Association between Impaired Renal Function and Subclinical Myocardial Dysfunction in Patients with Heart Failure with Preserved Ejection Fraction: Assessment Using Noninvasive Pressure-Strain Loop.

INTRODUCTION: The objective of this study was to evaluate the abnormal myocardial function in HFpEF patients with renal dysfunction (RD) and investigate the relationship between renal function and myocardial mechanical characteristics in patients with HFpEF. METHODS: 134 patients with HFpEF and 32 control subjects were enrolled in our study. Clinical and echocardiography data were collected for offline analysis. Global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE) were measured after noninvasive pressure-strain loop analysis. Univariate and multivariate analyses were used to determine the correlation between renal function and myocardial function in patients with HFpEF. RESULTS: In comparison to control subjects, patients with HFpEF tend to have higher GWW (78 [50-115] vs. 108 [65-160] mm Hg%, p < 0.05) and lower GWE (96 [95-97] vs. 95 [92-96] %, p < 0.05), while left ventricular ejection fraction (65.5 ± 3.3 vs. 64.3 ± 4.6%, p < 0.05) was comparable between them. Besides, increased GWW (86 [58-152] vs. 125 [94-187] mm Hg%, p < 0.05) and decreased GWE (96 [93-97] vs. 94 [92-96] %, p < 0.05) were detected in patients with RD compared to those with normal renal function. An independent correlation was found between estimated glomerular filtration rate and GWW after multivariate analysis. DISCUSSION/CONCLUSION: More severely impaired myocardial function was detected in HFpEF patients with RD compared to those with normal renal function. Estimated glomerular filtration rate was independently correlated to GWW in patients with HFpEF.

Diagnostic potential of myocardial early systolic lengthening for patients with suspected non-ST-segment elevation acute coronary syndrome.

BACKGROUND: During early systole, ischemic myocardium with reduced active force experiences early systolic lengthening (ESL). This study aimed to explore the diagnostic potential of myocardial ESL in suspected non-ST-segment elevation acute coronary syndrome (NSTE-ACS) patients with normal wall motion and left ventricular ejection fraction (LVEF). METHODS: Overall, 195 suspected NSTE-ACS patients with normal wall motion and LVEF, who underwent speckle tracking echocardiography (STE) before coronary angiography, were included in this study. Patients were stratified into the coronary artery disease (CAD) group when there was ≥ 50% stenosis in at least one major coronary artery. The CAD patients were further stratified into the significant (≥ 70% reduction of vessel diameter) stenosis group or the nonsignificant stenosis group. Myocardial strain parameters, including global longitudinal strain (GLS), duration of early systolic lengthening (DESL), early systolic index (ESI), and post-systolic index (PSI), were analyzed using STE and compared between groups. Receiver operating characteristic curve (ROC) analysis was performed to determine the diagnostic accuracy. Logistic regression analysis was conducted to establish the independent and incremental determinants for the presence of significant coronary stenosis. RESULTS: The DESL and ESI values were higher in patients with CAD than those without CAD. In addition, CAD patients with significant coronary stenosis had higher DESL and ESI than those without significant coronary stenosis. The ROC analysis revealed that ESI was superior to PSI for identifying patients with CAD, and further superior to GLS and PSI for predicting significant coronary stenosis. Moreover, ESI could independently and incrementally predict significant coronary stenosis in patients with CAD. CONCLUSIONS: The myocardial ESI is of great value for the diagnosis and risk stratification of clinically suspected NSTE-ACS patients with normal LVEF and wall motion.

Roflupram attenuates α-synuclein-induced cytotoxicity and promotes the mitochondrial translocation of Parkin in SH-SY5Y cells overexpressing A53T mutant α-synuclein.

