A new cross-sectional clinical study published in Kaohsiung Journal of Medical Sciences[1] adds to the evidence that statins, a heavily prescribed cholesterol medication, may enhance calcium accumulation in the arterial wall by inhibiting vitamin K-dependent proteins involved in vascular protection.

Statins are first‐line drugs in the prevention and treatment of established atherosclerotic cardiovascular disease. Paradoxically, intensive statin therapy has been shown to increase vascular calcification and accelerate its progression. The aim of the recently published study, “Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?”, was to find a putative relation between statin use, coronary calcification, and the vitamin K-dependent proteins as a possible mechanism mediating statins’ pro-calcification.

“According to the study, statins negatively influence vitamin K status. To that end, supplementation with Vitamin K2, which has been shown to effectively improve vitamin K status and activate extrahepatic K-dependent proteins, might prove beneficial for statin users,” says Dr. Hogne Vik, chief medical officer with NattoPharma, world leaders in Vitamin K2 research and development.

The study enrolled 98 patients – patients with established cardiovascular disease (CVD) and a control group of healthy patients at moderate risk for CVD – and split the groups into statin users and non‐users. The results revealed that both CVD and statin use are independently and significantly associated with vascular calcification. Among all the study participants, coronary artery calcification score (CACS) was more pronounced in statin users than non‐users; researchers found the same among the CVD patients and the controls. Moreover, the researchers found that statins influenced vitamin K status represented by the activation of osteocalcin (OC), a vitamin K-dependent protein. Inactive OC and the ratio of inactive and active form of OC (UCR) were significantly elevated in statin users, indicating vitamin K deficiency. According to researchers, statins also impacted the international normalized ratio and interacted with vitamin K antagonists.

These results are in agreement with the existing evidence about the positive association between statins and vascular calcification. A 2015 paper published in Expert Review Clinical Pharmacology[2] stated that statins may act as “mitochondrial toxins” with adverse effects on the heart and blood vessels not only via the depletion of coenzyme Q10 (CoQ10), but also by inhibiting “the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification.”

“NattoPharma has driven research confirming that Vitamin K2 as MK-7 (as MenaQ7) is the only known inhibitor of vascular calcification through the activation of matrix gla protein (MGP).[3,4] Yet this new study provides further evidence that statins interrupt the mechanism of action by which vitamin K2 is a cardio-protective nutrient,” Dr. Vik adds. “And while CoQ10 and vitamin K2 are both affected by statins, no recommendation exists for prescribing supplemental vitamin K2 to statin patients.

“NattoPharma continues to work with the medical community on trials exploring Vitamin K2 as a potential therapy for patients that express heavy calcification,” Dr. Vik concludes. “We hope to encourage K2 supplementation as a recommendation in the future for statin users; especially considering this new evidence.”

References:
1 Zhelyazkova-Savova MD, Yotov YT, Nikolova MN, Nazifova-Tasinova NF, Vankova DG, Atanasov AA, Galunska BT. “Statins, vascular calcification, and vitamin K-dependent proteins: Is there a relation?” Kaohsiung J Med Sci. 2021 Feb 26. Online ahead of print.
2 Okuyama H, Langsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Uchino H. “Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms.” Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99.
3 Knapen MHJ, Braam LAJLM, Drummen NE, Bekers O, Hoeks APG, Vermeer C. “Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women. A double-blind randomized clinical trial.” Thromb Haemost. 2015 May; 113(5):1135-44.
4 Vermeer C and Vik H. Effect of Menaquinone-7 (vitamin K2) on vascular elasticity in healthy subjects: results from a one-year study. 2020 Vascul Dis Ther, 5.

Adding to the already-strong body of clinical evidence confirming Vitamin K2 as MK-7 inhibits arterial calcification and acts as an antioxidant, a study recently published in Vascular Pharmacology shows K2 as MK-7 boosts nitric oxide (NO), improving NO-dependent endothelial function. The study used MenaQ7® Vitamin K2 as MK-7, supplied by NattoPharma.

Endothelial dysfunction has been associated with many health issues, including being a well-established response to cardiovascular risk factors and precedes the development of atherosclerosis, a disease of the arteries characterized by the development deposition of plaques of and by vascular inflammation fatty material on the inner walls. Given the fact that endothelial function determines cardiovascular health, researchers hypothesized that the positive effects of vitamin K2 intake on cardiovascular mortality could be linked to the vitamin K-dependent regulation of endothelial function. According to researchers, ”The aim was to examine the effects of vitamin K2 – MK-7 on endothelial dysfunction, in ApoE/LDLR-/- mice at the early and late stages of disease development, in the absence and in the presence of atherosclerotic plaques, respectively.”

”We are incredibly encouraged by the results of this study highlighting new pharmacological activity of Vitamin K2 as MK-7,” explains Hogne Vik, NattoPharma Chief Medical Officer.

In ApoE/LDLR-/- mice at the stage prior to atherosclerosis development, four-week treatment with K2-MK-7, given at a low dose (0.05 mg/kg), “improved acetylcholine- and flow-induced, endothelium-dependent vasodilation in aorta or in femoral artery, as assessed in vivo by MRI. This effect, was associated with an increased NO production, as evidenced by EPR measurements in ex vivo aorta.”

The study concluded that low dose of Vitamin K2 – MK-7 compatible with effective doses for K2 – MK-7 recommended for humans, to provide benefits for cardiovascular health, plays an important role in the regulation of endothelial function.

“The study demonstrated that vitamin K2 – MK-7 improved NO-dependent endothelial function in mice, and the results showed that K2 – MK-7 provided a vaso-protective effect independently whether endothelial dysfunction was treated with vitamin K2 – MK-7 prior to or concurrently with the occurrence of atherosclerotic plaques,” explains Vik. ”This contributes nicely to our already substantial body of research showing MenaQ7 is a cardio-protective nutrient, and reaffirms why the medical community is interested in ongoing study of this important nutrient for the betterment of global health.”

Reference:
Bar A, Kus K, et al. Vitamin K2-MK-7 improves nitric oxide-dependent endothelial function in ApoE/LDLR mice. Vascul Pharmacol. 2019 Aug 14: 106581. Doi: 1016/j.vph.2019.106581.

Arteriosclerosis, Thrombosis, and Vascular Biology has published a new paper examining the well-known and alternative pathways of Vitamin K, adding to the substantial argument that Vitamin K2 can greatly impact cardiovascular health. The paper was funded by a grant awarded to NattoPharma’s International Research Network by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant.

“NattoPharma has a long history of funding research and participating in collaborative research such as was provided in the Horizon 2020 grant. The body of evidence supporting cardiovascular health benefits continues to grow and we believe will help expand both awareness and consumer demand for Vitamin K2,” says NattoPharma CEO Kjetil Ramsøy,

Dr. Hogne Vik, NattoPharma Chief Medical Officer, explains: “According to at least five different epidemiological studies, Vitamin K2 – and not K1 – is cardio-protective. That is why the majority of new clinical trials, which are focused on cardiovascular health, are performed using K2 as MK-7. Moreover, Vitamin K2 was shown to be not only more potent form than Vitamin K1, but also the compound that possesses additional biological activity (not present in the case of K1).”

Aortic aneurysm is a vascular disease whereby the ECM (extracellular matrix) of a blood vessel degenerates, leading to dilation and eventually vessel wall rupture. Recently, it was shown that calcification of the vessel wall is involved in both the initiation and progression of aneurysms. To that end, the authors of the paper, “Role of Vascular Smooth Muscle Cell Phenotypic Switching and Calcification in Aortic Aneurysm Formation: Involvement of Vitamin K-Dependent Processes”, summarize the current literature on vascular smooth muscle cell phenotypic switching and vascular calcification in relation to aneurysm. Moreover, they address the role of vitamin K and vitamin K-dependent proteins (VKDPs) that are involved in vascular calcification and aneurysm.

The review highlighted well-known and alternative pathways of vitamin K activity:
• Vitamin K is known to activate Matrix Gla Protein (MGP), by which it inhibits vascular calcification.
• Vitamin K has the ability to scavenge free radicals, reduce oxidative stress, and decrease vascular calcification.

“Therefore, it is tempting to postulate that vitamin K deficiency plays a role in aneurysm formation,” the authors conclude. “Vitamin K supplementation holds the potential to lower the risk of aortic aneurysms and improve cardiovascular outcome.”

The paper is significant because it continues to build upon the argument that Vitamin K2 is an essential nutrient for protecting cardiovascular health, while also opening up new areas of benefits, according to Dr. Vik.

“Once again, Vitamin K is known to activate MGP, which inhibits vascular calcification,” says Vik. “This new paper also finds vitamin K has the ability to scavenge free radicals, reduce oxidative stress, and decrease calcification. We support the authors’ supposition that Vitamin K deficiency plays a role in aneurysm formation. Clearly, Vitamin K2 supplementation holds the potential to lower the risk of aortic aneurysms and improve cardiovascular outcomes.”

The review paper is the result of the Horizon 2020 grant awarded to NattoPharma’s International Research Network, coordinated by Queen Mary University of London. Other partners of the network are four highly ranked research university departments in Europe [University of Maastricht, University College Dublin (part of the national University of Ireland), Ludvig-Maximilians-Universitaet Muenchen, and Karolinska Institutet in Stockholm] and the independent life science medical research charity in the UK, the Medical Research Council Technology. The grant NattoPharma participates in is called “EVOLuTION” (European Vascular Interventions and Therapeutic Innovation Network), and the money will be utilized to provide training for 11 early-stage researchers (ESRs) in the management of chronic diseases in the field of cardiovascular disease.

Reference:
Petsophonsakul P, Furmanik M, Forsythe R, Dweck M, Schurink GW, Natour E, Reutelingsperger C, Jacobs M, Mees B,
Schurgers L. Role of Vascular Smooth Muscle Cell Phenotypic Switching and Calcification in Aortic Aneurysm Formation: Involvement of Vitamin K-Dependent Processes. Arterioscler Thromb Vasc Biol. 2019;39:00-00. DOI: 10.1161/ATVBAHA.119.312787.
PR: NattoPharma Named Partner For EU Research Grant

The American Heart Association has published a new study examining the effect excessive inactive Matrix Gla Protein (MGP) has on cardiovascular health, namely increased stiffening and calcification of large arteries. This stiffening increases cardiovascular stress, which can be accurately assessed using pulse wave velocity measurements, and can be alleviated by improving one’s Vitamin K2 status.

The study, “Central Hemodynamics in Relation to Circulating Desphospho-Uncarboxylated Matrix Gla Protein: A Population Study”, evaluated vitamin K status (dp-ucMGP) in 835 randomly recruited Flemish individuals. The researchers found that higher inactive dp-ucMGP was associated with greater pulse wave velocity (PWV), central pressure, forward pulse wave, and backward pulse wave.

The authors wrote: “Stiffening and calcification of the large arteries are forerunners of cardiovascular complications. MGP, which requires vitamin K–dependent activation, is a potent locally acting inhibitor of arterial calcification. We hypothesized that the central hemodynamic properties might be associated with inactive desphosphouncarboxylated MGP (dp-ucMGP).”

The authors concluded that, along with the current body of literature, the study’s findings show “In people representative for the general population, higher inactive dp-ucMGP was associated with greater PWV,
central pulse pressure, forward pulse wave, and backward pulse wave. These observations highlight new avenues for preserving vascular integrity and preventing cardiovascular complications (eg, by improving a person’s vitamin K status).”

The paper is significant because it articulates the importance of pulse wave velocity measurements in gauging cardiovascular impact, and adds to the significant body of evidence NattoPharma has cultivated showing that improving K status can provide true health benefits, according to NattoPharma Chief Medical Officer Dr. Hogne Vik.

