[Cluster Analysis and Ablation Success Rate in Atrial Fibrillation Patients Undergoing Catheter Ablation]. / æˆ¿é¢¤å°„é¢‘æ¶ˆèžæ‚£è€ çš„èšç±»åˆ†æžåŠæ¶ˆèžæˆåŠŸçŽ‡è¯„ä»·.

Objective: Atrial fibrillation (AF) is a disease of high heterogeneity, and the association between AF phenotypes and the outcome of different catheter ablation strategies remains unclear. Conventional classification of AF (e.g. according to duration, atrial size, and thromboembolism risk) fails to provide reference for the optimal stratification of the prognostic risks or to guide individualized treatment plan. In recent years, research on machine learning has found that cluster analysis, an unsupervised data-driven approach, can uncover the intrinsic structure of data and identify clusters of patients with pathophysiological similarity. It has been demonstrated that cluster analysis helps improve the characterization of AF phenotypes and provide valuable prognostic information. In our cohort of AF inpatients undergoing radiofrequency catheter ablation, we used unsupervised cluster analysis to identify patient subgroups, to compare them with previous studies, and to evaluate their association with different suitable ablation patterns and outcomes. Methods: The participants were AF patients undergoing radiofrequency catheter ablation at West China Hospital between October 2015 and December 2017. All participants were aged 18 years or older. They underwent radiofrequency catheter ablation during their hospitalization. They completed the follow-up process under explicit informed consent. Patients with AF of a reversible cause, severe mitral stenosis or prosthetic heart valve, congenital heart disease, new-onset acute coronary syndrome within three months prior to the surgery, or a life expectancy less than 12 months were excluded according to the exclusion criteria. The cohort consisted of 1102 participants with paroxysmal or persistent/long-standing persistent AF. Data on 59 variables representing demographics, AF type, comorbidities, therapeutic history, vital signs, electrocardiographic and echocardiographic findings, and laboratory findings were collected. Overall, data for the variables were rarely missing (<5%), and multiple imputation was used for correction of missing data. Follow-up surveys were conducted through outpatient clinic visits or by telephone. Patients were scheduled for follow-up with 12-lead resting electrocardiography and 24-hours Holter monitoring at 3 months and 6 months after the ablation procedure. Early ablation success was defined as the absence of documented AF, atrial flutter, or atrial tachycardia >30 seconds at 6-month follow-up. Hierarchical clustering was performed on the 59 baseline variables. All characteristic variables were standardized to have a mean of zero and a standard deviation of one. Initially, each patient was regarded as a separate cluster, and the distance between these clusters was calculated. Then, the Ward minimum variance method of clustering was used to merge the pair of clusters with the minimum total variance. This process continued until all patients formed one whole cluster. The "NbClust" package in R software, capable of calculating various statistical indices, including pseudo t2 index, cubic clustering criterion, silhouette index etc, was applied to determine the optimal number of clusters. The most frequently chosen number of clusters by these indices was selected. A heatmap was generated to illustrate the clinical features of clusters, while a tree diagram was used to depict the clustering process and the heterogeneity among clusters. Ablation strategies were compared within each cluster regarding ablation efficacy. Results: Five statistically driven clusters were identified: 1) the younger age cluster (n=404), characterized by the lowest prevalence of cardiovascular and cerebrovascular comorbidities but the highest prevalence of obstructive sleep apnea syndrome (14.4%); 2) a cluster of elderly adults with chronic diseases (n=438), the largest cluster, showing relatively higher rates of hypertension, diabetes, stroke, and chronic obstructive pulmonary disease; 3) a cluster with high prevalence of sinus node dysfunction (n=160), with patients showing the highest prevalence of sick sinus syndrome and pacemaker implantation; 4) the heart failure cluster (n=80), with the highest prevalence of heart failure (58.8%) and persistent/long-standing persistent AF (73.7%); 5) prior coronary artery revascularization cluster (n=20), with patients of the most advanced age (median: 69.0 years old) and predominantly male patients, all of whom had prior myocardial infarction and coronary artery revascularization. Patients in cluster 2 achieved higher early ablation success with pulmonary veins isolation alone compared to extensive ablation strategies (79.6% vs. 66.5%; odds ratio [OR]=1.97, 95% confidence interval [CI]: 1.28-3.03). Although extensive ablation strategies had a slightly higher success rate in the heart failure group, the difference was not statistically significant. Conclusions: This study provided a unique classification of AF patients undergoing catheter ablation by cluster analysis. Age, chronic disease, sinus node dysfunction, heart failure and history of coronary artery revascularization contributed to the formation of the five clinically relevant subtypes. These subtypes showed differences in ablation success rates, highlighting the potential of cluster analysis in guiding individualized risk stratification and treatment decisions for AF patients.