We have previously shown that inhibition of cAMP-specific 3',5'-cyclic phosphodiesterase 4 (PDE4) protects against cellular toxicity in neuronal cells. Since α-synuclein (α-syn) toxicity contributes to the neurodegeneration of Parkinson's disease (PD). The aim of this study was to explore the effects and mechanisms of PDE4 on α-syn-induced neuronal toxicity. Using mutant human A53T α-syn overexpressed SH-SY5Y cells, we found that PDE4B knockdown reduced cellular apoptosis. Roflupram (ROF, 20 µM), a selective PDE4 inhibitor, produced similar protective effects and restored the morphological alterations of mitochondria. Mechanistic studies identified that α-syn enhanced the phosphorylation of Parkin at Ser131, followed by the decreased mitochondrial translocation of Parkin. Whereas both PDE4B knockdown and PDE4 inhibition by ROF blocked the effects of α-syn on Parkin phosphorylation and mitochondrial translocation. Moreover, PDE4 inhibition reversed the increase in the phosphorylation of p38 mitogen-activated protein kinase (MAPK) induced by α-syn. ROF treatment also reduced the binding of p38 MAPK to Parkin. Consistently, overexpression of PDE4B blocked the roles of ROF on p38 MAPK phosphorylation, Parkin phosphorylation, and the subsequent mitochondrial translocation of parkin. Furthermore, PDE4B overexpression attenuated the protective role of ROF, as evidenced by reduced mitochondria membrane potential and increased cellular apoptosis. Interestingly, ROF failed to suppress α-syn-induced cytotoxicity in the presence of a protein kinase A (PKA) inhibitor H-89. Our findings indicate that PDE4 facilitates α-syn-induced cytotoxicity via the PKA/p38 MAPK/Parkin pathway in SH-SY5Y cells overexpressing A53T mutant α-synuclein. PDE4 inhibition by ROF is a promising strategy for the prevention and treatment of α-syn-induced neurodegeneration.

Subclinical left ventricular myocardial dysfunction in patients with obstructive sleep apnea syndrome: insights from noninvasive left ventricular myocardial work analysis.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with various cardiovascular diseases and has aroused public concern. Early detection for declining myocardial function is of great significance. This study was aimed at noninvasively evaluating the subclinical left ventricular (LV) myocardial dysfunction with LV pressure-strain loop (PSL) in patients with OSAS having normal LV ejection fraction. METHODS: We enrolled 200 patients with OSAS who visited the Beijing Chaoyang Hospital between February 2021 and December 2021. According to the apnea-hypopnea index (AHI), patients were divided into mild, moderate, and severe groups. The global longitudinal strain (GLS) of the left ventricle was analyzed by two-dimensional speckle tracking echocardiography. The LV PSL was used to assess global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE), and comparisons were made among groups. RESULTS: GLS was significantly lower in the severe group than in mild and moderate group. GWI, GCW, and GWE were lower in the severe group than in mild and moderate groups. GWW was significantly higher in the severe group than in the mild group. GLS, GWI, and GWE were moderately correlated with AHI (Spearman's ρ = -0.468, -0.321, and -0.319, respectively; P < 0.001), whereas GCW and GWW showed a weak correlation with AHI (Spearman's ρ = -0.226 and 0.255 respectively; P < 0.001). Multiple regression analyses revealed AHI was independently associated with GWI after adjusting for SBP, GLS, e', etc. AHI was independently associated with GCW after adjusting for SBP, GLS, etc. CONCLUSIONS: The LV PSL is a new technique to noninvasively detect myocardial function deterioration in patients with OSAS and preserved LV ejection fraction. Increased severity of OSAS was independent associated with both decreased GWI and GCW.

Inhibition of phosphodiesterase-4 suppresses HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress.

Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)-like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g.) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1ß. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.

Reduced mechanical function of the left atrial predicts adverse outcome in pregnant women with clustering of metabolic risk factors.

INTRODUCTION: The left atrial (LA) strain and strain rate are sensitive indicators of LA function. However, they are not widely used for the evaluation of pregnant women with metabolic diseases. The aim of this study was to assess the LA strain and strain rate of pregnant women with clustering of metabolic risk factors and to explore its prognostic effect on adverse pregnancy outcomes. MATERIALS AND METHODS: Sixty-three pregnant women with a clustering of metabolic risk factors (CMR group), fifty-seven women with pregnancy-induced hypertension (PIH group), fifty-seven women with gestational diabetes mellitus (GDM group), and fifty matched healthy pregnant women (control group) were retrospectively evaluated. LA function was evaluated with two-dimensional speckle-tracking imaging. Iatrogenic preterm delivery caused by severe preeclampsia, placental abruption, and fetal distress was regarded as the primary adverse outcome. RESULTS: The CMR group showed the lowest LA strain during reservoir phase (LASr), strain during contraction phase (LASct) and peak strain rate during conduit phase (pLASRcd) among the three groups (P < 0.05). LA strain during conduit phase (LAScd) and peak strain rate during reservoir phase (pLASRr) in the CMR group were lower than those in the control and GDM groups (P < 0.05). Multivariable Cox regression analysis demonstrated systolic blood pressure (HR = 1.03, 95% CI 1.01-1.05, p = 0.001) and LASr (HR = 0.86, 95% CI 0.80-0.92, p < 0.0001) to be independent predictors of iatrogenic preterm delivery. An LASr cutoff value ≤ 38.35% predicted the occurrence of iatrogenic preterm delivery. CONCLUSIONS: LA mechanical function in pregnant women with metabolic aggregation is deteriorated. An LASr value of 38.35% or less may indicate the occurrence of adverse pregnancy outcomes.

