Article

Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: Double-blind randomised clinical trial

Article

Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: Double-blind randomised clinical trial

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Abstract

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

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... In women with PCOS, among lipid profiles, serum triglycerides and very-low-density lipoprotein (VLDL) also reduced [17], whereas the lipid measures did not significantly change in patients with T2DM and CHD [18]. A clinical trial has initially designed to evaluate the effect of MK-7 on arterial stiffness in healthy postmenopausal women, reported no effect on blood glucose after supplementation with 80 µg/day MK-7 for 36 months [19]. Taken to gather, the effects of vitamin K on the metabolism of glucose and insulin are currently unclear due to inconsistency across the studies concerning participants, dosage and form of the vitamin K used, and duration of the study. ...
... Also, the efficiency of MK-7 for carboxylation of OC was greater than K 1 [15]. To date, few trials of evaluating the effects of MK on the metabolism of glucose and insulin reported inconsistent results [16][17][18][19]. Vitamin K 2 (menatetrenone; 30 mg/day) for four weeks in a placebo-controlled trial could improve insulin sensitivity index in healthy young men; however, it could not change the FPG levels [16]. ...
... Vitamin K 2 (menatetrenone; 30 mg/day) for four weeks in a placebo-controlled trial could improve insulin sensitivity index in healthy young men; however, it could not change the FPG levels [16]. A placebo-controlled trial designed to evaluate the effect of a daily dose of 180 µg MK-7 on bone strength in healthy postmenopausal women reported no significant effect on fasting glucose after 3 years [19]. Co-supplementing with MK-7 (180 µg/day), calcium, and vitamin D for 8 weeks in women with PCOS [17] and for 12 weeks in patients with diabetes and CHD [18] could reduce serum insulin, HOMA-IR, and HOMA-β without any significant effect on FPG. ...
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Purpose This study aimed to investigate the effects of vitamin K2 supplementation in the form of menaquinone-7 (MK-7) on glucose, insulin, and lipid metabolism in patients with type 2 diabetes mellitus (T2DM). Methods In this double-blinded, placebo-controlled, randomized trial, 68 insulin-independent people with diabetes received either 180 µg MK-7 twice a day or placebo for 12 weeks. We assessed fasting plasma glucose (FPG) and insulin concentrations (primary outcomes), glycated hemoglobin (HbA1c), insulin sensitivity indices, and lipid profiles (secondary outcomes) at baseline and end of the trial. Results At the end of the trial, FPG (effect size (ES) = − 0.68; p-adjusted = 0.031) and HbA1c (ES = − 0.36; p-adjusted = 0.004) were significantly lower in the vitamin K2 group compared with the placebo at the end of the trial. The number of participants achieved the target levels of glycemic control based on FPG, and HbA1c concentrations were significantly higher in the vitamin K2 group compared to the placebo group. Insulin concentrations (ES = − 0.29; p = 0.019) and homeostatic model assessment for insulin resistance (HOMA-IR) significantly decreased in the vitamin K2 group (ES = − 0.29; p = 0.019) compared to baseline, but their values were not significantly different compared to the placebo group at the end of the trial. No significant variation was observed in lipid profiles. Conclusion Daily intake of 360 µg Vitamin K2 in the form of MK-7 for 12-weeks reduces FPG and HbA1c in patients with T2DM but does not have a lipid-lowering effect.
... Four trials had either incomplete or unclear outcome data, whereas the risk of bias from selective outcome reporting was low in the majority of trials and unclear in two. [13] unclear unclear high low low low DeVriese [14] low low high low low low Fulton [15] low low low low unclear low Kurnatowska [17] low unclear low low low low Shea [19] low low low low low low Zwakenberg [20] low low low low low low Knapen [16] unclear unclear low unclear unclear unclear Oikonomaki [18] high unclear high unclear high unclear ...
... Mixed modeling revealed that the change in PWV over time was not significantly different across treatment arms. In a 36 month trial conducted in healthy post-menopausal women, the absolute change in PWV over time was significantly attenuated in the MK-7 group at study end [16]. However, a different measure of arterial stiffness, stiffness index β, which comprised the arterial diameter and distension during diastole and blood pressure, demonstrated no significant between-group differences over the 3 years of treatment. ...
... There was no report of thrombosis in any of the clinical trials. (2), Falls (7), Infections (5) Knapen [16] NR NR Kurnatowska [17] 3.4 0 Bowel Discomfort Oikonomaki [18] 0 0 Shea [19] 0 0 Zwakenberg [20] NR NR * multivitamin group; NR-not reported. ...
Article
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Matrix gla protein (MGP) is an important vitamin K-dependent inhibitor of vascular calcification. High levels of uncarboxylated, dephosphorylated MGP have been associated with vascular calcification and are responsive to vitamin K treatment. In this systematic review, we summarize the available evidence examining whether vitamin K supplementation improves surrogate measures of cardiovascular disease including artery and valve calcification, atherosclerosis and artery stiffening. Data from controlled trials of adults were obtained by searching Ovid MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and the Web of Science Core Collection. We identified nine randomized controlled trials for review, including trials of vitamin K1 or vitamin K2 supplementation, that assessed a surrogate measure of cardiovascular disease including arterial calcification, atherosclerosis or arterial stiffening. For each trial, the risk of bias was assessed applying Cochrane Collaboration methodology. The findings indicate that vitamin K does not consistently prevent progression of calcification, atherosclerosis or arterial stiffness. There may be some benefit in people with calcification at study entry. Studies were heterogenous, with relatively short follow-up and outcome measures were varied. While vitamin K supplementation clearly improves the carboxylation of dephosphoylated MGP, its role in mitigating vascular calcification is uncertain, based on current evidence.
... In a similar investigation, treating communitydwelling older adults with vitamin K1 (500 µg/day for 3 years) significantly decreased plasma dp-ucMGP levels. However, dp-ucMGP was not associated with vascular coagulation either at baseline or post-treatment [86]. Menopausal women receiving a multivitamin enhanced with 500 µg K1 for 3 years expressed a reduction in the progression of vascular coagulation compared with women receiving a multivitamin alone. ...
... In a double-blind, placebo-controlled trial, 244 healthy menopausal women were randomized to receive MK-7 or a placebo for 3 years. MK-7 treatment decreased circulating dp-ucMGP by 50%, which was accompanied by a significant improvement in arterial stiffness [86]. An investigation involving supplementing healthy adults with K1, as well as low and high doses of MK-7 (<75 µg/day and >75 µg/day) for 12 weeks, reported a significant reduction in dp-ucMGP only in participants receiving the high MK-7 dose [88]. ...
... An investigation involving supplementing healthy adults with K1, as well as low and high doses of MK-7 (<75 µg/day and >75 µg/day) for 12 weeks, reported a significant reduction in dp-ucMGP only in participants receiving the high MK-7 dose [88]. These findings suggest that MK-7 may protect against cardiovascular disorders by enhancing the carboxylation status of MGP [86,88]. Children (aged 10-12 years) and healthy adults (aged 40 years and above) who were supplemented with MK-7 (45 µg/day and 90 µg/day, respectively) responded better to treatment than their non-deficient counterparts; in terms of reduction of ucOC and dp-ucMGP. ...
Article
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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.
... Recent research has also reported functionality in bone health, as well as cardiovascular and metabolic health. Some clinical research has reported that MK-7 specifically has benefits on vascular health (Dalmeijer et al. 2012;Theuwissen et al. 2012;Knapen et al. 2015;Mansour et al. 2017). However, studies in this area are relatively limited, focusing mainly on MK-7 and consisting mainly of supplemented forms, with a lack of investigation on the health benefits of MKs from dietary sources such as cheese and a lack of work on other long-chain MKs. ...
... The authors observed a significant reduction of dp-ucMGP in those groups who received 90 lg and over 90 lg MK-7 supplementation daily (Theuwissen et al. 2012). A double-blind, placebo-controlled trial of 244 healthy postmenopausal women, given an MK-7 supplement (180 lg/day) for 3 years, demonstrated a reduction in mean carotid-femoral pulse wave velocity (cfPWV), a measurement of arterial stiffness, stiffness Index b and a 50% decrease in dp-ucMGP (Knapen et al. 2015). In another, study, using a single-arm design, with renal transplant recipients (n = 60), subjects underwent 360 lg/day of MK-7 supplementation for 8 weeks. ...
... Cheese and curd are the most important sources of long-chain MKs in the Western diet (Vermeer et al. 2018). Since a number of human intervention studies have shown that vitamin K2 (MK-7) can help to inhibit vascular calcification (Dalmeijer et al. 2012;Theuwissen et al. 2012;Knapen et al. 2015;Mansour et al. 2017), vitamin K is one potential nutrient of interest that may also play a role. However, this has not been widely explored to date, and the current intervention studies have only used vitamin K2 supplements. ...
Article
Vitamin K collectively describes fat‐soluble vitamins containing 2‐methyl‐1,4‐naphthoquinone, including two naturally‐occurring forms: phylloquinone (K1) and a range of menaquinones, MK4‐M13 (K2). Leafy vegetables are the main dietary source of K1, whereas K2 is mainly bacterially synthesised and found in fermented foods, including dairy foods, and some animal sources. Studies suggest that vitamin K may be important for cardiovascular health, due to its role in inhibiting vascular calcification, but food source data, particularly for K2 forms, is lacking. This information could help to clarify recent associations between cheese consumption and reduced CVD risk and would be of use in future epidemiological studies. An overview of Vitamin K in cheese, and the potential role in cardiovascular health.
... Previous studies have focused on the role of Vitamin K in blood coagulation (5,6). Besides its role in blood coagulation, Vitamin K improves bone health, prevents vascular calcification, and reduces the risk of cardiovascular diseases (10)(11)(12). Furthermore, it is considered to have beneficial effects against insulin resistance (13). ...
... Osteocalcin is a Vitamin-K dependent protein synthesized by osteoblasts (7). It has been thought that osteocalcin is the most common non-collagen protein in the bone and its concentration is positively correlated with osteoblast function and Vitamin K availability (12). Vitamin K acts as the cofactor of the gamma-glutamyl carboxylase enzyme which is essential for the synthesis of osteocalcin ( Figure 2). ...
