TAK1 mediates an activation signal from toll-like receptor(s) to nuclear factor-κB in lipopolysaccharide-stimulated macrophages

AbstractStimulation of monocytes/macrophages with lipopolysaccharide (LPS) results in activation of nuclear factor-κB (NF-κB), which plays crucial roles in regulating expression of many genes involved in the subsequent inflammatory responses. Here, we investigated roles of transforming growth factor-β activated kinase 1 (TGF-TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), in the LPS-induced signaling cascade. A kinase-negative mutant of TAK1 inhibited the LPS-induced NF-κB activation both in a macrophage-like cell line, RAW 264.7, and in human embryonic kidney 293 cells expressing toll-like receptor 2 or 4. Furthermore, we demonstrated that endogenous TAK1 is phosphorylated upon simulation of RAW 264.7 cells with LPS. These results indicate that TAK1 functions as a critical mediator in the LPS-induced signaling pathway

Decline in Left Ventricular Ejection Fraction during Follow-up in Patients with Severe Aortic Stenosis

Objectives: The aim of this study was to investigate the prognostic impact of the decline in left ventricular ejection fraction (LVEF) at 1-year follow-up in patients with severe aortic stenosis (AS) managed conservatively. Background: No previous study has explored the association between LVEF decline during follow-up and clinical outcomes in patients with severe AS. Methods: Among 3, 815 patients with severe AS enrolled in the multicenter CURRENT AS (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis) registry in Japan, 839 conservatively managed patients who underwent echocardiography at 1-year follow-up were analyzed. The primary outcome measure was a composite of AS-related deaths and hospitalization for heart failure. Results: There were 91 patients (10.8%) with >10% declines in LVEF and 748 patients (89.2%) without declines. Left ventricular dimensions and the prevalence of valve regurgitation and atrial fibrillation or flutter significantly increased in the group with declines in LVEF. The cumulative 3-year incidence of the primary outcome measure was significantly higher in the group with declines in LVEF than in the group with no decline (39.5% vs. 26.5%; p 10% declines in LVEF at 1 year after diagnosis had worse AS-related clinical outcomes than those without declines in LVEF under conservative management. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

Initial Surgical Versus Conservative Strategies in Patients With Asymptomatic Severe Aortic Stenosis

AbstractBackgroundCurrent guidelines generally recommend watchful waiting until symptoms emerge for aortic valve replacement (AVR) in asymptomatic patients with severe aortic stenosis (AS).ObjectivesThe study sought to compare the long-term outcomes of initial AVR versus conservative strategies following the diagnosis of asymptomatic severe AS.MethodsWe used data from a large multicenter registry enrolling 3,815 consecutive patients with severe AS (peak aortic jet velocity >4.0 m/s, or mean aortic pressure gradient >40 mm Hg, or aortic valve area <1.0 cm2) between January 2003 and December 2011. Among 1,808 asymptomatic patients, the initial AVR and conservative strategies were chosen in 291 patients, and 1,517 patients, respectively. Median follow-up was 1,361 days with 90% follow-up rate at 2 years. The propensity score–matched cohort of 582 patients (n = 291 in each group) was developed as the main analysis set for the current report.ResultsBaseline characteristics of the propensity score–matched cohort were largely comparable, except for the slightly younger age and the greater AS severity in the initial AVR group. In the conservative group, AVR was performed in 41% of patients during follow-up. The cumulative 5-year incidences of all-cause death and heart failure hospitalization were significantly lower in the initial AVR group than in the conservative group (15.4% vs. 26.4%, p = 0.009; 3.8% vs. 19.9%, p < 0.001, respectively).ConclusionsThe long-term outcome of asymptomatic patients with severe AS was dismal when managed conservatively in this real-world analysis and might be substantially improved by an initial AVR strategy. (Contemporary Outcomes After Surgery and Medical Treatment in Patients With Severe Aortic Stenosis Registry; UMIN000012140

A Risk Prediction Model in Asymptomatic Patients with Severe Aortic Stenosis under Conservative Management: CURRENT-AS risk score

Aims: Early aortic valve replacement (AVR) might be beneficial in selected high-risk asymptomatic patients with severe aortic stenosis (AS), considering their poor prognosis when managed conservatively. This study aimed to develop and validate a clinical scoring system to predict AS-related events within 1 year after diagnosis in asymptomatic severe AS patients. Methods and results: We analysed 1274 asymptomatic severe AS patients derived from a retrospective multicentre registry enrolling consecutive patients with severe AS in Japan (CURRENT AS registry), who were managed conservatively and completed 1-year follow-up without AVR. From a randomly assigned derivation set (N = 849), we developed CURRENT AS risk score for the AS-related event (a composite of AS-related death and heart failure hospitalization) within 1 year using a multivariable logistic regression model. The risk score comprised independent risk predictors including left ventricular ejection fraction <60%, haemoglobin ≤11.0 g/dL, chronic lung disease (2 points), diabetes mellitus, haemodialysis, and any concomitant valve disease (1 point). The predictive accuracy of the model was good with the area under the curve of 0.79 and 0.77 in the derivation and validation sets (N = 425). In the validation set, the 1-year incidence of AS-related events was much higher in patients with score ≥2 than in patients with score ≤1 (Score 0: 2.2%, Score 1: 1.9%, Score 2: 13.4%, Score 3: 14.3%, and Score ≥4: 22.7%, P < 0.001). Conclusion: The CURRENT-AS risk score integrating clinical and echocardiographic factors well-predicted the risk of AS-related events at 1 year in asymptomatic patients with severe AS and was validated internally