Roflupram protects against rotenone-induced neurotoxicity and facilitates α-synuclein degradation in Parkinson's disease models.

We have previously shown that roflupram (ROF) protects against MPP+-induced neuronal damage in models of Parkinson's disease (PD). Since impaired degradation of α-synuclein (α-syn) is one of the key factors that lead to PD, here we investigated whether and how ROF affects the degradation of α-syn in rotenone (ROT)-induced PD models in vivo and in vitro. We showed that pretreatment with ROF (10 µM) significantly attenuated cell apoptosis and reduced the level of α-syn in ROT-treated SH-SY5Y cells. Furthermore, ROF significantly enhanced the lysosomal function, as evidenced by the increased levels of mature cathepsin D (CTSD) and lysosomal-associated membrane protein 1 (LAMP1) through increasing NAD+/NADH and the expression of sirtuin 1 (SIRT1). Pretreatment with an SIRT1 inhibitor selisistat (SELI, 10 µM) attenuated the neuroprotection of ROF, ROF-reduced expression of α-syn, and ROF-increased expression levels of LAMP1 and mature CTSD. Moreover, inhibition of CTSD by pepstatin A (20 µM) attenuated ROF-reduced expression of α-syn. In vivo study was conducted in mice exposed to ROT (10 mg·kg-1·d-1, i.g.) for 6 weeks; then, ROT-treated mice received ROF (0.5, 1, or 2 mg·kg-1·d-1; i.g.) for four weeks. ROF significantly ameliorated motor deficits, which was accompanied by increased expression levels of tyrosine hydroxylase, SIRT1, mature CTSD, and LAMP1, and a reduced level of α-syn in the substantia nigra pars compacta. Taken together, these results demonstrate that ROF exerts a neuroprotective action and reduces the α-syn level in PD models. The mechanisms underlying ROF neuroprotective effects appear to be associated with NAD+/SIRT1-dependent activation of lysosomal function.

Impaired left ventricular mechanics and functional reserve are associated with reduced exercise capacity in patients with hypertrophic cardiomyopathy.

BACKGROUND: Reduced metabolic equivalents (METs) are an indicator of exercise intolerance, which predicts poor prognosis in hypertrophic cardiomyopathy (HCM) patients. We sought to evaluate the changes in left ventricular (LV) mechanics and functional reserves, as well as their association with functional capacity in HCM patients. METHODS: Seventy HCM patients and thirty controls were included in this study. LV mechanics were evaluated at rest and during exercise by echocardiography and two-dimensional speckle-tracking imaging to obtain parameters of functional reserve, LV global longitudinal strain (LVGLS), strain rate (SR), and circumferential strain. RESULTS: Hypertrophic cardiomyopathy (HCM) patients had lower LVGLS, systolic SR, early and late diastolic SR at rest and during exercise, and reduced absolute and relative systolic and diastolic reserve compared to controls. LV circumferential strain was significantly higher at rest but lower during exercise in HCM patients. Exercise capacity was markedly reduced in HCM patients, and peak exercise LVGLS (LVGLS-exe) significantly correlated with exercise capacity. Multivariate regression analyses showed that LVGLS-exe, LV filling pressure during exercise (E/e'-exe), and LV mass index (LVMI) were independent predictors of exercise capacity. Moreover, LVGLS-exe displayed incremental predictive value over E/e'-exe and LVMI for exercise intolerance. Receiver operating characteristic curve analysis showed LVGLS-exe had optimal accuracy for predicting exercise intolerance in HCM patients. CONCLUSIONS: Hypertrophic cardiomyopathy (HCM) patients have reduced LV mechanics at rest and during exercise and impaired mechanical reserve. LVGLS-exe is associated with exercise capacity and is an optimal predictive value for reduced exercise capacity in HCM patients.

Evaluation of the left atrial appendage by real time three-dimensional transesophageal echocardiography online.

