RNA Sequencing Screens the Key Genes and Pathways in a Mouse Model of HFpEF.

INTRODUCTION: Heart failure with preserved ejection fraction (HFpEF) is a common syndrome with high morbidity and mortality but without available evidence-based therapies. It is essential to investigate changes in gene expression profiles in preclinical HFpEF animal models, with the aim of searching for novel therapeutic targets. METHODS: Wild-type male C57BL/6J mice were administrated with a combination of high-fat diet (HFD) and inhibition of constitutive nitric oxide synthase using N-nitro-l-arginine methyl ester (l-NAME) for 5 and 7 weeks. RNA sequencing was conducted to detect gene expression profiles, and bioinformatic analysis was performed to identify the core genes, pathways, and biological processes involved. RESULTS: A total of 1,347 genes were differentially expressed in the heart at week 5 and 7 post-intervention. Gene Ontology enrichment analysis indicated that these greatly changed genes were involved mainly in cell adhesion, neutrophil chemotaxis, cell communication, and other functions. Using hierarchical cluster analysis, these differentially expressed genes were classified into 16 profiles. Of these, three significant profiles were ultimately identified. Gene co-expression network analysis suggested troponin T type 1 (Tnnt1) directly regulated 31 neighboring genes and was considered to be at the core of the associated gene network. CONCLUSION: The combined application of RNA sequencing, hierarchical cluster analysis, and gene network analysis identified Tnnt1 as the most important gene in the development of HFpEF.

Left ventricular reverse remodelling as a promising strategy for resolving left ventricular thrombus.

AIMS: Recent years, several studies have suggested that abnormal baseline left ventricular (LV) function and structure are associated with left ventricular thrombus (LVT) formation. Despite this, most studies have given less attention to the potential role of left ventricular reverse remodelling (LVRR), that is, the improvement of LV function and structure, in resolving LVT. In this study, we aim to investigate the clinical characteristics, prognosis, and LVT resolution in patients with LVRR. METHODS AND RESULTS: This is a retrospective study conducted at The First Affiliated Hospital of Dalian Medical University. Our cohort consists of patients diagnosed with LVT between 1 November 2015 and 31 May 2020. Enrolled patients were categorized into two groups: LVRR and Failure of LVRR. The primary endpoints included LVT resolution and embolic events. A total of 84 patients were included in the study, with 59 patients in the LVRR group and 25 patients in the Failure of LVRR group. In our study, patients in the LVRR group experienced higher incidence of LVT resolution and a lower risk of embolic events. Multivariate logistic analysis revealed that Failure of LVRR was the only independent negative predictor for LVT resolution and positive predictor for embolic events. CONCLUSIONS: Patients with LVRR experience higher incidence of LVT resolution and have lower risk of embolic events, highlighting the significance of identifying and mitigating risk factors that contribute to abnormal LV function and structure in management of patients with LVT.

Synergistically engineered in-situ self-assembled heterostructure composite nanofiber cathode with superior oxygen reduction reaction catalysis for solid oxide fuel cells.

The engineering and exploration of cathode materials to achieve superior oxygen reduction catalytic activity and resistance to CO2 are crucial for enhancing the performance of solid oxide fuel cells (SOFCs). Herein, a novel heterostructure composite nanofiber cathode comprised of PrBa0.5Sr0.5Co2O5+δ and Ce0.8Pr0.2O1.9 (PBSC-CPO-ES) was prepared for the first time through a synergistic approach involving in-situ self-assembly and electrostatic spinning techniques. PBSC-CPO-ES exhibits exceptionally high oxygen reduction catalytic activity and CO2 resistance, which is attributed to its unique nanofiber microstructure and abundant presence of heterointerfaces, significantly accelerating the charge transfer process, surface exchange and bulk diffusion of oxygen. The introduction of CPO not only effectively reduces the thermal expansion of PBSC but also changes the characteristics of oxygen ion transport anisotropy in layered perovskite materials, forming three-dimensional oxygen ion transport pathways. At 750 °C, the single cell employing the PBSC-CPO-ES heterostructure nanofiber attains an impressive peak power density of 1363 mW cm-2. This represents a notable 60.7 % improvement in comparison to the single-phase PBSC powder. Moreover, PBSC-CPO-ES exhibits excellent CO2 tolerance and performance recovery after CO2 exposure. This work provides new perspectives to the design and advancement of future high-performance and high-stability SOFC cathode materials.

