menaquinone-7 and Vascular-Calcification

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

Topics: Aged; Diabetes Mellitus, Type 2; Dietary Supplements; Double-Blind Method; Female; Humans; Male; Middle Aged; Vascular Calcification; Vitamin K 2

Coronary artery calcification (CAC) develops early in the pathogenesis of atherosclerosis and is a strong and independent predictor of cardiovascular disease (CVD). Arterial calcification is caused by an imbalance in calcification regulatory mechanisms. An important inhibitor of calcification is vitamin K-dependent matrix Gla protein (MGP). Both preclinical and clinical studies have shown that inhibition of the vitamin K-cycle by vitamin K antagonists (VKA) results in elevated uncarboxylated MGP (ucMGP) and subsequently in extensive arterial calcification. This led us to hypothesize that vitamin K supplementation may slow down the progression of calcification. To test this, we designed the VitaK-CAC trial which analyses effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The trial is a double-blind, randomized, placebo-controlled trial including patients with coronary artery disease (CAD). Patients with a baseline Agatston CAC-score between 50 and 400 will be randomized to an intervention-group (360 microgram MK-7) or a placebo group. Treatment duration will be 24 months. The primary endpoint is the difference in CAC-score progression between both groups. Secondary endpoints include changes in arterial structure and function, and associations with biomarkers. We hypothesize that treatment with MK-7 will slow down or arrest the progression of CAC and that this trial may lead to a treatment option for vascular calcification and subsequent CVD.

Topics: Adult; Arteries; Calcium; Calcium-Binding Proteins; Clinical Protocols; Coronary Artery Disease; Dietary Supplements; Disease Progression; Double-Blind Method; Extracellular Matrix Proteins; Humans; Matrix Gla Protein; Research Design; Vascular Calcification; Vitamin K 2; Vitamins

Haemodialysis patients suffer from accelerated vascular calcification. The vitamin K-dependent matrix Gla protein (MGP) is one of the most powerful inhibitors of vascular calcification. Haemodialysis patients have high levels of the inactive form of MGP (desphosphorylated-uncarboxylated-MGP, dp-uc-MGP) and may benefit from pharmacological doses of vitamin K2 (menaquinone) to improve the calcification inhibitory activity of MGP.. To determine the optimal dose of menaquinone-7 (MK-7) for MGP activation, 200 chronic haemodialysis patients were recruited to randomly receive 360, 720 or 1080 µg of MK-7 thrice weekly for 8 weeks. Dp-uc-MGP was measured at baseline and after 8 weeks. Dietary intake of vitamin K1 (phylloquinone) and menaquinone was estimated based on a detailed questionnaire.. At baseline, dp-uc-MGP was not associated with phylloquinone intake (P = 0.92), but correlated inversely with menaquinone intake (P = 0.023). MK-7 supplementation dose dependently reduced dp-uc-MGP. The levels decreased by 17, 33 and 46% in the respective groups. Drop-outs were mainly due to gastrointestinal side-effects related to the unpleasant smell of the tablets.. Chronic haemodialysis patients have high levels of inactive MGP, possibly related to a low dietary vitamin K intake. Pharmacological doses of MK-7 dose-dependently reduce dp-uc-MGP. Menaquinone supplementation may be a novel approach to prevent vascular calcifications in chronic haemodialysis patients.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Calcium-Binding Proteins; Dietary Supplements; Dose-Response Relationship, Drug; Extracellular Matrix Proteins; Female; Follow-Up Studies; Hemostatics; Humans; Male; Matrix Gla Protein; Middle Aged; Prognosis; Prospective Studies; Renal Dialysis; Single-Blind Method; Surveys and Questionnaires; Vascular Calcification; Vitamin K 1; Vitamin K 2; Vitamins; Young Adult

Osteopenia, sarcopenia, and vascular calcification (VC) are prevalent in patients with chronic kidney disease and often coexist. In the absence of proven therapies, it is necessary to develop therapeutic or preventive nutrients supplementation for osteopenia, sarcopenia, and VC. The present study investigated the effect of omega-3 fatty acid (FA) and menaquinone-7 (MK-7) on osteopenia, sarcopenia, and VC in adenine and low-protein diet-induced uremic rats.. Thirty-two male Sprague-Dawley rats were fed diets containing 0.75% adenine and 2.5% protein for three weeks. Rats were randomly divided into four groups that were fed diets containing 2.5% protein for four weeks: adenine control (0.9% saline), omega-3 FA (300 mg/kg/day), MK-7 (50 µg/kg/day), and omega-3 FA/MK-7. Von Kossa staining for aortic calcification assessment was performed. Osteoclast surface/bone surface ratio (OcS/BS) of bone and muscle fiber were analyzed using hematoxylin and eosin staining. Osteoprotegerin (OPG) immunohistochemical staining was done in the aorta and bone. Molecules related with sarcopenia were analyzed using western blotting.. Compared to the normal control, OcS/BS and aortic calcification, and OPG staining in the aorta and bone were significantly increased in the adenine controls. OPG staining and aortic calcification progressed the least in the group supplemented with both omega-3 FA/MK-7. In the adenine controls, the regular arrangement of muscle fiber was severely disrupted, and inflammatory cell infiltration was more prominent. These findings were reduced after combined supplementation with omega-3 FA/MK-7. Furthermore, decreased mammalian target of rapamycin and increased Forkhead box protein 1 expression was significantly restored by combined supplementation.. Combined nutrients supplementation with omega-3 FA and MK-7 may be helpful for aortic VC prevention, reducing osteoclast activation and improving sarcopenia-related molecules in adenine and low-protein diet induced uremic rats.

Topics: Adenine; Animals; Aortic Diseases; Bone Diseases, Metabolic; Drug Therapy, Combination; Fatty Acids, Omega-3; Male; Osteoclasts; Rats; Rats, Sprague-Dawley; Sarcopenia; Uremia; Vascular Calcification; Vitamin K 2

Cardiovascular calcification is prevalent in the aging population and in patients with chronic kidney disease (CKD) and diabetes mellitus, giving rise to substantial morbidity and mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. The aim of this study was to evaluate the impact of high-dose menaquinone-7 (MK-7) supplementation (100 µg/g diet) on the development of extraosseous calcification in a murine model. Calcification was induced by 5/6 nephrectomy combined with high phosphate diet in rats. Sham operated animals served as controls. Animals received high or low MK-7 diets for 12 weeks. We assessed vital parameters, serum chemistry, creatinine clearance, and cardiac function. CKD provoked increased aortic (1.3 fold; p < 0.05) and myocardial (2.4 fold; p < 0.05) calcification in line with increased alkaline phosphatase levels (2.2 fold; p < 0.01). MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. Furthermore, MK-7 supplementation increased aortic MGP messenger ribonucleic acid (mRNA) expression (10-fold; p < 0.05). CKD-induced arterial hypertension with secondary myocardial hypertrophy and increased elastic fiber breaking points in the arterial tunica media did not change with MK-7 supplementation. Our results show that high-dose MK-7 supplementation inhibits the development of cardiovascular calcification. The protective effect of MK-7 may be related to the inhibition of secondary mineralization of damaged vascular structures.

Topics: Animals; Dietary Supplements; Disease Models, Animal; Dose-Response Relationship, Drug; Echocardiography; Male; Phosphates; Rats; Rats, Wistar; Renal Insufficiency, Chronic; RNA, Messenger; Vascular Calcification; Vitamin K 2