Activated factor X stimulates atrial endothelial cells and tissues to promote remodeling responses through AT1R/NADPH oxidases/SGLT1/2.

AIMS: Atrial fibrillation (AF), the most common cardiac arrhythmia favoring ischemic stroke and heart failure involves left atrial remodeling, fibrosis and a complex interplay between cardiovascular risk factors. This study examined whether activated factor X (FXa) induces pro-remodeling and pro-fibrotic responses in atrial endothelial cells (AECs) and human atrial tissues and determined the underlying mechanisms. METHODS AND RESULTS: AECs were from porcine hearts and human right atrial appendages (RAA) from patients undergoing heart surgery. Protein expression levels were assessed by Western blot and immunofluorescence staining, mRNA levels by RT-qPCR, formation of reactive oxygen species (ROS) and NO using fluorescent probes, thrombin and angiotensin II generation by specific assays, fibrosis by Sirius red staining and senescence by senescence-associated beta-galactosidase (SA-ß-gal) activity.In AECs, FXa increased ROS formation, senescence (SA-ß-gal activity, p53, p21), angiotensin II generation and the expression of pro-inflammatory (VCAM-1, MCP-1), pro-thrombotic (tissue factor), pro-fibrotic (TGF-ß and collagen-1/3a) and pro-remodeling (MMP-2/9) markers whereas eNOS levels and NO formation were reduced. These effects were prevented by inhibitors of FXa but not thrombin, protease-activated receptors antagonists (PAR-1/2) and inhibitors of NADPH oxidases, ACE, AT1R, SGLT1/SGLT2. FXa also increased expression levels of ACE1, AT1R, SGLT1/2 proteins which was prevented by SGLT1/2 inhibitors. Human RAA showed tissue factor mRNA levels that correlated with markers of endothelial activation, pro-remodeling and pro-fibrotic responses and SGLT1/2 mRNA levels. They also showed protein expression levels of ACE1, AT1R, p22phox, SGLT1/2, and immunofluorescence signals of nitrotyrosine and SGLT1/2 colocalized with those of CD31. FXa increased oxidative stress levels which were prevented by inhibitors of the AT1R/NADPH oxidases/SGLT1/2 pathway. CONCLUSIONS: FXa promotes oxidative stress triggering premature endothelial senescence and dysfunction associated with pro-thrombotic, pro-remodeling and pro-fibrotic responses in AECs and in human RAA involving the AT1R/NADPH oxidases/SGLT1/2 pro-oxidant pathway. Targeting this pathway may be of interest to prevent atrial remodeling and the progression of atrial fibrillation substrate.

Predictors of Atrial Fibrillation After Coronary Artery Bypass Grafting: A Bayesian Analysis.

BACKGROUND: This study was conducted to identify preoperative predictors of postoperative atrial fibrillation (POAF) after isolated coronary artery bypass grafting (CABG) by using a Bayesian analysis that included information from prior studies. METHODS: We performed a prospective observational study from October 2008 to December 2013 of 1,481 patients who underwent isolated CABG with cardiopulmonary bypass and had no history of AF. Bayesian analysis was used to study the preoperative risks factors for POAF. RESULTS: The POAF incidence was 21%. Multivariate analysis identified the following independent predictors of POAF after CABG: high CHA2DS2-VASc (Congestive heart failure, Hypertension [blood pressure >140/90 mm Hg or treated hypertension on medication], Age ≥75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, vascular disease, Age 65 to 74 years, Sex category [female sex]) score (odds ratio [OR], 1.23; 95% credible interval [CI], 1.14 to 1.33 per 1-point increment, probability (Pr) [OR > 1] = 1), severe obesity with a body mass index of 35 kg/m2 or higher (OR, 1.28; 95% CI, 1.12 to 1.45; Pr [OR > 1] = 1), preoperative ß-blocker use (OR, 1.12; 95% CI, 1.06 to 1.20; Pr [OR > 1] = 1), preoperative antiplatelet therapy (OR, 1.75; 95% CI, 1.14 to 2.79, Pr [OR > 1] = 1), and renal insufficiency with a creatinine clearance of less than 60 mL/min (OR, 1.34; 95% CI, 1.03 to 1.74; Pr [OR > 1] = 1). CONCLUSIONS: This prospective Bayesian analysis identified five independent preoperative predictors of POAF after isolated CABG with cardiopulmonary bypass: CHA2DS2-VASc score, severe obesity, preoperative ß-blocker use, preoperative antiplatelet therapy, and renal failure. The main interest in the CHA2DS2-VASc score as a predictor of POAF is that it is a simple and widely used bedside tool. Patients with these independent predictors of POAF may constitute a target population to test preventive strategies, such as non-antiarrhythmic and antiarrhythmic drugs.

