High Serum Bilirubin Level Is Inversely Associated With the Presence of Carotid Plaque
2001; Lippincott Williams & Wilkins; Volume: 32; Issue: 2 Linguagem: Inglês
10.1161/01.str.32.2.580-b
ISSN1524-4628
AutoresNobukazu Ishizaka, Yuko Ishizaka, Eiko Takahashi, Minoru Yamakado, Hideki Hashimoto,
Tópico(s)Hemoglobin structure and function
ResumoHomeStrokeVol. 32, No. 2High Serum Bilirubin Level Is Inversely Associated With the Presence of Carotid Plaque Free AccessOtherPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessOtherPDF/EPUBHigh Serum Bilirubin Level Is Inversely Associated With the Presence of Carotid Plaque Nobukazu Ishizaka Yuko Ishizaka, Eiko Takahashi and Minoru Yamakado Hideki Hashimoto Nobukazu IshizakaNobukazu Ishizaka Department of Cardiovascular Medicine University of Tokyo Graduate School of Medicine Tokyo, Japan Yuko IshizakaYuko Ishizaka Center for Multiphasic Health Testing and Services Mitsui Memorial Hospital Mitsui, Japan , Eiko TakahashiEiko Takahashi Center for Multiphasic Health Testing and Services Mitsui Memorial Hospital Mitsui, Japan and Minoru YamakadoMinoru Yamakado Center for Multiphasic Health Testing and Services Mitsui Memorial Hospital Mitsui, Japan Hideki HashimotoHideki Hashimoto Department of Hygiene and Public Health Teikyo University School of Medicine Teikyo, Japan Originally published1 Feb 2001https://doi.org/10.1161/01.STR.32.2.580-bStroke. 2001;32:580–583To the Editor:The antioxidant property of bilirubin, the end product of heme catabolism in mammals, was first demonstrated by Stocker et al.1 In vitro studies have demonstrated that bilirubin exerts an antioxidant effect2 in either free or albumin-bound form.3 Studies in animal models45 and in humans67 show that antioxidative agents act against formation of atheromatous lesions, which suggests that reactive oxygen species are involved in the pathogenesis of atherosclerosis. Antiatherogenic effects of bilirubin in vivo have not been well established; however, some previous reports have described the relationship between serum bilirubin levels and coronary artery disease. Schwertner et al8 have shown that a 50% decrease in total bilirubin level was associated with a 47% increase in the odds of being in the severe coronary artery category in asymptomatic US Air Force pilots and navigators, and Hopkins et al9 have reported that coronary artery disease was less marked (60% to 90%) when serum bilirubin was in the upper 2 control quintiles compared with the lowest quintile in subjects with early familial coronary artery disease.To assess the possible association between serum bilirubin level and lower risk of atherosclerotic disease in a larger population, we analyzed 1741 subjects between April 1994 and February 1997 who underwent general health screening tests and high-resolution B-mode ultrasonography (Sonolayer SSA270A, Toshiba) equipped with a 7.5-MHz transducer (PLF-703ST, Toshiba) at Multiphasic Health Testing and Services, Mitsui Memorial Hospital. Carotid arteries were examined bilaterally at the levels of the common carotid, bifurcation, and internal carotid arteries from transverse and longitudinal orientations by trained sonographers. Results of carotid ultrasound studies were interpreted by an observer who was blinded to the results of laboratory tests. Plaque was defined as focal thickening of the intimal-medial layer with an intimal-medial thickness (IMT) of ≥1.3 mm at the common or internal carotid arteries or the carotid bulb.10Of 1741 subjects enrolled in the present study, 330 subjects (19%) were found to have carotid plaque in either or both of the carotid arteries. The distributions of serum bilirubin concentration in the subjects with or without carotid plaque are shown in the Figure, panel A. An unpaired t test showed that the subjects with carotid plaque had significantly lower serum bilirubin level than those without carotid plaque (14.4±3.8 versus 15.4±5.13 μmol/L; P 50 years (7.8; 6.0 to 10.0), systolic blood pressure ≥140 mm Hg (2.1; 1.8 to 2.4), HDL cholesterol ≥1.03 mmol/L (0.65; 0.56 to 0.74), triglyceride >1.69 mmol/L (1.8; 1.6 to 2.0), HbA1c ≥5.9% (2.1; 1.8 to 2.5), total bilirubin ≥17.1 μmol/L (0.7; 0.6 to 0.8), uric acid ≥416 μmol/L (1.5; 1.3 to 1.7), alanine transaminase >40 U/L (1.9; 1.6 to 2.4), and alkaline phosphatase (1.4; 1.2 to 1.6).After adjustment for sex and age, odds ratios compared with the lowest quartile were calculated (Figure, panel B). A 32% and 41% reduction in risk was seen at the highest and the second highest quartiles, respectively.Then the multivariate logistic regression analysis was performed with the