Article
The role of vitamin K, in bone metabolism and its effects on insulin resistance and Type-2 diabetes, have been discussed. The mechanism of vitamin K’s beneficial effect on insulin sensitivity and glucose homeostasis is not yet known. Various biological active molecules such as adiponectin, leptin, and resistin, which is secreted from adipose tissue and have important roles in glucose metabolism, have been proposed to regulate bone metabolism. Some studies have suggested that bone metabolism is also effective on adipose tissue and energy metabolism. It is thought that osteocalcin, a vitamin K dependent protein is effective in glucose metabolism. The role of Vitamin K in glucose metabolism is thought to be partly due to the modulation of diabetes-related cytokines and other metabolic risk markers, as inflammation lies at the bottom of chronic metabolic diseases. The aim of this review is to explain the effect of Vitamin K and osteocalcin on glucose metabolism and its possible mechanisms of action. Keywords: Vitamin K, osteocalcin, glucose metabolism, type 2 diabetes, insulin resistance
... Several clinical trials investigating the effect of vitamin K supplementation on arterial calcification have been performed. Despite a consistent decrease in the circulating inactive form of MPG (dephosphorylated-uncarboxylated (dp-uc) MGP) after vitamin K supplementation [28,31,35,36], these trials showed differing results on arterial calcification progression. One year treatment with vitamin K2 in hemodialysis patients did not affect aortic calcification progression [37], although the dose in this study was lower compared to our study. ...
... Selection of patients with severe vitamin K deficiency might be warranted for future trials. Despite these differing results on calcification progression, several trials showed a reduction of arterial stiffness progression with vitamin K supplementation [36,39,45]. This challenges our understanding of the role of MGP in vascular physiology. ...
Article
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Purpose Vitamin K-dependent proteins are involved in (patho)physiological calcification of the vasculature and the bones. Type 2 diabetes mellitus (DM2) is associated with increased arterial calcification and increased fractures. This study investigates the effect of 6 months vitamin K2 supplementation on systemic arterial calcification and bone mineral density (BMD) in DM2 patients with a history of cardiovascular disease (CVD). Methods In this pre-specified, post hoc analysis of a double-blind, randomized, controlled clinical trial, patients with DM2 and CVD were randomized to a daily, oral dose of 360 µg vitamin K2 or placebo for 6 months. CT scans were made at baseline and follow-up. Arterial calcification mass was quantified in several large arterial beds and a total arterial calcification mass score was calculated. BMD was assessed in all non-fractured thoracic and lumbar vertebrae. Results 68 participants were randomized, 35 to vitamin K2 (33 completed follow-up) and 33 to placebo (27 completed follow-up). The vitamin K group had higher arterial calcification mass at baseline [median (IQR): 1694 (812–3584) vs 1182 (235–2445)] for the total arterial calcification mass). Six months vitamin K supplementation did not reduce arterial calcification progression (β [95% CI]: − 0.02 [− 0.10; 0.06] for the total arterial calcification mass) or slow BMD decline (β [95% CI]: − 2.06 [− 11.26; 7.30] Hounsfield units for all vertebrae) when compared to placebo. Conclusion Six months vitamin K supplementation did not halt progression of arterial calcification or decline of BMD in patients with DM2 and CVD. Future clinical trials may want to pre-select patients with very low vitamin K status and longer follow-up time might be warranted. This trial was registered at clinicaltrials.gov as NCT02839044
... Its use has been associated with arterial stiffness in individuals with HF [44] and aortic valve calcification. There is data suggesting that vitamin K2 supplementation could reduce or improve arterial stiffness [45]. ...
... Cui et al [45]. ...
Article
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Arterial stiffness has been investigated as part of the physiopathology of arterial hypertension since the 1970s. Its role in increasing the “pulsatile load” imposed over the Left Ventricle (LV) has been intensely studied recently and has helped in understanding the mechanisms of Atrial Fibrillation (AF) in hypertensive patients. This paper aims to review the main evidence on this issue and establish possible mechanisms involved in the development of AF in patients with arterial stiffness. A PubMed search was performed, and selected articles were searched for references focusing on this topic. In the long term, lower blood pressure levels allow for arterial wall remodeling, leading to a lower stiffness index. To this day, however, there are no available treatments that directly promote the lowering of arterial wall stiffness. Most classes of anti-hypertensive drugs ‒ with stronger evidence for beta-blockers and diuretics ‒ could be effective in reducing arterial stiffness. There is strong evidence demonstrating an association between arterial stiffness and AF. New studies focusing on arterial stiffness and pre-fibrillatory stages would strengthen this causality relation.
... The role of VitK2 in vascular health has been demonstrated by several studies emphasizing an inverse relation between its intake and the development of VC or consequent risk of cardiovascular events (Table 3) [106,107]. ...
... Data from the Prospect-EPIC (European Prospective Investigation into Cancer and Nutrition) cohort study showed that a higher VitK2 intake was associated with a lower risk of Peripheral Arterial Disease (PAD) [120]. In a cross-sectional analysis among 564 post-menopausal women, MK use was correlated with reduced coronary calcification [106,121]. Table 3. Clinical evidence linking vitamin K2 supplementation and vascular health. ...
Article
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Osteoporosis (OP) and vascular calcification (VC) represent relevant health problems that frequently coexist in the elderly population. Traditionally, they have been considered independent processes, and mainly age-related. However, an increasing number of studies have reported their possible direct correlation, commonly defined as “bone-vascular crosstalk”. Vitamin K2 (VitK2), a family of several natural isoforms also known as menaquinones (MK), has recently received particular attention for its role in maintaining calcium homeostasis. In particular, VitK2 deficiency seems to be responsible of the so-called “calcium paradox” phenomenon, characterized by low calcium deposition in the bone and its accumulation in the vessel wall. Since these events may have important clinical consequences, and the role of VitK2 in bone-vascular crosstalk has only partially been explained, this review focuses on its effects on the bone and vascular system by providing a more recent literature update. Overall, the findings reported here propose the VitK2 family as natural bioactive molecules that could be able to play an important role in the prevention of bone loss and vascular calcification, thus encouraging further in-depth studies to achieve its use as a dietary food supplement.
... High dp-ucMGP reflects low vitamin K status and vice versa. Although increasing vitamin K consumption decreases dp-ucMGP (30)(31)(32) , its levels are not simply a biomarker of vitamin K intake but depend on other factors as well. Circulating dp-ucMGP concentration can best be regarded as a reflection of the total extrahepatic vitamin K deficit, that is, the amount of vitamin K that is Fig. 2. Micronutrient triage theory with regard to vitamin K. Particularly vitamin K 1 is preferentially transported to the liver. ...
... In vascular diseases (40) , as well as in the general population (43,44) , increased dp-ucMGP levels associate with higher all-cause mortality. Vitamin K supplementation reduces dp-ucMGP levels and has a favourable effect on progression of clinically relevant endpoints, including aortic valve calcification, arterial stiffness and bone loss (30)(31)(32) . ...
Article
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Coronavirus disease 2019 (Covid-19), caused by SARS-CoV-2, exerts far-reaching effects on public health and socioeconomic welfare. The majority of infected individuals have mild to moderate symptoms but a significant proportion develops respiratory failure due to pneumonia. Thrombosis is another frequent manifestation of Covid-19 that contributes to poor outcomes. Vitamin K plays a crucial role in activation of both pro- and anticlotting factors in the liver, and the activation of extrahepatically synthesised protein S which seems to be important in local thrombosis prevention. However, the role of vitamin K extends beyond coagulation. Matrix Gla protein (MGP) is a vitamin K-dependent inhibitor of soft tissue calcification and elastic fibre degradation. Severe extrahepatic vitamin K insufficiency was recently demonstrated in Covid-19 patients, with high inactive MGP levels correlating with elastic fibre degradation rates. This suggests that insufficient vitamin K-dependent MGP activation leaves elastic fibres unprotected against SARS-CoV-2 induced proteolysis. In contrast to MGP, Covid-19 patients have normal levels of activated factor II, in line with previous observations that vitamin K is preferentially transported to the liver for activation of procoagulant factors. We therefore expect that vitamin K-dependent endothelial protein S activation is also compromised, which would be compatible with enhanced thrombogenicity. Taking these data together, we propose a mechanism of pneumonia-induced vitamin K depletion, leading to a decrease in activated MGP and protein S, aggravating pulmonary damage and coagulopathy, respectively. Intervention trials should be conducted to assess whether vitamin K administration plays a role in prevention and treatment of severe Covid-19.
... At the tissue level, vitamin K 1 is converted to MK-4 [155] with vitamin K 2 being effective at lower doses than K 1 [156]. Supplementation with vitamin K has been shown to block age-related arterial stiffening in postmenopausal women [157] and retard postmenopausal bone loss [158,159]. Often prescribed to prevent thomboembolisms, vitamin K antagonists interfere with γ-carboxylation of Gla-proteins in mice [160]. ...
... In an RCT with 244 postmenopausal women using 180 µg MK-7 per day for 3 years, vitamin K2 supplementation decreased dp-ucMGP values by 50% (vs. controls) and significantly improved vascular stiffness indicators [157]. Subsequently, MK-7 supplementation has been reported to increase circulating c-OC and ucOC levels [167]. ...
Article
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The US Dietary Guidelines for Americans (DGA) provide dietary recommendations to meet nu-trient needs, promote health, and prevent disease. Despite 40 years of DGA, the prevalence of under-consumed nutrients continues in the US and globally, although dietary supplement use can help to fill shortfalls. Nutrient recommendations are based on Dietary Reference Intakes (DRIs) to meet the nutrient requirements for nearly all (97 to 98 percent) healthy individuals in a particular life stage and gender group and many need to be updated using current evidence. There is an opportunity to modernize vitamin and mineral intake recommendations based on biomarker or surrogate endpoint levels needed to ‘prevent deficiency’ with DRIs based on ranges of biomarker or surrogate endpoints levels that support normal cell/organ/tissue function in healthy individ-uals, and to establish DRIs for bioactive compounds. We recommend vitamin K and Mg DRIs be updated and DRIs be established for lutein and eicosapentaenoic and docosahexaenoic acid (EPA + DHA). With increasing interest in personalized (or precision) nutrition, we propose greater re-search investment in validating biomarkers and metabolic health measures and the development and use of inexpensive diagnostic devices. Data generated from such approaches will help elu-cidate optimal nutrient status, provide objective evaluations of an individual’s nutritional status, and serve to provide personalized nutrition guidance.
... The result suggests that SCD patients may require counselling on the elevated risk of CVD and may benefit from VK supplementation. Long-term VK supplementation was reported to prevent or reduce arterial stiffness in patients with higher CVD risk (Knapen et al. 2015). Although further research is needed to investigate how VK metabolism affects the vascular system in SCD patients, our study brings to light important insights into the molecular basis of SCD. ...
