Published Research – Vitamin K and Cardiac
On this page, we present an understanding of the research that has been done on vitamin K and cardiac health. Cardiovascular disease affects millions of people a year, and either there has been little effective treatment available for it, or the medical treatments have been invasive and surgical in nature, or the treatments have involved prescription medications that often have toxic side effects. It is well known that vitamin K2-dependent proteins activate a protective mechanism preventing the development of vascular calcification (Rees et al, 2010; Wen, et al, 2018).
The emerging research on vitamin K and heart health is tremendously exciting, and for once, it seems possible that a person can reverse heart disease. We review the trends in the research, the emerging understanding of the biochemistry of vitamin K in the body, the understanding of how a lack of vitamin K contributes to the process of heart disease, and how supplementing with vitamin K can restore health to your heart arteries and to your cardiovascular system in general. If you’d like to learn more, then read on. If you’d like to make a purchase of Koncentrated K, then click on Buy Now.
Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease. Atherosclerosis is a disease in which plaque forms and builds up in the walls of the arteries. The disease process of atherosclerosis begins with a vascular injury. A vascular injury can be either a mechanical “insult”, a chemical “insult”, or a bacterial/viral insult which can take place at any age. These “insults” or injuries then create a cascade of events which leads to subsequent inflammation (cells growing where they should not) in the arteries resulting in oxidative stress, and then plaque formation, and finally calcification at that site. Low grade inflammation was demonstrated to have an important role in atherogenesis, as shown by Ross (1999). The assessment of high sensitive C reactive protein (hs-CRP), a certified marker of inflammation, was fundamental in classifying the population with low, medium or high risk for CAD (Pearson et al, 2003).
Atherosclerosis is typical in children up to 5 years of age and then disappears. Atherosclerosis can then reappear as early as the second decade of life and is near-ubiquitous in the population by about 65 years of age (Shanahan, et al. 1998). The increase in extent and severity of calcification that occurs with increasing age is due to the patient’s harboring and surviving an active, spreading, inflammatory atherosclerosis for a long period of time. Atherosclerosis can affect any artery in the body, including arteries in the heart, brain, arms, legs, pelvis, neck, and kidneys, and occurs in association with a diverse range of diseases, including diabetes and uremia, Atherosclerosis is typically a chronic, slowly progressive and cumulative disease (Glass, 2001; Demer & Tintut, 2008).
Plaque is made up of fat, cholesterol, calcium, and other substances found in the blood. Over time plaque builds up and narrows or blocks your arteries, which limits the flow of oxygen-rich blood to your organs and other parts of your body. This is known as ischemia. Some plaques remain clinically silent and are considered generally stable over the long term. A stable plaque tends to be asymptomatic, and is rich in extracellular matrix and smooth muscle cells. The other plaques are unstable, and research has shown them to be rich in macrophages and foam cells with the extracellular matrix being weak and prone to rupture (Davies, 1990; Davies, 1996; Huang et al, 2001; Finn et al. 2010), as it can become brittle and calcify (Aikawa, et al., 2007; Alexopolous & Raggi 2009). The calcification decreases vessel elasticity and increases shear stress at the interface between calcified deposits and soft tissue (Wayhs et al, 2002; Spadaro et al., 2000; Keelan et al., 2001; Sangiori 1998; Vliegenthart et al, 2005), forming an aneurysm which can rupture (Derlin et al. 2011; Vengrenyuk et al., 2008; Rennenberg et al, 2009). Ruptures expose blood clots to the circulation that will rapidly slow or stop blood flow, leading to death of the tissues fed by the artery in approximately five minutes. This catastrophic event is called an infarction. A common scenario is a clot in the coronary artery, causing a myocardial infarction or heart attack. This same process in an artery to the brain is commonly called a stroke (Ehara et al., 2004).
Cardiovascular Disease: The Vascular-Bone Axis
Vascular calcification was previously viewed as an inevitable, passive, and degenerative process leading to mineral deposits accumulating in the vasculature that occurred at the end stages of atherosclerosis and was regarded as a disease of the aged (Schinke and Karsenty, 2000; Demer and Tintut, 2008). This opinion has changed and it is now understood that vascular calcification is a complex and actively regulated process involving vascular cells and a number of vitamin K dependent proteins, and sharing many features with osteogenesis or bone formation (Shanahan, et al. 2000; Bostrom, 2000; Campbell and Campbell, 2000; Canfield, et al. 2000; Mody et al. 2003; Doherty et al, 2003). Research indicates that MGP and osteopontin, both bone associated proteins, are highly expressed in human atheromatous plaques (Shanahan, et al, 1994; O’Brien et al, 1995; Shanahan et al, 1998; Dhore et al, 2001; Viegas et al., 2009), with the highest levels of MGP being found in the lipid rich areas of the plaque.
Research on vascular calcification has accelerated dramatically in the past decade, and diverse and highly regulated molecular signaling cascades controlling vascular calcification have been described. It appears that vascular calcification results from an imbalance of promoters and inhibitors of mineralization in the vascular wall, leading to the creation of an organized deposition of calcification (Willems et al, 2014). The underlying initiators of dysregulated calcification are diverse, ranging from the expression of bone-associated proteins, to the differentiation of smooth muscle cells to osteoblast-like cells, to the release of fragmented apoptotic bodies and mineralization by smooth muscle cells, which act as a nucleation site. Importantly, the process involves a complex interplay between vitamin K-dependent proteins, such as MGP, GRP and GAS6 (Tesfamariam, 2019).
Vascular calcification can be classified into two distinct subtypes depending on its location: within the intimal layer or the medial layer (Van den Bergh et al, 2019). Intimal calcification occurs on the surface of atherosclerotic plaques and indicates plaque burden and luminal narrowing, whereas medial calcification is associated with the muscular layer and manifests as stiffness and reduced vascular compliance. Intimal calcification is mostly observed in the coronary arteries. Medial calcification is more frequently observed in the peripheral arteries and is less abundant in coronary artery disease. It is associated with aging, diabetes, hypertension, osteoporosis, and chronic kidney disease (Giachelli, 2004). Medial calcification is described in terms of arterial hardening, loss of elasticity, and stiffness (Kamenskiy et al, 2018).
Current research involves efforts to define the complex interactions between cellular and molecular mediators of arterial calcification and the role of endogenous calcification inhibitors. (Belovici and Pandele, 2008). The research has highlighted that Vitamin K dependent proteins play an essential role in vascular calcification (Zak-Golab, 2011). Local and circulating molecules such as osteopontin, osteoprogerin, leptin, osteocalcin, and matrix Gla protein were identified as critical regulators of vascular calcification, and they all are dependent on vitamin K to be activated and utilized (Mazzini, et al, 2006; Luo et al, 2009; Nicoll et al, 2015; Tacey et al, 2018).
Low levels of vitamin K lead to the production of undercarboxylated proteins and impair activation of Gla-containing calcification inhibitors (Lomashvili et al, 2011). A failure of carboxylation leads to a cascade of events culminating in vascular calcification, or stroke (Wessinger et al, 2020) A decrease in carboxylated proteins or a decrease in the ration of carboxylated to inactive uncarboxylated forms favor calcification (Tesfamariam, 2019).
Vitamin K has also been linked to the elastin in the vascular system, which gives veins and arteries flexibility. Clinical trials are ongoing (De Brouwer et al, 2016; Janssen & Vermeer, 2017; Lindholt et al, 2018)
Cardiovascular Disease and Vitamin K Dependent Proteins
Several vitamin K dependent proteins (VKDP) have been identified as involved in the regulation of calcification and vascular calcium metabolism, including osteocalcin, gla rich protein, Gas6, and matrix Gla protein (Viegas et al, 2014; Willem et al. 2014; Kaesler et al, 2016). Among these proteins, the vitamin K dependent matrix Gla-protein (MGP) plays a dominant role (Hofbauer et al, 2007; Schurgers et al. 2008). Matrix Gla protein is a small vitamin K-dependent protein containing five gamma-carboxyglutamic acid (Gla) residues that are believed to be important in binding Ca (2+) calcium crystals and bone morphogenetic protein (Srivatsa et al, 1997; Luo, et al, 1997; Shanahan, et al, 1998; Price, et al. 1985). A bone morphogenetic protein refers to the proteins that generate the formation and structure of bone.
Gla containing proteins have glutamic acid residues that must be gamma-carboxylated by vitamin K-dependent gamma-glutamyl carboxylase, GGCX. Specific glutamic acid residues in the protein are catalyzed by an enzyme-mediated reaction to form a modified glutamic acid known as γ-carboxyglutamic acid in a number of VKD proteins to enable them to bind calcium and function normally and effectively. This enzyme reaction, known as γ-carboxylation, or gamma-carboxylation, requires vitamin K for the carboxylation and transformation to take place. This transformation is required for these proteins to function and bind calcium, which then permits abundant Gla-MGP to be found in the arterial wall, with a subsequent reduction in vascular calcification. When MGP binds calcium, it inhibits the calcification process (Jaminon et al, 2020).
Uniquely, MGP undergoes phosphorylation of its serine residues, a process that might further regulate its activity and also rely on vitamin K availability (Price et al, 1994). A serine is an amino acid used in the biosynthesis of proteins and phosphorylation is a major mechanism for regulating the activity of cell proteins. Both carboxylation of Glu and phosphorylation of serine residues of MGP contribute to its function as an inhibitor of VC (Schurgers et al, 2007; lDelanaye et al, 2014; O’Young et al, 2011, Rouymeliotis et al, 2020). Regardless of carboxylation status, the phosphorylated and dephosphorylated forms of MGP have different affinity for calcium/BMP-2 binding. Therefore, MGP is present in the circulation in several different states of phosphorylation and carboxylation (Cario-Toumaniantz et al, 2007):
the fully carboxylated and phosphorylated active form of MGP or pcMGP–
the uncarboxylated but phosphorylated form (ucMGP or pucMGP)–
the caboxylated but not phosphorylated, partially inactive form (dpcMGP)–
the uncarboxylated, dephosphorylated, fully inactive form (dpucMGP).
Matrix Gla protein is expressed predominantly by vascular smooth muscle cells (VSMCs stands for vascular smooth muscle cells) and by chrondrocytes (cartilage cells), and is the most important inhibitor of arterial mineralization currently known. MGP is synthesized in many soft tissues with the highest levels of expression in the heart, lung, kidney and cartilage (Fraser and Price, 1980). Animal models showed that MGP is a strong inhibitor of calcification of arterial vessel wall and cartilage, whereas genetically engineered mice without MGP exhibited a severe and rapid calcification leading to premature death due to spontaneous aortic rupture (Luo et al., 1997; Murshed et al., 2004). When rodents were given a high dose of MK7 as a supplement, calcification was inhibited. Overall the MK7 had a protective effect on damaged vascular structures (Scheiber et al, 2015).
MGP species in both tissues and the circulation have been detected in the healthy population and significant differences were found in patients with cardiovascular disease (Cranenburg, et al, 2008; Schurgers, et al., 2005; Jia et al, 2012; Silaghi et al, 2016; Wei et al, 2018). In arteries, MGP acts as a local inhibitor of media calcification (Price, et al, 1998; Murshed et al, 2004; Schurgers et el, 2007; Yao et al, 2010; Barrett et al, 2018). According to some, MGP is the most powerful natural calcium inhibitor found in the human body (Roumeliotis et al, 2019).
A study found that serum levels of tMGP were significantly higher in patients with vascular disease and osteoarticular disease, compared to a healthy population. And healthy participants under age 40 had higher levels of tMGP than subjects over age 40. And in healthy folks, tMGP levels were increased in smokers versus non smokers. The study established the reference interval for tMGP as 6-108 ug/L (Silaghi et al, 2019).
Advances in measurement have allowed the amount of circulating total uncarboxylated matrix Gla protein to be measured and it is associated with the extent of prevalent arterial calcification (Cranenburg et al, 2010; Theuweissen, et al, 2012; Rennenberger, et al, 2010; Dalmeijer et al, 2013; Dalmeijer et al, 2013A). Uncarboxylated MGP levels as measured in the blood were associated with increasing levels of heart disease severity and were markedly higher in patients who died from heart failure (Ueland et al, 2011). Patients in the highest tertial of uncarboxylated MGP level had increased all-cause mortality, meaning those with the least presence of vitamin K had increased death rates (Ueland et al, 2010; Ueland et al, 2011). It was also correlated with vascular calcification in hemodialysis patients (Delanaye et al, 2014). Liabeuf (et al, 2014) showed a significant association between uncarboxylated MGP and the peripheral arterial calcification score.
The precise molecular mechanism underlying the function of MGP is not yet fully understood, but seems to involve the inhibition of bone morphogenetic protein 2 and 4 (BMP-2 and-4) (Zebboudj, et. al., 2002; Yao et. al., 2006; Nakagawa, et. al., 2010; Ikeda, et. al., 2012; ), the suppression of osteochondrogenic transdifferentiation of vascular smooth muscle cells (Speer, et. al., 2009) so they don’t transform into cartilage in blood vessels (El Maadawy, et. al., 2003; Naik, 2012) and the direct inhibition of calcium-crystal growth (Schurgers et. al., 2007; O’Young et. al., 2011). Bone morphogenetic protein-2 is a principal osteogenic growth factor. Lack of vitamin K and hence carboxylated MGP leads those protein cells to transform into cartilage cells in the arteries and blood vessels (El-Maadawy et. al., 2003).
Vascular smooth muscle cells (VSMC) are highly specialized cells whose principal function is contraction and regulation of blood vessel tone, blood pressure, and blood flow. In a mature blood vessel, VSMCs exhibit a “contractile” of differentiated phenotype that allows it to assume the functions of a mature arterial wall, including flexibility. A recent animal study found that MK4, the most abundant menaquinone isoform in the human body, significantly reduced BMP-2 expression and preserved the contractile phenotype of the vascular smooth muscle cells (Mandatori et al, 2019).
As matrix Gla protein (MGP) is a vitamin K-dependent protein, it needs an adequate amount of vitamin K available in order to function effectively and inhibit calcium (Schurgers et al, 2008). Gla containing proteins have glutamic acid residues that must be gamma-carboxylated by vitamin K-dependent gamma-carboxylase to enable them to bind calcium and function normally and effectively. Specific glutamic acid residues in the protein are changed by an enzyme-mediated reaction to form a modified glutamic acid known as γ-carboxyglutamic acid. This enzyme reaction, known as γ-carboxylation, or gamma-carboxylation, requires vitamin K for the carboxylation and transformation to take place. This transformation is required for these proteins to function and bind calcium, which then permits abundant Gla-MGP to be found in the arterial wall, with a subsequent reduction in vascular calcification. When MGP binds calcium, it inhibits the calcification process (Jaminon et al, 2020).
Carboxylated MGP decreases the number of calcification foci, acts as an inhibitor of the deposits and crystallization of calcium, and inhibits the calcification process (Jaminon et al, 2020).
Other treatments have included bisphosphonates and phosphate binders, however they may cause severe adverse reactions, like osteonecrosis of the jaw (Patntirapong et al, 2019), and statins which seem to promote vascular calcification (Chen et al, 2017). By contrast, vitamin K is a safe, cost-effective alternative for inhibiting vascular calcification (Florea et al, 2021). Statins are widely used to treat patients at risk of with an established atherosclerotic cardiovascular disease. They aim to lower lipids. Currently statins are routinely recommended as first line drugs for cardiovascular prevention, based only on LDL-C levels and a calculated risk for patients (Mach et al, 2020).
One can take vitamin K and reduce the chances of heart disease. And one can take large amounts of vitamin K at a therapeutic dosage level and reduce the chances of heart disease without any identified health risk (Hariri et al, 2021; Popa et al, 2021). In other words, vitamin K is absorbed readily and easily by the body, without the risk from the medications often prescribed for heart disease, and without the risk of the surgeries often performed as an intervention for heart disease. And at the same time, the vitamin K you take in the form of Koncentrated K can help ward off other disease processes that are linked to vitamin K deficiency.
An interesting study looked at the dietary intake of MK4 and MK7, and subsequent bioavailability in healthy women. They found that after equal intake each of 420 micrograms, MK7 was well absorbed and reached maximal blood level at 6 hours after intake and was detected up to 48 hours after intake. However, at that intake level MK4 was undetectable (Sato et al, 2012). Another study (Takeuchi et al, 2005) showed that it took a dose of 1500 mcg of MK4 to improve carboxylation of osteocalcin, the VKDP.
Without adequate amounts of vitamin K, carboxylation cannot take place. The proteins, such as MGP, remain uncarboxylated and are not able to inhibit vascular calcium properly. A failure of carboxylation leads to a cascade of events culminating in vascular calcification. In vivo studies have shown that in the absence of activated MGP, vascular smooth muscle cells (VSMCs) differentiate into cells with properties of chondrocytes and osteoblasts, producing a matrix that favors calcium deposition (Murshed et al, 2004). MGP regulates calcification directly by inhibiting formation and solubilization of calcium crystals and through alternative calcification inhibitors such as fetuin-A, as well as indirectly via modulating transcription factors that suppress differentiation of VSMC to an osteoblast-like phenotype (Zebboudj et al, 2002; Price et al, 2003). A recent study looked at calcification in varicose and healthy veins and measured all forms of MGP, carboxylated, carboxylated and phosphorylated, uncarboxylated and uncarboxylated and unphosphorylated. They found total and phosphorylated MGP in the control group and in those with varicose veins who did not have calcification. In the group with vein calcification, there was no presence of uncarboxylated MGP or dephosphorylated MGP, affirming the anti-calcifying role of MGP when active (Gheorghe et al, 2021).
Calcific aortic valve stenosis (CAVS) represents an increasing health care burden, leading to either adverse events or the requirement for major heart surgery (Bonow & Greenland, 2015). The pathophysiological mechanisms involved in CAVS are being rapidly elucidated and include inflammation, fibrosis, and calcification. Once calcification becomes abundant, pro-osteogenic mechanisms become overwhelming, leading to severe calcification and valvular dysfunction. Disease progression is driven by calcific regulatory pathways including bone morphogenetic proteins (BMPs). Physiologically, BMP is inhibited by matrix Gla-protein (MGP) (Schurgers et al, 2013). Since Matrix Gla protein depends on vitamin K to be active, vitamin K supplementation is an attractive option to replenish vascular vitamin K stores to ensure optimal calcification inhibition. A recent study showed that Fetuin-A and Lipoprotein A were positively correlated with calcified aortic valve disease, while MGP and macrophage density were negatively correlated, meaning that the lower the MGP the greater the disease burden (Liu et al, 2022).
Indeed, several potential pharmacological treatments are under current investigation to achieve the ultimate goal, i.e. the inhibition of disease progression in CAVS. NCT01528800, ‘VitaVasK’. ClinicalTrials.gov identifier: NCT01742273, ‘VitaK-CAC trial’. ClinicalTrials.gov identifier: NCT01002157,‘BASIK2’. ClinicalTrials.gov identifier: NCT02917525).
Uncarboxylated matrix Gla-protein, formed as a result of vitamin K deficiency, is associated with the increased vascular calcification and cardiovascular disease (Hackeng et al 2001; Schurgers et al, 2013) as well as increased risk of arterial stiffness (Mitchell, 2009; Pivin et al, 2017; Wei et al, 2019), and valvular calcification (Mayer et al, 2016; Venardos et al, 2016; Lees et al, 2019). A review of thirteen clinical trials and fourteen longitudinal studies showed that supplementing with vitamin K led to a significant reduction in vascular calcification, but not vascular stiffness, though the doses were low (Lees et al, 2019). A review by Mozos (et al, 2017) found that menaquinones enables destiffening of the arteries by impairing and reversing calcification of arteries, suppressing the inflammatory reaction in the vascular wall and improving the lipid profile.
Arterial stiffness is a risk factor for cardiovascular disease, and it represents a functional disturbance of calcification. Arterial stiffness is consistently associated left ventricle diastolic dysfunction (Chow & Rabkin, 2015), and heart failure with preserved ejection fraction (HFpEF) (Oktay et al, 2013). A study looked at longitudinal changes in people from the Framingham Heart Study as to blood pressure and hypertension. They found an association between ucMGP levels and arterial stiffness and ejection fractions. A complementary mice study indicated a protective effect of MGP in arterial stiffness (Malhotra et al, 2022). Other work showed that inactive MGP was associated with arterial stiffness (Piven et al, 2015; Mayer et al, 2016; Chirinos et al, 2018).
Vascular stiffness may increase the systolic load on the ventricles and decrease aortic pressure during diastole, thereby increasing pulse pressure which is associated with left ventricle hypertrophy. These changes can lead to LF diastolic dysfunction. Women, after menopause, seem to be more prone to develop LV hypertrophy, compared to men (Levey et al, 2009). A study showed that high vitamin K status was associated with decreased left ventricular mass index in women and may prevent heart failure (Beulens et al, 2021).
Vitamin K may prevent vascular calcification through an anti-inflammatory mechanism as well as promotion of γ-carboxylation of MGP (Shioi et al, 2020). A recent study showed that within only one year, daily supplementation with MK7 improved arterial stiffness in post menopausal women (Vermeer & Vik, 2020; Vik, 2020).
Intestinal bacteria are the main source of vitamin K2 in humans. Diseases of the gastrointestinal tract interfere with the production of vitamin K2 and can contribute to atherosclerosis (De Marchi et al, 2013; Org et al, 2015; Singh et al, 2015). A recent study showed that patients afflicted with small intestinal bacterial overgrowth (SIBO) showed altered vitamin K2 production by intestinal bacteria, and/or low vitamin k2 intake (Ponziani et al, 2017).
The role of OC in cardiovascular health is manifested by the modulation of vascular calcification through activation of adiponectin, a protein that has been shown to inhibit osteoblastic differentiation of VSMCs (Luo et al, 2009). Moreover, OC has been shown to reduce arterial stiffness in diabetic rat model. These findings have been replicated in human studies, as OC is associated with adiponectin in patients with chronic kidney disease (CKD) (Bacchetta et al, 2009). Osteocalcin levels have been associated a lower risk of coronary heart disease in Chinese adults (Zhang et al, 2016). And Fusaro (2016) has found lower osteocalcin levels in patients with aortic and iliac calcifications as compared to patients without calcifications. Moreover, in a prospective study of 774 men aged 51–85 years from the MINOS cohort who were followed over 10 years with serial measurements of abdominal aortic calcification, higher baseline total OC was associated with a lower abdominal aortic calcification progression rate and lower 10-year all-cause mortality (Confavreaux et al, 2013). Serum osteocalcin levels were found to be a better measure of atherosclerotic cardiovascular disease risk as measured by carotid intima-media thickness scores (C-IMT) (Xu et al, 2018; Vassalle, 2018).
