In this cross-sectional study, conducted in a representative sample of the US population, the association between serum selenium levels and the prevalence of peripheral arterial disease was not statistically significant, although a U-shaped relation was suggested: the prevalence of peripheral arterial disease decreased with increasing serum selenium levels up to 150 ng/mL but increased with increasing selenium levels above 160 ng/mL. Selenium intake varies around the world primarily because of geographic variation in the amount of selenium in the soil (1
). In the United States, estimated selenium intake ranges from 60 μg/day to 220 μg/day (23
), higher than the recommended dietary allowance for healthy adults (55 μg/day) (4
). As a consequence, serum selenium levels in the United States are high: in NHANES 2003–2004, the median selenium level was 134 ng/mL, and 99% of study participants had serum selenium levels above 95 ng/mL. These concentrations are considerably higher than in other countries. In Europe, for instance, average serum selenium levels range from 50 ng/mL to 90 ng/mL (23
Very limited data are available on the association of selenium with peripheral arterial disease. Two small studies found similar selenium levels in patients with peripheral arterial disease compared with controls, but the dose-response relation was not evaluated (12
). For other cardiovascular outcomes, most prospective studies have been conducted in populations with suboptimal selenium levels in Europe or China (3
). These studies tended to report inverse associations between serum selenium levels and coronary heart disease incidence, but their sample sizes were too small for detailed dose-response analyses.
Findings from the only 2 prospective studies of serum selenium levels and coronary heart disease conducted in the United States, however, are consistent with a U-shaped relation (6
). In the Physicians’ Health Study, the relative risks for incident myocardial infarction comparing quintiles 2–5 of plasma selenium with the lowest quintile were 0.87, 0.82, 0.60, and 1.53, respectively (6
). The cutoff levels for quintiles 1 and 5 of serum selenium in this study were 92 ng/mL and 134 ng/mL, respectively. In the NHANES III Mortality Study, the relative risks for cardiovascular disease mortality comparing tertiles 2 and 3 of serum selenium with the lowest tertile were 0.90 and 0.98, respectively; for stroke mortality, the corresponding relative risks were 0.73 and 1.23 (8
). The cutoff levels for serum selenium tertiles in NHANES III were 117.3 ng/mL and 130.4 ng/mL, respectively. In this study, a dose-response analysis showed that cardiovascular and coronary heart disease mortality decreased with increasing serum selenium levels up to 120 ng/mL followed by an increase at higher levels, although the U-shaped relation was not statistically significant (8
). Finally, in the Health Professionals Follow-up Study, the odds ratios for incident coronary heart disease comparing quintiles 2–5 of toenail selenium levels with the first quintile were 1.03, 0.99, 1.32, and 0.86, respectively, with no clear dose-response relation (7
). Both serum and toenail selenium levels reflect selenium status, although toenails reflect longer-term exposure. It is unclear, however, whether both biomarkers are comparable in their ability to capture the different types of selenium compounds.
Few randomized trials have evaluated the effect of selenium supplementation on cardiovascular outcomes or atherosclerosis progression, and most of these studies combined selenium with other vitamins and minerals (3
). Only 2 of these trials were conducted in the United States, both reporting null results (38
). In the Nutritional Prevention of Cancer trial, the relative risk for cardiovascular disease incidence comparing 200 μg/day of selenium supplementation with placebo was 1.03 (95% confidence interval: 0.78, 1.37) (38
). In the HDL-Atherosclerosis Treatment Study, the progression of atherosclerosis measured by coronary angiography in patients with coronary artery disease was similar among participants randomized to an antioxidant supplement containing 100 μg/day of selenium, 800 IU/day of vitamin E, 1 g/day of vitamin C, and 25 mg/day of β-carotene and participants randomized to placebo (39
). Overall, limited evidence from randomized trials has not shown a protective effect of selenium supplementation in US studies. With respect to observational studies, those in the United States have not been able to detect a significant linear association between serum selenium and cardiovascular outcomes, but the dose-response associations in these studies were U-shaped.
