ArticlePDF Available

Abstract and Figures

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.
Content may be subject to copyright.
The Journal of Nutrition
Nutritional Epidemiology
Dietary Intake of Vitamin K Is Inversely
Associated with Mortality Risk
1–3
Mart´
ı Juanola-Falgarona,
4,6
Jordi Salas-Salvad ´
o,
4,6
*Miguel ´
Angel Mart´
ınez-Gonz´
alez,
6,7
Dolores Corella,
8
Ram ´
on Estruch,
6,9
Emili Ros,
6,10
Montserrat Fit ´
o,
6,12
Fernando Ar ´
os,
6,13
Enrique G ´
omez-Gracia,
6,14
Miquel Fiol,
15
Jos´
eLapetra,
16
Josep Basora,
4,6
Rosa Mar´
ıa Lamuela -Ravent ´
os,
11
Lluis Serra-Majem,
17
Xavier Pint ´
o,
18
Miguel ´
Angel Mun
˜oz,
19
Valentina Ruiz-Guti´
errez,
6,20
Joan Fern´
andez-Ballart,
5,6
and Mo
`nica Bull ´
o
4,6
*
4
Human Nutrition Unit, Department of Biochemistry and Biotechnology, Sant Joan de Reus University Hospital, Faculty of Medicine and
Health Sciences, Pere Virgili Institute of Health Research;
5
Department of Preventive Medicine and Public Health, Faculty of Medicine
and Health Sciences, Rovira i Virgili University, Reus, Spain;
6
CIBER Physiopathology of Obesity and Nutrition, Institute of Health
Carlos III, Madrid, Spain;
7
Department of Preventive Medicine and Public Health, University of Navarra, Pamplona, Spain;
8
Department
of Preventive Medicine, University of Valencia, Valencia, Spain;
9
Department of Internal Medicine,
10
Department of Endocrinology
and Nutrition Lipid Clinic, Biomedical Research Institute August Pi Sunyer, Hospital Cl´
ınic, and
11
Nutrition and Food Safety Research
Institute, University of Barcelona, Barcelona, Spain;
12
Cardiovascular Risk and Nutrition Research Group (Regicor Study Group),
Hospital del Mar Medical Research Institute, Barcelona, Barcelona, Spain;
13
Department of Cardiology, University Hospital
Txagorritxu, Vitoria, Spain;
14
Department of Preventive Medicine, University of Malaga, Malaga, Spain;
15
Institute of Health Sciences,
University of the Balearic Islands and Hospital Son Espases, Palma de Mallorca, Spain;
16
Department of Family Medicine, Primary
Care Division of Sevilla, San Pablo Health Center, Sevilla, Spain;
17
Department of Clinical Sciences, University of Las Palmas de Gran
Canaria, Las Palmas, Spain;
18
Lipids and Vascular Risk Unit, Internal Medicine, University Hospital of Bellvitge, Hospitalet de
Llobregat, Barcelona, Spain;
19
Primary Health Care Division and Research, Biomedical Research Institute August Pi i Sunyer-Jordi Gol,
Barcelona, Spain; and
20
Institute of Fats, Spanish National Research Council, Sevilla, Spain
Abstract
Vitamin K has been related to cardiovascular disease and cancer risk. However,data on total mortality are scarce. Theaim 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 (Prevenci´
on con Dieta
Mediterr´
anea) 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 adjudicationcommittee unaware of the dietaryhabits of participants afterthey had reviewed medical
records and linked up to the National Death Index.Cox proportional hazard models were fittedto 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. J. Nutr. doi: 10.3945/jn.113.187740.
Introduction
Vitamin K includes a group of fat-soluble vitamins that occur in
2 natural active forms: 1) phylloquinone (vitamin K-1), mainly
found in green leafy vegetables and vegetable oils; and 2) menaqui-
none [vitamin K-2 or menaquinone (MK)
21
-n], produced by intesti-
nal bacteria and found in fermented foods. Vitamin K acts as a
1
Supported by National Cardiovascular Research Center grant 06/2007, Health
Research Fund grants PI07/0473 and PI1002658, Ministry of Science and
Innovation grants AGL-2009-13906-C02 and AGL2010-22319-C03, Ministry of
Health–National Drug Plan grant 2010/087, Mapfre Foundation 2010,
Government of the Basque Country grant IT386-10, University of the Basque
Country grant UFI 11/32, and the Autonomous Government of Catalonia [joint
contract with Institute of Health Carlos III (Miguel Servet grant 06/00100)].
CIBER Physiopathology of Obesity and Nutrition and Thematic networks of
cooperative health research grant RD 06/0045 are initiatives of the Institute of
Health Carlos III.
2
Author disclosures: M. Juanola-Falgarona, J. Salas-Salvad´
o, M. ´
A. Mart´
ınez-Gonz´
alez,
D. Corella, R. Estruch, E. Ros, M. Fit´
o, F. Ar ´
os, E. G´
omez-Gracia, M. Fiol, J. Lapetra,
J. Basora, R. M. Lamuela-Ravent ´
os, L. Serra-Majem, X. Pint ´
o, M. ´
A. Mun˜oz,V.
Ruiz-Guti ´
errez, J. Fern´
andez-Ballart, and M. Bull ´
o, no conflicts of interest.
3
Supplemental Figure 1 and Supplemental Tables 1 and 2 are available from the
"Online Supporting Material" link in the online posting of the article and from the
same link in the online table of contents at http://jn.nutrition.org.
*To whom correspondence should be addressed. E-mail: monica.bullo@urv.cat
(M. Bull ´
o), jordi.salas@urv.cat (J. Salas-Salvad ´
o).
ã2014 American Society for Nutrition.
Manuscript received November 8, 2013. Initial review completed December 11, 2013. Revision accepted February 26, 2014. 1of8
doi: 10.3945/jn.113.187740.
The Journal of Nutrition. First published ahead of print March 19, 2014 as doi: 10.3945/jn.113.187740.
Copyright (C) 2014 by the American Society for Nutrition
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
cosubstrate for the enzyme g-glutamyl carboxylase in the carbox-
ylation of specific glutamic residues into g-carboxyglutamyl acid
residues in some proteins (1). Matrix g-carboxyglutamyl acid
protein, present in the vascular wall, is a powerful inhibitor of
vascular calcification (2). It has been proposed that vitamin K
deficiency can increase the amount of nonfunctional matrix
g-carboxyglutamyl acid protein, thus leading to increased calcium
deposition and cardiovascular disease (1). This is supported by
the results of a population-based survey conducted in elderly
individuals in whom lower concentrations of vitamin K were
associated with aortic calcification (3).
However, limited evidence shows that vitamins K-1 and K-2
should be expected to have different effects on the modulation of
aortic calcification or the risk of cardiovascular disease, mainly
attributed to their differences in plasma transport and delivery to
target tissues (4), and the results of prospective studies that sep-
arately analyze both forms of vitamin K are far from conclusive. In
the NursesÕHealth Study, a higher dietary phylloquinone intake
was inversely associated with the risk of coronary heart disease
(CHD) (5), although these results could not be replicated by the
same authors in men (6). Unfortunately, data on menaquinone
were not available in either study.
In the Rotterdam Study, the relative risk of CHD and all-
cause mortality was lower in the upper than the lower tertile
of dietary menaquinone intake (7). Data from the Prospect-
EPIC (European Prospective Investigation into Cancer and
Nutrition) study showed an inverse relation between dietary
menaquinone intake and the risk of CHD but no association
between phylloquinone intake and CHD risk in postmenopausal
women. After analyzing menaquinone subtypes, MK-7, MK-8,
and MK-9 were the subclasses that had the strongest associa-
tions with a decreased risk of CHD incidence (8).
Apart from its well-known physiologic function that acti-
vates coagulation, vitamin K exerts inhibitory effects on cell
growth in several cancer cell lines (9–11). Although most studies
focused on menadione (vitamin K-3)—a synthetic analogue that
acts as a provitamin—phylloquinone, and especially menaqui-
none, seem to have an antiproliferative capacity (9). These
results are supported by a randomized clinical trial conducted on
individuals with viral cirrhosis, in which the risk of hepatocel-
lular carcinoma at 6 y of follow-up was significantly lower in
individuals who were administered high doses of MK-4 for 2 y
than in the control group (12). However, few epidemiologic
studies evaluated the association between dietary vitamin K and
risk of cancer (13,14). Although no effect has been reported for
phylloquinone intake, an inverse association has been noted
between menaquinone intake and prostate cancer, total cancer
incidence, and mortality (14).
To our knowledge, this is the first study to evaluate the
specific association of both active forms of vitamin K (vitamins
K-1 and K-2), and their changes during the follow-up, with
cancer mortality, cardiovascular mortality, or all-cause mortality
in a prospective longitudinal study of Mediterranean individuals
at high cardiovascular disease risk and using repeated measure-
ments of dietary intake.
