Skip to main content
SpringerLink
Log in

Characterization of the effect of serum bilirubin concentrations on coronary endothelial function via measurement of high-sensitivity C-reactive protein and high-density lipoprotein cholesterol

  • Original Article
  • Published:
Heart and Vessels Aims and scope Submit manuscript

Abstract

Bilirubin can prevent oxidation of low-density lipoprotein (LDL) and may protect against atherosclerosis and coronary heart disease (CHD). The goal of this study was to characterize the relationship between bilirubin and CHD through measurements of bilirubin concentration, coronary endothelial function, and markers of oxidative stress, inflammation, and lipid/glucose metabolism. The study population consisted of 141 patients without CHD who underwent Doppler flow study. Vascular reactivity was examined by intracoronary administration of papaverine, acetylcholine (ACh) and nitroglycerin using a Doppler guide wire. Serum bilirubin, high-sensitivity C-reactive protein (hsCRP), malondialdehyde-modified LDL, LDL cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), fasting plasma glucose (FPG), and immunoreactive insulin were also measured. Homeostasis model assessment insulin resistance index and estimated glomerular filtration rate (eGFR) were calculated. Univariate analysis revealed that both percent change in coronary blood flow (CBF) and coronary artery diameter induced by ACh correlated positively with log-transformed bilirubin (r = 0.22, P < 0.05; r = 0.20, P < 0.05, respectively). Percent change in CBF in response to ACh correlated positively with eGFR (r = 0.24, P < 0.05) and correlated inversely with age, LDL-C, and log-transformed FPG (r = −0.24, P < 0.05; r = −0.17, P < 0.05, r = −0.22, P < 0.05, respectively). Multivariate analysis revealed that log-transformed bilirubin was the only independent predictor of percent change in CBF in response to ACh. Multivariate analysis revealed that log-transformed hsCRP and HDL-C were independent predictors of log-transformed bilirubin. These results suggest that a high level of bilirubin is associated with favorable coronary endothelial function, which may be mediated via the effect of bilirubin on inflammation and HDL-C.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN (1987) Bilirubin is an antioxidant of possible physiological importance. Science 235:1043–1046

    Article  PubMed  CAS  Google Scholar 

  2. Hopkins PN, Wu LL, Hunt SC, James BC, Vincent GM, Williams RR (1996) Higher serum bilirubin is associated with decreased risk for early familial coronary artery disease. Arterioscler Thromb Biol 16:250–255

    Article  CAS  Google Scholar 

  3. Erdogan D, Gullu H, Yildirim E, Tok D, Kirbas I, Ciftci O, Baycan ST, Muderrisoglu H (2006) Low serum bilirubin levels are independently and inversely related to impaired flow-mediated vasodilatation and increased carotid intima-media thickness in both men and women. Atherosclerosis 184:431–437

    Article  PubMed  CAS  Google Scholar 

  4. Schwertner HA, Jackson WG, Tolan G (1994) Association of low serum bilirubin with increased risk of coronary artery disease. Clin Chem 40:18–23

    PubMed  CAS  Google Scholar 

  5. Lin LY, Kuo HK, Hwang JJ, Lai LP, Chiang FT, Tseng CD, Lin JL (2009) Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents. Atherosclerosis 203:563–568

    Article  PubMed  CAS  Google Scholar 

  6. Torgerson JS, Lindroos AK, Sjostrom CD, Olsson R, Lissner L, Sjöström L (1997) Are elevated aminotransferases and decreased bilirubin additional characteristics of the metabolic syndrome? Obes Res 5:105–114

    Article  PubMed  CAS  Google Scholar 

  7. Ishizaka N, Ishizaka Y, Toda E, Nagai R, Yamamoto M (2005) Association between serum uric acid, metabolic syndrome, and carotid atherosclerosis in Japanese individuals. Arterioscler Thromb Vasc Biol 25:1038–1044

    Article  PubMed  CAS  Google Scholar 

  8. Vítek L, Jirsa M, Brodanová M, Kaláb M, Marecek Z, Danzig V, Novotny L, Kotal P (2002) Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels. Atherosclerosis 160:449–456