Papillary muscle avulsion following balloon mitral valvotomy evaluated with three-dimensional echocardiography.

BACKGROUND: Percutaneous balloon mitral valvotomy is a common therapeutic approach for rheumatic mitral stenosis. Avulsion of the papillary muscle is a rare but serious complication of balloon mitral valvotomy. The papillary muscles are derived from the trabecular layer of the developing ventricular walls. When subjected to a force, avulsion of papillary muscle from the trabecular layer may occur. CASE PRESENTATION: In this case report, we describe a patient with rheumatic mitral stenosis, who experienced avulsion of the mitral papillary muscle from the left ventricular wall after undergoing balloon mitral valvotomy. Papillary muscle alvusion resulted in severe mitral regurgitation, which was finally treated by mitral valve replacement. CONCLUSION: We successfully diagnosed avulsion of the papillary muscle following balloon mitral valvotomy. Three-dimensional transthoracic echocardiography provides more information on mitral apparatus structure than two-dimensional transthoracic echocardiography.

Impact of concomitant tricuspid annuloplasty on right ventricular remodeling in patients with rheumatic mitral valve disease.

BACKGROUND: Studies on the management of functional tricuspid regurgitation (TR) during mitral valve operations have drawn inconsistent conclusions. This study was designed to compare the treatment strategy of concomitant tricuspid annuloplasty (TAP) against isolated mitral valve replacement (MVR) in rheumatic mitral valve disease patients, and to assess the effect of concomitant TAP on postoperative right ventricular (RV) remodeling and function. METHODS: One hundred-seventy patients with rheumatic mitral valve disease receiving MVR were categorized into TAP group (n = 124) and non-TAP group (n = 46). Clinical and echocardiographic data were collected preoperatively and at 1-year follow-up. Three-dimensional echocardiographic indices of RV geometry and function were analyzed. RESULTS: At baseline, concomitant TAP group had larger RV end-diastolic volume, more decreased RV ejection fraction and RV longitudinal strain than non-TAP group (all P <  0.001). At 1-year follow-up, TAP group had improved RV geometry and function. While adverse changes were observed in non-TAP group. In analysis of variance, the above indices demonstrated significant interaction with different treatment group (all P <  0.001). In multivariate regression analysis, independent of age and Maze procedure, concomitant TAP was associated with postoperative RV volume reduction (P <  0.001), improvement of RV ejection fraction (P <  0.001), and relieved postoperative functional TR severity (P = 0.025). CONCLUSIONS: Our results suggest that concomitant TAP could improve RV remodeling and function for rheumatic mitral valve disease patients, while those with mild preoperative functional TR who had isolated MVR might experience RV dilation and deterioration of RV function at follow-up. Concomitant surgery for functional TR could be considered for patients undergoing MVR with rheumatic mitral valve disease.

A dissecting aneurysm of the sinus of Valsalva involving the inter-ventricsular septum in a patient with syphilis and a quadricuspid aortic valve.

Aneurysms of the sinus of Valsalva are rare, with dissecting aneurysms of the sinus of Valsalva that extend into the inter-ventricular septum being even more rare. This report describes a young patient with syphilis and a quadricuspid aortic valve who experienced a spontaneously dissecting aneurysm of the sinus of Valsalva and the basal inter-ventricular septum.

Correlation of electroencephalogram background evolution with the degree of brain injury in neonates with hypoxic-ischemic encephalopathy. / æ–°ç”Ÿå„¿ç¼ºæ°§ç¼ºè¡€æ€§è„‘ç— è„‘ç”µèƒŒæ™¯æ¼”å˜ä¸Žè„‘æŸä¼¤ç¨‹åº¦çš„ç›¸å ³æ€§ç ”ç©¶.

