The Effects of Menaquinone-7 Supplementation in Patients With Severe Coronary Calcifications

2. Introduction Ischemic heart disease causes 19% and 20% of all deaths among men and women,respectively, thus prevention is of outmost importance. Ischaemic heart disease is often silent until symptoms of myocardial infarction. However, subclinical coronary artery disease is easily detected by non-contrast cardiac CT scans as coronary artery calcifications (CAC). CAC increases with age, and men have higher CAC scores than women. In a population, in which CAC is absent, there is a very low risk of future CVD, but as the CAC score increases, so does the risk of ischaemic heart disease. Thus, to prevent CVD, identification and treatment of individuals with severe CAC is important.

Vitamin K and the calcification process Vascular calcification is a slowly progressive process and caused by an imbalance between the mechanisms that promote and inhibit the deposition of calcium in the vessel wall, and vitamin K-dependent proteins play an essential role in this inhibition. The most familiar K vitamin is phylloquinone (vitamin K1), as it is essential in activation of several coagulation factors. Menaquinone (vitamin K2) is another very important vitamin K species. Vitamin K2 is deemed necessary for γ-carboxylation of proteins related to the inhibition of arterial calcification, i.e. matrix-Gla proteins (MGP). Without these activated proteins, the balance of cellular calcium uptake and the mineralization process in bone and blood vessels is impaired. The inhibiting process of the vitamin K-dependent proteins was originally showed by Luo et al. in 1997. In a mice model they described activated (carboxylated) MGP to be an important inhibitor of vascular calcification. Likewise, observational human studies suggest that long-term use of vitamin K antagonist (which inhibits carboxylation of MGP) is associated with both increased coronary- and extra-coronary vascular calcification. Furthermore, combined low vitamins K and D status has been associated with increased all-cause mortality risk compared with adequate vitamins K and D status.

No recommendations of vitamin K2 supplementation are available; however, as demonstrated in a randomized controlled trial there is a dose-dependent decrease of uncarboxylated MGP concentrations by vitamin K2 supplementation (180 µg/day, 360 µg/day or placebo). Thus, we know that the daily intake in the Western world is not sufficient to meet the request for a complete activation of MGP. Additionally, there is no documented toxicity for vitamin K1 or vitamin K2, and the WHO has set no upper tolerance level for vitamin K intake.

The effect of high-dose vitamin K2 supplementation (720 µg/day) and vitamin D (25 µg/day) on aortic valve progression was examined in the very recent AVADEC trial. Aortic valve calcification progression was non-significantly decreased, however seemed to slow down the progression of CAC in patients with severe CAC (score > 400). In addition, the number of cardiac events and all-cause death was significantly lower (unpublished results). As this was a secondary outcome, a confirmatory trial is requested.

2.1. Hypothesis In a randomized setup, we test the hypothesis that supplementation with vitamin K2 (720 µg/day) and vitamin D (25 µg/day) in comparison to placebo will reduce the progression of CAC in patients with severe CAC.