Role of Vitamin K in reducing Risk of Coronary Heart Disease: The Rotterdam Study.

Vitamin K is obtained from the diet as phylloquinone (vitamin K-1) and menaquinone (MK-n, vitamin K-2). Phylloquinone is abundant in dark-green leafy vegetables and vegetable oils. On the other hand, the main dietary sources for menaquinone in Western populations are meats (MK-4) and fermented foods, especially cheese and curds (mainly MK-8 and MK-9). Though the mammalian bacterial intestinal flora can produce vitamin K₂, the amount produced is thought to be negligible (3). The adequate intake (AI) for vitamin K has been proposed to be 90 µg/day for women and 120 µg/day for men (4). Diets deficient in vitamin K can cause vitamin K deficiency in as fast as 7 days (5).

Vitamin K and Coronary Heart Disease:

Coronary artery calcification is a vital predictor of coronary heart disease (CHD) as calcification of vessel walls reduces elasticity thus increasing the cardiovascular disease risk.

With the crucial role that Vitamin K plays in the mechanism of blood coagulation, many studies have been done in the past to see if Vitamin K can play a role in reducing Coronary Artery Calcification. Studies done have pointed out that Vitamin K by reducing coronary calcification through matrix-Gla protein (MGP) reduces the risk of coronary heart diseases (9). This comes as Vitamin K activates the proteins Osteocalcin (OC) and MGP which are important regulators of calcium distribution (7). MGP identified in human atherosclerotic plaque, may prevent calcium precipitation as in bone. As a result, MGP when carboxylated by Vitamin K inhibits coronary calcification (8). With this mechanism, vitamin K may help reduce coronary calcification and thereby reduce the risk of CVD. (8)

With a major source of Vitamin K coming from the diet in the form of phylloquinone (K1) and menaquinone (K2), in 2004, Johanna M. Geleijnse published a study popularly known as 'Rotterdam Study' which examined the association of dietary intake of phylloquinone and menaquinone with the incidence of coronary heart disease (CHD), all-cause mortality, and aortic calcification.

The authors particularly hypothesized that an inadequate dietary intake of vitamin K may similarly result in undercarboxylation of vascular MGP, leading to enhanced calcification of atherosclerotic lesions and, consequently, an increased risk of coronary heart disease.

The Rotterdam Study

The Rotterdam Study was a prospective, population-based study to assess the occurrence of diseases of the elderly and to clarify their determinants. The cohort comprised 7983 men and women aged 55 years and over who were living in a district of Rotterdam. Data was collected From August 1990 until June 1993. Noninstitutionalized subjects who visited the study centre at baseline (82% of the cohort) were eligible for a dietary interview. Subjects who participated in the pilot study, subjects suspected of dementia, subjects with a history of MI, were excluded from the study.

The participants indicated on a checklist all foods and beverages that they consumed more than once a month during the preceding year. A validated, semiquantitative food-frequency questionnaire was used in the study. Concentrations of phylloquinone and menaquinone (MK-4 through MK-10) in a large series of Dutch foods were assessed at the laboratory Cardiovascular Research Institute Maastricht, University of Maastricht.

Height and weight of the participants were measured, and BMI was computed. Sitting systolic and diastolic blood pressure were measured twice with a random-zero sphygmomanometer by a trained research assistant after a 5-min rest and values were averaged. A standard electrocardiogram was obtained, Diabetes mellitus was considered present when the subject reported use of antidiabetic medication or insulin. Serum total cholesterol and HDL cholesterol levels were measured. Later, follow up data was collected from baseline (1990–1993) until January 1, 2000. Information on vital status was obtained at regular intervals from the municipal population registry. If reinfarctions occurred during follow-up, only the first event was included in the analysis. Events were considered fatal if death occurred within 28 d after the onset of symptoms.

For the Assessment of aortic calcification, a lateral radiographic film of the lumbar spine was made from a fixed distance and calcification was diagnosed by detecting calcified deposits in the abdominal aorta parallel and anterior to the lumbar spine. On a scale of 0 to 5, according to the length the severity of aortic calcification was graded as "absent or mild" (≤1 cm calcification), "moderate" (>1 and <5 cm), or "severe" (≥5 cm).

Data analyses were performed using SPSS 11.0.1 for Windows.