OBJECTIVES: To study the correlation of electroencephalogram (EEG) background evolution with the degree of brain injury in neonates with hypoxic-ischemic encephalopathy (HIE). METHODS: A retrospective analysis was performed for 56 neonates with HIE who underwent continuous video electroencephalogram (cVEEG) and brain magnetic resonance imaging (MRI) examinations. According to clinical symptoms, they were divided into a mild group with 3 neonates, a moderate group with 36 neonates, and a severe group with 17 neonates. EEG background grading and MRI score were determined for each group to analyze the correlation of EEG background evolution with the degree of brain injury. RESULTS: Compared with the moderate group, the severe group had significantly lower gestational age and Apgar score at 5 minutes after birth, a significantly higher resuscitation score, significantly lower base excess in umbilical cord blood or blood gas within 1 hour, a significantly higher proportion of neonates on mechanical ventilation, and a significantly higher incidence rate of short-term adverse outcomes (P<0.05). For the neonates in the mild and moderate groups, MRI mainly showed no brain injury (67%, 2/3) and watershed injury (67%, 16/24) respectively, and EEG showed mild abnormality in 62% (13/21) of the neonates on the 3rd day after birth. For the neonates in the severe group, MRI mainly showed basal ganglia/thalamus + brainstem injury (24%, 4/17) and whole brain injury (71%, 12/17), and EEG showed moderate or severe abnormalities on the 3rd day after birth. EEG background grading was correlated with clinical grading, MRI score, and short-term outcome on days 1, 2, 3 and 7-14 after birth (P<0.01). The highest correlation coefficient between EEG grading and MRI score was observed on the 3rd day after birth (rs=0.751, P<0.001), and the highest correlation coefficients between EEG grading and clinical grading (rs=0.592, P=0.002) and between EEG grading and short-term outcome (rs=0.737, P<0.001) were observed 7-14 days after birth. Among the neonates with severe abnormal EEG, the neonates without brain electrical activity had the highest MRI score, followed by those with status epileptics and persistent low voltage (P<0.05). CONCLUSIONS: There is a good correlation between EEG background grading and degree of brain injury in neonates with HIE, which can help to evaluate the degree and prognosis of brain injury in the early stage.

TRAF1 suppresses antifungal immunity through CXCL1-mediated neutrophil recruitment during Candida albicans intradermal infection.

BACKGROUND: Candida albicans is the most common opportunistic human fungal pathogen. The chemokine ligand CXCL1 plays a protective role in fungal infection through the recruitment of neutrophils. TRAF1 (tumor necrosis factor-associated factor 1) can be highly induced by proinflammatory stimuli such as LPS and TNF and has been implicated in septic shock. However, the role of TRAF1 in infection, especially fungal infection, remains elusive. Herein, we reveal that TRAF1 suppresses the antifungal immune response to Candida albicans intradermal infection through the regulation of CXCL1 induction and neutrophil recruitment. METHODS: A mouse model of C. albicans intradermal infection was established. The Traf1-/- mice and Traf1-/- immortalized human keratinocytes were generated. The p65 inhibitor triptolide, STAT1 inhibitor fludarabine, neutrophil-depletion antibody Ly6G, and neutralizing antibody for CXCL1 were utilized. The expression of proinflammatory cytokines and chemokines was assessed by real-time PCR and ELISA, and the activation of signaling molecules was analyzed by Western blotting. Hematoxylin and eosin staining and periodic acid Schiff staining were used for histology or fungal detection, respectively. The immunofluorescence and flow cytometry analyses were employed in the assessment of immune cell infiltration. Bone marrow transplantation and adoptive transfer experiments were conducted to establish a role for TRAF1 in the macrophage compartment in fungal skin infection. RESULTS: TRAF1-deficient mice demonstrated improved control of Candida albicans intradermal infection, and concomitant increase in neutrophil recruitment and reduction in fungal burden. The chemokine CXCL1 was upregulated in the TRAF1-deficient macrophages treated with heat-killed C. albicans. Mechanistically, TRAF1-deficient macrophages showed increased activation of transcription factor NFκB p65. The human CXCL8 was also highly induced in the TRAF1-deficient human keratinocytes upon TNF stimulation through decreasing the activation of transcription factor STAT1. TRAF1-deficient macrophages played a critical role in containing the C. albicans skin infection in vivo. CONCLUSION: TRAF1-deficient mice can better control fungal infection in the skin, a process attributable to the CXCL-neutrophil axis. Mechanistically, TRAF1 likely regulates CXCL1 expression in both macrophages and keratinocytes through the transcriptional factor NFκB and STAT1, respectively. Our finding offers new insight into the understanding of the immune regulatory mechanisms in host defense against C. albicans infection.

Left Atrial Appendage Parameters Assessed by Real-Time Three-Dimensional Transesophageal Echocardiography Predict Thromboembolic Risk in Patients With Nonvalvular Atrial Fibrillation.