The modified Rajan's heart failure risk score predicts all-cause mortality in patients hospitalized for heart failure with reduced ejection fraction: a retrospective cohort study.

Background: The dimensionless Rajan's heart failure (R-hf) risk score was proposed to predict all-cause mortality in patients hospitalized with chronic heart failure (HF) and reduced ejection fraction (EF) (HFrEF). Purpose: To examine the association between the modified R-hf risk score and all-cause mortality in patients with HFrEF. Methods: Retrospective cohort study included adults hospitalized with HFrEF, as defined by clinical symptoms of HF with biplane EF less than 40% on transthoracic echocardiography, at a tertiary centre in Dalian, China, between 1 November 2015, and 31 October 2019. All patients were followed up until 31 October 2020. A modified R-hf risk score was calculated by substituting brain natriuretic peptide (BNP) for N-terminal prohormone of BNP (NT-proBNP) using EF× estimated glomerular filtration rate (eGFR)× haemoglobin (Hb))/BNP. The patients were stratified into tertiles according to the R-hf risk score. The measured outcome was all-cause mortality. The score performance was assessed using C-statistics. Results: A total of 840 patients were analyzed (70.2% males; mean age, 64±14 years; median (interquartile range) follow-up 37.0 (27.8) months). A lower modified R-hf risk score predicted a higher risk of all-cause mortality, independent of sex and age [1st tertile vs. 3rd tertile: adjusted hazard ratio (aHR), 3.46; 95% CI: 2.11-5.67; P<0.001]. Multivariate Cox regression analysis indicated that a lower modified R-hf risk score was associated with increased cumulative all-cause mortality [univariate: (1st tertile vs. 3rd tertile: aHR, 3.45; 95% CI: 2.11-5.65; P<0.001) and multivariate: (1st tertile vs. 3rd tertile: aHR 2.21, 95% CI: 1.29-3.79; P=0.004)]. The performance of the model, as reported by C-statistic was 0.67 (95% CI: 0.62-0.72). Conclusion: The modified R-hf risk score predicted all-cause mortality in patients hospitalized with HFrEF. Further validation of the modified R-hf risk score in other cohorts of patients with HFrEF is needed before clinical application.

Prognostic value of left atrial reverse remodelling in heart failure with preserved ejection fraction.

OBJECTIVES: Left atrial reverse remodelling (LARR) reflects an improvement in the function or structure. However, it is unclear whether the presence of LARR is associated with better outcomes in patients with heart failure with preserved ejection fraction (HFpEF). METHODS: The study was a monocentric retrospective cohort one. Consecutive HFpEF patients admitted to the hospital between 1 January 2018 and 30 June 2020 were included. This cohort was divided into LARR and non-LARR groups based on the recovery of the left atrium. The primary endpoints were all-cause mortality, rehospitalization for heart failure, and the composite of death or readmission. Significant predictors of LARR were examined. RESULTS: A total of 409 patients were enrolled, including 90 cases in the LARR group and 319 in the non-LARR group. Kaplan-Meier analysis showed that compared with the non-LARR group, the LARR group had a lower incidence of rehospitalization for heart failure and the composite of death or readmission but not all-cause mortality. Similar results were observed in a subgroup analysis of patients with and without atrial fibrillation. Cox regression analysis demonstrated that the non-LARR group experienced higher risks of heart failure-related readmission [hazard ratio: 1.785, 95% confidence interval (CI) 1.236-3.215, P  = 0.037] and the composite outcome (hazard ratio: 1.684, 95% CI 1.254-2.865, P  = 0.044), but not all-cause mortality (hazard ratio: 1.475, 95% CI: 0.481-3.527, P  = 0.577) compared with the LARR group after adjusting for significant confounders. Logistic regression analysis showed that mild mitral regurgitation and the use of loop diuretics were two positive predictors of LARR in patients with HFpEF. CONCLUSION: LARR is an effective echocardiographic index that can be used to predict heart failure-related readmission in HFpEF. Therefore, regular assessment of left atrial size can provide a useful marker for risk stratification of heart failure.