OBJECTIVE: The objective of this study was to evaluate the feasibility of online real time three-dimensional transesophageal echocardiography (RT3DTEE) in the measurement of left atrial appendage (LAA) orifice size. We also analyzed the correlation between LAA ejection fraction (EF) and its peak empty velocity (PEV). METHODS: There were 91 subjects enrolled in this study, with 46 patients with AF and 45 individuals with sinus rhythm (SR). RT3DTEE was performed by four methods including iSlice and iCrop online and QLAB software 3DQ and GI-3DQ off-line which were used to measure LAA orifice area, long diameter, short diameter, depth in the largest LAA, and number of LAA lobes. These LAA parameters achieved by the four methods were compared, respectively. GI-3DQ off-line was used to measure LAA end-diastolic and end-systolic volumes to calculate EF of LAA. Two-dimensional (2D) TEE was applied to measure PEV of LAA. The correlation between EF and PEV was analyzed. RESULTS: There were no significant differences in all LAA parameters between any two RT3DTEE methods (All P > .05). There was a significant and positive correlation between PEV and EF (r = .423, P = .000). There were statistical differences in LAA EF and PEV between patients with AF and SR individuals (0.38 ± 0.12 vs 0.61 ± 0.07, 35.7 ± 12.1 vs 49.5 ± 10.0 cm/s, P = .000). CONCLUSION: Using online RT3DTEE for measuring LAA orifice size is feasible, and online RT3DTEE is more convenient than offline RT3DTEE. EF is positively correlated with PEV. LAA function is significantly decreased in patients with AF.

Dual-Responsive "Egg-Box" Shaped Microgel Beads Based on W1/O/W2 Double Emulsions for Colon-Targeted Delivery of Synbiotics.

In this study, for enhancing the resistance of probiotics to environmental factors, we designed a microgel beads delivery system loaded with synbiotics. Multiple droplets of W1/O/W2 emulsions stabilized with zein-apple pectin hybrid nanoparticles (ZAHPs) acted as the inner "egg," whereas a three-dimensional network of poly-L-lysine (PLL)-alginate-CaCl2 (Ca) crosslinked gel layers served as the outermost "box." ZAHPs with a mass ratio of 2:1 zein-to-apple pectin showed excellent wettability (three-phase contact angle = 89.88°). The results of the ζ-potentials and Fourier transform infrared spectroscopy demonstrate that electrostatic interaction forces and hydrogen bonding were the main forces involved in the formation of ZAHPs. On this basis, we prepared W1/O/W2 emulsions with other preparation parameters and observed their microstructures by optical microscopy and confocal laser scanning microscope. The multi-chambered structures of W1/O/W2 emulsions were successfully visualized. Finally, the W1/O/W2 emulsions were coated with PLL-alginate-Ca using the solution extrusion method. The results of the in vitro colonic digestion stage reveal that the survival rate of probiotics in the microgel beads was about 75.11%, which was significantly higher than that of the free. Moreover, probiotics encapsulated in microgel beads also showed positive storage stability. Apple pectin would serve as both an emulsifier and a prebiotic. Thus, the results indicate that the "egg-box" shaped microgel beads, designed on the basis of pH-sensitive and enzyme-triggered mechanisms, can enhance the efficiency of probiotics translocation in the digestive tract and mediate spatiotemporal controlled release.

Automated echocardiographic diastolic function grading: A hybrid multi-task deep learning and machine learning approach.

BACKGROUND: Assessing left ventricular diastolic function (LVDF) with echocardiography as per ASE guidelines is tedious and time-consuming. The study aims to develop a fully automatic approach of this procedure by a lightweight hybrid algorithm combining deep learning (DL) and machine learning (ML). METHODS: The model features multi-modality input and multi-task output, measuring LV ejection fraction (LVEF), left atrial end-systolic volume (LAESV), and Doppler parameters: mitral E wave velocity (E), A wave velocity (A), mitral annulus e' velocity (e'), and tricuspid regurgitation velocity (TRmax). The algorithm was trained and tested on two internal datasets (862 and 239 echocardiograms) and validated using three external datasets, including EchoNet-Dynamic and CAMUS. The ASE diastolic function decision tree and total probability theory were used to provide diastolic grading probabilities. RESULTS: The algorithm, named MMnet, demonstrated high accuracy in both test and validation datasets, with Dice coefficients for segmentation between 0.922 and 0.932 and classification accuracies between 0.9977 and 1.0. The mean absolute errors (MAEs) for LVEF and LAESV were 3.7 % and 5.8 ml, respectively, and for LVEF in external validation, MAEs ranged from 4.9 % to 5.6 %. The diastolic function grading accuracy was 0.88 with hard criteria and up to 0.98 with soft criteria which account for the top two probability in total probability theory. CONCLUSIONS: MMnet can automatically grade ASE diastolic function with high accuracy and efficiency by annotating 2D videos and Doppler images.

