Remote ischemic preconditioning reduces myocardial and renal injury after elective abdominal aortic aneurysm repair: a randomized controlled trial.

BACKGROUND: Myocardial and renal injury commonly contribute to perioperative morbidity and mortality after abdominal aortic aneurysm repair. Remote ischemic preconditioning (RIPC) is a phenomenon whereby brief periods of ischemia followed by reperfusion in one organ provide systemic protection from prolonged ischemia. To investigate whether remote preconditioning reduces the incidence of myocardial and renal injury in patients undergoing elective open abdominal aortic aneurysm repair, we performed a randomized trial. METHOD AND RESULTS; Eighty-two patients were randomized to abdominal aortic aneurysm repair with RIPC or conventional abdominal aortic aneurysm repair (control). Two cycles of intermittent crossclamping of the common iliac artery with 10 minutes ischemia followed by 10 minutes reperfusion served as the RIPC stimulus. Myocardial injury was assessed by cardiac troponin I (>0.40 ng/mL), myocardial infarction by the American College of Cardiology/American Heart Association definition and renal injury by serum creatinine (>177 micromol/L) according to American Heart Association guidelines for risk stratification in major vascular surgery. The groups were well matched for baseline characteristics. RIPC reduced the incidence of myocardial injury by 27% (39% versus 12% [95% CI: 8.8% to 45%]; P=0.005), myocardial infarction by 22% (27% versus 5% [95% CI: 7.3% to 38%]; P=0.006), and renal impairment by 23% (30% versus 7%; [95% CI: 6.4 to 39]; P=0.009). Multivariable analysis revealed the protective effect of RIPC on myocardial injury (OR: 0.22, 95% CI: 0.07 to 0.67; P=0.008), myocardial infarction (OR: 0.18, 95% CI: 0.04 to 0.75; P=0.006) and renal impairment were independent of other covariables. CONCLUSIONS: In patients undergoing elective open abdominal aortic aneurysm repair, RIPC reduces the incidence of postoperative myocardial injury, myocardial infarction, and renal impairment

Feasibility and physiological relevance of designing highly potent aminopeptidase-sparing leukotriene A4 hydrolase inhibitors

Abstract Leukotriene A4 Hydrolase (LTA4H) is a bifunctional zinc metalloenzyme that comprises both epoxide hydrolase and aminopeptidase activity, exerted by two overlapping catalytic sites. The epoxide hydrolase function of the enzyme catalyzes the biosynthesis of the pro-inflammatory lipid mediator leukotriene (LT) B4. Recent literature suggests that the aminopeptidase function of LTA4H is responsible for degradation of the tripeptide Pro-Gly-Pro (PGP) for which neutrophil chemotactic activity has been postulated. It has been speculated that the design of epoxide hydrolase selective LTA4H inhibitors that spare the aminopeptidase pocket may therefore lead to more efficacious anti-inflammatory drugs. In this study, we conducted a high throughput screen (HTS) for LTA4H inhibitors and attempted to rationally design compounds that would spare the PGP degrading function. While we were able to identify compounds with preference for the epoxide hydrolase function, absolute selectivity was not achievable for highly potent compounds. In order to assess the relevance of designing such aminopeptidase-sparing LTA4H inhibitors, we studied the role of PGP in inducing inflammation in different settings in wild type and LTA4H deficient (LTA4H KO) animals but could not confirm its chemotactic potential.  Attempting to design highly potent epoxide hydrolase selective LTA4H inhibitors, therefore seems to be neither feasible nor relevant