Trajectory change of left ventricular ejection fraction after rhythm control for atrial fibrillation in heart failure.

AIMS: Rhythm control therapy has shown great benefits for patients with atrial fibrillation (AF) and heart failure (HF). However, few studies have evaluated the effects of rhythm control on left ventricular ejection fraction (LVEF) trajectory across the whole HF spectrum. Our study explored the prevalence and predictors of LVEF trajectory changes and their prognostic implications following rhythm control. METHODS AND RESULTS: Depending on the treatment strategy, the cohort was classified into rhythm and rate control groups. Alterations in HF types and LVEF trajectory were recorded. The observational endpoints were all-cause mortality and HF-related admission. Predictors of LVEF trajectory improvement in the rhythm control group were evaluated. After matching, the two groups had similar age [mean age (years): rhythm/rate control: 63.96/65.13] and gender [male: rhythm/rate control: n = 228 (55.6%)/233 (56.8%)]. Based on baseline LVEF measurement, the post-matched cohort had 490 HF with preserved ejection fraction (rhythm/rate control: n = 260/230; median LVEF: 58.00%/57.00%), 99 HF with mildly reduced ejection fraction (rhythm/rate control: n = 50/49; median LVEF: 45.00%/46.00%), and 231 HF with reduced ejection fraction (rhythm/rate control: n = 100/131; median LVEF: 32.50%/33.00%). Trajectory analysis found that the rhythm control group had a greater percentage of LVEF trajectory improvement than the rate control group [80 (53.3%) vs. 71 (39.4%), P = 0.012]. Cox regression analysis also showed that the rhythm control group was more likely to have improved LVEF trajectory compared with the rate control group {hazard ratio [HR] 1.671 [95% confidence interval (CI) 1.196-2.335], P = 0.003}. In the survival analysis, the rhythm control group experienced significant lower risks of all-cause mortality [HR 0.600 (95% CI 0.366-0.983), P = 0.043] and HF-related admission [HR 0.611 (95% CI 0.496-0.753), P < 0.001]. In the rhythm control subgroup, E/e' [odds ratio (OR) 0.878 (95% CI 0.792-0.974), P = 0.014], left ventricular end-diastolic diameter [OR 0.874 (95% CI 0.777-0.983), P = 0.024], and CHA2DS2-VASc score (congestive HF, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, age 65-74 years, and sex category) [OR 0.647 (95% CI 0.438-0.955), P = 0.028] were identified as three independent predictors of LVEF trajectory improvement. CONCLUSIONS: Rhythm control is associated with improved LVEF trajectory and clinical outcomes and may thus be considered the optimal therapeutic strategy for patients with both HF and AF.

Effects of rhythm control on left atrial structure remodeling in atrial fibrillation and heart failure with preserved ejection fraction.

Background: The benefits of rhythm control for atrial fibrillation (AF) in heart failure with preserved ejection fraction (HFpEF) have not been conclusively determined. We assessed the effects of rhythm control on left atrial (LA) structure remodeling and prognosis in patients with AF and HFpEF. Methods: This was a retrospective, real-world, observational study involving patients diagnosed with AF and HFpEF. The cohort was divided into rhythm-control and rate-control groups depending on their treatment strategies. The primary outcomes were all-cause mortality, rehospitalization for any cause, HF-related rehospitalization, and stroke. Differences in follow-up LA structure parameters were also analyzed. Results: Compared to the rate-control group, patients in the rhythm-control group had a lower risk of HF-related rehospitalization even after adjusting for potential confounders (adjusted HR 0.605, 95% CI 0.413-0.887, p = 0.010). Moreover, rhythm-control therapy led to marked reductions in LA echocardiographic indicators and a higher proportion of LA reverse remodeling (LARR). Conclusions: Rhythm-control therapy reverses LA structure remodeling and is associated with improved clinical outcomes; therefore, it is an optimal treatment approach for AF in HFpEF patients.