“This research again confirms a link to vitamin K status and risk of cardiovascular health. NattoPharma’s research has shown that vitamin K2 supplementation can halt and even regress progression of arterial stiffness. This paper recognizes that stiffening and calcification of the large arteries are forerunners of cardiovascular complication, and the mechanism to prevent this is the vitamin K-dependent activation of MGP.”

“Importantly,” Vik continued, “only vitamin K2 intake has been linked to cardiovascular benefit as K2 is the most bioactive and longest-lasting form of vitamin K. Vitamin K1, for example, has not been linked to cardiovascular benefit as K2 seems to be the form of K active outside of the liver for cardiovascular health.”

Reference:
Wei F, Thijs L, Cauwenberghs N, Yang W, Zhang A, Yu C, Kuznetsova T, Nawrot T, Struijker-Boudier HA, Verhamme P, Vermeer C, Staessen JA. Central Hemodynamics in Relation to Circulating Desphospho-Uncarboxylated Matrix Gla Protein: A Population Study. J Am Heart Assoc. 2019;8:e01 1960.

Vitamin K is not a single vitamin – it is a family of vitamins comprised of vitamins K1 (phylloquinone) and K2 (menaquinone). While multiple observational studies and small-scale intervention studies suggest that high K intake is associated with improved markers for cardiovascular health – namely increased Matrix Gla protein (MGP) activation – a recent study published in Clinical Nutrition investigated the causal relationship between genetically predicted K concentrations and the risk of coronary heart disease (CHD), and found that K1 had no impact on MGP, noting that Vitamin K2 has a positive impact on cardiovascular health.

The study, “Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study”, examined data from three studies: the European Prospective Investigation into Cancer and Nutrition (EPIC)-CVD case cohort study, CARDIOGRAMplusC4D and the UK Biobank, resulting in 103,097 CHD cases. Genetically predicted vitamin K concentrations were measured using circulating phylloquinone and dephosphorylated uncarboxylated MGP (dp-ucMGP).

The authors wrote: “Using the genetic score for circulating phylloquinone, we found that circulating phylloquinone was not causually related to CHD risk (RR 1.00 (95%CI: 0.98; 1.04)). Lower genetically predicted dp-ucMGP concentration was associated with lower CHD risk with a RR of 0/96 (95%CI: 0.93; 0.99) for every 10 μg/L decrease in dpucMGP.

“This inconsistent result may reflect the influence of menaquinones in the association with CHD,” the authors concluded.

The paper is significant because it articulates the difference in health impact between vitamins K1 and K2, and highlights that vitamin K2 must be obtained for a cardiovascular benefit.

“While it is true that ‘improving K status’ will impact cardiovascular health, this paper helps to emphasize that all K vitamins are not the same. NattoPharma’s research has shown that vitamin K2 supplementation can halt and even regress progression of arterial stiffness, and that is accomplished through the activation of MGP,” says Eric Anderson, NattoPharma Senior Vice President of Global Marketing and Business Development. “NattoPharma has been at the forefront of making the industry aware of the research around Vitamin K2 and K-dependent proteins. Our long-term mission is to elucidate Vitamin K2’s benefits beyond Vitamin K1, as this Clinical Nutrition paper has shown, with the ultimate goal of securing a K2-specific recommended daily intake (RDI).”

Reference:
Zwakenberg SR, Burgess S, Sluijis I, Weiderpass E, Beulens JWJ, van der Schouw YT. Circulating phylloquinone, inactive Matrix Gla protein and coronary heart disease risk: A two-sample Mendelian Randomization study. Clin Nutr. 2019 May 7. pii: S0261-5614(19)30200-6.

The International Journal of Molecular Sciences has published a new review paper examining the differences between vitamins K1 and K2, showing that based on its very molecular structure K2 is available beyond the liver to support systems like the bone and vasculature through proper calcium utilization. The review paper, the result of the INTRICARE and EVOluTION grants awarded to NattoPharma’s International Research Network by the European Union within the Horizon 2020 Marie Skłodowska-Curie research and innovation program, is an important step in establishing the need for a Vitamin K2-specific recommended daily intake (RDI).

According to the authors, the paper “Vitamin K: Double Bonds beyond Coagulation Insights into Differences between Vitamin K1 and K2 in Health and Disease”, is the first to highlight differences between isoforms vitamin K1 and K2 by means of source, function, and extrahepatic activity. Prof. Schurgers states that functions of K2 are proving to be beneficial with regard to cardiovascular diseases and bone metabolism, yet there is a growing body of evidence suggesting vitamin K2 is involved in multiple cellular processes and might have a protective role in various organs throughout the human body. To that end it is important to consider an RDI reflective of these additional roles.

“When exploring the non-coagulation, extrahepatic activities of vitamin K, it is clear that K2 in its various forms is the highlight of such activity. Therefore, although history and nomenclature have classed K1 and K2 into the same category, these molecules can have a very different action in the body,” says Prof. Schurgers, Professor of Biochemistry of Vascular Calcification and Vice Chair of Biochemistry at the Cardiovascular Research Institute Maastricht (CARIM), Maastricht University; and senior author and leader of the research project. “Major health organizations, such as WHO, European Food Safety Authority (EFSA) and Food and Drug Administration (FDA) have established RDI for vitamin K, which is solely based on the dose of K1 to retain an appropriate blood clotting function. Differences between K1 and K2 merit recognition among national and international regulatory organizations, and remain open to research.”

The paper is significant because it is a necessary step towards recognizing the importance of a vitamin K2-specific RDI, an endeavor NattoPharma is currently spearheading with the help of its research partners, according to NattoPharma Chief Medical Officer Dr. Hogne Vik.

“This review paper continues to explore the differences between Vitamin K1 with its known benefit for coagulation and the newly recognized benefits of Vitamin K2 also to function extrahepatically to support bone and cardiovascular health,” says Vik. “Practically, the body of evidence today supports a dominant role for Vitamin K2 in the inhibition of calcification of soft tissues because of its better bioavailability and bioactivity. Observational studies and gold standard double-blind, placebo-controlled trials show that Vitamin K2 may inhibit vascular calcification and even hold progression of vascular stiffness.

“Recognition of Vitamin K2’s benefits as strong and significant elucidated inhibitor of vascular and soft tissue calcification is one of the core reasons a separate RDI should be established,” Vik adds. “We are proud that our partnership with Maastricht University and these prestigious grants have given us an opportunity to further the understanding of the necessity of obtaining adequate vitamin K2 for human health.”

The review paper is the result of the INTRICARE (grant agreement No 722609) and EVOluTION (grant agreement No 675111) grants funded by the European Union within the Horizon 2020 Marie Skłodowska-Curie research and innovation program, awarded to NattoPharma’s International Research Network to train a total of 26 Early Stage Researchers (ESRs) focusing on harnessing endogenous mechanisms for health and the effect of vitamin K to hold or regress microcalcification and subsequent cardiovascular disease.

Reference:
Halder M, Petsophonsakul P, Akbulut AC, Pavlic A, Bohan F, Anderson E, Maresz K, Kramann R, Schurgers L. Vitamin K: Double Bonds Beyond Coagulation Insights Into Differences Between Vitamin K1 and K2 in Health and Disease. Int J Mol Sci. 2019, 20, 896; doi:10.3390/ijms20040896
PR: NattoPharma Research Network Receives 4M€ Research Grant
PR: NattoPharma Named Partner for Horizon 2020 EU Research Grant

Frontiers in Cardiovascular Medicine has published a new review paper examining calcium supplementation’s impact on bone and cardiovascular health, and the role Vitamin K2 plays in proper calcium utilization. The review paper is the result of a grant from the Norwegian Research Council awarded to NattoPharma to fund a 4-year PhD project to document the effect of calcium metabolism in the body based on the presence or absence of vitamin K2, MK-7, where NattoPharma has provided MenaQ7® Vitamin K2 as MK-7 for research conducted at the University of Maastricht, led by Professor Leon Schurgers.*

According to the authors, the paper “The bone-vasculature axis: calcium supplementation and the role of vitamin K”, provides an update on current literature on calcium supplementation among post-menopausal women and chronic kidney disease (CKD) patients and discusses underlying molecular mechanisms of vascular calcification. Prof. Schurgers states that therapeutic strategies with vitamin K2 treatment should be considered to prevent or hold progression of vascular calcification as a consequence of excessive calcium intake.

“The work conducted in collaboration with NattoPharma under the Norwegian Research Council grant will provide further evidence that calcium without adequate vitamin K2 consumption might end up in the soft tissues where it is not wanted, rather than in the bone matrix, where it is needed,” says Prof. Schurgers, Professor of Biochemistry of Vascular Calcification and Vice Chair of Biochemistry at the Cardiovascular Research Institute Maastricht (CARIM), Maastricht University; and senior author and leader of the research project. “In a recent study by Bolland et al., it was shown that calcium supplementation of postmenopausal women was associated with a beneficial effect on bone, but also with increased myocardial infarction, suggesting detrimental effects on the vascular system possibly by inducing increased vascular calcification. As calcium supplementation is needed for bone, the precipitation in the vessel wall needs to be inhibited.”

The paper is significant because it adds to the growing body of evidence substantiating MenaQ7® Vitamin K2 as a bone- and cardiovascular-support nutrient, according to NattoPharma Chief Medical Officer Dr. Hogne Vik.

“Compromised bone and heart health are not merely age-related issues; rather, they are signs of a core nutrient deficiency: vitamin K2,” says Vik. “NattoPharma has driven the research confirming vitamin K2’s important health benefits, showing in human studies with healthy participants that the progression of hardening of the arteries can be halted and even regressed, and that bone strength can be improved with daily supplementation of MenaQ7 Vitamin K2.

“We are proud that our partnership with Maastricht University and this prestigious grant have given us an opportunity to further the understanding of the necessity of obtaining adequate vitamin K2 for human health,” Dr. Vik adds. “We hope these findings will earn the attention of manufacturers and consumers alike, helping them to recognize that all calcium supplementation must be paired with vitamin K2 so bone and heart health can be simultaneously supported.”

* Prof. Schurgers’ research is additionally funded in part via the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No. 722609 in which NattoPharma is partner.

References:
Wasilewski GB, Vervloet MG, Schurgers LJ. The Bone-Vasculature Axis: Calcium Supplementation and the Role of Vitamin K. Front. Cardiovasc. Med, 5 Feb 2019. https://doi.org/10.3389/fcvm.2019.00006

The Journal of Alzheimer’s Disease and Scientific Reports recently published papers that examined the role of aortic stiffness due to calcification as a contributing factor to dementia and retinal arteriolar health, respectively. Both conditions are impacted by the status of active Matrix Gla Protein (MGP), the most potent inhibitor of vascular calcification (once activated by Vitamin K2 as MK-7), the mechanism by which K2 is now recognized as a cardiovascular protector, and MenaQ7® from NattoPharma is the only Vitamin K2 as MK-7 clinically validated and patented for cardiovascular health.

According to “Aortic stiffness associated with Increased Risk of Dementia in Older Adults”[1], cardiovascular disease risk factors, including age, hypertension, and diabetes, contribute to aortic stiffness and subclinical cardiovascular and brain disease, increasing dementia risk. Aortic stiffness, measured by carotid-femoral pulse wave velocity (cfPWV), reduces the buffering of pulsatile blood flow, exposing cerebral small arteries to microvascular damage. The paper goes on to question whether interventions to slow arterial stiffening (such as K2 supplementation) can reduce the risk of dementia.

Meanwhile, the paper “Inactive matrix Gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans”[2] examined how active MGP, “a potent inhibitor of calcification in large arteries, protects against macrovascular complications.” The paper states that “recent studies suggested that active MGP helps maintaining the integrity of the renal and myocardial microcirculation, but its role in preserving the retinal microcirculation remains unknown.”

Studying a randomly recruited Flemish population, the researchers concluded that circulating inactive MGP (dp-ucMGP) is a long-term predictor of smaller retinal arteriolar diameter in the general population. “Our observations highlight the possibility that vitamin K supplementation might promote retinal health,” they stated.