Inflammation is common in chronic diseases (Legein et al, 2013). The interplay between inflammatory and pathological calcification processes is widely accepted and macrophages are known key players signaling ECM degradation, and calcification (Ikeda et al, 2012). Vitamin K has been demonstrated to induce anti-inflammatory responses in macrophages playing a protective role against inflammation (Ohsaki, et al, 2006; Shea et al, 2007; Fuji, Shimizu et al, 2015; Lee et al, 2020). Recent work demonstrated that GRP and MGP are expressed by leukocytes as carboxylated proteins that can be released into circulation or peripheral tissues as extracellular components. GRP was shown to be an anti-inflammatory agent, and appears to be a component of the immune system (Viegas et al, 2017). Increasingly the vitamin K dependent protein, GRP (Gla Rich Protein) is being studied for its role in calcifications, and it appears to act as an anti-inflammatory agent (Viegas et al, 2017; Cavaco et al, 2015) and as a calcification inhibitor (Viegas et al, 2015). Plus, GRP has been identified as an important mineralization inhibitor (Vietal et al, 2009; O'Grady et al, 2018). Without the presence of vitamin K, GRP lacks calcification inhibition activity.
A newer VKDP, Gas6, is highly expressed in lungs, hearts and kidneys and as been shown to regulate calcification of vascular smooth muscle cells (Son et al, 2006; Son et al, 2007; Hasanbasic et al, 2005). Gas6 acts as a protective factor in human atherosclerosis (Holden et al, 2019). With vitamin K, Gas6 expression is restored and activates downstream signaling which can inhibit smooth muscle cell calcification and apoptosis (Qiu et al, 2017; Jiang et al, 2016). Accumulating evidence indicates that Gas6 is significantly secreted in human atherosclerotic plaques, but there is no secretion in healthy blood vessels, and that the Gas6 stimulates the vessels to suppress the expression of inflammatory factors (Clauser et al, 2012). The active form of Gas6 plays a role in regulating cell death and protects against calcium crystal formation (Kaesler et al, 2016).
Genetic studies indicate that mutations in the genes that encode MGP are linked with the progression of vascular calcification and coronary artery disease (Hermann et al, 2000; Tuñón-Le Poultel et al, 2014; Karsli-Ceppioglu et al, 2019). This highlights the important role of matrix Gla protein and cardiovascular disease.
It is now understood that vitamin K dependent proteins play an essential role in vascular calcification (Rajamann, et al, 2003; Zak-Golab, 2011; Schwalfenbergm 2017) and they all are dependent on vitamin K to be activated and utilized (Mazzini & Schulze, 2006; Tesfamariam, 2019). There is increasing experimental and clinical evidence linking vitamin K deficiency to valve and arteriole calcification via a functional impairment of vitamin K–dependent calcification modulators (Krueger,et al, 2009; El Asmar et al, 2014: Roumeliotis et al, 2019), as well to arterial stiffness (Mayer et al 2016; Chirinos et al 2018). The amount of vitamin K in the diet has been correlated as a significant variable in death from cardiovascular disease in 168 countries (Cundiff & Aqutter, 2016; Danziger et al, 2016; Van Ballegooijen et al, 2017).
Coronary Artery Calcium Score
Coronary artery calcium (CAC) is a highly specific feature of coronary atherosclerosis. Early studies of CAC used chest x-ray, fluoroscopy, or digital subtraction fluoroscopy, and began to show the potential value of CAC in predicting the presence of obstructive coronary artery disease (CAD), as well as future coronary events. The CAC score is an independent marker of risk for cardiac events, cardiac mortality, and all-cause mortality (Neves et al, 2017). With the introduction of EBCT, more precise quantification of CAC became possible, allowing sufficient temporal resolution of the moving heart. EBCT scanners have since been superseded by multidetector computed tomography (MDCT) (Mao et al, 2018). CAC provides a summary measure of atherosclerotic disease, reflecting the cumulative lifetime effect of both measurable (i.e., risk factors) and unmeasurable (i.e., all genetic and environmental factors) risk determinants directly on vulnerable tissue. CAC scoring has emerged as a widely available, consistent, and reproducible means of assessing risk of major cardiovascular outcomes, especially useful in asymptomatic people. Clinical practice guidelines in the USA and Europe consider CAC scoring to be a potentially useful way of improving cardiovascular risk assessment (Goff et al, 2014; Task Force Members, 2016). There is convincing evidence of a strong association between CAC and major cardiovascular outcomes in asymptomatic people (Agatson et al, 1990). Coronary artery calcification has emerged as the most predictive single cardiovascular risk marker in asymptomatic individuals, capable of adding predictive information beyond the traditional cardiovascular risk factors (Greenland et al, 2018).
A calcium score (sometimes called an Agatston score) is calculated based on the amount of plaque observed in the CT scan. It may be converted to a percentile rank based on your age and gender. Your likelihood of having heart disease or a heart attack correlates with your calcium scoring. CAC scores have been in clinical practice for more than a decade (Faggiano et al, 2019). High artery calcium scores are associated with increased cardiovascular events (Agatston et al, 1990; Vliegenthart et al, 2002; Wayhs et al, 2002; Kondos et al, 2003; Budoff et al, 2007), and consideration is being given to coronary artery calcification volume as well as density (Criqui et al, 2017). Research shows that a high calcium score and a high osteocalcin ration (OCR)-reflecting low vitamin K status–is associated with ucMGP in the blood (Nasir et al., 2010). In other words, people who have high calcium scores also tend to have uncarboxylated matrix Gla protein in their blood, meaning they are deficient in vitamin K.
Cardiovascular Disease and Vitamin K Antagonists
Many of the forces that induce arterial calcification may act by disrupting the essential post-translational modification of Matrix Gla Protein (MGP), allowing Bone Morphogenic Protein-2 (BMP-2) to induce mineralization. Vitamin K deficiency, as well as drugs that act as vitamin K antagonists, and oxidant stress are significant forces that could prevent the formation of GLA residues on MGP.
Vitamin K deficiency is clinically characterized by a bleeding tendency due to the loss of function of vitamin K-dependent clotting factors. Vitamin K deficiency is usually associated with specific conditions, such as gastrointestinal disorders, antibiotics, an extremely poor diet, or drug interactions, such as coumarin based anticoagulants such as warfarin.
Gastrointestinal disorders include celiac disease, cystic fibrosis, ulcerative colitis, cholestasis, short bowel syndrome, or bariatric surgical intervention. These conditions might lead to a situation of inadequate absorption of vitamin K, and ultimately, to the status of a deficiency.
Antibiotics also interfere with vitamin K levels since they generally contribute to a decrease of vitamin K-producing bacteria in the gut (Conley et al, 1994). Vitamin K deficiency is currently observed in patients with prolonged antibiotic therapy (Cinaz et al, 2011; Aziz et al, 2015; Chen et al, 2016). A case-control study showed that people taking antibiotics more than 48 hours had an increased risk of bleeding events (Conley et al 1994). Some medications also interfere with vitamin K absorption, such as drugs to reduce cholesterol or drugs for obesity treatment (Vroonhof et al, 2003; MacWalter et al, 2013).
Vitamin K antagonists (VKA), warfarin, are the most frequently prescribed drugs to control blood coagulation, and clotting of patients with thrombosis and patients at risk of thromboembolic events. Treatment with VKAs inhibit the vitamin K cycle and the synthesis of the vitamin K-dependent, biologically active clotting factors II, VI, IX, and X. A widely prescribed vitamin K antagonist is coumadin. The use of vitamin K antagonists represents a model of functional vitamin K insufficiency.
Common inconvenient effects of VKAs include unpredictable pharmacokinetics and pharmacodynamics, drug and food interactions, slow onset and offset of action, considerable inter-individual and intra-individual variability in dose response and a narrow therapeutic window. In addition, frequent laboratory monitoring and dose adjustments are needed to keep patients within the INR (International Normalized Ratio) target range (Shikdar et al, 2019). Research has established that supplementing with vitamin K can prevent some of the instability caused by warfarin and diet (Ferland et al, 2019).
VKA therapy may have undesired side-effects in addition to the risk of bleeding because a number of proteins outside the coagulation system also require γ-glutamylcarboxylation to become biologically active (Chatrou, et al., 2011; Schurgers et al. 2012) meaning that the therapy aimed to prevent blood clots also disrupts the effectiveness of vitamin K on the proteins that inhibit calcification in the vascular system and elsewhere in the human body. Directly VKA treatment inhibits the carboxylation of MGP, an inhibitor of arterial calcification, activated protein-c an inhibitor of inflammation and endothelial cell apoptosis, and osteocalcin that may regulate metabolic dysfunction and arterial calcification (Booth, Centi, et al, 2013), creating a vitamin K deficiency. This deficiency enhances calcification in the vascular tree, thereby accelerating vascular calcification, particularly in the aortic and mitral valve (Chatrou et al, 2012: Koos et al, 2009; Lerner et al, 2009; Chatrou et al, 2012; Schurgers et al, 2012; Yamamoto et al, 2015; Han et al, 2016; Andrews et al, 2018). One study compared warfarin patient users and non-users. They found that arterial calcification was 44% greater in the patients on warfarin therapy (Han et al, 2016). One study found that VKA therapy was associated with a 8.5 fold higher PIVKA-II and 3 fold higher dp-ucMGP levels, indicating that VKA therapy exacerbated vitamin K deficiencies, while vitamin K supplemented improved levels (Rapp et al, 2021).
Numerous clinical studies and case reports illustrate that VKA treatment is associated with arterial calcification and upregulation of uncarboxylated MGP (ucMGP) (Price et al, 1994; Schurgers, et al, 2004; Koos et al, 2005; Weijs, et al, 2011; Rennenberg et al, 2010; Hashmath et al, 2019). Other research showed that in animals, treatment with vitamin K antagonists (VKA) resulted in arterial calcification within two to four weeks. The administration of high doses of the vitamin K antagonist, warfarin, has been shown to induce rapid calcification of the elastic lamellae in rat arteries and heart valves (Price et al, 1998). Also, Price demonstrated that rats treated with warfarin doses that specifically inhibited MGP γ-carboxylation showed extensive vascular calcification and accumulation of ucMGP (Price et al 2000; Kruger et al 2013; Namba et al, 2017). Other animal studies suggest that VKA treatment causes medial calcification similar to Monckeberg’s sclerosis (Spronk etal 2003; Essalihi et al, 2003).
One study created calcification in rodents using warfarin. Some received a vitamin K treatment. They found that even after the warfarin was discontinued, the calcification continued to progress. Those who received the vitamin K treatment showed 60% less calcification (Jiang et al, 2016). Another study demonstrated that VKA treatment increased both progression and calcification of atherosclerotic plaques in mice as well as increased the plaque size (van Gorp et al, 2021).
Whereas in humans, it has been demonstrated that oral anticoagulant treatment (vitamin K antagonists) is associated with substantially increased heart valve calcification (Schurgers et al, 2004; Chatrou, 2011; Weijs, et al., 2011; Schurgers, et al., 2012; Demer & Bostrom, 2015; Han & O'Neill, 2016; Andrews et al, 2018). One study looked at aortic valves obtained from patients undergoing heart transplantation. Some had received preoperative treatment with vitamin K antagonists, and in those patients they had 2-fold greater aortic valve calcification compared to matched controls who did not receive warfarin (Schurgers et al, 2004). In humans, the detrimental effect of VKAs on extra-coronary calcification has been shown on a small cross-sectional study in patients on long-term oral coumarin treatment (Renenberg et al, 2010). In another cohort study assessing 430 patients, the presence of calcification in peripheral arteries was compared between warfarin patient users and non-users. In this study, the prevalence of arterial calcification was 44% greater in patients on warfarin therapy versus without warfarin use (Han et al, 2016).
Recently, a large population-based cohort study including individuals from the Gutenberg health study comprising 287 VKAs users and 14,564 VKAs non-users demonstrated that patients on VKAs therapy had a higher cardiovascular burden. In this study, the authors suggest a relation between VKAs use and several parameters of clinical and subclinical CVD, such as with increased arterial stiffness, decreased cardiac systolic function, and higher left ventricular mass. This study also shows an association and dose-response effect of VKAs intake with low grade systemic inflammation. This was shown by the high levels of high-sensitivity C-reactive protein (hsCRP) found in long-term VKAs users when compared with short-term VKAs intake users (Eggebrecht et al 2018).
A post hoc analysis reviewed eight prospective randomized trials, utilizing serial coronary intravascular ultrasound examinations. Changes in coronary atheroma burden were compared between patients with coronary artery disease patients treated with (n = 171) and without (n = 4129) warfarin for 18 to 24 months. In this study, the authors concluded that warfarin use was independently associated with serial coronary calcification with no association with renal function, statin therapy, or changes in atheroma volume (Andrews et al, 2018).
A cross-sectional observational study including 236 atrial fibrillation patients were divided in three groups, according to the type of anticoagulation therapy (no oral anticoagulation, VKAs or DOACs). The main findings of this study pointed toward an increased prevalence of calcification of the thoracic aorta in patients treated with VKAs when compared to patients with DOACs treatment (Peeters et al, 2018).
Thus, vitamin antagonists induce vascular calcification by inhibiting gamma-carboxylation of vitamin K-dependent proteins, leading to reduced anticalcific capacity (Tsai, et al, 2018; Han & O’Neill, 2016; Tantisattamo et al, 2015). A new meta-analysis found that vitamin K antagonists (VKA) are strongly associated with vascular and aortic calcification, setting the stage for creating or worsening cardiovascular disease (Kosciusek et al, 2022).
Since administration of vitamin K restores MGP γ-carboxylation and enhances the reversal of warfarin-induced calcification in rats (Schurgers et al, 2007), providing a supplement of vitamin K may become a critical treatment adjunct for people on warfarin, or VKA treatment (Westenfeld, et al., 2008; Homes, et al., 2012; Theuwissen, et al., 2013).
And recent research found that people taking hypertensives, such as ACE inhibitors, or thiazide diuretics, were significantly more likely to have extreme coronary artery calcification progression, when they had low levels of vitamin K1, as measured in their blood (Shea, et al 2013). One in five adults in the US are treated for hypertension and about half of adults in the US may have low vitamin K status, leading the researchers to call for additional studies to explore why medicine for high blood pressure is related to coronary artery calcification, when vitamin K intake is low.
Cardiovascular Disease Helped by Vitamin K
The research clearly indicates that adequate amounts of vitamin K can improve cardiovascular disease (Shoi et al, 2020; Vossen et al, 2020). Both forms of vitamin K have been proposed to influence cardiovascular health through many mechanisms, including the reduction of systemic inflammation (Shea et al, 2008; Viegas et al, 2017; Cavaco et al, 2015; Shioi et al, 2020), maintenance of hemostasis (Mackie & Bull, 1989) and the inhibition of arterial calcification (Shea et al, 2009; Vietal et al, 2009; Clauser et al, 2012; Viegas et al, 2015; O’Grady et al, 2018).
A meta-analysis, including 21 studies on different population cohorts totaling over 200,000 patients pointed out an association of vitamin K with cardiovascular events and all-cause mortality. Higher dietary vitamin K consumption was associated with a significantly lower risk of coronary artery disease (Chen et al, 2019). There is a growing line of research highlighting the profound benefits of vitamin K for cardiac health. In a study of a ten year follow up of 4,500 elderly subjects (the Rotterdam study cohort) Geleijnse demonstrated that vitamin K2 intake is inversely correlated with cardiovascular disease and mortality. The more vitamin K in a person’s diet, the lower the rate of cardiovascular disease. In the Rotterdam study, the highest quartile for K2 intake was 45 ug/day (Geleijnse, et al., 2004). Gast later confirmed the findings from the Rotterdam study with over 16,000 participants in the Prospect study. In that study, a high intake of vitamin K2, menaquinones, especially MK7, MK8 and MK9 protected against coronary heart disease, and of those, vitamin MK7 turned out to have the most beneficial effects on cardiovascular disease with a mortality risk reduction of 9% for each 10 ug/day of extra intake (Gast, et al., 2009). In the Hordaland Health Study, a higher intake of vitamin K2 was associated with lower risk of CHD (Haugsgjerd et al, 2020). Beaulen also found that high intakes of menaquinone were associated with decreased risk of coronary calcification (Beulens et al, 2009). In the LASA study (Longitudinal Aging Study Amsterdam), vitamin K insufficiency was significantly associated with a higher incidence of first cardiovascular events in a large group of healthy elderly people (Van den Heuvel et al, 2014). A study in Japan found that coronary artery calcification correlated with markers of chronic vitamin K insufficiency (Torii et al, 2016). A large community based prospective study of participants in the Japan Collaborative Cohort study (JACC) found that higher dietary intakes of fat soluble vitamins K, E, and D were associated with a reduced risk of mortality from heart failure among Japanese women, but not men (Eshak et al, 2018). In the Danish Diet, Cancer, and Healthy Study, 53,372 Danish citizens were followed for 17-22 years of follow up. Participants with the highest intakes of vitamin K1 had a 21% lower risk of atherosclerotic cardiovascular disease hospitalization, and participants with the highest intakes of vitamin K2 had a 14% lower risk for hospitalization. The association between both forms of vitamin K and vascular disease was present for all subtypes, including ischemic stroke, peripheral artery disease and ischemic heart disease (Bellinge et al, 2021).
Knapen (et al, 2015) showed that supplementing with 180 ug of MK7 over three years significantly improved arterial stiffness, and other vascular measures in healthy, postmenopausal women. A second intervention trial was conducted with the same group of women, as well as men, people at an elevated risk for cardiovascular disease based on vitamin K insufficiency. They found both vitamin K status and carotid pulse wave velocity (the gold standard for arterial elasticity) were both favorably affected by MK7 after a year. The effects were mainly seen in the postmenopausal women (Vermeer & Vik, 2020). A recent study by Ikari (et al, 2020) found that replacing warfarin which interferes with vitamin K, significantly reduced arterial stiffness in the brachial-ankle vein. The improved availability of vitamin K led to improved arterial stiffness.
Visser et al (2016) showed that high intake of menaquinones was associated with a reduced risk of peripheral artery disease (PAD). Brandenburg (et al, 2017) showed in a controlled trial, that men who received vitamin K over a twelve month period had only a 10% progression in their aortic valve calcification score versus other men who had a 22% progression in their score. A recent study showed that atherosclerotic cardiovascular disease (ASCVD) was inversely associated with diets high in vitamin K1 or K2. In other words, there was a greater risk of disease if you had a low intake of vitamin K. Folks with the highest K1 intake had a 14% lower risk of ischemic heart disease, a 17% lower risk of stroke, and a 34% lower risk of a PAD-related hospitalization. This was true for intakes of both K1 and K2 (Bellinge et al, 2021).
A meta-analysis of cohort studies indicated that individuals presenting with measures of vitamin K insufficiency (dp-ucMGP) have a significantly higher mortality risk (Seidlerova et al, 2016; Zhang et al, 2019), and that it is predictive for total, non-cancer and cardiovascular mortality in a Flemish population (Liu et al, 2015). A study of patients with acute coronary syndrome showed they had a higher dp-ucMGP levels, which likely reflected a higher calcification burden and might aid in identifying patients at an increased risk of in-hospital mortality (Bilalic et al, 2021). A study of 894 patients found that they had high dp-ucMGP at least six months after a cardiac event, which was associated with a 2.4 to 3.5 higher risk of 5 year all cause mortality and cardiovascular mortality, respectively (Mayer et al, 2014). And an analysis of subjects in the PREVEND study found that 31% had a functional vitamin K insufficiency as measured by dp-ucMGP, with a significantly higher prevalence among subjects with type 2 diabetes, chronic kidney disease and cardiovascular disease (Riphagen et al, 2017). Thamratnopkoon (2017) found that plasma dp-ucMGP levels increase as CKD advances with the highest levels found in CKD stage 5.
Vitamin K has been shown to function as an anti-inflammatory factor, independent of its activity as a cofactor for GGCX. Vitamin K status was inversely associated with circulating markers of inflammation such as C-reactive protein (CRP) (Shea, Booth et al, 2008; Shea, Dallal et al, 2008; Shea et al, 2014), and it attentuates other inflammatory responses (Ohsaki et al, 2010; Pan et al, 2016). Atherosclerosis, Type 2 diabetes, and chronic kidney disease are chronic inflammatory diseases, typically resulting in vascular calcification. Vitamin K attenuated lipopolysaccharide (LPS)-induced inflammatory responses by blocking nuclear factor κB (NF-κB) signal transduction (Ohsaki et al, 2010; Pan et al, 2016). Vitamin K has been shown to have a protective effect against that calcification (Harshman & Shea, 2016).
During the last two decades it has been clear that vitamin K is needed for other physiological processes than blood clotting, and that it plays an important role in inhibiting vascular calcification (Lees et al, 2019). It seems however, that our dietary vitamin K intake is too low to support the carboxylation of at least some of the Gla Proteins. Unfortunately for most of the western population, our vitamin K intake from our diet is too low and the vitamin K requirement of the vascular system is not met, meaning that vitamin K supplements are required for optimal vascular health (Palmer et al, 2013).
According to the triage theory, when diet is poor, vitamins are preferentially utilized for immediate survival. In a healthy population, clotting factors are the first order of survival and vitamins are preferentially utilized for clotting first, with other bodily needs being deferred. When vitamin K is amply available, either through diet or nutritional supplements, those other body and health needs can be met. This means that long-term vitamin K inadequacy is a modifiable risk factor for the development of degenerative diseases including atheroslcerosis, osteoporosis, and cancer (Vermeer and Theuwissen, 2011; Vermeer, 2012).
Other research has indicated that a deficiency of vitamin K intake in adolescent is linked to later cardiac structure and function (Douthit et al, 2017).
And most exciting is that clinical trials are underway (Lindhilt et al, 2018). INTRICATE is a prospective double-blind placebo-controlled feasibility study, assessing the influence of combined vitamin k2 and vitamin D supplementaiton on micro-calcificaiton in carotid artery disease (Florea, et al, 2021). A recent trial was published showing that coronary artery calcium could be reversed using a functional medicine protocol, which included vitamins MK4 and MK7, magnesium, and vitamin D, as well as avoiding inflammatory foods, and no prescription medications (Moran, 2021).
One can take vitamin K and reduce the chances of heart disease. And one can take large amounts of vitamin K at a therapeutic dosage level and reduce the chances of heart disease without any identified health risk (Popa et al, 2021). In other words, vitamin K is absorbed readily and easily by the body, without the risk from the medications often prescribed for heart disease, and without the risk of the surgeries often performed as an intervention for heart disease. And at the same time, the vitamin K you take in the form of Koncentrated K can help ward off other disease processes that are linked to vitamin K deficiency.
The research cited below explores the link between forms of vitamin K and cardiovascular health. The research presents some of the key discoveries over the past decades, the changing understanding of the process of heart disease, and the growing awareness of the vascular-bone axis and the role of vitamin K in managing calcium within the body (Brandenburg et al 2015). It is exciting stuff and it is thrilling to consider how much vitamin K can change your life!
Keep in mind, vascular calcification is a highly-controlled multifactorial process that requires constant inhibition!
Dam, H. The antihaemorrhagic vitamin of the chick: Occurrence and chemical nature. Nature. 1935;135(3417):652-653.
Nelsestuen, GL, and Suttie, JW. The purification and properties of an abnormal prothrombin protein produced by dicumarol-treated cows: A comparison to normal prothrombin. J. Biol. Chem. 1972; 247:8176-82.
Esmon, CT, Sadowski, JA, and Suttie, JW. 1975. A new carboxylation reaction. The vitamin K-dependent incorporation of H14Co3 into prothrombin. J Biol. Chem. 1975;250:4744-48.
