HF cases are attributed to HF with preserved ejection fraction (HFpEF), an entity growing in prevalence and mortality. Although recent breakthroughs reveal the prognostic benefits of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in HFpEF, there is still a lack of effective pharmacological therapy available. This highlights a major gap in medical knowledge that must be addressed. Current evidence attributes HFpEF pathogenesis to an interplay between cardiometabolic comorbidities, inflammation, and renin-angiotensin-aldosterone-system (RAAS) activation, leading to cardiac remodelling and diastolic dysfunction. However, conventional RAAS blockade has demonstrated limited benefits in HFpEF, which emphasises that alternative therapeutic targets should be explored. Presently, there is limited literature examining the use of anti-inflammatory HFpEF therapies despite growing evidence supporting its importance in disease progression. Hence, this review aims to explore current perspectives on HFpEF pathogenesis, including the importance of inflammation-driven cardiac remodelling and the therapeutic potential of anti-inflammatory therapies.

Heart failure (HF) is a complex and heterogeneous syndrome resulting from any diastolic or systolic dysfunction of the cardiac muscle. In addition to comorbid conditions, pressure overload, and myocardial ischemia are associated with cardiac remodeling which manifests as extracellular matrix (ECM) perturbations, impaired cellular responses, and subsequent ventricular dysfunction.

The current review discusses the main aspects of the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway (cGMP-PKG) pathway modulators and highlights the promising outcomes of its novel pharmacological boosters.

Among several signaling pathways involved in the pathogenesis of pressure overload, ischemia and HF with preserved ejection fraction (HFpEF) is cGMP-PKG pathway. This pathway plays a pivotal role in the regulation of cardiac contractility, and modulation of cGMP-PKG signaling, contributing to the development of the diseases. Ventricular cardiomyocytes of HF patients and animal models are known to exhibit reduced cGMP levels and disturbed cGMP signaling including hypophosphorylation of PKG downstream targets. However, restoration of cGMP-PKG signaling improves cardiomyocyte function and promotes cardioprotective effects.

Although venous congestion secondary to elevated pulmonary artery pressure (PAP) has been hypothesized to worsen kidney function, the association of peak tricuspid regurgitation jet velocity (pTRV), a surrogate of PAP, with kidney outcomes remains uncertain in heart failure (HF) with preserved ejection fraction (HFpEF).

This post hoc analysis of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial analyzed participants with a left ventricular ejection fraction (LVEF) of ≥45% who had pTRV measured by echocardiography at baseline. For the cross-sectional analysis, the association of baseline pTRV with baseline estimated glomerular filtration rate (eGFR) was assessed using linear regression. For the longitudinal analysis, the association of baseline pTRV with decline in eGFR of ≥30% and doubling of serum creatinine was assessed using Cox proportional hazards models.

Among 450 participants, the mean (SD) baseline age, LVEF, pTRV, and eGFR were 72.3 (9.6) years, 58.2% (7.4%), 2.8 (0.5) m/s, and 62.1 (18.7) ml/min per 1.73 m2, respectively. Each 1 SD higher pTRV was associated with a lower baseline eGFR (coefficient, -1.79; 95% confidence interval [CI], -3.48 to -0.10 ml/min per 1.73 m2). Over a median (interquartile range) follow-up of 3.0 (2.0-4.4) years, 203 (45%) patients experienced ≥30% eGFR decline, and 48 (11%) experienced creatinine doubling. Each 1 SD higher pTRV was associated with a 20% higher risk of ≥30% eGFR decline (hazard ratio [HR], 1.20; 95% CI, 1.04-1.39) and a 45% higher risk of creatinine doubling (HR, 1.45; 95% CI, 1.09-1.94).

Higher pTRV was associated with lower eGFR at baseline, and higher risk of ≥30% eGFR decline and creatinine doubling among patients with HFpEF.

The efficacy of the angiotensin receptor neprilysin inhibitor (ARNI) sacubitril/valsartan (SV) in patients with chronic kidney disease (CKD) has been established. Two meta-analyses have demonstrated its significant role in enhancing ventricular remodeling. However, the effectiveness and safety of its use in patients with end-stage renal disease (ESRD) remain unclear.