Participants and Methods
Study population. A prospective cohort analysis was conducted in 7216
participants in the framework of the PREDIMED (Prevenci´
on con Dieta
Mediterr´
anea) cohort. The PREDIMED study is a large, parallel-group,
multicenter, controlled, randomized clinical trial aiming to assessthe effect
of Mediterranean diets on the primary prevention of cardiovascular
disease in elderly individuals at high cardiovascular disease risk. Full
details of the PREDIMED study protocol have been published previ-
ously, and the trial was registered at http://www.controlled-trials.com as
ISRCTN35739639 (15,16). Participants were community-dwelling men
and women, aged 55–80 and 60–80 y, respectively, with no cardiovas-
cular disease at enrollment and who had either type 2 diabetes mellitus
(T2DM) or $3 of the following cardiovascular disease risk factors: 1)
smoking; 2) hypertension; 3) dyslipidemia; 4) HDL cholesterol concen-
tration #40 mg/dL; 5) overweight or obesity (BMI $25 kg/m
2
); or 6)
family history of premature cardiovascular disease. The exclusion
criteria were as follows: 1) severe chronic illness; 2) drug or alcohol
addiction; 3) history of allergy or intolerance to olive oil or nuts; 4) a low
predicted likelihood of changing dietary habits according to Prochaska
and DiClementeÕs stages-of-change model; and 5) illiteracy and other
medical or social conditions that make compliance with the intervention
difficult. The protocol was approved by the institutional review boards
at all study locations, and participants provided written informed
consent.
Dietary assessment. At baseline and annually thereafter, participants
were assessed by trained dieticians who administered a validated 137-
item FFQ (17). Energy and nutrient intake and food groups were
calculated from Spanish food composition tables (18,19). Dietary
phylloquinone intake was calculated using the USDA nutrient database
(20). Menaquinone intake was calculated using previously published
composition data sources (21–23). Reproducibility and relative validity
of a self-administered FFQ used in the study was validated for dietary
phylloquinone and menaquinone intake. The FFQ was administered
twice to explore reproducibility at 1 y, and 4 3-d dietary records were used
as reference to explore validity. Reproducibility for dietary phylloquinone
and menaquinone intake estimated by the Pearson correlation coefficient
(r) was 0.755 and 0.655, respectively, and the intraclass correlation
coefficient was 0.860 and 0.798, respectively (P<0.001)(M.Juanola-
Falgarona, J. Salas-Salvad ´
o, J. Fern´
andez-Ballart, M. Bull ´
o, unpublished
data).
Mortality and medical records. Cardiovascular mortality, cancer
mortality, and all-cause mortality were the primary outcomes of our
analysis. Four different approaches were used to identify outcomes: 1)
repeated contact with participants; 2) contact with family physicians; 3)
annual review of medical records; and 4) consultation of the National
Death Index. The end-point adjudication committee, whose members
were unaware of the dietary information from participants, evaluated all
medical records related to end points. Additional information about
health status and medication use was collected directly from the
participants in the yearly programmed visits and their medical records.
Anthropometric and biochemical measurements. Baseline weight
and height were measured by trained personnel with calibrated scales and a
wall-mounted stadiometer, respectively. Waist circumference was measured
with an anthropometric tape midway between the lower rib and the supe rior
border of the iliac crest. Blood pressure was measured in triplicate with a
validated semiautomatic oscillometer (Omron HEM-705CP). Leisure-
time physical activity was evaluated using the validated Spanish version
of the Minnesota leisure-time physical activity questionnaire (24).
Statistical analysis. Descriptive data of participantsÕbaseline charac-
teristics were presented as means 6SDs, and categorical variables were
presented as percentages. Participants who were outside the predefined
values for total energy intake (>4000 or <800 kcal/d in men and >3500
or <500 kcal/d in women) were excluded from the analysis. All nutrients
were adjusted for total energy intake using the residuals method (25).
Energy-adjusted phylloquinone and menaquinone intake was divided
into quartiles on the basis of the total cohort. Survival time was
calculated as the number of days between entering the study and death or
end of follow-up, whichever occurred first. Time-to-event data were
analyzed using the Kaplan-Meier method. Cox proportional hazards
regression models were fitted to estimate HRs and the corresponding
21
Abbreviations used: CHD, coronary heart disease; MK, menaquinone; PREDIMED,
Prevenci ´
on con Dieta Mediterr ´
anea; T2DM, type 2 diabetes mellitus.
2 of 8 Juanola-Falgarona et al.
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
95% CIs for cardiovascular mortality, cancer mortality, and all-cause
mortality. Dietary intake of phylloquinone and menaquinone was
entered into the models categorized into energy-adjusted vitamin K
quartiles, with the lowest quartile as the reference category. Tests for
linear trend were performed by modeling the median values of
phylloquinone and menaquinone quartiles as continuous variables.
Additionally, 3 multivariate models were used: 1) model 1 was adjusted
for sex, age, BMI, recruiting center, intervention group, smoking (never,
current, past), leisure time activity (metabolic equivalent of task per
day), and education (primary education, secondary education, higher
education); 2) model 2 was additionally adjusted for history of diabetes,
hypertension, and hypercholesterolemia, use of oral antidiabetic med-
ication, use of antihypertensive medication, and use of statins; and 3)
model 3 was additionally adjusted for energy-adjusted dietary variables
in quintiles (vegetables, fruits, legumes, cereals, dairy products, meat,
fish, olive oil, nuts), alcohol, and alcohol squared in grams per day to
account for departures from linearity. Dietary phylloquinone intake and
dietary menaquinone intake were not adjusted for vegetables and dairy
products, respectively, because both dietary variables are the major
source of vitamin K types. We had yearly updated information on dietary
phylloquinone and menaquinone intake, so to take advantage of this
updated information, we repeated the analysis using generalized estimating
equations to assess the association between repeated measurements of
vitamin K consumption and mortality. For each 1-y period, we used as
exposure the mean phylloquinone or menaquinone intake of all repeated
measurements from baseline to the beginning of that yearly period.
Cox regression models were also fitted to estimate HRs for cardiovas-
cular mortality, cancer mortality, or all-cause mortality for participants
who increased their dietary phylloquinone intake compared with partic-
ipants who reduced or did not change their intake during the entire follow-
up. Additional Cox regression models were used to assess the risk of total
mortality, cardiovascular mortality, and cancer mortality according to the
increasing or not increasing total dietary phylloquinone intake and the
intervention group. Linear trends were also tested.
Interaction tests for sex, T2DM, and intervention group (sex 3
vitamin K intake, T2DM 3vitamin K intake, intervention group 3
vitamin K intake) were not statistically significant. All statistical tests
were 2-tailed, and the significance level was P< 0.05. Statistical analysis
was performed using SPSS 17.0 for Windows (SPSS) and STATA 12.0
(StataCorp).
Results
Of the 7447 participants randomly assigned to the PREDIMED
trial, 153 were excluded from the present analysis because their
total energy intake was outside the predefined limits, and an
additional 78 participants were also excluded because their
dietary data at baseline were incomplete. Selected baseline
participant characteristics across quartiles of energy-adjusted
dietary phylloquinone and menaquinone for the 7216 partici-
pants available for analyses are shown in Table 1.
Participants with higher intakes of dietary phylloquinone had a
lower BMI and waist circumference, were more physically active,
and were less likely to be current smokers. Those participants
allocated to the higher quartiles of dietary menaquinone intake
had higher BMI and waist circumference but they were more
physically active and fewer were smokers. A small but significant
correlation was found between total phylloquinone and menaqui-
none intake (r=0.05,P< 0.001). Participants in the upper quartile
of energy-adjusted dietary phylloquinone intake consumed nearly
twice as many vegetables (especially leafy green vegetables and
fruits) as those in the lower quartile. Increased menaquinone
intake was associated with higher consumption of dairy products
and meat (Supplemental Table 1). In a median follow-up of 4.8 y
(IQR: 2.8–5.8), 81 fatal cardiovascular events and 130 deaths
from cancer occurred. A total of 323 participants died from any
cause. The survival curves of cardiovascular mortality, cancer
mortality, or all-cause mortality by quartiles of energy-adjusted
dietary phylloquinone and menaquinone intake are shown in
Figure 1. The number of participants at risk by energy-adjusted
vitamin K intake quartiles at different time points is also shown in
Figure 1.
Multivariate-adjusted HRs for cardiovascular mortality,
cancer mortality, or all-cause mortality according to quartiles
of energy-adjusted phylloquinone and menaquinone intake are
shown in Table 2. Participants in the upper quartiles of
phylloquinone or menaquinone intake had a nonsignificantly
lower risk of cardiovascular mortality than those in the lowest
quartiles in all the fitted models (P> 0.1). Dietary phylloquinone
intake was inversely associated with cancer mortality risk (HR
for the highest and all-cause mortality compared with the lowest
quartile: 0.54; 95% CI: 0.30, 0.96; P-trend = 0.033). The
relation between dietary phylloquinone intake and cancer or
total mortality risk has an apparently inverse linear shape in all
the fitted models (P-trend < 0.05). When we used generalized
estimating equations to assess the association between yearly
updated measurements of total vitamin K consumption and all-
cause mortality risk, we also found a significant inverse associa-
tion. The fully adjusted RR was 0.68 (95% CI: 0.50, 0.93) with a
significant linear trend test. When we repeated the analysis using
generalized estimating equations to assess the association between
yearly updated measurements of dietary phylloquinone or mena-
quinone intake and mortality, the fully adjusted RR for the highest
compared with the lowest quintile were 0.55 (95% CI: 0.27, 1.14)
and 1.27 (95% CI: 0.73, 2.23) for cardiovascular mortality, 0.80
(95% CI: 0.46, 1.40) and 0.75 (95% CI: 0.42, 1.32) for cancer
mortality, and 0.81 (95% CI: 0.57, 1.15) and 1.12 (95% CI: 0.82,
1.54) for all-cause mortality. Linear trend tests were not significant
(P>0.1).