Early on there was little information about the functional role of vitamin K or its mechanism of action. This early research elucidated the role of vitamin K as a cofactor in glutamate carboxylation in prothrombin.
Esmon, CT and Suttie, JW. Vitamin K-dependent carboxylase. Solubilization and properties. J. Biol. Chem. 1976;251:6238-43.
Levy RJ, Lian JB, Gallop PM. Ý-carboxyglutamic acid and atherosclerotic plaque. In Suttie JW, editor. Vitamin K Metabolism and Vitamin K-Dependent Proteins. University Park Press; Baltimore, 1980. p 269-73.
This research team demonstrated for the first time, the presence of a Gla containing protein, (influenced by vitamin K) in atherosclerotic plaque, which they named atherocalcin. They believed that the functional significance of this finding was of great importance. At that time, they wondered whether the circulating levels of the Gla protein might correlate with disease status, and function as a clinical parameter.
Suttie JW. Vitamin K metabolism and vitamin K-dependent proteins. Baltimore: University Park Press; 1980.
Fraser JD, Price PA. Lung, heart, and kidney express high levels of mRNA for the vitamin K-dependent matrix Gla protein. Implications for the possible functions of matrix Gla protein and for the tissue distribution of the gamma-carboxylase. J Biol Chem. 1988;263:11033-36.
Van Haarlem LJM. Biosynthesis, occurrence and characterization of Gla-containing proteins with a potential importance for cardiovascular diseases. [Ph.D. thesis]. Netherlands: University of Limburg Maastricht; 1989.
Agatston AS, Janowitz WR, Hildner FJ, et al. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol. 1990;15:827-32.
Ultrafast computed tomography was used to detect and quantify coronary artery calcium levels in 584 subjects (mean age 48 +/- 10 years) with (n = 109) and without (n = 475) clinical coronary artery disease. Fifty patients who underwent fluoroscopy and ultrafast computed tomography were also evaluated. Twenty contiguous 3 mm slices were obtained of the proximal coronary arteries. Total calcium scores were calculated based on the number, areas and peak Hounsfield computed tomographic numbers of the calcific lesions detected. In 88 subjects scored by two readers independently, interobserver agreement was excellent with identical total scores obtained in 70. Ultrafast computed tomography was more sensitive than fluoroscopy, detecting coronary calcium in 90% versus 52% of patients. There were significant differences (p less than 0.0001) in mean total calcium scores for those with versus those without clinical coronary artery disease by decade: 5 versus 132, age 30 to 39 years; 27 versus 291, age 40 to 49 years; 83 versus 462, age 50 to 59 years; and 187 versus 786, age 60 to 69 years. Ultrafast computed tomography is an excellent tool for detecting and quantifying coronary artery calcium.
Davies M.J. A macro and microview of coronary vascular insult in ischemic heart disease. Circulation. 1990;82(suppl II):II38-46.
Gijsbers BLMG, van Haarlem LJM, Soute, BAM, Ebberink RHM, Vermeer C. Characterization of a GLA-containing protein from calcified human atherosclerotic plaques. Arteriosclerosis. 1990;10:991.
Schor AM, Allen TD, Canfield AE, Sloan P, Schor SL. Pericytes derived from the retinal microvasculature undergo calcification in vitro. J Cell Sci. 1990;97:449-61.
Bolton-Smith C. Vitamin K. In: James WPT and Garrow JS, Editors. Human nutrition and dietetics. Edinburgh: Churchill Livingstone; 1993. P. 208-38.
Bostrom K, Watson KE, Horn S, Wortham C, Herman IM, Demer LL. Bone morphogenetic protein expression in human atherosclerotic lesions. J Clin Invest. 1993;91:1800-9.
Price PA, Rice JS, Williamson MK. Conserved phosphorylation of serines in the Ser-X-Glu/Ser(P) sequences of the vitamin K-dependent matrix Gla protein from shark, lamb, rat, cow, and human. Protein Sci. 1994 May;3(5):822-30.
Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL. High expression of genes for calcification-regulating proteins in human atherosclerotic plaques. J. Clin Invest. 1994 Jun;93(6):2393-402.
Calcification is common in atheromatous plaques and may contribute to plaque rupture and subsequent thrombosis. Little is known about the mechanisms which regulate the calcification process. The study shows that high levels of osteopontin and MGP were found in association with necrotic lipid cores and areas of calcification. The predominant cell type was the macrophage-derived foam cell. The postulated function of OP and MGP as regulators of calcification in bone and the high levels and co-localization of both in plaques, suggest they have an important role in plaque pathogenesis and stability.
Jie KS, Bots ML, Vermeer C, Witteman JC, Grobbee DE. Vitamin K intake and osteocalcin levels in women with and without aortic atherosclerosis: A population based study. Atherosclerosis. 1995;116(1):117-123.
A population-based study of postmenopausal women, aged 60-79 years, found that women aged 60-69 with aortic calcifications had lower vitamin K intakes than those without aortic calcifications.
Shearer, MJ. Vitamin K. Lancet. 1995;345(8944):229-34.
Davies M.J. Stability and instability: two faces of coronary atherosclerosis. Circulation. 1996;94:2013–20.
Sokoll LJ, Booth SL, O’Brien ME, Davidson KW, Tsaioun KI, Sadowski JA. Changes in serum osteocalcin, plasma phylloquinone, and urinary carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr. 1997;65:779-84.
Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G. Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein. Nature. 1997 Mar 6;386(6620):78-81.
Matrix GLA protein (MGP), is a mineral binding extracellular matrix (ECM) protein synthesized by vascular smooth-muscle cells and chondrocytes, two cell types that produce an uncalcified ECM. Mice that lack MGP die as a result of arterial calcification which leads to blood vessel rupture. Additionally they exhibit inappropriate calcification of various cartilages, include the growth plate. This study demonstrates the importance of MGP for vascular health. Sufficient quantities of Vitamin K in the body are necessary for the activation of MGP in the body.
Ferland G. The vitamin K-dependent proteins: An update. Nutr. Review. 1998;56(8):223-30.
Historically known for its role in blood coagulation, vitamin K also has been shown to be required for the activation of numerous proteins that are not involved in hemostasis. Over the last 20 years, vitamin K–dependent proteins have been isolated in bone, cartilage, kidney, atheromatous plaque, and numerous soft issues. Although the precise mechanism of action remains to be determined, the discovery of these proteins has proven important from a physiologic point of view.
Price P, Faus S, Williamson M. Warfarin causes rapid calcification of the elastic lameliae in rat arteries and heart valves. Arterioscler Thromb Vasc Biol. 1998;18:1400-07.
High doses of warfarin cause focal calcification of the elastic lamellae in the media of major arteries and in aortic heart valves in the rat. Aortic calcification was first seen after 2 weeks of warfarin treatment and progressively increased in density at 3, 4, and 5 weeks of treatment. By 5 weeks, the highly focal calcification of major arteries could be seen on radiographs and by visual inspection of the artery. The calcification of arteries induced by warfarin is similar to that seen in the matrix Gla protein (MGP)–deficient mouse, which suggests that warfarin induces artery calcification by inhibiting gamma-carboxylation of MGP and thereby inactivating the putative calcification-inhibitory activity of the protein. Warfarin treatment markedly increased the levels of MGP mRNA and protein in calcifying arteries and decreased the level of MGP in serum.
Proudfoot D, Skepper JN, Shanahan CM, Weissberg PL. Calcification of human vascular cells in vitro is correlated with high levels of matrix Gla protein and low levels of osteopontin expression. Arterioscler Thromb Vasc Biol. 1998;18:379-88.
The cellular and molecular events leading to calcification in atherosclerotic lesions are unknown. They and others have shown that bone-associated proteins, particularly matrix Gla protein (MGP) and osteopontin (OP), can be detected in atherosclerotic lesions, thus suggesting an active calcification process. In the present study, they aimed to determine whether human vascular smooth muscle cells (VSMCs) could calcify in vitro and to determine whether MGP and OP have a role in vascular calcification. We established that human aortic VSMCs and placental microvascular pericytes spontaneously form nodules in cell culture and induce calcification. These studies reveal that human VSMCs are capable of inducing calcification and that MGP may have a role in human vascular calcification.
Sangiorgi G, Rumberger JA, Severson A, Edwards WD, Gregoire J, Fitzpatrick LA, Schwartz RS. Arterial calcification and not lumen stenosis is highly correlated with atherosclerotic plaque burden in humans: A histologic study of 723 coronary artery segments using nondecalcifying methodology. J Am Coll Cardiol. 1998;31:126–133.
Shanahan CM, Proudfoot D, Farzaneh-Far A, Weissberg PL. The role of Gla proteins in vascular calcification. Crit Rev Eukaryot Gene Rxpr. 1998:8(304):357-75.
Arterial calcification occurs with increasing age and in association with a diverse range of diseases, including atherosclerosis, diabetes, and uremia. Evidence is accumulating that vascular calcification is an active process that has many similarities with ossification, including local expression of bone-associated collagenous and noncollagenous proteins. Gla-containing proteins which respond to Vitamin K, which have the potential to regulate or contribute to vascular calcification are present in the human vasculature.
Furie B, Bouchard BA, Furie BC. Vitamin K-dependent biosynthesis of gamma-carboxyglutamic acid. Blood. 1999:93(6):1798-08.
Vitamin K, an essential vitamin, is a cofactor for a single known enzymatic reaction: the conversion of glutamic acid to γ-carboxyglutamic acid in vitamin K-dependent proteins during their biosynthesis. Since the discovery of vitamin K and its association with blood coagulation, many milestones have been passed on the road to understanding the biological role of vitamin K. Important early landmarks include the discovery of vitamin K antagonists and their introduction as pharmacologic agents for anticoagulation; the discovery of γ-carboxyglutamic acid in blood clotting proteins; the detection of an enzymatic activity (ie, the vitamin K-dependent γ-glutamyl-carboxylase) that catalyzes the incorporation of CO2 into glutamic acid. Because carboxylase activity is found in essentially all mammalian tissues and because γ-carboxyglutamic acid has been observed in both vertebrates and invertebrates, this amino acid must play an important biological role in protein function. The biosynthesis of γ-carboxyglutamic acid is the topic of this review.
Ross R, Atherosclerosis-an inflammatory disease. NEJM. 1999;340:115-26.
Seyama Y, et al, Comparative effects of vitamin K2 and vitamin E on experimental arteriosclerosis. Int J Vitamin Nutr Res. 1999 Jan;69(1):23-6.
Vitamin K deficiency appears to play a role in the development of osteoporosis and in the deposition of calcium into blood vessels.
Shanahan CM, Cary NR, Salisbury JR, Proudfoot D, Weisserg PL, Edmonds ME. Medial localization of mineralization-regulating proteins in association with Monckeberg’s sclerosis: evidence for smooth muscle cell-mediated vascular calcification. Circulation. 1999;100:2168-76.
The study showed that matrix Gla protein (MGP) is highly upregulated in Vascular Smooth Muscle Cells adjacent to sites of calcification. This finding led to the proposal of a feedback mechanism in which VSMCs sense neighboring calcification and upregulate MGP to attempt calcium clearance.
Tsaioun KI. Vitamin K-dependent proteins in the developing and aging nervous system. Nutr. Rev. 1999;57(8):231-40.
Although the warfarin embryopathy syndrome, with its neurologic and bone abnormalities, has been known for decades, the role of vitamin K in the brain has not been studied systematically. Recently, it was demonstrated that vitamin K-dependent carboxylase expression is temporally regulated in a tissue-specific manner with high expression in the nervous system during the early embryonic stages and with liver expression after birth and in adult animals. This finding, along with the discovery of wide distribution of the novel vitamin K-dependent growth factor, Gas6, in the central nervous system, provides compelling evidence of a biologic role of vitamin K during the development of the nervous system. Hence, the knowledge of the biologic role of vitamin K in the brain may be important for unveiling the mechanisms of normal and pathologic development and aging of the nervous system. The role of the vitamin K-dependent protein Gas6 in activation of signal transduction events in the brain, in light of the age-related changes in the nervous system is also discussed.
Arad Y, Spadaro LA, Goodman K, Newstein D, Guerci AD. Prediction of coronary events with electron beam computed tomography. J Am Coll Cardiol. 2000;36:1253-60.
Bostrom KI. Cell differentiation in vascular calcification. Z Kardiol. 2000;89:69-74.
Ectopic tissue formation is commonly found in calcified atherosclerotic plaques. This suggests that cell differentiation plays an important role in vascular calcification, even though the origin of the cells involved is unclear. Calcifying vascular cells (CVCs), have many characteristics in common with bone cells, but there are also differences suggesting mechanisms applicable to the problem of osteoporosis may be active in the setting of vascular calcification. Matrix GLA protein (MGP) deficient mice develop severe vascular calcification and die prematurely from heart failure and/or aortic rupture. It has been hypothesized that MGP acts as a calcification inhibitor by binding calcium, preventing mineral deposition in extracellular fluids near the saturation point for calcium and phosphate. Alternatively, MGP expression may be an attempt to regulate cell differentiation in the vascular wall, possibly by acting as an inhibitor to a factor able to induce cartilage and bone such as bone morphogenetic proteins (BMPs).
Campbell GR, Campbell J. Vascular smooth muscle and arterial calcification. Z Kardiol. 2000;89:54-62.
Smooth muscle cultures can calcify under certain circumstances. As a model system these cultures therefore provide information on why calcification occurs in atherosclerotic plaques. Whether all smooth muscle cells (under certain conditions), or only specific populations, can produce this mineralization has not been resolved. Demer's group has cloned calcifying vascular cells from subcultured bovine aorta and studied them in detail. The article argues that while the normal process of smooth muscle phenotypic modulation seen in arterial repair could account for the observations, this view may be too simplistic considering the complex nature of the artery wall. Certainly there is evidence for heterogeneity of smooth muscle cells in the artery wall and recent evidence suggests that stem cells can circulate in the blood and repopulate tissues. Further studies are required to resolve the important question as to the origin of cells which produce mineralization in atheroma.
Canfield AE, Doherty MJ, Wood AC, Farrington C, Ashton B, Begum N, et al. Role of pericytes in vascular calcification: a review. Z Kardiol. 2000;89 Suppl. 2):20-7.
Herrmann SM, Whatling C, Brand E, et al. Polymorphisms of the human matrix Gla protein (MGP) gene, vascular calcification, and myocardial infarction. Arterioscler Thromb Vasc Biol. 2000;20:2386–93.
Howe AM, Webster WS. Warfarin exposure and calcification of the arterial system in the rat. Int J Exp Pathol. 2000;81:51-56.
There is evidence from knock-out mice that the extrahepatic vitamin K-dependent protein, matrix gla protein, is necessary to prevent arterial calcification. The aim of this study was to determine if a warfarin treatment regimen in rats, designed to cause extra-hepatic vitamin K deficiency, would also cause arterial calcification. At the end of treatment the rats were killed and the vascular system was examined for evidence of calcification. All treated animals showed extensive arterial calcification. The cerebral arteries and the veins and capillaries did not appear to be affected. It is likely that humans on long-term warfarin treatment have extrahepatic vitamin K deficiency and hence they are potentially at increased risk of developing arterial calcification.
Price PA, Faus SA, Williamson MK. Warfarin-induced artery calcification is accelerated by growth and vitamin D. Arterioscler Thromb Vasc Biol. 2000;20:317-27.
The present studies demonstrate that growth and vitamin D treatment enhance and expand the artery calcification in rats given sufficient doses of Warfarin to inhibit gamma-carboxylation of matrix Gla protein, a calcification inhibitor. Treatment for 2 weeks with Warfarin caused massive focal calcification of the artery media in 20-day-old rats and less extensive focal calcification in 42-day-old rats. In contrast, no artery calcification could be detected in 10-month-old adult rats even after 4 weeks of Warfarin treatment. This observation suggests that increased susceptibility to Warfarin-induced artery calcification could be related to higher serum phosphate levels. The second set of experiments examined the possible synergy between vitamin D and Warfarin in artery calcification. Because Warfarin treatment had no effect on the elevation in serum calcium produced by vitamin D, the synergy between Warfarin and vitamin D is probably best explained by the hypothesis that Warfarin inhibits the activity of matrix Gla protein as a calcification inhibitor
Schinke T, Karsenty G. Vascular calcification – a passive process in need of inhibitors. Nephrol Dial Transplant. 2000;15:1272-4.
Mouse genetic studies have significantly improved our understanding of vascular calcification. Important information comes mostly from the knockout of MgP (Matrix Gla Protein): vascular calcification is a passive process that requires active inhibition. MgP is the molecule that is responsible for this inhibition in mice. Although the importance of MgP to prevent arterial calcification in humans has not been clearly established yet, theoretically it seems that up-regulating MgP expression in human arteries could be beneficial to prevent atherosclerotic calcification. MgP needs vitamin K to be fully effective in inhibiting calcification.
Schurgers LJ, Vermeer C. Determination of phylloquinone and menaquinones in food. Effect of food matrix on circulating vitamin K concentrations. Haemostasis. 2000 Nov-Dec;30(6):298-7.
To investigate the effect of the food matrix on vitamin K bioavailability, 6 healthy male volunteers consumed either a detergent-solubilized K(1) (3.5 micromol) or a meal consisting 400 g of spinach (3.5 micromol K(1)) and 200 g of natto (3.1 micromol K(2)). The absorption of pure K(1) was faster than that of food-bound K vitamins (serum peak values at 4 h vs. 6 h after ingestion). Moreover, circulating K(2) concentrations after the consumption of natto were about 10 times higher than those of K(1) after eating spinach. It is concluded that the contribution of K(2) vitamins (menaquinones) to the human vitamin K status is presently underestimated, and that their potential interference with oral anticoagulant treatment needs to be investigated.
Shanahan CM, Proudfoot D, Tyson KL, Cary NR, Edmonds M, Weissberg PL. Expression of mineralization-regulating proteins in association with human vascular calcification. Z Kardiol. 2000;89:63-8.
A number of studies have documented expression of mineralisation-regulating proteins in association with human atherosclerotic calcification leading to the suggestion that human vascular calcification may be a regulated process with similarities to developmental osteogenesis. These studies imply that both medial and intimal vascular calcification are regulated processes; however the aetiology of each pathology differs.
Shearer MJ. Role of vitamin K and Gla proteins in the pathophysiology of osteoporosis and vascular calcification. Curr Opin Clin Nutr Metab Care. 2000;3:433-38.
Among the proteins known or suspected to be involved in bone and vascular biology are several members of the vitamin K-dependent or Gla protein family. This review focuses on the role of two of these: osteocalcin and matrix Gla protein. Osteocalcin metabolism has been implicated in the pathogenesis of osteoporosis through an unknown mechanism that may be linked to suboptimal vitamin K status resulting in its undercarboxylation and presumed dysfunction. It has been recently determined that matrix Gla protein functions as a powerful inhibitor of calcification of arteries and cartilage.
Vermeer C, Schurgers LJ. A comprehensive review of vitamin K and vitamin K antagonists. Hematol Oncol Clin North Am. 2000 Apr;14(2):339-53.
Vitamin K is involved in many physiologic processes and recommended daily allowances must be redefined. According to a new consideration, a substantial part of the population is mildly deficient in vitamin K, and at later ages this deficiency may contribute to increased bone fracture risk, arterial calcification, and cardiovascular disease.
Booth SL, Lichtenstein AH, O’Brien-Morse M, et al. Effects of a hydrogenated form of vitamin K on bone formation and resorption. Am J Clin Nutr. 2001;74(6):783-90.
Hydrogenation of vegetable oils affects blood lipid and lipoprotein concentrations. However, little is known about the effects of hydrogenation on other components, such as vitamin K. Low phylloquinone (vitamin K1) intake is a potential risk factor for bone fracture, although the mechanisms of this are unknown. The objective was to compare the biological effects of phylloquinone and its hydrogenated form, dihydrophylloquinone, on vitamin K status and markers of bone formation and resorption. In a randomized crossover study, 15 young adults were fed a phylloquinone-restricted diet (10 microg/d) for 15 days followed by 10 days of repletion (200 microg/d) with either phylloquinone or dihydrophylloquinone. In comparison with phylloquinone, dihydrophylloquinone was less absorbed and had no measurable biological effect on measures of bone formation and resorption. Hydrogenation of plant oils appears to decrease the absorption and biological effect of vitamin K in bone.
Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, et al. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001;21:1998-03.
Analysis of normal vs. atherosclerotic human tissue shows constitutive expression of MGP in the vessel wall that is sustained during calcification.
Glass CK, Witztum JL. Atherosclerosis: The road ahead. Cell. 2001;104:503-16.
An article that reviews a narrow aspect of the research on atherosclerosis, and manages to never mention the burgeoning research on the vitamin K families and their relationship to calcification, coronary artery disease, and vitamin K dependent proteins. A remarkably restricted ‘road’ they seek to travel within medicine…
Huang H, Virmani R, Younis H, Burke A, Kamm R, et al. The impact of calcification on the biomechanical stability of atherosclerotic plaques. Circulation. 2001;103:1051-56.
Hendler SS, Rorvik DR, eds. PDR for Nutritional Supplements. Montvale: Medical Economics Company, Inc; 2001.
Kaneki M, Hodges, SJ, Hosoi T, Fukiwara S, Lyons A, Crean SJ, et al. Japanese fermented soybean food as the major determinant of the large geographic difference in circulating levels of vitamin K2: possible implications for hip-fracture risk. Nutrition. 2001:17(4):315-21.
Increasing evidence indicates a significant role for vitamin K in bone metabolism and osteoporosis. In this study, we investigated the effect of Japanese fermented soybean food, natto, on serum vitamin K levels. We analyzed the relation between the regional difference in natto intake and fracture incidence. A statistically significant inverse correlation was found between incidence of hip fractures in women and natto consumption in each prefecture throughout Japan. These findings suggest the possibility that higher MK-7 levels resulting from natto consumption may contribute to the relatively lower fracture risk in Japanese women.
Keelan PC, Bielak LF, Ashai K, Jamjoum LS, Denktas AE, Rumberger JA, et al. Long-term prognostic value of coronary calcification detected by electron-beam computed tomography in patients undergoing coronary angiography. Circulation. 2001; 104:412-17.
Schurgers LJ, Dissel PE, Spronk HM, et al. Role of vitamin K and vitamin K-dependent proteins in vascular calcification. Z Kardiol. 2001;90 Suppl 3:57-61.
Vitamin K has a key function in the synthesis of at least two proteins involved in calcium and bone metabolism, namely osteocalcin and matrix Gla-protein (MGP). MGP was shown to be a strong inhibitor of vascular calcification. Some hypothesized that insufficient dietary vitamin K nutritional status results in inadequate carboxylation and, presumably, inactive MGP. Accumulating data suggest that extrahepatic tissues such as bone and vessel walls require higher dietary intakes and have a preference for menaquinone rather than for phylloquinone. Thus, insufficient dietary vitamin K and undercarboxylation of MGP is a risk factor for vascular calcification and that the present recommended daily allowance values are too low to ensure full carboxylation of MGP.
Spronk HM, Soute BA, Schurgers LJ, Cleutjens JP, Thijssen HH, De Mey JG, Vermeer C. Matrix Gla protein accumulates at the border of regions of calcification and normal tissue in the media of the arterial vessel wall. Biochem Biophys Res Commun. 2001 Nov 30;289(2):485-90.