“Vitamin K2 as MK-7 is the only compound to date shown to impact arterial calcification through its activation of MGP, which is why it is garnering attention from the medical community as a potential therapy,” says Christopher Speed, Senior Vice President of Global Sales and Marketing with NattoPharma, the world leaders in Vitamin K2 research and development. “Our branded Vitamin K2, MenaQ7, is the only K2 on the market clinically proven to impact cardiovascular health through its activation of MGP, and the only K2 patented for cardiovascular health.

“We at NattoPharma are optimistic that these developments have come to light,” Speed continues. “There are 17 K-dependent proteins in the body, and we have a strong understanding of a few, which contribute to blood clotting, bone health, and cardiovascular health. These findings shine a light on the importance of continuing our research to articulate the health benefits of activating additional proteins, and the impact that can have on the global population.”

References:
1 Cui C, Sekikawa A, Kuller LH, Lopez OL, Newman AB, Kuipers AL, Mackey RH. “Aortic stiffness is associated with increased risk of incident dementia in older adults.” J Alzheimer’s Dis. 2018;66(1):297-306.
2 Wei FF, Huang QF, Zhang ZY, Van Keer K, Thijs L, et al. “Inactive matrix gla protein is a novel circulating biomarker predicting retinal arteriolar narrowing in humans.” Sci Rep. 2018 Oct 10;8(1):15088.

A new pilot study[1] evaluating vitamin D and K status in children with and without low-energy fractures has published in Nutrients, an international, peer-reviewed journal for studies related to Human Nutrition.

The publication of this study, “Decreased Levels of Circulating Carboxylated Osteocalcin in Children with Low Energy Fractures: A Pilot Study,” is significant because it adds to the growing body of evidence that Vitamin K2 is a beneficial nutrient for both children and adults, according to NattoPharma Chief Medical Officer Dr. Hogne Vik.

“This trial reaffirms the real health benefits improving K2 status delivers,” says Vik. “More importantly, it shines a light on the true impact improving K2 status has on children, our most precious resource.”

According to Dr. Vladimir Badmaev, author of the paper and principal and founder of American Medical Holdings, Inc., “The epidemiological evidence indicates a disturbing growth in the number of cases of low-energy fractures in healthy children and adolescents. There are multiple risk factors that may contribute to this growing health concern, and among the leading consideration are deficient or insufficient nutrition and nutrients, including calcium, vitamin D and vitamin K.”

Dr. Badmaev explains that the particular role of vitamin K2, especially menaquinone-7 (MK-7), has been highlighted in the literature and distinguished from vitamin K1 in maintaining calcium homeostasis and healthy skeletal system. “The epidemiological and clinical research provides a new nutritional paradigm for efficient, safe delivery of calcium that requires co-supplementation with both vitamins D and K.”

The gravitas for this study, which was recently presented at The World Congress on Osteoprosis, Osteoarthritis, and Musculoskeletal Diseases, the world’s leading clinical conference on bone, joint, and muscle health, is increased by Nutrients, a leading European journal with a high impact factor (a measure of how often it is cited by other researchers), selecting it for publication.

“It cannot be overstated the importance of every possible opportunity to advance industry and academic understanding of this essential nutrient,” Vik concludes. “The findings are so very significant, as they provide supporting evidence to the clinical research NattoPharma has already spearheaded. Not only has our research identified children as a group most deficient in Vitamin K2, but that just 45mcg of K2 (as NattoPharma’s MenaQ7®) daily improves K status and increases the activation of osteocalcin, the K-dependent protein responsible for binding calcium to the bone mineral matrix, therefore improving bone health.”

Reference:
Popko J, Karpinski M, Chojnowska S, Maresz K, Milewski R, Badmaev V, Schurgers L. Decreased Levels of Circulating Carboxylated Osteocalcin in Children with Low Energy Fractures: A Pilot Study. Nutrients 2018, 10(6), 734. https://doi.org/10.3390/nu10060734

A poster presented at The World Congress on Osteoporosis, Osteoarthritis, and Musculoskeletal Diseases, the world’s leading clinical conference on bone, joint, and muscle health, detailed recent research showing that low vitamin K status correlated with increased fracture risk in children.

The scientific program, developed by the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF) and the Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO), brought together the world’s best in the field of musculoskeletal health and disease from April 19-22, 2018 in Krakow, Poland. According to IOF and ESCEO, program’s intention is to “move the field forward on all fronts; from new understanding of bone metabolism and pathology, to new strategies and options in prevention, diagnosis, and treatment.”

The poster, “Roles of Vitamins D and K, Nutrition, and Lifestyle in Low-Energy Bone Fractures in Children and Young Adults”, was presented to this prestigious audience by authors Dr. Michael Karpinski from Medical School in Białystok and Dr. Katarzyna Maresz, president of the International Science and Health Foundation. According to Dr. Maresz, theirs was the only presentation that addressed the bone health benefits of Vitamin K.

“The main conclusion of our study was the tremendous impact Vitamin K has on bone health, in particular how Vitamin K2 deficiency seriously affects fracture risks of children,” says Dr. Maresz, whose group created VitaminK2.org. “While many presented studies on Vitamin D, ours was the only paper/poster that addressed both Vitamins K and D, two complementary nutrients for supporting bone health.

“Making these important nutrients part of the conversation with the medical community shows how the potential of future bone therapies could be positively impacted,” adds Maresz.

“The implications of Vitamin K2 being part of this important conference are immeasurable,” says Dr. Hogne Vik, chief medical officer at NattoPharma. “One of the main hurdles is that there is still no RDI established for Vitamin K2. Having K2 discussed at this conference from a bone-health perspective, while the medical community is also initiating studies to examine K2 as a potential cardiovascular therapy, shows we are making strides in overcoming that hurdle.

“It also cannot be overstated the importance of every possible opportunity to advance industry and academic understanding of this essential nutrient,” Vik concludes. “The findings presented by Drs Karpinski and Maresz are so very significant, as they provide supporting evidence to the clinical research NattoPharma has already spearheaded. Not only has our research identified children as a group most deficient in Vitamin K2, but that just 45mcg of K2 (as NattoPharma’s MenaQ7®) daily improves K status and increases the activation of osteocalcin, the K-dependent protein responsible for binding calcium to the bone mineral matrix, therefore improving bone health.”

NattoPharma is eager to announce that Nutrients has published a new paper[1], “Menaquinone Content of Cheese”, which examines the Vitamin K2 content of cheeses and other foods. Based on a global state of K2 deficiency and the strong evidence showing it is a cardio-protective nutrient, researchers recommend cheese as a component of a heart-healthy diet due to its Vitamin K2 content. But for those unable to consume enough cheese daily, NattoPharma has introduced its MenaQ7® Full Spectrum K2, which delivers the range of menaquinones found in foods.

The analysis was conducted by the expert researchers at VitaK, Maastricht University (the Netherlands). Vitamin K2 (menaquinone) concentrations were measured in a range of cheeses and the effects of fat content, ripening, and cheese origins were investigated. According to researchers: “It was found that cheese and curd are the most important sources of long-chain menaquinones in the Western diet. However, the actual menaquinone content varies substantially and is dependent on the type of cheese, the time of ripening, the fat content, and the geographic area where the cheeses are produced.”

The findings showed that the total amount of K2 in cheese was between 3 and 802 ng/g. To that end, the researchers’ recommendation for K2 is between 180-360mcg/day, which means one needs to eat at least 225/445g of French cheese a day (Münster) and at least two times more with cheese from Scandinavia.

In the past decade, increasing attention has been paid to the health benefits of the K2, notably the long-chain menaquinones MK-6 through MK-9. This research adds to important population-based studies[2-4] that have shown that food-derived vitamin K (such as from cheeses) improves long-term cardiovascular health outcomes because it more specifically delivers the spectrum of long-chain menaquinones.

“Interestingly, Vitamin K2 was first discovered in the fermented soy food called natto,” says Hogne Vik, Chief Medical Officer with NattoPharma. “However, in the early 2000s the researchers working with NattoPharma discovered that fermented cheese is also an excellent source of the menaquinones, ranging from menaquinones 5 through 10, while menaquinones 6, 7, and 9 are amongst the most bioactive.”

While fermented cheeses are the best dietary source of menaquinones in the West, most cannot consume enough daily to obtain optimal amounts of Vitamin K2, nor is cheese a practical source for extracting the menaquinones. To that end, NattoPharma has introduced MenaQ7® Full Spectrum K2, raw material unlike anything on the market that delivers the range of menaquinones found in foods.

The first and only Vitamin K2 to deliver a gamut of menaquinone isomers, MenaQ7® Full Spectrum is naturally fermented using chickpea protein, offering an all-trans K2 that is free from gluten, soy and all-known allergens, and is suitable for vegans. MenaQ7® Full Spectrum provides the vital menaquinone isomers for optimal K2 delivery with respect to absorption, half-life and biological activity.

“NattoPharma has once again created a raw material that speaks directly the natural dietary supplement consumer, who is drawn to comprehensive nutritional sources,” adds Eric Anderson, NattoPharma Senior Vice President of Marketing and Business Development. “No other material on the market offers such a comprehensive array of menaquinones specifically shown to support cardiovascular health. MenaQ7 Full Spectrum is the closest ingredient to actual food sources, delivering the range of menaquinones found in foods that support cardiovascular health.”

References:
1 Vermeer C, et al. Menaquinone Content of Cheese. Nutrients. Apri 4;10(4). Pii: E446 doi: 10.3390/nu10040446.
2 Geleijnse JM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: the Rotterdam Study. J Nutr. 2004;134:3100-5.
3 Beulens JW, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009;203:489-93.
4 Gast GC, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutr Metab Cardiovasc Dis. 2009;19:504-10.

NattoPharma is excited to announce that Nutrients has published a new paper, “Bicuspid Aortic Valve Stenosis and the Effect of Vitamin K2 on Calcification Using 18F-Sodium Fluoride Positron Emission Tomography/Magnetic Resonance: The BASIK2 Rationale and Trial Design”, which examines the benefits of MenaQ7® Vitamin K2 as MK-7 for patients with existing calcification.

Being conducted by the expert researchers at Maastricht University Medical Center and CARIM, the double-blind placebo-controlled study will randomize subjects into intervention and control groups, receiving an oral dose of 360 micrograms (mcg) menaquinone-7 (MK-7) or placebo, respectively. The MK-7 is MenaQ7® (provided by NattoPharma ASA, Oslo, Norway) and the total study duration is 18 months with 44 participants who have bicuspid aortic valve (BAV) and mild–moderate calcific aortic valve stenosis (CAVS).

According to Dr. Leon Schurgers, one of the paper’s authors: “18F-sodiumfluoride positron emission tomography (PET), magnetic resonance (MR) and computed tomography (CT) assessments will be performed showing for the first time providing incremental information to the standard methods (echocardiography and CT) used to measure aortic valve stenosis and calcification. In essence, the progression or regression of micro-calcification should be clearly observable for the first time.”

“This is a breakthrough study for individuals with existing calcifications, and noteworthy as the traditional medical community is initiating a study in diseased patients,” says Dr. Hogne Vik, NattoPharma Chief Medical Officer. “Previously published research in healthy populations show MenaQ7 can inhibit the progression of arterial stiffening, and even regress stiffening resulting in improved arterial flexibility. Now these researchers are looking to determine if vitamin K2 can regress calcification in patients with CAVS – while the only current treatment is valve replacement.”

BAV is associated with early development of CAVS and pathophysiologic mechanisms are incompletely defined. Numerous pharmaceutical therapies have been studied as potential intervention in the progression of CAVS, but have not yet presented successful treatment options. Therefore, the only treatment option currently available for severe CAVS is valve replacement.