Article
Purpose Schnyder corneal dystrophy (SCD) is a rare autosomal dominant disorder characterized by corneal lipid accumulation and caused by UBIAD1 pathogenic variants. UBIAD1 encodes a vitamin K (VK) biosynthetic enzyme. To assess the corneal and vascular VK status in SCD patients, we focused on matrix Gla protein (MGP), a VK‐dependent protein. Methods Conformation‐specific immunostainings of different MGP maturation forms were performed on corneal sections and primary keratocytes from corneal buttons of two SCD patients with UBIAD1 p.Asp112Asn and p.Asn102Ser pathogenic variants and unrelated donors. Native or UBIAD1‐transfected keratocytes were used for gene expression analysis. Plasma samples from SCD patients (n = 12) and control individuals (n = 117) were subjected for inactive desphospho‐uncarboxylated MGP level measurements with an ELISA assay. Results Substantial amounts of MGP were identified in human cornea and most of it in its fully matured and active form. The level of mature MGP did not differ between SCD and control corneas. In primary keratocytes from SCD patients, a highly increased MGP expression and presence of immature MGP forms were detected. Significantly elevated plasma concentration of inactive MGP was found in SCD patients. Conclusion High amount of MGP and the predominance of mature MGP forms in human cornea indicate that VK metabolism is active in the visual system. Availability of MGP seems of vital importance for a healthy cornea and may be related to protection against corneal calcification. Systemic MGP findings reveal a poor vascular VK status in SCD patients and indicate that SCD may lead to cardiovascular consequences.
... At year one, our vitamin K supplemented participants had a mean dp-ucMGP of 1290 pmol/L. Some earlier trials in non-dialysis patients indicated that vitamin K supplementation might have a beneficial effect on cfPWV and arterial calcification [31][32][33]. However, other studies were negative [34,35], and most recently, Witham et al reported an absence of vitamin K2 effect on cfPWV and AAC in a one-year double-blind placebo-controlled trial of patients with chronic kidney disease stage 3b-4 [36]. ...
Article
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Background Arterial calcification is associated with cardiovascular mortality in dialysis patients. Active matrix Gla-protein (MGP) is a vitamin K-dependent inhibitor of arterial calcification. Elevated plasma concentrations of inactive MGP, i.e. dephosphorylated-uncarboxylated MGP (dp-ucMGP), is prevalent in dialysis patients. MGP inactivity might contribute to arterial calcification. We investigated if vitamin K supplementation had an effect on arterial calcification in chronic dialysis patients. Methods In a two-year double-blind, placebo-controlled intervention trial, 48 dialysis patients were randomised to vitamin K (menaquinone-7 (MK-7), 360 µg daily), or placebo. MK-7 in serum and dp-ucMGP in plasma were used to assess vitamin K status. Carotid-femoral pulse wave velocity (cfPWV) and scores of coronary arterial calcification (CAC) and abdominal aorta calcification (AAC) were used to assess arterial calcification. Results Thirty-seven participants completed year one, 21 completed year two. At year two, serum MK-7 was 40-fold higher, and plasma dp-ucMGP 40% lower after vitamin K supplementation compared with placebo (mean dp-ucMGP difference: -1380 pmol/L (95% CI: -2029;-730)). There was no significant effect of vitamin K supplementation on cfPWV (mean difference at year two: 1.2 m/s (95% CI: -0.1; 2.4)). CAC Agatston score increased significantly in vitamin K supplemented participants, but not significantly different from placebo (mean difference at year two: 664 (95% CI: -554; 1881)). AAC scores increased in both groups, significantly so within the placebo group at year 1, but with no significant between-group differences. Conclusion Vitamin K supplementation improved vitamin K status, but did not hinder or modify the progression of arterial calcification in dialysis patients.
... Although MK7 was not included in Study 1, 2 H 7 MK7 was added in Study 2 as a relevant dietary form due to increased clinical interest of MK7 as a dietary supplement. 39,40 Mice were 19 weeks of age at nonfasted sacrifice, at which time cecal contents and feces were collected. ...
Article
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Vitamins have well-established roles in bacterial metabolism. Menaquinones (MKn, n = prenyl units in sidechain) are bacterially produced forms of vitamin K produced by the gut microbiota and consumed in the diet. Little is known about the influence of dietary vitamin K quinones on gut microbial composition and MKn production. Here, male and female C57BL6 mice were fed a vitamin K deficient diet or vitamin K sufficient diets containing phylloquinone (PK, plant-based vitamin K form), MK4, and/or MK9. DNA was extracted from cecal contents and 16S sequencing conducted to assess microbial composition. Cecal microbial community composition was significantly different in vitamin K deficient female mice compared to females on vitamin K sufficient diets (all p < .007). Parallel trends were seen in male mice, but were not statistically significant (all p > .05 but <0.1). Next, stable isotope-labeled vitamin K quinones were supplemented to male and female C57BL6 mice (2H7PK, 13C11MK4, 2H7MK7, 2H7MK9) and to an in vitro fermentation model inoculated with human stool (2H7PK, 2H7MK4, 2H7MK9, or vitamin K precursor 2H8-menadione). Vitamin K quinones in feces and culture aliquots were measured using LC-MS. In vivo, supplemented vitamin K quinones were remodeled to other MKn (2H7- or 13C6-labeled MK4, MK10, MK11, and MK12), but in vitro only the precursor 2H8-menadione was remodeled to 2H7MK4, 2H7MK9, 2H7MK10, and 2H7MK11. These results suggest that dietary vitamin K deficiency alters the gut microbial community composition. Further studies are needed to determine if menadione generated by host metabolism may serve as an intermediate in dietary vitamin K remodeling in vivo.
... CKD and hemodialysis patients could often present vascular VK deficiency due to significantly low VK intake, resulting in an elevated risk of VC and bone fractures [120]. After three years of 180 μg MK-7 daily intake, dp-ucMGP levels decreased by 50% compared to placebo [103]. Even after a shorter 12 week-period, ucMGP, an independent risk factor for arteriosclerosis and CVD, significantly decreased in the MK-7 supplementation groups compared to placebo [98]. ...
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As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with antiaging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Thus, vitamin K can carboxylate osteocalcin (a protein capable of transporting and fixing calcium in bone), activate matrix Gla protein (an inhibitor of vascular calcification and cardiovascular events) and carboxylate Gas6 protein (involved in brain physiology and a cognitive decline and neurodegenerative disease inhibitor). By improving insulin sensitivity, vitamin K lowers diabetes risk. It also exerts antiproliferative, proapoptotic, autophagic effects and has been associated with a reduced risk of cancer. Recent research shows that protein S, another vitamin K-dependent protein, can prevent the cytokine storm observed in COVID-19 cases. The reduced activation of protein S due to the pneumonia-induced vitamin K depletion was correlated with higher thrombogenicity and possibly fatal outcomes in COVID-19 patients. Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults ˃50 years old.
... Furthermore, a study of post-menopausal women found that K2 supplementation was associated with decreased aortic and common carotid stiffness. 74 Given the evidence for the positive role of vitamin K in inhibiting vascular calcification, its current efficacy in calciphylaxis has recently undergone clinical trials (NCT02278692). 75 Arguably as equally important as active treatment is the elimination of risk factors for calciphylaxis, which would potentially include withdrawal of warfarin (vitamin K antagonist), vitamin D and calcium-based phosphate binders. 1 Optimizing mineral bone disease (maintaining J o u r n a l P r e -p r o o f target ranges of calcium, phosphorus and parathyroid hormone-PTH), replacing activated vitamin D with cinacalcet to target goal PTH, and parathyroidectomy for severe refractory hyperparathyroidism are reasonable approaches as outlined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines KDIGO guidelines. ...
Article
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Calciphylaxis is a life-threatening complication most often associated with chronic kidney disease that occurs due to the deposition of calcium in dermal and adipose microvasculature. However, this condition may also be seen in patients with acute kidney injury. The high morbidity and mortality associated with calciphylaxis highlight the importance to correctly diagnose and treat this condition. However, calciphylaxis remains a diagnosis that may be clinically challenging to make. Here, we review the literature on uremic calciphylaxis with a focus on its pathophysiology, clinical presentation, advances in diagnostic tools, and treatment strategies. We also discuss the unique histopathological features of calciphylaxis and contrast it with those of other forms of general vessel calcification. This review emphasizes the need of multidisciplinary collaboration including nephrology, dermatology, and palliative care to ultimately provide the best possible care to patients with calciphylaxis.
... 53 In 1 double-blinded randomized clinical trial, where supplementation of menaquinone (180 mcg of MK-7) in 244 healthy post-menopausal women for a period of 3 years improved their arterial stiffness. 54 In CKD patients with vitamin K deficiency, it was noted that there is increased calcification of vascular SMC and demineralization of bone when calcium is supplemented. Whereas in vitamin K sufficient condition, the inverse in true. ...
Article
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Coronary artery calcification (CAC) is a well-known entity, with a high incidence amounting to a third of the total coronary artery disease (CAD) patients. It is also associated with a high complication rate during percutaneous transluminal coronary angioplasty, such as stent nontrackability, stent nonapposition, and underexpansion. The recent technological advances have helped to perform percutaneous coronary intervention in the calcified coronaries with better results. The management of calcified lesion was mainly concentrated on interventional techniques, this article gives a comprehensive review of CAC pathophysiology, its morphology, various diagnostic modalities, newer diagnostic tools, upcoming medical therapies, and interventional techniques. Newer therapies which include vitamin K and myoinositol hexaphosphate, their role in pathogenesis of CAC, and its future role in preventing and treating CAC are covered in this article.
... Another study of postmenopausal women strengthens the argument for the benefit of VK2 in cardiovascular health. A double-blind, placebo-controlled trial that followed 244 healthy postmenopausal women over three years demonstrated that supplementation with 180 mcg MK-7 improved arterial stiffness, especially in individuals who had a lower baseline arterial elasticity [107]. Interestingly, a much shorter trial that followed 68 men and women came to a different conclusion [108]. ...
Article
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Recent studies have highlighted the importance of vitamin K2 (VK2) in human health. However, there have been no clinical studies investigating the role of VK2 in the prevention or treatment of Alzheimer’s disease (AD), a debilitating disease for which currently there is no cure. In reviewing basic science research and clinical studies that have connected VK2 to factors involved in AD pathogenesis, we have found a growing body of evidence demonstrating that VK2 has the potential to slow the progression of AD and contribute to its prevention. In our review, we consider the antiapoptotic and antioxidant effects of VK2 and its impact on neuroinflammation, mitochondrial dysfunction, cognition, cardiovascular health, and comorbidities in AD. We also examine the link between dysbiosis and VK2 in the context of the microbiome’s role in AD pathogenesis. Our review is the first to consider the physiological roles of VK2 in the context of AD, and, given the recent shift in AD research toward nonpharmacological interventions, our findings emphasize the timeliness and need for clinical studies involving VK2.