The HRs for cardiovascular mortality, cancer mortality, and
all-cause mortality for individuals who increased their dietary
vitamin K intake along the follow-up compared with those who
reduced or did not change it are shown for Table 3. During the
follow-up, 3141 and 2572 participants increased their con-
sumption of phylloquinone and menaquinone, respectively. On
the contrary, 4057 and 4626, respectively, reduced or did not
change it. A decreased risk in cardiovascular mortality (HR:
0.52; 95% CI: 0.31, 0.86; P-trend = 0.012), cancer mortality
(HR: 0.64; 95% CI: 0.43, 0.95; P-trend = 0.026), and all-cause
mortality (HR: 0.57; 95% CI: 0.44, 0.73; P-trend < 0.001) was
observed in those participants who increased their intake of dietary
phylloquinone during the follow-up, even after adjusting for other
dietary confounders. Similarly, participants who increased their
intake of dietary menaquinone were likely to have a lower risk
of mortality by cancer and all-cause mortality (P< 0.001).
The multivariate adjusted HRs for total mortality, cardiovascu-
lar mortality, or cancer mortality by changes in both dietary
phylloquinone and menaquinone intakes and intervention group
are shown in Supplemental Figure 1 and Supplemental Table 2.
In the 3 arms of the trial, individuals who increased dietary
intake of both forms of vitamin K during the follow-up tended
to have a lower risk of mortality than those in the reference
category.
Discussion
To the best of our knowledge, the results of the present study
show, for the first time, an inverse association between an
increased intake of both dietary phylloquinone and menaqui-
none, and cancer mortality or all-cause mortality. Moreover,
Dietary vitamin K intake and mortality 3 of 8
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
TABLE 1 Baseline characteristics of 7216 Mediterranean adults at high cardiovascular disease risk by quartiles of energy-adjusted phylloquinone and menaquinone intakes
1
Energy-adjusted quartiles of phylloquinone intake
2
(mg/d) Energy-adjusted quartiles of menaquinone intake
3
(mg/d)
Variable Q1 Q2 Q3 Q4 P
4
Q1 Q2 Q3 Q4 P
4
Women, n(%) 966 (53.6) 1012 (56.1) 1051 (58.3) 1114 (61.8) ,0.001 940 (52.1) 1083 (60.0) 1097 (60.8) 1025 (56.8) ,0.001
Age, y67 67676667666766 0.083 67 66676667666766 0.001
BMI, kg/m
2
30.2 63.9 30.0 63.7 29.8 63.8 29.9 64.0 0.009 29.5 63.7 30.1 63.8 30.2 63.9 30.1 64.0 ,0.001
Waist circumference, cm 101.6 610.5 100.3 610.3 99.9 610.6 100.1 610.8 ,0.001 99.2 610.1 100.6 610.7 100.7 610.6 101.4 611.0 ,0.001
Smoking status, n(%)
Never 1056 (59) 1110 (61) 1123 (62) 1150 (64) 1048 (58) 1158 (64) 1139 (63) 1094 (61)
Current 279 (15) 268 (15) 249 (14) 208 (11) 297 (16) 220 (12) 244 (14) 243 (13)
Former 469 (26) 426 (24) 432 (24) 446 (25) 0.005 459 (25) 426 (24) 421 (23) 467 (26) 0.001
Education, n(%)
Primary education 1376 (77) 1333 (75) 1390 (79) 1372 (77) 1364 (76) 1410 (79) 1375 (79) 1322 (75)
Secondary education 276 (15) 313 (18) 245 (14) 262 (15) 282 (16) 262 (15) 249 (14) 303 (17)
Higher education 129 (7) 124 (7) 124 (7) 139 (8) 0.07 144 (8) 103 (6) 127 (7) 142 (8) 0.010
Type 2 diabetes, n(%) 835 (46) 846 (47) 863 (48) 965 (53) ,0.001 752 (42) 881 (49) 912 (51) 964 (53) ,0.001
Hypertension, n(%) 150 (84) 149 (83) 150 (83) 146 (81) 0.21 1501 (83) 1509 (84) 1497 (83) 1463 (81) 0.19
Hypercholesterolemia, n(%) 132 (73) 128 (71) 128 (71) 132 (74) 0.18 1349 (75) 1293 (72) 1334 (74) 1236 (69) ,0.001
Intervention group, n(%)
Mediterranean diet with EVOO 598 (33) 628 (35) 610 (34) 637 (35) 623 (35) 614 (34) 598 (33) 639 (35)
Mediterranean diet with nuts 540 (30) 569 (32) 647 (36) 602 (33) 581 (32) 582 (32) 596 (33) 601 (33)
Control diet 665 (37) 606 (34) 547 (30) 564 (31) ,0.001 600 (33) 608 (34) 610 (34) 564 (31) 0.64
Leisure-time physical activity, MET-min/d 209 6230 230 6233 238 6230 248 6260 ,0.001 246 6261 221 6224 226 6232 231 6237 0.011
1
Data are means 6SDs or n(%) unless otherwise indicated. n= 1804 participants in each quartile. EVOO, extra virgin olive oil; MET, metabolic equivalent of task; Q, quartile.
2
The mean energy-adjusted phylloquinone intakes for Q1, Q2, Q3, and Q4 were as follows: 170.5 mg/d, 276.1 mg/d, 349.7 mg/d, and 626.4 mg/d, respectively.
3
The mean energy-adjusted menaquinone intakes for Q1, Q2, Q3, and Q4 were as follows: 18.4 mg/d, 29.9 mg/d, 39.0 mg/d, and 57.5 mg/d, respectively.
4
Pvalues are based on the difference between quartiles of energy-adjusted dietary vitamin K intake (ANOVA for the continuous variables and x
2
test for categorical variables).
4 of 8 Juanola-Falgarona et al.
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
increasing dietary phylloquinone intake, but not menaquinone
intake, was related to a lower risk of cardiovascular mortality.
Interest in vitamin K has been aroused recently by evidence to
suggest that it has a physiologic role that goes beyond mere coag-
ulation processes. Vitamin K has acquired importance in the phys-
iopathology of vascular calcification and atherosclerotic diseases but
also in the modulation of bone metabolism and cancer initiation and
progression (26,27). Therefore, higher phylloquinone dietary intake
hasbeenassociatedwithalower risk of developing age-related
chronic diseases, such as abdominal aortic calcification (3), insulin
resistance (28), and osteoporosis (29). These beneficial effects could
be explained by several mechanisms involving vitamin K–dependent
proteins. However, there is evidence emerging from in vitro and in
vivo studies to indicate that the biochemical function of vitamin K
could be extended to other mechanisms [i.e., modulating inflam-
matory molecules (28,30,31) or controlling carcinogenesis (10,32)].
Few epidemiologic studies evaluated the role of the dietary
intake of vitamin K in cardiovascular disease and all-cause
mortality, and the results are far from consistent or conclusive.
Although most (7,8) but not all (5) published studies observed no
consistent association between phylloquinone intake and fatal
or nonfatal CHD, the available evidence seems to suggest that
menaquinone intake has a protective effect against the incidence of
fatal and nonfatal CHD or all-cause mortality (7,8). In our study,
we found no significant association between phylloquinone or
menaquinone dietary intake and cardiovascular mortality, although
we did find a significant inverse association between dietary
phylloquinone intake and all-cause mortality.
There may be several reasons for the apparent differences
between our results and those reported previously by other
cohorts. First, the PREDIMED study population was composed
of elderly individuals at high cardiovascular disease risk,
whereas the other studies were of healthy participants. Although
in our study Cox regression models were adjusted for several
cardiovascular disease risk factors, these factors still had a
residual effect on cardiovascular mortality, masking a potential
protective effect of vitamin K. Thus, in a sensibility analysis,
dietary vitamin K intake in those participants having #3
cardiovascular disease risk factors was significantly lower than
those at higher risk (mean 6SE: 352.91 62.73 vs. 363.54 6
4.75, respectively; P= 0.048). Second, the definition of the
outcome is not the same in all studies. In the Rotterdam Study
and the NursesÕHealth Study, the outcome was CHD incidence,
but in our study, we included within cardiovascular mortality
not only fatal CHD but also fatal stroke and other deaths from
atherosclerotic cardiovascular disease. Only 1 study evaluated
FIGURE 1 Nelson-Aalen estimates of inci-
dence of cardiovascular (A,B), cancer (C,D),
and total (E,F) mortality by quartiles of energy-
adjusted vitamin K intake. Q, quartile.
