Menaquinone Intake Research Articles

Perspective: Evidence before Enthusiasm—A Critical Review of the Potential Cardiovascular Benefits of Vitamin K

A protective role for vitamin K in cardiovascular disease (CVD), a leading cause of morbidity and mortality, has been proposed because vitamin K-dependent proteins, such as matrix Gla (γ-carboxyglutamic acid) protein (MGP), are present in vascular tissue. MGP functions as a vascular calcification inhibitor-but only when it is carboxylated, which requires vitamin K. There is more than one naturally occurring form of vitamin K. Phylloquinone (vitamin K1) is found in plant-based foods, whereas menaquinones (vitamin K2) are a class of vitamin K compounds found in animal-based and fermented foods. Phylloquinone and menaquinones are capable of carboxylating MGP and other vitamin K-dependent proteins. In rodent models, high intakes of either phylloquinone or menaquinone reduced vascular calcification. Evidence of the relative importance of phylloquinone and menaquinone to CVD in humans is limited and controversial. In some observational studies, higher dietary menaquinone intake, but not phylloquinone intake, was associated with less coronary artery calcification (a subclinical manifestation of CVD) and a lower risk for clinical CVD events. These findings have led to claims that menaquinones have unique cardiovascular health benefits compared with phylloquinone. However, this claim is not supported by the results of the limited number of intervention trials conducted to date. The purpose of this review is to evaluate the strengths and limitations of the available evidence regarding the role of vitamin K in vascular calcification, CVD, and mortality.

Vitamin K intake and breast cancer incidence and death: results from a prospective cohort study

Vitamin K prevents growth and metastasis of certain cancers, but there is little evidence regarding the association between dietary vitamin K and breast cancer incidence and death. We sought to examine whether intakes of total vitamin K, phylloquinone (vitamin K1) and menaquinones (MKs) (vitamin K2) may influence risks of breast cancer incidence and death in the US population. Herein, 2286 breast cancer cases and 207 breast cancer deaths were identified during 702,748 person-years of follow-up. Cox regression and competing risk regression were used to estimate multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (95% CIs) by dietary vitamin K intake quintile (Q) for risk of breast cancer incidence and mortality. After adjustment for confounders, the total MK intake was associated with an increased risk of breast cancer (HR Q5 vs Q1, 1.26; 95% CI, 1.05 to 1.52; Ptrend, 0.01) and death from breast cancer (HR Q5 vs Q1, 1.71; 95% CI, 0.97 to 3.01; Ptrend, 0.04). Non-linear positive dose-response associations with risks of breast cancer incidence and death were found for total MKs intake (Pnon-linearity<0.05). No statistically significant associations were observed between the intake of total vitamin K and phylloquinone and breast cancer. The present study suggests that total MK intake was associated with an altered risk of the occurrence and death of breast cancer in the general US population. If our findings are replicated in other epidemiological studies, reducing dietary intake of menaquinones may offer a novel strategy for breast cancer prevention.

Intakes and sources of menaquinones (vitamin K2) in the Irish population aged 1–90 years

AbstractRecent evidence suggests that menaquinones (Vitamin K2) may be important for both bone health and cardiovascular health. With the exception of menaquinone-4 which is formed from the tissue specific conversion of phylloquinone or menadione, menaquinones are synthesized by bacteria. They are typically found in foods of animal origin such as meat, dairy and fermented foods and may account for up to 25% of total vitamin K intake. There are few data available on menaquinone intakes in population groups due to lack of available composition data. The Irish food composition database however has recently been updated to include data on menaquinones. Therefore, the aim of this study was to use these data to estimate the intakes and key dietary sources of menaquinones (menaquinone-4 &amp; menaquinone-5–10) in the Irish population.Analyses included data from four nationally representative surveys of the Irish population; The National Pre-School Nutrition Survey (1–4y; 2010–2011), the National Children's Food Survey (5–12y; 2003–2004), the National Teens’ Food Survey (13–17y; 2005–2006) and the National Adult Nutrition Survey (18–90y; 2008–2010) (www.iuna.net). For all of the surveys, food and beverage intake data (including supplements) were collected using food records and quantified using food scales, photographic atlases, household measures and standard portion sizes. Mean daily intakes of menaquinone-4 and menaquinone-5–10 were estimated using UK food composition tables and analytical values from published papers. The percent contribution of food groups to menaquinone intake was calculated by the mean proportion method (which provides information about the sources that are contributing to the nutrient intake ‘per person’). Statistical analyses were carried out using SPSS© V22.Mean intakes of menaquinone-4 ranged from 8–12μg/d and 10–14μg/d in children aged 1–17 years and adults aged 18–90 years, respectively. Mean combined intakes of menaquinone-5–10 ranged from 32–43μg/d and 32–50μg/d in children aged 1–17 years and adults aged 18–90 years, respectively. ‘Meat &amp; meat products’ were the top contributor of menaquinone-4 (50–66%) intakes across all population groups followed by ‘milks’ (9–25%). ‘Meat &amp; meat products’ (44–61%) and ‘cheeses’ (21–37%) were important contributors to menaquinone-5–10 intakes across all population groups examined.This study is the first of its kind to report the intakes and sources of menaquinones in the Irish population. ‘Meat &amp; meat products’, ‘cheeses’ and ‘milks’ are important contributors to intakes of menaquinones in the Irish diet. Further research is required to fully understand the role of the menaquinones in human health.

