High dietary menaquinone intake is associated with reduced coronary calcification
Introduction
Vitamin K is a fat-soluble vitamin that occurs in two biologically active forms; vitamin K1 (phylloquinone) and vitamin K2 (menaquinone; MK-4 through MK-10). Phylloquinone, the most common form, is present in green, leafy vegetables and certain vegetable oils [1], while menaquinones mostly occur in animal products like meat, eggs, and cheese [2]. Vitamin K functions as a cofactor in the gamma-glutamyl carboxylation of certain glutamic acid (Gla) residues of vitamin K-dependent proteins for their activation [3]. Such Gla-proteins include coagulation factors prothrombin, Factor VII, IX, and X [3]. Phylloquinone is effectively cleared from the circulation by the liver, the main site for clotting factor synthesis and is therefore thought to be particularly important for blood coagulation [4].
Vitamin K also functions as a cofactor for activation of Gla-proteins in extrahepatic tissues such as bone (osteocalcin) and the vessel wall (matrix Gla-protein) (MGP). Matrix Gla-protein is a powerful inhibitor of vascular calcification [5]. Vascular vitamin K deficiency could therefore increase the amount of undercarboxylated, non-functional MGP and lead to increased calcium deposition. Coronary calcification is a strong, independent predictor of coronary events [6] and this is an actively regulated process [7] that could be regressed by vitamin K, carbonic anhydrase, and bisphosphonates [8]. Vitamin K deficiency could therefore lead to cardiovascular disease (CVD) [3], [9]. Indeed, MGP-knock out mice develop severe coronary calcification [10]. In addition, the drug warfarin, inhibiting Gla residue formation, was shown to increase coronary calcification in rats and humans [11], [12]. Studies showed that vitamin K rich diets could prevent these effects in warfarin-treated rats [13], but these effects on coronary calcification were particularly due to menaquinone and not phylloquinone [13].
Results from human, observational studies investigating relations between vitamin K intake and cardiovascular diseases are inconsistent. The Nurses’ Health Study showed a modest risk reduction of coronary heart disease (CHD) for high phylloquinone intakes [14], while no significant associations were observed in the Health Professionals Follow-up Study and the Rotterdam Study [15], [16]. On the other hand, in the Rotterdam Study a strong inverse association between menaquinone intake and coronary heart disease mortality and severe aortic calcification was observed [16]. These inconsistencies may relate to different effects of phylloquinone and menaquinone on coronary calcification. So far, only the Rotterdam Study investigated both phylloquinone and menaquinone intake, while relations of different menaquinone subtypes with coronary calcification have not been studied. We investigated the association between dietary intake of both phylloquinone and menaquinone, including its subtypes, with coronary calcification in a cross-sectional study of 564 Dutch women.
Section snippets
Study population
We used data from a cross-sectional study among 564 post-menopausal healthy women as has been detailed earlier [17]. In short, these women were selected from participants of the PROSPECT study, one of the two Dutch cohorts participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). In PROSPECT 17,357 healthy participants of a nationwide population-based breast-cancer screening programme, aged 49–70 years, living in Utrecht and surroundings were enrolled between
Results
Table 1 shows the baseline characteristics of our study population. Sixty-two percent of the women had coronary calcification based on 1.5-mm thick slices. Higher intake of menaquinone was associated with increasing educational attainment, prevalence of diabetes and energy-adjusted intakes of protein and calcium.
Table 2 shows associations of quartiles of phylloquinone and menaquinone with coronary calcification. Intake of phylloquinone was not associated (ptrend = 0.09) with increased coronary
Discussion
This study shows that high intakes of menaquinone are associated with decreased coronary calcification. Intake of phylloquinone, however, was not associated with coronary calcification.
Strengths of this study include the complete information on cardiovascular risk factors and measurement of coronary calcium data. Nevertheless, certain limitations should be addressed. The main limitation of this study is the relative validity of our FFQ to estimate intake of vitamin K. Relative validity of our
Conflict of interest
None declared.
References (35)
- et al.
Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid
Blood
(1999) - et al.
ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography) developed in collaboration with the Society of Atherosclerosis Imaging and Prevention and the Society of Cardiovascular Computed Tomography
J Am Coll Cardiol
(2007) - et al.
Matrix Gla protein accumulates at the border of regions of calcification and normal tissue in the media of the arterial vessel wall
Biochem Biophys Res Commun
(2001) - et al.
Relation of oral anticoagulation to cardiac valvular and coronary calcium assessed by multislice spiral computed tomography
Am J Cardiol
(2005) - et al.
Oral anticoagulant treatment: friend or foe in cardiovascular disease?
Blood
(2004) - et al.
Phylloquinone intake and risk of cardiovascular diseases in men
Nutr Metab Cardiovasc Dis
(2007) - et al.
Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study
J Nutr
(2004) Vitamin K and human nutrition
J Am Diet Assoc
(1992)- et al.
Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health
J Nutr
(1996) - et al.
Tea and coffee brews are not dietary sources of vitamin K-1 (phylloquinone)
J Am Diet Assoc
(1995)
Vitamin K-1 (phylloquinone) content of foods: a provisional table
J Food Comp Anal
Quantification of coronary artery calcium using ultrafast computed tomography
J Am Coll Cardiol
Differential lipoprotein transport pathways of K-vitamins in healthy subjects
Biochim Biophys Acta
The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis
J Thromb Haemost
Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7
Blood
Compilation of a provisional UK database for the phylloquinone (vitamin K1) content of foods
Br J Nutr
Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations
Haemostasis
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