Genetic Variants in P-Selectin and C-Reactive Protein Influence Susceptibility to Cognitive Decline After Cardiac Surgery

ObjectivesWe hypothesized that candidate gene polymorphisms in biologic pathways regulating inflammation, cell matrix adhesion/interaction, coagulation-thrombosis, lipid metabolism, and vascular reactivity are associated with postoperative cognitive deficit (POCD).BackgroundCognitive decline is a common complication of coronary artery bypass graft (CABG) surgery and is associated with a reduced quality of life.MethodsIn a prospective cohort study of 513 patients (86% European American) undergoing CABG surgery with cardiopulmonary bypass, a panel of 37 single-nucleotide polymorphisms (SNPs) was genotyped by mass spectrometry. Association between these SNPs and cognitive deficit at 6 weeks after surgery was tested using multiple logistic regression accounting for age, level of education, baseline cognition, and population structure. Permutation analysis was used to account for multiple testing.ResultsWe found that minor alleles of the CRP1059G/C SNP (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.16 to 0.78; p = 0.013) and the SELP1087G/A SNP (OR 0.51, 95% CI 0.30 to 0.85; p = 0.011) were associated with a reduction in cognitive deficit in European Americans (n = 443). The absolute risk reduction in the observed incidence of POCD was 20.6% for carriers of the CRP1059C allele and 15.2% for carriers of the SELP1087A allele. Perioperative serum C-reactive protein (CRP) and degree of platelet activation were also significantly lower in patients with a copy of the minor alleles, providing biologic support for the observed allelic association.ConclusionsThe results suggest a contribution of P-selectin and CRP genes in modulating susceptibility to cognitive decline after cardiac surgery, with potential implications for identifying populations at risk who might benefit from targeted perioperative antiinflammatory strategies

Acadesine inhibits neutrophil CD11b up-regulation in vitro and during in vivo cardiopulmonary bypass

AbstractGranulocyte adhesion to ischemic tissue, mediated in large part by β2 integrin receptors, is important in the pathophysiology of reperfusion injury. Acadesine, a drug that modulates adenosine levels in ischemic tissue, has been shown to reduce reperfusion injury in animal models of ischemia. The purpose of this study was to measure changes in granulocyte CD11b/CD18 in an in vitro assay and in an in vivo trial of acadesine administered during cardiopulmonary bypass to determine whether this incubated with acadesine or control diluent, stimulated with N-formyl-methionyl-leucylphenylalanine, and granulocyte CD11b measured. Acadesine significantly ( p < 0.01) inhibited N-formyl-methionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation by a mean of 61%. In similar experiments, adenosine also inhibited N-formylmethionyl-leucyl-phenylalanine-induced granulocyte CD11b up-regulation ( p < 0.01). In vivo, 34 patients at our institution participating in a multicenter trial of acadesine during cardiopulmonary bypass were randomized to placebo, low-dose, or high-dose acadesine infusion perioperatively. Combining low-and high-dose treatment groups, There was significant ( p = 0.05) inhibition of granulocyte CD11b up-regulation in patients receiving acadesine; granulocyte CD11b expression in the acadesine group peaked at 2.8 times baseline versus 4.3 for placebo. By contrast, monocyte CD11b up-regulation (peaking after cardiopulmonary bypass at 3 times baseline) was not affected by acadesine. Acadesine and adenosine inhibit up-regulation of granulocyte cardiopulmonary bypass. This inhibition may contribute to the ability of these agents to decrease in vivo reperfusion injury. (J THORAC CARDIOVASC SURG 1995; 109: 448-56)

Platelet Pl A2 Polymorphism and Platelet Activation Are Associated with Increased Troponin I Release after Cardiopulmonary Bypass

Background: The Pl A2 polymorphism of platelet glycoprotein IIIa has been identified as a prothrombotic risk factor in a number of cardiovascular settings. The aim of this study was to determine whether the Pl A2 polymorphism of platelet glycoprotein IIIa and degree of platelet activation were associated with more severe myocardial injury as indicated by troponin I release following cardiopulmonary bypass. Methods: The Pl A genotype was determined in 66 patients undergoing elective coronary artery bypass grafting requiring cardiopulmonary bypass. Troponin I concentrations and the percentage of circulating, activated (CD62P؉) platelets were measured at predetermined intervals perioperatively. Results: Forty-six patients were Pl A1,A1 , and 20 were Pl A1,A2 or Pl A2,A2 . Patients with at least one Pl A2 allele had significantly greater postoperative troponin I concentrations than Pl A1 homozygotes (P ‫؍‬ 0.006, analysis of variance). Peak troponin I concentrations also correlated significantly with the increase in circulating, activated platelets (P ‫؍‬ 0.02, Spearman rank correlation). Conclusions: The Pl A2 allele of platelet glycoprotein IIIa is associated with higher troponin I concentrations following cardiopulmonary bypass surgery, suggesting that this platelet polymorphism contributes to perioperative myocardial injury