Effects of Rhythm Control for Atrial Fibrillation on Cardiac Remodeling and Valvular Regurgitation in Patients with Heart Failure.

PURPOSE: Previous studies investigating cardiac remodeling and functional regurgitation of rhythm control for atrial fibrillation (AF) in heart failure (HF) are limited. Therefore, this study aimed to evaluate the impact of rhythm control for AF on cardiac remodeling and functional regurgitation in the spectrum of HF. Its effect on prognosis was explored. METHODS: According to the treatment strategies of AF, the cohort was classified into the rhythm control and rate control groups. To further detect the implications of rhythm control on cardiac remodeling, functional regurgitation, and outcomes in HF subtypes, patients were further divided into HF with reduced ejection fraction (HFrEF), HF with mildly reduced ejection fraction, and HF with preserved ejection fraction (HFpEF) subgroups. RESULTS: A total of 828 patients were enrolled, with 307 patients in the rhythm control group and 521 patients in the rate control group. Over a median follow-up time of 3.8 years, patients with rhythm control treatments experienced improvements in biatrial structure parameters, left ventricular ejection fraction, and functional regurgitation (mitral and tricuspid regurgitation) compared with rate control treatment (p < 0.05). Cox regression analysis demonstrated that rhythm control reduced the risks of all-cause mortality (HR 0.436 [95% CI, 0.218-0.871], p = 0.019) in HFpEF and HF-related admissions in HFrEF (HR 0.500 [95% CI, 0.330-0.757], p = 0.001) and HFpEF (HR 0.541 [95% CI, 0.407-0.720], p < 0.001); these associations were similar after adjusting for multiple confounders. CONCLUSIONS: Rhythm control therapy can be considered an appropriate treatment strategy for the management of AF in HF to improve cardiac remodeling, functional regurgitation, and prognosis.

Effect of sodium-glucose cotransporter 2 inhibitors on left atrial remodeling and prognosis in patients with type 2 diabetes and heart failure with reduced ejection fraction.

AIMS: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been found to minimize hospitalization for heart failure and cardiovascular death. Cardiac reverse remodeling may be a mechanism responsible for the favorable clinical efficacy of SGLT2is on heart failure. To date, few studies have examined their effects on the left atrium. Therefore, the purpose of this study was to explore whether SGLT2is improve left atrial adverse remodeling in patients with type 2 diabetes and heart failure with reduced ejection fraction (HFrEF). METHODS: A single-center, retrospective, observational study was conducted. Consecutive patients with type 2 diabetes and HFrEF hospitalized at the First Affiliated Hospital of Dalian Medical University for acute decompensated heart failure between 1 January 2019 and 1 March 2022 were identified. On the basis of their treatment strategies, the enrolled participants were classified into SGLT2i and non-SGLT2i groups. The primary end point was all-cause mortality. Changes in left atrial echocardiographic indices from baseline to follow-up were also assessed. RESULTS: A total of 198 patients (mean age: 63.96 ±â€Š12.11 years, 20.71% women) were included. Greater reductions from baseline were seen with SGLT2i in the left atrial diameter ( P  < 0.001), left atrial superior-inferior diameter ( P  = 0.027), left atrial transverse diameter ( P  = 0.020), left atrial volume ( P  = 0.005), and left atrial volume index ( P  = 0.004). Moreover, 48 cases (48.48%) in the SGLT2i group and 33 (33.33%) in the non-SGLT2i group showed left atrial reverse remodeling ( P  = 0.003). Survival analysis demonstrated significantly lower overall mortality in the SGLT2i group compared with the non-SGLT2i group. CONCLUSION: This study found that SGLT2i therapy promoted left atrial structure reverse remodeling. This beneficial effect may be a vital mechanism by which SGLT2i improved clinical outcomes in patients with HFrEF.