Trends in isolated coronary artery bypass grafting over the last decade.

OBJECTIVES: The purpose of this study was to assess the impact on hospital mortality and morbidity of extensive myocardial revascularization, using arterial grafts in patients undergoing isolated coronary artery bypass grafting (CABG). METHODS: Our prospective perioperative database was used to define two groups of patients who underwent isolated CABG with cardiopulmonary bypass, based on the years in which the operation was performed: Group A (2000-2003; 898 patients) and Group B (2009-2012; 1249 patients). The baseline and operative characteristics and outcomes were compared. RESULTS: Several significant changes in perioperative variables were observed. Group B included higher percentages of patients aged over 80 years (+58.1%), with diabetes (+32.0%) and with a history of percutaneous coronary intervention (+24.9%). The mean EuroSCORE II was significantly increased from 2.5 ± 4.4% in Group A to 3.2 ± 5.7% in Group B (P= 0.001). The mean number of distal anastomoses was significantly increased over time (total: 2.6 ± 0.8 vs 3.1 ± 1.0, P< 0.0001 and with arterial grafts: 1.6 ± 0.8 vs 2.6 ± 0.9, P< 0.0001). In-hospital mortality was low and did not significantly differ between Groups A and B (1.3 vs 2.4%; P= 0.08). Significant increases of new-onset atrial fibrillation (11.7 vs 21.9%, P= 0.017) and deep sternal infection (0.2 vs 1.1%, P= 0.017) were observed in Group B, compared with Group A. In multivariate analysis, extensive use of arterial grafts was not a risk factor of hospital mortality or sternal morbidity. CONCLUSIONS: Despite the increasing risk profiles of patients undergoing CABG, extensive myocardial revascularization using arterial grafts is associated with good early results.

The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass.

BACKGROUND: Obesity is suggested to reduce postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) but perioperative hemostasis variations have not been studied. Therefore, we investigated the effects of severe obesity (body mass index [BMI] ≥35kg/m(2)) on chest tube output (CTO) and hemostasis in patients undergoing cardiac surgery with CPB. MATERIALS AND METHODS: We prospectively investigated 2799 consecutive patients who underwent coronary and/or valve surgery using CPB between 2008 and 2012. 204 patients (7.3%) presented a severe obesity. RESULTS: In the severe obesity group, the 6-h and 24-h CTO were significantly reduced by -21.8% and -14.8% respectively (P<0.0001) compared with the control group. A significant reduction of the mean number of red blood cell units transfused at 24h was observed in the severe obesity groups (P=0.01). On admission to the intensive care unit, a significant increase of platelet count (+9.2%; P<0.0001), fibrinogen level (+12.2%; P<0.0001) and prothrombin time (+4.1%; P<0.01) and a significant decrease of the activated partial thromboplastin time (-4.2%; P<0.01) were observed in the severe obesity group compared with the control group. In multivariate analysis, severe obesity was significantly associated to a decreased risk of excessive bleeding (24-h CTO >90th percentile; Odds ratio: 0.37, 95% CI: 0.17 to 0.82). No significant differences were observed regarding postoperative thromboembolic events between the two groups. CONCLUSIONS: Severe obesity is associated with a prothrombotic postoperative state that leads to a reduction of postoperative blood loss in patients undergoing cardiac surgery with CPB.

Cardiopulmonary bypass is associated with altered vascular reactivity of isolated pulmonary artery in a porcine model: therapeutic potential of inhaled tezosentan.

