Vitamin K2 Effect on Vascular Stiffening in Subjects With a Poor Vitamin K-status

Study Overview
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Brief Summary
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Vitamin K is required for the activation of the inhibitor of vascular calcification: Matrix Gla Protein (MGP). In an earlier study the beneficial effect of menaquinone-7 (MK-7), a vitamin K2 form, was observed on the stiffness of the vessel wall in postmenopausal women. It decreased the circulating form of inactive MGP and improved the vascular elasticity (local) and aortic pulse wave velocity (regional). The decrease of circulating inactive MGP was observed after 2-3 months MK-7 supplementation and the effect of MK-7 on the clinical endpoints was observed within 3 years of supplementation. It is demonstrated in several studies that cardiovascular risk increases with decreasing vitamin K intake and increasing levels of inactive MGP. In this study the investigators select subjects in the highest tertile of circulating inactive MGP. This study group will consist of subjects with increased cardiovascular risk and it is expected that effects of MK-7 on clinical endpoints in this group will be measurable within 1 year of supplementation. Vascular stiffness can be determined with different techniques. The vascular characteristics determined with Pulse Wave Velocity (PWV), ultrasound of the common carotid artery and accelerated plethysmography (APG) with a fingertip device will be compared in a follow-up study.

Detailed Description
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This study will be a double-blind randomized placebo-controlled intervention study. In total 240 healthy men and women between 40 and 70 years will be recruited in the province of Limburg through small advertisements in local newspapers. Eligible participants will be randomized into 2 study groups: Group 1: MK-7 (1 tablet: MK-7 dosage is 180 μg) Group 2: Placebo (1 tablet: MK-7 dosage is 0 µg) Each group will consist of 120 participants. A double-blind design is chosen to avoid the occurrence of bias during the study. After randomization, the participants consume the placebo or MK-7 tablets once daily with either breakfast or dinner during one year. People who are interested to participate will come to the research laboratory of VitaK for a screening visit (day -14). During this visit, the investigator will check whether the volunteers are eligible for inclusion based on the in- and exclusion criteria. After meeting the inclusion criteria and none of the exclusion criteria, volunteers will be assigned a randomization number from a computer-generated randomization list. A stratified block randomization will be performed for gender, in order to avoid unequal distribution of men and women among the 2 treatment groups. On-site measurements will be performed at t=0 and after 1 year of treatment: the carotid-femoral Pulse Wave Velocity (cfPWV; primary outcome) and echotracking of the common carotid artery to assess the vascular stiffness (secondary outcome). A Whole Body scan with DXA will be performed to determine total fat and lean mass of the participants. Blood will be taken after an overnight fasting period at t=0 and after 1 year to measure the circulating level of inactive MGP. Results from our previous study (NCT00642551) showed significant changes in vascular characteristics, pulse wave velocity after a 3 year intervention period with a daily dosage of 180 µg MK-7 in 240 postmenopausal women. After 1 year MK-7 intervention inactive MGP levels (improvement of vascular vitamin K status) were decreased 50% compared to placebo and remained at this level during the following 2 years of intervention. Recently published population-based studies show that the unfavorable cardiovascular outcomes are mainly attributable to those within the highest quartile of circulating dp-ucMGP. We expect, therefore, that an intervention study among preselected subjects with poor vascular vitamin K status (inactive MGP levels > 400 pmol/L) and treatment with the same dosage MK-7 (i.e. 180 µg/day) during one year will have a more pronounced effect on arterial stiffening and pulse wave velocity. The follow-up study will be performed at the end of the intervention period of 1 year, with participants who have completed the one year intervention study. From this study population eligible participants (men and women) will be selected. In total 100 participants will be invited. Measurements will be performed at the same day: the carotid-femoral Pulse Wave Velocity (cfPWV), echotracking of the common carotid artery to assess the vascular stiffness and accelerated plethysmography measurements (APG) will be assessed using an fingertip oximeter StiffnoGraph (Taiwan): heart rate, SpO2 (oxygen saturation) and stiffness score.

Official Title
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Intervention Study on the Effect of Vitamin K2 (Menaquinone-7) Supplementation on the Vascular Stiffness in Subjects With Poor Vitamin K-status

Conditions
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Vascular Stiffness

Intervention / Treatment
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* Dietary Supplement: Menaquinone-7
* Dietary Supplement: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women between 40 and 70 years old Subjects with body weight and height according to BMI between 20 and 35 kg/m2 Subjects of Caucasian race Subject has given written consent to take part in the study Subjects with circulating dp-ucMGP higher than 400 pmol/L Exclusion Criteria: Subjects with cardiovascular disease Subjects with hyperlipidaemia Subjects with (a history of) metabolic or gastrointestinal disease Subjects presenting chronic degenerative and/or inflammatory disease Use of more than 3 units alcohol/day Subjects receiving oestrogen treatment (women) Subjects using corticosteroids Subjects using oral anticoagulants and subjects with clotting disorders Subjects using vitamin K containing multivitamins or supplements

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Menaquinone-7<br>Menaquinone-7 180 microgram tablet, by mouth, daily for 1 year | Dietary Supplement: Menaquinone-7<br>* 1 tablet containing 180 micrograms MK-7 taken orally every day during 1 year<br>* Other names: MK-7;|
| Placebo Comparator: Placebo<br>Placebo tablet, by mouth, daily for 1 year | Dietary Supplement: Placebo<br>* 1 tablet without MK-7 taken orally every day during 1 year<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline carotid-femoral Pulse Wave Velocity (PWV) at 1 year | PWV (in m/s) will be assessed noninvasively by measuring carotid-femoral PWV, using mechanotransducers applied directly on the skin. | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline diameter of the common carotid artery at 1 year | The diameter of the common carotid artery will be measured using a linear array transducer connected to an ultrasound scanner. The diameter will be assessed in mm. | 1 year | 
| Diameter of the common carotid artery | The diameter of the common carotid artery will be measured using a linear array transducer connected to an ultrasound scanner. The diameter will be assessed in mm. | up to 1 year post-intervention | 
| Change from baseline distension of the common carotid artery at 1 year | The distension of the common carotid artery will be measured using a linear array transducer connected to an ultrasound scanner. The distension will be assessed in micrometer. | 1 year | 
| Distension of the common carotid artery | The distension of the common carotid artery will be measured using a linear array transducer connected to an ultrasound scanner. The distension will be assessed in micrometer. | up to 1 year post-intervention | 
| Change from baseline intima-media thickness (IMT) of the common carotid artery at 1 year | The IMT of the common carotid artery will be measured using a linear array transducer connected to an ultrasound scanner. The IMT will be assessed in micrometer. | 1 year | 
| Intima-media thickness (IMT) of the common carotid artery | The IMT of the common carotid artery will be measured using a linear array transducer connected to an ultrasound scanner. The IMT will be assessed in micrometer. | up to 1 year post-intervention | 
| circulating inactive Matrix Gla Protein (dp-ucMGP) | Dp-ucMGP (in pM) will be measured using a sandwich ELISA, based on monoclonal antibodies. | baseline and 1 year | 
| carotid-femoral Pulse Wave Velocity (PWV) | PWV (in m/s) will be assessed noninvasively by measuring carotid-femoral PWV, using mechanotransducers applied directly on the skin. | up to 1 year post-intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Vitamin K, Menaquinone-7, Matrix Gla Protein, Vascular stiffness