The influence of a single water molecule on the reaction of BrO + HO2.

The influence of a single water molecule on the BrO + HO2 hydrogen extraction reaction has been explored by taking advantage of CCSD(T)/aug-cc-pVTZ//B3LYP/6-311 + + G(d,p) method. The reaction in the absence of water have two distinct kinds of H-extraction channels to generate HOBr + O2 (1Δg) and HBr + O3, and the channel of generation of HOBr + O2 (1Δg) dominated the BrO + HO2 reaction. The rate coefficient of the most feasible channel for the BrO + HO2 reaction in the absence of water is estimated to be 1.44 × 10-11 cm3 molecule-1 s-1 at 298.15 K, which is consistent with the experiment. The introduction of water made the reaction more complex, but the products are unchanged. Four distinct channels, beginning with HO2…H2O with BrO, H2O…HO2 with BrO, BrO…H2O with HO2, H2O…BrO with HO2 are researched. The most feasible channels, stemming from H2O…HO2 with BrO, and BrO…H2O with HO2, are much slower than the reaction of BrO + HO2 without water, respectively. Thus, the existence of water molecule takes a negative catalytic role for BrO + HO2 reaction.

Del1 Is a Growth Factor for Skeletal Progenitor Cells in the Fracture Callus.

Failure to properly form bone or integrate surgical implants can lead to morbidity and additional surgical interventions in a significant proportion of orthopedic surgeries. While the role of skeletal stem cells (SSCs) in bone formation and repair is well-established, very little is known about the factors that regulate the downstream Bone, Cartilage, Stromal, Progenitors (BCSPs). BCSPs, as transit amplifying progenitor cells, undergo multiple mitotic divisions to expand the pool of lineage committed progenitors allowing stem cells to preserve their self-renewal and stemness. Del1 is a protein widely expressed in the skeletal system, but its deletion led to minimal phenotype changes in the uninjured mouse. In this paper, we demonstrate that Del1 is a key regulator of BCSP expansion following injury. In Del1 knockout mice, there is a significant reduction in the number of BCSPs which leads to a smaller callus and decreased bone formation compared with wildtype (WT) littermates. Del1 serves to promote BCSP proliferation and prevent apoptosis in vivo and in vitro. Moreover, exogenous Del1 promotes proliferation of aged human BCSPs. Our results highlight the potential of Del1 as a therapeutic target for improving bone formation and implant success. Del1 injections may improve the success of orthopedic surgeries and fracture healing by enhancing the proliferation and survival of BCSPs, which are crucial for generating new bone tissue during the process of bone formation and repair.

A theoretical study of the gas-phase reactions of propadiene with NO3: mechanism, kinetics and insights.

In this study, the conversion mechanisms and kinetics of propadiene (CH2[double bond, length as m-dash]C[double bond, length as m-dash]CH2) induced by NO3 were researched using density functional theory (DFT) and transition state theory (TST) measurements. The NO3-addition pathways to generate IM1 (CH2ONO2CCH2) and IM2 (CH2CONO2CH2) play a significant role. P3 (CH2CONOCHO + H) was the dominant addition/elimination product. Moreover, the results manifested that one H atom from the -CH2- group has to be abstracted by NO3 radicals, leading to the final product h-P1 (CH2CCH + HNO3). Due to the high barrier, the H-abstraction pathway is not important for the propadiene + NO3 reaction. In addition, the computed ktot value of propadiene reacting with NO3 at 298 K is 3.34 × 10-15 cm3 per molecule per s, which is in accordance with the experimental value. The computed lifetime of propadiene oxidized by NO3 radicals was assessed to be 130.16-6.08 days at 200-298 K and an altitude of 0-12 km. This study provides insights into the transformation of propadiene in a complex environment.

Understanding the insight into the mechanisms and dynamics of the OH-initiated oxidation of CHF2CF2OCHF2 and the subsequent reactions in the presence of NO and O2.