... 6 Both forms of vitamin K have been proposed to influence cardiovascular health through many mechanisms, 7 including the reduction of systemic inflammation, 8 maintenance of hemostasis, 9 and the inhibition of arterial calcification. 10 Observational studies have demonstrated an inverse relationship between biomarkers of dietary vitamin K intake and ASCVD risk, [11][12][13][14] and supplementing with vitamin K increases circulating concentrations of these biomarkers 15,16 in a dose-dependent fashion. 17 These observations and others 18 suggest a causal role of vitamin K in the prevention of ASCVD. ...
Article
Background Dietary vitamin K (K 1 and K 2 ) may reduce atherosclerotic cardiovascular disease (ASCVD) risk via several mechanisms. However, studies linking vitamin K intake with incident ASCVD are limited. We aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. Methods and Results In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food‐frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K 1 and vitamin K 2 were estimated from the food‐frequency questionnaire, and their relationship with ASCVD hospitalizations was determined using Cox proportional hazards models. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52–60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17–22) years of follow‐up. Compared with participants with the lowest vitamin K 1 intakes, participants with the highest intakes had a 21% lower risk of an ASCVD‐related hospitalization (hazard ratio, 0.79; 95% CI: 0.74–0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K 2 , the risk of an ASCVD‐related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K 2 intake (hazard ratio, 0.86; 95% CI, 0.81–0.91). Conclusions Risk of ASCVD was inversely associated with diets high in vitamin K 1 or K 2 . The similar inverse associations with both vitamin K 1 and K 2 , despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.
... The researchers also found that the CV conditions improved as the subjects were administered a nutritional dose of vitamin K2 in the form of MK-7 (as MenaQ7). Moreover, if vitamin K2 is taken on a daily basis, there is a high chance of preventing the hardening of arteries [23,24]. ...
Chapter
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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.
... 9 In addition, the role of MK7 in bone health has been highlighted by several studies showing how natto consumption reduces the incidence of hip fractures in women in Japan 10,11 and recently confirmed by a large prospective cohort study. 12 This evidence, along with a large set of clinical studies, highlights the beneficial effects of MK7 supplementation in the prevention of osteoporosis [13][14][15] and in the reduction of vascular stiffness, 16,17 making MK7 essential for the prevention of bone and cardiovascular disease (CVD). Therefore, its supplementation is recommended in developmental stages and in those who have a CVD and osteopenic risk. ...
Article
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Carboxylative enzymes are involved in many pathways and their regulation plays a crucial role in many of these pathways. In particular, γ‐glutamylcarboxylase (GGCX) converts glutamate residues (Glu) into γ‐carboxyglutamate (Gla) of the vitamin K‐dependent proteins (VKDPs) activating them. VKDPs include at least 17 proteins involved in processes such as blood coagulation, blood vessels calcification, and bone mineralization. VKDPs are activated by the reduced form of vitamin K, naturally occurring as vitamin K1 (phylloquinone) and K2 (menaquinones, MKs). Among these, MK7 is the most efficient in terms of bioavailability and biological effect. Similarly to other trans isomers, it is produced by natural fermentation or chemically in both trans and cis. However, the efficacy of the biological effect of the different isomers and the impact on humans are unknown. Our study assessed carboxylative efficacy of trans and cis MK7 and compared it with other vitamin K isomers, evaluating both the expression of residues of carboxylated Gla‐protein by western blot analysis and using a cell‐free system to determine the GGCX activity by HPLC. Trans MK7H2 showed a higher ability to carboxylate the 70 KDa GLA‐protein, previously inhibited in vitro by warfarin treatment. However, cis MK7 also induced a carboxylation activity albeit of a small extent. The data were confirmed chromatographically, in which a slight carboxylative activity of cis MK7H2 was demonstrated, comparable with both K1H2 and oxidized trans MK7 but less than trans MK7H2. For the first time, a difference of biological activity between cis and trans configuration of menaquinone‐7 has been reported.
... One intervention trial studied the effect of 180 µg MK-7 VK vs. placebo on arterial stiffness in healthy postmenopausal women. After 3 years, the beta stiffness index, a measure of mechanical arterial properties, decreased significantly in the treated group compared to the placebo [82]. Supplementation of 500 mg/day of phylloquinone (K1) for 36 months showed a positive effect on insulin resistance in older adults, but not in postmenopausal women, and either did not change weight and BMI for both genders [169]. ...
Article
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The prevalence of metabolic syndrome and cardiovascular disease has increased and continues to be the leading cause of mortality worldwide. The etiology of these diseases includes a complex phenotype derived from interactions between genetic, environmental, and nutritional factors. In this regard, it is common to observe vitamin deficiencies in the general population and even more in patients with cardiometabolic diseases due to different factors. Vitamins are essential micronutrients for cellular metabolism and their deficiencies result in diseases. In addition to its role in nutritional functions, increasingly, vitamins are being recognized as modulators of genetics expression and signals transduction, when consumed at pharmacological concentrations. Numerous randomized preclinical and clinical trials have evaluated the use of vitamin supplementation in the prevention and treatment of metabolic syndrome and cardiovascular disease. However, it is controversy regarding its efficacy in the treatment and prevention of these diseases. In this review, we investigated chemical basics, physiological effect and recommended daily intake, problems with deficiency and overdose, preclinical and clinical studies, and mechanisms of action of vitamin supplementation in the treatment and prevention of metabolic syndrome and cardiovascular disease.
... 38) Furthermore, in numerous trials with healthy and diseased patient cohorts, vitamin K2 has been proven to have a long-term protective effect against the development of calcification. 39,40) These reports, together with our present findings, led us to believe that vitamin K2 can be a candidate for the treatment of pediatric patients with chronic atopic dermatitis. Our present data suggest that vitamin K2 regulates T-cell mediated immunity through the manipulation of the mitogen-activated protein kinase, -Mek1-ERK1/2 and SAPK/JNK signaling pathways, which results in the inhibition of immune cell proliferation and inflammatory responses. ...
Article
Vitamin K2 is suggested to have a suppressive effect on the peripheral blood mononuclear cells (PBMCs) of pediatric atopic dermatitis patients. We examined the molecular targets of vitamin K2 to suppress proliferation and cytokine production in T-cell mitogen-activated PBMCs of atopic dermatitis patients from the viewpoint of mitogen-activated protein kinase signaling molecules. The study population included 16 pediatric vitamin K2 patients and 21 healthy subjects. The effect of vitamin K2 on concanavalin A-activated PBMC proliferation was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and cell counting assays. T-helper (Th)1/Th2/Th17 cytokine profiles in plasma and PBMC-culture supernatants were analyzed by a cytometric beads array assay. Mitogen-activated protein kinase signaling molecules in concanavalin A-activated PBMCs were examined by enzyme-linked immunosorbent assay (ELISA) assays. At 10–100 µM, vitamin K2 significantly suppressed the proliferation of mitogen-activated PBMCs derived from atopic dermatitis patients and healthy subjects (p < 0.05). The interleukin (IL)-10 concentrations in plasma and the PBMC culture supernatants of atopic dermatitis patients were significantly higher than those of healthy subjects (p < 0.05). The IL-2 concentrations in the culture supernatants of atopic dermatitis PBMCs were significantly lower than those of healthy PBMCs (p < 0.05). Vitamin K2 significantly inhibited the IL-17A, IL-10, and tumor necrosis factor α (TNF-α) production (p < 0.05), and increased the IL-2 production (p < 0.01) in the culture supernatant of atopic dermatitis PBMCs. At 10–100 µM, vitamin K2 markedly decreased the of Mek1, extracellular signal-regulated kinases (ERK)1/2 mitogen-activated protein kinase, and SAPK/c-Jun N-terminal kinase (JNK) expression in atopic dermatitis PBMCs (p < 0.05). Vitamin K2 is suggested to attenuate activated T-cell immunity in atopic dermatitis patients through the inhibition of mitogen-activated protein kinase-Mek1-ERK1/2 and SAPK/JNK signaling pathways. Graphical Abstract Fullsize Image
... Most remarkably, MK-7 not only suppressed arterial stiffening but also resulted in an unprecedented statistically significant improvement of vascular elasticity, both measured with ultrasound techniques and PWV in a healthy population. 4 A 1-year follow-up placebo-controlled, randomized clinical trial study also showed cardiovascular benefit after K2 supplementation in both genders. In the total study group-243 subjects (40-70 years old) characterized by an elevated risk for cardiovascular disease due to vitamin K-insufficiency (i.e., dp-ucMGP > 400 pmol/L)-MK-7 (180 µg/day of K2 as MenaQ7®) induced a significant decrease of both dp-ucMGP and carotid-femoral pulsewave velocity (cfPWV). ...
... Limited data from realized interventional studies with surrogate markers showed a doubtful conclusion. Three years, placebo-controlled interventional trial with vitamin K2 (menaquinone-7) in healthy postmenopausal women by Knapen and colleagues [37] observed along with a decrease of dp-ucMGP also a significant benefit in terms of arterial stiffening, which can be explained by the effectiveness of menaquinone-7 treatment on the dynamics of vascular calcifications. In contrast, another similarly designed interventional study failed to demonstrate the effect of menaquinone-7 on arterial stiffness in chronic kidney disease patients (grade 3a or 4) [38]. ...
Article
Aim: We explored whether matrix Gla protein (MGP, natural calcification inhibitor) and sclerostin (glycoprotein responsible for osteoblast differentiation) interact in terms of mortality risk in coronary patients. Methods: 945 patients after myocardial infarction and/or coronary revascularization were followed in a prospective study. All-cause death, fatal or nonfatal cardiovascular events and heart failure hospitalizations were registered. Results: Either high desphospho-uncarboxylated MGP (dp-ucMGP) or high sclerostin were independently associated with 5-year all-cause/cardiovascular mortality. However, we observed an additional mortality risk in the coincidence of both factors. Concomitantly high dp-ucMGP (≥884 pmol/l) plus sclerostin (≥589 ng/l) were associated with increased all-cause mortality risk compared with 'normal' concentrations of both factors (HRR 3.71 [95% CI: 2.07-6.62, p < 0.0001]), or if only one biomarker has been increased. A similar pattern was observed for fatal, but not for nonfatal cardiovascular events. Conclusion: Concomitantly high MGP and sclerostin indicate increased mortality risk, which probably reflects their role in cardiovascular calcifications.