OBJECTIVES: In nonvalvular atrial fibrillation (NVAF) patients, the effect of left atrial appendage (LAA) morphology, structure, and hemodynamic characteristics evaluated by real-time 3D transesophageal echocardiography (RT3D-TEE) on thromboembolic risk has not been elucidated. METHODS: A total of 444 NVAF patients who underwent clinically indicated RT3D-TEE were enrolled in the study. The orifice size, orifice area, depth, and volume measurements of the LAA were assessed using Philips QLAB 9.0. The LAA characteristics were compared among different CHA2 DS2 -VASc thromboembolic risk subgroups, as well as between the thromboembolic event and nonevent groups. RESULTS: The orifice size, orifice area, and end-diastolic volumes of the LAA were increased with an increasing CHA2 DS2 -VASc risk score in the NVAF patients, whereas the emptying rate was decreased. The NVAF patients with LAA thrombus exhibited a significantly increased end-diastolic volume (7.39 ± 3.47 versus 5.21 ± 2.59 mL, P = .003) and higher prevalence of the cauliflower shaped LAA (64.3% versus 25%, P = .004) compared with those without thrombus. Logistic regression indicated that the LAA end-diastolic volume (P = .002; odds ratio 1.556; 95% confidence interval 1.176-2.057) and cauliflower shape (P = .001; odds ratio, 10.177; 95% confidence interval, 2.458-42.140) were independent predictors of thromboembolic events in patients with NVAF following adjustment for the CHA2 DS2 -VASc score. CONCLUSIONS: The LAA end-diastolic volume and cauliflower phenotype predict thromboembolic events independent of the CHA2 DS2 -VASc score, and these data improve stroke prediction in NVAF patients.

[Assessment of Left Atrial Appendage Size and Morphology by Enhanced Cardiac Computed Tomography in Patients with Non-valvular Atrial Fibrillation].

OBJECTIVE: This study was designed to investigate left atrial appendage (LAA) size and morphology characteristics in patients with non-valvular atrial fibrillation (NVAF) by enhanced cardiac computed tomography (CT) scanning,and to evaluate the predictive value of these parameters for thromboembolic risk. METHODS: A total of 189 NVAF patients were prospectively enrolled during December 2012 to January 2014 in West China Hospital of Sichuan University. Fifty-two atrial tachycardia patients without organ dysfunction were also recruited as controls. All subjects were scheduled for radiofrequency ablation and underwent enhanced cardiac CT scan. The clinical characteristics,comorbid diseases,anticoagulant therapy,and AF chronicity were collected and CHA2DS2-VASc score was calculated for the assessment of thromboembolic risk. The NVAF cohort was also divided further into LAA thrombus present (n=13) and absent (n=176) subgroup according to LAA with thrombus or not. Differencesin size and morphology characteristics of the LAA were compared among controls and different CHA2DS2-VASc thromboembolic risk subgroups,and between LAA thrombus and non-thrombus group. In addition,logistic regression analysis was used to identify whether these parameters predict thrombus formation independent of the CHA2DS2-VASc score in NVAF patients. RESULTS: Compared with controls,NVAF patients had significantly bigger orifice size. Windsock and cactus-type LAA were main morphology in controls,while the distribution of the four kinds of LAA types were similar in NVAF patients. The orifice and volume of the LAA were increased with increasing CHA2DS2-VASc riskscore,and chicken wing-type LAA was the predominant prevalence in low-intermediate thromboembolic risk subgroup while cauliflower in high thromboembolic risk subgroup. Compared with non-thrombus patients,LAA-thrombussubgroup exhibited a significantly increased orifice and volume,and higher prevalenceof the cauliflower shaped LAA. Logistic regression showed that the LAA orifice and cauliflower shape were independent predictors for thrombus formation in patients with NVAF following adjustment for the CHA2DS2-VASc score. CONCLUSION: Cardiac images obtained with CTis feasible for the analysis of LAA size and morphology,and these parameters provide incremental value in assessing the LAA thrombus risk in patients with NVAF.

Assessment of Left Ventricular Dissipative Energy Loss by Vector Flow Mapping in Patients With End-Stage Renal Disease.

OBJECTIVES: Dissipative energy loss derived from vector flow mapping represents the viscous dissipation of turbulent blood flow. We aimed to determine the left ventricular (LV) energy loss in patients with end-stage renal disease (ESRD). METHODS: Patients with ESRD and a preserved LV ejection fraction, who consisted of a group receiving peritoneal dialysis, a group receiving hemodialysis, and a group receiving preparation for dialysis initiation, were examined by echocardiography; a group of healthy control participants were examined as well. Vector flow mapping analysis was then performed from the apical 4-chamber view to calculate the energy loss during diastole and systole in the left ventricle. RESULTS: Conventional transthoracic echocardiography and LV energy loss calculations were successfully performed in 63 cases and 50 controls. The patients with ESRD had significantly higher diastolic energy loss [median (interquartile range), 71.73 (46.08-106.75) versus 23.32 (17.17-29.26) mW/m; P < .001] and higher systolic energy loss [25.28 (19.03-33.93) versus 12.52 (9.35-16.47) mW/m; P < .001]. A significant difference in diastolic energy loss between the peritoneal dialysis and preparation groups was found [54.92 (39.28-89.94) versus 84.82 (62.58-171.4) mW/m; P = .04]. In patients with ESRD, the log-transformed diastolic energy loss had a significant association with the peak early diastolic transmitral flow velocity (P = .011), peak early diastolic transmitral flow velocity-to-peak early diastolic mitral annular flow velocity ratio (P = .001), LV mass index (P = .017), and heart rate (P = .003). CONCLUSIONS: Impaired blood flow efficiency was detected in patients with ESRD by using dissipative energy loss derived from vector flow mapping. The energy loss value could be a novel parameter for evaluating the ventricular workload of uremic hearts in terms of fluid mechanics.

