Urban Alehagen

Background: Inflammation in epicardial adipose tissue (EAT) contributes to cardiovascular disease through the local production of pro-inflammatory cytokines affecting the adjacent myocardium. Selenium (Se) is essential for selenoprotein-mediated antioxidant and anti-inflammatory functions. We investigated associations between Se status and inflammatory markers in EAT and in the circulation in patients with coronary artery disease (CAD). Methods: Patients with CAD undergoing coronary artery bypass grafting (n = 52) and valve disease patients receiving valve replacement serving as controls (n = 22) were included from the ATICH study. EAT biopsies were obtained during open-chest chest surgery. Serum Se was measured by inductively coupled plasma mass spectrometry. Associations between Se and EAT mRNA expression of Nod-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome components and cytokines, as well as circulating inflammatory markers, were assessed using Spearman’s rho and group comparisons based on median Se levels. Results: Se concentrations were lower in CAD patients than controls (0.9 vs. 1.1 µmol/L, p = 0.025). In CAD patients, Se levels correlated with EAT expression of CASP1 and IL18, and with circulating IL-6. Se levels above the median were associated with lower EAT expression of CASP1 and NLRP3 and reduced IL-6 levels (p < 0.05, all). Our analysis of publicly available RNA seq data demonstrated selenoprotein’s presence in EAT. Conclusion: Lower Se status in CAD was associated with increased systemic and EAT inflammation, suggesting a role for selenoprotein-dependent antioxidant mechanisms in regulating cardiac adipose tissue inflammation.

Background: Low selenium intake and age-related decline of coenzyme Q₁₀ (CoQ₁₀) have been associated with an increased risk of cardiovascular disease (CVD) and oxidative stress. In a randomised placebo-controlled trial (RTC) in elderly people with low selenium levels, the supplementation with selenium and CoQ₁₀ reduced CVD and mortality. However, whether the supplementation elicited sex-specific benefits remained to be explored. Methods: Elderly Swedish persons (n = 443; balanced sex ratio) receiving selenium yeast (200 µg/day) and CoQ₁₀ (200 mg/day) combined or a placebo for four years were followed for additional six years. The response to supplementation, cardiovascular (CV) mortality, and risk factors were determined at four and ten years. Kaplan–Meier analyses, ANCOVA, repeated measurements of variance, and Cox proportional hazard regression analyses were performed. Results: The measured 10-year CV mortality rate was lower in females, and supplementation reduced this risk to a greater extent compared to in males. The improved survival rate apparently kicked in later in females than in males. At baseline, males had a higher smoking rate, increased inflammation and oxidative stress, and a higher prevalence of more advanced ischaemic heart disease (IHD) and signs of heart failure. When stratified by sex, in individuals with IHD, the intervention improved CV survival in both sexes, whereas supplementation had a more pronounced effect in females without IHD at inclusion. Supplementation diminished inflammation and oxidative stress, impaired the increase of NT-proBNP, and improved renal function in both sexes. Conclusions: The supplementation improved CV survival, especially in women. The higher prevalence of structural CVD and smoking in males may have contributed to the observed greater supplementation benefits in females. The preventive impact of selenium and CoQ₁₀ supplementation in elderly males and females may be particularly strong and meaningful in the early stages of CVD development.

The Cluster of Differentiation 5-like protein (CD5L) is produced by tissue-resident macrophages. It is an innate immune mediator protein with a multitude of functions, such as binding of invading microorganisms and oxidised LDL, and it is associated with clinical conditions, i.e., atherosclerosis and inflammation. The circulating CD5L level has been reported to correlate to selenium status and thyroid hormone activity. In order to test this hypothesis, we analysed CD5L in serum samples from a randomized controlled trial (RCT) with selenium and coenzyme Q₁₀ supplementation and examined associations between CD5L and thyroid hormones, health-related quality-of-life (Hr-QoL), and mortality in an elderly population low in selenium. Circulating levels of CD5L and thyroid hormones were determined in 359 elderly community-living individuals enrolled in an RCT at inclusion and after 48 months of supplementation (179 received selenium and coenzyme Q₁₀, and 180 placebo). Hr-QoL was recorded at both time-points using Short Form 36. Pre-intervention plasma selenium was low, mean 67 µg/L. CD5L correlated positively to free tri-iodothyronine (fT3) and showed an inverse relation with thyroid stimulating hormone (TSH). Low CD5L concentrations at inclusion in the placebo group were associated with increased cardiovascular mortality during 10 years of follow-up, and impaired Hr-QoL at 48 months. Selenium and coenzyme Q₁₀ supplementation significantly increased CD5L and fT3 levels, in association with a better health outcome. The data indicate that circulating CD5L positively responds to selenium and coenzyme Q₁₀ supplementation, correlates with thyroid hormone status, and associates with positive health indices. The observed effect may be due to increased selenium-dependent deiodinase isozyme expression that converts thyroxine (T4) to T3 locally and supports thyroid hormone activities. Whether the observed associations with Hr-QoL and cardiovascular mortality are a direct effect of circulating CD5L or local thyroid hormone activity is unclear and should be further investigated.