... Independently from diabetes, higher baseline AGE levels have been associated with plaque progression in acute coronary syndrome and with the degree of severity of coronary atherosclerosis [80]. In addition, several clinical trials explored the relationship between AGEs and endothelial function in healthy subjects [51][52][53]. Kimuya et al. reported the effect of atorvastatin in decreasing serum levels of AGEs in nonalcoholic steatohepatitis (NASH) patients with dyslipidaemia, and suggested the usefulness of AGEs as a biomarker for the attenuation of NASH [82]. The reliability of AGEs measured by ELISA as biomarkers have also been explored in nephropathies [76][77][78][79], fractures [83] and pancreatic cancer risk [84]. ...
Article
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Advanced glycation end-products (AGEs) are heterogeneous compounds of irreversible adducts principally derived from nonenzymatic glycation and glycoxidation of proteins. An increase in AGEs may be involved in the pathogenesis of metabolic and cardiovascular diseases, chronic degenerative diseases, neurological diseases and cancer, and it has been suggested as a biomarker of oxidative stress. AGEs have been evaluated in different biological fluids, as well as in tissues. The most utilized techniques for AGE measurement can be divided into immunochemical methods, such as ELISA, and bioanalytical methods, including fluorescence spectroscopy, high-performance liquid chromatography, liquid chromatography-mass spectroscopy, gas chromatography-mass spectroscopy. However, the lack of reference values, well-established standard molecules, and standardized methods to measure these compounds, could limit the application of AGE evaluation for clinical purpose. Aim of this review is to provide an overview on the state of the art of the most employed techniques for detection and measurement of AGEs and their application in clinical practice.
... The current adequate intake level of vitamin K for pregnant and nursing women is 90 mcg. Likewise, research suggests that 45-50 mcg/day MK-7 is an appropriate intake range for children [107][108][109]. ...
Article
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Abstract: Vitamin K2 activates vitamin K-dependent proteins that support many biological functions, such as bone mineralization, the inhibition of vascular stiffness, the improvement of endothelial function, the maintenance of strong teeth, brain development, joint health, and optimal body weight. Due to the transformation of food habits in developed countries over the last five decades, vitamin K and, specifically, vitamin K2 intakes among parents and their offspring have decreased significantly, resulting in serious health implications. The therapeutics used in pediatric practice (antibiotics and glucocorticoids) are also to blame for this situation. Low vitamin K status is much more frequent in newborns, due to both endogenous and exogenous insufficiencies. Just after birth vitamin K stores are low, and since human milk is relatively poor in this nutrient, breast-fed infants are at particular risk of a bleeding disorder called vitamin K deficiency bleeding. A pilot study showed that better vitamin K status is associated with lower rate of low-energy fracture incidence. An ongoing clinical trial is intended to address whether vitamin K2 and D3 supplementation might positively impact the biological process of bone healing. Vitamin K2 as menaquinone-7 (MK-7) has a documented history of safe and effective use. The lack of adverse effects of MK-7 makes it the ideal choice for supplementation by pregnant and nursing women and children, both healthy and suffering from various malabsorptions and health disorders, such as dyslipidemia, diabetes, thalassemia major (TM), cystic fibrosis (CF), inflammatory bowel diseases (IBD), and chronic liver diseases. Additionally, worthy of consideration is the use of vitamin K2 in obesity-related health outcome
... Fulton et al. [46] reported a reduction of dp-ucMGP in participants aged ≤70 years old who had a history of CVD, after 6 months of supplementation with 100 mcg/day of MK-7. The long-term effects of MK-7 on dp-ucMGP have also been studied by Knapen et al. [47], in which postmenopausal women were supplemented with 180 mcg/day of MK-7 over a three year period. After the intervention period, dp-ucMGP was reduced by 50%, compared with the placebo group. ...
Article
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Background: Type 2 diabetes mellitus (T2DM) is a common disorder that is characterized by chronic hyperglycemia and chronic inflammation, which also have a reinforcing effect on each other. The present research studied the effects of menaquinone (MK-7) supplementation on serum dp-ucMGP (dephospho uncarboxylated Matrix Gla Protein), PIVKAII (Prothrombin Induced by Vitamin K Absence), inflammatory markers and body composition indices in type 2 diabetes mellitus (T2DM) patients. Methods: This 12-week double-blind placebo-controlled randomized clinical trial allocated 60 T2DM patients equally into a MK-7 (200 mcg/day) group or a placebo group. All patients also received dietary advice at the beginning of study and their dietary intakes were checked using a 3-day food record. The body composition of each patient was also measured and their vitamin K status was assessed using the ELISA method to measure serum dp-ucMGP and PIVKAII. In addition, inflammatory status indices were also measured, including hsCRP (high-sensitivity C-reactive protein), IL-6 (interleukin-6) and TNF-α (tumor necrosis factor alpha). All measurements were made both before and after the intervention period. Results: In total 45 patients completed the trial (MK-7 group = 23 and placebo group = 22). The calorie and macronutrient intake of the two groups were similar pre and post intervention. There were statistically significant increases in dietary vitamin K intake for both groups over the course of the study (p < 0.05), but the intergroup differences were not significant. The body composition indices (i.e., body fat percentage, fat mass, fat free mass, muscle mass, bone mass and total body water) were not significantly different between groups or across the trial. The serum levels of the vitamin K markers, PIVKAII and dp-ucMGP, decreased significantly in the MK-7 group over the course of the study (p < 0.05), but there was no decrease in the placebo group. However, after adjusting for the baseline levels and changes in vitamin K intake, the between group differences were only significant for PIVKAII (p < 0.05). Following the intervention, the serum levels of the inflammatory markers (hsCRP, IL-6, and TNF-α) were significantly lower in the MK-7 group (p < 0.05), but not in the placebo group. However, the between group differences in the inflammatory markers were not statistically significant. Conclusions: Although further studies are needed, it appears that MK-7 supplementation can be effective in improving PIVKAII levels, but not for improving dp-ucMGP, inflammatory status or the body composition indices of T2DM patients. Trial registration number: This study was prospectively registered at the Iranian Registry of Clinical Trials on the 20th of May 2019 (ID: IRCT20100123003140N22).
... Furthermore, high-dose vitamin K3 has been questioned to be potentially toxic (e.g., liver damage, hemolytic anemia, etc.) [18], and its administration in humans is not worldwide recommended. However, vitamin K3 is easily and inexpensively produced, and it is very stable also because is not degraded by light, and low-dose could be used to treat vitamin K deficiency [18,126,127]. By the way, there are still not enough studies regarding its supplementation in these patients. ...
Article
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Chronic kidney disease (CKD) is commonly associated with vitamin K deficiency. Some of the serious complications of CKD are represented by cardiovascular disease (CVD) and skeletal fragility with an increased risk of morbidity and mortality. A complex pathogenetic link between hormonal and ionic disturbances, bone tissue and metabolism alterations, and vascular calcification (VC) exists and has been defined as chronic kidney disease–mineral and bone disorder (CKD-MBD). Poor vitamin K status seems to have a key role in the progression of CKD, but also in the onset and advance of both bone and cardiovascular complications. Three forms of vitamin K are currently known: vitamin K1 (phylloquinone), vitamin K2 (menaquinone), and vitamin K3 (menadione). Vitamin K plays different roles, including in activating vitamin K-dependent proteins (VKDPs) and in modulating bone metabolism and contributing to the inhibition of VC. This review focuses on the biochemical and functional characteristics of vitamin K vitamers, suggesting this nutrient as a possible marker of kidney, CV, and bone damage in the CKD population and exploring its potential use for promoting health in this clinical setting. Treatment strategies for CKD-associated osteoporosis and CV disease should include vitamin K supplementation. However, further randomized clinical studies are needed to assess the safety and the adequate dosage to prevent these CKD complications.
... It can also be metabolized into cysteine with the help of vitamin B6 and removed from the circulation. In recent years, more and more studies have shown that high plasma concentration of homocysteine, enhances the risk of atherothrombotic vascular disease (Knapen et al., 2015;Fulton et al., 2016). High homocysteine levels are an independent risk factor for atherosclerosis. ...
Article
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Atherosclerosis is the basic pathological process of many diseases, such as coronary atherosclerosis and stroke. Nutrients can affect the occurrence and development of atherosclerosis. At present, in nutrition science, the research on atherosclerosis focuses on which nutrients play an important role in its prevention strategy, and what are the possible mechanisms of its action. In the current study, the process of atherosclerosis can be affected by adjusting the proportion of nutrients in the diet. In this review, we pay attention to the effects of phytosterols, omega-3-polyunsaturated fatty acids, polyphenol, vitamin, and other nutrients on atherosclerosis, pay attention to their current epidemiological status, current nutritional research results, and prevention or a possible mechanism to reduce the risk of development of atherosclerosis. So that more personalized nutritional approaches may be more effective in terms of nutritional intervention responses to atherosclerosis.
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Background: Matrix Gla protein (MGP) is a vitamin K dependent peptide which has an established role in suppression of vascular calcification. Recent studies have pointed to a possible link between immunomodulatory effect of MGP and inflammatory bowel disease (IBD). Aim: To compare plasma levels of dephosphorylated and uncarboxylated MGP (dp-ucMGP) between IBD patients and controls. Methods: This cross-sectional study was conducted on 70 patients with IBD (30 patients with ulcerative colitis and 40 patients with Crohn's disease) and 60 age and gender matching healthy controls. Plasma dp-ucMGP levels were analyzed from blood samples by CLIA method using IDS-iSYS InaKtif MGP (Immunodiagnostic Systems, Frankfurt, Germany) according to the manufacturer's instructions. fecal calprotectin (FC) levels were determined from stool samples by turbidimetric immunoassay method using Bühlmann fecal calprotectin turbo assay (Bühlmann Laboratories Aktiengesellschaft, Schonenbuch, Switzerland). Other parameters were analyzed according to the standard laboratory procedures. Results: Plasma levels of dp-ucMGP were significantly higher in patients with IBD compared to the healthy control group (629.83 ± 124.20 pmol/mL vs 546.7 ± 122.09 pmol/mL, P < 0.001), and there was no significant difference between patients with Crohn's disease and patients with ulcerative colitis (640.02 ± 131.88 pmol/mL vs 616.23 ± 113.92 pmol/mL, P = 0.432). Furthermore, a significant positive correlation of plasma dp-ucMGP levels was found with both FC levels (r = 0.396, P < 0.001) and high sensitivity C-reactive protein (hsCRP) levels (r = 0.477, P < 0.001). Moreover, in the total study population a significant positive correlation was found between dp-ucMGP with age (r = 0.210, P = 0.016) and waist circumference (r = 0.264, P = 0.002). Multiple linear regression analysis showed that dp-ucMGP levels retained significant association with FC (β ± SE, 0.06 ± 0.02, P = 0.003). Conclusion: Study results support experimental data of MGP immunomodulatory IBD effect and indicate potential involvement in the pathophysiology of the disease, and possibly extraintestinal manifestations.