Dietary vitamin K intake and mortality 5 of 8
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
TABLE 2 Adjusted HRs of cardiovascular, cancer, and all-cause mortality according to quartile
categories of vitamin K intake of 7216 Mediterranean adults at high cardiovascular disease risk
1
Energy-adjusted quartiles of vitamin K intake, HR (95% CI)
Q1 (n= 1804) Q2 (n= 1804) Q3 (n= 1804) Q4 (n= 1804) P-trend
Cardiovascular mortality
Phylloquinone
2
(mg/d) 170.5 276.1 349.7 626.4
Person-years 7672 7858 7955 7594
Cases 25 21 21 14
Crude model 1 (Reference) 0.81 (0.45, 1.44) 0.79 (0.44, 1.41) 0.55 (0.29, 1.06) 0.08
Model 1
3
1 (Reference) 0.78 (0.43, 1.41) 0.82 (0.46, 1.49) 0.54 (0.28, 1.07) 0.09
Model 2
4
1 (Reference) 0.76 (0.42, 1.37) 0.77 (0.43, 1.40) 0.50 (0.25, 1.00) 0.06
Model 3
5
1 (Reference) 0.89 (0.49, 1.64) 1.04 (0.56, 1.92) 0.63 (0.31, 1.28) 0.20
Menaquinone
2
(mg/d) 18.4 29.9 39.0 57.5
Person-years 7940 7721 7626 7792
Cases 18 18 19 26
Crude model 1 (Reference) 1.04 (0.54, 2.01) 1.11 (0.58, 2.12) 1.48 (0.81, 2.70) 0.17
Model 1 1 (Reference) 1.08 (0.56, 2.08) 1.02 (0.52, 1.98) 1.57 (0.86, 2.87) 0.13
Model 2 1 (Reference) 1.04 (0.54, 2.01) 0.93 (0.47, 1.82) 1.44 (0.79, 2.65) 0.23
Model 3 1 (Reference) 1.04 (0.52, 2.06) 0.89 (0.44, 1.83) 1.18 (0.60, 2.34) 0.63
Cancer mortality
Phylloquinone (mg/d) 170.5 276.1 349.7 626.4
Person-years 7672 7858 7955 7594
Cases 38 36 39 17
Crude model 1 (Reference) 0.91 (0.58, 1.44) 0.95 (0.61, 1.49) 0.48 (0.27, 0.84) 0.009
Model 1 1 (Reference) 0.86 (0.54, 1.37) 0.95 (0.60, 1.50) 0.49 (0.28, 0.87) 0.014
Model 2 1 (Reference) 0.87 (0.54, 1.38) 0.94 (0.59, 1.48) 0.49 (0.28, 0.87) 0.014
Model 3 1 (Reference) 0.90 (0.56, 1.45) 1.01 (0.63, 1.62) 0.54 (0.30, 0.96) 0.033
Menaquinone (mg/d) 18.4 29.9 39.0 57.5
Person-years 7940 7721 7626 7792
Cases 34 34 34 38
Crude model 1 (Reference) 1.04 (0.65, 1.68) 1.07 (0.66, 1.72) 0.85 (0.52, 1.41) 0.55
Model 1 1 (Reference) 1.03 (0.53, 1.98) 0.99 (0.51, 1.93) 1.52 (0.83, 2.78) 0.08
Model 2 1 (Reference) 1.12 (0.69, 1.82) 1.14 (0.70, 1.86) 0.90 (0.54, 1.50) 0.66
Model 3 1 (Reference) 0.88 (0.55, 1.43) 1.00 (0.60, 1.67) 0.62 (0.32, 1.21) 0.45
All-cause mortality
Phylloquinone (mg/d) 170.5 276.1 349.7 626.4
Person-years 7672 7858 7955 7594
Cases 93 84 92 54
Crude model 1 (Reference) 0.87 (0.65, 1.17) 0.92 (0.69, 1.23) 0.59 (0.42, 0.82) 0.002
Model 1 1 (Reference) 0.85 (0.63, 1.14) 0.96 (0.71, 1.28) 0.61 (0.44, 0.86) 0.006
Model 2 1 (Reference) 0.83 (0.62, 1.13) 0.92 (0.69, 1.24) 0.59 (0.42, 0.83) 0.003
Model 3 1 (Reference) 0.90 (0.67, 1.22) 1.03 (0.76, 1.40) 0.64 (0.45, 0.90) 0.011
Menaquinone (mg/d) 18.4 29.9 39.0 57.5
Person-years 7940 7721 7626 7792
Cases 79 85 72 87
Crude model 1 (Reference) 1.12 (0.83, 1.53) 0.97 (0.70, 1.33) 1.13 (0.84, 1.54) 0.58
Model 1 1 (Reference) 1.21 (0.89, 1.65) 1.00 (0.72, 1.39) 1.24 (0.92, 1.69) 0.28
Model 2 1 (Reference) 1.17 (0.86, 1.60) 0.96 (0.69, 1.33) 1.16 (0.85, 1.58) 0.55
Model 3 1 (Reference) 1.14 (0.83, 1.58) 0.89 (0.62, 1.26) 1.02 (0.72, 1.43) 0.81
1
Cox regression models were used to assess the risk of mortality according to the quartile of energy-adjusted dietary vitamin K intake.
MET, metabolic equivalent of task; Q, quartile.
2
Phylloquinone and menaquinone intake are expressed as mean.
3
Model 1 was adjusted for sex, age, BMI, recruiting center, intervention group, smoking (never, current, past), leisure time activity (MET/d),
and education (primary education, secondary education, higher education).
4
Model 2 was additionally adjusted for history of diabetes, hypertension, and hypercholesterolemia, use of oral antidiabetic medication, use
of antihypertensive medication, and use of statin medication.
5
Model 3 was additionally adjusted for dietary variables in energy-adjusted quintiles (vegetables, fruits, legumes, cereals, dairy products,
meat, fish, olive oil, nuts) and alcohol and alcohol squared in grams per day. Dietary phylloquinone intake and dietary menaquinone intake
were not adjusted for vegetables and dairy products, respectively, because both dietary variables are the major source of vitamin K types.
6 of 8 Juanola-Falgarona et al.
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
the association between vitamin K intake and cancer mortality.
That study showed that cancer mortality was significantly
lower among individuals with higher intakes of menaquinone
but not phylloquinone. However, the reduction in cancer risk
associated with menaquinone intake was only significant in
men, and no results for cancer mortality separated by sex were
reported previously (14). Our study showed inverse associations
between increased dietary intake of both phylloquinone and
menaquinone and total cancer mortality, and this association
remained when it was assessed in men and women separately,
which is additional evidence suggesting a possible protective role
of vitamin K intake. These discrepancies with the previous study
could be partly due to differences in study population and in food-
database and dietary assessment instruments used, thus explaining
the substantially higher dietary intake of vitamin K observed in
the PREDIMED study compared with the cohort studied by
Nimptsch et al. (14). It is important to note that results of both
cross-sectional and longitudinal analysis in our study are in the
same direction, although no statistical differences were observed
in the first case. This could be explained by the fact that multiple
assessments of the FFQ may reduce misclassification from a
single FFQ, but we also have to consider that longitudinal
analysis preserves the temporal sequence and it is better
protected against several biases, especially if a dietary interven-
tion has been conducted.
Because this was a nutritional epidemiologic study that did
not use biomarkers, 1 of the main limitations of our study was
the relative validity of estimating dietary intake of vitamin K by
data from FFQs. We cannot discount that vitamin K intake has
been overestimated because of the use of FFQs and the USDA
food-database composition. However, analyzing the data of a
previous validation study conducted in this population (17), the
Pearson correlation coefficient between the 3-d dietary records
and the FFQ was reasonable for phylloquinone (r= 0.78) and
menaquinone (r= 0.66). These correlations compared favorably
with results of the validation studies described previously
(33,34). Moreover, although there is no 1:1 correlation between
vitamin K intake and vitamin K absorption, a significant
association between dietary phylloquinone intake and plasma
phylloquinone was reported previously (35). Dietary intake
of menaquinone has also been reflected in the menaquinone
serum concentrations of a healthy Japanese cohort of regular con-
sumers of natt
o, a fermented soybean product, the richest
menaquinone food product (36). The individuals in our study
reported a higher dietary intake of phylloquinone than those
enrolled in previous epidemiologic studies, probably because
the PREDIMED study participants are from a Mediterranean
country in which the consumption of fruit and vegetables is
quite high. In other populations with a lower consumption of
phylloquinone or poorer nutrition, it is unknown whether or not
an increase in dietary vitamin K would be much more beneficial
in terms of mortality. Another limitation of our analysis is that it
has been conducted in individuals consuming a healthy Medi-
terranean diet, which could partly account for a reduction in
mortality risk. The individuals classified in the highest quartiles
of dietary vitamin K generally had a healthier diet, and they were
also more physically active and less likely to be smokers. To
minimize the potential residual confounding effects of a
healthy lifestyle on mortality, we adjusted the Cox regression
models for several dietary and lifestyle confounding variables.
Even so, the possibility of residual or incompletely controlled
confounding cannot be excluded. Thus, because the design of
our study does not reveal whether or not phylloquinone is a
marker of leafy green vegetable intake or an independent
causality factor, the results of the present study should be
interpreted cautiously. Finally, an important strength of our
study is the prospective and longitudinal analysis with repeated
measurements of dietary vitamin K intake because this reduces
misclassification and enables longitudinal changes in exposure
to be assessed.
Overall, our results suggest that the dietary intake of both active
forms of vitamin K has a potential protective role in cardiovascular
mortality, cancer mortality, and all-cause mortality in a cohort of
Mediterranean individuals at high cardiovascular disease risk with
a relatively high consumption of this vitamin.