Vitamin K-dependent matrix Gla protein (MGP) has been suggested to play a role in the inhibition of soft-tissue calcification. Their data demonstrate the close association between MGP and calcification. It is suggested that undercarboxylated MGP is biologically inactive and that poor vascular vitamin K status that results, may form a risk factor for vascular calcification.
Tintut Y, Demers LL. Recent advances in multifactorial vascular calcification. Current Opinion in Lipidology. 2001;12(5):555-60.
Vermeer C, Braam L. Role of K vitamins in the regulation of tissue calcification. J Bone Miner Metab. 2001;19:201-6.
Dietary menaquinones may be more efficiently absorbed than phylloquinone, leading to the proposal that even though phylloquinone comprises a large amount of vitamin K intake, phlloquinone and menaquinones may both contribute similarly to nutriture.
Schurgers LJ, Vermeer C. Differential lipoprotein transport pathways of K-vitamins in healthy subjects. Biochim Biophys Acta. 2002 Feb 15;1570(1):27-32.
Following intestinal absorption of K1 and K2, the serum transport of these lipophilic compounds to their target tissues take place via lipoproteins. During the first four hours after intake all K-vitamins were found to be associated with triacylglycerol-rich lipoprotein (TGLRP). This suggests that initially most of the K-vitamins are transported to the liver. However, both menaquinones were found in TGRLP and low-density lipoproteins, and MK4 was even present in high density lipoprotein. It explains why menaquinones may have a relatively large impact on extra hepatic vitamin K status than generally assumed, and that MK7 may form a more constant source of vitamin K.
Schurgers LJ, Shearer MJ, Soute BA, Elmadfa I, Harvey J, Wagner KH, et al. Novel effects of diets enriched with corn oil or with an olive oil/sunflower oil mixture on vitamin K metabolism and vitamin K-dependent proteins in young men. J Lipid Res. 2002 Jun;43(6):878-84.
They concluded that both oils affected vitamin K absorption and/or metabolism which may increase the requirements for gamma-carboxylation.
Shoji S. Vitamin K and vascular calcification. Clin Calcium. 2002 Aug;12(8):1123-8.
The role of vitamin K in the synthesis of some coagulation factors is well known. The implication of vitamin K in vascular health was demonstrated in many surveys and studies conducted over the past years on the vitamin K-dependent proteins non-involved in coagulation processes. The vitamin K-dependent matrix Gla protein is a potent inhibitor of the arterial calcification, and may become a non-invasive biochemical marker for vascular calcification. Vitamin K(2) is considered to be more important for vascular system, if compared to vitamin K(1).
Vliegenthart R, Hollander M, Breteler MM, van der Kulp DA, Hofman A, Oudkerk M, et al. Stroke is associated with coronary calcification as detected by electron-beam CT: the Rotterdam Coronary Calcification Study. Stroke. 2002;33:462-465.
Wayhs R, Zelinger A, Raggi P. High coronary artery calcium scores pose an extremely elevated risk for hard events. J Am Coll Cardiol. 2002;39:225-30.
We sought to assess the natural history of a cohort of asymptomatic individuals with very high (> or = 1,000) calcium scores (CSs) on a screening electron beam tomography (EBT). We also compared our prospective cohort with that of historical controls with severe abnormalities on myocardial perfusion imaging (MPI). Coronary calcium detected on EBT imaging has been shown to correlate with the total plaque burden. Ninety-eight asymptomatic subjects were followed for an average of 17 +/- 11 months for the occurrence of hard coronary events (HCEs), defined as myocardial infarction or coronary death. All patients had an initial calcium score > or = 1,000. During the follow-up period, 35 patients (36%) suffered an HCE. All events were recorded in the first 28 months of follow-up. A high Calcium Score (> or = 1,000) on a screening EBT in an asymptomatic person portends a very high risk of an Hard Coronary Event in the short term.
Booth SL, Martini L, Peterson JW, Saltzman E, Dallal GE, Wood RJ. Dietary phylloquinone depletion and repletion in older women. J Nutr. 2003;133:2565-69.
Biological markers indicative of poor vitamin K status have been associated with a greater risk for hip fracture in older men and women. However, the dietary phylloquinone intake required to achieve maximal carboxylation of hepatic and extrahepatic vitamin K–dependent proteins is not known. In an 84 day study in a metabolic unit, 21 older (60–80 y) women were fed a phylloquinone-restricted diet (18 μg/d) for 28 days, followed by stepwise repletion of 86, 200 and 450 μg/d of phylloquinone. The γ-carboxylation of prothrombin was restored to normal levels in response to phylloquinone supplementation at 200 μg/day. In contrast, all other biochemical markers of vitamin K status remained below normal levels after short-term supplementation of up to 450 μg/day of phylloquinone. These data support previous observations in rats that hepatic vitamin K–dependent proteins have preferential utilization of phylloquinone in response to phylloquinone dietary restriction. Moreover, our findings suggest that the current recommended Adequate Intake levels of vitamin K (90 μg/d) in women do not support maximal osteocalcin γ-carboxylation in older women.
Doherty TM, Asota K, Fitzpatrick LA, Qiao J-H, Wilkin DJ, Detrano RC, et al. Calcification in atherosclerosis: Bone biology and chronic inflammation at the arterial crossroads. Proc Natl Acad Sci. 2003;100:11201-206.
Essalihi R, Dao H, Yamaguchi N, Moreau P. A new model of isolated systolic hypertension induced by chronic warfarin and vitamin K1 treatment. Am J Hypertens. 2003;16:103-10.
El-Maadawy A, Kaartinen MT, Schinke T, Murshed M, Karsenty G, McKee MD. Cartilage formation and calcification in arteries of mice lacking matrix Gla protein. Connect Tissue Res. 2003;44 Supple 1:272-9.
Matrix Gla protein (MGP) is a protein expressed predominantly by vascular smooth muscle cells and by chrondrocytes. Mice lacking MGP die after 1-3 months due to calcification of elastic fibers and the rupture of large elastic arteries such as the aorta. This study provides evidence that the absence of MGP triggers chondrocyte differentiation and cartilage formation in blood vessels.
Kondos GT, Hoff JA, Sevrukov A, Daviglus ML, Garside DB, Devries SS, et al. Electron-beam tomography coronary artery calcium and cardiac events. Circulation. 2003 May;107(20):2571-2576.
MacWalter R., Fraser H., Armstrong K. Orlistat Enhances Warfarin Effect. Ann. Pharmacother. 2003;37:510–512.
Mody N, Tintut Y, Radcliff K, Demer LL. Vascular calcification and its relation to bone calcification: possible underlying mechanisms. J Nucl Cardiol. 2003;10:177-83.
Vascular calcification occurs frequently in atheromas and carries significant risk for future cardiac events. The constituents of bone matrix and mineralization are present in atherosclerotic lesions, and a population of cells that secrete these products in vitro has been identified. The phenotype of these cells and their capacity to secrete osteoid are under the control of numerous inflammatory mediators and are thought to be regulated by similar molecular mechanisms as osteogenesis.
Pearson TA, Mensah GA, Alexander RW, Anderson JL, Cannon RO, Ciqui M, et al. Markers of inflammation and cardiovascular disease: application of clinical and public health practice: a statement for healthcare professionals from the Centers for Disease Control and Prevention and the American Heart Association. Circulation 2003;107:499-522.
Spronk HM, Soute BA, Schurgers LJ, Thijssen HH, De Mey JG, Vermeer C. Tissue-specific utilization of menaquinone-4 results in the prevention of arterial calcification in warfarin-treated rats. J Vasc Res. 2003 Nov-Dec;40(6):531-7.
MK4, not K1, inhibits warfarin-induced arterial calcification. The observed differences between K1 and MK4 may be explained by differences in their tissue biovavailability and cofactor utilization in the carboxylase reaction.
Sweatt A, Sane DC, Hutson SM, Wallin R. Matrix Gla protein (MGP) and bone morphogenetic protein-2 in aortic calcified lesions of aging rats. J Thromb Haemost. 2003;1:178-85.
Vroonhof K., Van Rijn H.J.M., Van Hattum J. Vitamin K deficiency and bleeding after long-term use of cholestyramine. Neth. J. Med. 2003;61:19–21.
Allison MA, Criqui MH, Wright CM. Patterns and risk factors for systemic calcified artherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:331-36.
Whole-body electron beam computed tomography scans were performed on 650 asymptomatic subjects to assess the carotid, coronary, proximal, and distal aorta and iliac vessels for atherosclerotic calcification. The mean age was 57.3 and 53% were male. Correlation patterns were similar in both genders, with the largest interbed correlations between the distal aorta and iliac vessels (r=0.51 to 0.60). The average man and woman had calcium earliest in the coronaries (younger than age 50 years) and the distal aorta (age 50 to 60), respectively. The prevalence of calcium was greater than 80% for most beds in men older than age 70 and greater than 60% in all beds for women. Approximately one third of subjects younger than 50 were free of calcified disease, whereas all subjects older than 70 were found to have some calcium. Age and hypertension were the dominant risk factors for systemic calcified atherosclerosis.
Abedin M, Tintut Y, Demer LL. Vascular calcification: mechanisms and clinical ramifications. Arterioscler Thromb Vasc Biol. 2004 Jul;24(7):1161-70.
Vascular calcification, long thought to result from passive degeneration, involves a complex, regulated process of biomineralization resembling osteogenesis. Evidence indicates that proteins controlling bone mineralization are also involved in the regulation of vascular calcification. Artery wall cells grown in culture are induced to become osteogenic by inflammatory and atherogenic stimuli. Furthermore, osteoclast-like cells are found in calcified atherosclerotic plaques, and active resorption of ectopic vascular calcification has been demonstrated. The relationship between calcification and clinical events likely relates to mechanical instability introduced by calcified plaque at its interface with softer, noncalcified plaque. Vascular calcification is exacerbated in certain clinical entities, including diabetes, menopause, and osteoporosis.
Berkner, KL, Runge KW. The physiology of vitamin K nutriture and vitamin K-dependent protein function in atherosclerosis. J Thromb Haemost. 2004;2(12):2118-32.
Recent advances in the discovery of new functions for vitamin K-dependent (VKD) proteins have led to a substantial revision in our understanding of vitamin K physiology. The only unequivocal function for vitamin K is as a cofactor for the carboxylation of VKD proteins which renders them active. VKD proteins are now known to be present in virtually every tissue and to be important to bone mineralization, arterial calcification, apoptosis, phagocytosis, growth control, chemotaxis, and signal transduction. The development of improved methods for analyzing vitamin K has shed considerable insight into the relative importance of different vitamin K forms in the diet and their contribution to hepatic vs. non-hepatic tissue. New assays that measure the extent of carboxylation in VKD proteins have revealed that while the current recommended daily allowance for vitamin K is sufficient for maintaining functional hemostasis, the undercarboxylation of at least one non-hemostatic protein is frequently observed in the general population.
Braam L, McKeown J, Jacques P, Lichtenstein A, Vermeer C, Wilson P, et al. Dietary phylloquinone intake as a potential marker for a heart-healthy dietary pattern in the Framingham Offspring cohort. J Am Diet Assoc. 2004; 104:1410-14.
Dietary phylloquinone intakes were assessed by a food frequency questionnaire in 1,338 men and 1,603 women (mean age, 54 years) participating in the Framingham Heart Study. Cross-sectional associations with lifestyle characteristics and lipid profiles, including total cholesterol, low-density lipoprotein and high-density lipoprotein cholesterol, and triglyceride concentrations, were estimated across categories of phylloquinone intakes. Participants in the highest quintile category of phylloquinone intake consumed more fruit, vegetables, fish, dietary fiber, and dietary supplements ( P <.001), and consumed less meat and less saturated fat ( P <.001). Higher phylloquinone intakes were also associated with lower triglyceride concentrations ( P <.001). In conclusion, a high phylloquinone intake may be a marker for an overall heart-healthy dietary pattern.
Doherty T, Fitzpatrick L, Inoue D, Qiao J, Fishbein M, et al. Molecular, endocrine, and genetic mechanisms of arterial calcification. Endrocr Rev. 2004;25:629-72.
Ehara S, Kobayashi Y, Yoshiyama M, Shimada K, Shimada Y, et al. Spotty calcification typifies the culprit plaque in patients with acute myocardial infarction: an intravascular ultrasound study. Circulation. 2004;110:3424-29.
Geleijnse JM, Vermeer C, Grobbee DE, Schurgers LJ, Knapen MH, van der Meer IM, et al. Dietary intake of menaquinone is associated with a reduced risk of coronary heart disease: The Rotterdam Study. J. Nutr. 2004;134(11):3100-5.
Ten year follow up of 4,500 elderly subjects (the Rotterdam study cohort). A population based study demonstrating that high dietary intake of vitamin k2 influences cardiovascular health and reduced cardiovascular mortality. In this study dietary vitamin k2 appeared to be superior to vitamin K1. Vitamin K2 intake is inversely correlated with cardiovascular disease and mortality. This population based study, which took place over a ten year period, followed 4807 initially healthy men and women 55 years or more old. Findings from the study indicate that eating foods rich in natural vitamin k2 (at least 32 mcg per day) results in 50% reduction in arterial calcification, 50% reduction of cardiovascular death, and 25% reduction of all cause mortality.
Giachelli CM. Mechanisms of vascular calcification in uremia. Semin Nephrol. 2004;24:401-402.
Atherosclerosis is a multi-factorial process involving vitamins, proteins, hormones, and calcium.
Higdon J. (May 2004). "Vitamin K" (http://lpi.oregonstate.edu/infocenter/vitamins/vitaminK/ ). Linus Pauling Institute, Oregon State University. Updated by Victoria J Drake, Ph.D., LPI. Retrieved 2012-12-12.
Murshed M, Schinke, T, McKee MD, Karsenty G. Extracellular matrix mineralization is regulated locally: Different roles of two gla-containing proteins. J Cell Biol. 2004;165(5):625-30.
Extracellular matrix mineralization (ECMM) is a physiologic process in the skeleton and in teeth and a pathologic one in other organs. The molecular mechanisms controlling ECMM are poorly understood. Inactivation of Matrix gla protein (MGP) revealed that MGP is an inhibitor of ECMM. The fact that MGP is present in the general circulation raises the question of whether ECMM is regulated locally and/or systemically. Here, we show that restoration of MGP expression in arteries rescues the arterial mineralization phenotype of Mgp−/− mice, whereas its expression in osteoblasts prevents bone mineralization. In contrast, raising the serum level of MGP does not affect mineralization of any ECM. In vivo mutagenesis experiments show that the anti-ECMM function of MGP requires four amino acids which are γ-carboxylated (gla residues), and which can be found in vitamin K.
Jono S, Ikari Y, Vermeer C, Dissel P, Hawegawsa K, Shioi A, et al. Matrix Gla protein is associated with coronary artery calcification as assessed by electron-beam computed tomography. Thromb Haemost. 2004;91:790-4.
Matrix Gla protein (MGP) is an extracellular matrix protein with wide tissue distribution. It has been demonstrated that the expression of MGP is detected not only in the normal blood vessels but also in calcified atherosclerotic plaques, and that MGP deficient mice develop extensive arterial calcification. MGP is thought to be a regulator of vascular calcification. We evaluated the severity of CAC, and measured serum MGP levels in 115 subjects with suspected coronary artery disease. The serum MGP levels were lower in patients with CAC than in those without CAC (p<0.001). As the severity of CAC increased, there was a significant decrease in serum MGP levels. We found that serum MGP levels are inversely correlated with the severity of CAC.
Schurgers LJ, Aebert H, Vermeer C, Bultmann B, Janzen J. Oral anticoagulant treatment: Friend or foe in cardiovascular disease? Blood. 2004;104:3231-32.
Calcification is a common complication in cardiovascular disease and may affect both arteries and heart valves. Matrix gamma-carboxyglutamic acid (Gla) protein (MGP) is a potent inhibitor of vascular calcification, the activity of which is regulated by vitamin K. In animal models, vitamin K antagonists (oral anticoagulants [OACs]) were shown to induce arterial calcification. To investigate whether long-term OAC treatment may induce calcification in humans also, we have measured the grade of aortic valve calcification in patients with and without preoperative oral anti-coagulant treatment. OAC-treated subjects were matched with nontreated ones for age, sex, and disease. Calcifications in patients receiving preoperative OAC treatment were significantly (2-fold) larger than in nontreated patients. These observations suggest that OACs, which are widely used for antithrombotic therapy, may induce cardiovascular calcifications as an adverse side effect.
Schori TR, Stungis GE. Long-term warfarin treatment may induce arterial calcification in humans: case report. Clin Invest Med. 2004;27:107-9.
Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C, Szulc P, Hodges S, Walter P, Rambeck W, Stöcklin E, Weber P. Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health. Eur J Nutr. 2004 Dec;43(6):325-35.
From the available dietary data, it would appear that daily intakes of between 200 and 500μg/day of dietary vitamin K may be required for optimal gamma-carboxylation of OC, which may in turn benefit bone health. There is growing evidence to suggest that vitamin K may be acting synergistically with vitamin D, calcium and possible other micronutrients to maximally influence bone mineral accretion and potentially inhibit vascular calcification. As such, health benefits may accrue from supplemental vitamin K being combined with vitamin D and minerals. Considerably more work is required in the area of vitamin K including understanding relative bioavailability, optimal tissue-specific status indicators, and the relative importance of gamma-carboxylation status to the growing number of health outcomes that may be influenced by vitamin K inadequacy.
Adams, J, Pepping J (2005). Vitamin K in the treatment and prevention of osteoporosis and arterial calcification. Am J Health Syst Pharm 62(15):1574-81.
Current dosage recommendations for vitamin K may be too low.
Bernker KL. The vitamin K-dependent carboxylase. Annu Rev Nutr. 2005;25:127-49.
Csiszar A, Smith KE, Koller A, Kaley G, Edwards JG, et al. Regulation of bone morphogenetic protein-2 expression in endothelial cells: Role of nuclear factor-kappa B activation by tumor necrosis factoro-alpha, H202, and high intravascular pressure. Circulation. 2005;111:2364-72.
Erkkila AT, Booth SL, Hu FB, Jacques PF, Manson JE, Rexrode KM, et al. Phylloquinone intake as a marker for coronary heart disease risk but not stroke in women. Eur J Clin Nutr 2005;59:196-04.
Fujii K, Carlier SG, Mintz GS, Takebayashi H, Yasuda T, et al. Intravascular ultrasound study of patterns of calcium in ruptured coronary plaques. The Am J of Cardio. 2005;96:352-57.
Hasanbasic I, Rajotte I, Blostein M. The role of gamma-carboxylation in the anti-apoptotic function of Gas6. J Thromb Haemost. 2005;3:2790–7.
Hruska Ka, Mathew S, Saab G. Bone morphogenetic proteins in vascular calcification. Circulation. 2005;97:105-14.
Vascular calcification is a common problem among the elderly and those with chronic kidney disease (CKD) and diabetes. The process of vascular calcification in CKD appears to involve a change in the vascular smooth muscle cell (VSMC) resulting in mineralization of the extracellular matrix. The bone morphogenetic proteins (BMPs) are important regulators in orthotopic bone formation, and their localization at sites of vascular calcification raises the question of their role. In this review, we will discuss the actions of the BMPs in vascular calcification.
Koos R, Mahnken A, Muhlenbruch G, Brandenburg V, Pfleuger B, et al. Relation of oral anticoagulation to cardiac vascular and coronary calcium assessed by multislice spiral computed tomography. Am J Cardiol. 2005;96:747-49.
Nadra I, Mason J, Philippidis P, Florey O, Smythe C, et al. Proinflammatory activation of macrophages by basic calcium phosphate crystals via protein Kinase C and MAP Kinase Pathways: A vicious cycle of inflammation and arterial calcification? Circ Res. 2005;96:1248-56.
Sato Y, Nakamura R, Satoh M, Fujishita K, Mori S, Ishida S, et al. Thyroid hormone targets matrix Gla protein gene associated with vascular smooth muscle calcification. Circ Res. 2005 Sep 16;97(6):550-7.
The study suggest that thyroid hormone directly facilitates MGP gene expression in smooth muscle cells via thyroid hormone nuclear receptors, leading to the prevention of vascular calcification in vivo.
Schurgers, LJ, Teunissen KJ, Knapen MH, et al. Novel conformation-specific antibodies against matrix gamma-carboxyglutamic acid (GLA) protein: undercarboxylated matrix GLA protein as marker for vascular calcification. Arterioscler Thromb Vas Biol. 2005;25(8):1629-33.
A small human study that employed conformation-specific antibodies against MGP to examine whether impaired carboxylation of this protein possibly contributes to arterial calcification. In healthy subjects, undercarboxylated MGP (ucMGP) was not detected in the innermost lining of the carotid artery; in contrast, the majority of MGP in the carotid arterial lining of patients with atherosclerosis was undercarboxylated.
Vengrenyuk Y, Cardoso L, Weinbaum S. Micro-CT based analysis of a new paradigm for vulnerable plaque rupture: Cellular microcalcifications in fibrous caps. Mol Cell Biomech. 2008;5:37-47.
Villines TC, Hatzigeorgiou C, Feuerstein IM, O’Malley PG, Taylor AJ. Vitamin K1 intake and coronary calcification. Coron Artery Dis. 2005;16(3):199-03.
A prospective cohort study in 807 men and women, aged 39 to 45 years, did not find a correlation between dietary vitamin K1 intake and coronary artery calcification, as measured by electron-beam computed tomography (EBT).
Vliegenthart R, Oudkerk M, Hofman A, Oei HH, van Dijck W, van Rooij FJ, Witteman JC. Coronary calcification improves cardiovascular risk prediction in the elderly. Circulation. 2005; 112: 572-77.
Clarke M, Figg N, Maguire J, Davenport A, Goddard M, et al. Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis. Nat Med. 2006;12:1075-80.
Johnson RC, Leopold JA, Loscalzo J. Vascular calcification: Patho-biological mechanisms and clinical implications. Circ Res. 2006;99:1044-59.
Mazzini MJ, Schulze PC. Proatherogenic pathways leading to vascular calcification. Eur J Radio. 2006 Mar;57(3):384-92.
Cardiovascular disease is the leading cause of morbidity and mortality in the western world and atherosclerosis is the major common underlying disease. The pathogenesis of atherosclerosis involves local vascular injury, inflammation and oxidative stress as well as vascular calcification. Recent studies identified vascular calcification in early stages of atherosclerosis and its occurrence has been linked to clinical events in patients with cardiovascular disease. They review the current knowledge on molecular pathways of vascular calcification and their relevance for the progression of cardiovascular disease.
Proudfoot D, Shanahan CM. Molecular mechanisms mediating vascular calcification: Role of matrix Gla protein. Nephrology (carlton). 2006 Oct;11(5):455-61.
Patients with chronic kidney disease (CKD) have a higher incidence of vascular calcification and a greatly increased risk of cardiovascular death. MGP inhibits calcium deposits. MGP is a vitamin K-dependent protein that is also highly expressed by vascular smooth muscle cells. It potentially acts in several ways to regulate calcium deposits including (i) binding calcium ions and crystals (ii) antagonizing bone morphogenetic protein and altering cell differentiation (iii) binding to extracellular matrix components (iv) regulating apoptosis. Strategies that increase MGP expression may inhibit calcification in kidney disease.