Article
Background: Vascular calcification, a risk factor for cardiovascular disease, is common among patients with CKD and is an independent contributor to increased vascular stiffness and vascular risk in this patient group. Vitamin K is a cofactor for proteins involved in prevention of vascular calcification. Whether or not vitamin K supplementation could improve arterial stiffness in patients with CKD is unknown. Methods: To determine if vitamin K supplementation might improve arterial stiffness in patients in CKD, we conducted a parallel-group, double-blind, randomized trial in participants aged 18 or older with CKD stage 3b or 4 (eGFR 15-45 ml/min per 1.73 m2). We randomly assigned participants to receive 400 μg oral vitamin K2 or matching placebo once daily for a year. The primary outcome was the adjusted between-group difference in carotid-femoral pulse wave velocity at 12 months. Secondary outcomes included augmentation index, abdominal aortic calcification, BP, physical function, and blood markers of mineral metabolism and vascular health. We also updated a recently published meta-analysis of trials to include the findings of this study. Results: We included 159 randomized participants in the modified intention-to-treat analysis, with 80 allocated to receive vitamin K and 79 to receive placebo. Mean age was 66 years, 62 (39%) were female, and 87 (55%) had CKD stage 4. We found no differences in pulse wave velocity at 12 months, augmentation index at 12 months, BP, B-type natriuretic peptide, or physical function. The updated meta-analysis showed no effect of vitamin K supplementation on vascular stiffness or vascular calcification measures. Conclusions: Vitamin K2 supplementation did not improve vascular stiffness or other measures of vascular health in this trial involving individuals with CKD.
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The cardinal biological role of vitamin K is to act as cofactor for the carboxylation of a number of vitamin K-dependent proteins, some of which are essential for coagulation, bone formation and prevention of vascular calcification. Functional vitamin K deficiency is common and severe among dialysis patients and has garnered attention as a modifiable risk factor in this population. However, no single biochemical parameter can adequately assess vitamin K status. For each biological function of vitamin K, the degree of carboxylation of the relevant vitamin K-dependent protein most accurately reflects vitamin K status. Dephosphorylated uncarboxylated matrix Gla protein (dp-ucMGP) is the best biomarker for vascular vitamin K status when cardiovascular endpoints are studied. Dp-ucMGP levels are severely elevated in haemodialysis patients and correlate with markers of vascular calcification and mortality in some but not all studies. The aetiology of vitamin K deficiency in haemodialysis is multifactorial, including deficient intake, uraemic inhibition of the vitamin K cycle and possibly interference of vitamin K absorption by phosphate binders. The optimal vitamin K species, dose and duration of supplementation to correct vitamin K status in dialysis patients are unknown. Dp-ucMGP levels dose-proportionally decrease with supraphysiological vitamin K2 supplementation, but do not normalize even with the highest doses. In the general population, long-term vitamin K1 or K2 supplementation has beneficial effects on cardiovascular disease, bone density and fracture risk, and insulin resistance, although some studies reported negative results. In haemodialysis patients, several trials on the effects of vitamin K on surrogate markers of vascular calcification are currently ongoing.
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Vitamin K (VK) is a fat-soluble vitamin that is indispensable for the activation of vitamin K-dependent proteins (VKDPs). It has been shown to play an important role in the proper calcium deposit at the bone level, hindering that on the vascular walls. The deficiency of this vitamin in European populations is frequent and unknown. It is related to several factors, poor dietary intake, altered intestinal absorption or altered production by bacteria, indicating possible dysbiosis. For Vitamin K2 (VK2), there is currently no official reference daily intake (RDI). However, the effects of VK2 on the improvement of health in cardiovascular diseases, on bone metabolism, on chronic kidney diseases have been the subject of research in recent decades. The microbiota in the gastrointestinal tract plays an important role: Bacteroides are primarily capable of synthetizing very long chain forms of menaquinones and, in addition to the bacteria present in the intestinal flora, VK2 is also produced by bacteria used in food fermentation processes. This review provides an update on the current literature regarding the origin of VK2 and its implications in what is called the “calcium paradox”, namely the lack of calcium in the bone and its storage in the wall of the vessel.
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In 2019, the EPMA celebrated its 10th anniversary at the 5th World Congress in Pilsen, Czech Republic. The history of the International Professional Network dedicated to Predictive, Preventive and Personalised Medicine (PPPM / 3PM) is rich in achievements. Facing the coronavirus COVID-19 pandemic it is getting evident globally that the predictive approach, targeted prevention and personalisation of medical services is the optimal paradigm in healthcare demonstrating the high potential to save lives and to benefit the society as a whole. The EPMA World Congress Supplement 2020 highlights advances in 3P medicine.
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A protective role for vitamin K in cardiovascular disease (CVD), a leading cause of morbidity and mortality, has been proposed because vitamin K–dependent proteins, such as matrix Gla (γ-carboxyglutamic acid) protein (MGP), are present in vascular tissue. MGP functions as a vascular calcification inhibitor—but only when it is carboxylated, which requires vitamin K. There is more than one naturally occurring form of vitamin K. Phylloquinone (vitamin K1) is found in plant-based foods, whereas menaquinones (vitamin K2) are a class of vitamin K compounds found in animal-based and fermented foods. Phylloquinone and menaquinones are capable of carboxylating MGP and other vitamin K–dependent proteins. In rodent models, high intakes of either phylloquinone or menaquinone reduced vascular calcification. Evidence of the relative importance of phylloquinone and menaquinone to CVD in humans is limited and controversial. In some observational studies, higher dietary menaquinone intake, but not phylloquinone intake, was associated with less coronary artery calcification (a subclinical manifestation of CVD) and a lower risk for clinical CVD events. These findings have led to claims that menaquinones have unique cardiovascular health benefits compared with phylloquinone. However, this claim is not supported by the results of the limited number of intervention trials conducted to date. The purpose of this review is to evaluate the strengths and limitations of the available evidence regarding the role of vitamin K in vascular calcification, CVD, and mortality.
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Premature cardiovascular disease and death with a functioning graft are leading causes of death and graft loss respectively in kidney transplant recipients (KTR). Vascular stiffness and calcification are markers of cardiovascular disease that are prevalent in KTR and associated with subclinical vitamin K deficiency. We performed a single‐centre, phase II, parallel‐group, randomised, double‐blind, placebo‐controlled trial (ISRCTN22012044) to test whether vitamin K supplementation reduced vascular stiffness (MRI‐based aortic distensibility) or calcification (coronary artery calcium score on computed tomography) in KTR over 1 year of treatment. The primary outcome was between‐group difference in vascular stiffness (ascending aortic distensibility). KTR were recruited between September 2017 and June 2018, and randomised 1:1 to vitamin K (Menadiol diphosphate 5mg; n=45) or placebo (n=45) thrice‐weekly. Baseline demographics, clinical history and immunosuppression regimens were similar between groups. There was no impact of vitamin K on vascular stiffness (treatment effect ‐0.23 (95% CI ‐0.75 to 0.29) x10‐3 mmHg‐1; p=0.377), vascular calcification (treatment effect ‐141 (95% CI ‐320 to 38) units; p=0.124), nor any other outcome measure. In this heterogeneous cohort of prevalent KTR, vitamin K supplementation did not reduce vascular stiffness or calcification over 1 year. Improving vascular health in KTR is likely to require a multifaceted approach.
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In this study, in vitro digestion and fermentation was employed to simulate the consumption of fermented okara and hence, evaluate its potential as a functional food ingredient. This is to develop a method of utilizing okara without producing secondary waste. Fermentation increased the amount of soluble dietary fiber by 187%. Bioaccessibility of amino acids, fatty acids, and vitamin K2 MK-7 is higher in the digestion supernatant of fermented okara. Bacillus subtilis also remained viable after digestion. Supernatants of fermented okara exhibited higher bio accessibility of total phenolic content and higher DPPH radical scavenging activity in the small and large intestines. Similarly, the concentrations of acetic acid, propionic acid, and butyric acid were 44.4%, 46.9%, and 51.8% higher, respectively. The gut microbiota was also found to be different in the fermentation supernatants between fermented and unfermented okara. Results demonstrated the potential of fermented okara as a functional food ingredient.
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Purpose of review: Vascular calcification is a common and important cardiovascular risk factor in patients with chronic kidney disease (CKD). Recent advances in the understanding of the biology of vascular calcification implicate vitamin K-dependent proteins as important regulators in this process. This review highlights recent key advances in vascular biology, epidemiology, and clinical trials in this rapidly evolving field. Recent findings: Vitamin K deficiency is associated with increasing severity of vascular calcification among patients with CKD, but the relationship with cardiovascular disease and mortality is inconsistent. Vitamin K may reduce calcification propensity by improving the activity of vitamin K-dependent calcification inhibitors or by down-regulating components of the innate immune system to reduce inflammation. However, recent randomized controlled trials in patients with diabetes, CKD, renal transplant, and on hemodialysis have failed to demonstrate improvement in vascular calcification or stiffness after vitamin K treatment. Summary: Current evidence does not support a clinically useful role for vitamin K supplementation to prevent or reverse vascular calcification in patients with CKD. Knowledge gaps remain, particularly whether higher doses of vitamin K, longer duration of supplementations, or use a vitamin K as a part of a package of measures to counteract vascular calcification might be effective.
Chapter
Supplement use remains common in USA, primarily due to public interest in improving health and well-being. Vitamins, minerals, and macronutrient supplement formulations remain some of the most commonly used; however, few have been systematically studied regarding their role in promoting cardiovascular health. Fairly consistently, diets rich in many of these compounds have been found in epidemiologic studies to confer benefit; however, existing interventional or cohort studies generally have failed to find pervasive evidence of benefit with some exception. Notably, the heterogeneity of different compounds is paralleled by the heterogeneity of studies, with differing formulations, dosing, populations studied, and outcomes limiting interpretation and generalizability. Still, both consumer and research interest remain strong in evaluating the impact these supplements have on improving cardiovascular health. This chapter will outline existing literature for some of the most commonly used supplements, including major limitations—and promise—for the use of these supplements in populations with average and elevated risk for cardiovascular disease and outcomes.
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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.