The effect of menaquinone-7 supplementation on vascular calcification in patients with diabetes: a randomized, double-blind, placebo-controlled trial

ABSTRACTBackgroundVitamin K occurs in the diet as phylloquinone and menaquinones. Observational studies have shown that both phylloquinone and menaquinone intake might reduce cardiovascular disease (CVD) risk. However, the effect of vitamin K on vascular calcification is unknown.ObjectivesThe aim of this study was to assess if menaquinone supplementation, compared to placebo, decreases vascular calcification in people with type 2 diabetes and known CVD.MethodsIn this double-blind, randomized, placebo-controlled trial, we randomly assigned men and women with type 2 diabetes and CVD to 360 µg/d menaquinone-7 (MK-7) or placebo for 6 mo. Femoral arterial calcification at baseline and 6 mo was measured with 18sodium fluoride positron emission tomography (18F-NaF PET) scans as target-to-background ratios (TBRs), a promising technique to detect active calcification. Calcification mass on conventional computed tomography (CT) scan was measured as secondary outcome. Dephosphorylated–uncarboxylated matrix Gla protein (dp-ucMGP) concentrations were measured to assess compliance. Linear regression analyses were performed with either TBR or CT calcification at follow-up as the dependent variable, and treatment and baseline TBR or CT calcification as independent variables.ResultsWe randomly assigned 35 patients to the MK-7 group (33 completed follow-up) and 33 to the placebo group (27 completed follow-up). After the 6-mo intervention, TBR tended to increase in the MK-7 group compared with placebo (0.25; 95% CI: −0.02, 0.51; P = 0.06), although this was not significant. Log-transformed CT calcification mass did not increase in the intervention group compared with placebo (0.50; 95% CI: −0.23, 1.36; P = 0.18). MK-7 supplementation significantly reduced dp-ucMGP compared with placebo (−205.6 pmol/L; 95% CI: −255.8, −155.3 pmol/L). No adverse events were reported.ConclusionMK-7 supplementation tended to increase active calcification measured with 18F-NaF PET activity compared with placebo, but no effect was found on conventional CT. Additional research investigating the interpretation of 18F-NaF PET activity is necessary. This trial was registered at clinicaltrials.gov as NCT02839044.

Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study

Multiple observational studies and small-scale intervention studies suggest that high vitamin K intake is associated with improved markers for cardiovascular health. Circulating phylloquinone solely represents phylloquinone (vitamin K1) intake, while dephosphorylated uncarboxylated Matrix Gla Protein (dp-ucMGP) represents both phylloquinone and menaquinone (vitamin K2) intake. This study aims to investigate the causal relationship between genetically predicted vitamin K concentrations and the risk of CHD via a two-sample Mendelian Randomization approach. We used data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case-cohort study, CARDIOGRAMplusC4D and the UK Biobank, resulting in 103,097 CHD cases. Genetically predicted vitamin K concentrations were measured using SNPs related to circulating phylloquinone and dp-ucMGP. We calculated a genetic risk score (GRS) including four SNPs (rs2108622, rs2192574, rs4645543 and rs6862071) related to circulating phylloquinone levels from a genome wide association study. Rs4236 was used as an instrumental variable for dp-ucMGP. Inverse-variance weighted (IVW) analysis was used to obtain Risk Ratios (RRs) for the causal relationship between phylloquinone and dp-ucMGP concentrations and CHD risk. Using the genetic score for circulating phylloquinone, we found that circulating phylloquinone was not causally related to CHD risk (RR 1.00 (95%-CI: 0.98; 1.04)). Lower genetically predicted dp-ucMGP concentration was associated with a lower CHD risk with a RR of 0.96 (95%-CI: 0.93; 0.99) for every 10μg/L decrease in dp-ucMGP. This study did not confirm a causal relationship between circulating phylloquinone and lower CHD risk. However, lower dp-ucMGP levels may be causally related with a decreased CHD risk. This inconsistent result may reflect the influence of menaquinones in the association with CHD.

