Dr. Ron’s Research Review – October 18, 2017

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This week’s research review focuses on Vitamin K and coronary artery calcification

Vitamin K1 (Phylloquinone)

CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. (Shea et al., 2009)

Vitamin K2, MK-4

A study enrolled 26 patients and examined the effects of 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (-0.7 %), respectively. In patients with high PIVKA-2, -18 % annual reduction of baPWV was observed.  Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (-0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. (Ikari et al., 2016)
A study found that MK-4 (animal source) supplementation did not increase serum MK-4 (produced by bacterial fermentation as found in natto) levels. However, consecutive administration of MK-7 increased serum MK-7 levels significantly in all subjects. (Sato et al., 2012)
A major difference between the K1 and MK-7 is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. (Schurgers et al., 2007)

 

Dr. Ron

 

 

Articles

Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.
            (Ikari et al., 2016) Download
BACKGROUND:  Dietary intake of vitamin K has been reported to reduce coronary artery calcification (CAC) and cardiovascular events. However, it is unknown whether supplemental menaquinone (MK)-4 can reduce CAC or arterial stiffness. To study the effect of MK-4 supplementation on CAC and brachial ankle pulse wave velocity (baPWV). METHODS:  This study is a single arm design to take 45 mg/day MK-4 daily as a therapeutic drug for 1 year. Primary endpoint was CAC score determined using 64-slice multislice CT (Siemens), and the secondary endpoint was baPWV measured before and 1 year after MK-4 therapy. RESULTS:  A total of 26 patients were enrolled. The average age was 69 ± 8 years and 65 % were female. Plasma levels of phylloquinone (PK), MK-7, and MK4 were 1.94 ± 1.38 ng/ml, 14.2 ± 11.9 ng/ml and 0.4 ± 2.0 ng/ml, respectively, suggesting that MK-7 was the dominant vitamin K in the studied population. Baseline CAC and baPWV were 513 ± 773 and 1834 ± 289 cm/s, respectively. At 1 year following MK-4 supplementation, the values were 588 ± 872 (+14 %) and 1821 ± 378 cm/s (-0.7 %), respectively. In patients with high PIVKA-2, -18 % annual reduction of baPWV was observed. CONCLUSION:  Despite high dose MK-4 supplementation, CAC increased +14 % annually, but baPWV did not change (-0.7 %). The benefits of MK-4 supplementation were only observed in patients with vitamin K insufficiencies correlated with high PIVKA-2 baseline levels, reducing baPWV but not CAC. TRIAL REGISTRATION:  This study was registered as UMIN 000002760.


 

Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women.
            (Sato et al., 2012) Download
BACKGROUND:  Vitamin K₂ contributes to bone and cardiovascular health. Therefore, two vitamin K₂ homologues, menaquinone-4 (MK-4) and menaquinone-7 (MK-7), have been used as nutrients by the food industry and as nutritional supplements to support bone and cardiovascular health. However, little is known about the bioavailability of nutritional MK-4. To investigate MK-4 and MK-7 bioavailability, nutritional doses were administered to healthy Japanese women. FINDINGS:  Single dose administration of MK-4 (420 μg; 945 nmol) or MK-7 (420 μg; 647 nmol) was given in the morning together with standardized breakfast. MK-7 was well absorbed and reached maximal serum level at 6 h after intake and was detected up to 48 h after intake. MK-4 was not detectable in the serum of all subjects at any time point. Consecutive administration of MK-4 (60 μg; 135 nmol) or MK-7 (60 μg; 92 nmol) for 7 days demonstrated that MK-4 supplementation did not increase serum MK-4 levels. However, consecutive administration of MK-7 increased serum MK-7 levels significantly in all subjects. CONCLUSIONS:  We conclude that MK-4 present in food does not contribute to the vitamin K status as measured by serum vitamin K levels. MK-7, however significantly increases serum MK-7 levels and therefore may be of particular importance for extrahepatic tissues.

Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.
            (Schurgers et al., 2007) Download
Vitamin K is a cofactor in the production of blood coagulation factors (in the liver), osteocalcin (in bone), and matrix Gla protein (cartilage and vessel wall). Accumulating evidence suggests that for optimal bone and vascular health, relatively high intakes of vitamin K are required. The synthetic short-chain vitamin K(1) is commonly used in food supplements, but recently the natural long-chain menaquinone-7 (MK-7) has also become available as an over-the-counter (OTC) supplement. The purpose of this paper was to compare in healthy volunteers the absorption and efficacy of K(1) and MK-7. Serum vitamin K species were used as a marker for absorption and osteocalcin carboxylation as a marker for activity. Both K(1) and MK-7 were absorbed well, with peak serum concentrations at 4 hours after intake. A major difference between the 2 vitamin K species is the very long half-life time of MK-7, resulting in much more stable serum levels, and accumulation of MK-7 to higher levels (7- to 8-fold) during prolonged intake. MK-7 induced more complete carboxylation of osteocalcin, and hematologists should be aware that preparations supplying 50 mug/d or more of MK-7 may interfere with oral anticoagulant treatment in a clinically relevant way.


 

Vitamin K supplementation and progression of coronary artery calcium in older men and women.
            (Shea et al., 2009) Download
BACKGROUND:  Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. OBJECTIVE:  The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. DESIGN:  CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). RESULTS:  In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. CONCLUSIONS:  Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.

 

References

Ikari, Y, et al. (2016), ‘Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.’, Nutr J, 15 (1), 53. PubMed: 27175730
Sato, T, LJ Schurgers, and K Uenishi (2012), ‘Comparison of menaquinone-4 and menaquinone-7 bioavailability in healthy women.’, Nutr J, 11 93. PubMed: 23140417
Schurgers, LJ, et al. (2007), ‘Vitamin K-containing dietary supplements: comparison of synthetic vitamin K1 and natto-derived menaquinone-7.’, Blood, 109 (8), 3279-83. PubMed: 17158229
Shea, MK, et al. (2009), ‘Vitamin K supplementation and progression of coronary artery calcium in older men and women.’, Am J Clin Nutr, 89 (6), 1799-807. PubMed: 19386744