[Aortic and Mitral Annuli Coupling and Its Association with Cardiac Function in Patients with Dilated Cardiomyopathy.]

OBJECTIVES: To compare the mitral and aortic annuli excursion (AE) and aortomitral angle (AMA) variations between patients with and without dilated cardiomyopathy (DCM) using speckle tracking echocardiography (STE),and determine the role of annuli dynamics and coupling behaviors in the left ventricular function. METHODS: Thirty-five patients with DCM and thirty-five age and sex matched healthy adults underwent transthoracic echocardiographic examinations.In the parasternal long-axis view,the AE and AMA variations were measured using Philips QLAB 9.0 software.In the apical four chamber view,the left ventricular ejection fraction (LVEF),longitudinal,circumferential,and radial strain were measured using Tomtec Arene 1.0 software. RESULTS: The DCM patients had significantly smaller AE and AMAmax-min,bigger AMAmax and AMAmin,and varied cardiac cycle compared with the healthy adults.The AMA of DCM patients increased to its maximal value earlier in diastole with little variation.AE was positively correlated with LVEF and multidirectional strain.AMAmax and AMAmin were negatively correlated with AE,LVEF and multidirectional strain (P<0.05).Significant correlations were also found between AMAmax-min and AE,LVEF and multidirectional strain (P<0.05). CONCLUSIONS: AE,AMA,LVEF and multidirectional strain can be quantified using STE.The coupling of mitral and aortic annuli in DCM patients is abnormal and correlated well with left ventricular systolic function.AE and AMA can be conveniently used for estimation of integral and regional cardiac function.

[Real-time Three-dimensional Dobutamine Stress Echocardiography for the Evaluation of Ischemic Mitral Regurgitation].

OBJECTIVE: To evaluate mitral regurgitation (MR) and left ventricular myocardial function in the patients with ischemic mitral regurgitation (IMR) by real-time three-dimensional dobutamine stress echocardiography (RT3D-DSE). METHODS: Seventy two consecutive in-patients with myocardial infarction and MR were enrolled in the study during 2006-2012. Each patient underwent RT3D-DSE examination before treatment. Three-dimensional (3D) heart full-volume data and 3D MR were obtained at baseline and each stress state. Quantitative parameters including: left ventricular end-diastolic/systolic volume (LVEDV/LVESV), left ventricular ejection fraction (LVEF) , left ventricular diastolic /systolic mass (LVMd/s). The time to the point of minimal regional systolic volume (Tmsv) was measured from the time volume curves of 17 segments, the standard deviation (Tmsv-SD) and maximal difference (Tmsv-Dif) of Tmsv were calculated. Excursion max (Emax), excursion SD (Esd), vena contarcta area (VCA) also were measured. RESULTS: 94.4% patients reached dobutamine (Dob) at 30 µg/(kg · min), 69.4% patients completed Dob 40 µg/(kg · min), only 38.9% patients completed Dob at 50 µg/(kg · min). At different stress state, VCA decreased significantly, and the decrement was up to the largest at 30 µg/(kg · min). 2D-LVEF, 3D-LVEF increased gradually, but decreased at 50 µg/(kg · min). 2D-LVESV and LVMd decreased, but increased at 50 µg/(kg · min). Tmsv-16/12/6 SD%, Tmsv-16/12/6 Dif% decreased, but increased at 50 µg/(kg · min). Eave and Esd increased, but decreased at 40-50 µg/(kg · min). Compared each with the baseline, LV remodeling parameters and VCA were statistically significant. CONCLUSION: IMR patients showed a biphasic response during RT3D-DSE. The decrease of VCA is associated with an improvement of LV remodeling and synchronization when Dob ≤ 40 µg/(kg · min).

[Assessment of left ventricular global systolic function using real-time three-dimensional speckle-tracking echocardiography in patients with hypothyroidism].