Son B-K, Kozaki K, Iijima K, et al. Statins protect human aortic smooth muscle cells from inorganic phosphate-induced calcification by restoring Gas6-Axl survival pathway. Circ Res .2006;98:1024–31.
Suttie, JW. Vitamin K. In: Shils ME, Shilke M, Ross Ac, Caballero B, Cousins RJ, Editors. Modern nutrition in health and disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006. p. 412-25.
Aikawa E, Nahrendorf M, Figueiredo J, et al. Osteogenesis associates with inflammation in early-stage atherosclerosis evaluated by molecular imaging in vivo. Circulation. 2007;116:2841-50.
Budoff MJ, Shaw LJ, Liu St, et al. Long-term prognosis associated with coronary calcification. J Am Coll Cariol. 2007;49:1860-1870.
Cario-Toumaniantz C, Boularan C, Schurgers LJ, Heymann MF, et al. Identification of differentially expressed genes in human varicose veins: involvement of matrix Gla protein in extracellular matrix remodeling. J Vasc Res. 2007;44:444-459.
Hofbauer LC, Brueck CC, Shanahan CM, Schoppet M. Vascular calcification and osteoporosis - From clinical observation towards molecular understanding. Osteopor Int. 2007;18:251-59.
Discusses how MGP is one of the key proteins to inhibit arterial calcification.
Maas HA, van der Schouw YT, Beijerinck D, Deurenberg JJ, Mali WP, Grobbee DE, et al. Vitamin K intake and calcifications in breast arteries. Maturitas. 2007;56(30:273-79.
The study did not find vitamin K1 intake to be associated with calcification of breast arteries ina cross-sectional study of 1,689 women, aged 49 to 70 years.
Maree AO, Jneid H, Palacios IF, Rosenfield K, MacRae CA, Fitzgerald DJ. Growth arrest specific gene (GAS) 6 modulates platelet thrombus formation and vascular wall homeostasis and represents an attractive drug target. Curr Pharm Des. 2007; 13(26):2656-61.
Motoyama S, Kondo T, Sarai M, Sugiura A, Harigaya H, et al. Multislice computed tomographic characteristics of coronary lesions in acute coronary syndromes. J of the Am College of Cardio. 2007;50:319-26.
Schurgers, LJ, Spronk HM, Soute BA, Schiffers PM, DeMey JGR, et al. Regression of warfarin-induced medial elastocalcinosis by high intake of K vitamins in rats. Blood. 2007 Nov 30;109:2823-31.
An adequate intake of vitamin K2 has been shown to positively influence the cardiovascular system. Vitamin K2 activates matrix Gla Protein (MGP) which inhibits calcium from depositing in the vessel walls. Calcium will be removed in a coordinated system of activated MGP, soluble factors, cells and tissues, keeping the arteries healthy and flexible. This was the first study in rats demonstrating that arterial calcification and stiffness can be reverse by high vitamin K intake.
Schurgers LJ, Spronk HM, Skepper JN, Hackeng TM, Shanahan CM, Vermeer C, et al. Post-translational modifications regulate matrix Gla protein function: Importance for inhibition of vascular smooth muscle cell calcification. J Thromb Haemost. 2007 Dec;5(12):2503-11.
Matrix Gla protein (MGP) is a small vitamin K-dependent protein containing five gamma-carboxyglutamic acid (Gla) residues that are believed to be important in binding Ca (2+) calcium crystals and bone morphogenetic protein. The study investigated the effects of MGP in human vascular smooth muscle cell monolayers that undergo calcification after exposure to an increase in Ca(2+) concentration. The data demonstrated that both gamma-glutamyl carboxylation and serine phosphorylation of matrix gla protein contribute to its function as a calcification inhibitor via binding to the cell surface and to vesicle like structures.
Schurgers LJ, Teunissen KJF, Hamulyak K, Knapen MHJ, Vik H, Vermeer C. Vitamin K-containing dietary supplements: Comparison of synthetic vitamin K1 and natto-derived menaquinone-7. Blood. 2007;109:3279-83.
Son B-K, Kozaki K, Iijima K, et al. Gas6/Axl-PI3K/Akt pathway plays a central role in the effect of statins on inorganic phosphate-induced calcification of vascular smooth muscle cells. Eur J Pharmacol. 2007;556:1–8.
Belovici MI, Pandele, GI. Arterial media calcification in patients with type 2 diabetes mellitus. Rev Med Chir Soc Med Nat Lasi. 2008 Jan-Mar;112(1):21-34.
Arterial calcification was previously viewed as an inevitable, passive, and degenerative process that occurred at the end stages of atherosclerosis. Recent studies, however, have demonstrated that calcification of arteries is a complex and regulated process. It may occur in conjunction with atherosclerosis or in an isolated form that is commonly associated with diabetes and renal failure. Higher artery calcium scores are associated with increased cardiovascular events, and some aspects of arterial calcification are similar to the biology of forming bone. Arterial calcification can thus be viewed as a distinct inflammatory arteriopathy, much like atherosclerosis and aneurysms, with its own contribution to cardiovascular morbidity and mortality.
Clarke M, LittlewoodT, Figg N, Maguire J, Davenport A, et al. Chronic apoptosis of vascular smooth muscle cells accelerates atherosclerosis and promotes calcificationand medial degeneration. Circ Res. 2008;102:1529-38.
Cranenburg EC, Vermeer C Koos R, Boumans ML, Hackeng TM, Bouwman FG, et al. The circulating inactive form of matrix Gla protein (ucMGP) as a biomarker for cardiovascular calcification. J Vasc Res. 2008;45(5):427-36.
Matrix gamma-carboxyglutamate (Gla) protein (MGP) is a vitamin K-dependent protein and a strong inhibitor of vascular calcification. Vitamin K deficiency leads to inactive uncarboxylated MGP (ucMGP), which accumulates at sites of arterial calcification. We hypothesized that as a result of ucMGP deposition around arterial calcification, the circulating fraction of ucMGP is decreased. All four patient populations had significantly lower ucMGP levels. In angioplasty patients and in those with aortic stenosis, some overlap was observed with the control population. However, in the hemodialysis and calciphylaxis populations, virtually all subjects had ucMGP levels below the normal adult range. Serum ucMGP may be used as a biomarker to identify those at risk for developing vascular calcification. This assay may become an important tool in the diagnosis of cardiovascular calcification.
Demer L, Tintut Y. Vascular calcification: Pathobiology of a multifaceted disease. Circulation. 2008;117:2938-48.
Clinically, vascular calcification is now accepted as a valuable predictor of coronary heart disease. Achieving control over this process requires understanding mechanisms in the context of a tightly controlled regulatory network, with multiple, nested feedback loops and cross talk between organ systems, in the realm of control theory. Thus, treatments for osteoporosis such as calcitriol, estradiol, bisphosphonates, calcium supplements, and intermittent PTH are likely to affect vascular calcification, and, conversely, many treatments for cardiovascular disease such as statins, antioxidants, hormone replacement therapy, angiotensin-converting enzyme inhibitors, fish oils, and calcium channel blockers may affect bone health. As we develop and use treatments for cardiovascular and skeletal diseases, we must give serious consideration to the implications for the organ at the other end of the bone-vascular axis.
Ewence AE, Bootman M, Roderick HL, Skepper JN, McCarthyG, et al. Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: A potential mechanism in atherosclerotic plaque destabilization. Circulation Res. 2008;103:328-34.
Schurgers LJ, Cranenburg ECM, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008;100:593-603.
Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Its pivotal importance for vascular health is demonstrated by the fact that there seems to be no effective alternative mechanism for calcification inhibition in the vasculature. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. Significant differences were found in patients with cardiovascular disease (CVD). Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection. These assays may have potential value for identifying patients as well as apparently healthy subjects at high risk for CVD and/or cardiovascular calcification and for monitoring the treatment of CVD and vascular calcification.
Shea MK, Dallal GE, Dawson-Hughes B, Ordovas JM, O’Donnell CJ, Gundberg CM, Peterson JW, Booth SL. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am. J. Clin. Nutr. 2008;88:356–363.
Shea M.K., Booth S.L., Massaro J.M., Jacques P.F., D’Agostino R.B., Sr., Dawson-Hughes B., Ordovas J.M., O’Donnell C.J., Kathiresan S., Keaney J.F., Jr., et al. Vitamin K and vitamin D status: Associations with inflammatory markers in the Framingham Offspring Study. Am. J. Epidemiol. 2008;167:313–320.
Shearer MJ, Newman P. Metabolism and cell biology of vitamin K. Thromb Haemost. 2008;100:530-47.
Structural differences in vitamin K compounds govern many facets of the metabolism of K vitamins, including the way they are transported, taken up by target tissues, and subsequently excreted. In the post-prandial state, phylloquinone is transported mainly by TRL, and long-chain menaquinones mainly by LDL. One K2 form, MK4, has a highly specific tissue distribution suggestive of local synthesis. MK4 specifically upregulates two genes suggesting a novel MK4 signalling pathway. Many studies have shown clinical benefits of MK4 at pharmacologic doses for osteoporosis and cancer. Vitamin K also functions to suppress inflammation, prevention of brain oxidative damage, and a role in sphingolipid synthesis. Anticoagulant drugs block vitamin K recycling and reduce the availability. A daily supplement of K2 shows potential to improve coagulation control.
Westenfeld R, Kruger T, Schlieper G, et al. Vitamin K2 supplementation reduces the elevated inactive form of the calcification inhibitor matrix gla protein in hemodialysis patients. Am Soc Nephrol. 2008;TH-FC044.
Demer LL, Tintut Y. Vascular calcification: Pathobiology of a multifaceted disease. Circulation. 2008;117:2938-48.
Erkkila AT, Booth SL. Vitamin K intake and atherosclerosis. Curr Opin Lipidol. 2008;19(1): 39-42.
Found menaquinone (vitamin K2) but not K1 intake to be associated with reduced risk of CHD mortality, all cause mortality and severe aortic calcification.
Shea MK, Dallal GE, Dawson-Hughes B, Ordovas JM, O'Donnell CJ, Gundberg CM, Peterson JW, Booth SL. Vitamin K, circulating cytokines, and bone mineral density in older men and women. Am J Clin Nutr. 2008 Aug; 88(2):356-63.
Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008 Oct:100(4):593-03.
Among the proteins involved in vascular calcium metabolism, the vitamin K-dependent matrix Gla-protein (MGP) plays a dominant role. Although on a molecular level its mechanism of action is not completely understood, it is generally accepted that MGP is a potent inhibitor of arterial calcification. An optimal vitamin K intake is therefore important to maintain the risk and rate of calcification as low as possible. Using ELISA-based assays, uncarboxylated MGP (ucMGP) was demonstrated to be a promising biomarker for cardiovascular calcification detection.
Wallin R, Schurgers L, Wajih N. Effects of the blood coagulation vitamin K as an inhibitor of arterial calcification. Thromb Res. 2008;122(3):411.
Our findings suggest that MK4 could inhibit vessel wall calcification. Our data from the MK4 gene expression studies are supportive of the current use of MK4 in medicine. MK4 has been shown conclusively to reduce osteoporosis and has been used for this purpose in Japan for several years. MK4 intake has also been reported reduce aortic calcification.
Alexopolous N, Raggi P. Calcification in atherosclerosis. Nat Rev Cardiol. 2009;6:681-88.
Bacchetta J, Boutroy S, Guebre-Egziabher F, et al. . The relationship between adipokines, osteocalcin and bone quality in chronic kidney disease. Nephrol Dial Transplant 2009;24:3120–5.
Beulens JW, Bots ML, Atsma F, Bartelink ML, Prokop M, Geleijnse JM, et al. High dietary menaquinone intake is associated with reduced coronary calcification. Atherosclerosis. 2009 Apr;203(2):489-93.
A high dietary intake of menaquinone, vitamin K2, was found to be associated with decreased coronary calcification in 564 post menopausal women. Researched the association between the intake of both phylloquinone and menaquinone, including its subtypes (MK4-MK10) with coronary calcification in a cross-sectional study among 564 post-menopausal women. Intake was estimated using a food frequency questionnaire. Menaquinone intake was associated with decreased coronary calcification. They concluded that adequate menaquinone intakes could therefore be important to prevent cardiovascular disease
Danziger J. Vitamin K-dependent proteins, warfarin, and vascular calcification. Clin J Am Soc Nephrol. 2009 Sep;3(5):1504-10.
Vitamin K dependent proteins (VKDP) require carboxylation to be come biologically active. Matrix Gla Protein (MGP) and Growth Arrest Specific Gene 6 (Gas-6) are two important VKDPs and their roles in vascular biology are just beginning to be understood. Both function to protect the vasculature. MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell aptosis and movements. Warfarin prevents the activation of these proteins and in animals, induces vascular calcification. Given the high risk of vascular calcification in patients with kidney disease, it will be important to research warfarin’s effect on VKDPs.
Gast GCM, de Roos NM,, Sluijs I, Bots ML, Beulens JWJ, Geleijnse JM, et al. A high menaquinone intake reduces the incidence of coronary heart disease. Nutri, Metab & Cardiov Diseases. 2009;19(7):504-10.
Vitamin K dependent proteins inhibit vascular calcification. However there is limited data on the effect of vitamin K intake on coronary heart disease (CHD) risk. This study looked at the relationship between dietary vitamins K1 and K2 intake and the incidence of CHD, using data from the Prospect-EPIC cohort consisting of 16,057 women, aged 49-70 years who were free of CHD at baseline. The results indicated an association between vitamin K2 subtypes MK7, MK8 and MK9. Vitamin K1 intake was not significantly related to CHD. The results from this study how that high intake of natural vitamin K2, menaquinones, over an 8 year period protected from cardiovascular events and CHD, with more research necessary to define optimal intake levels. The researchers found that for every 10 mcg vitamin k2 consumed, the risk of coronary heart disease was reduced by 9%. This supported the Rotterdam Study findings.
Jiang L, Liu CY, Yang QF, Wang P, Rhang W. Plasma level of growth arrest-specific 6 (GAS6) protein and genetic variations in the GAS6 gene in patients with acute coronary neovascularization of myocardial ischemia. Circulation. 2009.131:738-743.
Koos R, Krueger T, Westenfeld R, Kuhl HP, Brandenburg V, Mahnken AH, et al. Relation of circulating Matrix Gla-Protein and anticoagulation status in patients with aortic valve calcification. Thromb Haemost. 2009 Apr;101():706-13.
This study tested the association between circulating MGP levels in humans and MGP expression in mice. They also tested the association between circulating inactive MGP levels and the presence and severity of vascular calcification in aortic valve disease. The results showed that patients with valve calcification had significantly lower levels of circulating MGP and they found that patients on long-term oral anticoagulants had significantly increased valve calcification scores.
Krueger T, Westenfield R, Schurgers L, Brandenburg V. Coagulation meets calcification: The vitamin K system. Int J Artif Organs. 2009;32:67-74.
Morbidity and mortality are massively increased in patients with chronic kidney disease (CKD) and patients with end-stage renale disease (ESRD). Bone disease (renal osteodystrophy) and vascular disease (accelerated arteriosclerosis) are two typical entities contributing to this excess morbidity and mortality. Vitamin K and vitamin K-dependent-proteins play pivotal roles in the physiology of mineralization and in preventing ectopic calcification. Vitamin K deficiency impairs the physiological function of osteocalcin and MGP and, therefore, presumably contributes to bone demineralisation and vascular calcification (the so-called calcification paradox). We present a summary of data describing the potential role of vitamin K deficiency and supplementation in bone and vascular disease in patients with CKD or ESRD.
Lerner RG, Aronow WS, Sekhri A, Palaniswamy C, Ahn C, Sing T, et al. Warfarin use and the risk of valvular calcification. J Thromb Haemost. 2009 Dec;7(12):2023-7.
Use of warfarin in patients with AFib is associated with an increased prevalence of Mitral Valve Calcium (MVC), Mitral Annular Calcium (MAC), or Aortic Valve Calcium (AVC). Warfarin affects the synthesis and function of the matrix Gla-protein, a vitamin K-dependent protein, which is a potent inhibitor of tissue calcification. When MGP is interfered with, calcification results.
Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI et al. A new equation to estimate flomerular filtration rate. Ann Intern Med. 2009;150(9):963-5.
Luo HX, Zhao L-L, Yuan L-Q, Wang M, Xie H, Liao E-Y. Development of arterial calcification in adiponectin-deficient mice: adiponectin regulates arterial calcification. J Bone Miner Res. 2009;24(8):1461-8.
Arterial calcification is common, but the mechanisms remain unclear. This study was undertaken to investigate the arterial calcification in adiponectin-deficient mice in vivo and the effects of adiponectin on cultured vascular smooth muscle cells in vitro. Our findings showed that adiponectin(-/-) mice developed arterial calcification, and this could be attributed to the loss of inhibitory action of adiponectin on osteoblastic differentiation of CVSMCs. It suggested that adiponectin plays a protective role against arterial calcification.
Mao SS, Pal RS, McKay CR, et al. Comparison of coronary artery calcium scores between electron beam computed tomography and 64-multidetector computed tomographic scanner. J Comput Assist Tomogr. 2009;33:175–8.
Mitchell GF. Arterial stiffness and wave reflection: biomarkers of cardio-vascular risk. Artery Res. 2009;3(2):56-64.
Rennenberg RJMW, Kells AGH, Schurgers LJ, van Engelshoven JMA, de Leeuw PW, et al. Vascular calcifications as a marker of increased cardiovascular risk: A meta-analysis. Vasc Health and Risk Managemt. 2009;5:185-97.
Shea MK, O’Donnell CJ, Hoffmann U, Dallal GE, Dawson-Hughes B, Ordovas JM, et al. Vitamin K supplementation and progression of coronary artery calcium in older men and women. Am J Clin Nutr. 2009 June;89(6):1799-07.
Coronary artery calcification (CAC) is an independent predictor of cardiovascular disease. A preventive role for vitamin K in CAC progression has been proposed on the basis of the properties of matrix Gla protein (MGP) as a vitamin K–dependent calcification inhibitor. The objective was to determine the effect of phylloquinone (vitamin K1) supplementation on CAC progression in older men and women. CAC was measured at baseline and after 3 years of follow-up in 388 healthy men and postmenopausal women; 200 received a multivitamin with 500 μg phylloquinone per day (treatment), and 188 received a multivitamin alone (control). Phylloquinone-associated decreases in CAC progression were independent of changes in serum MGP. MGP carboxylation status was not determined. Phylloquinone supplementation slows the progression of CAC in healthy older adults with preexisting CAC, independent of its effect on total MGP concentrations.
Speer MY, Yang H-Y, Brabb T, Leaf E, Look A, et al. Smooth muscle cells give rise to osteochondrogenic precursors and chondrocytes in calcifying arteries. Circ Res. 2009;104:733-41.
Suttie, John W. Vitamin K in health and disease. CRC Press. 2009.
Viegas C, Cavaco S, Neves P, et al. Gla-rich protein is a novel vitamin K-dependent protein present in serum that accumulates at sites of pathological calcifications. Am J Pathol. 2009;175:2288-98.
We have recently identified in sturgeon a new VKD protein, Gla-rich protein (GRP), which contains the highest ratio between number of Gla residues and size of the mature protein so far identified. We show that GRP is a circulating protein that is also expressed and accumulated in soft tissues of rats and humans, including the skin and vascular system, when affected by pathological calcifications. The high number of Gla residues and consequent mineral binding affinity properties strongly suggest that GRP may directly influence mineral formation, thereby playing a role in processes involving connective tissue mineralization.
Cranenburg ECM, Koos R, Schurgers LJ, et al. Characterisation and potential diagnostic value of circulating matrix Gla protein (MGP) species. Thromb Haemost 2010;104:811-22.
Matrix γ-carboxyglutamate (Gla) protein (MGP) is an important local inhibitor of vascular calcification, which can undergo two post-translational modifications: vitamin K-dependent γ-glutamate carboxylation and serine phosphorylation. While carboxylation is thought to have effects upon binding of calcium ions, phosphorylation is supposed to affect the cellular release of MGP. Since both modifications can be exerted incompletely, various MGP species can be detected in the circulation. MGP levels were measured in patients with rheumatic disease, aortic valve disease, and end-stage renal disease, as well as in volunteers after vitamin K supplementation (VKS) and treatment with vitamin K antagonists (VKA). Major differences were found between the MGP assays, including significantly different behaviour with regard to vascular disease and the response to VKA and VKS. The dual-antibody assay measuring non-phosphorylated, non-carboxylated MGP (dp-ucMGP) was particularly sensitive for these changes and would be suited to assess the vascular vitamin K status.
Finn AV, Nakano M, Narula J, Kolodgie FD, Virmani R. Concept of vulnerable/unstable plaque. Arterioscler Thromb VascBiol. 2010 July;30(7): 1282–92.
Nakagawa Y, Ikeda K, Akakabe Y, Koide M, Uraoka M, et al. Paracrine osteogenic signals via bone morphogenetic protein-2 accelerate the atherosclerotic intimal calcification in vivo. Arterioscler Thromb Vasc Biol. 2010;30:1908-15.
We generated BMP-2-transgenic mice and crossed them with apoE-deficient mice (BMP-2-transgenic/apoE-knockout). Significantly accelerated atherosclerotic intimal calcification was detected in BMP-2-transgenic/apoE-knockout mice, although serum lipid concentration and atherosclerotic plaque size were not different from those in apoE-knockout mice. Enhanced calcification appeared to be associated with the frequent emergence of osteoblast-like cells in atherosclerotic intima in BMP-2-transgenic/apoE-knockout mice. The findings collectively demonstrate an important role of dedifferentiated VSMCs in the pathophysiology of atherosclerotic calcification through activating paracrine BMP-2 osteogenic signals.
Nasir K, Rivera JJ, Yoon YE, Chang SA, Choi SI, Chun EJ, et al. Variation in atherosclerotic plaque composition according to increasing coronary artery calcium scores on computed tomography angiography. Int J Cardiovasc Imaging. 2010;26:923-32.
Absence of CAC (Coronary Artery Calcium) is associated with a negligible presence of any atherosclerotic disease as detected by Coronary Computed Tomagraphy Angiography in 1043 asymptomatic South Korean population. A higher CACS is more likely to be associated with heterogeneous coronary plaque (combination of calcified, non-calcified, and mixed plaques), and appears to be more strongly associated with a higher burden of mixed plaque.
Ohsaki Y, Shirakawa H, Miura G, Giriwono PE, Sato S, Ohashi A, et al. Vitamin K suppresses the lipopolysaccharide-induced expression of inflammatory cytokines in cultured macrophage-like cells via the inhibition of the activation of nuclear factor kB through the repression of IKKα/β phosphorylation. J Nutr. Biochem. 2010 Nov;21(11):1120-6.
Rees K, Guraew al S, Wong YL, Majanbu DL, Mavrodaris A, Stranges S, et al. Is vitamin K consumption associated with cardio-metabolic disorders? A systematic review. Maturitas. 2010 Oct;67(2):121-28.
