Serum Bilirubin in the Czech Population　- Relationship to the Risk of Myocardial Infarction in Males.

BACKGROUND: The potential antiatherogenic role of bilirubin is generally acknowledged, so the aim of this study was to determine serum bilirubin concentrations and the prevalence of Gilbert syndrome (GS) in the Czech general population with particular reference to its relationship to the risk of myocardial infarction (MI).Methods and Results:Biochemical markers were analyzed in 2 independent Czech post-MONICA studies (in total, n=3,311), and in 741 male MI patients. TheUGT1A1promoter gene variant (rs81753472) was analyzed in these MI patients and in the first control population cohort (n=717). Medians of serum bilirubin concentrations in the 2 Czech general population cohorts were 9.6 and 9.8 µmol/L (10.7 and 11.3 µmol/L in males, and 8.3 and 8.8 µmol/L in females; P<0.01). The prevalence of GS was 8.9%, twice as high in males compared with females (11.6 vs. 6.1%; P<0.01). TheUGT1A1(TA)7/7promoter repeats significantly influenced serum bilirubin concentrations in the controls, but not in the MI patients. Serum bilirubin concentrations were significantly lower in MI patients (7.7 vs. 10.7 µmol/L; P<0.01), with almost 5-fold lower prevalence of GS. CONCLUSIONS: Serum bilirubin concentrations and the prevalence of GS were determined in the Czech general population. Significantly lower serum bilirubin concentrations were observed in male MI patients.

Association between plasma bilirubin and mortality.

INTRODUCTION AND AIM: It has been proposed that plasma concentration of bilirubin, an endogenous antioxidant, is protective against diseases mediated by increased oxidative stress, including cardiovascular diseases (CVD) and cancer. To examine this hypothesis, we investigated the relationship between plasma bilirubin concentrations and bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations (associated with increased bilirubin concentrations) with total/CVD and cancer mortality. MATERIALS AND METHODS: A nested case-control study was conducted within the Polish arm of the HAPIEE cohort. At baseline in 2002-2005, participants were examined in detail. Mortality follow-up (median (IQR) between blood draw and death was 3.7 (2.1-5.1) years) was performed by linkage with regional and national death registers. Plasma biomarkers were analysed in all subjects who died from any cause (cases, n=447) and in a random subsample of survivors (controls, n=1423). RESULTS: There was a strong negative association between plasma bilirubin levels and total and cancer mortality, expressed more profoundly in men. The adjusted OR of deaths from all causes and cancer, comparing the highest vs. lowest plasma bilirubin categories were 0.61 (95% CI: 0.42-0.87) and 0.39 (0.24-0.65), respectively. There was no association of bilirubin with CVD mortality. The UGT1A1*28 allele, a genetic marker of raised bilirubin, was also negatively associated with total/cancer mortality, although the associations were not statistically significant. DISCUSSION: Both the observational and genetic associations support the negative relationship between bilirubin and total mortality; this association appears to be driven by cancer mortality, while that with CVD mortality is not evident.

Placental growth factor may predict increased left ventricular mass index in patients with mild to moderate chronic kidney disease--a prospective observational study.

BACKGROUND: Placental growth factor [PlGF) is a cardiovascular (CV) risk marker, which is related to left ventricle hypertrophy (LVH) in animal models. Currently there are no data available regarding the possible relationship of PlGF and the development of LVH or diastolic dysfunction in patients with chronic kidney disease (CKD) and the relationship of PlGF to other CV risk factors in CKD patients. The aim of our study was to determine the possible association of PlGF and several other CV risk markers to echocardiographic parameters in CKD population. METHODS: We prospectively examined selected laboratory (PlGF, fibroblast growth factor-23 -FGF23, vitamin D, parathyroid hormone, extracellular newly identified RAGE-binding protein - EN-RAGE, B-type natriuretic peptide - BNP) and echocardiographic parameters in 62 patients with CKD 2-4. Mean follow-up was 36 ±10 months. Laboratory and echocardiographic data were collected 2-3 times, at the shortest interval of 12 months apart. Multivariate regression analysis was used to detect independent correlations of variables. RESULTS: Increased left ventricular mass index (LVMI, g/m2.7) was found in 29% patients with CKD 2-4, left ventricular (LV) diastolic dysfunction was detected in 74.1% patients (impaired LV relaxation in 43.5% patients and pseudonormal pattern in 30.6% patients). After 36 ± 10 months increased LVMI was found in 37.1% patients with CKD 2-4, LV diastolic dysfunction was detected in 75.8% patients (impaired LV relaxation in 43.5% patients and pseudonormal pattern in 32.3% patients). Following independent correlations were found: LVMI was related to PlGF, cholesterol, BNP, systolic blood pressure and serum creatinine. EN-RAGE correlated positively with left atrial diameter and inversely with E/A ratio. During the follow-up we found a significant increase in LVMI and left atrial diameter, whereas a significant decrease in LVEF was noted. CONCLUSION: According to our data, PlGF is independently related to increased LV mass in CKD, whereas EN-RAGE is more likely related to diastolic dysfunction in this population.

Lipid-lowering effect of fluvastatin in relation to cytochrome P450 2C9 variant alleles frequently distributed in the Czech population.

