Lower Serum Indirect Bilirubin Levels are Inversely Related to Carotid Intima-Media Thickness Progression

Author(s): Xiaoxiao Tao , Jianwei Wu , Anxin Wang , Chenghua Xu , Zhimin Wang* , Xingquan Zhao* .

Journal Name: Current Neurovascular Research

Volume 16 , Issue 2 , 2019

Become EABM
Become Reviewer

Abstract:

Background: Bilirubin has been recognized as a potential endogenous inhibitor of atherosclerosis, being inversely associated with carotid intima-media thickness (CIMT). However, little information is available concerning the correlation between serum indirect bilirubin (IBIL), especially long-term IBIL level, and early atherosclerosis progression. This study was designed to evaluate the relationship between serum IBIL level and CIMT progression.

Methods: A total of 2205 participants were enrolled in this Asymptomatic Polyvascular Abnormalities Community study (APAC study). CIMT was measured at baseline and 2-year follow-up. The participants were divided into four groups based on their serum IBIL levels at baseline. Both baseline and average serum IBIL values during the 2-year follow up were used in the analysis. Multivariable logistic regression and linear regression were used to assess the associations between serum IBIL and CIMT progression.

Results: The results showed that 51.93% (1145/2205) of participants were diagnosed with CIMT progression during the 2-year follow-up. Baseline serum IBIL level was significantly associated with the incidence of CIMT progression after adjusting for other potential confounding factors. Compared with the first quartile, adjusted odds ratios (OR) of the second, third, and fourth quartiles of IBIL were 0.70 [95% confidence interval (CI), 0.55-0.90], 0.68 (95% CI, 0.52-0.87), and 0.63 (95% CI, 0.49-0.82) (P = 0.0006), respectively. Serum IBIL level during the follow-up was also associated with CIMT progression in the univariate analysis (P = 0.0022), although no longer significant after adjusting for potential confounders in the multiple linear regression.

Conclusion: The study demonstrated the inverse relationship between serum IBIL and CIMT progression. Lower serum IBIL level is an independent predictor of subclinical atherosclerosis.

Keywords: Atherosclerosis, bilirubin, carotid intima-media thickness (CIMT), serum, antioxidants, gilbert syndrome.