“Recognizing that medical therapies are proving ineffective, researchers are shining a light on efficacious supplemental alternatives, which leads them to the clinical research that NattoPharma has spearheaded. Specifically, our three-year cardiovascular study in healthy postmenopausal women taking just 180 mcg daily of Vitamin K2 as MK-7 (as MenaQ7), which demonstrated a cessation and even regression in arterial stiffness.

“The relevance of our three-year study has resulted in several studies by the medical community for patients with existing coronary artery calcification, aortic valve calcification, and peripheral artery calcification,” adds Dr. Vik.

A new one-year clinical trial has just been completed showing that a daily nutritional dose of MenaQ7® Vitamin K2 as MK-7 improved vascular health in both male and female healthy participants. This study adds support to the substantial body of evidence confirming Vitamin K2 is a cardiovascular-support nutrient.

Completed by the expert researchers at VitaK, the placebo-controlled randomised clinical trial demonstrated the benefits of 180 µg/day of MK-7 (as MenaQ7® from NattoPharma) on vascular health and body composition in 243 healthy subjects (77 men and 166 women) with a poor vitamin K status, as measured by dp-ucMGP (inactive Matrix Gla Protein, a marker for cardiovascular health).

According to the researchers, “We enrolled participants with poor K status; however, in West most are K deficient as measured by activation of K-dependent proteins.”

In the total group, MK-7 decreased dp-ucMGP significantly compared to placebo after 1 year. The researchers conclude that 1-year supplementation of MK-7 tended to improve vascular health in men and women with a poor vitamin K status. The beneficial effect was more pronounced in post-menopausal women and in subjects with a high Stiffness Index.

“This study is extremely important because this is the second trial to demonstrate benefits of MenaQ7 for cardiovascular health. But where participants in our first study were healthy postmenopausal women, this is the first trial where the effects were examined in both men and women,” says Hogne Vik, NattoPharma Chief Medical Officer. “In this study, the participants taking MenaQ7 maintained arterial flexibility and the stiffness did not increase, whereas placebo group became stiffer and less flexible.

Vik continues, “These results mirror what we have seen in epidemiological studies, where populations who consume a lot of dietary Vitamin K2 have healthier hearts and more flexible arteries.”

The Journal of the American College of Nutrition has published an important review paper that highlights the impact correcting nutritional insufficiencies, most importantly Vitamin K2 in combination with vitamin D and calcium, leading to a significantly less incidence of low-energy bone fractures in children and young adults.

According to Dr. Vladimir Badmaev, author of the paper and principal and founder of American Medical Holdings, Inc., “The epidemiological evidence indicates a disturbing growth in the number of cases of low-energy fractures in healthy children and adolescents. There are multiple risk factors that may contribute to this growing health concern, and deficient or insufficient nutrition and nutrients, including calcium, vitamin D and vitamin K are among leading considerations.”

Dr. Badmaev led an international research consortium with representatives in the United States and Poland to review the expansive body of research (epidemiological and human clinical) that shows environmental and nutritional factors that contribute to children’s bone health, the mechanisms and biological roles by which nutrients contribute to bone health in children and young adults, and the status of nutrient insufficiency and deficiency of these nutrients.

Badmaev explains that the the particular role of vitamin K2, especially menaquinone-7 (MK-7), has been highlighted in the literature recently and distinguished from vitamin K1 in maintaining calcium homeostasis and healthy skeletal system. “The epidemiological and clinical research provides a new nutritional paradigm for efficient and safe delivery of calcium that requires co-supplementation with both fat-soluble vitamins D and K.”

“This review is so very significant, providing supporting evidence to the clinical research NattoPharma has already spearheaded,” says Dr. Hogne Vik, chief medical officer with NattoPharma ASA, world leaders in vitamin K2 reseaerch and development. “Not only has our research identified children as a group most deficient in Vitamin K2, but that just 45mcg of K2 (as NattoPharma’s MenaQ7®) daily improves K status and increases the activation of osteocalcin, the K-dependent protein responsible for binding calcium to the bone mineral matrix, therefore improving bone health.”

Badmaev concludes, “The new proposed nutritional regimen may not only prevent low-energy fractures among children and young adults, but will also contribute to building the ‘bone bank’, therefore helping to prevent development of osteoporosis later in life and prevent untoward cardiovascular risk.”

Reference:
Karpinski M, Popko J, Maresz K, Badmaev V, Stohs SJ. Roles of Vitamins D and K, Nutrition, and Lifestyle in Low-Energy Bone Fractures in Children and Young Adults. J Am Coll Nutr. 017 Jul;36(5):399-4012. Doi: 10.1080/07315724.2017.1307791.

A new study[1] of renal transplant recipients, a group shown to express subclinical vitamin K deficiency, examined whether K2 supplementation would correct this deficiency and thus improve arterial stiffness. The study has published in Journal of the American Society of Hypertension, and the vitamin K2 used in the study was MenaQ7® Vitamin K2 as MK-7 from NattoPharma.

This Lebanese study evaluated in the KING trial (a single-arm pilot study) to see if there is an association between vitamin K2 supplementation and the change in both subclinical vitamin K status and indices of arterial stiffness among 60 renal transplant recipients with stable graft function. The results showed that 8 weeks of MK-7 supplementation (360 mcg/day as MenaQ7®) was associated with significant improvement in arterial stiffness and 24-hour peripheral and central pressures. The mean reduction in cfPWV was 1.4 m/s, which was well beyond the reduction of 1 m/s recommended for a clinically relevant vascular effect.

“While our previous cardiovascular study in healthy postmenopausal women showed an improvement in arterial elasticity after 3 years of supplementation, the results collected in this trial are staggering, especially as the statistically significant effect was seen very quickly,” says Hogne Vik, chief medical officer of NattoPharma. “After just 8 weeks of MK-7 supplementation, low vitamin K status represented by dpucMGP level was significantly reduced by 55.1%. Moreover, supplementation was associated with a 14.2% reduction in mean cfPWV.

“One can assume that longer MK-7 supplementation may lead to even better results, and secure improvement in cardiovascular outcomes in renal transplant patients.”

According to the researchers, prior observational studies have shown the prevalence of subclinical vitamin K deficiency has been reported to be as high as 80% in the renal transplant population. Moreover, in kidney transplant recipients, Vitamin K insufficiency, expressed as a high circulating level of dp-ucMGP (dephosphorylated-uncarboxylated matrix Gla protein, or “inactive” MGP, a K-dependent protein), is associated independently with increased risk of mortality. However, any studies to date have not addressed whether vitamin K supplementation may lead to improved outcomes after kidney transplantation.

In addition, MK-7 supplementation improved vitamin K status, which was represented by the reduction in dp-ucMGP concentrations. A positive correlation was present between the reduction in arterial stiffness, a surrogate of early cardiovascular disease, and the circulating concentration of dp-ucMGP, a marker of subclinical vascular vitamin K deficiency and calcification.

The main conclusion was that, among renal transplant recipients with stable graft function, vitamin K2 supplementation was associated with improvement in subclinical K deficiency and arterial stiffness. According to the researchers, the findings from this trial support the hypothesis that subclinical vitamin K deficiency may be a modifiable cardiovascular risk factor and may improve with MK-7 supplementation.

“NattoPharma was excited to participate in this clinical trial,” adds Dr. Vik. “We have dedicated ourselves to cultivating an understanding of the benefits Vitamin K2 offers to human health, and in that work have recognized that vitamin K2 deficiency can have serious implications on arterial health. This study adds to the body of evidence confirming the cardiovascular support MenaQ7® Vitamin K2 as MK-7 provides, and continues to solidify the hope this important nutrient offers the global population.”

Reference:
1 Mansour AG et al. Vitamin K2 supplementation and arterial stiffness among renal transplant recipients – a single-arm, single-center clinical trial. J Am Soc Hypertens. 2017 Jul 13. Pii: S1933-1711(17)30255-3.

A new study[1] of hemodialysis patients examined the risk factors and response to Vitamin K2 supplementation, and confirmed this population’s specific need to correct Vitamin K2 deficiency. The study published in BMC Nephrology, and the vitamin K2 used in the study was MenaQ7® Vitamin K2 as MK-7 from NattoPharma.

According to the researchers, the scientific data showed that the vitamin K2 intake in hemodialysis patients is estimated to be 40 percent lower than in the healthy individual group. It has been accepted by the European medical society that hemodialysis patients are vitamin K deficient, and they can benefit from vitamin K2 supplementation. However, this aspect had not yet been evaluated in Eastern Mediterranean populations.

“NattoPharma was excited to participate in this clinical intervention trial,” says Hogne Vik, chief medical officer of NattoPharma. “We have long recognized the important implications correcting a vitamin K2 deficiency can have on human health, particularly in patient populations who suffer intense vascular calcification as a result of their condition. This study adds to the body of evidence confirming the cardiovascular support MenaQ7® Vitamin K2 as MK-7 provides, and continues to solidify NattoPharma as the global leader in K2 research and development.”

The study, based in Lebanon, assessed if there is a correlation between vitamin K status and vascular calcification score in hemodialysis patients, and if K2 supplementation would improve extra-hepatic vitamin K status in this Eastern Mediterranean populations.

Fifty hemodialysis patients were enrolled in this clinical study, and received daily 360 μg of menaquinone-7 (MenaQ7®) for 4 weeks. Extrahepatic vitamin K status represented as the level of dpucMGP (dephosphorylated-uncarboxylated matrix Gla protein, or “inactive” MGP, a K-dependent protein) and vascular calcification scores (AC-24) were measured at the beginning and at the end of the vitamin K2 treatment.

The main conclusion was that hemodialysis patients have profound vitamin K deficiency as assessed by high dp-ucMGP plasma levels. High dpucMGP level was significantly correlated with high aortic calcification scores and thus can be used as a non-invasive marker for vascular calcifications.

According to the researchers, “The daily administration of 360 μg of vitamin K2 (MK-7) decreased dpucMGP by 86 percent after 4 weeks and it was well tolerated. Further studies should be conducted to assess the change in vascular calcifications after an extended duration of therapy.”

Reference:
Aoun M et al. High Dephosphorylated-Uncarboxylated MGP in Hemodialysis patients: risk factors and response to vitamin K2, a pre-post intervention clinical trial. BMC Nephrol. 2017 Jun 7;18(1):191. doi: 10.1186/s12882-017-0609-3.

Nephron¸ a kidney research and clinical journal, and the American Journal of Hypertension have each just published new papers linking the vitamin K-dependent protein MGP (matrix GLA-protein) to vascular calcification, vascular and arterial stiffness. The two studies, “Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease,” and “Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus,” respectively, have linked increased risk of arterial calcification and stiffness to a lack of the active protein. One set of authors even recommended supplementation of vitamin K as a potential treatment.

“The mechanism of MGP inhibiting arterial calcification has been clearly established in cellular, animal and now human studies,” says Hogne Vik, chief medical officer with NattoPharma, world pioneer in vitamin K2 product development. “In fact, adequate vitamin K is required to activate MGP. It is widely recognized that vitamin K2 as Menaquinone-7 is the most bioavailable and bioactive form of vitamin K available as a supplement today.”

Vik continued, “These new clinical investigations have documented correlations between arterial calcification and high amounts of inactive MGP – both in diabetic patients and in patients with CKD. The good news is that Vitamin K2 – our MenaQ7® brand MK-7 ingredient – is demonstrated to reduce the levels of ‘inactive’ dp-uc-MGP, and that MenaQ7 is documented to reduce arterial stiffness in healthy individuals as well as in kidney patients.”

The Nephron trial[2] was a cross-sectional study which enrolled 83 CKD stages 3–5 patients. Vascular calcification scores were determined by measuring calcific lesions in the abdominal aorta, vascular stiffness was assessed using a cardio-ankle vascular index (CAVI) and pulse wave velocity, while plasma dpucMGP, or inactive MGP, levels were measured using an ELISA method. The study selected factors that were independently associated with vascular calcification and vascular stiffness.