The present study aimed to investigate the impact of hypothyroidism on left ventricular systolic function using real-time three-dimensional speckle tracking imaging (RT3D-STI). Thirty hypothyroidism patients and forty healthy volunteers were recruited and received RT3DSTI measurement of global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and global area strain (GAS). A comparison of differences between the hypothyroidism patients and those in the healthy group was carried out and we obtained the results as followings. The values of GLS were (-18.93 +/- 3.89) vs. (-21.44 +/- 1.99), with P < 0.01, GRS were (51.13 +/- 11.95) vs. (56.10 +/- 5.76), with P < 0.0; and GAS were (-31.63 +/- 5.38) vs. (-34.40 +/- 2.32), with P < 0.01, i.e. they were lower in hypothyroidism group than those in the health group. While GCS were (-17.75 +/- 1.92) vs. 17.03 +/- 3.45), with P > 0.05, which were not significantly different between the two groups. In linear regres sion, GLS showed significant correlation with both TSH (b = -0.69, P < 0.01) and FT3 (b = 0.71, P < 0.01). Meanwhile, the GRS (b = 2.98, P < 0.05) and GAS (b = 3.11, P < 0.05) linearly correlated with FT3 level. In conclusion, the present study shows that the global longitudinal and radial moves of left ventricular are weaker in patients with hypothyroidism than healthy controls. And the impairment of left ventricular function would aggravate as FSH rises or FT3 declines.

Neutrophil-macrophage communication via extracellular vesicle transfer promotes itaconate accumulation and ameliorates cytokine storm syndrome.

Cytokine storm syndrome (CSS) is a life-threatening systemic inflammatory syndrome involving innate immune hyperactivity triggered by various therapies, infections, and autoimmune conditions. However, the potential interplay between innate immune cells is not fully understood. Here, using poly I:C and lipopolysaccharide (LPS)-induced cytokine storm models, a protective role of neutrophils through the modulation of macrophage activation was identified in a CSS model. Intravital imaging revealed neutrophil-derived extracellular vesicles (NDEVs) in the liver and spleen, which were captured by macrophages. NDEVs suppressed proinflammatory cytokine production by macrophages when cocultured in vitro or infused into CSS models. Metabolic profiling of macrophages treated with NDEV revealed elevated levels of the anti-inflammatory metabolite, itaconate, which is produced from cis-aconitate in the Krebs cycle by cis-aconitate decarboxylase (Acod1, encoded by Irg1). Irg1 in macrophages, but not in neutrophils, was critical for the NDEV-mediated anti-inflammatory effects. Mechanistically, NDEVs delivered miR-27a-3p, which suppressed the expression of Suclg1, the gene encoding the enzyme that metabolizes itaconate, thereby resulting in the accumulation of itaconate in macrophages. These findings demonstrated that neutrophil-to-macrophage communication mediated by extracellular vesicles is critical for promoting the anti-inflammatory reprogramming of macrophages in CSS and may have potential implications for the treatment of this fatal condition.

Stiffness sensing via Piezo1 enhances macrophage efferocytosis and promotes the resolution of liver fibrosis.

Tissue stiffening is a predominant feature of fibrotic disorders, but the response of macrophages to changes in tissue stiffness and cellular context in fibrotic diseases remains unclear. Here, we found that the mechanosensitive ion channel Piezo1 was up-regulated in hepatic fibrosis. Macrophages lacking Piezo1 showed sustained inflammation and impaired spontaneous resolution of early liver fibrosis. Further analysis revealed an impairment of clearance of apoptotic cells by macrophages in the fibrotic liver. Macrophages showed enhanced efferocytosis when cultured on rigid substrates but not soft ones, suggesting stiffness-dependent efferocytosis of macrophages required Piezo1 activation. Besides, Piezo1 was involved in the efficient acidification of the engulfed cargo in the phagolysosomes and affected the subsequent expression of anti-inflammation genes after efferocytosis. Pharmacological activation of Piezo1 increased the efferocytosis capacity of macrophages and accelerated the resolution of inflammation and fibrosis. Our study supports the antifibrotic role of Piezo1-mediated mechanical sensation in liver fibrosis, suggesting that targeting PIEZO1 to enhance macrophage efferocytosis could induce fibrosis regression.

PRL2 regulates neutrophil extracellular trap formation which contributes to severe malaria and acute lung injury.

Excessive host immune responses contribute to severe malaria with high mortality. Here, we show that PRL2 in innate immune cells is highly related to experimental malaria disease progression, especially the development of murine severe malaria. In the absence of PRL2 in myeloid cells, Plasmodium berghei infection results in augmented lung injury, leading to significantly increased mortality. Intravital imaging revealed greater neutrophilic inflammation and NET formation in the lungs of PRL2 myeloid conditional knockout mice. Depletion of neutrophils prior to the onset of severe disease protected mice from NETs associated lung injury, and eliminated the difference between WT and PRL2 CKO mice. PRL2 regulates neutrophil activation and NET accumulation via the Rac-ROS pathway, thus contributing to NETs associated ALI. Hydroxychloroquine, an inhibitor of PRL2 degradation alleviates NETs associated tissue damage in vivo. Our findings suggest that PRL2 serves as an indicator of progression to severe malaria and ALI. In addition, our study indicated the importance of PRL2 in NET formation and tissue injury. It might open a promising path for adjunctive treatment of NET-associated disease.