Vitamin K intake and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial

Vitamin K inhibits prostate cancer cells, and an altered expression of vitamin K-dependent proteins in prostate tumors has been linked to their aggressiveness and progression. However, little is known about the effect of vitamin K intake on prostate cancer in human populations. We evaluated the associations of dietary intake of phylloquinone (vitamin K-1), menaquinones (vitamin K-2), and total vitamin K with the development of prostate cancer among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial. Dietary intake of vitamin K was assessed with the Dietary Questionnaire (DQX) at baseline and the Dietary History Questionnaire (DHQ) at the third anniversary of randomization by using high-performance liquid chromatography-based food-composition data obtained from the USDA and published studies. During a median follow-up of 11.8 y, 2978 cases of prostate cancer (including 490 advanced cases) were identified from the 28,356 men who completed DQX. Similarly, 2973 cases of prostate cancer (including 647 advanced cases) were documented from the 48,090 men who completed DHQ. Cox proportional hazards regression was used to estimate prostate cancer risk in relation to the dietary intake of vitamin K. After adjustment for confounders, dietary intakes of phylloquinone, menaquinones, and total vitamin K, assessed with either the DQX or DHQ, were not significantly associated with the risk of advanced, nonadvanced, and total prostate cancer. These results remained virtually the same when vitamin K intake was modeled as a categorical (divided into quintiles) or continuous (per IQR increase) variable or after outliers of total vitamin K intake (defined as a value that falls above the sum of third quartile and twice the IQR) were excluded. The present study does not suggest that vitamin K intake influences the occurrence of total and advanced prostate cancer in the general US population.

Abstract P272: Dietary Intake of Vitamin K and the Risk of Incident Pulmonary Embolism in the Nurses’ Health Study

Introduction: Vitamin K, which is consumed as phylloquinone (K 1 ) and menaquinone (K 2 ), impacts some vitamin-K dependent proteins involved in hemostasis. It is unknown whether dietary intake of phylloquinone and menaquinone are associated with incident pulmonary embolism (PE) risk. Hypotheses: Dietary intake of phylloquinone and menaquinone will be positively associated with the risk of incident PE and, in secondary analyses, idiopathic PE. Methods: Eligible women were Nurses’ Health Study participants free of venous thromboembolism (VTE) at 1984 baseline (n=74,821). Participants completed a food frequency questionnaire every four years (1984-2010) and we calculated intake of phylloquinone and menaquinone. Eligible PE cases were confirmed via medical record review or participant reconfirmation, or self-reported among persons with prior cancer. Cases were defined as idiopathic in the absence of cancer, recent surgery, and trauma. Cox Proportional Hazards models estimated hazard ratios and 95% confidence intervals for PE associated with time-varying energy-adjusted quintiles of phylloquinone, and separately, menaquinone. Two models adjusted for time-varying covariates, first including lifestyle and medical factors and next adding energy-adjusted nutrients. Secondary analyses estimated idiopathic PE risk. Results: We identified 568 incident PE events during 1,328,669 person-years. In analyses adjusted for lifestyle and medical factors, there was no evidence of a linear association between incident PE risk and energy-adjusted quintiles of phylloquinone intake (linear p-trend across quintile medians = 0.37) or menaquinone intake (linear p-trend = 0.57). Results for idiopathic PE risk were similarly null, as were results after further adjustment for nutrients (Table). Conclusions: In this study of U.S. women, there was no evidence of a linear association between energy-adjusted quintiles of phylloquinone or menaquinone intake and incident PE risk, before or after adjustment for other nutrients.

Reproducibility and relative validity of a food frequency questionnaire to estimate intake of dietary phylloquinone and menaquinones.

This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status. In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross-sectionally among 507 postmenopausal women. Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (rs=0.28) than men (rs=0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long-chain menaquinones showed good relative validity (rs=0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (rs=0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (rs=-0.09 (-0.18; -0.01)) and long-chain menaquinones (rs=-0.13 (-0.21; -0.04)), but not with short-chain menaquinones (rs=-0.04 (-0.13; 0.05)). The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake.