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Vitamin K2 (VK2) is one of the two types of vitamin K present most in the human diet. VK2 seems to have a beneficial effect on inflammation related to type 2 diabetes mellitus. The aim of this study was to evaluate the influence of VK2 on lipid precursors of inflammation in lipid-overloaded human liver hepatocellular carcinoma cells. Cells were incubated with VK2 and/or palmitic acid (PA). The concentrations of lipid fractions and their fatty acid compositions were measured by gas-liquid chromatography. The expression of proteins involved in the inflammatory process was detected using western blotting. The concentration of triacylglycerols (TAGs), activities of the n-3 pathway in TAGs, and lipooxygenase 15 expression were significantly elevated in cells incubated with PA and VK2. In the same group, a marked elevation in diacylglycerol (DAG) 20:4 was observed. VK2 supplementation lowered the expression of tumour necrosis factor-alpha and interleukin-6 compared to that in the PA group. The data indicate that VK2 redirects fatty acid metabolism into the deposition of a safe TAG fraction by increasing the concentration of anti-inflammatory n-3 polyunsaturated fatty acids in this fraction. Moreover, VK2 stimulates the synthesis of anti-inflammatory factors and has anti-inflammatory effects by reducing DAG 20:4.
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Vascular calcification (VC) is highly prevalent in Chronic Kidney Disease (CKD) patients, progresses gradually with deterioration of kidney function and is a strong, independent predictor of cardiovascular (CV) mortality. Matrix Gla Protein (MGP), the most potent inhibitor of VC, requires vitamin K as a co-factor to become biologically active. Accumulating epidemiological data have associated vitamin K depletion with VC progression and CV outcomes. CKD patients are characterized by poor vitamin K status and at the same time, pronounced CV calcification. In early and advanced CKD, including end-stage kidney disease, exogenous supplementation of vitamin K (especially with menaquinone 7, its most bioavailable form) might decrease the inactive form of MGP (dephosphorylated, uncarboxylated MGP) and probably retard the progression or even reverse VC. Here, we focus and discuss the interventional human studies of vitamin K supplementation in CKD patients and suggest future directions in this area of interest.
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Background: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis. Methods: In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 μg MK-7 plus 25 μg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events. Results: From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001). Conclusions: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression.
Article
Use of chronic vitamin K antagonist (VKA) induces a long-term deficiency of vitamin K, which may cause arterial stiffness and bone-related disease. Switching from VKA to rivaroxaban could induce rapid sufficiency of vitamin K and improvement of arterial stiffness. The K2 SUMMIT-3 study is a multicenter, open-label, prospective, and randomized design. Patients with atrial fibrillation who have been taking VKA for more than 6 months but less than 10 years were randomly assigned to two groups; those switching from VKA to rivaroxaban and those continuing with VKA medication. The primary endpoint was the percentage difference of brachial-ankle pulse wave velocity (baPWV) in 3 months. A total of 77 patients were randomly assigned to receive rivaroxaban (n = 38) or VKA (n = 39). The average age was 74 ± 9 years. The duration for which VKA was prescribed prior to randomization was 90 ± 87 months.Abnormally high levels of Des-gamma carboxyprothrombin (PIVKA-II) or uncarboxylated osteocalcin (ucOC) indicating vitamin K insufficiency were observed in 100% or 82% of the patients at baseline but it reduced to 2% (p < 0.0001) or 55% (p = 0.01) at 3 months in the rivaroxaban group. To the contrary, theses data had no changes in the VKA group. The percentage difference in baPWV was − 1.4 ± 10.0% vs. 3.5 ± 14.7% in the rivaroxaban and the VKA groups, respectively. (p = 0.02). Switching from VKA to rivaroxaban resulted in rapid sufficiency of vitamin K and reduction of arterial stiffness in 3 months.
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Matrix Gla protein (MGP) is an important inhibitor of calcification. The objective of the present study of patients with type 2 diabetes and normal or slightly altered kidney function was to evaluate levels of inactive, dephospho-uncarboxylated MGP(dp-ucMGP) and total uncarboxylated MGP(t-ucMGP) and assess their links with biological and clinical parameters (including peripheral vascular calcification). The DIACART study is a cross-sectional cohort study of 198 patients with type 2 diabetes and normal or slightly altered kidney function. Matrix Gla protein levels were measured with an ELISA and all patients underwent multislice spiral computed tomography scans to score below-knee arterial calcification. In the study population as a whole, the mean dp-ucMGP and t-ucMGP levels were 627 +/- 451 pM and 4868 +/- 1613 nM, respectively. Glomerular filtration rate, age and current vitamin K antagonist use were independently associated with dp-ucMGP levels. When the study population was divided according to the median peripheral arterial calcification score, patients with the higher score displayed significantly lower t-ucMGP and significantly higher dp-ucMGP levels. Furthermore, plasma dp-ucMGP was positively associated with the peripheral arterial calcification score (independently of age, gender, previous cardiovascular disease and t-ucMGP levels). High dp-ucMGP levels were independently associated with below-knee arterial calcification score in patients with type 2 diabetes and normal or slightly altered kidney function. The reversibility of the elevation of dp-ucMGP levels and the latter's relationship with clinical events merit further investigation.
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We have investigated whether low-dose vitamin K2 supplements (menaquinone-7, MK-7) could beneficially affect bone health. Next to an improved vitamin K status, MK-7 supplementation significantly decreased the age-related decline in bone mineral density and bone strength. Low-dose MK-7 supplements may therefore help postmenopausal women prevent bone loss. Introduction Despite contradictory data on vitamin K supplementation and bone health, the European Food Safety Authorities (EFSA) accepted the health claim on vitamin K’s role in maintenance of normal bone. In line with EFSA’s opinion, we showed that 3-year high-dose vitamin K1 (phylloquinone) and K2 (short-chain menaquinone-4) supplementation improved bone health after menopause. Because of the longer half-life and greater potency of the long-chain MK-7, we have extended these investigations by measuring the effect of low-dose MK-7 supplementation on bone health. Methods Healthy postmenopausal women (n = 244) received for 3 years placebo or MK-7 (180 μg MK-7/day) capsules. Bone mineral density of lumbar spine, total hip, and femoral neck was measured by DXA; bone strength indices of the femoral neck were calculated. Vertebral fracture assessment was performed by DXA and used as measure for vertebral fractures. Circulating uncarboxylated osteocalcin (ucOC) and carboxylated OC (cOC) were measured; the ucOC/cOC ratio served as marker of vitamin K status. Measurements occurred at baseline and after 1, 2, and 3 years of treatment. Results MK-7 intake significantly improved vitamin K status and decreased the age-related decline in BMC and BMD at the lumbar spine and femoral neck, but not at the total hip. Bone strength was also favorably affected by MK-7. MK-7 significantly decreased the loss in vertebral height of the lower thoracic region at the mid-site of the vertebrae. Conclusions MK-7 supplements may help postmenopausal women to prevent bone loss. Whether these results can be extrapolated to other populations, e.g., children and men, needs further investigation.
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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
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AimsCommon carotid artery intima-media thickness (CCIMT) is widely used as a surrogate marker of atherosclerosis, given its predictive association with cardiovascular disease (CVD). The interpretation of CCIMT values has been hampered by the absence of reference values, however. We therefore aimed to establish reference intervals of CCIMT, obtained using the probably most accurate method at present (i.e. echotracking), to help interpretation of these measures.Methods and resultsWe combined CCIMT data obtained by echotracking on 24 871 individuals (53% men; age range 15-101 years) from 24 research centres worldwide. Individuals without CVD, cardiovascular risk factors (CV-RFs), and BP-, lipid-, and/or glucose-lowering medication constituted a healthy sub-population (n = 4234) used to establish sex-specific equations for percentiles of CCIMT across age. With these equations, we generated CCIMT Z-scores in different reference sub-populations, thereby allowing for a standardized comparison between observed and predicted ('normal') values from individuals of the same age and sex. In the sub-population without CVD and treatment (n = 14 609), and in men and women, respectively, CCIMT Z-scores were independently associated with systolic blood pressure [standardized βs 0.19 (95% CI: 0.16-0.22) and 0.18 (0.15-0.21)], smoking [0.25 (0.19-0.31) and 0.11 (0.04-0.18)], diabetes [0.19 (0.05-0.33) and 0.19 (0.02-0.36)], total-to-HDL cholesterol ratio [0.07 (0.04-0.10) and 0.05 (0.02-0.09)], and body mass index [0.14 (0.12-0.17) and 0.07 (0.04-0.10)].Conclusion We estimated age- and sex-specific percentiles of CCIMT in a healthy population and assessed the association of CV-RFs with CCIMT Z-scores, which enables comparison of IMT values for (patient) groups with different cardiovascular risk profiles, helping interpretation of such measures obtained both in research and clinical settings.
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In 2001, the US Food and Nutrition Board concluded that there were insufficient data with which to establish a RDA for vitamin K, in large part because of a lack of robust endpoints that reflected adequacy of intake. Knowledge of the relative bioavailability of multiple vitamin K forms was also poor. Since then, stable isotope methodologies have been applied to the assessment of the bioavailability of the major dietary form of vitamin K in its free state and when incorporated into a plant matrix. There is a need for stable isotope studies with enhanced sensitivity to expand knowledge of the bioavailability, absorption, disposition, and metabolism of different molecular forms of vitamin K. Another area for future research stems from evidence that common polymorphisms or haplotypes in certain key genes implicated in vitamin K metabolism might affect nutritional requirements. Thus far, much of this evidence is indirect via effects on warfarin dose requirements. In terms of clinical endpoints, vitamin K deficiency in early infancy continues to be a leading cause of intracranial bleeding even in developed countries and the reasons for its higher prevalence in certain Asian countries has not been solved. There is universal consensus for the need for vitamin K prophylaxis in newborns, but the effectiveness of any vitamin K prophylactic regimen needs to be based on sound nutritional principles. In contrast, there is still a lack of suitable biomarkers or clinical endpoints that can be used to determine vitamin K requirements among adults.
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Aims - Carotid–femoral pulse wave velocity (PWV), a direct measure of aortic stiffness, has become increasingly important for total cardiovascular (CV) risk estimation. Its application as a routine tool for clinical patient evaluation has been hampered by the absence of reference values. The aim of the present study is to establish reference and normal values for PWV based on a large European population. Methods and results - We gathered data from 16 867 subjects and patients from 13 different centres across eight European countries, in which PWV and basic clinical parameters were measured. Of these, 11 092 individuals were free from overt CV disease, non-diabetic and untreated by either anti-hypertensive or lipid-lowering drugs and constituted the reference value population, of which the subset with optimal/normal blood pressures (BPs) (n = 1455) is the normal value population. Prior to data pooling, PWV values were converted to a common standard using established conversion formulae. Subjects were categorized by age decade and further subdivided according to BP categories. Pulse wave velocity increased with age and BP category; the increase with age being more pronounced for higher BP categories and the increase with BP being more important for older subjects. The distribution of PWV with age and BP category is described and reference values for PWV are established. Normal values are proposed based on the PWV values observed in the non-hypertensive subpopulation who had no additional CV risk factors. Conclusion - The present study is the first to establish reference and normal values for PWV, combining a sizeable European population after standardizing results for different methods of PWV measurement.
