Matrix Gla protein (MGP) is a natural inhibitor of tissue calcification. In a previous study, we ... more Matrix Gla protein (MGP) is a natural inhibitor of tissue calcification. In a previous study, we observed the positive association between abnormal concentrations of uncarboxylated MGP species and increased mortality risk in stable vascular patients. We explore whether co-incidence of abnormal status of uncarboxylated MPG and heart failure (HF) affects the mortality risk. We examined 799 patients (mean age 65.1 years) with stable vascular disease and followed them in a prospective study. Both, desphospho-uncarboxylated and total uncarboxylated MGP (dp-ucMGP or t-ucMGP) were quantified by pre-commercial ELISA assays. Elevated (>100 ng/L) circulating brain natriuretic peptide (BNP) and abnormal status of plasma uncarboxylated MGP species (i.e.: dp-ucMGP ≥ 977 pmol/L or t-ucMGP ≤ 2825 nmol/L) were all identified as robust predictors of all-cause 5-year mortality. However, their co-incidence represented a substantial additional risk. We observed the highest mortality risk in patients...
Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female a... more Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female athletes. To quantify the rate of bone loss in healthy female athletes and investigate the effects of estrogen and vitamin K supplementation on bone loss. Prospective cohort study. We classified 115 female endurance athletes into amenorrheic, eumenorrheic, or estrogen-supplemented groups and randomized them to receive either placebo or vitamin K(1). The bone mineral densities of the subjects' femoral neck and lumbar spine were measured at baseline and after 2 years. Bone mineral density in the lumbar spine remained constant, but bone density in the femoral neck had decreased significantly after 2 years in all three subgroups. The decrease was higher in amenorrheic (-6.5% +/- 4.0%) than in eumenorrheic (-3.2% +/- 4.1%) and estrogen-supplemented athletes (-3.9% +/- 3.1%). Supplementation with vitamin K did not affect the rate of bone loss. The rate of bone loss in all three subgroups of female athletes was unexpectedly high; neither estrogen nor vitamin K supplementation prevented bone loss. High-intensity training maintained over several years must be regarded in women as a risk factor for osteoporosis, and protocols for optimal treatment should be developed.
Population-based studies have shown an inverse association between dietary menaquinones (MK-n, vi... more 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); 28 µg 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 efficien...
The Journal of Clinical Endocrinology & Metabolism, 2015
The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with incr... more 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. To examine whether the intake and/or status of vitamin K is associated with MetS and its components. 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 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 follow-up. Cross-sectionally, high menaquinones intakes were associated (Ptrend=0.08) with a lower prevalence of MetS with a prevalence ratio (PR) of 0.74 (95%CI: 0.54;1.03) for the highest versus the lowest tertile. At follow-up, 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 (Ptrend=0.01) 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.
Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor ... more Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7...
The Journal of clinical endocrinology and metabolism, Jan 2, 2015
The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with incr... more 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. To examine whether the intake and/or status of vitamin K is associated with MetS and its components. 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 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 follow-up. Cross-sectionally, high menaqui...
Vitamin K-dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular c... more Vitamin K-dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular calcification. Activation of these proteins via carboxylation depends on the availability of vitamin K. We examined whether dietary intake of phylloquinone (vitamin K-1) and menaquinone (vitamin K-2) were related to aortic calcification and coronary heart disease (CHD) in the population-based Rotterdam Study. The analysis included 4807 subjects with dietary data and no history of myocardial infarction at baseline (1990-1993) who were followed until January 1, 2000. The risk of incident CHD, all-cause mortality, and aortic atherosclerosis was studied in tertiles of energy-adjusted vitamin K intake after adjustment for age, gender, BMI, smoking, diabetes, education, and dietary factors. The relative risk (RR) of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone compared to the lower tertile [RR = 0.73 (95% CI: 0.45, 1.17) and 0.43 (0.24, 0.77), respectively]. In...
Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female a... more Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female athletes. To quantify the rate of bone loss in healthy female athletes and investigate the effects of estrogen and vitamin K supplementation on bone loss. Prospective cohort study. We classified 115 female endurance athletes into amenorrheic, eumenorrheic, or estrogen-supplemented groups and randomized them to receive either placebo or vitamin K(1). The bone mineral densities of the subjects' femoral neck and lumbar spine were measured at baseline and after 2 years. Bone mineral density in the lumbar spine remained constant, but bone density in the femoral neck had decreased significantly after 2 years in all three subgroups. The decrease was higher in amenorrheic (-6.5% +/- 4.0%) than in eumenorrheic (-3.2% +/- 4.1%) and estrogen-supplemented athletes (-3.9% +/- 3.1%). Supplementation with vitamin K did not affect the rate of bone loss. The rate of bone loss in all three subgroups of...