The mechanism and dynamics of CHF2CF2OCHF2 initiated by OH radical evaluated through the density functional theory and variflex code. The solvation pattern of PCM was utilized to analyze the influence of water on the CHF2CF2OCHF2 + OH reaction. The most feasible reaction channel is resulting in the product CF2CF2OCHF2 with H2O by hydrogen abstraction. The computed rate coefficient is consistent with the experimental data. The results turned out that aqueous water act as a disincentive to the title reaction. In the atmosphere, the computation results testified that OH, H2O, NH3 and HCOOH could not accelerate the degradation of the CHF2CF2OCHF2 through OH-initiated in view of the Gibbs free barriers. The research of the follow-up oxidation procedure of the products CHF2CF2OCF2 and CF2CF2OCHF2 with O2/NO reactions indicated that CF2O and CHF2 were the most feasible products. The atmospheric lifetimes of CHF2CF2OCHF2 were in the scope of 71.10-4.74 years in altitude of 0-12 km and at 200-300 K. This research supplies discernment into the conversion of CHF2CF2OCHF2 in a complex environment.

Ultra-Stretchable Spiral Hybrid Conductive Fiber with 500%-Strain Electric Stability and Deformation-Independent Linear Temperature Response.

Stretchable configuration occupies priority in devising flexible conductors used in intelligent electronics and implantable sensors. While most conductive configurations cannot suppress electrical variations against extreme deformation and ignore inherent material characteristics. Herein, a spiral hybrid conductive fiber (SHCF) composed of aramid polymeric matrix and silver nanowires (AgNWs) coating is fabricated through shaping and dipping processes. The homochiral coiled configuration mimicked by plant tendrils not only enables its high elongation (958%), but also generates a superior deformation-insensitive effect to existing stretchable conductors. The resistance of SHCF maintains remarkable stability against extreme strain (500%), impact damage, air exposure (90 days), and cyclic bending (150 000 times). Moreover, the thermal-induced densification of AgNWs on SHCF achieves precise and linear temperature response toward a broad range (-20 to 100 °C). Its sensitivity further manifests high independence to tensile strain (0%-500%), allowing for flexible temperature monitoring of curved objects. Such unique strain-tolerant electrical stability and thermosensation hold broad prospects for SHCF in lossless power transferring and expeditious thermal analysis.

Inhibition of Fap Promotes Cardiac Repair by Stabilizing BNP.

BACKGROUND: Myocardial infarction (MI) elicits cardiac fibroblast activation and extracellular matrix (ECM) deposition to maintain the structural integrity of the heart. Recent studies demonstrate that Fap (fibroblast activation protein)-a prolyl-specific serine protease-is an important marker of activated cardiac fibroblasts after MI. METHODS: Left ventricle and plasma samples from patients and healthy donors were used to analyze the expression level of FAP and its prognostic value. Echocardiography and histological analysis of heart sections were used to analyze cardiac functions, scar formation, ECM deposition and angiogenesis after MI. RNA-Sequencing, biochemical analysis, cardiac fibroblasts (CFs) and endothelial cells co-culture were used to reveal the molecular and cellular mechanisms by which Fap regulates angiogenesis. RESULTS: We found that Fap is upregulated in patient cardiac fibroblasts after cardiac injuries, while plasma Fap is downregulated and functions as a prognostic marker for cardiac repair. Genetic or pharmacological inhibition of Fap in mice significantly improved cardiac function after MI. Histological and transcriptomic analyses showed that Fap inhibition leads to increased angiogenesis in the peri-infarct zone, which promotes ECM deposition and alignment by cardiac fibroblasts and prevents their overactivation, thereby limiting scar expansion. Mechanistically, we found that BNP (brain natriuretic peptide) is a novel substrate of Fap that mediates postischemic angiogenesis. Fap degrades BNP to inhibit vascular endothelial cell migration and tube formation. Pharmacological inhibition of Fap in Nppb (encoding pre-proBNP) or Npr1 (encoding the BNP receptor)-deficient mice showed no cardioprotective effects, suggesting that BNP is a physiological substrate of Fap. CONCLUSIONS: This study identifies Fap as a negative regulator of cardiac repair and a potential drug target to treat MI. Inhibition of Fap stabilizes BNP to promote angiogenesis and cardiac repair.

