Serum bilirubin and risk of ischemic heart disease in middle-aged British men

Abstract

The possibility that low concentrations of serum bilirubin may be associated with increased risk of ischemic heart disease has been examined in a prospective study of 7685 middle-aged British men. During 11.5 years there were 737 major ischemic heart disease (IHD) events. A U-shaped relationship was observed between serum bilirubin and risk of IHD. Low bilirubin was associated with several cardiovascular risk factors, in particular smoking, low concentrations of high-density lipoprotein cholesterol, low forced expiratory volume in 1 s, and low serum albumin. The U-shaped relationship persisted even after adjusting for several risk factors. Compared with men in the lowest fifth of the distribution (bilirubin < 7 mumol/L), those in the middle range (8-9 mumol/L) showed a 30% reduction in relative risk [RR = 0.68 (95% confidence intervals 0.51-0.89)] in IHD, whereas men in the top fifth (> 12 mumol/L) showed similar risk to the lowest fifth [RR = 0.99 (95% confidence intervals 0.73-1.34)], which persisted after exclusion of men with bilirubin > 17 mumol/L. The significance of this U-shaped relationship is unclear, but it could be interpreted as support for the role of endogenous antioxidants in the etiology of IHD.

Decreased oxidation susceptibility of plasma low density lipoproteins in patients with Gilbert's syndrome

“…Correction of this subgroup only to hyperbilirubinemic patients without elevated liver enzyme reveals that these subjects had surprisingly the lowest incidence rate of IHD among all the other groups examined. 19 This fact, although not noted by the authors, is consistent with other results. Low bilirubin concentrations may be associated with increases in oxidized lipids and lipoproteins and therefore with enhanced atherogenic plaque formation.…”

“…6 Bilirubin is an important bile pigment with prominent cytoprotective activity against oxidative stress because of its potent antioxidant properties. [9][10][11][12][13] Besides being an antioxidant, bilirubin also has anticomplement properties that protect against inflammation. 14 To explain plausible mechanisms of bilirubin action in preventing atherosclerosis, several mechanisms have been suggested to play a potential role in the atherogenic and cardioprotective effects of bilirubin.…”

“…12,15 Considering the known involvement of oxidized LDL in the development of atherosclerosis and the ability of bilirubin to serve as a potent lipid chain-breaking antioxidant under physiological conditions, it has been suggested that increased physiological concentrations of plasma bilirubin may reduce atherogenic risk. [16][17][18] In only one study, 19 a subset of hyperbilirubinemic subjects was examined and these patients were not protected from development of IHD. However, this subgroup was not well defined and involved also subjects with raised liver enzymes.…”

“…The effects of bilirubin on development of IHD have already been studied only under conditions of physiological bilirubin concentrations. [9][10][11] The oxidative status of LDL was monitored following the formation of conjugated dienes. In this study, we aimed to investigate the influence of physiologically acceptable amounts of bilirubin on the susceptibility of LDL to oxidation in GS.…”

Bilirubin Prevents Atherosclerotic Lesion Formation in Low‐Density Lipoprotein Receptor‐Deficient Mice by Inhibiting Endothelial VCAM‐1 and ICAM‐1 Signaling

“…1 Since this initial report, a number of epidemiological analyses have provided corroborating evidence that individuals with a higher serum bilirubin level exhibit a lower risk of cardiovascular events. [2][3][4][5] Notably, heme oxygenase (HO), the rate-limiting enzyme in bilirubin synthesis, has an inducible isoform (HO-1) that plays an important role in attenuating inflammation, 6 including processes that can lead to atherogenesis. HO-1 induction has been shown to suppress venular leukocyte adhesion, an effect that is abolished by HO inhibitors and reconstituted by bilirubin, 7,8 whereas knockdown of HO-1 accelerates plaque formation in apolipoprotein E (apoE)-deficient mice.…”