    Article  PubMed  Google Scholar 

  9. Davignon J, Ganz P (2004) Role of endothelial dysfunction in atherosclerosis. Circulation 109:III27–III32

    PubMed  Google Scholar 

  10. Nagashima H, Endo M (2011) Pitavastatin prevents post endothelial dysfunction via reduction of the serum triglyceride level in obese male subjects. Heart Vessels 26:428–434

    Article  PubMed  Google Scholar 

  11. Schachinger V, Britten MB, Zeiher AM (2000) Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation 101:1899–1906

    Article  PubMed  CAS  Google Scholar 

  12. Ridker PM (2003) Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 107:63

    Article  Google Scholar 

  13. Al Suwaidi J, Higano ST, Holmes DR Jr, Lennon R, Lerman A (2001) Obesity is independently associated with coronary endothelial dysfunction in patients with normal or mildly diseased coronary arteries. J Am Coll Cardiol 37:1523–1528

    Article  PubMed  CAS  Google Scholar 

  14. Doucette JW, Corl PD, Payne HM, Flynn AE, Goto M, Nassi M, Segal J (1992) Validation of a Doppler guidewire for intravascular measurement of coronary artery flow velocity. Circulation 85:1899–1911

    Article  PubMed  CAS  Google Scholar 

  15. Kataoka T, Hamasaki S, Ishida S, Saihara K, Okui H, Fukudome T, Shinsato T, Mizoguchi E, Ninomiya Y, Otsuji Y, Minagoe S, Tei C (2004) Contribution of increased minimal coronary resistance and attenuated vascular adaptive remodeling to myocardial ischemia in patients with systemic hypertension and ventricular hypertrophy. Am J Cardiol 94:484–487

    Article  PubMed  Google Scholar 

  16. WHO/IASO/IOTF (2000) The Asia-Pacific perspective: redefining obesity and its treatment. Health communications Australia Pty Ltd

  17. Kotani K, Maekawa M, Kanno T, Kondo A, Toda N, Manabe M (1994) Distribution of immunoreactive malondialdehyde-modified low-density lipoprotein in human serum. Biochim Biophys Acta 1215:121–125

    Article  PubMed  CAS  Google Scholar 

  18. Huggett AS, Nixon DA (1957) Use of glucose oxidase, peroxidase and O-dianisidine in determination of blood and urinary glucose. Lancet 273:368–370

    Article  PubMed  CAS  Google Scholar 

  19. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28:412–419

    Article  PubMed  CAS  Google Scholar 

  20. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, Yamagata K, Tomino Y, Yokoyama H, Hishida A (2009) Collaborators developing the Japanese equation for estimated GFR. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 53:982–992

    Article  PubMed  CAS  Google Scholar 

  21. Schwertner HA (1998) Association of smoking and low serum bilirubin antioxidant concentrations. Atherosclerosis 136:383–387

    Article  PubMed  CAS  Google Scholar 

  22. Madhavan M, Wattigney WA, Srinivasan SR, Berenson GS (1997) Serum bilirubin distribution and its relation to cardiovascular risk in children and young adults. Atherosclerosis 131:107–113

    Article  PubMed  CAS  Google Scholar 

  23. Bhuiyan AR, Srinivasan SR, Chen W, Sultana A, Berenson GS (2008) Association of serum bilirubin with pulsatile arterial function in asymptomatic young adults: the Bogalusa Heart Study. Metabolism 57:612–616

    Article  PubMed  CAS  Google Scholar 

  24. Fluiter K, Sattler W, De Beer MC, Connell PM, van der Westhuyzen DR, van Berkel TJ (1999) Scavenger receptor BI mediates the selective uptake of oxidized cholesterol esters by rat liver. J Biol Chem 274:8893–8899

    Article  PubMed  CAS  Google Scholar 

  25. Crisby M, Kublickiene K, Henareh L, Agewall S (2009) Circulating levels of autoantibodies to oxidized low-density lipoprotein and C-reactive protein levels correlate with endothelial function in resistance arteries in men with coronary heart disease. Heart Vessels 24:90–95

    Article  PubMed  Google Scholar 

  26. Tokac M, Ozen A, Aktan M, Altunkeser BB, Ozdemir K, Duzenli A, Gok H (2003) The role of inflammation markers in triggering acute coronary events. Heart Vessels 18:171–176