TABLE 3 Adjusted HRs of cardiovascular, cancer, and total
mortality among Mediterranean adults at high cardiovascular
disease risk (n= 3141) who increased their dietary phylloquinone
or menaquinone intake during the follow-up compared with those
(n= 2572) who reduced or did not change intake
1
HR (95% CI) P
Cardiovascular mortality
Phylloquinone
Crude model 0.56 (0.35, 0.90) 0.017
Model 1
2
0.50 (0.30, 0.82) 0.006
Model 2
3
0.50 (0.30, 0.83) 0.007
Model 3
4
0.52 (0.31, 0.86) 0.012
Menaquinone
Crude model 0.69 (0.43, 1.12) 0.14
Model 1 0.73 (0.43, 1.25) 0.25
Model 2 0.74 (0.44, 1.26) 0.27
Model 3 0.76 (0.44, 1.29) 0.31
Cancer mortality
Phylloquinone
Crude model 0.81 (0.57, 1.15) 0.23
Model 1 0.62 (0.42, 0.91) 0.014
Model 2 0.65 (0.44, 0.95) 0.027
Model 3 0.64 (0.43, 0.95) 0.026
Menaquinone
Crude model 0.48 (0.31, 0.72) ,0.001
Model 1 0.40 (0.26, 0.63) ,0.001
Model 2 0.41 (0.26, 0.64) ,0.001
Model 3 0.41 (0.26, 0.64) ,0.001
Total mortality
Phylloquinone
Crude model 0.63 (0.50, 0.80) ,0.001
Model 1 0.54 (0.42, 0.69) ,0.001
Model 2 0.55 (0.43, 0.71) ,0.001
Model 3 0.57 (0.44, 0.73) ,0.001
Menaquinone
Crude model 0.56 (0.44, 0.73) ,0.001
Model 1 0.55 (0.42, 0.72) ,0.001
Model 2 0.55 (0.42, 0.72) ,0.001
Model 3 0.55 (0.42, 0.73) ,0.001
1
Cox regression models were used to assess the risk of cardiovascular, cancer, and
all-cause mortality.
2
Model 1 was adjusted for sex, age, changes in BMI, recruiting center, intervention
group, smoking (never, current, past), changes in leisure time activity (MET/d), and
education (primary education, secondary education, higher education).
3
Model 2 was additionally adjusted for history of diabetes, hypertension, and
hypercholesterolemia, use of oral antidiabetic medication, use of antihypertensive
medication, and use of statins.
4
Model 3 was additionally adjusted for dietary variables in energy-adjusted quintiles
(vegetables, fruits, legumes, cereals, dairy products, meat, fish, olive oil, nuts), alcohol
and alcohol squared in grams per day, and changes in energy intake. Dietary
phylloquinone intake and dietary menaquinone intake were not adjusted for vegetables
and dairy products, respectively, because both dietary variables are the major sources
of vitamin K types.
Dietary vitamin K intake and mortality 7 of 8
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
Acknowledgments
M.A.M.-G., D.C., R.E., E.R., F.A., J.L., E.G.-G., M.A.M.,
R.M.L.-R., L.S.-M., X.P., and J.S.-S. designed the research;
M.J.-F., M.B., M.A.M.-G., D.C., E.R., R.E., E.G.-G.,
M. Fit ´
o, F.A., J.L., M. Fiol, R.M.L.-R., L.S.-M., X.P., V.R.-G.,
M.A.M., J.B., J.F.-B., and J.S.-S. conducted the research; M.J.-F.,
M.B., and J.S.-S. analyzed the data; M.J.-F., M.B., and J.S.-S.
wrote the paper; M.A.M., D.C., R.E., M.A.M.-G., L.S.-M., X.P.,
and J.S.-S. were the coordinators of participant recruitment at the
outpatient clinics; and M.B. and J.S.-S. had primary responsibili-
ty for final content. All authors read and approved the final
manuscript.
Literature Cited
1. Shearer MJ. Vitamin K. Lancet. 1995;345:229–34.
2. Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue
calcification. Adv Nutr. 2012;3:166–73.
3. Jie KS, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Vitamin K intake
and osteocalcin levels in women with and without aortic atherosclerosis: a
population-based study. Atherosclerosis. 1995;116:117–23.
4. Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of
K-vitamins in healthy subjects. Biochim Biophys Acta. 2002;1570:27–32.
5. Erkkila
¨AT, Booth SL, Hu FB, Jacques PF, Manson JE, Rexrode KM,
Stampfer MJ, Lichtenstein AH. Phylloquinone intake as a marker for
coronary heart disease risk but not stroke in women. Eur J Clin Nutr.
2005;59:196–204.
6. Erkkila
¨AT, Booth SL, Hu FB, Jacques PF, Lichtenstein AH. Phylloqui-
none intake and risk of cardiovascular diseases in men. Nutr Metab
Cardiovasc Dis. 2007;17:58–62.
7. Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van
der Meer IM, Hofman A, Witteman JC. Dietary intake of menaquinone
is associated with a reduced risk of coronary heart disease: the
Rotterdam Study. J Nutr. 2004;134:3100–5.
8. Gast GC, de Roos NM, Sluijs I, Bots ML, Beulens JW, Geleijnse JM,
Witteman JC, Grobbee DE, Peeters PH, van der Schouw YT. A high
menaquinone intake reduces the incidence of coronary heart disease.
Nutr Metab Cardiovasc Dis. 2009;19:504–10.
9. Wu FY, Liao WC, Chang HM. Comparison of antitumor activity of
vitamins K1, K2 and K3 on human tumor cells by two (MTT and SRB)
cell viability assays. Life Sci. 1993;52:1797–804.
10. Tokita H, Tsuchida A, Miyazawa K, Ohyashiki K, Katayanagi S, Sudo
H, Enomoto M, Takagi Y, Aoki T. Vitamin K2-induced antitumor
effects via cell-cycle arrest and apoptosis in gastric cancer cell lines. Int J
Mol Med. 2006;17:235–43.
11. Akiyoshi T, Matzno S, Sakai M, Okamura N, Matsuyama K. The
potential of vitamin K3 as an anticancer agent against breast cancer that
acts via the mitochondria-related apoptotic pathway. Cancer Chemo-
ther Pharmacol. 2009;65:143–50.
12. Habu D, Shiomi S, Tamori A, Takeda T, Tanaka T, Kubo S, Nishiguchi
S. Role of vitamin K2 in the development of hepatocellular carcinoma in
women with viral cirrhosis of the liver. JAMA. 2004;292:358–61.
13. Nimptsch K, Rohrmann S, Linseisen J. Dietary intake of vitamin K and
risk of prostate cancer in the Heidelberg cohort of the European
Prospective Investigation into Cancer and Nutrition (EPIC-Heidelberg).
Am J Clin Nutr. 2008;87:985–92.
14. Nimptsch K, Rohrmann S, Kaaks R, Linseisen J. Dietary vitamin K intake
in relation to cancer incidence and mortality: results from the Heidelberg
cohort o f the European Prospective Investigat ion into Cancer a nd
Nutrition (EPIC-Heidelberg). Am J Clin Nutr. 2010;91:1348–58.
15. Mart´
ınez-Gonz´
alez MA, Corella D, Salas-Salvado J, Ros E, Covas MI,
Fiol M, Warnberg J, Aros F, Ruiz-Gutierrez V, Lamuela-Raventos RM,
et al. Cohort profile: design and methods of the PREDIMED study. Int J
Epidemiol. 2012;41:377–385.
16. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-
Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, et al. Primary prevention
of cardiovascular disease with a Mediterranean diet. N Engl J Med.
2013;368:1279–90.
17. Fern´
andez-Ballart JD, Pinol JL, Zazpe I, Corella D, Carrasco P, Toledo
E, Perez-Bauer M, Martinez-Gonzalez MA, Salas-Salvado J, Martin-
Moreno JM. Relative validity of a semi-quantitative food-frequency
questionnaire in an elderly Mediterranean population of Spain. Br J
Nutr. 2010;103:1808–16.
18. Moreiras O, Carbajal A, Cabrera L, Cuadrado C. Tablas de composici´
on
de los alimentos. Madrid: Pir´
amide; 2005.
19. Mataix Verd ´
u J. Tabla de composicion de alimentos. Granada, Spain:
Universidad de Granada; 2003.
20. USDA. National nutrient database for standard reference. [cited 2011
Dec 7]. Available from: http://ndb.nal.usda.gov/ndb/search/list.
21. Schurgers LJ, Vermeer C. Determination of phylloquinone and
menaquinones in food. Effect of food matrix on circulating vitamin K
concentrations. Haemostasis. 2000;30:298–307.
22. Kamao M, Suhara Y, Tsugawa N, Uwano M, Yamaguchi N, Uenishi K,
Ishida H, Sasaki S, Okano T. Vitamin K content of foods and dietary
vitamin K intake in Japanese young women. J Nutr Sci Vitaminol
(Tokyo). 2007;53:464–70.
23. Elder SJ, Haytowitz DB, Howe J, Peterson JW, Booth SL. Vitamin k
contents of meat, dairy, and fast food in the U.S. Diet. J Agric Food
Chem. 2006;54:463–7.
24. Schro
¨der H, Fito M, Estruch R, Martinez-Gonzalez MA, Corella D,
Salas-Salvado J, Lamuela-Raventos R, Ros E, Salaverria I, Fiol M, et al.
A short screener is valid for assessing Mediterranean diet adherence
among older Spanish men and women. J Nutr. 2011;141:1140–5.
25. Willett WC, Howe GR, Kushi LH. Adjustment for total energy intake in
epidemiologic studies. Am J Clin Nutr. 1997;65:1220S–8S; discussion
1229S–31S.
26. Lamson DW, Plaza SM. The anticancer effects of vitamin K. Altern Med
Rev. 2003;8:303–18.
27. Apalset EM, Gjesdal CG, Eide GE, Tell GS. Intake of vitamin K1 and
K2 and risk of hip fractures: the Hordaland Health Study. Bone.
2011;49:990–5.