BACKGROUND: CYP2C9*3 allele has been reported to correlate with increased plasma concentration of fluvastatin active form in healthy volunteers. We analyzed the correlation between the CYP2C9 genotype and cholesterol-lowering effect of fluvastatin in human hypercholesterolemic patients. MATERIAL/METHODS: The study was prospective, without any interventions to standard procedures of hypolipidemic treatment. CYP2C9 genotype was determined by PCR-RFLP assay in 87 patients on concomitant fluvastatin therapy, in 48 patients on monotherapy, and in a control group of 254 healthy volunteers of Czech nationality. Biochemical and clinical data were collected before the initiation of fluvastatin treatment and 12 weeks later. RESULTS: The frequency of CYP2C9 alleles did not differ significantly among groups of patients and volunteers. The most frequently observed allele was CYP2C9*2. Treatment with 80 mg of fluvastatin daily of 48 patients on monotherapy for 12 weeks resulted in mean low-density lipoprotein cholesterol (LDL-C) reduction by 25%, mean serum total cholesterol (TC) reduction by 21%, and mean triglyceride (TG) reduction by 28%. The CYP2C9*1/*3 genotype was associated with a decrease in LDL-C levels (by 40.0% for CYP2C9*1/*3, but only by 22.4% for CYP2C9*1/*1), and with the reduction of TC (by 28.6% in CYP2C9*1/*3 versus 20.2% in CYP2C9*1/*1). CONCLUSIONS: In hypercholesterolemic patients, LDL-C serum concentration was decreased more significantly in fluvastatin-treated subjects bearing the CYP2C9*1/*3 genotype compared to CYP2C9*1/*1 genotype. However, due to rare occurrence of some CYP genotypes, it was impossible to report a definitive positive genotype-fluvastatin effect association.

Serum Bilirubin and Markers of Oxidative Stress and Inflammation in a Healthy Population and in Patients with Various Forms of Atherosclerosis.

Oxidative stress and inflammation contribute significantly to atherogenesis. We and others have demonstrated that mildly elevated serum bilirubin levels protect against coronary and peripheral atherosclerosis, most likely due to the antioxidant and anti-inflammatory activities of bilirubin. The aim of the present study was to assess serum bilirubin and the markers of oxidative stress and inflammation in both healthy subjects and patients with various forms of atherosclerosis. The study was performed in patients with premature myocardial infarction (n = 129), chronic ischemic heart disease (n = 43), peripheral artery disease (PAD, n = 69), and healthy subjects (n = 225). In all subjects, standard serum biochemistry, UGT1A1 genotypes, total antioxidant status (TAS), and concentrations of various pro- and anti-inflammatory chemokines were determined. Compared to controls, all atherosclerotic groups had significantly lower serum bilirubin and TAS, while having much higher serum high-sensitivity C-reactive protein (hsCRP) and most of the analyzed proinflammatory cytokines (p < 0.05 for all comparisons). Surprisingly, the highest inflammation, and the lowest antioxidant status, together with the lowest serum bilirubin, was observed in PAD patients, and not in premature atherosclerosis. In conclusion, elevated serum bilirubin is positively correlated with TAS, and negatively related to inflammatory markers. Compared to healthy subjects, patients with atherosclerosis have a much higher degree of oxidative stress and inflammation.

Serum Bilirubin Levels and Promoter Variations in HMOX1 and UGT1A1 Genes in Patients with Fabry Disease.

The aim of our study was to assess the possible relationships among heme oxygenase (HMOX), bilirubin UDP-glucuronosyl transferase (UGT1A1) promoter gene variations, serum bilirubin levels, and Fabry disease (FD). The study included 56 patients with FD (M : F ratio = 0.65) and 185 healthy individuals. Complete standard laboratory and clinical work-up was performed on all subjects, together with the determination of total peroxyl radical-scavenging capacity. The (GT)n and (TA)n dinucleotide variations in the HMOX1 and UGT1A1 gene promoters, respectively, were determined by DNA fragment analysis. Compared to controls, patients with FD had substantially lower serum bilirubin levels (12.0 versus 8.85 µmol/L, p = 0.003) and also total antioxidant capacity (p < 0.05), which showed a close positive relationship with serum bilirubin levels (p = 0.067) and the use of enzyme replacement therapy (p = 0.036). There was no association between HMOX1 gene promoter polymorphism and manifestation of FD. However, the presence of the TA7 allele UGT1A1 gene promoter, responsible for higher systemic bilirubin levels, was associated with a twofold lower risk of manifestation of FD (OR = 0.51, 95% CI = 0.27-0.97, p = 0.038). Markedly lower serum bilirubin levels in FD patients seem to be due to bilirubin consumption during increased oxidative stress, although UGT1A1 promoter gene polymorphism may modify the manifestation of FD as well.

Gilbert syndrome and ischemic heart disease: a protective effect of elevated bilirubin levels.

BACKGROUND: Oxidation processes play an important role in atherogenesis. Bilirubin IXalpha is recognised as a potent antioxidant. In the present study, we assessed the role of elevated serum bilirubin levels in the prevention of ischemic heart disease (IHD). METHODS: The occurrence of IHD was determined in Gilbert syndrome (GS) patients above 40 years (n=50). The diagnosis was based on past medical history and ECG criteria. The occurrence was related to that of the comparable general population (n=2296). Serum biochemistry, including the total antioxidant status was evaluated in the GS subjects, IHD patients (n=38) and control subjects (n=38). RESULTS: The prevalence of IHD in GS subjects (aged 49.7+/-9.0 years) was 2% (0.05-10.7%, 95% confidence interval), compared to 12.1% in a general population (P<0.05). Bilirubin, total antioxidant capacity and high density lipoprotein (HDL) cholesterol were found to be significantly higher in GS subjects compared to control groups (P<0.05). According to linear discriminant analysis, hyperbilirubinemia rather than elevation of HDL cholesterol levels seemed to be more important in protection from IHD. CONCLUSIONS: In the present study, low prevalence of IHD in GS subjects was detected. It may be presumed that chronic hyperbilirubinemia prevent the development of IHD by increasing the serum antioxidant capacity.