Abstract 5312: No association between vitamin K intake and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)

Abstract Prostate cancer is one of the most common cancers worldwide. The etiology of prostate cancer largely remains unclear, with almost all established risk factors (e.g. age, race, family history) being not modifiable. Ecological, migrant, and temporal trend studies suggest that diet plays role in the occurrence of prostate cancer, but few nutrients that alter its risk have been identified from case-control and cohort studies. Vitamin K has two forms that naturally occur in foods, i.e., phylloquinone (vitamin K1) and menaquinone (vitamin K2). While phylloquinone is abundant in green leafy vegetables and some vegetable oils, menaquinone is primarily derived from fermented food products (e.g. cheese). Although experimental studies have shown that vitamin K inhibits the growth of various cancer cell lines (including prostate cancer cells), only one epidemiologic study has investigated the association between vitamin K intake and prostate cancer risk. In that German study, a significant inverse association with advanced prostate cancer was observed for menaquinone intake. The present study thus sought to investigate the associations between intake of vitamin K (from both dietary and supplemental sources) and the risk of total and advanced prostate cancer among 28,356 PLCO participants. A total of 2978 cases of prostate cancer (including 490 advanced cases) have been documented during a median follow up of 11.8 years. Advanced prostate cancer were defined as disease in stage II with a Gleason score of 8-10, stage III, or stage IV. Usual dietary intake among study subjects was assessed with Dietary Questionnaire (DQX) at baseline and Dietary History questionnaire (DHQ) at year 3, both of which were developed and validated by the National Cancer Institute. Dietary intake of phylloquinone and menaquinones were calculated using the USDA National Nutrient Database for Standard Reference (Release 23), supplemented with menaquinone data from published studies. Cox proportional hazards regression was performed to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for dietary intake of phylloquinone and menaquinones in relation to prostate cancer risk. After adjustment for confounders, no statistically significant associations were found between vitamin K intake estimated from the DQX and prostate cancer risk [HR (95% CI) for the highest quintile vs. the lowest quintile: 0.99 (0.87, 1.13) for total vitamin K, 0.99 (0.87, 1.12) for phylloquinone, and 1.02 (0.87, 1.18) for total menaquinones]. Overall null results were also observed when additional analysis was carried out by the stage of the disease (i.e. advanced and non-advanced cases) and for vitamin K intake data assessed with the DHQ. In summary, the present study revealed that intake of total vitamin K and its two natural forms was not associated with the risk of total and advanced prostate cancer. Citation Format: Maggie Hoyt, Michael Reger, Jianjun Zhang. No association between vitamin K intake and prostate cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5312. doi:10.1158/1538-7445.AM2017-5312

Vitamin K intake and all-cause and cause specific mortality

Vitamin K has been associated with various health outcomes, including non-fatal cardiovascular diseases (CVD) and cancer. However, little is known about the association between vitamin K intake and all-cause and cause specific mortality. This study aims to investigate the association between vitamin K intake and all-cause and cause-specific mortality. This prospective cohort study included 33,289 participants from the EPIC-NL cohort, aged 20-70years at baseline and recruited between 1993 and 1997. Dietary intake was assessed at baseline with a validated food frequency questionnaire and intakes of phylloquinone, and total, short chain and long chain menaquinones were calculated. Information on vital status and causes of death was obtained through linkage to several registries. The association between the different forms of vitamin K intake and mortality was assessed with Cox proportional hazards, adjusted for risk factors for chronic diseases and nutrient intake. During a mean follow-up of 16.8 years, 2863 deaths occurred, including 625 from CVD (256 from coronary heart disease (CHD)), 1346 from cancer and 892 from other causes. After multivariable adjustment, phylloquinone and menaquinones were not associated with all-cause mortality with hazard ratios for the upper vs. the lowest quartile of intake of 1.04 (0.92;1.17) and 0.94 (0.82;1.07) respectively. Neither phylloquinone intake nor menaquinone intake was associated with risk of CVD mortality. Higher intake of long chain menaquinones was borderline significantly associated (ptrend=0.06) with lower CHD mortality with a HR10μg of 0.86 (0.74;1.00). None of the forms of vitamin K intake were associated with cancer mortality or mortality from other causes. Vitamin K intake was not associated with all-cause mortality, cancer mortality and mortality from other causes.