The authors concluded the inactive MGP levels in blood plasma increase according to the severity of chronic kidney disease. Also, inactive MGP levels were positively associated with increased vascular calcification and might be utilized as an early marker for vascular calcification in CKD patients.

The American Journal of Hypertension trail[1] sought to identify pathways related to arterial stiffness to provide novel therapeutic targets to help reduce arterial stiffness in diabetes patients as large artery stiffness is increased in diabetes which increases the burden to the heart and microvasculature. Looking at a group of 66 diabetes type 2 patients, pulse wave velocity (PWV) was used as a measure of stiffness, and inactive or dp-ucMGP was measured by the vitamin K experts at VitaK, the Netherlands.

The authors concluded that inactive MGP was independently associated with pulse wave velocity in these diabetes patients. The authors noted: “This suggests that deficient vitamin K-dependent activation of MGP may lead to large artery stiffening and could be targeted with vitamin K supplementation in the patients with diabetes.”
“NattoPharma recognizes and is appreciative of the growing body of evidence definitively linking vitamin K status and active vitamin K-dependent proteins to health outcomes,” notes Dr. Vik. “NattoPharma is the world-wide pioneer in developing and providing MenaQ7 products as dietary supplements, and the recent publications are increasing the recognition of intake of vitamin K2 as a pathway to better health outcomes. Our three-year interventional study confirmed that adding vitamin K2 to one’s daily diet improves arterial health and flexibility.”

References:
1 Mayank Sardana, Izzah Vasim, Swapna Varakantam, Uzma Kewan, Ali Tariq, Maheshwara R. Koppula, Amer Ahmed Syed, Melissa Beraun, Nadja E.A. Drummen, Cees Vermeer, Scott R. Akers, and Julio A. Chirinos Inactive Matrix Gla-Protein and Arterial Stiffness in Type 2 Diabetes Mellitus. Am J Hypertens 2016 : hpw146v1-hpw146 http://ajh.oxfordjournals.org/content/early/2016/12/06/ajh.hpw146.abstract

2 Thamratnopkoon S.a · Susantitaphong P.a · Tumkosit M.b · Katavetin P.a · Tiranathanagul K.a · Praditpornsilpa K.a · Eiam-Ong S.a. Correlations of Plasma Desphosphorylated Uncarboxylated Matrix Gla Protein with Vascular Calcification and Vascular Stiffness in Chronic Kidney Disease. Nephron. 2016 Dec 13. [Epub ahead of print] DOI: 10.1159/000453368 https://www.karger.com/Article/Abstract/453368

Cureus has published a new study[1] that explores the extent that vitamin K2 deficiency is tied to cardiovascular disease (CVD). The results showed that Vitamin K2 was inversely correlated with early CVD mortality to the same degree that tobacco use was positively correlated.

“Animal trials and human observational studies have demonstrated that Vitamin K2 deficiency (mainly the long-chain menaquinones, like MK-7) – whether it be dietary or K inhibition caused by warfarin – contributes to CVD by stiffening and calcifying coronary arteries and other vessels,” says Hogne Vik, chief medical officer with NattoPharma, world leader in vitamin K2 R&D and exclusive global supplier of MenaQ7® Vitamin K2 as MK-7. “Nutrition researchers recently recognized that Vitamin K2 deficiency is widespread and contributes to CVD. The recent study, where multiple regression analysis of female and male cohort data worldwide (168 countries) have been used to relate early death from CVD with major CVD risk factors, has once more confirmed the importance of regular intake of vitamin K2 to secure a healthy CV system.”

For this trial, entitled “Cardiovascular Disease Death Before Age 65 in 168 Countries Correlated Statistically with Biometrics, Socioeconomic Status, Tobacco, Gender, Exercise, Macronutrients, and Vitamin K,” researchers, using publicly available sources, collected food commodity availability data and derived nutrient profiles including vitamin K2 for people from 168 countries. They also collected female and male cohort data on early death from CVD (ages 15-64 years), insufficient physical activity, tobacco, biometric CVD risk markers, socioeconomic risk factors for CVD, and gender. The outcome measures included (1) univariate correlations of early death from CVD with each risk factor, (2) a multiple regression-derived formula relating early death from CVD (dependent variable) to macronutrient profile, vitamin K1 and K2 and other risk factors (independent variables), (3) for each risk factor appearing in the multiple regression formula, the portion of CVD risk attributable to that factor, and (4) similar univariate and multivariate analyses of body mass index (BMI), fasting blood sugar (FBS) (simulated from diabetes prevalence), systolic blood pressure (SBP), and cholesterol/ HDLC ratio (simulated from serum cholesterol) (dependent variables) and dietary and other risk factors (independent variables).

Results showed that female and male cohorts in countries that have vitamin K2 < 5μg per 2000 kcal/day per capita (n = 70) had about 2.2 times the rate of early CVD deaths as people in countries with > 24 μg/day of vitamin K2 per 2000 kcal/day (n = 72). A multiple regression-derived formula relating early death from CVD to dietary nutrients and other risk factors accounted for about 50% of the variance between cohorts in early CVD death. The attributable risks of the variables in the CVD early death formula were: too much alcohol (0.38%), too little vitamin K2 (6.95%), tobacco (6.87%), high blood pressure (9.01%), air pollution (9.15%), early childhood death (3.64%), poverty (7.66%), and male gender (6.13%).

The authors concluded that worldwide dietary vitamin K2 data derived from food commodities add much understanding to the analysis of CVD risk factors and the etiology of CVD. Vitamin K2 in food products should be systematically quantified. Public health programs should be considered to increase the intake of vitamin K2-containing fermented plant foods such as sauerkraut, miso, and natto.

“It is important to open the eyes of nutritionists and add Vitamin K2 information to nutrition tables,” add Vik. “Supplementing with products containing MenaQ7 Vitamin K2 as MK-7 is a viable route to combatting Vitamin K2 deficiency, but the problem of concretely identifying this deficiency in the population remains a hurdle. Our hope is that the activity of vitamin K-dependent proteins, such as dpucMGP or ucOC, should become an accessible test for any physician to administer, and would be recognized by the medical community as a way to identify vitamin K deficiency.

“Our three-year interventional study[2] confirmed that adding vitamin K2 to one’s daily intake improves arterial health and flexibility,” Vik adds. “We are excited to see additional studies confirming the dangers of K2 deficiency, and encourage the nutritional community to embrace Vitamin K2 for its unique and specific benefits,” Vik concludes.

References:
1 Cundiff D K, Agutter P S (August 24, 2016) Cardiovascular Disease Death Before Age 65 in 168 Countries Correlated Statistically with Biometrics, Socioeconomic Status, Tobacco, Gender, Exercise, Macronutrients, and Vitamin K. Cureus 8(8): e748. DOI 10.7759/cureus.748

2 Knapen MH et al, Braam LAJL, Drummen NE, Bekers O, Hoeks APG, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial. Thrombosis and Haemostasis. 2015 113 5: 1135-1144. doi: 10.1160/TH14-08-0675.

Clinical Nutrition has published a new long-term study[1] that explores if there is a relationship between intake of phylloquinone and menaquinones (vitamins K1 and K2, respectively) and all-cause and cause-specific mortality. The results showed that high intake of menaquinones (vitamin K2) was associated with a reduced risk of CHD (coronary heart disease) (at least in hypertensive participants), while high intake of phylloquinone (vitamin K1) was not associated with any reduced risks.

“As with the Rotterdam Study (2004) and Prospect-EPIC Study (2009), a link has been established between intake of long-chain menaquinones and cardiovascular health. Improving one’s K2 status results in less calcification of the arteries and soft tissues, leading to improved long-term health outcomes,” says Hogne Vik, chief medical officer with NattoPharma, world leader in vitamin K2 R&D and exclusive global supplier of MenaQ7® Vitamin K2 as MK-7. “These benefits are recognized with Vitamin K2, but not K1, which is important because there is a misconception that daily recommended intake (RDI) of the vitamin K1 is sufficient to protect the arteries for developing arterial diseases. This is not the case, since vitamin K1 is only documented and recognized to meet our needs for coagulation.

“It is, however, vitamin K2, the menaquinones, that are responsible for the cardiovascular benefits, and not vitamin K1,” adds Vik.

This prospective cohort study, entitled “Vitamin K intake and all-cause and cause-specific mortality”, included 33,289 participants from the EPIC-NL cohort, aged 20-70 years at baseline and recruited between 1993 and 1997. Dietary intake was assessed at baseline with a validated food frequency questionnaire and intakes of phylloquinone, and total, short-chain and long-chain menaquinones were calculated. Information on vital status and causes of death was obtained through linkage to several registries. The association between the different forms of vitamin K intake and mortality was assessed with Cox proportional hazards, adjusted for risk factors for chronic diseases and nutrient intake.

During a mean follow-up of 16.8 years, 2,863 deaths occurred, including 625 from cardiovascular disease (CVD; 256 from CHD), 1,346 from cancer, and 892 from other causes. After multivariable adjustment, phylloquinone and menaquinones were not associated with all-cause mortality with hazard ratios for the upper vs. the lowest quartile of intake, and neither phylloquinone intake nor menaquinone intake was associated with risk of CVD mortality. However, the researchers concluded that higher intake of long-chain menaquinones was borderline significantly associated (Ptrend = 0.06) with lower CHD mortality with a HR10mg of 0.86 (0.74;1.00). None of the forms of vitamin K intake were associated with cancer mortality or mortality from other causes.

“Our three-year interventional study2 confirmed that adding vitamin K2 to one’s daily intake improves arterial health and flexibility,” Vik adds. “We are enthused to see additional studies confirming this mechanism and encourage the nutritional community to embrace Vitamin K2 for its unique and specific benefits.”

Atherosclerosis has published a new long-term study[1] that explores if there is a relationship between intake of phylloquinone and menaquinones (vitamins K1 and K2, respectively) and risk of peripheral arterial disease (PAD). The results showed that high intake of menaquinones (vitamin K2) was associated with a reduced risk of PAD (at least in hypertensive participants), while high intake of phylloquinone (vitamin K1) was not associated with a reduced risk of PAD. PAD is similar to coronary artery disease (CAD) in that respect that both are caused by atherosclerosis that narrows and blocks arteries in various critical regions of the body.

“Like the Rotterdam Study (2004) and Prospect-EPIC Study (2009), the cardiovascular benefits of K vitamins are only recognized with vitamin K2, not vitamin K1,” says Hogne Vik, chief medical officer with NattoPharma, world leader in vitamin K2 R&D and exclusive global supplier of MenaQ7® Vitamin K2 as MK-7. “This is important because there is a misconception that daily recommended intake (RDI) of the vitamin K1 is sufficient to protect the arteries for developing arterial diseases. This is not the case, since vitamin K1 is only documented and recognized to meet our needs for coagulation. It is, however, vitamin K2, the menaquinones, that are responsible for the cardiovascular benefits, and not vitamin K1.”

“Like the Rotterdam Study (2004) and Prospect-EPIC Study (2009), the cardiovascular benefits of K vitamins are only recognized with vitamin K2, not vitamin K1,” says Hogne Vik, chief medical officer with NattoPharma, world leader in vitamin K2 R&D and exclusive global supplier of MenaQ7® Vitamin K2 as MK-7. “This is important because there is a misconception that daily recommended intake (RDI) of the vitamin K1 is sufficient to protect the arteries for developing arterial diseases. This is not the case, since vitamin K1 is only documented and recognized to meet our needs for coagulation. It is, however, vitamin K2, the menaquinones, that are responsible for the cardiovascular benefits, and not vitamin K1.”

A low vitamin K status, as indicated by high dephosphoundercarboxylated MGP (duc-MGP) levels, has been associated with an increased risk of PAD among type 2 diabetes patients in previous research. To explore a possible clinical applicability for the relationship between low vitamin K status and PAD, the authors aimed to investigate the relationship between dietary intake of phylloquinone and menaquinones and risks of PAD. Furthermore, they examined this association in a general population and explored effects of modification through cardiovascular risk factors such as sex, hypertension, and diabetes.

