Effects of magnesium citrate, magnesium oxide and magnesium sulfate on arterial stiffness 113 6 Introduction Arterial stiffness is an independent predictor of coronary heart disease and stroke 1. Although arterial stiffness increases with age, lifestyle changes such as weight loss and lowering dietary salt and alcohol intake have been shown to reduce arterial stiffening 2–4. In addition, increasing dietary magnesium intake may improve arterial stiffness 5. Magnesium acts as a natural calcium channel blocker and has been suggested to modulate vasomotor tone and peripheral blood flow 6,7. Preclinical studies demonstrated a protective role of magnesium on vascular calcification 8,9, which may in turn lead to reduced arterial stiffening. We previously investigated the effect of long-term oral magnesium supplementation on vascular function markers and blood pressure 10.We observed a significant improvement of arterial stiffness after 24-wk of magnesium citrate supplementation compared with placebo. Yet, it is unknown whether the effect was induced by magnesium itself or by the counterbalancing anion citrate, as the study was based on a single comparison between magnesium citrate and placebo. Citrate binds calcium and may therefore be able to inhibit the growth of calcium crystals and inhibit vascular calcification 11,12, which may have contributed to the observed effect on arterial stiffness. Furthermore, in our previous study we found no effect on blood pressure, while blood pressure is a major determinant of arterial stiffness. One explanation could be that the total daily dose of magnesium was too low to exert an effect on blood pressure, as suggested by two meta-analyses 13,14. To date, no study has performed a head-to-head comparison between various magnesium formulations and their potential effects on vascular function markers and blood pressure. Differences between organic and inorganic formulations might be of interest as bioavailability may vary between formulations 15. Several studies have shown that magnesium citrate has a higher bioavailability 16,17. On the other hand, a metaanalysis has shown that inorganic formulations, such as magnesium oxide, exhibited a greater increase in circulating magnesium levels than organic formulations 18. The main objective of this randomized, double-blind, placebo-controlled intervention trial was to demonstrate the effect of magnesium citrate supplementation, in a higher dose than in our previous study, on carotid-to-femoral pulse wave velocity (c-fPWV) 10. To further explore whether the previously observed effect was induced by magnesium itself or by the counterbalancing anion citrate, we studied whether two inorganic formulations of magnesium, magnesium oxide and magnesium sulfate, are non-inferior
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