Myocardial work by pressure-strain loop is associated with molecular imaging of fibroblast activation in hypertensive hearts using 99mTc-HFAPI SPECT.

99mTc-HFAPI can visualize fibroblast activation in hypertensive hearts. Myocardial work (MW) reflects the cardiac mechanical properties after accounting for the afterload in hypertensive patients. We investigated whether MW was associated with increased uptake of 99mTc-HFAPI. A total of 97 hypertensive patients and 41 healthy volunteers were prospectively recruited. Global work index (GWI), global constructive work (GCW), global wasted work (GWW) and global work efficiency (GWE) were analyzed. According to whether myocardial uptake of FAPI was higher than the adjacent blood pool, hypertensive patients were divided into two groups, namely: FAPI + and FAPI- group, respectively. GWI, GCW and GWE of the FAPI + group were lower than the FAPI- group. The value of GWW in the FAPI + group was higher than in the FAPI- group. Multiple regression analyses revealed GWI, GWW and GWE were independently associated with early myocardial fibrosis. According to receiver operating characteristics (ROC) analysis, the best cutoff points for FAPI + of GWI, GWW and GWE were 1968.50 mmHg% (AUC: 0.687, 95% CI: 0.581-0.793, P = 0.002), 133.00 mmHg% (AUC: 0.778, 95% CI: 0.688-0.869, P < 0.001) and 95.07% (AUC: 0.813, 95% CI: 0.730-0.896, P < 0.001), respectively. GWI, GWW and GWE were impaired in hypertensive patients with cardiac 99mTc-HFAPI uptake and were associated with fibroblast activation in hypertensive hearts.

Exploring the impact of coffee consumption on liver health: A comprehensive bibliometric analysis.

The study indicates that while research has demonstrated the potential of coffee to mitigate liver damage, a comprehensive quantitative analysis of its effects has yet to be conducted. This study seeks to explore the current landscape and focal points of research on coffee consumption's impact on the liver from 2013 to 2023. Articles published within this timeframe were retrieved from the Web of Science database and subjected to analysis using R software, VOSviewer, and CiteSpace software. A total of 1106 articles primarily focused on coffee's impact on liver health were analyzed. The frequency of publication exhibited a significant increase from 2013 to 2023. The United States emerged as the leading contributor in publications and international collaborations, particularly with institutions such as Harvard Medical School and Harvard T.H. Chan School of Public Health. Noteworthy journals in this domain included "Nutrients" and "Hepatology" Commonly occurring keywords encompassed components, chlorogenic acids, oxidative stress, and liver. The study highlighted coffee's potential benefits in preventing cardiovascular and liver diseases, attributed to mechanisms such as antioxidant activity and modulation of hepatic cells. Through bibliometric analysis, this study offers valuable insights into the research status and emphasis on coffee's effects on liver health, serving as a significant reference for future investigations in this area.

Usefulness of layer-specific strain for evaluating and predicting recovery of left ventricular myocardial function in patients undergoing hybrid coronary revascularization.

PURPOSE: This study aimed to determine if layer-specific strain (LSS) can be used to evaluate and predict left ventricular (LV) recovery in patients with multi-vessel coronary artery disease (CAD) undergoing hybrid coronary revascularization (HCR) using speckle tracking echocardiography (STE). METHODS: A total of 187 consecutive CAD patients who received HCR in our hospital were prospectively enrolled. 30 healthy individuals with matched age and gender were enrolled as a control group. Echocardiography was performed for CAD patients before and 1, 2, and 6 months after HCR. Comprehensive conventional and LSS echocardiography parameters were collected. LV recovery was defined as improvement in LV ejection fraction (LVEF) > 5% at 6-months follow-up compared with baseline. Logistic regression analysis was used to test the correlates of LV recovery. Receiver operating characteristic curve analysis was used to determine the optimal cutoff value of correlates for predicting LV recovery. RESULTS: LVEF and LV strain in CAD patients were significantly decreased compared with control subjects. Endocardial global longitudinal strain (Endo-GLS) improved significantly at 1-month follow-up (14.2 ± 1.6% vs. 13.8 ± 1.5%, P < 0.05), and LVGLS and global circumferential strain (GCS) improved significantly at 2-months follow-up. Multivariate regression revealed that Endo-GLS, GLS, and SYNTAX score before HCR were independently correlated to LV recovery. Endo-GLS had an optimal cutoff value of 13.2% for predicting LV recovery with sensitivity of 91% and specificity of 78%. CONCLUSION: LV myocardial systolic function in CAD patients was impaired before HCR and significantly improved after HCR. Endo-GLS was independently correlated to and has optimal predictive value for LV recovery.