The study examined the association between vitamin K intake and cardio-metabolic outcomes including cardiovascular disease, type 2 diabetes and metabolic syndrome. A systematic review of the literature produced five studies. Due to the heterogeneity of designs, the exposures/interventions and outcomes, it was not possible to do a meta-analysis. In these studies, no associations were found between vitamin K2 intake and coronary heart disease (CHD) or stroke, or prevalence of diabetes. Two cohorts found significant associations where higher vitamin K2 intake was associated with fewer CHD events.
Rennenberg RJMW, van Varik BJ, Schurgers LJ, Hamulyak K, Ten Cate H, et al. Chronic coumarin treatment is associated with increased extracoronary arterial calcification in humans. Blood. 2010;115:5121-123.
Because MGP activation is vitamin K dependent, we performed a cross-sectional study investigating the relationship between the use of vitamin K antagonists and extracoronary vascular calcification. From the Dutch thrombosis services we selected 19 patients younger than 55 years who had no other cardiovascular risk factors and who had used coumarins for more than 10 years, and compared these to 18 matched healthy controls. MGP was measured, and a plain x-ray of the thighs was taken to assess femoral arterial calcifications. The odds ratio for calcification in patients versus controls was 8.5 (95% confidence interval [CI] 2.01-35.95). Coumarin use and MGP were associated with calcification, even after adjusting for other risk factors. We conclude that long-term use of coumarins is associated with enhanced extracoronary vascular calcification.
Rennenberg RJ, de Leeuw PW, Kessels AG, Schurgers LJ, Vermeer C, van Engelshoven JM, et al. Calcium scores and matrix Gla protein levels: Association with vitamin K status. Eur J Clin Invest. 2010 Apr;40(4):344-9.
Carboxylated matrix Gla protein (cMGP) inhibits vascular calcification. Vitamin K is an essential cofactor to activate the matrix Gla protein so that it prevents calcification. They hypothesized that arterial calcification and a low vitamin K status, measured by the osteocalcin ratio, would be associated with ucMGP. The study found a positive association between the total arterial calcium score and a high osteocalcin ratio (OCR) (which reflects low vitamin K status) with ucMGP levels in the blood.
Ueland T, Gullestad L, Dahl CP, Aukrust P, Aakhus S, Solberg OG, et al. Undercarboxylated matrix Gla protein is associated with development of heart failure and mortality in symptomatic aortic stenosis. J Int Med. 2010;268:483-92.
Yao Y, Bennett BJ, Wang X, Rosenfeld ME, Giachelli C, et al. Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification. Circ Res. 2010;107:485-94.
The bone morphogenetic proteins (BMPs), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall. Their results indicate that BMP (Bone Morphogenic Protein) signaling is a key regulator of vascular disease, requiring careful control to maintain normal vascular homeostasis.
Chatrou ML, Reutelingsperger CP, Schurgers LJ. Role of vitamin K-dependent proteins in the arterial vessel wall. Hamostaseologie. 2011;31:251-57.
Vitamin K-dependent proteins are involved in the regulation of vascular smooth muscle cell migration, apoptosis, and calcification. Vascular calcification has become an important independent predictor of cardiovascular disease. Vitamin K-antagonists induce inactivity of inhibitors of vascular calcification, leading to accelerated calcification. The involvement of vitamin K-dependent proteins such as MGP in vascular calcification mean that calcification is amenable for intervention with high intake of vitamin K.
Cinaz SY, Tavi B, Sari S, Cinaz P. Vitamin K deficiency because of cetriaxone usage and prolonged diarrhoea. JPCH. 2011;47:314-315.
Derlin T, Wisotzki C, richter U, et al. In vivo imaging of mineral deposition in carotid plaque using 184_sodium fluoride PET/CT: Correlation with atherogenic risk factors. J Nucl Med. 2001; 52:362-68.
Hurtado B, Munoz X, Recarte-Pelz P, Garcia N, Luque A, Krupinski J, et al. Expression of the vitamin K-dependent proteins GAS 6 and protein S and the TAM receptor tyrosine kinases in human atherosclerotic carotid plaques. Thrombosis and Haemostasis. 2011 May;105(5):873-82.
O’Young J, Liao Y, Xiao Y, Jalkanen J, Lajoie G, et al. Matrix gla Protein inhibits ectopic calcification by a direct interaction with hydroxyapatite crystals. J Am Chem soc. 2011;133:18406-412.
Palaniswamy C, Sekhri A, Aronow WS, Kalra A, Peterson SJ. Assocation of warfarin use with valvular and vascular calcification: A review. Clin Cardiol. 2011;34(2):74-81.
Vitamin K is required for the activity of various biologically active proteins in our body. Apart from clotting factors, vitamin K-dependent proteins include regulatory proteins like protein C, protein S, protein Z, osteocalcin, growth arrest-specific gene 6 protein, and matrix Gla protein. Glutamic acid residues in matrix Gla protein are γ-carboxylated by vitamin K-dependent γ-carboxylase, which enables it to inhibit calcification. Warfarin, being a vitamin K antagonist, inhibits this process, and has been associated with calcification in various animal and human studies. Drugs including statins, alendronate, osteoprotegerin, and vitamin K are currently under study as therapies to prevent or treat warfarin-associated calcification.
Roijers RB, Debernardi N, Cleutjens JP, Schurgers LJ, Mutsaers PH, et al. Microcalcifications in early intimal lesions of atherosclerotic human coronary arteries. The Am J of Path. 2011;178:2879-87.
Schlieper G, Westenfeld R, Kruger T, Cranenburg EC, Magdeleyns EJ, Brandenburg VM, et al. Circulating nonphosphorylated carboxylated matrix gla protein predicts survival in ESRD. J Am Soc Nephrol. 2011 Feb;22(2):387-95.
Dialysis patients exhibit profound vitamin K deficiency which may impair carboxylation of the calcification inhibitor matrix gla protein (MGP). The study tested whether distinct circulating inactive vitamin K-dependent proteins are associated with all-cause or just cardiovascular mortality. They compared hemodialysis patients with subjects with normal renal function. They found pronounced vitamin K deficiency in the dialysis patients, and a Kaplan-Meier analysis showed that these patients had an increased risk for both all-cause and for cardiovascular mortality.
Ueland T, Dahl CP, Gullestad L, Aakhus S, Broch K, Skaardal R, et al. Circulating levels of non-phosphorylated undercarboxylated matrix Gla protein are associated with disease severity in patients with chronic heart failure. Clinical Science. 2011;121(3):119-127.
This study examined carboxylated and uncarboxylated Matric Gla Protein as measured in the blood of 179 patients with chronic heart failure and matched them to a healthy control group. They found elevated levels of uncarboxylated MGP associated with disease severity, and was markedly higher in patients who died from the progression of heart disease. They concluded that a dysregulated MGP system could be involved in left ventricular dysfunction in patients with chronic heart failure.
Weijs B, Blaauw Y, Rennenberg RJMW, Schurgers LJ, Timmermans CCMM, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: An observational study in low-risk atrial fibrillation patients. European Heart J. 2011;32:2555-62.
Zak-Golab A, Okopien B, Chudek J. Vitamin K, bone metabolism and vascular calcification in chronic kidney disease. Przegl Lek. 2011;68(9):629-32.
Atherosclerosis is the main cause of premature death in patients with chronic kidney disease, especially if on dialysis. Vitamin K dependent proteins play an essential role in the pathogenesis of mineral and bone disorders related to kidney disease, including vascular calcification. Vitamin K dependent proteins require carboxylation for biological activation. The role of matrix Gla protein (MGP), Growth Arrest Specific Gene 6 (Gas-6) and osteocalcin has been recently discovered. MGP prevents vascular calcification and Gas-6 affects vascular smooth muscle cell apoptosis and movement. Carboxylation of osteocalcin promotes bone formation. The restrictive diet recommended for dialysis patients increases the chance for vitamin K deficiency. More research needs to be done on the clinical consequences of vitamin K deficiency for the peripheral tissues.
Chatrou ML, Winckers K, Hackeng TM, Reutelingsperger CP, Schurgers LJ. Vascular calcification: the price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev. 2012 Jul;26(4):155-66.
Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs. Several lines of evidence indicate, however, that vascular calcification is one of the side-effects of VKA. Vascular calcification is an actively regulated process involving vascular cells and a number of vitamin K-dependent proteins. This review addresses vitamin K-cycle and vitamin K-dependent processes of vascular calcification that are affected by VKA. We conclude that there is a growing need for better understanding of the effects of anticoagulants on vascular calcification and atherosclerosis.
Clauser S, Meilhac O, Biech I, Raynal P, Bruneval P, Michel JB, et al. Increased secretion of Gas6 by smooth muscle cells in human atherosclerotic carotid plaques. Thromb Haemost. 2012;107:140-149.
Dalmeijer GW, van der Schouw YT, Vermeer, C, Magdeleyns, EJ, Schurgers LJ, Beulens JWJ. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. J of Nutri Biochem. July 2012.
This cross-sectional study investigated the association of Matrix Gla Protein (MGP) with coronary artery calcification and vitamin K status among 200 healthy women. The ratio of uncarboxylated to carboxylated osteocalcin was used a proxy of vitamin K status. The results showed that circulating levels of uncarboxylated MGP may serve as a biomarker of vitamin K status, and may also be a reflection of coronary artery calcification status.
Holmes MV, Hunt BJ, Shearer MJ. The role of dietary vitamin K in the management of oral vitamin K antagonists. Blood Reviews. 2012 Jan;26(1):1-14.
Preliminary evidence suggests that the stability of anticoagulation therapy may be improved by daily vitamin K supplementation, but further studies are needed whether this, or other dietary interventions can improve anticoagulant control in routine clinical practice.
Jia G, Stormont RM, Gangahar DM, Agrawal DK. Role of matrix Gla protein in angiotensin II-induced exacerbation of vascular calcification. Am J Physiol Heart Circ Physiol. 2012;303(5):H523-H532.
Recently, angiotensin II (ANGII) was found to play a key role in vascular calcification with both growth-promoting and inflammatory effects. This study investigated the effect of matrix Gla-protein in vascular calcification induced by ANG II in human vascular smooth muscle cells. The results found three new functions for MGP: inhibition of calcium deposition, suppression of inflammation, and increase in cell survival.
Naik V, Leaf EM, Hu JH, Yang H-Y, Nguyen NB, et al. Sources of cells that contribute to atherosclerotic intimal calcification: an in vivo genetic fate mapping study. Cardiovascular Research. 2012;94:545-554.
Schurgers LJ, Joosen IA, Laufer EM, Chatrou MLL, Herfs M, et al. Vitamin K-antagonists accelerate atherosclerotic calcification and induce a vulnerable plaque phenotype. PlosS ONE 7(8):e43229. Available at www.plosone.org/article/info:doi/10.1371/journal.pone.0043229.
Studied groups of patients using vitamin K antagonists (VKA), such as Coumadin, and those who were not using VKA. The results indicate that VKA use is associated with an increase of atherosclerotic plaque calcification. The study demonstrated that VKA treatment is associated with accelerated calcification of atherosclerotic plaques in humans, and demonstrated in a mouse model that VKA affects plaque negatively by making plaques more unstable and vulnerable to rupture.
Theuwissen E, Smit E, Vermeer C. The role of vitamin K in soft-tissue calcification. Adv Nutr March 2012;3:166-73.
Seventeen vitamin K-dependent proteins have been identified to date of which several are involved in regulating soft-tissue calcification. Osteocalcin, matrix Gla protein (MGP), and possibly Gla-rich protein are all inhibitors of soft-tissue calcification and need vitamin K-dependent carboxylation for activity. MGP is synthesized by vascular smooth muscle cells and is the most important inhibitor of arterial mineralization currently known. Remarkably, the extrahepatic Gla proteins mentioned are only partly carboxylated in the healthy adult population, suggesting vitamin K insufficiency. Because carboxylation of the most essential Gla proteins is localized in the liver and that of the less essential Gla proteins in the extrahepatic tissues, a transport system has evolved ensuring preferential distribution of dietary vitamin K to the liver when vitamin K is limiting. This is why the first signs of vitamin K insufficiency are seen as undercarboxylation of the extrahepatic Gla proteins. Vitamin K intervention studies have shown that MGP carboxylation can be increased dose dependently, but thus far only 1 study with clinical endpoints has been completed. This study showed maintenance of vascular elasticity during a 3-y supplementation period, with a parallel 12% loss of elasticity in the placebo group. More studies, both in healthy subjects and in patients at risk of vascular calcification, are required before conclusions can be drawn.
Chatrou MLL, Winckers K, Hackeng TM, Reutlingsperger CP, Schurgers LJ. Vascular calcification: The price to pay for anticoagulation therapy with vitamin K-antagonists. Blood Rev. 2012; Jul;26(4):155-66.
Vitamin K-antagonists (VKA) are the most widely used anti-thrombotic drugs with substantial efficacy in reducing risk of arterial and venous thrombosis. Several lines of evidence indicate, however, that VKA inhibit not only post-translational activation of vitamin K-dependent coagulation factors but also prevent the synthesis of functional extra-hepatic vitamin K-dependent proteins thereby eliciting undesired side-effects. Vascular calcification is one of the recently revealed side-effects of VKA. Vascular calcification is an actively regulated process involving vascular cells and a number of vitamin K-dependent proteins. This review addresses the vitamin K-cycle and vitamin K-dependent processes of vascular calcification that are affected by VKA. We conclude that there is a growing need for better understanding of the effects of anticoagulants on vascular calcification and atherosclerosis.
Dalmeijer GW, van der Schouw YT, Magdeleyns E, Ahmed N, Vermeer C, Beulens JWJ. The effect of menaquinone-7 supplementation on circulating species of matrix Gla protein. Atherosclerosis. 2012 Dec;225(2):397-402.
A randomized, double-blind, placebo controlled trials was conducted to investigate whether MK7 supplementation increased the carboxylation of matrix Gla protein. Participants were randomly allocated to receive a placebo, 180 ug, or 140 ug of MK7 for twelve weeks. The results showed that those who received the MK7 increased the amount of carboxylated MGP circulating in their blood, by 31% and 46%. These changes were evident within four weeks of beginning supplementation.
Ikeda K, Souma Y, Akakabe Y, Kitamura Y, Matsuo, Shimoda Y, et al. macrophages play a unique role in the plaque calcification by enhancing the osteogenic signals exerted by vascular smooth muscle cells. Biochem Biophys Res Commun. 2012;425:39-44.
Booth SL, Centi A, Smith SR, Gundberg C. The role of osteocalcin in human glucose metabolism: marker or mediator? Nat Rev Endocrinol. 2013;9:43-55.
Dalmeijer GW, van der Schouw YT, Magdeleyns EJ, Vermeer C, Elias SG, Velthuis BK, de Jong PA, Beulens JW. Circulating species of matrix Gla protein and the risk of vascular calcification in healthy women. Int J Cardiol. 2013;168:e168–e170.
Dalmeijer GW, van der Schouw YT, Vermeer C, Magdeleyns EJ, Schurgers LJ, Beulens JW. Circulating matrix Gla protein is associated with coronary artery calcification and vitamin K status in healthy women. J Nutr Biochem. 2013;24:624–628.
Circulating MGP species with different conformations have been investigated as markers for coronary artery calcification (CAC). This cross-sectional study investigated the association of MGP species with CAC, vitamin K status among 200 healthy women. These results show that dp-ucMGP may serve as a biomarker of vitamin K status. Circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of CAC, but these findings need to be confirmed.
De Marchi S, Chiarioni G, Prior M, Arosio E. Young adults with coeliac disease may be at increased risk of early atherosclerosis. Aliment Pharmacol Ther. 2013;38:162–169.
Kruger T, Oelenberg S, Kaesler N, Schurgers LJ, van de Sandt AM, Boor P, et al. Warfarin induces cardiovascular damage in mice. Arerioscl, Thromb and Vasc Biol. 2013;33:2618-2624.
We know that vascular calcification is actively prevented by proteins acting systemically (fetuin-A) or locally (matrix Glal protein). Warfarin is widely prescribed to reduce coagulation but it also interferes with vitamin K and its activation of proteins that prevent calcification, particularly matrix Gla protein. In this study, warfarin was given to mice, and calcification was rapidly induced in the aorta and the heart. At the same time, matrix Gla protein gene expression decreased and inactive matrix Gla protein expression increased. Administering vitamin K2 reduced the development of calcification, but did not change the gene expression that had been triggered.
Legein B, Temmerman L, Blessen EA, Lutgens E. Inflammation and immune system interactions in atherosclerosis. Cell Mol Life Sci. 2013;70:3847.
Palmer CR, Blekkenhorst LC, Lewis JR, Ward NC, Schultz CJ. Quantifying dietary vitamin K and its link to cardiovascular health: a narrative review. Food & Function. 2013;11(4):2826-2837.
Epidemiological data suggest that high dietary MK intake may be protective again coronary heart disease mortality and coronary artery calcification. Further investigation using vitamin K supplementation and its effect on clinical outcomes are still needed. Preceding this, national databases of the vitamin K and K2 content of food need to be expanded, leading to comprehensive region-specific vitamin K databases.
Reid IR. Cardiovascular effects of calcium supplements. Nutrients. 2013;5(7):2522-2529.
A meta-analysis of trials with calcium supplements was conducted to assess their safety. This meta-analysis found a 27-31% increase in risk of myocardial infarction and a 12-20% increase in risk of stroke for folks taking calcium supplements. Administering the calcium with vitamin D did not lessen the adverse effects. They concluded from the data, that the risks of calcium supplements outweigh any skeletal benefits and that calcium supplements appear to be unnecessary for the efficacy of other osteoporosis treatments.
Schurgers LJ, Uitto J, Reutelingsperger CP. Vitamin K-dependent carboxylation of matrix Gla-protein: a crucial switch to control ectopic mineralization. Trends in MOl Med. 2013 Apr;19(4):217-226.
Vascular mineralization is currently recognized as an actively regulated process with cellular and humoral contributions. It is also a risk factor for cardiovascular morbidity and mortality. This review focuses on molecular mechanisms of vascular mineralization involving matrix Gla protein, which is a strong inhibitor of vascular calcification, and discusses the potential for treatments.
Shea MK, Booth SL, Miller ME, Burke GL, Chen H, Cushman M, et al. Association between circulating vitamin K1 and coronary calcium progression in community-dwelling adults: the Multi-Ethnic Study of Atherosclerosis. Am J Clin Nutr. 2013;98:197-208.
This study tested the hypothesis that low vitamin K status is associated with greater coronary artery calcification over a 2.5 year follow up. The 850 participants were part of the MESA cohort, which is an ongoing study of coronary vascular disease. Low vitamin K status was associated with a 34% higher odds of extreme CAC progress. The most notable finding was that folks taking antihypertensive medication were more than twice as likely to have extreme CAC progress if they had low serum vitamin K1. The hypertensive meds involved were primarily ACE inhibitors and thiazide diuretics. Given that one in five adults in the USA are treated for hypertension, and about half of all US adults may have low vitamin K status, the researchers called for intervention trials to determine whether improving vitamin K status reduces CAC progress for people being treated for hypertension.
Theuwissen E, Badmaev V, Vermeer C. Calcium intake and cardiovascular disease mortality: Is there a critical role for vitamin K? JAMA Internal Medicine. 2013;173:1841.
In a comment on other research published on calcium intake, these authors report that arterial calcification is an actively regulated process with a key function for vitamin K-dependent matrix Gla protein. Mature MGP is a powerful inhibitor of soft-tissue calcification and is abundantly expressed by vascular smooth muscle cells. Calcium supplements have been widely used for the prevention and treatment of osteoporosis. However, when nutritional vitamin K intake is low, the vitamin K-dependent proteins involved in calcium homeostasis are only partly activated, resulting in suboptimal control of tissue mineralization: one of the consequences may be excessive mineralization of the arteries. Recent studies demonstrate that MGP carboxylation can be improved significantly with supplemental vitamin K2 (menaquinone) thus eliminating uncarboxylated MGP. They recommend that vitamin K intake or MGP carboxylation be included as a potential confounder when analyzing the association between calcium intake and cardiovascular disease. The use of calcium with vitamin D supplements clearly increases the calcium load of the body and may need optimal control of calcium homeostasis.
Theuwissen E, Teunissen KJ, Srponk HMH, Hamulyak K, Ten Cate H, Shearer MJ, et al. Effect of low-dose supplements of menaquinone-7 (vitamin K2) on the stability of oral anticoagulant treatment: dose-response relationship in healthy volunteers. J of Thrombosis and Haemotosis. 2013 Jun;11(6):1085-1092.
Dalmeijer GW, van de Schouw YT, Booth SL, de Jong PA, Beulens JWJ. Phylloquinone concentrations and the risk of vascular calcification in healthy women. Arterioscler Thromb Vasc Biol. 2014;34:1587-90.
Observational studies consistently show that high intakes of menaquinone are associated with reduced arterial calcification and cardiovascular disease risk. However, these studies do not show the association between phylloquinone intake and the incidence of cardiovascular disease. This study attempts to elucidate the impact of phylloquinone intake on a cohort of 508 postmenopausal women, as to vascular calcification. The results did not show reduced vascular calcification, but the dosages in the study were quite a bit lower, suggesting that the protective effect of K1 can only be reached by taking supplements and not only with dietary intake.
Delanaye P, Krzesinski JM, Warling X, et al. Dephosphorylated-uncarboxylated Matrix Gla protein concentration is predictive of vitamin K status and is correlated with vascular calcification in a cohort of hemodialysis patients. BMC Nephrol. 2014;15:145.
El Asmar MS, Naoum JJ, Arbid EJ. Vitamin K dependent proteins and the role of vitamin K2 in the modulation of vascular calcification: a review. Oman Med J. 2014 May;29(3):172-7.
Vascular calcification is an actively regulated process involving vitamin K dependent proteins (VKDPs). The factors involved in the regulation of calcification are being studied, including matrix Gla protein (MGP) and vitamin K2 or menaquinones. Vitamin K2 has been shown to exhibit profound effects on reducing vascular calcification and has promising potential to be used as a treatment prevention for vascular calcification. Clinical trials studying the effect of VK2 on preventing calcification are underway. In recognition of the promise of VK2 on reducing the risk of heart disease, the International Life Science Institute (ILSI Europe) recommends that the amount of VK2 be considered in addition to VK1, when calculating the daily recommended value of vitamin K.
Goff DC, Jr, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Published correction appears in: J Am Coll Cardiol 2014;63:3026] J Am Coll Cardiol. 2014;63:2935–59.
Liabeuf S, Bourron O, Olivier B, Vemeer C, Theuwissen E, Magdeleyns E, et al. Vascular calcification in patients with type 2 diabetes: the involvement of matrix Gla protein. Cardiovasc Diabetol. 2014 Apr 24;13:85.
The objective of the present study of patients with type 2 diabetes and normal or slightly altered kidney function was to evaluate levels of inactive, dephospho-uncarboxylated MGP(dp-ucMGP) and total uncarboxylated MGP(t-ucMGP) and assess their links with biological and clinical parameters (including peripheral vascular calcification). They found that high dp-ucMGP levels were independently associated with below-knee arterial calcification score in patients with type 2 diabetes and normal or slightly altered kidney function.