Up to October 2023, we searched the PubMed, Embase, and Web of Science databases for studies involving ESRD patients treated with ARNI. The quality of the included studies was evaluated using the Newcastle-Ottawa Scale. Effect sizes were reported as mean differences (MD) with 95% confidence intervals (CIs). We included 10 studies, encompassing 649 patients. ARNI was associated with improvements in blood pressure and left ventricular (LV) function in ESRD patients, including systolic blood pressure (SBP) (MD -12.76 mmHg; 95% CI, -18.03 to -7.5 mmHg), diastolic blood pressure (DBP) (MD -6.41 mmHg; 95% CI, -8.10 to -4.72 mmHg), and left ventricular ejection fraction (LVEF) (MD, 4.61%; 95% CI, 1.78%-7.44%). Hemoglobin levels improved, but there were no significant statistical differences in other biomarkers for dialysis. Sacubitril/valsartan was generally well tolerated in ESRD patients. Improved indices of left ventricular function were noted at 6 months and were more pronounced at 12 months. A linear relationship between LVEF and left ventricular end-diastolic volume (LVEDV) was observed, as indicated by a high correlation coefficient (r-value).

ARNI effectively reduces blood pressure and enhances left ventricular function in dialysis patients, with early treatment associated with greater benefits. ARNI also demonstrates a favorable safety profile in this population. Further prospective studies are required to fully understand the long-term efficacy and safety of sacubitril/valsartan in dialysis patients.

Comprehensive knowledge of the left atrium (LA) and its pathophysiology has emerged as an important clinical and research focus in the heart failure (HF) arena. Although studies on HF focusing on investigating left ventricular remodeling are numerous, those on atrial structural and functional changes have received comparatively less attention. Studies on LA remodeling have recently received increasing attention, and LA pressure (LAP) has become a novel target for advanced monitoring and is a potential therapeutic approach for treating HF. Various devices specifically designed for the direct measurement of LAP have been developed to optimize HF treatment by reducing LAP. This review focuses on LA hemodynamic monitoring and effective LAP decompression.

LCZ696 (sacubitril/valsartan) exerts cardioprotective effects. Recent studies have suggested that it improves the endothelial function; however, the underlying mechanisms have not been thoroughly investigated. We investigated whether LCZ696 ameliorates diabetes-induced endothelial dysfunction.

Diabetes was induced using streptozotocin in 8-week-old male C57BL/6 mice. Diabetic mice were randomly assigned to receive LCZ696 (100 mg/kg/day), valsartan (50 mg/kg/day), or a vehicle for three weeks. The endothelium-dependent and endothelium-independent vascular responses of the aortic segments were determined based on the response to acetylcholine and sodium nitroprusside, respectively. Human umbilical vein endothelial cells (HUVEC) and aortic segments obtained from C57BL/6 mice were used to perform in vitro and ex vivo experiments, respectively.

LCZ696 and valsartan reduced the blood pressure in diabetic mice (P＜0.05). The administration of LCZ696 (P＜0.001) and valsartan (P＜0.01) ameliorated endothelium-dependent vascular relaxation, but not endothelium-independent vascular relaxation, under diabetic conditions. LCZ696, but not valsartan, increased eNOSSer1177 (P=0.06) and Akt (P＜0.05) phosphorylation in the aorta. In HUVEC, methylglyoxal (MGO), a major precursor of advanced glycation end products, decreased eNOSSer1177 phosphorylation (P＜0.05) and increased eNOSThr495 phosphorylation (P＜0.001). However, atrial natriuretic peptide (ANP) reversed these effects. ANP also ameliorated the MGO-induced impairment of endothelium-dependent vascular relaxation in the aortic segments (P＜0.05), although L-NAME completely blocked this effect (P＜0.001).

LCZ696 ameliorated diabetes-induced endothelial dysfunction by increasing the bioavailability of ANP. Our findings suggest that LCZ696 has a vascular protective effect in a diabetic model and highlight that it may be more effective than valsartan.