OBJECTIVE: Whereas it is established that endothelin-1 elicits sustained deleterious effects on the cardiovascular system during cardiopulmonary bypass (CPB), presently it remains unknown whether the inhaled administration of the dual ETA and ETB antagonist tezosentan prevents the development of pulmonary endothelial dysfunction. DESIGN: A prospective, randomized laboratory investigation. SETTING: University research laboratory. PARTICIPANTS: Landrace swine. INTERVENTIONS: Three groups of animals underwent a 90-minute period of full bypass followed by a 60-minute period of reperfusion. Among treated groups, one received tezosentan through inhalation prior to CPB, whereas the other one received it intravenously at weaning from CPB; the third group remained untreated. Pulmonary vascular reactivity studies, realized on a total of 285 rings, were performed in all groups, including 1 sham. MEASUREMENTS AND MAIN RESULTS: The contractility of pulmonary arteries to prostaglandin F2α and to the thromboxane A2 mimetic U46619 was preserved in animals submitted to CPB. By contrast, there were significant increases both in the maximal contraction to endothelin-1 and in the plasma levels of the peptide 60 minutes after reperfusion. Tezosentan administered by inhalation or intravenously did not prevent the development of pulmonary CPB-associated endothelial dysfunction. However, while hemodynamic disturbances were improved with both routes, the inhaled administration had a beneficial effect on oxygen parameters over intravenous administration. CONCLUSIONS: Despite the blockade of the endothelin-1 pathway with tezosentan, the development of the pulmonary endothelial dysfunction associated with CPB still occurred. However, only the inhalation route had a significant impact on gas exchange during CPB.

Plasma fibrinogen level on admission to the intensive care unit is a powerful predictor of postoperative bleeding after cardiac surgery with cardiopulmonary bypass.

INTRODUCTION: Evidence regarding the behavior of fibrinogen levels and the relation between fibrinogen levels and postoperative bleeding is limited in cardiac surgery under cardiopulmonary bypass (CPB). To evaluate perioperative fibrinogen levels as a predictor of postoperative bleeding in patients undergoing cardiac surgery with CPB. MATERIALS AND METHODS: In this prospective, single-center, observational cohort study of 1956 patients following cardiac surgery with CPB, fibrinogen level was measured perioperatively. Excessive bleeding group was defined as patients with a 24-h chest tube output (CTO) exceeded the 90th percentile of distribution. RESULTS: The median 24-h CTO was 728.6±431.1ml. A total of 189 patients (9.7%) were identified as having excessive bleeding. At admission to the intensive care (Day 0), the fibrinogen levels were 2.5±0.8g/l and 2.1±0.8g/l in the control and excessive bleeding groups, respectively (P<0.0001). The fibrinogen level on Day 0 was significantly correlated with the 24-h CTO (rho=-0.237; P<0.0001). Multivariate analysis demonstrated that the fibrinogen level at Day 0 was the best perioperative standard laboratory test to predict excessive bleeding (P=0.0001; odds ratio, 0.5), whereas preoperative fibrinogen level was not a predictor. Using receiver operating characteristics curve analyses, the best Day 0 fibrinogen level cutoff to predict postoperative bleeding was 2.2g/l. CONCLUSIONS: In this large prospective study, the fibrinogen level upon admission to the intensive care unit after CPB predicted the risk of postoperative bleeding. Our data add to the concern regarding the fibrinogen level threshold that might require fibrinogen concentrate infusion to reduce postoperative blood loss.

Exclusive low-molecular-weight heparin as bridging anticoagulant after mechanical valve replacement.

BACKGROUND: Unfractionated heparin has been the standard anticoagulant used immediately after mechanical heart valve replacement (MHVR). The purpose of this study was to assess a postoperative anticoagulation protocol with low-molecular-weight heparin (LMWH) immediately after MHVR without the use of unfractionated heparin or anti-factor Xa monitoring. METHODS: We performed a prospective, single-center, observational study of 1,063 consecutive patients undergoing elective MHVR with postoperative LMWH anticoagulation treatment. The exclusion criteria were as follows: renal failure, intraaortic balloon counterpulsation, critical perioperative state, or a recent neurologic event. The postoperative anticoagulation protocol used subcutaneous enoxaparin as a bridging anticoagulant treatment beginning on the first postoperative day and continuing until vitamin K antagonist treatment was fully effective. Patients were followed for 6 weeks. The primary endpoints were the incidence of thromboembolic or major bleeding events. RESULTS: Eleven (1%) thromboembolic events occurred. Ten of these events were transient or permanent strokes. Major bleeding events occurred in 44 patients (4.1%), 7 of which were observed before the enoxaparin treatment period. At the time of discharge, 570 patients (53.6%) were no longer receiving LMWH treatment due to achieving the target international normalized ratio. The mean length of hospital stay was 8.5 ± 2.9 days. There were no deaths during the 6-week follow-up period. CONCLUSIONS: In our highly selected population, after MHVR, postoperative anticoagulation using LMWH is associated with a low rate of thromboembolic and major bleeding events. This large observational study demonstrates that the use of LMWH as an anticoagulant is effective and safe after MHVR.

