Systematic Review and Meta-Analysis of Preventative Strategies for Acute Kidney Injury in Patients Undergoing Abdominal Aortic Aneurysm Repair.

BACKGOUND: To assess the effect of various preventative interventions for reducing the incidence of postoperative acute kidney injury (AKI) in patients undergoing elective abdominal aortic aneurysm (AAA) repair. METHODS: We included randomized controlled trials of 10 patients or more which tested a preventative intervention versus standard therapy or placebo in patients undergoing elective AAA repair using the open or endovascular approach. Studies including mixed patient populations such as those with aortic occlusive disease, thoracoabdominal aneurysms or ruptured aneurysms were ineligible for review. We searched Medline (1966-2019), EMBASE (1947-2019), CINAHL (1961-2019), Web of Science (1945-2019), Scopus (1966-2019), and The Cochrane Library (1996-2019) for trials available as published manuscripts in English. Study quality was assessed using the Cochrane Collaboration risk of bias tool. Where possible we pooled the results of similar interventions using random effects meta-analysis. RESULTS: We included 17 trials involving 1443 participants. Most trials were small, single-center studies, with varying definitions of AKI and a high or moderate risk of bias. The preventative strategies with possible protective effects were mannitol, a composite of antioxidant supplements, an open extraperitoneal approach, and human atrial natriuretic peptide (hANP). Curcumin, methylprednisolone, carbon dioxide contrast medium, hemodynamic monitoring and N-acetylcysteine were found to be ineffective. Six trials with a total of 355 participants reported on remote ischemic preconditioning (RIPC) and our meta-analysis showed no statistically significant difference between RIPC and standard treatment (OR 1.20, 95% CI 0.37, 3.89); although the results should be interpreted with caution due to considerable statistical heterogeneity (I2 = 70%). None of the interventions studied significantly reduced receipt of renal replacement therapy (RRT). CONCLUSIONS: Interventions that have shown some potential to reduce AKI after AAA repair include mannitol, a composite of antioxidant supplements, an open extraperitoneal approach and hANP. These conclusions are limited by the small size, high risk of bias and inconsistency of the included trials. Large, high quality, multi-center randomized trials will help determine which interventions are effective in reducing the incidence of postoperative AKI among patients undergoing elective AAA repair.

Molecular basis for activation and biased signaling at the thrombin-activated GPCR proteinase activated receptor-4 (PAR4).

Proteinase-activated receptor (PAR)-4 is a member of the proteolytically-activated PAR family of G-protein-coupled receptors (GPCR) that represents an important target in the development of anti-platelet therapeutics. PARs are activated by proteolytic cleavage of their receptor N terminus by enzymes such as thrombin, trypsin, and cathepsin-G. This reveals the receptor-activating motif, termed the tethered ligand that binds intramolecularly to the receptor and triggers signaling. However, PARs are also activated by exogenous application of synthetic peptides derived from the tethered-ligand sequence. To better understand the molecular basis for PAR4-dependent signaling, we examined PAR4-signaling responses to a peptide library derived from the canonical PAR4-agonist peptide, AYPGKF-NH2, and we monitored activation of the Gαq/11-coupled calcium-signaling pathway, ß-arrestin recruitment, and mitogen-activated protein kinase (MAPK) pathway activation. We identified peptides that are poor activators of PAR4-dependent calcium signaling but were fully competent in recruiting ß-arrestin-1 and -2. Peptides that were unable to stimulate PAR4-dependent calcium signaling could not trigger MAPK activation. Using in silico docking and site-directed mutagenesis, we identified Asp230 in the extracellular loop-2 as being critical for PAR4 activation by both agonist peptide and the tethered ligand. Probing the consequence of biased signaling on platelet activation, we found that a peptide that cannot activate calcium signaling fails to cause platelet aggregation, whereas a peptide that is able to stimulate calcium signaling and is more potent for ß-arrestin recruitment triggered greater levels of platelet aggregation compared with the canonical PAR4 agonist peptide. These findings uncover molecular determinants critical for agonist binding and biased signaling through PAR4.

Postoperative atrial fibrillation is not pulmonary vein dependent: results from a randomized trial.

BACKGROUND: Although often short-lived and self-limiting, postoperative atrial fibrillation (POAF) is a well-recognized postoperative complication of cardiac surgery and is associated with a 2-fold increase in cardiovascular mortality and morbidity. OBJECTIVE: Our aim was to determine whether intraoperative bilateral pulmonary vein radiofrequency ablation decreases the incidence of POAF in patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 175 patients undergoing CABG was prospectively randomized to undergo adjuvant bilateral radiofrequency pulmonary vein ablation in addition to CABG (group A; n = 89) or CABG alone (group B; n = 86). Intraoperative pulmonary vein isolation was confirmed by the inability to pace the heart via the pulmonary veins after ablation. All patients received postoperative ß-blocker. RESULTS: There was no difference in the incidence of POAF in the treatment group who underwent adjuvant pulmonary vein ablation (group A; 37.1%) compared with the control group who did not (group B; 36.1%) (P = .887). There were no differences in postoperative inotropic support, antiarrhythmic drug use, need for oral anticoagulation, and complication rates. The mean length of postoperative hospital stay was 8.2 ± 6.5 days in the ablation group and 6.7 ± 4.6 days in the control group (P < .001). CONCLUSION: Adjuvant pulmonary vein isolation does not decrease the incidence of POAF or its clinical impact but increases the mean length of stay in the hospital. The mechanism of POAF does not appear to depend on the pulmonary veins.