Association between left ventricular geometry and global myocardial work in patients with heart failure with preserved ejection fraction: assessment using strain-pressure loop.

Concentric LV remodeling and hypertrophy are common structural abnormalities in patients with heart failure with preserved ejection fraction (HFpEF) and tend to be accompanied by impaired LV function. Assessment of global myocardial work (GMW) using strain-pressure loop may provide more comprehensive assessment of LV myocardial function, overcoming the limitations of the conventional parameters. We investigated the value of GMW in patients with HFpEF and assessed the relationship of GMW with concentric remodeling and hypertrophy. Consecutive patients with HFpEF (n = 107) and sex-matched healthy controls (n = 32) were prospectively enrolled. Clinical and conventional echocardiography variables were obtained. Further analyses of offline data were performed to obtain GMW indices including global work index (GWI), global constructive work (GCW), global waste work (GWW), and global work efficiency (GWE). Association of concentric remodeling and hypertrophy with GMW was analyzed by univariate and multivariate analysis. HFpEF patients showed lower GWE (94% vs 96%, P < 0.001) and higher GWW (114 mmHg% vs 78 mmHg%, P = 0.003) than control group, while GWI (2111 mmHg% vs 2146 mmHg%, P = 0.877) and GCW (2369 mmHg% vs 2469 mmHg%, P = 0.733) were comparable in the two groups. HFpEF patients with relative wall thickness (RWT) > 0.42 had reduced GWE (94% vs 95%, P = 0.034) compared to HFpEF patients with RWT ≤ 0.42, while GWI, GCW, and GWW were comparable between these two subgroups. Multivariate analysis showed an independent association of RWT with GWI, GCW, and GWE, respectively. Impaired global myocardial work was detected in patients with HFpEF. Impaired LV GMW may be associated with increased RWT.

Effects of 3-month dapagliflozin on left atrial function in treatment-naïve patients with type 2 diabetes mellitus: Assessment using 4-dimensional echocardiography.

BACKGROUND: The sodium-glucose transporter-2 (SGLT-2) inhibitor dapagliflozin can improve left ventricular (LV) performance in patients with type 2 diabetes mellitus (T2DM). However, the effects on left atrial (LA) function in treatment-naïve T2DM patients remain unclear. The aim of our study was 1) to investigate the effects of 3-month treatment with dapagliflozin on LA function in treatment-naïve patients with T2DM using 4-dimensional automated LA quantification (4D Auto LAQ) and 2) to explore linked covariation patterns of changes in clinical and LA echocardiographic variables. METHODS: 4D Auto LAQ was used to evaluate LA volumes, longitudinal and circumferential strains in treatment-naïve T2DM patients at baseline, at follow-up, and in healthy control (HC). Sparse canonical correlation analysis (sCCA) was performed to capture the linked covariation patterns between changes in clinical and LA echocardiographic variables within the treatment-naïve T2DM patient group. RESULTS: This study finally included 61 treatment-naïve patients with T2DM without cardiovascular disease and 39 healthy controls (HC). Treatment-naïve T2DM patients showed reduced LA reservoir and conduit function at baseline compared to HC, independent of age, sex, BMI, and blood pressure (LASr: 21.11 ± 5.39 vs. 27.08 ± 5.31 %, padjusted = 0.017; LAScd: -11.51 ± 4.48 vs. -16.74 ± 4.51 %, padjusted = 0.013). After 3-month treatment with dapagliflozin, T2DM patients had significant improvements in LA reservoir and conduit function independent of BMI and blood pressure changes (LASr: 21.11 ± 5.39 vs. 23.84 ± 5.74 %, padjusted < 0.001; LAScd: -11.51 ± 4.48 vs. -12.75 ± 4.70 %, padjusted < 0.001). The clinical and LA echocardiographic parameters showed significant covariation (r = 0.562, p = 0.039). In the clinical dataset, changes in heart rate, insulin, and BMI were most associated with the LA echocardiographic variate. In the LA echocardiographic dataset, changes in LAScd, LASr, and LASr_c were most associated with the clinical variate. CONCLUSION: Compared with HC, treatment-naïve patients with T2DM had lower LA function, and these patients benefited from dapagliflozin administration, particularly in LA function.