following variables: sex, age, status of cigarette smoking, hypertension, serum levels of total cholesterol, HDL cholesterol, triglyceride, HbA1c, total bilirubin, and uric acid. An increase of 17.1 μmol/L in serum bilirubin concentration was associated with an odds ratio of 0.37 (95% CI, 0.28 to 0.49). The odds ratio associated with a bilirubin of ≥17.1 μmol/L was 0.64 (95% CI, 0.56 to 0.75) when bilirubin was entered into the model as a continuous variable.In the present study we demonstrated that serum bilirubin level was inversely correlated with carotid plaque. Nieto et al11 have reported that the level of serum uric acid, but not serum bilirubin, was significantly higher in cases with atherosclerotic carotid artery lesions than in normal counterparts. Different findings between their study and ours may be explained by differences in positive criteria of carotid atherosclerosis (Nieto et al defined their cases by the top decile of mean IMT in a series of 1410 participants; in the present study, focal thickening of the intimal-medial layer with IMT of ≥1.3 mm was considered to be carotid plaque) or differences in race or age range.In summary, we showed an odds ratio of 0.37 for carotid plaque associated with an increase of 17.1 μmol/L (ie, 1.0 mg/dL) in serum bilirubin concentration. We do not know the mechanism linking serum bilirubin to a decreased risk of carotid plaque, although it may possibly be that bilirubin exerts an antiatherogenic effect through its antioxidant property. Whether lower serum bilirubin is a cause or a result of carotid plaque formation, and thus atheromatous disease, awaits further investigation.Download figureDownload PowerPoint Figure 1. A, Distribution of serum bilirubin concentrations in subjects with or without carotid plaque. B, Sex- and age-adjusted odds ratio for carotid plaque according to serum bilirubin levels. Subjects were divided into 4 subgroups according to their serum bilirubin levels. *P=0.048, †P=0.001 compared with lowest quartile of serum bilirubin level. References 1 Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science.1987; 235:1043–1046.CrossrefMedlineGoogle Scholar2 Wu TW, Fung KP, Wu J, Yang CC, Weisel RD. Antioxidation of human low density lipoprotein by unconjugated and conjugated bilirubins. Biochem Pharmacol.1996; 51:859–862.CrossrefMedlineGoogle Scholar3 Neuzil J, Stocker R. Free and albumin-bound bilirubin are efficient co-antioxidants for alpha-tocopherol, inhibiting plasma and low density lipoprotein lipid peroxidation. J Biol Chem.1994; 269:16712–16719.CrossrefMedlineGoogle Scholar4 Singh RB, Singh NK, Rastogi SS, Wander GS, Aslam M, Onouchi Z, Kummerow FA, Nangia S. Antioxidant effects of lovastatin and vitamin E on experimental atherosclerosis in rabbits. Cardiovasc Drugs Ther.1997; 11:575–580.CrossrefMedlineGoogle Scholar5 Crawford RS, Kirk EA, Rosenfeld ME, LeBoeuf RC, Chait A. Dietary antioxidants inhibit development of fatty streak lesions in the LDL receptor-deficient mouse. Arterioscler Thromb Vasc Biol.1998; 18:1506–1513.CrossrefMedlineGoogle Scholar6 Schreiner PJ. Lipoprotein(a) as a risk factor for preclinical atherosclerotic disease in a biracial cohort: the Atherosclerosis Risk in Communities (ARIC) Study. Chem Phys Lipids. 1994;67–68:405–410.Google Scholar7 Azen SP, Qian D, Mack WJ, Sevanian A, Selzer RH, Liu CR, Liu CH, Hodis HN. Effect of supplementary antioxidant vitamin intake on carotid arterial wall intima-media thickness in a controlled clinical trial of cholesterol lowering. Circulation.1996; 94:2369–2372.CrossrefMedlineGoogle Scholar8 Schwertner HA, Jackson WG, Tolan G. Association of low serum concentration of bilirubin with increased risk of coronary artery disease. Clin Chem.1994; 40:18–23.CrossrefMedlineGoogle Scholar9 Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR. Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Vasc Biol.1996; 16:250–255.CrossrefMedlineGoogle Scholar10 Yamakado M, Fukuda I, Kiyose H. Ultrasonographically assessed carotid intima-media thickness and risk for asymptomatic cerebral infarction. J Med Syst.1998; 22:15–18.CrossrefMedlineGoogle Scholar11 Nieto FJ, Iribarren C, Gross MD, Comstock GW, Cutler RG. Uric acid and serum antioxidant capacity: a reaction to atherosclerosis? Atherosclerosis.2000; 148:131–139.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails February 2001Vol 32, Issue 2Article InformationMetrics Download: 120 Copyright © 2001 by American Heart Associationhttps://doi.org/10.1161/01.STR.32.2.580-b Originally publishedFebruary 1, 2001 PDF download Advertisement
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