Results:

With the study, the authors came out with the following results

• Men had higher intakes of vitamin K than women, but the associations were reversed after adjustment for total energy intake (253.5 vs. 241.1 µg/d for phylloquinone and 29.2 vs. 26.9 µg/d for menaquinone, respectively).
• Phylloquinone intake was not correlated with menaquinone intake.
• Phylloquinone intake was positively associated with dietary fibre, calcium, vitamin antioxidants, flavanols, and BMI and inversely associated with smoking (all P < 0.001).
• Menaquinone intake was positively associated with intake of total fat and SFA, dietary calcium, BMI, and diabetes mellitus and inversely associated with intake of PUFA (all P < 0.001).
• In 4581 subjects not treated with lipid-reducing agents, positive associations of phylloquinone intake with serum total cholesterol (0.044 mmol/ L /100µg, P = 0.003) and serum HDL (0.016 mmol/ L /100µg, P < 0.001) were found.
• Menaquinone intake was inversely associated with serum total cholesterol (-0.025 mmol /L 10 /µg, P = 0.055), and positively associated with serum HDL (0.015 mmol/ L/ 10 µg, P < 0.001).
• Incidence of CHD and all-cause mortality-From baseline until January 1, 2000, 144 first nonfatal MI and 99 fatal coronary events occurred. phylloquinone was not associated with risk of nonfatal MI, incident CHD (fatal and nonfatal events combined), CHD mortality, and all-cause mortality. Menaquinone was associated with an inverse relationship with nonfatal MI.
• Atherosclerosis- Aortic calcification was mild or absent in 2874 subjects (64.3%), moderate in 1359 subjects (30.4%), and severe in 240 subjects (5.4%). Mean intake of phylloquinone intake was similar in categories of aortic calcification. Menaquinone intake was lower in subjects with severe aortic calcification (25.6 µg /d) than in subjects with moderate or mild calcification (28.6 and 28.8 µg /d, respectively; P=0.001). Intake of phylloquinone was not significantly associated with moderate or severe aortic calcification. Menaquinone intake also showed no significant association with moderate calcification but for severe calcification, a strong inverse relationship with menaquinone intake persisted.

The authors hypothesised that menaquinones in cheese (MK-8 and MK-9) could exert a beneficial effect in the cardiovascular system and that the high cheese consumption may possibly account for the lower prevalence of CHD. The authors explained the inverse association of menaquinone with aortic calcification and CHD, noting that it may be due to the under carboxylation of vascular MGP and consequently enhanced calcification of atherosclerotic lesions.

The researchers also added that there is a differential effect of Vitamin K on the cardiovascular system. Menaquinone but not phylloquinone prevented warfarin-induced arterial calcification despite the similar in vitro activity of ɤ- carboxylase, they noted.

Thus, the researchers concluded that there was a protective effect of dietary menaquinone intake against CHD in older men and women. The inverse association with all-cause mortality indicated that a high intake of menaquinone does not increase the risk for other major diseases, such as cancer. There was no consistent association of phylloquinone intake with CHD, mortality, or aortic calcification.

The above article has been published by Medical Dialogues under the MD Brand Connect Initiative. For more details on Vitamin K, click here

References:

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2. DiNicolantonio JJ, Bhutani J, O'Keefe JH. The health benefits of vitamin K. Open 0Heart. 2015;2(1):e000300. Published 2015 Oct 6. doi:10.1136/openhrt-2015-000300
3. Booth SL, Suttie JW. Dietary intake and adequacy of vitamin K. J Nutr 1998;128:785–8.
4. Dietary reference intakes for vitamin A, vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. Washington DC: The National Academies Press, 2001:800.
5. Israels LG, Israels ED, Saxena SP. The riddle of vitamin K1 deficit in the newborn. Semin Perinatol 1997;21:90–6. 10.1016/S0146-0005(97)80024-9.
6. Walther B, Karl JP, Booth SL, Boyaval P. Menaquinones, bacteria, and the food supply: the relevance of dairy and fermented food products to vitamin K requirements. Adv Nutr. 2013;4(4):463-473. Published 2013 Jul 1. doi:10.3945/an.113.003855
7. Buchanan, MD, Grant S.; Melvin, Thomas; Merritt, Brandon; Bishop, MD, Charles; and Shuler, MD, PhD, Franklin D. (2016) "Vitamin K2 (menaquinone) Supplementation and its Benefits in Cardiovascular Disease, Osteoporosis, and Cancer," Marshall Journal of Medicine: Vol. 2: Iss. 3, Article 8.
8. Beulens JW, Booth SL, van den Heuvel EG, Stoecklin E, Baka A, Vermeer C. The role of menaquinones (vitamin K₂) in human health. Br J Nutr. 2013;110(8):1357-1368.
9. Beulens JW, Bots ML, Atsma F, et al. (2009) High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis 203, 489–493.
10. Dalmeijer GW, van der Schouw YT, Magdeleyns E, Ahmed N, Vermeer C, Beulens JW. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012;225(2):397-402.
11. A randomized, double-blind, placebo-controlled trial by Dalmeijer et al on the effect of menaquinone-7 (MK-7) supplementation and carboxylation of MGP found that Menaquinone supplementation dose-dependently decreases desphospho-uncarboxylated MGP and it may also serve as a non-invasive marker of vitamin K status (10).