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Vitamin K is required for the carboxylation of Gla-proteins in the liver (coagulation factors) and extra-hepatic tissues, such as bone (osteocalcin, OC), and arterial wall (matrix Gla-protein, MGP). Although the coagulation factors are essentially fully carboxylated under normal conditions, 10-40 % of OC and MGP remains undercarboxylated. We were therefore interested to study the dose-response effects of extra intake of menaquinones on the carboxylation of the extra-hepatic Gla-proteins. A total of forty-two healthy Dutch men and women aged between 18 and 45 years were randomised into seven groups to receive: placebo capsules or menaquinone-7 (MK-7) capsules at a daily dose of 10, 20, 45, 90, 180 or 360 μg. Circulating uncarboxylated OC (ucOC), carboxylated OC (cOC) and desphospho-uncarboxylated MGP were measured by ELISA. The ucOC:cOC ratio was calculated from circulating ucOC and cOC values. Endogenous thrombin potential and peak height were determined by calibrated automated thrombography. To increase the statistical power, we collapsed the treatment groups into three dosage groups: placebo, low-dose supplementation (doses below RDA, Commission Directive 2008/100/EC), and high-dose supplementation (doses around RDA, Commission Directive 2008/100/EC). MK-7 supplementation at doses in the order of the RDA (Commission Directive 2008/100/EC) increased the carboxylation of circulating OC and MGP. No adverse effects on thrombin generation were observed. Extra MK-7 intake at nutritional doses around the RDA (Commission Directive 2008/100/EC) improved the carboxylation of the extra-hepatic vitamin K-dependent proteins. Whether this improvement contributes to public health, i.e. increasing the protection against age-related diseases needs further investigation in specifically designed intervention trials.
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Despite routine ultrasound mapping of upper extremity arteries and veins, early thrombosis and nonmaturation remain frequent complications following vascular access (VA) surgery. Besides vascular diameters, brachial artery stiffness is assumed to play an important role; however, reproducibility of measurements has never been established. The purpose of this study was to determine within-session and between-session variabilities of pulse wave velocity (PWV) assessment by using ultrasonography and blood pressure registration. Beat-to-beat changes in brachial artery diameter and pressure were obtained in 21 subjects in measurement sessions on Day 1 and Day 3. Each session consisted of three acquisitions. For each acquisition, systolic and diastolic diameter and pressure were determined and used for calculation of brachial artery PWV. Within-session variability of diameter and pressure, as well as the estimated PWV, was expressed using the intraclass correlation coefficient with corresponding coefficient of variation (CoV). Between-session variability was reported using Bland-Altman analysis in combination with CoV analysis. Significant agreement (P < 0.001) was obtained for all diameter and pressure measurements obtained on Day 1 and Day 3. Within-session CoV of pulse pressure, diastolic diameter and distension were 7.0, 1.6 and 18.3%, respectively. Subsequent estimation of local PWV resulted in a CoV of 10.6%. Between-session CoV was 15.1, 3.8 and 18.9% for pulse pressure, diastolic diameter and distension, respectively. For PWV estimation, this resulted in a CoV of 13.5%. Diameter and pressure can be recorded accurately over the cardiac cycle, and calculations of distensibility, pulse pressure and PWV show a slight to moderate degree of variation. Larger studies elaborating on interindividual differences need to determine the clinical efficacy of PWV measurements prior to VA creation.
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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]. Intake of menaquinone was also inversely related to all-cause mortality [RR = 0.91 (0.75, 1.09) and 0.74 (0.59, 0.92), respectively] and severe aortic calcification [odds ratio of 0.71 (0.50, 1.00) and 0.48 (0.32, 0.71), respectively]. Phylloquinone intake was not related to any of the outcomes. These findings suggest that an adequate intake of menaquinone could be important for CHD prevention.
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Both cardiovascular disease and osteoporosis are important causes of morbidity and mortality in the elderly. The co-occurrence of cardiovascular disease and osteoporosis prompted us to review the evidence of an association between cardiovascular (CV) disease and osteoporosis and potential shared common pathophysiological mechanisms. A systematic literature search (Medline, Pubmed and Embase) was conducted to identify all clinical studies that investigated the association between cardiovascular disease and osteoporosis. Relevant studies were screened for quality according to guidelines as proposed by the Dutch Cochrane Centre and evidence was summarized. Seventy studies were included in this review. Due to a large heterogeneity in study population, design and outcome measures a formal meta-analysis was not possible. Six of the highest ranked studies (mean n = 2,000) showed that individuals with prevalent subclinical CV disease had higher risk for increased bone loss and fractures during follow-up compared to persons without CV disease (range of reported risk: hazard ratio (HR) 1.5; odds ratio (OR) 2.3 to 3.0). The largest study (n = 31,936) reported a more than four times higher risk in women and more than six times higher risk in men. There is moderate evidence that individuals with low bone mass had higher CV mortality rates and incident CV events than subjects with normal bone mass (risk rates 1.2 to 1.4). Although the shared common pathophysiological mechanisms are not fully elucidated, the most important factors that might explain this association appear to be, besides age, estrogen deficiency and inflammation. The current evidence indicates that individuals with prevalent subclinical CV disease are at increased risk for bone loss and subsequent fractures. Presently no firm conclusions can be drawn as to what extent low bone mineral density might be associated with increased cardiovascular risk.
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Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium-ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured with two commercially available competitive and two novel sandwich assays in healthy controls, in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status. We conclude that the different assays for particular circulating MGP species allows the assessment of various aspects of the MGP system.
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Vitamin K-dependent matrix Gla protein (MGP) acts as a calcification inhibitor in vitro and in vivo. The present study was performed to (1) determine plasma levels of the inactive, dephosphorylated, uncarboxylated MGP (dp-ucMGP) in a cohort of patients at different stages of chronic kidney disease (CKD) and (2) evaluate the association between dp-ucMGP levels on one hand and aortic calcification and mortality on the other. 107 patients (67 +/- 13 years; 60% male; 32% at CKD stages 2 to 3, 31% at stages 4 to 5, 37% at stage 5D) were assayed for dp-ucMGP and underwent multislice spiral computed tomography scans to quantify aortic calcification at baseline. They were prospectively monitored for mortality. Plasma dp-ucMGP levels augmented progressively with CKD stage, with a significant difference from CKD stage 4. CKD stage, hemoglobin, age, and coumarin use were independently associated with plasma dp-ucMGP levels. Furthermore, plasma dp-ucMGP and age were positively and independently associated with the aortic calcification score. During follow-up (802 +/- 311 days), 34 patients died (20 from cardiovascular events). In a crude analysis, [plasma dp-ucMGP] > 921 pM was associated with overall mortality; this association was lost after adjusting for both age and the calculated propensity score. Plasma dp-ucMGP increased progressively in a CKD setting and was associated with the severity of aortic calcification. Plasma dp-ucMGP could thus be a surrogate marker for vascular calcification in CKD.
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Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K-dependent calcification inhibitor. The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. CAC was measured at baseline and after 3 y of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 microg phylloquinone/d (treatment), and 188 received a multivitamin alone (control). In an intention-to-treat analysis, there was no difference in CAC progression between the phylloquinone group and the control group; the mean (+/-SEM) changes in Agatston scores were 27 +/- 6 and 37 +/- 7, respectively. In a subgroup analysis of participants who were > or =85% adherent to supplementation (n = 367), there was less CAC progression in the phylloquinone group than in the control group (P = 0.03). Of those with preexisting CAC (Agatston score > 10), those who received phylloquinone supplements had 6% less progression than did those who received the multivitamin alone (P = 0.04). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations. Because our data are hypothesis-generating, further studies are warranted to clarify this mechanism. This trial was registered at clinicaltrials.gov as NCT00183001.
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Vitamin K dependent proteins have been demonstrated to inhibit vascular calcification. Data on the effect of vitamin K intake on coronary heart disease (CHD) risk, however, are scarce. To examine the relationship between dietary vitamins K(1) and K(2) intake, and its subtypes, and the incidence of CHD. We used data from the Prospect-EPIC cohort consisting of 16,057 women, enrolled between 1993 and 1997 and aged 49-70 years, who were free of cardiovascular diseases at baseline. Intake of vitamin K and other nutrients was estimated with a food frequency questionnaire. Multivariate Cox proportional hazards models were used to analyse the data. After a mean+/-SD follow-up of 8.1+/-1.6 years, we identified 480 incident cases of CHD. Mean vitamin K(1) intake was 211.7+/-100.3 microg/d and vitamin K(2) intake was 29.1+/-12.8 microg/d. After adjustment for traditional risk factors and dietary factors, we observed an inverse association between vitamin K(2) and risk of CHD with a Hazard Ratio (HR) of 0.91 [95% CI 0.85-1.00] per 10 microg/d vitamin K(2) intake. This association was mainly due to vitamin K(2) subtypes MK-7, MK-8 and MK-9. Vitamin K(1) intake was not significantly related to CHD. A high intake of menoquinones, especially MK-7, MK-8 and MK-9, could protect against CHD. However, more research is necessary to define optimal intake levels of vitamin K intake for the prevention of CHD.
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Vitamin K modulates cytokines involved in bone turnover, including interleukin-6 (IL-6) and osteoprotegerin in vitro. The objective of this study was to assess 1) associations between measures of vitamin K status [plasma phylloquinone and serum percentage of undercarboxylated osteocalcin (%ucOC)] and IL-6, osteoprotegerin, and C-reactive protein (CRP) concentrations and 2) the effect of daily 500 mug phylloquinone supplementation for 3 y on cytokine concentrations. Concentrations of IL-6, osteoprotegerin, and CRP and bone mineral density (BMD) were measured at baseline and after 3 y of follow-up in 379 healthy men and women (60-81 y; 58.5% women) participating in a randomized trial that studied the effect of vitamin K supplementation on bone loss. Cross-sectionally, plasma phylloquinone was inversely associated with IL-6 and CRP, whereas serum %ucOC was inversely associated with IL-6. Osteoprotegerin was associated positively with plasma phylloquinone and inversely with %ucOC. No differences were observed in the 3-y change in IL-6, osteoprotegerin, and CRP concentrations between participants who received phylloquinone supplementation and those who did not. Overall, no association was observed between the 3-y changes in circulating cytokines and BMD. Poor vitamin K status was associated with high concentrations of cytokines involved in bone turnover, but vitamin K supplementation did not confer a decrease in cytokine concentrations. The healthy status of this cohort may explain a lack of effect of vitamin K supplementation on cytokine concentrations. This trial was registered with www.clinicaltrials.gov as NCT00183001.
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