Journal of gravitational physiology : a journal of the International Society for Gravitational Physiology, 1998
Rapid bone loss is a serious health problem for astronauts during long lasting missions in space.... more Rapid bone loss is a serious health problem for astronauts during long lasting missions in space. We have recorded the changes of biochemical markers for bone metabolism in one of the astronauts during the 6-month space flight of the EUROMIR-95 mission. Immediately after launch both bone resorption markers and urinary calcium excretion increased about two fold, whereas bone formation markers remained unchanged. After 12 1/2 weeks the astronaut received vitamin K1 (10 mg/day for 6 weeks). Vitamin K is known to be involved in the formation of gamma-carboxyglutamate (Gla) in proteins, such as the calcium-binding bone Gla-proteins osteocalcin and matrix Gla-protein. Concomitant with the start of vitamin K treatment, the calcium-binding capacity of osteocalcin increased, and so did the urinary excretion of free Gla. This is suggestive for a subclinical vitamin K-deficiency in the astronaut before vitamin K-supplementation. During periods of high vitamin K status markers for bone formatio...
In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a c... more In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes. In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss. In the present paper we report an intervention study among eight female athletes, four of whom had been amenorrhoeic for more than one year, whereas the others had been using oral contraceptives. All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment. At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin. In all subjects increased vitamin K was associated with an increa...
Matrix Gla protein (MGP) is a natural inhibitor of tissue calcification. In a previous study, we ... more Matrix Gla protein (MGP) is a natural inhibitor of tissue calcification. In a previous study, we observed the positive association between abnormal concentrations of uncarboxylated MGP species and increased mortality risk in stable vascular patients. We explore whether co-incidence of abnormal status of uncarboxylated MPG and heart failure (HF) affects the mortality risk. We examined 799 patients (mean age 65.1 years) with stable vascular disease and followed them in a prospective study. Both, desphospho-uncarboxylated and total uncarboxylated MGP (dp-ucMGP or t-ucMGP) were quantified by pre-commercial ELISA assays. Elevated (>100 ng/L) circulating brain natriuretic peptide (BNP) and abnormal status of plasma uncarboxylated MGP species (i.e.: dp-ucMGP ≥ 977 pmol/L or t-ucMGP ≤ 2825 nmol/L) were all identified as robust predictors of all-cause 5-year mortality. However, their co-incidence represented a substantial additional risk. We observed the highest mortality risk in patients...
Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female a... more Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female athletes. To quantify the rate of bone loss in healthy female athletes and investigate the effects of estrogen and vitamin K supplementation on bone loss. Prospective cohort study. We classified 115 female endurance athletes into amenorrheic, eumenorrheic, or estrogen-supplemented groups and randomized them to receive either placebo or vitamin K(1). The bone mineral densities of the subjects' femoral neck and lumbar spine were measured at baseline and after 2 years. Bone mineral density in the lumbar spine remained constant, but bone density in the femoral neck had decreased significantly after 2 years in all three subgroups. The decrease was higher in amenorrheic (-6.5% +/- 4.0%) than in eumenorrheic (-3.2% +/- 4.1%) and estrogen-supplemented athletes (-3.9% +/- 3.1%). Supplementation with vitamin K did not affect the rate of bone loss. The rate of bone loss in all three subgroups of female athletes was unexpectedly high; neither estrogen nor vitamin K supplementation prevented bone loss. High-intensity training maintained over several years must be regarded in women as a risk factor for osteoporosis, and protocols for optimal treatment should be developed.
Population-based studies have shown an inverse association between dietary menaquinones (MK-n, vi... more 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); 28 µg 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 efficien...
The Journal of Clinical Endocrinology & Metabolism, 2015
The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with incr... more 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. To examine whether the intake and/or status of vitamin K is associated with MetS and its components. 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 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 follow-up. Cross-sectionally, high menaquinones intakes were associated (Ptrend=0.08) with a lower prevalence of MetS with a prevalence ratio (PR) of 0.74 (95%CI: 0.54;1.03) for the highest versus the lowest tertile. At follow-up, 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 (Ptrend=0.01) 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.
Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor ... more Increased pulse wave velocity (PWV) is a marker of aortic stiffness and an independent predictor of mortality. Matrix Gla-protein (MGP) is a vascular calcification inhibitor that needs vitamin K to be activated. Inactive MGP, known as desphospho-uncarboxylated MGP (dp-ucMGP), can be measured in plasma and has been associated with various cardiovascular markers, cardiovascular outcomes, and mortality. In this study, we hypothesized that high levels of dp-ucMGP are associated with increased PWV. We recruited participants via a multicenter family-based cross-sectional study in Switzerland. Dp-ucMGP was quantified in plasma by sandwich ELISA. Aortic PWV was determined by applanation tonometry using carotid and femoral pulse waveforms. Multiple regression analysis was performed to estimate associations between PWV and dp-ucMGP adjusting for age, renal function, and other cardiovascular risk factors. We included 1001 participants in our analyses (475 men and 526 women). Mean values were 7...
The Journal of clinical endocrinology and metabolism, Jan 2, 2015
The Metabolic Syndrome (MetS) is a cluster of metabolic abnormalities and is associated with incr... more 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. To examine whether the intake and/or status of vitamin K is associated with MetS and its components. 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 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 follow-up. Cross-sectionally, high menaqui...
Vitamin K-dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular c... more Vitamin K-dependent proteins, including matrix Gla-protein, have been shown to inhibit vascular calcification. Activation of these proteins via carboxylation depends on the availability of vitamin K. We examined whether dietary intake of phylloquinone (vitamin K-1) and menaquinone (vitamin K-2) were related to aortic calcification and coronary heart disease (CHD) in the population-based Rotterdam Study. The analysis included 4807 subjects with dietary data and no history of myocardial infarction at baseline (1990-1993) who were followed until January 1, 2000. The risk of incident CHD, all-cause mortality, and aortic atherosclerosis was studied in tertiles of energy-adjusted vitamin K intake after adjustment for age, gender, BMI, smoking, diabetes, education, and dietary factors. The relative risk (RR) of CHD mortality was reduced in the mid and upper tertiles of dietary menaquinone compared to the lower tertile [RR = 0.73 (95% CI: 0.45, 1.17) and 0.43 (0.24, 0.77), respectively]. In...
Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female a... more Low bone mass leading to stress fractures is a well-known and yet unsolved problem among female athletes. To quantify the rate of bone loss in healthy female athletes and investigate the effects of estrogen and vitamin K supplementation on bone loss. Prospective cohort study. We classified 115 female endurance athletes into amenorrheic, eumenorrheic, or estrogen-supplemented groups and randomized them to receive either placebo or vitamin K(1). The bone mineral densities of the subjects' femoral neck and lumbar spine were measured at baseline and after 2 years. Bone mineral density in the lumbar spine remained constant, but bone density in the femoral neck had decreased significantly after 2 years in all three subgroups. The decrease was higher in amenorrheic (-6.5% +/- 4.0%) than in eumenorrheic (-3.2% +/- 4.1%) and estrogen-supplemented athletes (-3.9% +/- 3.1%). Supplementation with vitamin K did not affect the rate of bone loss. The rate of bone loss in all three subgroups of...
Journal of gravitational physiology : a journal of the International Society for Gravitational Physiology, 1998
Rapid bone loss is a serious health problem for astronauts during long lasting missions in space.... more Rapid bone loss is a serious health problem for astronauts during long lasting missions in space. We have recorded the changes of biochemical markers for bone metabolism in one of the astronauts during the 6-month space flight of the EUROMIR-95 mission. Immediately after launch both bone resorption markers and urinary calcium excretion increased about two fold, whereas bone formation markers remained unchanged. After 12 1/2 weeks the astronaut received vitamin K1 (10 mg/day for 6 weeks). Vitamin K is known to be involved in the formation of gamma-carboxyglutamate (Gla) in proteins, such as the calcium-binding bone Gla-proteins osteocalcin and matrix Gla-protein. Concomitant with the start of vitamin K treatment, the calcium-binding capacity of osteocalcin increased, and so did the urinary excretion of free Gla. This is suggestive for a subclinical vitamin K-deficiency in the astronaut before vitamin K-supplementation. During periods of high vitamin K status markers for bone formatio...
In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a c... more In female elite athletes strenuous exercise may result in hypoestrogenism and amenorrhoea. As a consequence a low peak bone mass and rapid bone loss are often seen in relatively young athletes. In postmenopausal women, increased intake of vitamin K may result in an increase of serum markers for bone formation, a decrease of urinary markers for bone resorption, and a decrease in urinary calcium loss. In the present paper we report an intervention study among eight female athletes, four of whom had been amenorrhoeic for more than one year, whereas the others had been using oral contraceptives. All participants received vitamin K supplementation (10 mg/day) during one month, and various bone markers were measured before and after treatment. At baseline the athletes not using oral contraceptives were biochemically vitamin K-deficient as deduced from the calcium binding capacity of the circulating bone protein osteocalcin. In all subjects increased vitamin K was associated with an increa...
Uploads
Papers by Marjo Knapen