Low-selenium status was associated with impaired renal function, which improved after selenium and coenzyme Q₁₀ supplementation in an RCT. Here, we evaluated serum glutathione peroxidase-3 (GPx3) and its relation to serum selenium, selenoprotein P (SELENOP), renal function, mortality, and the impact of supplementation, which are all important, especially in elderly individuals. In total, 383 study participants (197 receiving selenium yeast and coenzyme Q₁₀ and 186 on a placebo) were evaluated. We applied benchmark dose modelling to determine GPx3 saturation, ANCOVA, Kaplan–Meier, and multivariate Cox proportional regression analyses for mortality evaluations. Selenium and GPx3 activity were modestly correlated. In comparison with SELENOP, GPx3 levelled off at a much lower value, 100 vs. 150 µg Se/L. GPx3 was associated with renal function, but not SELENOP. Supplementation increased glomerular function by ≈23% with an increase in GPx3. Being low in GPx3 displayed twice the risks of mortality in both placebos and active treatments. At serum selenium <100 µg/L, GPx3 activity was dependent on both selenium status and renal function. As renal function is reduced in the elderly, GPx3 is not an appropriate marker of selenium status. Low GPx3 was associated with an increased risk of mortality dependent of selenium status and independent of renal function.

Background: Selenium-dependent deiodinases play a central role in thyroid hormone regulation and metabolism. In many European countries, insufficient selenium intake may consequently lead to adverse effects on thyroid function. In this randomised placebo-controlled double-blind study, we examined the effect of supplementation with selenium and coenzyme Q₁₀ on thyroid hormonal status, cardiovascular (CV) mortality and health-related quality of life (Hr-QoL). Methods: Free T3, free T4, reverse T3, and TSH were determined in 414 individuals at baseline, and the effect of selenium yeast (200 µg/day) and coenzyme Q₁₀ (200 mg/day) supplementation on hormone concentrations, CV mortality and Hr-QoL was evaluated after 48 months using Short Form 36 (SF-36). Pre-intervention plasma selenium was low, mean 67 µg/L, corresponding to an estimated intake of 35 µg/day. Changes in concentrations of thyroid hormones following the intervention were assessed using T-tests, repeated measures of variance, and ANCOVA analyses. Results: In the total population, the group with the lowest selenium concentration at baseline presented with significantly higher levels of TSH and lower levels of fT3 as compared to subjects with the highest selenium concentration. Supplementation with selenium and coenzyme Q₁₀ for 4 years significantly increased fT3 and rT3, decreased fT4, and diminished the increase in TSH levels compared with placebo treatment (p = 0.03, all). In the placebo group, TSH and fT4 values above the median were associated with an increase in 10-year CV mortality, as compared with the mortality rate among those with TSH and fT4 below the median (p < 0.04, both), with no difference in mortality rate according to TSH and fT4 levels in the active intervention group. Similarly, TSH > median and fT3 < median were associated with a decline in mental Hr-QoL measures vs. TSH < and fT3 > median in the placebo group during 4 years of follow-up, but this was wiped out in the active group. Conclusions: Supplementation with selenium and coenzyme Q₁₀ had a beneficial effect on thyroid hormones with respect to CV mortality and Hr-QoL outcomes. The initial deficient selenium status was associated with an impaired thyroid function and the changes in thyroid hormone levels can be explained by increased activity of deiodinases. We conclude that a substantial part of the elderly study population might suffer from suboptimal thyroidal function with adverse clinical implications due to selenium deficiency. Trial registration: This study was registered at ClinicalTrials.gov and has the identifier NCT01443780. Since it was not mandatory to register at the time the study began, the study has been registered retrospectively.

The observation that the extent of artery calcification correlates with the degree of atherosclerosis was the background for the alternative treatment of cardiovascular disease with chelator ethylenediamine tetraacetate (EDTA). Recent studies have indicated that such chelation treatment has only marginal impact on the course of vascular disease. In contrast, endogenous calcium chelation with removal of calcium from the cardiovascular system paralleled by improved bone mineralization exerted, i.e., by matrix Gla protein (MGP) and osteocalcin, appears to significantly delay the development of cardiovascular diseases. After post-translational vitamin-K-dependent carboxylation of glutamic acid residues, MGP and other vitamin-K-dependent proteins (VKDPs) can chelate calcium through vicinal carboxyl groups. Dietary vitamin K is mainly provided in the form of phylloquinone from green leafy vegetables and as menaquinones from fermented foods. Here, we provide a review of clinical studies, addressing the role of vitamin K in cardiovascular diseases, and an overview of vitamin K kinetics and biological actions, including vitamin-K-dependent carboxylation and calcium chelation, as compared with the action of the exogenous (therapeutic) chelator EDTA. Consumption of vitamin-K-rich foods and/or use of vitamin K supplements appear to be a better preventive strategy than EDTA chelation for maintaining vascular health.