Differential effects of inhaled and intravenous sildenafil in the prevention of the pulmonary endothelial dysfunction due to cardiopulmonary bypass.

The objective of the present study was to evaluate the effects of inhaled and intravenous sildenafil on the pulmonary endothelium-dependent relaxations, the hemodynamic profile and oxygenation after cardiopulmonary bypass. Five groups of Landrace swine were compared: 1) control; 2) cardiopulmonary bypass: 90 min of normothermic cardiopulmonary bypass; 3) precardiopulmonary bypass sildenafil nebulization; 4) postcardiopulmonary bypass sildenafil nebulization; 5) intravenous sildenafil administration prior to cardiopulmonary bypass. All groups underwent a 60-min period of pulmonary reperfusion after cardiopulmonary bypass. Vascular reactivity of second-degree pulmonary arteries was evaluated in response to acetylcholine and bradykinin. Cardiopulmonary bypass caused a significant decrease in endothelium-dependent relaxations to both agonists; this dysfunction was prevented by administration of sildenafil, both intravenous and inhaled (P < 0.05). Both administration routes prevented the significant increase in mean pulmonary arterial pressure with a safe hemodynamic profile. Moreover, intravenous and inhaled sildenafil after cardiopulmonary bypass also prevented the increase in alveoloarterial gradient (P < 0.05). Both sildenafil formulations of administration prevent the occurrence of pulmonary endothelial dysfunction. Depending on the administration moment and the route, the administration of sildenafil improves the hemodynamic profile and post-cardiopulmonary bypass oxygenation.

Use of the Purified Poloxamer 407 for Temporary Coronary Occlusion in Off-Pump CABG Does Not Cause Myocardial Injury.

OBJECTIVE: : The new poloxamer 407 (LeGoo), a thermoreversible gel, previously showed efficiency in temporarily occluding coronary arteries and preserving endothelial function. However, its long-term effect on the myocardium after dissolution in bloodstream is uncertain. METHODS: : Two groups of pigs (12 total) were compared after being submitted to a 10-minute coronary occlusion either with silastic loops (snare group) or with poloxamer 407 injection (P407 group). Reflow was procured by snare removal or P407 dissolution with topical cooling. Animals were kept alive for 3 days with creatine kinase-MB and troponin T (TnT) plasmatic measurement at 3 hours and 3 days after surgery, when they were killed for myocardial histopathologic study. RESULTS: : Each animal survived during the study. Baseline plasmatic levels of cardiac enzymes were similar between both groups. No variation in creatine kinase-MB level throughout the study was seen in either group. A significant rise in TnT from baseline was noted 3 hours after reperfusion in both groups, with a peak level significantly lower in the P407 group (P < 0.05). TnT plasmatic levels returned to baseline level in both groups on the day the animals were killed (3 days). Histopathologic examinations of the stained myocardial samples showed no evidence of myocardial infarction either in the snare group or in the P407 group. CONCLUSIONS: : Poloxamer 407 does not cause myocardial damage after elimination in the bloodstream. The safety of this hemostatic device is now established, and application for FDA approval for human clinical studies is under way.

Combined myocardial and mesenteric surgical revascularization.

Chronic mesenteric ischemia is a rare disorder that is frequently associated with coronary artery disease. Myocardial ischemia is a leading cause of morbidity and mortality after revascularization of the splanchnic arteries. The optimal treatment of concomitant chronic mesenteric ischemia and myocardial ischemia is unknown. We report a case of this condition in a 57-year-old man who required revascularization of both the left anterior descending coronary and superior mesenteric arteries with venous grafts anastomosed to the ascending aorta. The patient remains asymptomatic after a 3-year follow-up. This good result argues for one-stage combined myocardial and mesenteric revascularization in selected symptomatic patients.