Role of cellular senescence and NOX4-mediated oxidative stress in systemic sclerosis pathogenesis.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by progressive fibrosis of skin and numerous internal organs and a severe fibroproliferative vasculopathy resulting frequently in severe disability and high mortality. Although the etiology of SSc is unknown and the detailed mechanisms responsible for the fibrotic process have not been fully elucidated, one important observation from a large US population study was the demonstration of a late onset of SSc with a peak incidence between 45 and 54 years of age in African-American females and between 65 and 74 years of age in white females. Although it is not appropriate to consider SSc as a disease of aging, the possibility that senescence changes in the cellular elements involved in its pathogenesis may play a role has not been thoroughly examined. The process of cellular senescence is extremely complex, and the mechanisms, molecular events, and signaling pathways involved have not been fully elucidated; however, there is strong evidence to support the concept that oxidative stress caused by the excessive generation of reactive oxygen species may be one important mechanism involved. On the other hand, numerous studies have implicated oxidative stress in SSc pathogenesis, thus, suggesting a plausible mechanism in which excessive oxidative stress induces cellular senescence and that the molecular events associated with this complex process play an important role in the fibrotic and fibroproliferative vasculopathy characteristic of SSc. Here, recent studies examining the role of cellular senescence and of oxidative stress in SSc pathogenesis will be reviewed

Bleeding in Patients Treated with Ticagrelor or Clopidogrel Before Coronary Artery Bypass Grafting.

BACKGROUND: We evaluated perioperative bleeding after CABG in patients preoperatively treated with ticagrelor or clopidogrel, stratified by discontinuation of these P2Y12 inhibitors. METHODS: All patients from the prospective, European multicenter registry on Coronary Artery Bypass Grafting (E-CABG) treated with ticagrelor or clopidogrel undergoing isolated primary CABG were eligible. Primary outcome measure was severe or massive bleeding defined according to the Universal Definition of Perioperative Bleeding (UDPB), stratified by P2Y12 inhibitor discontinuation. Secondary outcome measures included four additional definitions of major bleeding. Propensity score matching was performed to adjust for differences in pre- and perioperative covariates. RESULTS: 2311 patients were included, of whom 1293 (55.9%) received clopidogrel and 1018 (44.1%) ticagrelor preoperatively. Mean time between discontinuation and surgery was 4.5 ± 3.2 days for clopidogrel and 4.9 ± 3.0 days for ticagrelor. In the propensity score-matched cohort, ticagrelor-treated patients had a higher incidence of major bleeding according to UDPB when ticagrelor was discontinued 0-2 days compared with 3 days before surgery (16.0 vs. 2.7%, p=0.003). Clopidogrel-treated patients had a higher incidence of major bleeding according to UDPB when clopidogrel was discontinued 0-3 days compared with 4-5 days before surgery (15.6 vs. 8.3%, p=0.031). CONCLUSIONS: In patients receiving ticagrelor 2 days before surgery and in those receiving clopidogrel 3 days before surgery, there was an increased rate of severe bleeding. Postponing non-emergent CABG for at least 3 days after discontinuation of ticagrelor and 4 days after clopidogrel should be considered

Hospital volume and outcome after bilateral internal mammary artery grafting

none22Background: Bilateral internal mammary artery (BIMA) grafting largely is underutilized in patients undergoing coronary artery bypass grafting (CABG), partly because of the perceived increased complexity of the procedure. Aims: In this study, we evaluated whether BIMA grafting can safely be performed also in centers, where this revascularization strategy infrequently is adopted. Methods: Out of 6,783 patients from the prospective multicenter E-CABG study, who underwent isolated non-emergent CABG from January 2015 to December 2016, 2,457 underwent BIMA grafting and their outcome was evaluated in this analysis. Results: The mean number of BIMA grafting per center was 82 cases/year and hospitals were defined as high or low volume, according to this cutoff value. Six hospitals were considered as centers with a high volume of BIMA grafting (no. of procedures ranging from 120 to 267/year; overall: 2,156; prevalence: 62.2%) and nine hospitals as centers with a low volume of BIMA grafting (no. of procedures ranging from 2 to 39/year; overall: 301; prevalence: 9.1%). Multilevel mixed-effects regression analysis showed that the low- and high-volume cohorts had similar outcomes. Propensity score one-to-one matching analysis of 292 pairs showed that the low-volume cohort had a significantly shorter intensive care unit stay (2.2 ± 2.3 versus 2.9 ± 4.8 days, P = .020). The rates of in-hospital death (1.0% versus 0.3%, P = .625), deep sternal wound infection/mediastinitis (3.8% versus 3.1%, P = .824), and 1-year survival (98.1% versus 99.7%, P = .180) as well as other outcomes were similar between the high- and low-volume cohorts. Conclusions: BIMA grafting can be safely performed also in centers in which this revascularization strategy is infrequently performed.openPerrotti A.; Reichart D.; Gatti G.; Faggian G.; Onorati F.; de Feo M.; Chocron S.; Dalen M.; Santarpino G.; Rubino A.S.; Maselli D.; Gherli R.; Salsano A.; Nicolini F.; Zanobini M.; Bounader K.; Rosato S.; Tauriainen T.; Juvonen T.; Mariscalco G.; Ruggieri V.G.; Biancari F.Perrotti, A.; Reichart, D.; Gatti, G.; Faggian, G.; Onorati, F.; de Feo, M.; Chocron, S.; Dalen, M.; Santarpino, G.; Rubino, A. S.; Maselli, D.; Gherli, R.; Salsano, A.; Nicolini, F.; Zanobini, M.; Bounader, K.; Rosato, S.; Tauriainen, T.; Juvonen, T.; Mariscalco, G.; Ruggieri, V. G.; Biancari, F