Background: Ageing is associated with cardiovascular disease (CVD). As no single biomarker reflects the full ageing process, we aimed to investigate five CVD- and age-related markers and the effects of selenium and coenzyme Q10 intervention to elucidate the mechanisms that may influence the course of ageing. Methods: This is a sub-study of a previous prospective double-blind placebo-controlled randomized clinical trial that included 441 subjects low in selenium (mean age 77, 49% women). The active treatment group (n = 220) received 200 µg/day of selenium and 200 mg/day of coenzyme Q10, combined. Blood samples were collected at inclusion and after 48 months for measurements of the intercellular adhesion molecule (ICAM-1), adiponectin, leptin, stem cell factor (SCF) and osteoprotegerin (OPG), using ELISAs. Repeated measures of variance and ANCOVA evaluations were used to compare the two groups. In order to better understand and reduce the complexity of the relationship between the biomarkers and age, factor analyses and structural equation modelling (SEM) were performed, and a structural model is presented. Results: Correlation analyses of biomarker values at inclusion in relation to age, and relevant markers related to inflammation, endothelial dysfunction and fibrosis, demonstrated the biomarkers’ association with these pathological processes; however, only ICAM1 and adiponectin were directly correlated with age. SEM analyses showed, however, that the biomarkers ICAM-1, adiponectin, SCF and OPG, but not leptin, all had significant associations with age and formed two independent structural factors, both significantly related to age. While no difference was observed at inclusion, the biomarkers were differently changed in the active treatment and placebo groups (decreasing and increasing levels, respectively) at 48 months (p ≤ 0.02 in all, adjusted), and in the SEM model, they showed an anti-ageing impact. Conclusions: Supplementation with selenium/Q10 influenced the analysed biomarkers in ways indicating an anti-ageing effect, and by applying SEM methodology, the interrelationships between two independent structural factors and age were validated.

Background: Selenium and coenzyme Q₁₀ (SeQ₁₀) possess antioxidant and anti-inflammatory properties, potentially mediated via Sirtuin1 (SIRT1). We aimed to investigate the influence of a SeQ₁₀ intervention on SIRT1 concentration, with potential interactions with microRNAs. Methods: In this sub-study of a prospective double-blind placebo-controlled clinical trial, healthy subjects (mean age 76 years) were randomized to receive an active treatment (n = 165, combined 200 µg/day of Se and 200 mg/day of Q₁₀) or a placebo (n = 161). SIRT1 concentration and microRNAs were measured with ELISA and PCR, respectively. Results: After four years, SIRT1 concentration was increased in the active treatment group, with mean (SD) ng/mL of 469 (436) vs. 252 (162), p < 0.001, and decreased in the placebo group, 190 (186) vs. 269 (172), p = 0.002, and the differences between the groups were significant (p = 0.006, adjusted). Those who suffered CV death during a 10-year follow-up (n = 25 and n = 52 in the active treatment and placebo groups, respectively) had significantly lower baseline SIRT1 concentrations compared to the survivors (p < 0.001). MiR-130a-3p was significantly downregulated during the intervention and correlated inversely with SIRT1 at baseline (r = −0.466, p = 0.007). Conclusion: The increased SIRT1 concentration after the SeQ₁₀ intervention associated with reduced CV mortality, partly mediated via miR-1303a-3p, suggests that SIRT1 is an additional mediator of the intervention, preventing vascular ageing.

Short telomeres have been associated with ageing and cardiovascular disease. The influence on leukocyte telomere length (LTL) of long-term intervention with combined selenium and coenzyme Q₁₀ is unknown. Our aim was to determine whether 42 months of selenium and coenzyme Q₁₀ supplementation prevented telomere attrition and further cardiovascular mortality. The investigation is an explorative sub-study of a double-blind, placebo-controlled, randomized trial. Swedish citizens low in selenium (n = 118), aged 70–80 years, were included. Intervention time was 4 years, with 10 years’ follow-up time. LTL was relatively quantified with PCR at baseline and after 42 months. At baseline, LTL (SD) was 0.954 (0.260) in the active treatment group and 1.018 (0.317) in the placebo group (p = 0.23). At 42 months, less shortening of LTL was observed after active treatment compared with placebo (+0.019 vs. −0.129, respectively, p = 0.02), with a significant difference in change basing the analysis on individual changes in LTL (p < 0.001). Subjects suffering future death presented with significantly shorter LTL at 42 months than survivors [0.791 (0.190) vs. 0.941 (0.279), p = 0.01], with a significant difference in change of LTL according to cardiovascular mortality and survival (p = 0.03). To conclude, preservation of LTL after selenium and coenzyme Q₁₀ supplementation associated with reduced cardiovascular mortality.