[1]
Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: A major physiologic cytoprotectant. Proc Natl Acad Sci USA 2002; 99: 16093-8.
[2]
Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043-6.
[3]
Kawamura K, Ishikawa K, Wada Y, et al. Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol 2005; 25: 155-60.
[4]
Kang SJ, Lee C, Kruzliak P. Effects of serum bilirubin on atherosclerotic processes. Ann Med 2014; 46: 138-47.
[5]
Bulmer AC, Blanchfield JT, Toth I, Fassett RG, Coombes JS. Improved resistance to serum oxidation in Gilbert’s syndrome: A mechanism for cardiovascular protection. Atherosclerosis 2008; 199: 390-6.
[6]
Bosma PJ, Chowdhury JR, Bakker C, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert’s syndrome. N Engl J Med 1995; 333: 1171-5.
[7]
Vitek L, Jirsa M, Brodanova M, et al. Gilbert syndrome and ischemic heart disease: A protective effect of elevated bilirubin levels. Atherosclerosis 2002; 160: 449-56.
[8]
Vitek L, Novotny L, Sperl M, Holaj R, Spacil J. The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis 2006; 21: 408-14.
[9]
Kimm H, Yun JE, Jo J, Jee SH. Low serum bilirubin level as an independent predictor of stroke incidence. Stroke 2009; 11: 3422-7.
[10]
Li RY, Cao ZG, Zhang JR, Li Y, Wang RT. Decreased serum bilirubin is associated with silent cerebral infarction. Arterioscler Thromb Vasc Biol 2014; 34: 946-51.
[11]
O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SJ. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med 1999; 340: 14-22.
[12]
Den Ruijter HM, Peters SA, Anderson TJ, et al. Common carotid intima-media thickness measurements in cardiovascular risk prediction: A meta-analysis. JAMA 2012; 308: 796-803.
[13]
Zhou Y, Li Y, Xu L, et al. Asymptomatic Polyvascular Abnormalities in Community (APAC) study in China: Objectives, design and baseline characteristics. PLoS One 2013; 8e84685
[14]
Tek VL, Novotn L, Perl M, Holaj R. Sp IlJ, The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovasc Dis 2006; 21: 408-14.
[15]
Novotny L, Vitek L. Inverse relationship between serum bilirubin and atherosclerosis in men: A meta-analysis of published studies. Exp Biol Med (Maywood) 2003; 228: 568-71.
[16]
Akboga MK, Canpolat U, Sahinarslan A, et al. Association of serum total bilirubin level with severity of coronary atherosclerosis is linked to systemic inflammation. Atherosclerosis 2015; 240: 110-4.
[17]
Kang SJ, Kim D, Park HE, et al. Elevated serum bilirubin levels are inversely associated with coronary artery atherosclerosis. Atherosclerosis 2013; 230: 242-8.
[18]
Breimer LH, Wannamethee G, Ebrahim S, Shaper AG. Serum bilirubin and risk of ischemic heart disease in middle-aged British men. Clin Chem 1995; 41: 1504-8.
[19]
Troughton JA, Woodside JV, Young IS, et al. Bilirubin and coronary heart disease risk in the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Eur J Cardiovasc Prev Rehabil 2007; 14: 79-84.
[20]
Kundur AR, Singh I, Bulmer AC. Bilirubin, platelet activation and heart disease: A missing link to cardiovascular protection in Gilbert’s syndrome? Atherosclerosis 2015; 239: 73-84.
[21]
Vitek L, Jirsa M, Brodanova M, et al. Gilbert syndrome and ischemic heart disease: A protective effect of elevated bilirubin levels. Atherosclerosis 2002; 160: 449-56.
[22]
Inoguchi T, Sasaki S, Kobayashi K, Takayanagi R, Yamada T. Relationship between Gilbert syndrome and prevalence of vascular complications in patients with diabetes. JAMA 2007; 298: 1398-400.
[23]
Boon A, Hawkins CL, Bisht K, et al. Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome. Free Radic Biol Med 2012; 52: 2120-7.
[24]
Tapan S, Karadurmus N, Dogru T, et al. Decreased small dense LDL levels in Gilbert’s syndrome. Clin Biochem 2011; 44: 300-3.
[25]
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: 859-62.
[26]
Vitek L, Jirsa M, Brodanova M, et al. Gilbert syndrome and ischemic heart disease: A protective effect of elevated bilirubin levels. Atherosclerosis 2002; 160: 449-56.
[27]
Perlstein TS, Pande RL, Beckman JA, Creager MA. Serum total bilirubin level and prevalent lower-extremity peripheral arterial disease: National Health and Nutrition Examination Survey (NHANES) 1999 to 2004. Arterioscler Thromb Vasc Biol 2008; 28: 166-72.
[28]
Lapenna D, Ciofani G, Pierdomenico SD, Giamberardino MA, Ucchino S, Davì G. Association of serum bilirubin with oxidant damage of human atherosclerotic plaques and the severity of atherosclerosis. Clin Exp Med 2018; 18: 119-24.
[29]
Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: A systematic review and meta-analysis. Circulation 2007; 115: 459-67.
[30]
Kawamoto R, Ninomiya D, Hasegawa Y, et al. Mildly elevated serum bilirubin levels are negatively associated with carotid atherosclerosis among elderly persons. PLoS One 2014; 9e114281
[31]
Hamur H, Duman H, Demirtas L, et al. Total bilirubin levels predict subclinical atherosclerosis in patients with prediabetes. Angiology 2016; 67: 909-15.
[32]
Dullaart RPF, Kappelle PJWH, de Vries R. Lower carotid intima media thickness is predicted by higher serum bilirubin in both non-diabetic and Type 2 diabetic subjects. Clin Chim Acta 2012; 414: 161-5.
[33]
Lai X, Fang Q, Yang L, et al. Direct, indirect and total bilirubin and risk of incident coronary heart disease in the Dongfeng-Tongji cohort. Ann Med 2018; 50: 16-25.
[34]
Boon AC, Hawkins CL, Bisht K, et al. Reduced circulating oxidized LDL is associated with hypocholesterolemia and enhanced thiol status in Gilbert syndrome. Free Radic Biol Med 2012; 52: 2120-7.
[35]
Bakrania B, Du Toit EF, Ashton KJ, et al. Hyperbilirubinemia modulates myocardial function, aortic ejection, and ischemic stress resistance in the Gunn rat. Am J Physiol Heart Circ Physiol 2014; 307: H1142-9.
[36]
Stocker R. Antioxidant activities of bile pigments. Antioxid Redox Signal 2004; 6: 841-9.
[37]
Bulmer AC, Verkade HJ, Wagner KH. Bilirubin and beyond: A review of lipid status in Gilbert’s syndrome and its relevance to cardiovascular disease protection. Prog Lipid Res 2013; 52: 193-205.
[38]
Keshavan P, Deem TL, Schwemberger SJ, et al. Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration. J Immunol 2005; 174: 3709-18.
[39]
Hwang HJ, Lee SW, Kim SH. Relationship between bilirubin and C-reactive protein. Clin Chem Lab Med 2011; 49: 1823-8.
[40]
Wallner M, Bulmer AC, Molzer C, et al. Haem catabolism: A novel modulator of inflammation in Gilbert’s syndrome. Eur J Clin Invest 2013; 43(9): 912-9.
[41]
Wallner M, Marculescu R, Doberer D, et al. Protection from age-related increase in lipid biomarkers and inflammation contributes to cardiovascular protection in Gilbert’s syndrome. Clin Sci (Lond) 2013; 125: 257-64.
[42]
Rodella L, Lamon BD, Rezzani R, et al. Carbon monoxide and biliverdin prevent endothelial cell sloughing in rats with type I diabetes. Free Radic Biol Med 2006; 40: 2198-05.
[43]
Mazzone GL, Rigato I, Ostrow JD, et al. Bilirubin inhibits the TNFalpha-related induction of three endothelial adhesion molecules. Biochem Biophys Res Commun 2009; 386: 338-44.
[44]
Kawamura K, Ishikawa K, Wada Y, et al. Bilirubin from heme oxygenase-1 attenuates vascular endothelial activation and dysfunction. Arterioscler Thromb Vasc Biol 2005; 25: 155-60.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Page: [148 - 155]
Pages: 8
DOI: 10.2174/1567202616666190412153735
Price: $58

Article Metrics

PDF: 17
HTML: 2