Variation in preoperative antithrombotic strategy, severe bleeding, and use of blood products in coronary artery bypass grafting: Results from the multicentre E-CABG registry

Aims No data exists on inter-institutional differences in terms of adherence to international guidelines regarding the discontinuation of antithrombotics and rates of severe bleeding in coronary artery bypass grafting (CABG). Methods and results This is an analysis of 7118 patients from the prospective multicentre European CABG (E-CABG) registry who underwent isolated CABG in 15 European centres. Preoperative pause of P2Y12 receptor antagonists shorter than that suggested by the 2017 ESC guidelines (overall 11.6%) ranged from 0.7% to 24.8% between centres (adjusted P < 0.0001) and increased the rate of severe-massive bleeding [E-CABG bleeding grades 2-3, OR 1.66, 95% confidence interval (CI) 1.27-2.17; Universal Definition of Perioperative Bleeding (UDPB) bleeding grades 3-4, OR 1.50, 95% CI 1.16-1.93]. The incidence of resternotomy for bleeding (overall 2.6%) ranged from 0% to 6.9% (adjusted P < 0.0001), and surgical site bleeding (overall 59.6%) ranged from 0% to 84.6% (adjusted P = 0.003). The rate of the UDPB bleeding grades 3-4 (overall 8.4%) ranged from 3.7% to 22.3% (P < 0.0001), and of the E-CABG bleeding grades 2-3 (overall 6.5%) ranged from 0.4% to 16.4% between centres (P < 0.0001). Resternotomy for bleeding (adjusted OR 5.04, 95% CI 2.85-8.92), UDPB bleeding grades 3-4 (adjusted OR 6.61, 95% CI 4.42-9.88), and E-CABG bleeding grades 2-3 (adjusted OR 8.71, 95% CI 5.76-13.15) were associated with an increased risk of hospital/30-day mortality. Conclusions Adherence to the current guidelines on the early discontinuation of P2Y12 receptor antagonists is of utmost importance to reduce excessive bleeding and early mortality after CABG. Inter-institutional variation should be considered for a correct interpretation of the results in multicentre studies evaluating perioperative bleeding and use of blood products

Preoperative risk stratification of deep sternal wound infection after coronary surgery.

Objective: To develop a risk score for deep sternal wound infection (DSWI) after isolated coronary artery bypass grafting (CABG). Design: Multicenter, prospective study. Setting: Tertiary-care referral hospitals. Participants: The study included 7,352 patients from the European multicenter coronary artery bypass grafting (E-CABG) registry. Intervention: Isolated CABG. Methods: An additive risk score (the E-CABG DSWI score) was estimated from the derivation data set (66.7% of patients), and its performance was assessed in the validation data set (33.3% of patients). Results: DSWI occurred in 181 (2.5%) patients and increased 1-year mortality (adjusted hazard ratio, 4.275; 95% confidence interval [CI], 2.804–6.517). Female gender (odds ratio [OR], 1.804; 95% CI, 1.161–2.802), body mass index ≥30 kg/m2 (OR, 1.729; 95% CI, 1.166–2.562), glomerular filtration rate &lt;45 mL/min/1.73m2 (OR, 2.410; 95% CI, 1.413–4.111), diabetes (OR, 1.741; 95% CI, 1.178–2.573), pulmonary disease (OR, 1.935; 95% CI, 1.178–3.180), atrial fibrillation (OR, 1.854; 95% CI, 1.096–3.138), critical preoperative state (OR, 2.196; 95% CI, 1.209–3.891), and bilateral internal mammary artery grafting (OR, 2.088; 95% CI, 1.422–3.066) were predictors of DSWI (derivation data set). An additive risk score was calculated by assigning 1 point to each of these independent risk factors for DSWI. In the validation data set, the rate of DSWI increased along with the E-CABG DSWI scores (score of 0, 1.0%; score of 1, 1.8%; score of 2, 2.2%; score of 3, 6.9%; score ≥4: 12.1%; P &lt; .0001). Net reclassification improvement, integrated discrimination improvement, and decision curve analysis showed that the E-CABG DSWI score performed better than other risk scores. Conclusions: DSWI is associated with poor outcome after CABG, and its risk can be stratified using the E-CABG DSWI score