Abstract
Low activities of glutathione peroxidase 1 (GPx1), a selenium-dependent antioxidant enzyme, have been associated with increased risk of cardiac events in patients with coronary artery disease. In addition, genetic variants in the gene encoding for GPx1 have been associated with lower enzyme activity and these genotypes have been linked to an increased risk of coronary artery disease. The aim of the research presented in this thesis was to investigate the effect of increasing GPx1 activity on risk of recurrent cardiac events and biomarkers of inflammation and oxidative stress in high-risk coronary artery disease patients. Furthermore, we wished to investigate the influence of genetic variants in the GPx1 gene on GPx activity. The low selenium environment in New Zealand makes this an ideal setting for investigating the relation between selenium, GPx1 and coronary artery disease.
The effect of increasing GPx1 activity on the risk of recurrent cardiac events was examined in a 2-year, randomised, placebo controlled clinical trial (RCT) involving 148 coronary artery disease patients recruited from the cardiac surgery waiting list. Participants received a daily supplement containing 100 μg of selenium, as L-selenomethionine (SeMet) or a placebo. Plasma selenium concentrations, whole blood glutathione peroxidase (GPx) activity, high sensitivity C-reactive protein (CRP), and biomarkers of oxidative stress were measured at baseline and 12 weeks after enrolment into the study. Whole blood GPx activities in the selenium group at week 12 were 14% (6 U/g Hb) higher than the placebo group (P<0.001), however, no differences in the 2-year rates of clinical cardiac events were noted (HR 0.99, 95%CI 0.50, 1.95). In addition, selenium supplementation did not alter any biomarker of oxidative stress or inflammation.
Percutaneous coronary intervention is associated with increased inflammation, which plays a crucial role in the pathogenesis of restenosis. We investigated whether selenium supplementation reduced plasma markers of inflammation in a 12-week, RCT involving 136 percutaneous coronary intervention patients. Participants received a daily supplement containing 100 μg of SeMet or placebo. Plasma selenium, whole blood GPx activity, CRP, soluble vascular adhesion molecule-1, soluble intercellular adhesion molecule-1, paraoxanase-1, and blood lipids were measured at baseline and at week 12. GPx activity was higher in the selenium group, by 16% (P<0.001), yet there were no significant differences between the selenium and placebo groups in any of the plasma markers of inflammation.
To determine if inherited genotypes in two single nucleotide polymorphism of GPx1 modified the effect of selenium supplementation on GPx1 activity, 277 patients from the above studies were genotyped for a single nucleotide polymorphism at codon 198 (Pro198Leu) and a sub-group (n=105) were genotyped for the polyalanine repeat sequence in exon 1 (Ala5, Ala6 or Ala7) of the GPx1 gene. Mean whole blood GPx activity in the selenium group was 14% higher than in the placebo group at 3 months (P<0.001), however, the magnitude of increase in enzyme activity with selenium supplementation did not differ by genotype.
In conclusion, our results do not support the use of selenium supplementation as an adjuvant therapy for New Zealand coronary artery disease patients.