[Value of three-dimensional speckle-tracking echocardiography and the novel area strain in detecting wall motion abnormalities of coronary artery diseases].

OBJECTIVE: To investigate the value of three-dimensional speckle tracking echocardiography (3DSTE) and the novel areas train (AS) in detecting wall motion abnormalities caused by coronary artery diseases. METHODS: Conventional and 3D echocardiography was done on forty-six patients suspected with coronary heart diseases, immediately before they received cardiac catheterization. Segmental wall-motion score (WMS) and WMS index (WMSI) were assessed on conventional two-dimensional (2D) images, and strain-derived parameters were analyzed by speckle tracking technique based on 3D images. The accuracy of echocardiographic parameters to assess the regional myocardial ischemia was tested against coronary angiography results using ROC curve analysis and linear regression. RESULTS: Compared with controls, patients with severe coronary stenosis (> or = ;70% coronary stenosis) had lower left ventricular ejection fraction, higher WMSI and lower global strains. ROC curve analysis demonstrated that segmental WMS had relatively poor sensitivity for regional myocardial ischemia and infarction. The segmental strains measured using 3DSTE provided accurate assessment of the regional wall motion abnormalities. The segmental area strain > -25% yielded the best sensitivity and specificity for detecting the ischemic and infracted segments among all four strain parameters. CONCLUSION: 3DSTE provides a swift and accurate assessment of regional myocardial motion. The novel area strain derived by 3DSTE is an accurate and reproducible index for regional wall motion abnormality.

A novel reporter mouse line for studying alveolar macrophages.

Alveolar macrophages (AMs) are self-maintained immune cells that play vital roles in lung homeostasis and immunity. Although reporter mice and culture systems have been established for studying macrophages, an accurate and specific reporter line for alveolar macrophage study is still not available. Here we reported a novel Rspo1-tdTomato gene reporter mouse line that could specifically label mouse AMs in a cell-intrinsic manner. Using this reporter system, we visualized the dynamics of alveolar macrophages intravitally under steady state and characterized the alveolar macrophage differentiation under in vitro condition. By performing ATAC-seq, we found that insertion of the tdTomato cassette in the Rspo1 locus increased the accessibility of a PPARE motif within the Rspo1 locus and revealed a potential regulation by key transcription factor PPAR-γ for alveolar macrophage differentiation in vitro and in vivo. Consistently, perturbation of PPAR-γ by its agonist rosiglitazone or inhibitor GW9662 resulted in corresponding alteration of tdTomato expression in alveolar macrophages together with the transcription of PPAR-γ downstream target genes. Furthermore, global transcriptomic analyses of AMs from the wild type mice and the Rspo1-tdTomato mice showed comparable gene expression profiles, especially those AM-specific genes, confirming that the insertion of the tdTomato cassette in the Rspo1 locus does not impact the cell identity and biological function of AMs under normal condition. Taken together, our study provides an alternative tool for in vivo and in vitro labeling of alveolar macrophages with high specificity which could also be utilized as an indicator of PPAR-γ activity for future development of PPAR-γ specific targeting drugs.

Vinblastine resets tumor-associated macrophages toward M1 phenotype and promotes antitumor immune response.

BACKGROUND: Massive tumor-associated macrophage (TAM) infiltration is observed in many tumors, which usually display the immune-suppressive M2-like phenotype but can also be converted to an M1-like antitumor phenotype due to their high degree of plasticity. The macrophage polarization state is associated with changes in cell shape, macrophage morphology is associated with activation status. M1 macrophages appeared large and rounded, while M2 macrophages were stretched and elongated cells. Manipulating cell morphology has been shown to affect the polarization state of macrophages. The shape of the cell is largely dependent on cytoskeletal proteins, especially, microtubules. As a microtubule-targetting drug, vinblastine (VBL) has been used in chemotherapy. However, no study to date has explored the effect of VBL on TAM shape changes and its role in tumor immune response. METHOD: We used fluorescent staining of the cytoskeleton and quantitative analysis to reveal the morphological differences between M0, M1, M2, TAM and VBL-treated TAM. Flow cytometry was used to confirm the polarization states of these macrophages using a cell surface marker-based classification. In vivo antibody depletion experiments in tumor mouse models were performed to test whether macrophages and CD8+ T cell populations were required for the antitumor effect of VBL. VBL and anti-PD-1 combination therapy was then investigated in comparison with monotherapy. RNA-seq of TAM of treated and untreated with VBL was performed to explore the changes in pathway activities. siRNA mediated knockdown experiments were performed to verify the target pathway that was affected by VBL treatment. RESULTS: Here, we showed that VBL, an antineoplastic agent that destabilizes microtubule, drove macrophage polarization into the M1-like phenotype both in vitro and in tumor models. The antitumor effect of VBL was attenuated in the absence of macrophages or CD8+ T cells. Mechanistically, VBL induces the activation of NF-κB and Cyba-dependent reactive oxygen species generation, thus polarizing TAMs to the M1 phenotype. In parallel, VBL promotes the nuclear translocation of transcription factor EB, inducing lysosome biogenesis and a dramatic increase in phagocytic activity in macrophages. CONCLUSIONS: This study explored whether manipulating cellular morphology affects macrophage polarization and consequently induces an antitumor response. Our data reveal a previously unrecognized antitumor mechanism of VBL and suggest a drug repurposing strategy combining VBL with immune checkpoint inhibitors to improve malignant tumor immunotherapy.