28. Juanola-Falgarona M, Salas-Salvado J, Estruch R, Portillo MP, Casas R,
Miranda J, Martinez-Gonzalez MA, Bullo M. Association between
dietary phylloquinone intake and peripheral metabolic risk markers
related to insulin resistance and diabetes in elderly subjects at high
cardiovascular risk. Cardiovasc Diabetol. 2013;12:7.
29. Feskanich D, Weber P, Willett WC, Rockett H, Booth SL, Colditz GA.
Vitamin K intake and hip fractures in women: a prospective study. Am J
Clin Nutr. 1999;69:74–9.
30. Ohsaki Y, Shirakawa H, Hiwatashi K, Furukawa Y, Mizutani T, Komai
M. Vitamin K suppresses lipopolysaccharide-induced inflammation in
the rat. Biosci Biotechnol Biochem. 2006;70:926–32.
31. Ohsaki Y, Shirakawa H, Miura A, Giriwono PE, Sato S, Ohashi A, Iribe
M, Goto T, Komai M. Vitamin K suppresses the lipopolysaccharide-
induced expression of inflammatory cytokines in cultured macrophage-
like cells via the inhibition of the activation of nuclear factor kappaB
through the repression of IKKalpha/beta phosphorylation. J Nutr
Biochem. 2010;21:1120–6.
32. Bouzahzah B, Nishikawa Y, Simon D, Carr BI. Growth control and gene
expression in a new hepatocellular carcinoma cell line, Hep40:
inhibitory actions of vitamin K. J Cell Physiol. 1995;165:459–67.
33. Beulens JW, van der ADL, Grobbee DE, Sluijs I, Spijkerman AM, van
der Schouw YT. Dietary phylloquinone and menaquinones intakes and
risk of type 2 diabetes. Diabetes Care. 2010;33:1699–705.
34. Presse N, Shatenstein B, Kergoat MJ, Ferland G. Validation of a semi-
quantitative food frequency questionnaire measuring dietary vitamin K
intake in elderly people. J Am Diet Assoc. 2009;109:1251–5.
35. Thane CW, Bates CJ, Shearer MJ, Unadkat N, Harrington DJ, Paul AA,
Prentice A, Bolton-Smith C. Plasma phylloquinone (vitamin K1)
concentration and its relationship to intake in a national sample of
British elderly people. Br J Nutr. 2002;87:615–22.
36. Kaneki M, Hodges SJ, Hosoi T, Fujiwara S, Lyons A, Crean SJ, Ishida
N, Nakagawa M, Takechi M, Sano Y, et al. Japanese fermented soybean
food as the major determinant of the large geographic difference in
circulating levels of vitamin K2: possible implications for hip-fracture
risk. Nutrition. 2001;17:315–21. Erratum in: Nutrition. 2006;22:1075.
8 of 8 Juanola-Falgarona et al.
at UNIVERSIDAD ROVIRA I VIRGILI on March 22, 2014jn.nutrition.orgDownloaded from
... Vitamin K 1 is hypothesised to have anticancer effects and has been found to inhibit some human tumour cell lines, but the evidence is weak [9,10]. Evidence from observational studies is limited and provides conflicting reports as to the association between vitamin K 1 and both all-cause [11][12][13][14] and cause-specific mortality, including CVD- [11,13,14] and cancer-related mortality [11,13,15,16]. The inconsistent findings between observational studies warrants further investigation of the potential associations in a large cohort setting. ...
... Vitamin K 1 is hypothesised to have anticancer effects and has been found to inhibit some human tumour cell lines, but the evidence is weak [9,10]. Evidence from observational studies is limited and provides conflicting reports as to the association between vitamin K 1 and both all-cause [11][12][13][14] and cause-specific mortality, including CVD- [11,13,14] and cancer-related mortality [11,13,15,16]. The inconsistent findings between observational studies warrants further investigation of the potential associations in a large cohort setting. ...
... Vitamin K 1 is hypothesised to have anticancer effects and has been found to inhibit some human tumour cell lines, but the evidence is weak [9,10]. Evidence from observational studies is limited and provides conflicting reports as to the association between vitamin K 1 and both all-cause [11][12][13][14] and cause-specific mortality, including CVD- [11,13,14] and cancer-related mortality [11,13,15,16]. The inconsistent findings between observational studies warrants further investigation of the potential associations in a large cohort setting. ...
Article
Full-text available
Reported associations between vitamin K 1 and both all-cause and cause-specific mortality are conflicting. The 56,048 participants from the Danish Diet, Cancer, and Health prospective cohort study, with a median [IQR] age of 56 [52–60] years at entry and of whom 47.6% male, were followed for 23 years, with 14,083 reported deaths. Of these, 5015 deaths were CVD-related, and 6342 deaths were cancer-related. Intake of vitamin K 1 (phylloquinone) was estimated from a food-frequency questionnaire (FFQ), and its relationship with mortality outcomes was investigated using Cox proportional hazards models. A moderate to high (87–192 µg/d) intake of vitamin K 1 was associated with a lower risk of all-cause [HR (95%CI) for quintile 5 vs quintile 1: 0.76 (0.72, 0.79)], cardiovascular disease (CVD)-related [quintile 5 vs quintile 1: 0.72 (0.66, 0.79)], and cancer-related mortality [quintile 5 vs quintile 1: 0.80 (0.75, 0.86)], after adjusting for demographic and lifestyle confounders. The association between vitamin K 1 intake and cardiovascular disease-related mortality was present in all subpopulations (categorised according to sex, smoking status, diabetes status, and hypertension status), while the association with cancer-related mortality was only present in current/former smokers (p for interaction = 0.002). These findings suggest that promoting adequate intakes of foods rich in vitamin K 1 may help to reduce all-cause, CVD-related, and cancer-related mortality at the population level.
... The prospective, cohort PRED-IMED study showed that subjects who increased their dietary supply of phylloquinone or menaquinones during the follow-up period compared with subjects who decreased or did not change their dietary supply of these components had a lower risk of cancer death and death overall. A significant relationship was also shown for dietary supply of phylloquinone, but not menaquinones, as well as risk of cardiovascular death [17]. A study in Norway conducted by Haugsgjerd et al. [18] also showed an association between higher dietary supply of vitamin K2 and reduced risk of incident ischemic heart disease, but no such relation was found for vitamin K1. ...
... A review paper published in 2020 by Palmer et al. [26] noted that few studies have assessed the vitamin K content of Western diets. Vitamin K content was assessed in different populations characterized by various dietary habits, i.e., the Netherlands [4], Spain [17], Norway [18], Germany [27], and Japan [28]. The content of vitamin K in the diet of Poles has not been studied as its content in food is not reported in the Polish Food Composition and Nutritional Value Tables [29]. ...
Article
Full-text available
The aim of the study was to estimate the content of K1, K2 (MK-n) as well as total K vitamins and their sources in the diets of 1985 PURE Poland study participants based on the FFQ questionnaire. Due to the pleiotropic effect of K vitamins, it is important to know their food sources depending on different eating habits. Total vitamin K in the diets amounted to 331.1 ± 151.5 µg/d and 358.6 ± 181.0 µg/d for men and women, respectively. Dietary patterns (DPs) were identified in the study group, and the relationship between them and vitamin K intake was assessed. The proportion of dominant products as sources of vitamin K in the fourth quartile of each of the three identified DPs did not change significantly compared to the proportion of these products as sources of vitamin K in all subjects. In the fourth quartile of individual DPs, vitamin K1 came mainly from vegetables (56.5–76.8%); K2 mainly from processed meat and high-fat cheese and cream (70.1–77.6%); and total K mainly from vegetables and processed meat (57.6–67.8%). Intakes of K vitamins were high and similar in terms of predominant vitamin K provider products, in groups of subjects whose diets were most consistent with the particular DP. In the absence of global findings on the most appropriate dietary content of MK-n vitamins other than phylloquinone, the estimated high content of these vitamins in the diets of the subjects compared with other nations suggests that their level in diets was satisfactory. Future studies should aim to determine the need for MK-n vitamins in terms of fulfilling all their functions in the body.
... Vitamin K is a group of lipid-soluble vitamins that has two natural forms: vitamin K 1 (phylloquinone) and vitamin K 2 (menaquinone) [175]. Vitamin K 1 can be found in green leafy vegetables and olive and soybean oils, while vitamin K 2 is mainly present in fermented food such as cheese, natto, and curds, endogenously generated by intestinal bacteria [176]. ...
... In the prospective cohort study of the European Prospective Investigation into Cancer and Nutrition-Heidelberg, dietary intake of vitamin K 2 had an inverse association with cancer mortality [177]. An alternate prospective cohort analysis in a Mediterranean population also indicated that dietary intake of vitamin K is inversely associated with the risk of cancer mortality [175]. Vitamin K 2 also increases nonapoptotic cell death with autophagy in TNBC cells [42]. ...
Article
Full-text available
Since Otto Warburg’s first report on the increased uptake of glucose and lactate release by cancer cells, dysregulated metabolism has been acknowledged as a hallmark of cancer that promotes proliferation and metastasis. Over the last century, studies have shown that cancer metabolism is complex, and by-products of glucose and glutamine catabolism induce a cascade of both pro- and antitumorigenic processes. Some vitamins, which have traditionally been praised for preventing and inhibiting the proliferation of cancer cells, have also been proven to cause cancer progression in a dose-dependent manner. Importantly, recent findings have shown that the nervous system is a key player in tumor growth and metastasis via perineural invasion and tumor innervation. However, the link between cancer–nerve crosstalk and tumor metabolism remains unclear. Here, we discuss the roles of relatively underappreciated metabolites in cancer–nerve crosstalk, including lactate, vitamins, and amino acids, and propose the investigation of nutrients in cancer–nerve crosstalk based on their tumorigenicity and neuroregulatory capabilities. Continued research into the metabolic regulation of cancer–nerve crosstalk will provide a more comprehensive understanding of tumor mechanisms and may lead to the identification of potential targets for future cancer therapies.
