Chapter 7 158 As magnesium is involved in over 600 enzymatic reactions in the human body, it is important that changes in magnesium status and magnesium deficiencies can be accurately detected 1. Magnesium status is often assessed by means of its serum or plasma concentration, which is a feasible and affordable way to monitor changes in magnesium status. However, since magnesium is mainly located in bones and cells, and because it is highly regulated, the extracellular concentration is unlikely to very well reflect the intracellular concentration 2. In fact, it is possible that intracellular concentrations are depleted, while serum or plasma concentrations are within the normal range. In that case, magnesium deficiency will be overlooked when monitoring only the extracellular concentration in serum or plasma. Several observational cohort studies have shown inverse associations between dietary magnesium intake and cardiovascular disease risk 3–5. Particularly, higher dietary magnesium intake has been associated with a lower risk of stroke, heart failure, and all-cause mortality 6. To date, large well-designed randomized clinical trials (RCTs) investigating the effects of increased dietary magnesium intake on cardiovascular endpoints are scarce. Furthermore, heterogeneity among RCTs investigating effects of magnesium supplementation on cardiovascular end points, driven by among others differences in study design and study population, limits the validity of meta-analyses combining these data. Further major issues are the lack of solid data on bio-availability of magnesium supplements and the limited possibilities to judge whether observed effects are to be attributed to magnesium or to the counterbalancing anion.To overcome these issues in magnesium research, we performed a relatively large RCT in which we assessed effects of multiple magnesium formulations on cardiovascular health. The primary endpoint was carotid-to-femoral pulse wave velocity (c-fPWV), a measure of arterial stiffness and strong predictor of cardiovascular health 7. Increased arterial stiffness is a major predictor of future cardiovascular diseases, including coronary heart disease and stroke. Increased arterial stiffness can be a consequence of hypertension, metabolic diseases, T2D, obesity and nonalcoholic fatty liver disease, and overall poor cardiovascular health 8. In our RCT, we selected a high-risk population (overweight and slightly obese middle-aged and elderly adults) that was expected to have a relatively high chance of increased arterial stiffness at baseline 9,10. Further, in order to gain insight into a potential mechanism by which magnesiummay improve cardiovascular health,we performed post-hoc analyses of a previous RCT that found a significant improvement of magnesium supplementation on arterial stiffness 10. In this post-hoc study, we assessed effects of oral magnesium citrate supplementation on glucocorticoid metabolism, specifically on the excretion of urinary cortisol, cortisone and their metabolites, as well
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