The relationship between vitamin K and peripheral arterial disease

Background and aimsA high dietary intake of vitamin K1 (phylloquinone) and vitamin K2 (menaquinones) is thought to decrease cardiovascular disease risk by reducing vascular calcification. The objective of this study is to explore if there is a relationship between phylloquinone and menaquinones intake and risk of PAD. MethodsWe investigated the association between intake of phylloquinone and menaquinones with PAD in a prospective cohort with 36,629 participants. Occurrence of PAD was obtained by linkage to national registries. Baseline intake of phylloquinone and menaquinones was estimated using a validated food-frequency questionnaire. Multivariate Cox regression was used to estimate adjusted hazard ratio's for the association. ResultsDuring 12.1 years (standard deviation 2.1 years) of follow-up, 489 incident cases of PAD were documented. Menaquinones intake was associated with a reduced risk of PAD with a hazard ratio (HR) of 0.71, 95% CI; 0.53–0.95 for the highest versus lowest quartile. A stronger association was observed (p interaction 0.0001) in participants with hypertension (HRQ4 versus Q1 0.59; 95% CI 0.39–0.87) or diabetes (HRQ4 versus Q1 0.56; 95% CI 0.18–1.91), though confidence intervals were wide in the small (n = 530) diabetes stratum. Phylloquinone intake was not associated with PAD risk. ConclusionsHigh intake of menaquinones was associated with a reduced risk of PAD, at least in hypertensive participants. High intake of phylloquinone was not associated with a reduced risk of PAD.

Vitamin K2 (menaquinone) Supplementation and its Benefits in Cardiovascular Disease, Osteoporosis, and Cancer

Vitamin K is known to play an essential role in the coagulation cascade; however, a growing body of research has found that a subtype of this vitamin, vitamin K2 (menaquinone) may have a beneficial effect in osteoporosis, cardiovascular disease, and cancer. This purpose of this article is to provide a comprehensive review of recent literature regarding menaquinone and its role in human health. This review discusses the physiology of menaquinone, its clinical benefits in cardiovascular disease, osteoporosis, and cancer, and how it may interact with certain medications. The authors conclude that menaquinone supplementation has been shown to improve carboxylation of osteocalcin and matrix-Gla protein to their active forms, two proteins that possess important roles in calcium distribution. In the setting of cardiovascular disease, menaquinone intake has been shown to lower the risk of coronary calcification and coronary heart disease, and a randomized controlled trial has demonstrated that it can reduce arterial stiffness. In osteoporosis, menaquinone has been shown by numerous randomized controlled trials to decrease the rate of bone loss at the lumbar spine and forearm and reduce the risk of fracture. In cancer, menaquinone intake has been shown to reduce overall incidence and mortality; clinical trials have suggested that it may have a role in reducing recurrence and death from hepatocellular carcinoma. However, in all clinical settings, more large randomized controlled trials are needed to definitively determine the clinical benefits of menaquinone supplementation, as many studies have failed to show any significant benefit. Lastly, more research is needed to determine how menaquinone supplementation interacts with medications such as warfarin, bile-acid sequestrants, orlistat, mineral oil and CYP3A4 substrates.

Abstract P151: Vitamin K Intake and All-cause and Cause Specific Mortality

Background: Vitamin K has been associated with various health outcomes, including non-fatal cardiovascular diseases and cancer. However, little is known about the association between vitamin K intake and all-cause and cause specific mortality. Objective: To investigate the association between vitamin K intake and all-cause and cause specific mortality. Methods: This prospective cohort study included 33,289 participants, aged 21-70 years from the EPIC-NL cohort. Participants were recruited between 1993 and 1997 and the follow-up is complete until December 2012. Dietary intake was assessed at baseline with a 178-item validated food frequency questionnaire and intakes of total vitamin K intake and its sub forms, phylloquinone, menaquinones (MK), short-chain menaquinones (SMK) and long-chain menaquinones (LMK) were calculated. Information on vital status and causes of death was obtained through linkage to several registries. The association between the different forms of vitamin K intake and mortality was assessed with Cox proportional hazard regression, adjusted for risk factors for chronic diseases (gender, age, BMI, physical activity, smoking status, education level) and nutrient intake. Results: During a median follow-up of 16.8 years, 2,863 deaths occurred, including 625 from CVD (256 CHD specific), 1,346 from cancer and 894 from other causes. After multivariable adjustment, vitamin K intake was not associated with all-cause mortality with hazard ratios for the upper vs. the lowest quartile of phylloquinone and menaquinone intake of 1.04 (0.93-1.17) and 0.94 (0.82-1.07) respectively. Phylloquinone intake nor menaquinone intake was associated with risk of CVD mortality. Higher intake of LMK was borderline significantly associated (p trend = 0.06) with lower CHD mortality with a HR per 10 μg of 0.87 (0.75-1.01). None of the forms of vitamin K intake were associated with cancer mortality or mortality from other causes. Conclusions: Vitamin K intake was not associated with all-cause mortality, cancer mortality and mortality from other causes. A higher intake of LMK tended to be associated with a lower risk of CHD mortality.

Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomised clinical trial.

Observational data suggest a link between menaquinone (MK, vitamin K2) intake and cardiovascular (CV) health. However, MK intervention trials with vascular endpoints are lacking. We investigated long-term effects of MK-7 (180 µg MenaQ7/day) supplementation on arterial stiffness in a double-blind, placebo-controlled trial. Healthy postmenopausal women (n=244) received either placebo (n=124) or MK-7 (n=120) for three years. Indices of local carotid stiffness (intima-media thickness IMT, Diameter end-diastole and Distension) were measured by echotracking. Regional aortic stiffness (carotid-femoral and carotid-radial Pulse Wave Velocity, cfPWV and crPWV, respectively) was measured using mechanotransducers. Circulating desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP) as well as acute phase markers Interleukin-6 (IL-6), high-sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α) and markers for endothelial dysfunction Vascular Cell Adhesion Molecule (VCAM), E-selectin, and Advanced Glycation Endproducts (AGEs) were measured. At baseline dp-ucMGP was associated with IMT, Diameter, cfPWV and with the mean z-scores of acute phase markers (APMscore) and of markers for endothelial dysfunction (EDFscore). After three year MK-7 supplementation cfPWV and the Stiffness Index βsignificantly decreased in the total group, whereas distension, compliance, distensibility, Young's Modulus, and the local carotid PWV (cPWV) improved in women having a baseline Stiffness Index β above the median of 10.8. MK-7 decreased dp-ucMGP by 50 % compared to placebo, but did not influence the markers for acute phase and endothelial dysfunction. In conclusion, long-term use of MK-7 supplements improves arterial stiffness in healthy postmenopausal women, especially in women having a high arterial stiffness.

Association Between Vitamin K and the Metabolic Syndrome: A 10-Year Follow-Up Study in Adults.

The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with increased risk of diabetes and cardiovascular diseases. Phylloquinone, menaquinones, and vitamin K status are associated with several components of MetS, but the association with MetS has hardly been studied to date. This study aimed to examine whether the intake and/or status of vitamin K is associated with MetS and its components. This study comprised two cohorts, one of 402 women and one of 400 men (age 40-80 y). At followup 625 participants were still alive and willing to participate. Data were analyzed both cross sectionally and longitudinally with Poisson and linear regression adjusted for multiple confounders. Baseline phylloquinone/menaquinone intakes were measured with a validated food frequency questionnaire and vitamin K status with serum desphospho-uncarborxylated matrix-Gla protein level. At baseline 270 (34.5%) participants had MetS and 171 (35.7%) at followup. Cross sectionally, high menaquinones intakes were associated (P(trend) = .08) with a lower prevalence of MetS with a prevalence ratio (PR) of 0.74 (95% confidence interval [CI], 0.54-1.03) for the highest vs the lowest tertile. At followup, the highest tertiles of menaquinones intake (PR = 0.62; 95% CI, 0.40-0.95) and vitamin K status (PR = 0.57; 95% CI, 0.38-0.87) were associated (P(trend) = .01) with a lower occurrence of MetS. These associations were mainly driven by relations with lower triacylglycerol concentrations for menaquinones and lower waist circumference for vitamin K status. Phylloquinone intake was not associated with MetS prevalence. This study shows that a high intake of menaquinones and high vitamin K status are associated with a lower occurrence of MetS.