    Article  PubMed  Google Scholar 

  27. Ridker PM (2007) C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 49:2129–2138

    Article  PubMed  CAS  Google Scholar 

  28. Ohnaka K, Kono S, Inoguchi T, Yin G, Morita M, Adachi M, Kawate H, Takayanagi R (2010) Inverse associations of serum bilirubin with high sensitivity C-reactive protein, glycated hemoglobin, and prevalence of type 2 diabetes in middle-aged and elderly Japanese men and women. Diabetes Res Clin Pract 88:103–110

    Article  PubMed  CAS  Google Scholar 

  29. Tapan S, Dogru T, Tasci I, Ercin CN, Ozgurtas T, Erbil MK (2009) Soluble CD40 ligand and soluble P-selectin levels in Gilbert’s syndrome: a link to protection against atherosclerosis? Clin Biochem 42:791–795

    Article  PubMed  CAS  Google Scholar 

  30. Yang XF, Chen YZ, Su JL, Wang FY, Wang LX (2009) Relationship between serum bilirubin and carotid atherosclerosis in hypertensive patients. Intern Med 48:1595–1599

    Article  PubMed  Google Scholar 

  31. Gonzalez MA, Selwyn AP (2003) Endothelial function, inflammation, and prognosis in cardiovascular disease. Am J Med 115(Suppl 8A):99S–106S

    Google Scholar 

  32. Andersson C, Weeke P, Fosbøl EL, Brendorp B, Køber L, Coutinho W, Sharma AM, Van Gaal L, Finer N, James WP, Caterson ID, Rode RA, Torp-Pedersen C, SCOUT Executive Steering Committee; SCOUT investigators (2009) Acute effect of weight loss on levels of total bilirubin in obese, cardiovascular high-risk patients: an analysis from the lead-in period of the Sibutramine Cardiovascular Outcome trial. Metabolism 58:1109–1115

    Article  PubMed  CAS  Google Scholar 

  33. Melissas J, Malliaraki N, Papadakis JA, Taflampas P, Kampa M, Castanas E (2006) Plasma antioxidant capacity in morbidly obese patients before and after weight loss. Obes Surg 16:314–320

    Article  PubMed  Google Scholar 

  34. Tani S, Matsumoto M, Anazawa T, Kawamata H, Furuya S, Takahashi H, Iida K, Washio T, Kumabe N, Kobori M, Nagao K, Hirayama A (2011) Development of a model for prediction of coronary atherosclerotic regression: evaluation of high-density lipoprotein cholesterol level and peripheral blood monocyte count. Heart Vessels. doi:10.1007/s00380-011-0130-8

Download references

Author information

Authors and Affiliations

  1. Department of Cardiovascular, Respiratory and Metabolic Medicine, Graduate School of Medicine, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima, 890-8520, Japan

    Satoshi Yoshino, Shuichi Hamasaki, Sanemasa Ishida, Tetsuro Kataoka, Akiko Yoshikawa, Naoya Oketani, Keishi Saihara, Hitoshi Ichiki, So Kuwahata, Shoji Fujita, Takuro Takumi, Issei Yoshimoto, Mitsuhiro Nakazaki & Chuwa Tei

Authors
  1. Satoshi Yoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shuichi Hamasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sanemasa Ishida
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tetsuro Kataoka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Akiko Yoshikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Naoya Oketani
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Keishi Saihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hitoshi Ichiki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. So Kuwahata
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shoji Fujita
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Takuro Takumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Issei Yoshimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Mitsuhiro Nakazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Chuwa Tei
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shuichi Hamasaki.

Additional information

A portion of this study was reported at the 59th American College of Cardiology meeting, 2010.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yoshino, S., Hamasaki, S., Ishida, S. et al. Characterization of the effect of serum bilirubin concentrations on coronary endothelial function via measurement of high-sensitivity C-reactive protein and high-density lipoprotein cholesterol. Heart Vessels 28, 157–165 (2013). https://doi.org/10.1007/s00380-011-0228-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00380-011-0228-z

Keywords

Search

Navigation