The co-administration of dapagliflozin (DPF) and sacubitril/valsartan (LCZ696) has emerged as a promising therapeutic approach for managing heart failure. Given that DPF and LCZ696 are substrates for P-glycoprotein, there is a plausible potential for drug-drug interactions when administered concomitantly. To investigate the pharmacokinetic changes when these drugs are co-administered, we have established and validated a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method capable of simultaneously detecting DPF, LBQ657 (the active metabolite of sacubitril) and valsartan in rat plasma. This method has demonstrated selectivity, sensitivity, and accuracy. Drug-drug interactions were examined by the LC-MS/MS method. The mechanisms were investigated using everted intestinal sac models and Caco-2 cells. The results showed that DPF significantly increased the area under the curve (AUC(0-t)) (3,563.3 ± 651.7 vs. 7,146.5 ± 1,714.9 h μg/L) of LBQ657 (the active metabolite of sacubitril) and the AUC(0-t) (24,022.4 ± 6,774.3 vs. 55,728.3 ± 32,446.3 h μg/L) of valsartan after oral co-administration. Dapagliflozin significantly increased the amount of LBQ657 and valsartan in intestinal sacs by 1- and 1.25-fold at 2.25 h. Caco-2 cell uptake studies confirmed that P-glycoprotein is the transporter involved in this interaction. This finding enhances the understanding of drug-drug interactions in the treatment of heart failure and provides a guidence for clinical therapy.

Sacubitril/valsartan, being both a neprilysin inhibitor and angiotensin receptor blocker, exhibits a renin-angiotensin-aldosterone system (RAAS) inhibitory effect. However, no study has investigated the administration of sacubitril/valsartan in patients early after surgery using cardiopulmonary bypass.

This was a prospective observational study of 63 patients who underwent open heart surgery and were treated with sacubitril/valsartan. No serious adverse events occurred. Among the 63 patients, sacubitril/valsartan was discontinued in 13 due to hypotension (n=10), renal dysfunction (n=2), and dizziness (n=1). Atrial natriuretic peptide concentrations increased significantly from Day 3 of treatment (P=0.0142 vs. Postoperative Day 1) and remained high thereafter. In contrast, plasma renin activity was significantly suppressed from Day 3 onwards (P=0.00206 vs. Postoperative Day 1). A decrease in creatinine concentrations and an increase in the estimated glomerular filtration rate were observed on Day 3; this improvement in renal function was not observed in the historical control group, in which patients did not receive sacubitril/valsartan. New postoperative atrial fibrillation was less frequent in the study group compared with the historical control (12.7% vs. 38.0%; P=0.0034).

Sacubitril/valsartan administration was safe immediately after open heart surgery in patients without postoperative hypotension. It enhanced serum atrial natriuretic peptide concentrations and suppressed RAAS activation.

LCZ696 blocks both angiotensin receptor type 1 (ATR1) and neprilysin (NEP), which are intricate in the degradation of natriuretic peptides (NPs) and other endogenous peptides. It has been shown NEP inhibitors and LCZ696 could be effectively in the management of atherosclerosis (AS). However, the underlying mechanism of LCZ696 in AS is needed to be clarified entirely. Hence, this review is directed to reconnoiter the mechanistic role of LCZ696 in AS. The anti-inflammatory role of LCZ696 is related to the inhibition of transforming growth factor beta (TGF-β)-activated kinase 1 (TAK) and nod-like receptor pyrin 3 receptor (NLRP3) inflammasome. Moreover, LCZ696, via inhibition of pro-inflammatory cytokines, oxidative stress, apoptosis and endothelial dysfunction can attenuate the development and progression of AS. In conclusion, LCZ696 could be effective in the management of AS through modulation of inflammatory and oxidative signaling. Preclinical and clinical studies are recommended in this regard.

Coronary microvascular dysfunction (CMD) plays a crucial role across the spectrum of heart failure (HF) pathology, contributing to disease development, progression, and outcomes. The pathophysiological mechanisms linking CMD to HF are complex and still not completely understood and include chronic inflammation, oxidative stress, and neurohormonal activation. Despite the diagnostic and prognostic relevance in patients with HF, there is no specific therapeutic strategy targeting CMD to date. Moreover, the diagnosis of this clinical condition is challenging. In this review article, we aim to discuss the different clinical pathogenetic mechanisms linking CMD to HF across the different spectra of these diseases, their prognostic relevance, and the possible therapeutic targets along with the remaining knowledge gaps in the field.