Roflumilast, a cyclic nucleotide phosphodiesterase 4 inhibitor, protects against cerebrovascular endothelial injury following cerebral ischemia/reperfusion by activating the Notch1/Hes1 pathway.

The loss of tight junction (TJ) and adherens junction (AJ) proteins leads to the damage of the blood-brain barrier (BBB) during cerebral ischemia. Inhibition of cyclic nucleotide phosphodiesterase 4 (PDE4) by roflumilast (Roflu) protects against ischemic stroke-induced neuronal damage. However, the effects of Roflu on vascular endothelial injury and BBB integrity remain unknown. Here, we investigated whether and how Roflu protects against cerebrovascular endothelial injury caused by cerebral ischemia/reperfusion. We demonstrated that PDE4B knocking-down increased the expression of TJ and AJ proteins in human brain microvascular endothelial cells (HBMECs) subjected to oxygen-glucose deprivation reperfusion (OGD/R). Inhibition of PDE4 by Roflu (1.0 µM) showed similar effects as PDE4B knocking-down. We then found that Roflu activated Notch1/Hairy and enhancer of split 1 (Hes1) signaling. Consistently, the effects of Roflu on TJ and AJ proteins were reversed by the γ-secretase inhibitor DAPT or Hes1 knocking-down. Furthermore, Roflu (1.0 mg/kg) improved neurobehavioral outcomes and ameliorated BBB disruption in rats following ischemic stroke. Roflu also increased the levels of TJ proteins and AJ proteins in vivo. Collectively, these data suggest that Roflu is a promising compound for the prevention of BBB damage. The protective effects of Roflu are mediated through activation of the Notch1/Hes1 pathway.

The Effects of Leaders' Prosocial Orientation on Employees' Organizational Citizenship Behavior - The Roles of Affective Commitment and Workplace Ostracism.

PURPOSE: According to leadership trait theory, leaders' personality traits are stable factors in organizational situations and exert significant effects on employees' organizational behaviors. However, studies related to this topic are very limited. In this study, from the leadership trait perspective and based on social identity theory and social exchange theory, the influencing mechanisms of leaders' prosocial tendencies on affiliation-oriented and challenge-oriented organizational citizenship behaviors are investigated. Specifically, leadership prosocial tendency, affective commitment and workplace ostracism are selected as the independent variable, mediating variable and moderating variable, respectively. METHODS: The data collection is conducted in two stages in which the leader-employee pairing method is adopted. Ultimately, 347 valid questionnaires are collected from 73 teams. Later, the hierarchical regression analysis and bootstrap methods are used to test the study's hypotheses. RESULTS: Leadership prosocial tendencies have significant positive effects on affective commitment (ß = 0.282, p < 0.001), affiliation-oriented (ß = 0.648, p < 0.001) and challenge-oriented organizational citizenship behaviors (ß = 0.521, p < 0.001). There is a significant positive effect of affective commitment on affiliation-oriented (ß = 0.103, p < 0.05) and challenge-oriented organizational citizenship behaviors (ß = 0.122, p < 0.05). At the same time, the influence of leadership prosocial tendencies on affiliation-oriented (ß = 0.619, p < 0.001) and challenge-oriented organizational citizenship behaviors (ß = 0.487, p < 0.001) remains significant. In other words, affective commitment partially mediates the relationships between leaders' prosocial tendencies and affiliation-oriented, challenge-oriented organizational citizenship behaviors. Workplace ostracism plays a negative moderating role between leaders' prosocial tendencies and affective commitment (ß = -0.098, p < 0.05). Furthermore, workplace ostracism can also mediate the mediating role of affective commitment with 95% bias-corrected confidence intervals [-0.146, -0.017] and [-0.114, -0.003]. CONCLUSION: The results show that leaders' prosocial tendencies have significant positive effects on both affiliation-oriented and challenge-oriented organizational citizenship behaviors. Affective commitment partially mediates the relationships between leaders' prosocial tendencies and affiliation-oriented and challenge-oriented organizational citizenship behaviors. Workplace ostracism significantly negatively moderates the relationship between leaders' prosocial tendencies and affective commitment. Moreover, the study verifies that the mediating effect of workplace ostracism on affective commitment has a significant moderating effect.