Juanola-Falgarona M, Salas-Salvado J, Martinez-Gonzalez MA, Corella D, Estruch R, Ros E, Fito M, et al. Dietary intake of vitamin K is inversely associated with mortality risk. J Nutr. 2014. jn.113.1877740; first published online March 29, 2014.
A controlled trial assessed the association between the dietary intake of different types of vitamin K and mortality in a Mediterranean population at high cardiovascular risk. They found that vitamin K (phylloquinone) intake was inversely associated with a significantly reduced risk of cancer and all-cause mortality. People who increased their intake of vitamin K1 or K2 (menaquinone) during follow-up had a lower risk of cancer and all-cause mortality when compared to people who decreased or did not change their intake. Also people who increased their intake of vitamin K1 had a lower risk of cardiovascular mortality.
Mayer O Jr. Seidlerova J, Bruthans J, Filipovsky J, Timoracka K, Vanek J et al. Dephospho-uncarboxylated matrix Gla-protein is associated with mortality risk in patients with chronic stable vascular disease. Atherosclerosis. 2014 Jul;235(1):162-8.
Vitamin K is the essential co-factor for activation of matrix Gla protein, the natural inhibitor of tissue calcification. Dephospho-uncarboxylated MGP (dp-ucMGP) is a marker of vascular vitamin K status and is described to predict mortality in patients with heart disease and aortic stenosis. dp-ucMGP reflects low dietary intake of vitamin K resulting in less efficient inhibition of calcification. This study followed 799 patients who suffered from heart events in a cohort study for more than five years. They found that circulating dp-ucMGP and dp-cMGP were independently associated with all-cause and cardiovascular mortality. Patients who had high levels of dp-ucMGP (meaning vitamin K intake was too low) had a 90% increase of death in five years. They concluded that high levels of dp-ucMGP is a risk marker for cardiovascular disease.
Shea MK, Cushman M, Booth SL, Burke GL, Chen H, Kritchevsky SB. Associations between vitamin K status and haemostatic and inflammatory biomarkers in community-dwelling adults. The Multi-Ethnic Study of Atherosclerosis. Thromb Haemost. 2014 Sep 2; 112(3):438-44.
To test the hypothesis that higher vitamin K status is associated with lower haemostatic activation and inflammation in community-dwelling adults, we analysed the cross-sectional association between serum phylloquinone (vitamin K1) with haemostatic and inflammatory biomarkers in 662 participants in the Multi-Ethnic Study of Atherosclerosis (MESA). These findings are consistent with laboratory-based studies that suggest a possible anti-inflammatory role for vitamin K.
Tuñón-Le Poultel D, Cannata-Andía JB, Román-García P, et al. Association of matrix Gla protein gene functional polymorphisms with loss of bone mineral density and progression of aortic calcification. Osteoporos Int 2014;25:1237–46.
van den Heuvel EGHM, van Schoor NM, Lips P, Magdeleyns EJP, Deeg DJH, Vermeer C, et al. Circulating uncarboxylated matrix Gla protein, a marker of vitamin K status, as a risk factor of cardiovascular disease. Maturitas. 2014 Feb;77(2):137-41.
Vitamin K plays a pivotal role in the synthesis of matrix Gla protein (MGP), a calcification inhibitor in vascular tissue. Vascular calcification has become an important predictor of cardiovascular disease. The aim of this current study was to examine the potential association of circulating dephosph-carboxylated and uncarboxylated MGP, reflecting vitamin K status, with the incidence of cardiovascular events and disease (CVD) in older individuals. 577 community dwelling older men and women of the Longitudinal Aging Study Amsterdam (LASA), aged >55 years, who were free of cardiovascular disease at baseline were followed for 5.6 years, and 40 incident cases of CVD were identified. They concluded that vitamin K insufficiency, as assessed by high plasma dp-ucMGP concentration is associated with increased risk for cardiovascular disease, independent of classical risk factors and vitamin D status. They recommended larger epidemiological studies followed by clinical trials to test whether vitamin K-rich diets will lead to a decreased risk for cardiovascular events.
Viegas CSB, Rafael MS, Enriquez JL, Teixeira A, Vitorino R, Luis IM, et al. Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arteriosclerosis, Thrombosis & Vascular Biology. Published online before print, December 23, 2014.
Vascular calcifications are pathological processes regulated by a complex interplay between calcification promoters and inhibitors, resembling skeletal metabolism. This study examined the role of vitamin K dependent Gla-rich proteins (GRP) in vascular and valvular calcification processes. Using an ex vivo model of vascular calcification, carboxylated GRP, but not undercarboxylated GRP was shown to inhibit calcification and osteochondrogenic differentiation. They concluded that GRP is an inhibitor of vascular and valvular calcification and is involved in calcium homeostasis, dependent on the availability of vitamin K for carboxylation.
Vörös K, Cseh K, Kalabay L. The role of fetuin-A in cardiovascular diseases. Orv Hetil. 2014 Jan 5;155(1):16-23.
Fetuin-A (also known as α2-Heremans-Schmid glycoprotein), is a multifunctional molecule secreted by the liver. Its level in the blood correlates with insulin resistance. It is also a natural inhibitor of tissue and vascular calcification, acting as a protective factor in atherosclerosis. The potential role and prognostic value of fetuin-A in arterial calcification and cardiovascular disease is discussed in this review.
Willems BAG, Vermeer C, Reutelingsperger CPM, Schurgers LJ. The realm of vitamin K dependent proteins: shifting from coagulation toward calcification. Molec Nutri & Food Research. 2014 Aug;58(8):1620-35.
In the past few decades, vitamin K has emerged from a single-function "haemostasis vitamin " to a "multi-function vitamin". More than 14 proteins have been identified that depend on vitamin K and they fall into two groups; hepatic, which are involved in blood coagulation, and extrahepatic, which are involved with other bodily tissues outside of the liver. Proteins that depend on vitamin K are involved in pathological calcification. A deficiency of vitamin K entails the risk of soft tissue calcification and vascular disease. Research results suggest that the use of vitamin K is potentially beneficial in attenuating the progression of vascular calcification and several outcome trials are currently underway.
Aziz F, Patil P. Role of Prophylactic Vitamin K in Preventing Antibiotic Induced Hypoprothrombinemia. Indian J. Pediatr. 2015;82:363–367.
Bonow RO, Greenland P.. Population-wide trends in aortic stenosis incidence and outcomes. Circulation 2015;131:969–971.
Brandenburg VM, Schurgers LJ, Kaesler N, Pusche K, van Gorp RH, Leftheriotis G, Reinartz S, et al. Prevention of vasculopathy by vitamin K supplementation: can we turn fiction into fact? Atherosclerosis. May 2015;240(1):10-16.
Vitamin K is a key factor in the regulation of bone and soft tissue calcification (due to its ability to activate matrix Gla protein. Data from experimental animal models reveal that high intake of vitamin K can prevent and even reverse vascular calcifications. Clinical data indicate that taking vitamin K antagonists, such as warfarin can accelerate vascular calcification. No negative events were recorded even when 45 mg vitamin K2 were taken daily for three years in 2185 postmenopausal osteoporotic women.
Cavaco S, Viegas CS, Rafael, MS Ramos A, Magalhaes J, et al. Gla-rich protein is involved in the cross-talk between calcification and inflammation in osteoarthritis. Cell Mol Life Sci. 2015;73:1051-1065.
Chow B, Rabkin SW. The relationship between arterial stiffness and heart failure with preserved ejection fraction: a systemic meta-analysis. Herat Fail Rev. 2015;20(3):291-303.
Demer LL, Bostrom KI. Editorial: Conflicting forces of warfarin and matrix Gla protein in the artery wall. Arteriosclerosis, Thrombosis and Vascular Biology. 2015;35:9-10.
14 years ago it was discovered that after only 2 weeks of warfarin treatment, rats presented with massive calcification of the artery wall. The phenomenon was so robust that warfarin was often used to create calcification experimentally in the lab. There continues to be ample evidence that vascular calcification is greater in women taking warfarin and that it only increases. Over time, research has clarified the mechanisms by which warfarin interferes with vitamin K, which interferes with the function of matrix Gla protein, which is a key inhibitor of arterial mineralization or calcification. Warfarin also increases the risk of developing arterial malformations (AVMs) in mice. While there are some clinical benefits of warfarin in preventing blood clot events, there are now alternative anticoagulants that do not interfere with the benefits of vitamin K. Further clinical research on those alternatives are now warranted.
Knapen MHJ, Braam LAJLM, Drummen NE, Bekers O, Hoeks APG, Vermeer C. Menaquinone-7 supplementation improves arterial stiffness in healthy postmenopausal women: double-blind randomised clinical trial. Thromb Haemost. 2015 (Feb 19);113(5). epub ahead of print.
This study investigated long-term effects of MK7 supplementation (180 ug/day) on arterial stiffness in a double-blind, placebo-controlled trial. Stiffening of the arteries influences how hard the heart has to work to pump blood through the body. Stiff artery walls means your blood is pumped under higher pressure and the heart has to work harder and often faster. Healthy postmenopausal women received either placebo or MK7 for three years. After three years of MK7 supplementation, carotid femoral pulse wave velocity (cfPWF) and arterial stiffness significantly decreased in the total group and other vessel measures improved significantly. Long-term use of MK7 supplements improves arterial stiffness in healthy women.
Liu H-P, Gu Y-M, Thijs L, Knapen MHJ, Salvi E, Citterio L, et al. Inactive matrix Gla protein is causally related to adverse health outcomes. A Mendelian randomization study in a Flemish population. Hypertension. 2015;65(2):463-70.
Matrix Gla-protein is a vitamin K-dependent protein that strongly inhibits arterial calcification. Vitamin K deficiency leads to production of inactive nonphosphorylated and uncarboxylated matrix Gla protein (dp-ucMGP). In a Flemish population study, we measured circulating dp-ucMGP at baseline (1996-2011), genotyped MGP, recorded adverse health outcomes, and assessed the multivariable-adjusted associations of adverse health outcomes with dp-ucMGP. They found that higher dp-ucMGP (or vitamin K deficiency) predicts total, non-cancer and cardiovascular mortality, but lower coronary risk.
Mayer Jr O, Seidlerova J, Wohlfart P, Filipovsky J Vanek J, Cifkova R, et al. Dephosph-uncarboxylated matrix Gla protein is associated with increased aortic stiffness in a general population. J Human Hyperten. 2016;30:418-423.
Matrix Gla protein (MGP), a natural inhibitor of calcification, strongly correlates with the extent of coronary calcification. Vitamin K is the essential cofactor for the activation of MGP. The nonphosphorylated-uncarboxylated isoform of MGP (dp-ucMGP) reflects the status of this vitamin. We investigated whether there is an association between dp-ucMGP and stiffness of elastic and musculartype large arteries in a random sample from the general population. We found that subjects in the top quartile of dp-ucMGP (⩾ 671 pmol l−1 ) had a higher risk of elevated aortic PWV. In conclusion, increased dp-ucMGP, which is a circulating biomarker of vitamin K status and vascular calcification, is independently associated with aortic stiffness, but not with stiffness of distal muscular-type arteries.
Nicoll R, Howard JM, Henein MY. A review of the effect of diet on cardiovascular calcification. Int J Mol Sci. 2015;15:8861-8883.
Although there are insufficient studies of intake or serum levels of nutrients to draw firm conclusions, in general intake of long chain ω3 PUFAs, calcium, magnesium, vitamins B, D and K and antioxidants should be increased. In practice this amounts to avoiding sugar and processed foods and increasing oily fish, fruits and vegetables. Animal studies have shown that many of the micronutrients discussed here may be effective in lowering or preventing CV calcification. In particular, it would be worth testing the effects of long chain ω3 PUFAs, magnesium and vitamin K.
Org E, Mehrabian M, Lusis AJ. Unraveling the environmental and genetic interactions in atherosclerosis: Central role of the gut micobiota. Atherosclerosis. 2015;241:387-99.
Piven E, Ponte B, Pruijm M, Ackermann D, Guessous I, Ehret G, et al. Inactive matrix Gla-protein is associated with arterial stiffness in an adult population-based study. Hypertension. 2015;66:85-92.
Increased pulse wave velocity (PWV) is a marker of aortic stiffness and is also an independent predictor of mortality. Matrix Gla-protein is a vascular calcification inhibitor that needs vitamin K to be activated. This study looked at the relationship between high levels of dp-ucMGP and increased PWV. 1001 participants from Switzerland were tracked. They found that high levels of dp-ucMGP are independently and positively associated with arterial stiffness, and if you have a deficiency of vitamin K in your system, your risk of having arterial stiffness is high. Vitamin K supplements stabilize vascular arterial properties.
Scheiber D, Veulemans V, Horn P, Chatrou ML, Potthoff SA, Kelm M, et al. High-dose menaquinone-7 supplementation reduces cardiovascular calcification in a murine model of extraosseous calcification. Nutrients. 2015 Aug 18;7(8):6991-7011.
Cardiovascular calcification is prevalent in the aging population and in patients with kidney disease and diabetes, cause high rates of mortality. Vitamin K-dependent matrix Gla-protein (MGP) is an important inhibitor of calcification. This study evaluated the impact of high-dose MK7 supplementation (100ug/g diet) on the development of calcification in rodents. The data showed that MK7 supplementation inhibited cardiovascular calcification and decreased aortic alkaline phosphatase tissue concentrations. It had a protective effect on the secondary mineralization of damaged vascular structures.
Singh S, Kullo IJ, Pardi DS, Loftus EV. Epidemiology, risk factors and management of cardiovascular diseases in IBD. Nat Rev Gastroenterol Hepatol. 2015;12:26–35.
Tantisattamo E, Han KH, O'Neill C. Increased vascular calcification in patients receiving warfarin. Arteriosclerosis, Thrombosis and Vascular Biology. 2015;35:237-42.
Mammograms from women with current, past or future warfarin use were examined for arterial calcification and compared with mammograms obtained in untreated women matched for age and diabetes mellitus. In 451 women with mammograms performed after more than one month of warfarin therapy, the prevalence of arterial calcification was 50% greater than in 451 untreated women. The findings indicate that the prevalence of breast arterial calcification is increased in women with current or past warfarin use. This effect appears to be cumulative and may be irreversible.
Varsha MK, Thiagarajan R, Manikandan R, Dhanasekaran G. Vitamin K1 alleviates streptozotocin-induced type 1 diabetes by mitigating free radical stress, as well as inhibiting NF-kB activation and iNOS expression in rat pancreas. Nutrition. 2015 Jan; 31(1):214-22.
Viegas CS, Rafael MS, Enriquez JL, Teixeira A, Vitorino R, Luis IM, et al. Gla-rich protein acts as a calcification inhibitor in the human cardiovascular system. Arterioscler Thromb Vasc Biol. 2015 Feb;35(2):399-408.
Vascular and heart valve calcifications are pathological processes regulated by local cells and dependent on a complex interplay between calcification promoters and inhibitors. This study looks a Gla-rich protein (GRP), a vitamin K dependent protein. Using mass spectrometry, carboxylated GRP, but not undercarboxylated GRP was shown to inhibit calcification and osteochondrogenic differentiation. GRP was part of an MGP-Fetuin-A complex at the sites of vascular calcification. They concluded that GRP was an inhibitor of vascular and valvular calcification involved in calcium homeostasis, and was dependent on being carboxylated, which requires vitamin K.
Yamamoto K, Yamamoto H, Takeuchi M, et al. Risk factors for progression of degenerative aortic valve disease in the Japanese- the Japanese aortic stenosis study (JASS) prospective analysis. Circ J. 2015;79:CJ-15-0499.
Chen L, Hsiao F, Shen L, Wu FL, Tsay W. Use of hypoprothrombinemia-inducing cephalosporins and the risk of hemorrhagic events: a nationwide nested case-control study. PLoS ONE. 2015;27:e0158407.
Authors/Task Force Members. Piepoli MF, Hoes AW, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR) Eur J Prev Cardiol. 2016;23:NP1–NP96.
Cundiff DK, Aqutter PS. Cardiovascular disease death before age 65 in 168 countries correlated statistically with biometrics, socioeconomic status, tobacco, gender, exercise, macronutrients, and vitamin K. Cureus. 2016 Aug 24;8(8):e748.
Danziger J, Young RL, Shea MK, Tracy RP, Ix JH, Jenny NS, et al. Vitamin K-dependent protein activity and incident ischemic cardiovascular disease: The multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. 2016 May;36(5):1037-42.
Vitamin K-dependent proteins (VKDPs) activity was determined by measuring circulating Des-gamma-carboxy Prothrombin (DCP) concentrations in 709 multi-ethnic adults free of cardiovascular disease. Lower DCP reflect greater VKDP activity. Subjects were followed for over 11 years. Their analysis suggested that VKDP activity is associated with the incidence of ischemic cardiovascular disease, and improving intake of vitamin K can reduce the incidence of cardiovascular disease.
De Brouwer B, Spanbroek M, Drummen NE, et al. Low vitamin K status is associated with COPD and accelerated degradation of mature elastin. Am J Respir Crit Care Med. 2016;193:A4134.
There is an inverse correlation between vitamin K status and the rate of elastin degradation in both patients with chronic obstructive pulmonary disease (COPD) and controls with no lung disease.
Fusaro M, Giannini S, Gallieni M, Noale M, Tripepi G, Rossini M, et al. Calcimimet and vitamin D analog use in hemodialyzed patients is assocated with increased levels of vitamin K dependent proteins. Endocrine. 2016;54(2):333-41.
Matrix Gla protein (MGP) and bone Gla protein (BGP) are two vitamin K-dependent proteins (VKDPs) involved in the regulation of vascular calcification (VC). We carried out a secondary analysis of the VIKI study to evaluate associations between drug consumption and vitamin K dependent protein levels in 387 hemodialyzed patients. The VIKI study assessed the prevalence of vitamin K deficiency in hemodialysis patients. We evaluated drug consumption, determined BGP and MGP levels, and verified the presence of any vertebral fractures (VF) and VC by spine radiographs. Total BGP levels were twice as high with calcimimetics versus no calcimimetics, and 69 % higher with vitamin D analogs. Total MGP was 19 % higher with calcimimetics and no difference was found with vitamin D analogs. Pending studies on vitamin K supplementation, calcimimetics, and vitamin D analogs may play a role in preserving vitamin K-dependent protein activity, thus contributing to bone and vascular health in CKD patients.
Han KH, O'Neill WC. Increased peripheral arterial calcification in patients receiving warfarin. J Am Heart Assoc. 2016;5:e002665. doi: 10.1161/JAHA.115.002665.
Harshman S.G., Shea M.K. The Role of Vitamin K in Chronic Aging Diseases: Inflammation, Cardiovascular Disease, and Osteoarthritis. Curr. Nutr. Rep. 2016;5:90–98. Inflammation is recognized as a crucial component of many chronic aging diseases and evidence suggests vitamin K has an anti-inflammatory action that is independent of its role as an enzyme co-factor. Vitamin K-dependent proteins and inflammation have been implicated in cardiovascular disease and osteoarthritis, which are leading causes of disability and mortality in older adults. The purpose of this review is to summarize observational studies and randomized trials focused on vitamin K status and inflammation, cardiovascular disease, and osteoarthritis.
Ikari Y, Torii S, Shioi A, Okano T. Impact of menaquinone-4 supplementation on coronary artery calcification and arterial stiffness: an open label single arm study.
Jiang X, Tao H, Qiu C, Ma X, Li S, Guo X, Lv A. Vitamin K2 regression aortic calcification induced by warfarin via Gas6?Axl survival pathway in rats. European J of Pharma. 2016 May;786:10-18.
This study induced aortic calcification in 54 rats, using warfarin. They then divided that rats into groups, and looked at the effect vitamin K2 had on the calcification created by the warfarin. There were two groups, the calcification group who were on a diet containing warfarin and K1, and the control group, which received no warfarin and no extra vitamin K. The rats in each group were killed at 1,4,6, and 12 weeks. The results showed that the vitamin K2 treatment significantly decreased the amount of calcium deposited. In the 12 week, there was 60% less calcium deposited. Whether or not the warfarin intervention was stopped at six weeks or not, the calcification continued. They concluded that vitamin K2 significantly reversed warfarin induced aortic calcification. The authors wonder if the mechanism of vitamin K2 reversal was through the Gas6 pathway, another vitamin K dependent protein.
Kaesler N, Immendorf S, Ouyang C, Herf M, Drummen N, Carmeliet P,et al. Gas6 protein: its role in cardiovascular calcification. BMC Nephrol; 2016 May;17(1):52.
Pan MH, Maresz K, Lee PS, Wu JC, Ho CT, Popko J, et al. Inhibition of TNF--α, IL-1α, and IL-1β 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.
Seidlerová J, Vaněk J, Vaněk J, et al. The abnormal status of uncarboxylated matrix Gla protein species represents an additional mortality risk in heart failure patients with vascular disease. Int J Cardiol. 2016;203:916–22.
Silaghi CN, Gheorge SR, Fodor D, Craciun AM. Circulating matrix Gla protein in patients with vascular pathology. Human and Veterinary Medicine. 2016 Dec;8(4):187-191.
Matrix Gla protein (MGP) is a vitamin K-dependent protein and an inhibitor of vascular calcification. Vitamin K is required for the carboxylation of MGP and can thereby reduce calcification. Circulating MGP species with different conformations have been investigated as markers for coronary artery calcification (CAC). In high-risk populations, high total uncarboxylated MGP (t-ucMGP) was associated with decreased CAC, while high non-phosphorylated uncarboxylated MGP (dp-ucMGP) was associated with a poor vitamin K status. This cross-sectional study investigated the association of MGP species with CAC, vitamin K status among 200 healthy women. These results show that dp-ucMGP may serve as a biomarker of vitamin K status. Circulating dp-ucMGP and t-ucMGP may serve as markers for the extent of CAC, but these findings need to be confirmed.
Torii S, Ikari Y, Tanabe K, Kakuta T, Hatori M, Shioi A, et al. Plasma phylloquinone, menaquinone-4 and menaquinone-7 levels and coronary artery calcification. J of Nutri Sci. 2016;5(e48):1-6.
This study found that coronary artery calcification correlated with markers of chronic insufficiency of vitamin K, suggesting that the chronic intake of sufficient vitamin K may have an inhibitory effect of CAC.
Venardos N, Bennett D, Weyant MJ, Reece TB, Meng X, Fullerton D. Matrix Gla protein regulates calcification of the aortic valve. J Surg Res. 2016 Nov 1;199(1):106.
This study researched the relationship between matrix Gla protein and diseased aortic valve interstitial cells (AVIC), via MGP expression, using normal valves obtained from patients undergoing valve and heart transplants. They found that diseased AVICs secreted significantly lower levels of MGP compared to normal AVICs, ranging from mRNA to fully formed secreted protein. The results suggested that an important anti-calcification protein was lacking in diseased AVICs. Diseased AVICs seem to be incapable of expressing adequate amounts of MGP.
Zhang Y, Qi L, Gu W, Yan Q, Dai M, Shi J, et al. Relation of serum osteocalcin level to risk of coronary heart disease in Chinese adults. Am J Cardiology. 2016;106(10):1461-65.
This study investigated whether serum osteocalcin concentration was associated with coronary heart disease (CHD) and metabolic profiles in Chinese adults. 461 subjects were studied. Results showed that serum osteocalcin levels were significantly lower in the CHD group. There was a linear relationship between serum osteocalcin and CHD risk.