Assessment of mitral valve geometry in nonvalvular atrial fibrillation patients with or without ventricular dysfunction: insights from high volume rate three-dimensional transesophageal echocardiography.

Meticulous understanding of the mechanisms underpinning mitral regurgitation in atrial fibrillation (AF) patients is crucial to optimize therapeutic strategies. The morphologic characteristics of mitral valves in atrial functional mitral regurgitation (FMR) patients with and without left ventricular (LV) dysfunction were evaluated by high volume rate (HVR) three-dimensional transesophageal echocardiography (3D-TEE). In our study, 68 of 265 AF patients who underwent 3D-TEE were selected, including 36 patients with AF, FMR, and preserved LV function (AFMR group) and 32 patients with AF, FMR, and LV dysfunction (VFMR group). In addition, 36 fever patients without heart disease were included in the control group. Group comparisons were performed by one-way analysis of variance for continuous variables. The left atrium (LA) was enlarged in the AFMR and VFMR groups compared with the control group. The mitral annulus (MA) in the AFMR group was enlarged and flattened compared with the control group and was smaller than in the VFMR group. The annulus area fraction was significantly diminished in the AFMR and VFMR groups, indicative of reduced MA contractility. The posterior mitral leaflet (PML) angle was smallest in the AFMR group and largest in the control group, whereas the distal anterior mitral leaflet angle did not significantly differ among the three groups. LA remodeling causes expansion of the MA and reduced MA contractility, disruption of the annular saddle shape, and atriogenic PML tethering. Comparison of atrial FMR patients with and without LV dysfunction indicates that atriogenic PML tethering is an important factor that aggravates FMR. HVR 3D-TEE improves the 3D temporal resolution greatly.

Short-term associations of PM2.5 and PM2.5 constituents with immune biomarkers: A panel study in people living with HIV/AIDS.

Studies on associations of fine particulate matter (PM2.5) with immunity in people living with HIV/AIDS (PLWHA) were absent. We aimed to explore whether changes of immune biomarkers were associated with short-term exposure to PM2.5 in PLWHA. Based on a panel study in Wuhan, we selected 163 PLWHA as participants with up to 4 repeated visits from March 2020 to January 2021. Immune biomarkers, including CD4+T cell count, CD8+T cell count, HIV viral load (VL) and CD4+T/CD8+T ratio were tested for all participants at each visit. Residential exposures of PM2.5 and PM2.5 constituents for each participant were assessed using spatial-temporal models. Linear mixed-effect models and general linear mixed models were applied to evaluate the associations between PM2.5 and immune biomarkers. To estimate the combined effect of PM2.5 constituents, weighted quantile sum regression and Bayesian kernel machine regression were employed. Each 10 µg/m3 increase of 7-day average PM2.5 concentrations was associated with an 8.75 cells/mm3 (95%CI: -15.55, -1.98) decrease in CD4+T cell count and a 92% (OR: 1.92, 95%CI: 1.43, 2.58) increased odds ratio of detectable HIV VL. However, the odds ratio of inverted CD4+T/CD8+T was only positively associated with PM2.5 concentrations at lag2 day (OR:1.27, 95%CI:1.02, 1.57). CD4+T may be a potential mediator between PM2.5 and detectable HIV VL with 3.83% mediated proportion. Besides, the combined effect of PM2.5 chemical constituents indicated that NO3- and SO42- were the main constituents in reducing CD4+T cell count and increasing odds ratio of detectable HIV VL. Our finding revealed that short-term exposure to PM2.5 was negatively associated with CD4+T cell count but positively related to the odds ratio of detectable HIV VL in PLWHA. This research may provide new evidence in associations between PM2.5 and immune biomarkers as well as improving prognosis of PLWHA.