Reverse Atrial Remodeling in Heart Failure With Recovered Ejection Fraction.

Background Heart failure with recovered ejection fraction (HFrecEF) has been a newly recognized entity since 2020. However, the concept has primarily focused on left ventricular ejection fraction improvement, with less focus on the recovery of the left atrium. In this study, we investigated changes in left atrial (LA) echocardiographic indices in HFrecEF. Methods and Results An inpatient cohort with heart failure with reduced ejection fraction (HFrEF) was identified retrospectively and followed up prospectively in a single tertiary hospital. The enrolled patients were classified into HFrecEF and persistent HFrEF groups. Alternations in LA parameters by echocardiography were calculated. The primary outcome was a composite of cardiovascular death or heart failure rehospitalization. A total of 699 patients were included (HFrecEF: n=228; persistent HFrEF: n=471). Compared with persistent HFrEF, the HFrecEF group had greater reductions in LA diameter, LA transverse diameter, LA superior-inferior diameter, LA volume, and LA volume index but not in LA sphericity index. Cox regression analysis showed that the HFrecEF group experienced lower risks of prespecified end points than the persistent HFrEF group after adjusting for confounders. Additionally, 136 (59.6%) and 62 (13.0%) patients showed LA reverse remodeling (LARR) for the HFrecEF and persistent HFrEF groups, respectively. Among the HFrecEF subgroup, patients with LARR had better prognosis compared with those without LARR. Multivariate logistic analysis demonstrated that age and coronary heart disease were 2 independent negative predictors for LARR. Conclusions In HFrecEF, both left ventricular systolic function and LA structure remodeling were improved. Patients with HFrecEF with LARR had improved clinical outcomes, indicating that the evaluation of LA size provides a useful biomarker for risk stratification of heart failure.

Inhibition of fibroblast activation protein ameliorates cartilage matrix degradation and osteoarthritis progression.

Fibroblast activation protein (Fap) is a serine protease that degrades denatured type I collagen, α2-antiplasmin and FGF21. Fap is highly expressed in bone marrow stromal cells and functions as an osteogenic suppressor and can be inhibited by the bone growth factor Osteolectin (Oln). Fap is also expressed in synovial fibroblasts and positively correlated with the severity of rheumatoid arthritis (RA). However, whether Fap plays a critical role in osteoarthritis (OA) remains poorly understood. Here, we found that Fap is significantly elevated in osteoarthritic synovium, while the genetic deletion or pharmacological inhibition of Fap significantly ameliorated posttraumatic OA in mice. Mechanistically, we found that Fap degrades denatured type II collagen (Col II) and Mmp13-cleaved native Col II. Intra-articular injection of rFap significantly accelerated Col II degradation and OA progression. In contrast, Oln is expressed in the superficial layer of articular cartilage and is significantly downregulated in OA. Genetic deletion of Oln significantly exacerbated OA progression, which was partially rescued by Fap deletion or inhibition. Intra-articular injection of rOln significantly ameliorated OA progression. Taken together, these findings identify Fap as a critical pathogenic factor in OA that could be targeted by both synthetic and endogenous inhibitors to ameliorate articular cartilage degradation.

Efficacy of guideline-directed medical treatment in heart failure with mildly reduced ejection fraction.