... However, an increased intake of vitamin K 1 , but not vitamin K 2, during the study significantly attenuated cardiovascular mortality. 206 Explaining this difference is not easy. One should emphasize that the intake of vitamin K 1 was apparently much higher in the Spanish study, which is quite logical, given the difference in vegetable consumption between these two countries. ...
... Higher levels of uncarboxylated dephosphorylated MGP are associated with all-cause mortality, and this supports the possible impact of vitamin K. 207,208,212 The Spanish PREDIMED epidemiological study found that a higher intake of vitamin K 1 or vitamin K 2 decreased both all-cause mortality and cancer mortality. 206 The effect of vitamin K 1 on all-cause mortality was contrarily not observed in the most recent study data obtained from the extension of the Dutch EPIC study, which also reported a positive influence of long-chain vitamin K 2 forms only, and then only in 1 of 3 models. 205 Also, a recent meta-analysis did not find an impact from either form of vitamin K on all-cause mortality. ...
Article
Full-text available
Vitamin K is traditionally connected with blood coagulation, since it is needed for the posttranslational modification of 7 proteins involved in this cascade. However, it is also involved in the maturation of another 11 or 12 proteins that play different roles, encompassing in particular the modulation of the calcification of connective tissues. Since this process is physiologically needed in bones, but is pathological in arteries, a great deal of research has been devoted to finding a possible link between vitamin K and the prevention of osteoporosis and cardiovascular diseases. Unfortunately, the current knowledge does not allow us to make a decisive conclusion about such a link. One possible explanation for this is the diversity of the biological activity of vitamin K, which is not a single compound but a general term covering natural plant and animal forms of vitamin K (K1 and K2) as well as their synthetic congeners (K3 and K4). Vitamin K1 (phylloquinone) is found in several vegetables. Menaquinones (MK4–MK13, a series of compounds known as vitamin K2) are mostly of a bacterial origin and are introduced into the human diet mainly through fermented cheeses. Current knowledge about the kinetics of different forms of vitamin K, their detection, and their toxicity are discussed in this review.
... Nevertheless, data from National Health and Nutrition Examination Surveys examined the data of 5296 individuals with a minimum age of 50 years and concluded that vitamin K1 shows an independent assessment of high arterial pulse pressure [69]. In another prospective cohort study, 7216 participants were assessed by different types of vitamin K intake and mortality [82]. This study concluded that a high vitamin K intake is linked to the reduced risk of CVD in a Mediterranean population [82]. ...
... In another prospective cohort study, 7216 participants were assessed by different types of vitamin K intake and mortality [82]. This study concluded that a high vitamin K intake is linked to the reduced risk of CVD in a Mediterranean population [82]. Vitamin K has shown promising results against vascular calcification in vitamin K-deficient individuals. ...
Chapter
Full-text available
This chapter reviews the physiological and cellular functions of vitamin K in the cardiovascular system based on the latest pre-clinical and clinical evidence. Vitamin K belongs to a family of structurally similar fat-soluble vitamins, actively required by the body for the synthesis of essential proteins as well as regulate blood clotting, bone metabolism and calcium level. The authors emphasize the quintessential association between dietary vitamin K2 and cardiovascular diseases shown in various studies. The association, through the vitamin K - dependent hormones, plays a primary role in regulating calcification of different cell types, especially their role in calcification of the vascular endothelial cells. The consequences of vitamin K deficiency in the vascular system are unfavorable, shown in various clinical studies on statins - well-known inhibitors of vitamin K production in the body. New clinical insights suggest that vitamin K levels in the body and its dietary supplementation play a crucial role in cardiovascular disease prevention. There is negative influence of these antagonist’s pate in vascular composition and functions. Therefore, there is a need for prospective studies to make more in-depth exploration and increase the current understanding of this critical relationship to confidently apply such knowledge to prevent cardiovascular diseases and improve their outcomes.
... However, retinol-binding protein 4 contributes to IR and atherosclerosis in T2DM and could be used as an early predictor of CVD [160,161]. The role of vitamin K needs to be clarified since it was associated with a reduced risk of CVD in Mediterranean individuals [162] and menaquinone intake (vitamin K2) could be essential for CHD prevention [163,164]; however, no evidence exists of the role of phylloquinone (vitamin K1) in cardiometabolic disorders, including CVD and diabetes [164]. In addition, vitamin K-dependent protein activity was associated with incident ischemic cardiovascular events [165]. ...
Article
Full-text available
Cardiovascular disease (CVD) is the most common cause of morbidity and mortality in developed countries. The prevalence of CVD is much higher in patients with type 2 diabetes mellitus (T2DM), who may benefit from lifestyle changes, which include adapted diets. In this review, we provide the role of different groups of nutrients in patients with T2DM and CVD, as well as dietary approaches that have been associated with better and worse outcomes in those patients. Many different diets and supplements have proved to be beneficial in T2DM and CVD, but further studies, guidelines, and dietary recommendations are particularly required for patients with both diseases.
... 113 In the prospective PREDIMED (Prevención con Dieta Mediterránea) Study, the authors investigated the impact of dietary vitamin K 1 and K 2 on all-cause mortality among 7216 participants who were followed for a median of 4.8 years. 114 They found a significant and inverse relationship between dietary vitamin K 1 intake and risk of all-cause mortality after controlling for potential confounders (HR=0.64, 95% CI: 0.45 to 0.90). ...
Article
Full-text available
Vitamin K 2 serves an important role in cardiovascular health through regulation of calcium homeostasis. Its effects on the cardiovascular system are mediated through activation of the anti-calcific protein known as matrix Gla protein. In its inactive form, this protein is associated with various markers of cardiovascular disease including increased arterial stiffness, vascular and valvular calcification, insulin resistance and heart failure indices which ultimately increase cardiovascular mortality. Supplementation of vitamin K 2 has been strongly associated with improved cardiovascular outcomes through its modification of systemic calcification and arterial stiffness. Although its direct effects on delaying the progression of vascular and valvular calcification is currently the subject of multiple randomised clinical trials, prior reports suggest potential improved survival among cardiac patients with vitamin K 2 supplementation. Strengthened by its affordability and Food and Drug Adminstration (FDA)-proven safety, vitamin K 2 supplementation is a viable and promising option to improve cardiovascular outcomes.
... Longitudinal data derived from 7216 Mediterranean participants show a significant decrease in the incidence of cancer, cardiovascular diseases, and all-cause mortality in individuals who increased their intake of vitamin K. These effects were most vivid in individuals prone to cardiovascular diseases [90]. Aggregate data from three cohorts involving 3891 participants (mean age 65 ± 11 y) uncovered an increased risk of all-cause mortality (not cardiovascular disorders) in individuals with low circulating levels of PK [91]. ...
Article
Full-text available
Vitamin K deficiency is evident in severe and fatal COVID-19 patients. It is associated with the cytokine storm, thrombotic complications, multiple organ damage, and high mortality, suggesting a key role of vitamin K in the pathology of COVID-19. To support this view, we summarized findings reported from machine learning studies, molecular simulation, and human studies on the association between vitamin K and SARS-CoV-2. We also investigated the literature for the association between vitamin K antagonists (VKA) and the prognosis of COVID-19. In addition, we speculated that fermented milk fortified with bee honey as a natural source of vitamin K and probiotics may protect against COVID-19 and its severity. The results reported by several studies emphasize vitamin K deficiency in COVID-19 and related complications. However, the literature on the role of VKA and other oral anticoagulants in COVID-19 is controversial: some studies report reductions in (intensive care unit admission, mechanical ventilation, and mortality), others report no effect on mortality, while some studies report higher mortality among patients on chronic oral anticoagulants, including VKA. Supplementing fermented milk with honey increases milk peptides, bacterial vitamin K production, and compounds that act as potent antioxidants: phenols, sulforaphane, and metabolites of lactobacilli. Lactobacilli are probiotic bacteria that are suggested to interfere with various aspects of COVID-19 infection ranging from receptor binding to metabolic pathways involved in disease prognosis. Thus, fermented milk that contains natural honey may be a dietary manipulation capable of correcting nutritional and immune deficiencies that predispose to and aggravate COVID-19. Empirical studies are warranted to investigate the benefits of these compounds.
Article
Glucosinolates, lipid-soluble vitamins E and K contents, primary metabolites and plant hormones were analyzed from topped radish root and detached leaf during storage at 1 °C. The topped root was analyzed at 0, 5, 15, 30, and 90 days after storage while the detached leaf was analyzed at 0, 5, 15, 30, and 45 days in an airtight storage atmosphere environment. The results showed that aliphatic glucosinolates were gradually decreased in leaf but not in root. There was a highly significant correlation between tryptophan and 4-methoxyindoleglucobrassicin in both tissues (r = 0.922, n = 10). There was no significant difference in vitamins E and K in leaf and root during storage. Plant hormones partially explained the significantly changed metabolites by tissue and time, which were identified during cold storage. Phenylalanine, lysine, tryptophan, and myo-inositol were the most important biomarkers that explained the difference in leaf and root tissue during cold storage. The most different metabolism between leaf and root tissue was starch and sucrose metabolism. Therefore, different postharvest technology or regimes should be applied to these tissues.