Abstract P050: Vitamin K Intake and Risk of Coronary Heart Disease and Stroke in the Rotterdam Study

Introduction: Vitamin K serves as a cofactor in the carboxylation of vitamin K-dependent proteins that play a role in blood coagulation and the regulation of vascular calcification. Therefore, vitamin K intake may decrease the risk of cardiovascular diseases (CVD). We aimed to investigate the associations of phylloquinone (vitamin K1) and menaquinone (vitamin K2; MK-4 through MK-10) intake with risk of coronary heart disease (CHD) and stroke in a Dutch population-based cohort study. Methods: The analyses included 4,108 participants of the Rotterdam Study, aged 55 years and older, who were free of CVD and diabetes at baseline. Nutrient intake was estimated using a 170-item semi-quantitative food frequency questionnaire. To estimate the phylloquinone and menaquinone intake we compiled a new vitamin K food composition table using analytical and literature-based values. The occurrence of CHD and stroke was confirmed through medical records. Associations of phylloquinone and menaquinone intake with CHD and stroke incidence were examined using multivariable Cox proportional hazard models. Results: Participants had a mean phylloquinone intake of 191.7 mcg/day and a mean menaquinone intake of 49.4 mcg/day. During follow-up from 1990 to 2011, 460 CHD cases and 546 stroke cases were confirmed. In multivariable-adjusted analyses, we found no associations of phylloquinone (HR: 0.94; 95%CI: 0.72-1.23) or menaquinone intake (0.97; 0.75-1.26) with CHD incidence when comparing the highest to the lowest tertile of intake. Stroke incidence was also not associated with phylloquinone (1.22; 0.96-1.55) or menaquinone intake (0.86; 0.68-1.10). Moreover, we found no associations with CHD or stroke incidence when analysing the intake of short-chain (MK-4 through MK-6) and long-chain menaquinones (MK-7 through MK-10) separately. Conclusion: In this study, phylloquinone and menaquinone intake were not associated with risk of CHD or stroke.

Abstract P308: The Association of Vitamin K Intake and Status With the Metabolic Syndrome: A 10 Year Follow-Up Study

Background: The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with increased risk of type 2 diabetes, cardiovascular diseases and all-cause mortality. Vitamin K intake (phylloquinone/menaquinones) and vitamin K status are associated with several components of MetS, but the association with MetS has hardly been studied to date. Objective: To examine whether dietary intake and/or status of vitamin K are associated with occurrence of MetS and its components. Design: This study comprised of two cohorts, one of 402 women and one of 400 men (40-80 years). At follow-up 625 participants were still alive and willing to participate. Data were analyzed both cross-sectionally and longitudinally with Poisson and linear regression analyses adjusted for lifestyle and dietary factors. Baseline phylloquinone and menaquinone intake were measured with a validated food frequency questionnaire and dephospho-uncarborxylated matrix Gla protein was used as a marker for vitamin K status. Results: At baseline 285 (35.6%) participants had MetS and 172 (35.7%) at follow-up. Cross-sectionally, a high intake of menaquinones was associated (P trend =0.03) with a lower prevalence of MetS with a prevalence ratio (PR) of 0.70 (95%CI: 0.51-0.96) for the highest versus the lowest tertile. A high vitamin K status was also associated (P trend =0.02) with a reduced prevalence of MetS in cross-sectional analyses (PR T3 vs. T1 =0.73; 0.54-0.98) At follow-up, the highest tertiles of menaquinone intake (PR=0.62; 0.40-0.95) and vitamin K status (PR=0.61; 0.40-0.92) were associated (P trend &lt;0.02) with a lower occurrence of MetS. These associations were mainly driven by relations with lower triglyceride concentrations for menaquinones and lower waist circumference in women for vitamin K status. Phylloquinone intake was not associated with MetS prevalence. Conclusion: This study shows that a high intake of menaquinones and high vitamin K status are associated with a lower prevalence of MetS. This is mainly driven by the associations of high menaquinones intake with lower triglycerides concentrations and high vitamin K status with lower waist circumference in women.

Yogurt drink fortified with menaquinone-7 improves vitamin K status in a healthy population.