AIMS: Heart failure with mildly reduced ejection fraction (HFmrEF) has received increasing attention following the publication of the latest ESC guidelines in 2021. However, it remains unclear whether patients with HFmrEF could benefit from guideline-directed medical treatment (GDMT), referring the combination of ACEI/ARB/ARNI, ß-blockers, and MRAs, which are recommended for those with reduced ejection fraction. This study explored the efficacy of GDMT in HFmrEF patients. METHODS: This was a retrospective cohort study of HFmrEF patients admitted to The First Affiliated Hospital of Dalian Medical University between 1 September 2015 and 30 November 2019. Propensity score matching (1:2) between patients receiving triple-drug therapy (TT) and non-triple therapy (NTT) based on age and sex was performed. The primary outcome was all cause death, cardiac death, rehospitalization from any cause, and rehospitalization due to worsening heart failure. RESULTS: Of the 906 patients enrolled in the matched cohort (TT group, n = 302; NTT group, N = 604), 653 (72.08%) were male, and mean age was 61.1 ± 11.92. Survival analysis suggested that TT group experienced a significantly lower incidence of prespecified primary endpoints than NTT group. Multivariable Cox regression showed that TT group had a lower risk of all-cause mortality (HR 0.656, 95% CI 0.447-0.961, P = 0.030), cardiac death (HR 0.599, 95% CI 0.380-0.946, P = 0.028), any-cause rehospitalization (HR 0.687, 95% CI 0.541-0.872, P = 0.002), and heart failure rehospitalization (HR 0.732, 95% CI 0.565-0.948, P = 0.018). CONCLUSIONS: In patients with HFmrEF, combined use of neurohormonal antagonists produces remarkable effects in reducing the occurrence of the primary outcome of rehospitalization and death. Thus, the treatment of HFmrEF should be categorized as HFrEF due to the similar benefit of neurohormonal blocking therapy in HFrEF and HFmrEF.

The predictive value of changes in left atrial volume index for rehospitalization in heart failure with preserved ejection fraction.

AIMS: Left atrial volume index (LAVI) is an adequate analysis to predicate the left ventricle (LV) filling pressures, providing a powerful predictive marker of LV diastolic dysfunction. LAVI is a dynamic morphophysiological marker, and whether LAVI changes can predicate clinical outcomes in HF with preserved ejection fraction (HFpEF) is unknown. METHODS: HFpEF patients were retrospectively studied from the First Affiliated Hospital of Dalian Medical University. Patients were classified into deteriorated, stable and improved groups according to the change in LAVI. Rehospitalization was defined as the main endpoint, the composite outcome of rehospitalization or all-cause death was defined as the secondary endpoint. RESULTS: A total of 409 patients were included. In this cohort, the percentage of deteriorated, stable, and improved LAVI were 99 (24.2%), 235 (57.4%), and 75 (18.4%), respectively. During the 22 months follow-up period, 168 patients (41.1%) were rehospitalized, 31 patients (7.5%) died and 182 patients (44.5%) experienced a composite outcome. Multivariate Cox regression showed that compared to improved LAVI, those with deteriorated and stable LAVI experienced higher risk of rehospitalization. Logistic regression showed atrial fibrillation (AF) and higher creatinine were independent predictors of deteriorated LAVI, whereas the use of loop diuretics, calcium channel blockers (CCB), and high level of high-density lipoprotein cholesterol (HDL-C) were significantly associated with improved LAVI. CONCLUSIONS: Change in LAVI provides a powerful and dynamic morphophysiological marker of LV filling status and can be used to evaluate the rehospitalization in HFpEF patients.

The influence of (H2O)1-2 in the HOBr + HO2 gas-phase reaction.

The HOBr + HO2 reaction in the absence of water has three different channels for the abstraction of H to generate the corresponding products. The dominant channel is the generation of BrO + H2O2. The introduction of water molecules influences this dominant reaction via the way the reactants interact with the water molecules. The addition of water molecules decreases the energy barrier and increases the rate coefficient of the reaction. Interestingly, water works as a catalyst and we obtain BrO + H2O2, like in the reaction without water, or the water works as a reactant and we obtain products other than BrO + H2O2. The rate coefficients of the HOBr + HO2 reaction in the presence of water are calculated to be faster than the reaction in the absence of water. However, other pathways in the presence of water are slower than the reaction in the absence of water. The water-assisted effective rate coefficients for the HOBr + HO2 reaction are also larger than those for the reaction in the absence of water. The influence of a water dimer is not as important when compared with one water molecule. In summary, a single water molecule has a positive catalytic influence in enhancing the HOBr + HO2 reaction.