Article
Full-text available
Objective The identification of methodology for modelling cardiovascular disease (CVD) risk using longitudinal data and risk factor trajectories. Methods We screened MEDLINE-Ovid from inception until 3 June 2020. MeSH and text search terms covered three areas: data type, modelling type and disease area including search terms such as “longitudinal”, “trajector*” and “cardiovasc*” respectively. Studies were filtered to meet the following inclusion criteria: longitudinal individual patient data in adult patients with ≥3 time-points and a CVD or mortality outcome. Studies were screened and analyzed by one author. Any queries were discussed with the other authors. Comparisons were made between the methods identified looking at assumptions, flexibility and software availability. Results From the initial 2601 studies returned by the searches 80 studies were included. Four statistical approaches were identified for modelling the longitudinal data: 3 (4%) studies compared time points with simple statistical tests, 40 (50%) used single-stage approaches, such as including single time points or summary measures in survival models, 29 (36%) used two-stage approaches including an estimated longitudinal parameter in survival models, and 8 (10%) used joint models which modelled the longitudinal and survival data together. The proportion of CVD risk prediction models created using longitudinal data using two-stage and joint models increased over time. Conclusions Single stage models are still heavily utilized by many CVD risk prediction studies for modelling longitudinal data. Future studies should fully utilize available longitudinal data when analyzing CVD risk by employing two-stage and joint approaches which can often better utilize the available data.
Article
Full-text available
Plasma phylloquinone (vitamin K1) concentration and its relationship to intake in a national sample of British elderly people - Volume 88 Issue 4 - C. W. Thane, C. J. Bates, M. J. Shearer, N. Unadkat, D. J. Harrington, A. A. Paul, A. Prentice, C. Bolton-Smith
Article
Full-text available
Background Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. Methods In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. Results A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. Conclusions Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government's Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639 .).
Article
Full-text available
BACKGROUND: Observational cohort studies and a secondary prevention trial have shown an inverse association between adherence to the Mediterranean diet and cardiovascular risk. We conducted a randomized trial of this diet pattern for the primary prevention of cardiovascular events. METHODS: In a multicenter trial in Spain, we randomly assigned participants who were at high cardiovascular risk, but with no cardiovascular disease at enrollment, to one of three diets: a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). Participants received quarterly individual and group educational sessions and, depending on group assignment, free provision of extra-virgin olive oil, mixed nuts, or small nonfood gifts. The primary end point was the rate of major cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes). On the basis of the results of an interim analysis, the trial was stopped after a median follow-up of 4.8 years. RESULTS: A total of 7447 persons were enrolled (age range, 55 to 80 years); 57% were women. The two Mediterranean-diet groups had good adherence to the intervention, according to self-reported intake and biomarker analyses. A primary end-point event occurred in 288 participants. The multivariable-adjusted hazard ratios were 0.70 (95% confidence interval [CI], 0.54 to 0.92) and 0.72 (95% CI, 0.54 to 0.96) for the group assigned to a Mediterranean diet with extra-virgin olive oil (96 events) and the group assigned to a Mediterranean diet with nuts (83 events), respectively, versus the control group (109 events). No diet-related adverse effects were reported. CONCLUSIONS: Among persons at high cardiovascular risk, a Mediterranean diet supplemented with extra-virgin olive oil or nuts reduced the incidence of major cardiovascular events. (Funded by the Spanish government's Instituto de Salud Carlos III and others; Controlled-Trials.com number, ISRCTN35739639.).
Article
Full-text available
Vitamin K has been related to glucose metabolism, insulin sensitivity and diabetes. Because inflammation underlies all these metabolic conditions, it is plausible that the potential role of vitamin K in glucose metabolism occurs through the modulation of cytokines and related molecules. The purpose of the study was to assess the associations between dietary intake of vitamin K and peripheral adipokines and other metabolic risk markers related to insulin resistance and type 2 diabetes mellitus. Cross-sectional and longitudinal assessments of these associations in 510 elderly participants recruited in the PREDIMED centers of Reus and Barcelona (Spain). We determined 1-year changes in dietary phylloquinone intake estimated by food frequency questionnaires, serum inflammatory cytokines and other metabolic risk markers. In the cross-sectional analysis at baseline no significant associations were found between dietary phylloquinone intake and the rest of metabolic risk markers evaluated, with exception of a negative association with plasminogen activator inhibitor-1. After 1-year of follow-up, subjects in the upper tertile of changes in dietary phylloquinone intake showed a greater reduction in ghrelin (−15.0%), glucose-dependent insulinotropic peptide (−12.9%), glucagon-like peptide-1 (−17.6%), IL-6 (−27.9%), leptin (−10.3%), TNF (−26.9%) and visfatin (−24.9%) plasma concentrations than those in the lowest tertile (all p<0.05). These results show that dietary phylloquinone intake is associated with an improvement of cytokines and other markers related to insulin resistance and diabetes, thus extending the potential protection by dietary phylloquinone on chronic inflammatory diseases. Trial registration http://www.controlled-trials.com as ISRCTN35739639
Article
Full-text available
Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla protein (MGP), and possibly Gla-rich protein are all inhibitors of soft-tissue calcification and need vitamin K-dependent carboxylation for activity. A common characteristic is their low molecular weight, and it has been postulated that their small size is essential for calcification inhibition within tissues. MGP is synthesized by vascular smooth muscle cells and is the most important inhibitor of arterial mineralization currently known. Remarkably, the extrahepatic Gla proteins mentioned are only partly carboxylated in the healthy adult population, suggesting vitamin K insufficiency. Because carboxylation of the most essential Gla proteins is localized in the liver and that of the less essential Gla proteins in the extrahepatic tissues, a transport system has evolved ensuring preferential distribution of dietary vitamin K to the liver when vitamin K is limiting. This is why the first signs of vitamin K insufficiency are seen as undercarboxylation of the extrahepatic Gla proteins. New conformation-specific assays for circulating uncarboxylated MGP were developed; an assay for desphospho-uncarboxylated matrix Gla protein and another assay for total uncarboxylated matrix Gla protein. Circulating desphospho-uncarboxylated matrix Gla protein was found to be predictive of cardiovascular risk and mortality, whereas circulating total uncarboxylated matrix Gla protein was associated with the extent of prevalent arterial calcification. Vitamin K intervention studies have shown that MGP carboxylation can be increased dose dependently, but thus far only 1 study with clinical endpoints has been completed. This study showed maintenance of vascular elasticity during a 3-y supplementation period, with a parallel 12% loss of elasticity in the placebo group. More studies, both in healthy subjects and in patients at risk of vascular calcification, are required before conclusions can be drawn.
Article
Fluctuations in international normalized ratio values are often ascribed to dietary changes in vitamin K intake. Here we present a database with vitamin K1 and K2 contents of a wide variety of food items. K1 was mainly present in green vegetables and plant margarins, K2 in meat, liver, butter, egg yolk, natto, cheese and curd cheese. To investigate the effect of the food matrix on vitamin K bioavailability, 6 healthy male volunteers consumed either a detergent-solubilized K1 (3.5 µmol) or a meal consisting 400 g of spinach (3.5 µmol K1) and 200 g of natto (3.1 µmol K2). The absorption of pure K1 was faster than that of food-bound K vitamins (serum peak values at 4 h vs. 6 h after ingestion). Moreover, circulating K2 concentrations after the consumption of natto were about 10 times higher than those of K1 after eating spinach. It is concluded that the contribution of K2 vitamins (menaquinones) to the human vitamin K status is presently underestimated, and that their potential interference with oral anticoagulant treatment needs to be investigated.
Article
Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we found a large geographic difference in serum vitamin K2 (menaquinone-7; MK-7) levels in postmenopausal women. Serum MK-7 concentrations were 5.26 ± 6.13 ng/mL (mean ± SD) in Japanese women in Tokyo, 1.22 ± 1.85 in Japanese women in Hiroshima, and 0.37 ± 0.20 in British women. We investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. Natto contains a large amount of MK-7 and is eaten frequently in eastern (Tokyo) but seldom in western (Hiroshima) Japan. Serum concentrations of MK-7 were significantly higher in frequent natto eaters, and natto intake resulted in a marked, sustained increase in serum MK-7 concentration. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings indicate that the large geographic difference in MK-7 levels may be ascribed, at least in part, to natto intake and suggest the possibility that higher MK-7 level resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.
Article
Scientists need specific data on the amounts of vitamin D in foods and dietary supplements to facilitate the assessment of vitamin D dietary intake. This vitamin is available in foods both naturally and from fortification. The Nutrient Data Laboratory of the US Depart- mentofAgriculture(USDA)iscollaboratingwithvitaminDexperts to review and develop methods for analyzing the vitamin D content of foods and to use these methods to analyze the vitamin D content of certain foods and dietary supplements. In this article, we review existingsourcesofvitaminDdataonfoodsanddietarysupplements, describe the USDA's Dietary Supplements Ingredients Database, and discuss the development of the USDA's vitamin D database for foods. In addition, we define the challenges and needs related to providing updated data on the vitamin D content of foods and supplements. After we analyze the vitamin D content of these food samples, we will disseminate the current values in the Na- tional Nutrient Database for Standard Reference (Internet: http://www.ars.usda.gov/nutrientdata). Am J Clin Nutr 2008;88(suppl):551S-3S.