Population-based studies have shown an inverse association between dietary menaquinones (MK-n, vitamin K2) intake, coronary calcification and CHD risk, suggesting a potential role of vitamin K in vascular health. To date, the effects of increased menaquinone intake on (markers of) vascular health have been investigated using predominantly food supplements. Dairy products contain many essential nutrients and can serve as a good matrix for food fortification in order to support health. We were therefore interested to study the effects of a menaquinone-fortified yogurt drink (menaquinone as menaquinone-7 (MK-7); 28µg MK-7/yogurt drink) on vitamin K status and markers of vascular health. The yogurt drink was also fortified with n-3 PUFA, vitamin D, vitamin C, Ca and Mg to support vascular and/or general health. Healthy men (n 32) and postmenopausal women (n 28) with a mean age of 56 (sd 5) years received either basic or fortified yogurt drink twice per d for 12 weeks. MK-7 was efficiently absorbed from the fortified yogurt drink. Levels of circulating MK-7 were significantly increased from 0·28 to 1·94ng/ml. In accordance, intake of the fortified yogurt drink improved vitamin K status, as measured by significant decreases in uncarboxylated osteocalcin and desphospho-uncarboxylated matrix Gla-protein. No effects were, however, seen on markers of inflammation, endothelial dysfunction and lipid metabolism. In summary, consumption of a yogurt drink fortified with low doses of among others MK-7 for 3 months significantly improved vitamin K status in a healthy population.

Dietary Intake of Vitamin K Is Inversely Associated with Mortality Risk1–3

Vitamin K has been related to cardiovascular disease and cancer risk. However, data on total mortality are scarce. The aim of the present study was to assess the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular disease risk. A prospective cohort analysis was conducted in 7216 participants from the PREDIMED (Prevención con Dieta Mediterránea) study (median follow-up of 4.8 y). Energy and nutrient intakes were evaluated using a validated 137-item food frequency questionnaire. Dietary vitamin K intake was calculated annually using the USDA food composition database and other published sources. Deaths were ascertained by an end-point adjudication committee unaware of the dietary habits of participants after they had reviewed medical records and linked up to the National Death Index. Cox proportional hazard models were fitted to assess the RR of mortality. Energy-adjusted baseline dietary phylloquinone intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality after controlling for potential confounders (HR: 0.54; 95% CI: 0.30, 0.96; and HR: 0.64; 95% CI: 0.45, 0.90, respectively). In longitudinal assessments, individuals who increased their intake of phylloquinone or menaquinone during follow-up had a lower risk of cancer (HR: 0.64; 95% CI: 0.43, 0.95; and HR: 0.41; 95% CI: 0.26, 0.64, respectively) and all-cause mortality (HR: 0.57; 95% CI: 0.44, 0.73; and HR: 0.55; 95% CI: 0.42, 0.73, respectively) than individuals who decreased or did not change their intake. Also, individuals who increased their intake of dietary phylloquinone had a lower risk of cardiovascular mortality risk (HR: 0.52; 95% CI: 0.31, 0.86). However, no association between changes in menaquinone intake and cardiovascular mortality was observed (HR: 0.76; 95% CI: 0.44, 1.29). An increase in dietary intake of vitamin K is associated with a reduced risk of cardiovascular, cancer, or all-cause mortality in a Mediterranean population at high cardiovascular disease risk. This trial was registered at >http://www.controlled-trials.com as ISRCTN35739639.

The cost of ignoring acute kidney injury.

diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost 2010; 104: 811–822 12. Westenfeld R, Krueger T, Schlieper G et al. Effect of vitamin K2 supplementation on functional vitamin K deficiency in hemodialysis patients: a randomized trial. Am J Kidney Dis 2012; 59: 186–195 13. Geleijnse JM, Vermeer C, Grobbee DE et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr 2004; 134: 3100–3105 14. Fusaro M, Noale M, Viola V et al. Vitamin K Italian (VIKI) Dialysis Study Investigators. Vitamin K, vertebral fractures, vascular calcifications, and mortality: VItamin K Italian (VIKI) dialysis study. J Bone Miner Res 2012; 27: 2271–2278 15. Hayashi M, Takamatsu I, Kanno Y et al. Japanese Calciphylaxis Study Group. A case-control study of calciphylaxis in Japanese end-stage renal disease patients. Nephrol Dial Transplant 2012; 27: 1580–1584 16. Nigwekar SU, Bhan I, Turchin A et al. Statin use and calcific uremic arteriolopathy: a matched case-control study. Am J Nephrol 2013; 37: 325–332 17. Vissers LE, Dalmeijer GW, Boer JM et al. Intake of dietary phylloquinone and menaquinones and risk of stroke. J Am Heart Assoc 2013; 2: e000455 18. Lonn E, Yusuf S, Arnold MJ et al. Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567–1577 19. Krueger T, Schlieper G, Schurgers L et al. Vitamin K1 to slow vascular calcification in haemodialysis patients (VitaVasK trial): a rationale and study protocol. Nephrol Dial Transplant 2013; doi: 10.1093/ndt/gft459