The biologic mechanisms underlying a potential effect of selenium on cardiovascular disease are likely complex, but they may be related to the dual role of selenium as an essential and toxic element. Selenium is an essential micronutrient that is incorporated into glutathione peroxidases and other selenoproteins (4
). Increasing serum selenium levels increase the concentration and activity of glutathione peroxidases, but this dose-response relation reaches a plateau at serum selenium levels of 70–90 ng/mL (4
). As a consequence, higher selenium levels could potentially prevent atherosclerosis development and progression in populations whose selenium exposure is below the levels needed to maximize glutathione peroxidases (1
). In selenium-replete populations such as in the United States, in which virtually all participants have serum selenium levels above 70–90 ng/mL, the mechanisms underlying a potential beneficial effect of increased selenium levels are unclear. Since selenium supplementation is actively promoted in the United States, and large randomized controlled trials testing the efficacy of selenium supplementation in prostate cancer prevention are under way (40
), mechanistic studies are urgently needed to establish the biologic basis for a protective effect of selenium in populations whose selenium status is already high.
Selenium, however, has a narrow therapeutic range (4
), and it may even be harmful at intake levels below the current tolerable Upper Intake Level of 400 μg/day (2
). In fact, some selenium compounds have been documented to generate reactive oxygen species (42
), and the upturn in peripheral arterial disease prevalence that we observed at selenium levels above 160 ng/mL could be associated with selenium-induced increased oxidative stress. This upturn in risk is also consistent with recent reports showing increased risk of diabetes (45
) and elevated lipid levels (47
) with high selenium levels in US populations. For instance, the Nutritional Prevention of Cancer trial showed an increased risk of diabetes for participants receiving 200 μg/day of selenium compared with placebo (hazard ratio
1.50, 95% confidence interval: 1.03, 2.33) (46
). Interestingly, the excess risk was limited to participants in the upper tertile of the serum selenium distribution (>121.6 ng/mL), who had a hazard ratio for diabetes of 2.70 (95% confidence interval: 1.30, 5.61). Further research is needed to establish the mechanisms underlying the association of high-normal selenium levels with peripheral arterial disease and with metabolic abnormalities, and to determine whether the change point in risk associated with elevated selenium levels depends on genetic polymorphisms in candidate genes for selenium metabolism (48
Several limitations of our study need to be considered. The use of a cross-sectional design and of prevalent cases of peripheral arterial disease limited our ability to determine the direction and the causality of the observed association. It is possible that the pathophysiologic changes of atherosclerosis could modify serum selenium levels or that participants with peripheral arterial disease change their health behaviors, including selenium intake through diet and dietary supplements. As a consequence, our findings must be confirmed in prospective studies with incident cases of peripheral arterial disease. Another limitation of our study is the use of a single measurement of serum selenium, which reflects short-term selenium intake and may be subject to high within-person variability (49
). Furthermore, our study measured only total serum selenium, and we did not have information on selenoprotein levels or activity or about nonspecific incorporation of selenium as selenomethionine in other plasma proteins. More detailed analysis of different compartments of serum selenium will be needed to better understand the association of selenium with peripheral arterial disease. The strengths of our study come from the rigorous sampling design and the quality of the study measurements used in NHANES; the representativeness of the NHANES sample; and the use of ABI, a noninvasive measure of subclinical atherosclerosis.
In summary, the association between serum selenium levels and the prevalence of peripheral arterial disease in NHANES 2003–2004 was not statistically significant, although a U-shaped relation was suggested. Other sources of evidence (6
) also suggest a U-shaped relation between serum selenium levels and cardiovascular outcomes in the United States, a selenium-replete population. In many populations worldwide, selenium intake is lower than in the United States (1
). At these lower levels of selenium intake, the association of selenium with peripheral arterial disease remains unknown. Prospective studies of selenium status across populations with different levels of selenium intake and randomized trials stratified by baseline selenium status are needed to establish the optimal selenium levels to minimize the risk of cardiovascular and other chronic diseases.