The study, “The relationship between vitamin K and peripheral arterial disease,” followed up with 36,629 men and women over 12.1 years. During that time, 489 incident cases of PAD were documented. Menaquinones intake was associated with a reduced risk of PAD with a hazard ratio (HR) of 0.71, 95% CI; 0.53-0.95 for the highest versus lowest quartile.

According to the researchers, a stronger association was observed (p interaction 0.0001) in study participants with hypertension (HRQ4 versus Q1 0.59; 95% CI 0.39-0.87) or diabetes (HRQ4 versus Q1 0.56; 95% CI 0.18-1.91), though confidence intervals were wide in the small (n = 530) diabetes stratum. Phylloquinone intake (vitamin K1) was not associated with PAD risk.

The researchers concluded: “A high intake of menaquinones (vitamin K2) was significantly associated with a reduced risk of PAD, at least in hypertensive participants. A high menaquinone intake may be associated with a reduced risk of PAD in participants with diabetes as well, though no statistically significant results were observed. High phylloquinone intake (vitamin K1) does not seem associated with PAD risk.”

“Based on our three-year interventional study[2], it was shown that adding vitamin K2 to one’s daily intake improves arterial health and flexibility,” Vik adds. “We are excited and thankful to see additional studies confirming this mechanism and encourage the nutritional community to embrace vitamin K2 for its unique and specific benefits.”

References:
1 Vissers LET, Dalmeijer GW, Boer JMA, Verschuren WMM, van der Schouw YT, Beulens JWJ. The relationship between vitamin K and peripheral aterial disease. Atherosclerosis 252 (2016) 15-20. DOI: http://dx.doi.org/10.1016/j.atherosclerosis.2016.07.915
2 Knapen MH et al, Braam LAJL, Drummen NE, Bekers O, Hoeks APG, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial. Thrombosis and Haemostasis. 2015 113 5: 1135-1144. doi: 10.1160/TH14-08-0675.

Open Heart has published a new paper that explores better strategies for optimizing bone strength and reducing risk of fracture, while at the same time decreasing risk of cardiovascular disease. The paper found that Vitamin K2 is recognized, along with calcium, vitamin D, and magnesium, as essential in supporting strong bones and healthy arteries.

In the paper, “Nutritional strategies for skeletal and cardiovascular health: hard bones, soft arteries, rather than vice versa,” the authors cite a US Surgeon General’s Report that states that one in two Americans over age 50 is expected to have or to be at risk of developing osteoporosis, which causes 8.9 million fractures annually, with an estimated cumulative cost of incident fractures predicted at $474 billion over the next 20 years in the USA. Further, a Mayo Clinic study reported that compared to 30 years ago, forearm fractures have risen more than 32% in boys and 56% in girls.

Meanwhile, strong epidemiological associations exist between decreased bone mineral density (BMD) and increased risk of cardiovascular (CV) disease. For example, individuals with osteoporosis have a higher risk of coronary artery disease, and vice versa. This problem will be magnified, according to the paper, if the therapies for osteoporosis (e.g., calcium supplements) independently increase risk of myocardial infarction.

To that end, the authors conducted a comprehensive and systematic review of the scientific literature to determine the optimal dietary strategies and nutritional supplements for long-term skeletal health and cardiovascular health. They summarized what is helpful for building strong bones while maintaining soft and supple arteries:

• Obtain calcium from dietary sources (the best choice is a calcium-hydroxyapatite) with the adequate animal protein, fruit and vegetables intake;
• Concomitantly increase potassium consumption while reducing sodium intake should be taken into account;
• Maintain vitamin D levels in the normal range; and
• Increase the intake of foods rich in vitamins K1 and K2.

The study notes: “A meta-analysis concluded that while supplementation with phytonadione (vitamin K1) improved bone health, Vitamin K2 was even more effective in this regard. This large and statistically rigorous meta-analysis concluded that high Vitamin K2 levels were associated with reduced vertebral fractures by approximately 60%, hip fractures by 77% and all non-vertebral fractures by approximately 81%. Supplementation with Vitamin K2 as MK-7 increased bone strength in postmenopausal women in three-year clinical study.

“Additionally, increased Vitamin K2 intake has been associated with decreased arterial calcium deposition and the ability to reverse vascular calcification in animal models. Moreover clinical trial proved that vitamin K2 supplementation increases elasticity of the arteries [over three years],” the paper stated.

The authors recommend increasing the intake of foods rich in vitamins K1 and K2 to secure skeletal and cardiovascular health. While relevant dietary sources for vitamin K1 are referred to in Table 3 on page 4, the authors also state that “the positive health potential of vitamin K2 is more effective than for vitamin K1”. Yet Dr. Hogne Vik, chief medical officer with NattoPharma, world leader in Vitamin K2 R&D, exclusive global supplier of MenaQ7® Vitamin K2 as MK-7, and sponsor of the three-year studies cited in the paper, explains that it is not possible to get sufficient amounts of vitamin K2 through a European or US diet. “The only food that contains enough Vitamin K2 is the Japanese dish Natto. This means that if you want to get enough vitamin K2 into your body, then you have to take dietary supplements or functional foods containing Vitamin K2.

“We are gratified, but not surprised, that our three-year clinical studies were cited in this paper,” Dr. Vik continues. “NattoPharma has driven the clinical research that has demonstrated Vitamin K2’s benefits for human health, and our breakthrough studies provided the first intervention data confirming the associations that observational studies made previously: That vitamin K2 as MK-7 is available beyond the liver to support bone and cardiovascular health. And it does this by activating proteins that help the body to properly utilize calcium – there by simultaneously supporting both skeletal and cardiovascular health.”

Reference:
O’Keefe JH, Bergman N, Carrera-Bastos P, et al. Nutritional strategies for skeletal and cardiovascular health: hard bones, soft arteries, rather than vice versa Open Heart 2016;3:e000325. doi:10.1136/openhrt-2015-000325.

A new review paper published in leading journal, Pharmacology, examines the positive associations observed between cardiovascular disease (CVD) and type 2 diabetes mellitus (DM), and the negative effect of medications prescribed to both groups of patients share a common mechanism: to inhibit vitamin K2-dependent processes, which was interpreted to lead to increased onset of CVD, DM, chronic kidney disease, bone fracture, and even mental disorder.

The authors of the review paper[1], “Medicines and Vegetable Oils as Hidden Causes of Cardiovascular Disease and Diabetes,” note that impaired vitamin K2-dependent processes by some types of vegetable oils and medicines, but not plasma high low-density lipoprotein cholesterol, were proposed as the cause of CVD, DM and other lifestyle-related diseases.

“Once again the scientific community recognizes that the inhibition of vitamin K2 synthesis by common medications carries serious, newly recognized repurcussions,” says Hogne Vik, chief medical officer with NattoPharma, the world leader in vitamin K2 research and development, adding that while it has been well known for some time that statins inhibit CoQ10, a 2015 review paper[2] finally highlighted that statins also inhibit K2 synthesis. ”Recognized Vitamin K2 antagonists significantly inhibit Vitamin K activity outside the liver with serious, unintended consequences.”

The function of K vitamins is unique among other vitamins and important throughout all life stages. Vitamin K2 activates proteins that are made in different organs in the body – clotting factors in the liver, osteocalcin in bones, and Matrix Gla Protein (MGP) in the vasculature. These proteins help coagulate blood, bind calcium to the surface of bones, and keep calcium from depositing in the arteries and soft tissues.

While the function of Vitamin K2 is vital to ensuring that the body properly utilizes calcium, studies have shown that 97 percent of Western populations are Vitamin K2 deficient/insufficient.[3]

“We are not only finally seeing recognition that Vitamin K2 is woefully insufficient in the diet, but the is a growing body of evidence that pharmaceuticals further exacerbate the problem of our limited Vitamin K2 status, delivering potentially dangerous consequences for human health,” Vik continues.

References:
1 Okuyama H et al. Medicines and Vegetable Oils as Hidden Causes of Cardiovascular Disease and Diabetes. Pharmacology 2016;98:134–170. DOI: 10.1159/000446704.
2 Okuyama H et al. Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99. doi: 10.1586/17512433.2015.1011125. Epub 2015 Feb 6.
3 Shea MK et al. Circulating uncarboxylated matrix gla protein is associated with vitamin K nutritional status, but not coronary artery calcium, in older adults. J Nutr. 2011 Aug;141(8):1529‐34.

Journal of Medicinal Food has published a new study that successfully tested and confirmed the role of vitamin K2 as MK-7 (menaquinone-7; MenaQ7® provided by NattoPharma) in modulation of the immune and inflammatory biomarkers.

The study, “Inhibition of TNF-a, IL-1a, and IL-1b by Pretreatment of Human Monocyte-Derived Macrophages with Menaquinone-7 and Cell Activation with TLR Agonists In Vitro,” is significant because it confirms another mechanism by which vitamin K2 supports cardiovascular health by impact markers of inflammation.

“Chronic inflammation is considered an underlying pathology of many diseases that remain poorly understood and treated,” the researchers wrote. “Cardiovascular disease (CVD), a leading cause of mortality in the world, is not only considered as a disorder of lipid accumulation, but also as a disease characterized by low-grade inflammation of the endothelial cells and an inappropriate healing response of the vascular lining.”

The commonly recognized function of vitamin K is a cofactor for c-glutamyl carboxylase, an endoplasmic enzyme involved in the posttranslational carboxylation (activation) of proteins with glutamic acid (Glu) residues into c-carboxyglutamate (Gla). With the carboxylation of glutamic acid residues on the protein substrate, a negative chemical group is formed that attracts and binds positively charged calcium cation. Vitamin K2, in particular, is responsible for carboxylation and activation of osteocalcin, which is essential for physiology of bone-building cells, osteoblasts. Vitamin K2 helps in carboxylation and activation of another protein besides osteocalcin, that is, matrix GLA protein (MGP), important for elasticity and prevention of calcification of blood vessels.

To that end, researchers evaluated high-purity natural vitamin K2 (98.4% menaquinone-7, MK-7, as MenaQ7) in vitro for its potential to inhibit gene expression and production of pro-inflammatory markers by human monocyte-derived macrophages (hMDMs) from two sources (hMDMs and THP-1).

The results showed that the MK-7 form of vitamin K2 is able to dose- dependently inhibit TNF-a, IL-1a, and IL-1b gene expression and protein production by healthy hMDMs in vitro. According to the researchers, “In view of these encouraging findings on the anti-inflammatory properties of MK-7, we plan to test additional biomarkers of immune and inflammatory response in this form of vitamin K2 in vitro. This work may elucidate the anti-inflammatory mechanism of vitamin K2 and establish the potential biomarker targets in clinical testing of the role of MK-7 in the cardiovascular health as well as other chronic degenerative conditions.”

“All of the work showing the efficacy of MK-7 inhibiting cardiovascular and soft tissue calcification is recognized to the extent that scientific experts continue to explore new benefits and mechanisms,” says Hogne Vik, NattoPharma chief medical officer. “These findings are very exciting and promising, and we are thrilled that we could offer the research team our vitamin K2 material – providing another piece of evidence that MenaQ7 is a clinically validated ingredient delivering true benefits for human health.”

Reference:
Pan MH, Maresz K, Lee PS, Wu JC, Ho CT, Popko J, Mehta DS, Stohs S??J, Badmaev V. Inhibition of TNF-a, IL-1a, and IL-1b by Pretreatment of Human Monocyte-Derived Macrophages with Menaquinone-7 and Cell Activation with TLR Agonists In Vitro. J Med Food.2016 Jul;19(7):663-9.