Roflupram, a novel phosphodiesterase 4 inhibitor, inhibits lipopolysaccharide-induced neuroinflammatory responses through activation of the AMPK/Sirt1 pathway.

Roflupram (ROF) is a novel phosphodiesterase 4 inhibitor. We previously found that ROF suppressed the production of pro-inflammatory factors in microglial cells; however, the underlying mechanisms are largely unknown. The present study aimed to elucidate the underlying molecular mechanisms of the anti-neuroinflammatory effects of ROF in lipopolysaccharide (LPS)-activated microglial cells and LPS-challenged mice. Treatment with ROF suppressed LPS-induced expression of interleukin (IL)-6 and tumor necrosis factor (TNF)-α in BV-2 microglia cell line. Immunofluorescence and Western blotting analysis showed that ROF significantly inhibited the activation of microglia, as evidenced by decreased expression of ionized calcium binding adaptor molecule-1 (Iba1). Similar results were obtained in primary cultured microglial cells. ROF induced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Sirtuin 1 (Sirt1). Interestingly, the AMPK inhibitor, compound C, blocked the role of ROF in both the phosphorylation of AMPK and the expression of Sirt1 in BV-2 cells stimulated with LPS. More importantly, the Sirt1 inhibitor, EX527, abolished the inhibitory role of ROF on the production of pro-inflammatory factors, and reactivated BV-2 cells. In mice challenged with LPS, ROF improved cognition and decreased the levels of IL-6 and TNF-α in both the cortex and hippocampus. In contrast, EX527 weakened the effects of ROF on cognitive enhancement and reduction of pro-inflammatory factors in the cortex and hippocampus. Furthermore, EX527 blocked the inhibitory role of ROF in the activation of microglial cells in both the hippocampus and cortex. Taken together, our results indicated that ROF attenuated LPS-induced neuroinflammatory responses in microglia, and the AMPK/Sirt1 pathway is essential for the anti-inflammatory effects of ROF.

Roflumilast prevents ischemic stroke-induced neuronal damage by restricting GSK3ß-mediated oxidative stress and IRE1α/TRAF2/JNK pathway.

Inhibition of phosphodiesterase 4 (PDE4) protects against neuronal apoptosis induced by cerebral ischemia. However, the exact mechanisms responsible for the protection of PDE4 inhibition have not been completely clarified. Roflumilast (Roflu) is an FDA-approved PDE4 inhibitor for the treatment of chronic obstructive pulmonary disease. The potential protective role of Roflu against ischemic stroke-associated neuronal injury remains unexplored. In this study, we investigated the effect and mechanism of Roflu against ischemic stroke using in vitro oxygen-glucose deprivation reperfusion (OGD/R) and in vivo rat middle cerebral artery occlusion (MCAO) models. We demonstrated that Roflu significantly reduced the apoptosis of HT-22 cells exposed to OGD/R, enhanced the nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf-2), and reduced oxidative stress. Treatment with Roflu increased the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase 3ß (GSK3ß) but decreased the level of phosphorylated inositol requiring enzyme 1α (IRE1α). Interestingly, constitutively active GSK3ß (S9A) mutation abolished the effects of Roflu on oxidative stress and IRE1α phosphorylation. Moreover, Roflu decreased the binding of IRE1α to tumor necrosis factor receptor-associated factor 2 (TRAF2) and attenuated the phosphorylation of c-Jun N-terminal kinase (JNK). We also found that PDE4B knockdown reduced the phosphorylation of both IRE1α and JNK, while overexpression of PDE4B antagonized the role of PDE4B knockdown on the activation of IRE1α and JNK. Besides, the inhibition of PDE4 by Roflu produced similar effects in primary cultured neurons. Finally, Roflu ameliorated MCAO-induced cerebral injury by decreasing infarct volume, restoring neurological score, and reducing the phosphorylation of IRE1α and JNK. Collectively, these data suggest that Roflu protects neurons from cerebral ischemia reperfusion-mediated injury via the activation of GSK3ß/Nrf-2 signaling and suppression of the IRE1α/TRAF2/JNK pathway. Roflu has the potential as a protective drug for the treatment of cerebral ischemia.