Background: This study examines the predictive value of a novel systemic immuneinflammation index (SII, platelet × neutrophil/lymphocyte ratio) in coronary artery disease (CAD) patients. Methods: A total of 5602 CAD patients who had undergone a percutaneous coronary intervention (PCI) were enrolled. They were divided into two groups by baseline SII score (high SII vs low SII) to analyse the relationship between SII groups and the long-term outcome. The primary outcomes were major cardiovascular events (MACE) which includes nonfatal myocardial infarction (MI), nonfatal stroke and cardiac death. Secondary outcomes included a composite of MACE and hospitalization for congestive heart failure. Results: An optimal SII cut-off point of 694.3 × 10 9 was identified for MACE in the CAD training cohort (n = 373) and then verified in the second larger CAD cohort (n = 5602). Univariate and multivariate analyses showed that a higher SII score (≥694.3) was independently associated with increased risk of developing cardiac death (HR: 2.02; 95% CI: 1.43-2.86), nonfatal MI (HR: 1.42; 95% CI: 1.09-1.85), nonfatal stroke (HR: 1.96; 95% CI: 1.28-2.99), MACE (HR: 1.65; 95% CI: 1.36-2.01) and total major events (HR: 1.53; 95% CI: 1.32-1.77). In addition, the SII significantly improved risk stratification of MI, cardiac death, heart failure, MACE and total major events than conventional risk factors in CAD patients by the significant increase in the C-index (P < .001) and reclassification risk categories by significant NRI (P < .05) and IDI (P < .05). Conclusions: SII had a better prediction of major cardiovascular events than traditional risk factors in CAD patients after coronary intervention. K E Y W O R D Scoronary artery disease, inflammation, percutaneous coronary intervention 2 of 11 | YANG et Al.

Heme oxygenase is a rate-limiting enzyme in heme degradation, leading to the generation of free iron, biliverdin, and carbon monoxide. Induction of heme oxygenase-1 is implicated in the antioxidant defense mechanism and can modulate vascular function. To test the association of microsatellite polymorphism in the promoter region of human HO-1 gene with the risk of coronary artery disease (CAD) in type 2 diabetic patients, we examined the allele frequencies of (GT) (n) repeats in HO-1 gene in 474 patients with CAD and in 322 controls. A transient-transfection assay with HO-1 promoter/luciferase fusion constructs carrying various lengths of (GT) (n) repeats was performed to explore the regulatory effect of (GT) (n) repeats on HO-1 gene expression in cultured rat aortic smooth muscle cells. Serum thiobarbituric acid-reactive substances (TBARs), a measure of lipid peroxidation, was significantly higher in subjects carrying the L/L genotype (> or =32 repeats). Among type 2 diabetic subjects, the frequencies of the L alleles and proportion of genotypes with L alleles were significantly higher in those with CAD than in those without CAD. The adjusted odds ratio for CAD in type 2 diabetic patients with L alleles was 4.7 (95% confidence interval, 1.9-12.0, P=0.001). Transfection experiments in aortic smooth muscle cells revealed that HO-1 promoter/luciferase fusion constructs containing longer (GT) (n) repeats exhibited lower transcriptional activity. These results imply that the length polymorphism in the HO-1 gene promoter modulate the transcription of the gene in vascular cells. Type 2 diabetics carrying longer (GT) (n) repeats might have higher oxidative stress and increased susceptibility to the development of CAD.

OBJECTIVE -Heme oxygenase (HO) leads to the generation of free iron, carbon monoxide, and bilirubin. A length polymorphism of GT repeats in the promoter of human HO-1 gene has been shown to modulate gene transcription. The aim of this study was to assess the association of the length of (GT) n repeats in the HO-1 gene promoter with serum bilirubin, markers of iron status, and the development of coronary artery disease (CAD).RESEARCH DESIGN AND METHODS -We screened the allelic frequencies of (GT) n repeats in the HO-1 gene promoter in 986 unrelated individuals who underwent coronary angiography. Serum bilirubin and markers of iron status were evaluated.RESULTS -The distribution of numbers of (GT) n repeats was divided into two subclasses: class S included shorter (Ͻ27) repeats, and class L included longer (Ն27) repeats. Among those with diabetes, subjects with the L/L genotype had significantly lower bilirubin levels than those with S/S and S/L genotypes (0.70 Ϯ 0.22 vs. 0.81 Ϯ 0.24 mg/dl, P ϭ 0.001) and higher serum ferritin values (4.76 Ϯ 0.72 vs. 4.28 Ϯ 1.05 g/l for log ferritin, P ϭ 0.001). Compared with those carrying the S allele, diabetic subjects with the L/L genotype had an almost threefold increase in CAD risk after controlling for conventional risk factors (odds ratio 2.81, [95% CI 1.22-6.47], P ϭ 0.015). With adjustment for both serum bilirubin and ferritin, the effect of HO-1 promoter polymorphism on susceptibility to CAD disappeared.CONCLUSIONS -Length polymorphism in the HO-1 gene promoter is correlated with susceptibility to CAD in diabetic patients, and this effect might be conveyed through its influence on serum bilirubin and ferritin.

No abstract

SummaryBackground and objectives Bilirubin is a protective factor with antioxidant and anti-inflammatory properties, but its association with clinical outcomes of hemodialysis patients is unknown. Bilirubin degradation is mainly determined by the activity of hepatic bilirubin uridine diphosphate-glucuronosyltransferase (UGT1A1), which is significantly influenced by a TA-repeat polymorphism in the gene's promoter, an allele designated UGT1A1*28. The study aimed to clarify the association between serum bilirubin and UGT1A1*28 polymorphism and their respective effect on outcomes of chronic hemodialysis patients. Design, setting, participants, & measurementsThe cohort study comprised 661 chronic hemodialysis patients who were prospectively followed for 12 years. The endpoints were cardiovascular events (CVEs) and allcause mortality.Results After adjustment for traditional and dialysis-related risk factors, individuals with bilirubin in the upper tertile had an adjusted hazard ratio of 0.32 for CVEs and 0.48 for all-cause mortality compared with those in the lower tertile. Individuals homozygous for UGT1A1*28 (genotype 7/7) had significantly higher bilirubin levels than those with 6/6 and 7/6 genotypes. In the same multivariable-adjusted model, individuals with 7/7 had approximately one tenth the risk for CVEs and one fourth the risk for all-cause mortality as compared with carriers of the 6 allele.Conclusions A graded, reverse association was noted between serum bilirubin and adverse outcomes among chronic hemodialysis patients. Moreover, the UGT1A1*28 polymorphism had strong effects on bilirubin levels and the 7/7 genotype might have an important effect on reducing CVEs and death.