Arteriosclerosis, Thrombosis, and Vascular Biology, the journal for the American Heart Association, just published an 11-year study that draws a clear line between vitamin K deficiency and an increased risk of coronary heart disease.[1]

To date, 19 Vitamin K–dependent proteins (VKDPs) have been described, with important roles in coagulation, platelet function, and vascular biology. Produced in an inactive form, all VKDPs obtain biological activity through the conversion of a glutamic acid residue into glutamate, a complex process requiring vitamin K.

“Western populations are not afflicted with blood diseases because of a vitamin K1 deficiency. Clearly we get enough vitamin K in our diets to effectively coagulate blood; however, our total K status outside the liver – particularly Vitamin K2 status – plays an important role in maintaining and supporting our heart and bone health,” says Dr. Hogne Vik, chief medical officer with NattoPharma, world leader in vitamin K2 research and development and exclusive global supplier of MenaQ7® Vitamin K2 as MK-7.

The authors investigated whether VKDP activity was associated with cardiovascular disease in a random sample of 709 multi-ethnic adults free of cardiovascular disease drawn from the Multi-Ethnic Study of Atherosclerosis (MESA), who were followed up with for 11 years. The circulating des-γ-carboxy prothrombin (DCP) concentrations were measured to indicate lower VKDP activity. [Note: des-γ-carboxy prothrombin (DCP) is also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II).]

The results showed that ischemic cardiovascular disease incidence rates were higher with greater concentration of DCP. Further, that subjects with the lowest activity of VKDP revealed two-times higher risk of cardiovascular events than people with the highest activity of VKDP.

“The study showed that a total of 84% of the cohort participants had a DCP >2 ng/mL (considered the threshold for VKDP inactivity), so the majority of participants were vitamin K subdeficient. Moreover, it has been shown that participants with higher DCP concentrations (i.e., lower VKDP activity) tended to be older,” continues Dr. Vik, adding that a similar finding was shown by E. Theuwissen et al. (2014)[2]: that adults above 40 years showed the largest tissue-specific vitamin deficiency after children.

Further, there are other studies where VKDP correlates with cardiovascular survival risk:
• Schlieper et al. 2011[3] showed that lower levels of circulating dp-cMGP may serve a s predictor of mortality in dialysis patients.
• Mayer et al. 2016[4] concluded that concomitant abnormality of uncarboxylated MGP leads to about a two-fold increase of the relative mortality risk in chronic patients with vascular disease.
• Liu et al. 2015[5] showed that higher dp-ucMGP predicts total non-cancer and cardiovascular mortality, but lower coronary risk.

“Researchers have identified populations that consume large amounts of Vitamins K1 and K2 have better heart and bone health outcomes. Intervention studies have also demonstrated that adding vitamin K reduces cardiovascular risk factors,” concludes Dr. Vik. “This is yet another important study showing that a lack of K vitamins, particularly vitamin K2, results in increased cardiovascular risk. This finding should raise awareness of this important class of proteins as a potential contributor to cardiovascular disease protection.”

References:
1 Danzinger J, Young RL, Shea MK, Tracy RP, Ix JH, Jenny NS, Mukamal KJ. Vitmain K-Dependent Protein Activity and Incident Ischemic Cardiovascular Disease: The Multi-Ethnic Study of Atherosclerosis. Athero, Thrombo, and Vasc Bio. 2016;36:1037–1042.
2 Theuwissen et al. Vitamin K status in healthy volunteers. Food & Function. 2014;5(2):229-34.
3 Schlieper et al. Circulating Nonphosphorylated Carboxylated Matrix Gla Protein Predicts Survival in ESRD . J Am Soc Nephrol 2011; 22: 387–395.
4 Mayer et al. The abnormal status of uncarboxylated matrix Gla protein species represents an additional mortality risk in heart failure patients with vascular disease. International Journal of Cardiology 203 (2016) 916–922.
5Liu YP et al. Inactive matrix Gla protein is causally related to adverse health outcomes: a Mendelian randomization study in a Flemish population. Hypertension. 2015 Feb;65(2):463-70.

European Journal of Clinical Nutrition recently published a study[1] that adds to the growing body of evidence showing that Vitamin K2 as MenaQ7® can be delivered and is highly bioavailable through yogurt and soft gel capsules, making the nutrient safe, effective, and available to an even larger population.

The researchers previously studied the effects of vitamin K status after 8 weeks of intake of a yogurt fortified with MenaQ7 PURE and enriched with vitamins C and D3, magnesium, and polyunsaturated fatty acids. For this new study, the researchers compared the fasting plasma concentrations of MK-7 from (a) yogurt enriched with MK-7, vitamins D3 and C, magnesium, n-3 poly unsaturated fatty acids (n-3 PUFA) and fish oil (yogurt Kplus); (b) yogurt fortified with MK-7 only (yogurt K); and (c) soft gel capsules containing only MK-7 for 42 days in healthy men and postmenopausal women between 45 and 65 years of age. The MK-7 in the yogurts and the capsules was MenaQ7 from NattoPharma ASA.

Circulating MK-7, 25-hydroxy vitamin D (25(OH)D) and markers for vitamin K status [uncarboxylated osteocalcin (ucOC) and desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP)] were assessed. The increase in plasma MK-7 with the yogurt Kplus product was more pronounced than the increase in MK-7 with the capsules. However, circulating dp-ucMGP and ucOC were significantly lowered after consumption of both the yogurt products and the MK-7 capsules, reflecting vitamin K status improvement from both delivery methods.

“This important study validates obtaining Vitamin K2 from food sources is essentially equivalent to Vitamin K2 delivered in supplements,” says Hogne Vik, chief medical officer with NattoPharma, exclusive global supplier of MenaQ7. “Clearly getting Vitamin K2 from diet is ideal, be it cheese, natto, or enriched yogurts. However, as most Western populations are deficient in this essential nutrient, they are not getting enough from diet, making supplementation a viable alternative.

“This study further affirms that MenaQ7 is a safe and effective as either a supplement or a functional food,” adds Vik. “We see this as support for further exploring the use of MenaQ7 in yogurt and other dairy products so we can reach an even wider audience.”

Reference:
1 Knapen MHJ, Braam LAJL, Teunissen KJ, van’t Hoofd CM, Zwijsen RML, van den Heuvel EGHM, Vermeer C. Steady-state vitamin K2 (menaquinone-7) plasma concentrations after intake of dairy products and soft gel capsules. European Journal of Clinical Nutrition (2016), 1–6.

A new study shows that consumption of yogurt fortified with MenaQ7® improves Vitamin K2 status significantly for healthy people, contributing to improved cardiovascular health.

The Journal of Nutritional Science recently published a study that adds to the growing body of evidence showing that Vitamin K2 is a safe and effective supplement. Additionally, it shows that Vitamin K2 as MenaQ7® can be absorbed through yogurt, which makes the nutrient available to an even larger population.

“Consumers already recognize yogurt as a healthy choice. The fact that we can now enrich yogurt with a vitamin that the majority of the population is deficient is a major breakthrough. The study’s results imply that we, by adding MenaQ7 to a popular food item, can bring significant health benefits to a larger percentage of people,” says Eric Anderson, senior vice president of global sales and marketing at NattoPharma, exclusive global supplier of MenaQ7 Vitamin K2 as MK-7.

A number of studies have previously shown that supplementation with MenaQ7 Vitamin K2 improved cardiovascular health by reducing age-related arterial calcification, and improved bone health by increasing bone density and mass. The new study, in which healthy patients received low doses of MK7 in a yogurt drink for three months, shows that the benefits of Vitamin K2 can be obtained through other delivery systems than traditional dietary supplements.

“This study not only confirms that short-term use of MenaQ7 can improve health, but also that yogurt is an effective way of providing the public with this important nutrient,” says Hogne Vik, CEO of NattoPharma. “We already have clinical documentation showing that children generally have a deficiency of Vitamin K2. The confirmation that our ingredient also works in a yogurt product is an important step forward. This means that we can make the nutrient available to more people, reach a younger audience, and create a healthier generation.”

Reference:

Knapen MHJ, Braam LAJLM, Teunissen KJ, Zwijsen RML, Theuwissen E, Vermeer C. Yogurt drink fortified with menauqinione07 improves vitamin K status in a healthy population. J Nutr Sci, 4, E35. Doi:10.1017/jns.2015.25.

Nutrients, an international, peer-reviewed journal for studies related to Human Nutrition, has approved a new study rational that aims to show the protective effect of vitamin K2 as MK-7 (menaquinone-7; MenaQ7® PURE provided by NattoPharma ASA) supplementation on holding the progression of coronary artery calcification for publication in October 2015.

The study, “Menaquinone-7 supplementation to reduce vascular calcification in patients with coronary artery disease: rationale and study protocol (VitaK-CAC trial),” will be significant because it will add to the substantial body of evidence demonstrating the cardiovascular benefits of Vitamin K2 as MK-7, lending further understanding to the mechanism by which it inhibits calcification to cardiovascular muscle.

“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,” says Dr. Leon Schurgers, associate professor and senior scientist at the department of biochemistry, the Cardiovascular Research Institute CARIM of University of Maastricht (The Netherlands), and researcher on the study. “This led us hypothesize that supplementation with vitamin K2 as MK-7 may slow down progression of CAC.

The researchers designed the VitaK-CAC trial to analyze the effects of menaquinone-7 (MK-7) supplementation on progression of CAC. The double-blind, placebo-controlled trial will randomize patients with coronary artery disease (CAD) with a baseline Agatston CAC-score between 50 and 400 into an intervention-group (360 microgram MK-7) or placebo-group for 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.

The researchers hope that the MK-7 supplementation will slow down the progression of CAC in patients with CAD. The results of this study are expected by the end of 2017.

“So far, no treatment options are available for limiting or holding the progression of vascular calcification,” adds Dr. Schurgers, “and this trial may lead to a novel treatment option for vascular calcification and cardiovascular disease.” “All of the work showing the efficacy of MK-7 inhibiting cardiovascular and soft tissue calcification is recognized to the extent that scientific experts are conducting clinical studies in advanced CAC patients,” says Hogne Vik, NattoPharma CEO. “We hope this trial demonstrates the benefit of vitamin K2 as MK-7 (as our MenaQ7 PURE material) for diseased populations, lending further support and understanding to the mechanism of action by which this essential nutrient inhibits arterial calcification.”

Kidney International, a journal of the Nature group and the International Society of Nephrology, has approved for publication in October 2015 a new paper showing the protective effect vitamin K2 on arteriovenous fistula failure, a common complication suffered by chronic kidney disease (CKD) patients requiring hemodialysis.

The study, “Vitamin K- antagonist aggravate CKD induced neointimal hyperplasia and calcification in arterialized veins: potential role for vitamin K2 to prevent AVF failure”, is significant because it adds to the growing body of evidence demonstrating the dangers of vitamin K antagonists (i.e., oral anticoagulants), a common traditional cardiovascular therapy inducing severe vitamin K deficiency, and how vitamin K2 provides an alternative impactful therapy to combat vascular damage.

“Arteriovenous fistula (AVFs) is a frequently used vascular access type for chronic kidney disease patients requiring hemodialysis. AVF failure is a complication leading to high hospitalization rates and morbidity. Whereas early AVF failure is caused by thrombosis or the veins’ inability to dilate, later-course AVF failure is induced by stenosis and thrombosis resulting from neointimal hyperplasia (NIH) and calcification,” says Dr. Leon Schurgers, associate professor and senior scientist at the department of biochemistry, the Cardiovascular Research Institute CARIM of University of Maastricht (The Netherlands), and researcher on the study. “Vascular calcification is a frequent complication in CKD patients; diagnosed as arterial calcification and calcification of arterialized veins. Recent work indicates that AVF calcification contributes to AVF failure.” 

Dr. Schurgers notes that CKD patients have significantly lower circulating vitamin K concentrations compared to the general population and hemodialysis patients have a poor overall vitamin K status due to low vitamin K intake. In addition, a high number of CKD patients at risk of arterial and venous thrombosis receive oral anticoagulants (vitamin K-antagonists; VKA). VKAs interfere with carboxylation of coagulation factors, but also impair the activation of Matrix Gla Protein (MGP), a vitamin K-dependent protein produced by vascular smooth muscle cells that is a powerful vascular calcification inhibitor.

“These constellations make CKD patients and patients undergoing VKA therapy, such as warfarin, prone to vascular calcification,” he explains. “Treatment of CKD patients with vitamin K2 has been a suggested option to inhibit vascular calcification by counteracting the vitamin K deficiency.”

To that end, AVF was generated in 190 rats. CKD was induced using adenine-enriched diet. Effects of CKD, VKA and K2 on AVF remodeling were evaluated using histology, morphometric analysis and immunohistochemistry. Examination of native and arterialized human veins was performed.

Results showed that arterialization, CKD and VKA significantly enhanced AVF failure. K2 supplementation reduced AVF failure in healthy and CKD animals.

The data showed that K2 enhanced matrix Gla protein (MGP) carboxylation in control and CKD animals. Human vein samples showed inactive MGP at calcification and NIH sites, indicating local vitamin K-deficiency. “We show that VKA treatment has detrimental effects on AVF remodeling,” says Dr. Schurgers. “K2 supplementation reduced NIH and calcification – and thus AVF failure – indicating vasoprotective effects. In arterialized veins, K2 should be considered as therapeutic approach to prevent AVF failure.”

“Clearly oral anticoagulant vitamin K antagonists thin blood at the expense of other essential metabolic functions, such as proper calcium utilization for bone support and cardiovascular protection,” says Hogne Vik, CEO of NattoPharma, makers of MenaQ7® Vitamin K2 as MK-7. “It is time the medical community change the standard of care away from ‘rat poison.’”

Reference:

Zaragatski E, Grommes J, Schurgers LJ, Langer S, Kees L, Tamm M, Koeppel TA, Kranz J, Hackhofer T, Arakelyan K, Jacobs MJ, Kokozidou M. Vitamin K- antagonist aggravate CKD induced neointimal hyperplasia and calcification in arterialized veins: potential role for vitamin K2 to prevent AVF failure. Kidney Int. 2016 Mar;89(3):601-11.

Nutrients, an international, peer-reviewed journal for studies related to Human Nutrition, has approved for publication in September 2015 a new study showing the protective effect inhibiting muscle damage from calcification of Vitamin K2 as MK-7 (menaquinone-7; MenaQ7® PURE provided by NattoPharma) supplementation on cardiovascular calcification.

The study, “High-Dose Menaquinone-7 Supplementation Reduces Cardiovascular Calcification in a Murine Model of Extraosseous Calcification,” is significant because it adds to the substantial body of evidence demonstrating the cardiovascular benefits of Vitamin K2 as MK-7, lending further understanding to the mechanism by which it inhibits calcification damage to cardiovascular muscle.

“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,” says Dr. Leon Schurgers, associate professor and senior scientist at the department of biochemistry, the Cardiovascular Research Institute CARIM of University of Maastricht (The Netherlands), and lead researcher on the study. “The aim of this study was to evaluate the impact of high-dose MK-7 supplementation on the development of cardiovascular calcification and the impact on cardiovascular function in a murine model of chronic kidney disease characterized by extraosseous calcification.”

As it is well documented that kidney disease patients frequently suffer cardiovascular complications like calcification of the aorta and coronary arteries, the scientists applied an in-vivo rat model system for kidney disease.

The animals were divided into four groups: Two control groups with intact kidneys and on standard diet with respect to content of Phosphate and Calcium ± supplementation with 100µg Vitamin K2 as MK-7 (MenaQ7 ® PURE from NattoPharma)/g; and two treatment groups where 5/6 of their kidneys were removed (mimicking kidney patients) receiving a diet with high content of both Phosphate and Calcium ± supplementation with 100µg MK-7/g.

After 12 weeks, the animals were examined for calcification of the aorta, the myocardium, and in kidneys, as well as for certain other changes in the tissues. Using a sensitive technique for arterial calcification (atomic absorption spectroscopy), this study shows that high-dose MK-7 inhibits calcification in aorta and in the myocardium – parts of the arterial bed most often affected in kidney patients. MK-7 also normalized the kidney disease-induced high serum phosphate level.

Interestingly, a 10-fold increase in matrix Gla protein (MGP) gene expression in the MK-7 supplemented animals was recorded. According to the authors, this is the first time that MK-7 has been shown to affect the synthesis of MGP in the vascular wall – and not only locally in the arterial wall. This indicates an increased amount of MGP available for activation to inhibit calcification.

The researchers stated that MK-7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphate tissue concentrations. The effect of MK-7 was – at least in part – mediated via MGP and subsequent inhibition of ectopic calcification. Since vitamin K has no reported side effects, it seems a promising therapeutic agent for CKD patients, the researchers concluded.

“NattoPharma has enjoyed a long-standing R&D program with the University of Maastricht and CARIM with the specific goal of understanding and validating the benefits of Vitamin K2 as MK-7 for human health,” says Hogne Vik, NattoPharma CEO. “This study is monumental because it shows that our MenaQ7 Vitamin K2 protected smooth muscle cells from calcification. Being able to provide the researchers with our new nature-identical MenaQ7 PURE to add to our growing body of clinical validation marks a true milestone for us.”

Few consumers read Expert Review Clinical Pharmacology, but NattoPharma, makers of MenaQ7™ Vitamin K2 as MK-7, feels a new paper published in the March issue should be part of doctors’ conversations with their patients before they prescribe a statin therapy.

The paper[1] states that statins may act as “mitochondrial toxins” with negative effects on the heart and blood vessels not only via the depletion of coenzyme Q10 (CoQ10), but also by inhibiting “the synthesis of vitamin K2, the cofactor for matrix Gla-protein activation, which in turn protects arteries from calcification.

Vitamin K2 plays a critical role in the activation of matrix Gla protein (MGP), which inhibits soft tissue and cardiovascular calcification. MGP is present in bone, blood vessel, lung, heart, and kidney soft tissues. MGP binds calcium and protects blood vessels from calcification, but only when in its active form, which requires adequate intakes of vitamin K2. Unfortunately, statins inhibit vitamin K2 synthesis in the body, thereby accelerating coronary artery calcification, an important marker of the progress of atherosclerosis, according to researchers.

“This new paper speaks directly to statins interrupting the mechanism of action by which vitamin K2 inhibits calcification,” said Hogne Vik, NattoPharma CEO. “Conversely, research clearly demonstrates that increasing dietary vitamin K2, specifically vitamin K2 as menaquinone-7, can improve vitamin K2 levels in the blood and tissues, thus promoting cardiovascular health.”

Supporting Vik’s statement, a new study, “Menaquinone-7 Supplementation Improves Arterial Stiffness in Healthy Postmenopausal Women,” published in the journal Thrombosis and Haemostasis[2], demonstrated the positive impact of MenaQ7® brand Vitamin K2 as MK-7 (menaquinone-7) on cardiovascular health through its improvement of arterial flexibility. This study is significant because it is an interventional study with a vitamin K2 dietary supplement, MenaQ7, confirming  what previous population-based studies have shown: a positive correlation of vitamin K2 consumption from dietary sources attributes to less arterial calcification and reduced risk of coronary heart disease.

Researchers at the R&D Group VitaK of Maastricht University in the Netherlands monitored 244 healthy post-menopausal women for three years using pulse wave velocity and ultrasound techniques. The participants, aged 55-65 years, were randomly assigned to take 180 mcg of MenaQ7 daily for three years, or placebo capsules. Results confirmed that MenaQ7 Vitamin K2 not only inhibited age-related stiffening of the artery walls, but also made an unprecedented statistically significant improvement of vascular elasticity.

References:

1 Okuyama H, Lagsjoen PH, Hamazaki T, Ogushi Y, Hama R, Kobayashi T, Ochino H. Statins stimulate atherosclerosis and heart failure: pharmacological mechanism. Expert Rev Clin Pharmacol. 2015 Mar;8(2):189-99.

2 Knapen MH et al, Braam LAJL, Drummen NE, Bekers O, Hoeks APG, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial. Thrombosis and Haemostasis. 2015 113 5: 1135-1144.

Thrombosis and Haemostasis, The International Journal for Vascular Biology and Medicine, has approved for publication in its May 2015 print issue a new study showing the positive impact of MenaQ7® Vitamin K2 as MK-7 (menaquinone-7) on cardiovascular health through its improvement of arterial flexibility.

The study titled “Menaquinone-7 Supplementation Improves Arterial Stiffness in Healthy Postmenopausal Women”[1] is significant because it confirms what previous population-based studies have only been able to show an association, according to Cees Vermeer, renowned vitamin K2 scientist and Chief Innovation Officer at the R&D Group VitaK of the Maastricht University Holding (the Netherlands), who led the study’s research team.

“This is the first study showing that long-term use of vitamin K2 in the form of MK-7 beneficially affects cardiovascular health,” says Vermeer. “Previous population-based studies have shown an association between vitamin K2 intake and cardiovascular risk, but this is the first intervention trial focused on Vitamin K2 supplementation with cardiovascular endpoints.”

Researchers at the R&D Group VitaK of the Maastricht University Holding in the

Netherlands monitored 244 healthy post-menopausal women for three years using pulse wave velocity and ultrasound techniques. The participants, aged 55-65 years, were randomly assigned to take 180 mcg of MenaQ7® daily for three years, or placebo capsules. Results confirmed that MenaQ7® Vitamin K2 not only inhibited age-related stiffening of the artery walls, but also made an unprecedented statistically significant improvement of vascular elasticity.

“Our data demonstrated that a nutritional dose of vitamin K2 in fact improves cardiovascular outcomes,” Vermeer continues.

This same cohort was examined for another study proving MenaQ7’s bone benefits that published in Osteoporosis International in 2013[2]. 

“Both studies are significant because they are long-term – three years of participation and then examination of the results,” said Hogne Vik, NattoPharma CEO. “Observing changes in heart health, and bone health for that matter, take time. Our patience and perserverence has paid off with a study accepted by a highly prestigious medical journal that proves what we have known all along: that MenaQ7 Vitamin K2 truly delivers benefits for hearts and bones.”

“This cardiovascular study is significant because it shows that vitamin K2 not only benefits our bone health, but is also important to heart health,” said Dennis Goodman, MD, board-certified cardiologist and Director of Integrative Medicine at NYU Langone Medical Center in New York. “Vitamin K2 ensures calcium binds to the bone mineral matrix and stays out of the arteries. This is important because if calcium accumulates in the arteries, it may cause blockages that can lead to serious cardiovascular events, such as heart disease and strokes.”

Dr. Goodman, who is completing a new book explaining the important role that vitamin K2 plays in achieving both bone and heart health, says flexibility of the arteries also has a direct connection to a person’s longevity. Calcification in the arteries has been shown to add 10 years to a person’s biological age, according to a study published in The New England Journal of Medicine (Rosenhek, et al., 2000). Another study published in the  scientific journal Atherosclerosis (Shaw et al., vol. 188, 206) shows your biological age could decrease or increase by 10 years based on the level of age-related arterial calcification.

“This study, which is actually showing an improvement in endothelial function, has the potential to dramatically impact the way we view prevention when it comes to cardiovascular health,” Goodman adds. “Further clinical studies will be important to confirm these exciting findings.”

References:

1 Knapen MH et al, Braam LAJL, Drummen NE, Bekers O, Hoeks APG, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial. Thrombosis and Haemostasis. 2015 113 5: 1135-1144. 2 Knapen MH, Drummen NE, Smit E,, Vermeer C, Theuwissen E. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int. 2013 Sep;24(9):2499-507.