Brandenburg VM, Reinartz S, Kaesler N, et al. Slower progress of aortic valve calcification with vitamin K supplementation: results from a prospective interventional proof-of-concept study. Circulation. 2017;135(21):2081-3.
Calcific aortic stenosis is characterized by progressive aortic valve calcification (AVC). Medical treatment options are sparse. Data points to vitamin K as a potential protective factor for cardiovascular health, and vitamin K supplementation might retard the progression of calcification. They performed a 12 month prospective, single center, open label, randomized interventional trial in patient with asymptomatic or mildly symptomatic AVC. They received either K1 or a placebo. CT scans were conducted baseline and at the end of study. The trial cohort included 99 patients. Over 12 months, the AVC volume score progressed only 10% in patients receiving vitamin K, compared to 22% in the placebo group. This is the first controlled trial in men to demonstrate that vitamin K supplementation might decelerate the progression of calcification. They considered the results to represent the first proof of concept in the evaluation of the potential anti-calcification effects of vitamin K treatment in human calcific AVD.
Criqui MH, Knox JB, Denenberg JO, et al. Coronary artery calcium volume and density: potential interactions and overall predictive value. The Multi-Ethnic Stufy of Atherosclerosis. JACC Cardiovas Imaging. 2017;10:845-854.
Douthit MK, Fain ME, Nguyen JT, Williams CF, Jasti AH, Gutin B, et al. Phylloquinone intake is associated with cardiac structure and function in adolescents. J Nutr. 2017 Oct 1;147(10):1960-67.
This study looked at the associations between childhood vitamin K consumption and cardiac structure and function. They assessed the diet of 766 adolescents and their heart status, and concluded that the left ventricular structure hypertrophy decreased as phylloquinone intake increased. They concluded that cardiac structure and function variables are most favorable at higher phylloquinone intakes.
Janssen R, Vermeer C. Vitamin K deficit and elastolysis theory in pulmonary elasto-degenerative diseases. Medical Hypotheses. 2017;108:38-41.
Elastin is an absolute basic requirement for circulation and respiration. Matric Gla protein the most potent natural inhibitor of elastin calcification and requires vitamin K for its activation. The ‘vitamin K deficit and elastolysis theory posits that elastin degradation causes a rise in the vitamin K deficit and implies that vitamin K supplementation could be preventing elastin degradation. They hypothesize that vitamin K supplementation would reduce the rate of elastin degradation and thereby disease progression in pulmonary elasto-degenerative diseases, such as AATD, bronchiectasis, COPD and CF. They are testing the hypothesis in clinical trials in patients with AAT.
Mozos I, Stoian D, Luca CT. Crosstalk between vitamins A, B12, D, K, C, and E status and arterial stiffness. Disease Markers. 2017;;2017:8784971. doi: 10.1155/2017/8784971. Epub 2017 Jan 12.
Arterial stiffness is associated with cardiovascular risk, morbidity, and mortality. The present paper reviews the main vitamins related to arterial stiffness and enabling destiffening, their mechanisms of action, providing a brief description of the latest studies in the area, and their implications for primary cardiovascular prevention, clinical practice, and therapy. Vitamins A, B12, C, D, E, and K status is important in evaluating cardiovascular risk, and vitamin supplementation may be an effective, individualized, and inexpensive destiffening therapy.
Namba S, Yamaoka-Tojo M, Kakizaki R, Nemoto T, Fujiyoshi K, Kitasato L, et al. Effects on bone metabolism markers and arterial stiffness by switching to rivaroxaban from warfarin in patients with atrial fibrillation. Heart and Vessels. 2017;32:977-82.
Warfarin is an endogenous vitamin K antagonist; therefore, patients who are taking warfarin must be prohibited from taking vitamin K. Vitamin K is an essential cofactor required for the ɤ-carboxylation of vitamin K-dependent proteins including coagulation factors, osteocalcin (OC), matrix Gla protein (MGP), and the growth arrest-specific 6 (GAS6). This study aimed to evaluate the effects of changing from warfarin to rivaroxaban on bone mineral metabolism, vascular calcification, and vascular endothelial dysfunction. Switching to rivaroxaban from warfarin in patients with atrial fibrillation was associated with an increase of bone formation markers and a decrease of bone resorption markers, and also improvements of PWV and AI.
Neves PO, Andrade J, Moncao H. Coronary artery calcium score: current status. Radiol Bras. 2017 May-Jun;50(3):182-189.
The coronary artery calcium score plays an Important role In cardiovascular risk stratification, showing a significant association with the medium- or long-term occurrence of major cardiovascular events. Here, we discuss the following: protocols for the acquisition and quantification of the coronary artery calcium score by multidetector computed tomography; the role of the coronary artery calcium score in coronary risk stratification and its comparison with other clinical scores; its indications, interpretation, and prognosis in asymptomatic patients; and its use in patients who are symptomatic or have diabetes.
Ponziani FR, Pompili M, Di Stasio E, Zocco MA, Gasbarrini A, flore R. Subclinical atheroslcerosi sis linked to small intestinal bacterial overgrowth via vitamin K2-dependent mechanisms. World J Gastroenterol. 2017 Feb 21;23(7):1241-49.
SIBO is associated with reduced matrix Gla-protein activation as well as arterial stiffening, both of which are important indicators of subclinical atherosclerosis.
Qiu C, Zheng H, Tao H, Yu W, Jiang X, Li A, et al. Vitamin K2 inhibits rat vascular smooth muscle cell calcification by restoring the Gas6/Axl/Akt anti-apoptotic pathway. Mol Cell Biochem. 2017;433:149-159.
Riphagen IJ, Keyzer CA, Drummen NE, de Borst MH, Beulens JWJ, Gansevoort RT, et al. Prevalence and effects of functional vitamin K insufficiency: The PREVEND study. Nutrients. 2017 Dec;9(12):1334.
Matrix Gla Protein (MGP) is a strong vitamin K-dependent inhibitor of soft tissue calcification. This study assessed the prevalence of functional vitamin K insufficiency, as derived from plasma desphospho-uncarboxylated MGP (dp-ucMGP), and investigated whether plasma dp-ucMGP is associated with all-cause and cardiovascular mortality in a large general population-based cohort. We included 4275 subjects (aged 53 ± 12 years, 46.0% male) participating in the prospective general population-based Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. The prevalence of functional vitamin K insufficiency (i.e., dp-ucMGP > 500 pmol/L) was 31% in the total study population. This prevalence was significantly higher among elderly and subjects with comorbidities like hypertension, type 2 diabetes, chronic kidney disease, and cardiovascular disease (~50%). These associations remained significant after adjustment for potential confounders. Whether the correction of vitamin K insufficiency.
Schwalfenberg GK. Vitamins K1 and K2: The Emerging Group of Vitamins Required for Human Health. Journal of nutrition and metabolism. 2017;2017:6.
Vitamin K2 may be a useful adjunct for the treatment of osteoporosis, along with vitamin D and calcium, rivaling bisphosphonate therapy without toxicity. It may also significantly reduce morbidity and mortality in cardiovascular health by reducing vascular calcification. Vitamin K2 appears promising in the areas of diabetes, cancer, and osteoarthritis. Vitamin K use in warfarin therapy is safe and may improve INR control, although a dosage adjustment is required.
Shea MK, Booth SL, Weiner DE, Brinkley TE, Kanaya AM, Murphy RA, et al. Circulating vitamin K is inversely associated with incident cardiovascular disease risk among those treated for hypertension in the Health, Aging, and Body composition Study. J Nutr. 2017 May;147(5):888-895.
There is a role for vitamin K in coronary artery calcification, a manifestation of cardiovascular disease, because vitamin K-dependent proteins are present in vascular tissue. This study looked at phylloquinone (vitamin K1) and found that K1 status was not significantly associated with CVD risk overall, but that low levels of K1 was associated with a higher CVD risk in older adults treated for hypertension. (Typically MK7 is the vitamin associated with alleviating heart disease - not K1).
Van Ballegooijen AJ, Beulens JW. The role of vitamin K status in cardiovascular health: Evidence from observational and clinical studies. Curr Nutr Rep. 2017;6(3):197-205.
Vitamin K is a fat soluble vitamin required for the activation of several vitamin K-dependent proteins to confer functioning. Observational studies indicate that low vitamin K status plays a potential role in cardiovascular disease development. Assessing vitamin K status in prospective studies and randomized trials would provide an important insight as to whether vitamin K status is causally related to diseases.
Viegas CSB, Costa RM, Santos L, Videira PA, Silva Z, Araujo N, et al. Gla-rich protein function as an anti-inflammatory agent in monocytes/macrophages: Implications for calcification-related chronic inflammatory diseases. PLoS One. 2017;12(5):e0177829.
Calcification involves a complex interplay between inflammation and calcification events driving disease progression. Gla-rich protein (GRP) is a vitamin K dependent protein that functions as a calcification inhibitor in cardiovascular and articular tissues, and is proposed to be an anti-inflammatory agent. This study focused on GRP in the cell inflammatory response, and found that GRP acts as endogenous mediatory of inflammation in monocytes/macrophages, and has potential therapeutic applications.
Vissers LE, Dalmeijer GW, Boer JM, Verschuren WM, Van der Schouw YT, Beulens JW. The relationship between vitamin K and peripheral arterial disease. Atherosclerosis. 2017 Sep;252:15-20.
The relationship between phylloquinone and menaquinone intake and the risk of peripheral artery disease (PAD) was explored. They followed 36,629 participants for twelve years, with 489 cases of PAD being documented. The results showed that a high intake of menaquinones was associated with a reduced risk of PAD. A high intake of phylloquinone was not associated with a reduced risk of PAD.
Andrews J, Psaltis PJ, Bayturan O, Shao M, Stegman B, Elshazly M, et al. Warfarin Use Is Associated With Progressive Coronary Arterial Calcification: Insights From Serial Intravascular Ultrasound. JACC Cardiovasc. Imaging. 2018;11:1315–1323.
Warfarin blocks the synthesis and activity of matrix Gla protein, a vitamin K-dependent inhibitor of arterial calcification. Longitudinally, warfarin therapy was found to be associated with progressive coronary atheroma calcification independent of changes in atheroma volume.
Barrett H, O’Keeffe M, Kavanagh E, Walsh M, O’Connor EM. Is matrix Gla protein associated with vascular calcification? A systemic review. Nutrients. 2018;10(4):415;doi:10.3390/nu10040415
This systemic review examines twenty-eight studies which assess the relationship between circulating protein expressions of matrix Gla protein (MGP) species and vascular calcification in different arterial beds. The included studies examined participants with atherosclerosis, chronic kidney disease, diabetes, healthy participants, vitamin K supplementation and vitamin K antagonist usage. The review suggests that different underlying molecular mechanisms can accelerate local disease progression within the vasculature. They describe the directions for future research that could refine our knowledge of MGP and calcification.
Chirinos JA, Sardana M, Syed AA, Koppula MR, Varakantam S, Vasim I, Oldland HG, Phan TS, Drummen NEA, Vermeer C, Townsend RR, Akers SR, Wei W, Lakatta EG, Fedorova OV. Aldosterone, inactive matrix gla-protein, and large artery stiffness in hypertension. J Am Soc Hypertens. 2018;12:681–689.
Eggebrecht L., Prochaska H., Schulz A., Arnold N., Junger C., Gobel S., Laubert-reh D., Binder H., Beutel M.E., Pfeiffer N., et al. Intake of Vitamin K Antagonists and Worsening of Cardiac and Vascular Disease: Results From the Population-Based Gutenberg Study. J. Am. Heart Assoc. 2018;7:e008650.
Eshak ES, Iso H, Yamagishi K, Cui R, Tamakoshi A. Dietary intakes of fat soluble vitamins as predictors for mortality from heart failure in a large prospective cohort study. Nutrition. 2018 Mar;47:50-55.
This study looked at the relation of dietary intakes of fat-soluble vitamins A, K,E, and D with mortality from heart failure in Japanese population. During a median 19.3 year follow up they found that high dietary intakes of fat soluble vitamins K, E, And D were associated with a reduced risk for heart failure mortality in women but not in men.
Greenland P, Blaha M, Budoff MJ, Erbel R, Watson KE. Coronary calcium score and cardiovascular risk. J Am Coll Cardiol. 2018;72(4):434-447.
This review summarizes evidence concerning CAC, including its pathobiology, modalities for detection, predictive role, use in prediction scoring algorithms, CAC progression, evidence that CAC changes the clinical approach to the patient and patient behavior, novel applications of CAC, future directions in scoring CAC scans, and new CAC guidelines.
Kamenskiy A, Poulson W, Sim S, Reilly A, Luo J, MacTaggart J. Prevalence of calcification in human femoropopliteal arteries and its association with demographics, risk factors, and arterial stiffness. Arterioscler Thromb Vasc Biol. 2018;38(4):e48-e57.
Lindholt JS, Frandsen NE, Fredgart MH, Øvrehus KA, Dahl JS, Møller JE, et al. Effects of menaquinone-7 supplementation in patients with aortic valve calcification: study protocol for a randomized controlled trial. BMJ Open. 2018 Aug;8(8): e022019.
Aortic stenosis is a common heart valve disease, and due to the growing elderly population, the prevalence is increasing. The disease is progressive with increasing calcification of the valve cusps. A few attempts with medical preventive treatment have failed; thus, presently, the only effective treatment of aortic stenosis is surgery. This study will examine the effect of menaquinone-7 (MK-7) supplementation on progression of aortic valve calcification (AVC). We hypothesize that MK-7 supplementation will slow down the calcification process.
Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al. 2018 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European atherosclerosis society (EAS). Eur Heart J. 2020;41(1):111-188.
O’Grady S, Morgan MP. Microcalcifications in breast cancer: From pathophysiology to diagnosis and prognosis. Biochim Biophys Acta Rev Cancer. 2018;1869:310-320.
Peeters F, Dudink E, Kimenai D, Weijs B, Altintas S, Heckman L, Mihl C, Schurgers L, et al. Vitamin K antagonists, non-vitamin K antagonist oral anticoagulants, and vascular calcification in patients with atril fibrillation. TH Open. 2018;2:e391-e398.
Peeters FECM, Meex SJR, Dweck MR, Aikawa E, Crijns HJGM, Schurgers LJ, Kietselaer BLJH. Calcific aortic valve stenosis: hard disease in the heart. Eur Heart J. 2018 Jul 21;39(28):2618-2624.
Calcific aortic valve stenosis (CAVS) is common in the ageing population and set to become an increasing economic and health burden. Once present, it inevitably progresses and has a poor prognosis in symptomatic patients. No medical therapies are proven to be effective in holding or reducing disease progression. Therefore, aortic valve replacement remains the only available treatment option. Improved knowledge of the mechanisms underlying disease progression has provided us with insights that CAVS is not a passive disease. Rather, CAVS is regulated by numerous mechanisms with a key role for calcification. Aortic valve calcification (AVC) is actively regulated involving cellular and humoral factors that may offer targets for diagnosis and intervention. The discovery that the vitamin K-dependent proteins are involved in the inhibition of AVC has boosted our mechanistic understanding of this process and has opened up novel avenues in disease exploration.
Reutelingsperger C, Schurgers L. Coronary artery calcification: A Janus-faced biomarker? JACC: Cardiovascular Imaging. 2018;11(9):1324-26.
Coronary artery calcification (CAC) is highly prevalent in coronary heart disease and is associated with increased mortality. It was long regarded as an end-stage product resulting from chronic inflammation. This view has changed dramatically and it is now understood as a regulated process. Current technology and tools do now yet allow for some key measurements of CAC, such as microcalcifications and activity of the calcification process. It will be helpful when more features can be visualized and metrically measured from new noninvasive imaging protocols.
Tacey A, Qaradakhi T, Brennan-Speranza T, Hayes A, Zulli A, Levinger I. Potential role for osteocalcin in the development of atherosclerosis and blood vessel disease. Nutrients. 2018 Oct 4;10(10): pii: E1426
There is increasing evidence for the involvement of the skeleton in the regulation of atherosclerotic vascular disease. This review examines the evidence for a role of osteocalcin in atherosclerosis development and progression and in vascular calcification. Current literature suggests that undercarboxylated osteocalcin may protect endothelial cells and prevent atherogenesis (the process of forming plaques). It’s not yet settled whether osteocalcin acts as a mediator or a marker of vascular calcification. Further studies are called for to examine each form of osteocalcin as it relates to atherosclerosis, and whether it functions independently of metabolic factors.
Tsai, MT, Chen, YY, Chang, WJ, Li, SY. Warfarin accelerated vascular calcification and worsened cardiac dysfunction in remnant kidney mice. J Chin Med Assoc. 2018;81(4):324–330.
Vassalle C. New biomarkers and traditional cardiovascular risk scores: any crystal ball for current effective advice and future exact prediction? Clin Chem Lab Med. 2018;56(11):1803-05.
Wen L, Chen J, Duan L, Li S. Vitamin K-dependent proteins involved in bone and cardiovascular health (Review) Mol. Med. Rep. 2018;18:3–15.
In postmenopausal women and elderly men, bone density decreases with age and vascular calcification is aggravated. This condition is closely associated with vitamin K2 deficiency. A total of 17 different vitamin K-dependent proteins have been identified to date. Vitamin K-dependent proteins are located within the bone, heart and blood vessels. These vitamin K-dependent proteins may exert their functions following γ-carboxylation with vitamin K, and different vitamin K-dependent proteins may exhibit synergistic effects or antagonistic effects on each other. This review describes and briefly discusses several important vitamin K-dependent proteins that serve an important role in bone and the cardiovascular system. The results of the review suggest that the vascular calcification and osteogenic differentiation of vascular smooth muscle cells may be associated with the location of the bone and cardiovascular system during embryonic development.
Wang Z, Wang Z, Zhu J, Long X, Yan J. Vitamin K2 can suppress the expression of Toll-like receptor 2 (TLR2) and TLR4, and inhibit calcification of aortic intima in ApoE -/- mice as well as smooth muscle cells. Vascular. 2018 Feb;2691:18-26.
Vascular calcification is a common complication in atherosclerosis. Toll-like receptors are a class of proteins that play a key role in the immune system, usually expressed on macrophages and dendritic cells, and which initiate the immune response. Evidence shows that TLRs mediate pro-inflammatory and atherosclerosis. This study looked at the effects of vitamin K on TLR2 and TLR4. Mice who had a high fat died in ApoE-/- and received vitamin K, showed significantly lower calcium build up, and ALP (alkaline phosphatase), and lower levels of TLR2 and 4. They concluded that Vitamin K2 can inhibit intimal calcification of the aortic artery induced by a high fat diet and may be related to the Toll like receptors.
Wei FF, Trenson S, Monney P, et al Epidemiological and histological findings implicate matrix Gla protein in diastolic left ventricular dysfunction. PLoS One. 2018;13:e0193967 doi: 10.1371/journal.pone.0193967
Inactive uncarboxylated MGP was abundant in fibrotic areas of diseased hearts, around the nuclei of interstitial cells and in the perivascular matrix. Inactive unphosphorylated MGP was almost absent in vessel walls and in fibrotic areas but was abundant in cardiomyocytes of all hearts and co-localized with active carboxylated MGP.
Xu Y, Ma X, Ziong Q, Zhang X, Shen Y, Bao Y. Osteocalcin value to identify subclinical atherosclerosis over atherosclerotic cardiovascular disease (ASCVD) risk score in middle-aged and elderly Chinese asymptomatic men. Clin Chem Lab Med. 2018 Oct;56(11):1962-69.
Chen H-G, Sheng L-T, Zhang Y-B, Cao A-L, Lai Y-W, Kunutsor SK, et al. Association of Vitamin K with cardiovascular events and all-cause mortality: A systematic review and meta-analysis. Eur J Nutr. 2019 Sep;58(6):2191-2205.
This meta-analysis systematically assessed the association between vitamin K and cardiovascular disease events and all-cause mortality. They found that higher dietary vitamin K consumption was associated with a moderately lower risk of coronary heart disease.
Di Lullo L,Tripepi G, Ronco C, et al. Cardiac valve calcification and use of anticoagulants: preliminary observation of a potentially modifiable risk factor. Int J Cardiol. 2019;278:243–9.
Faggiano P, Dasseni N, Gaibazzi N, et al. Cardiac calcification as a marker of sub-clinical atherosclerosis and predictor of cardiovascular events: a review of the evidence. Eur J Prev Cardiol. 2019;26:1191-1204.
Ferland G, CHahine S, Presse N, Dube MP, Nigam A, Blostein M, et al. Increasing dietary vitamin K intake stabilizes anticoagulation therapy in warfarin-treated patients with a history of instability: A 24-week randomized controlled trial (OR36-04-19). Curr Dev Nutr. 2019;3(Suppl.1).
Warfarin (W) is a highly prescribed anticoagulant for the treatment and prevention of thromboembolic diseases. However, anticoagulation stability is often a challenge due to the narrow therapeutic range of the drug. In recent years, dietary vitamin K (VK) has emerged as an important modulator of long-term anticoagulation stability. In trials, patients receiving small doses of supplemental VK (100–150 mg/d) spend significantly more time in the therapeutic range (%TTR) and present fewer bleeding and thrombotic complications. Whether similar beneficial effects can be achieved through diet remains unknown. We determined whether increasing dietary VK intake by ≥150 µg/day improves anticoagulation stability of W-treated patients with a history of INR instability.
Hashmath Z, Lee J, Gaddam S, Ansari B, Oldland G, Javaid K, Mustafa A, Vasim I, Akers S, Chirinos JA. Vitamin K status, warfarin use, and arterial stiffness in heart failure. Hypertension. 2019;73:364–370.
Holden RM, Hetu MF, Li TY, Ward EC, Couture LE, Herr JE, et al. Circulating Gas6 is associated with reduced human carotid atherosclerotic plaque burden in high risk cardiac patients. Clin Biochem. 2019;64:6-11.
Lees JS, Chapman FA, Witham MD, Jardine AG, Mark PD. Vitamin K status, supplementation and vascular disease: A systematic review and meta-analysis. Heart. 2019 June;105(12):938-45.
This article did a systematic review and meta-analysis of vitamin K supplementation on vascular stiffness and vascular calcification. The review indicated that supplementing with vitamin K significantly reduced calcification but not stiffness.
Mandatori D, Pipino C, Di Torno P, Chiavone V, Ranieri A, Pantalone S, et al. Osteogenic transdifferentiation of vascular smooth muscle cells isolated from spontaneously hypertensive rats and potential menaquinone-4 inhibiting effect. J of Cell Physio. 2019 Apr 1;234(11):19761-773.
Vascular calcification (VC) is an active and cell‐mediated process that shares many common features with osteogenesis. Vascular smooth muscle cells (vSMCs) can lose their contractile phenotype and transdifferentiate into osteoblastic‐like cells, contributing to VC development. The aim of this study was to investigate the possible role of menaquinone‐4 (MK‐4), an isoform of MKs family, in the modulation of the vSMCs phenotype. The results showed that MK‐4 preserves the contractile phenotype through a γ‐glutamyl carboxylase‐dependent pathway, highlighting its capability to inhibit one of the mechanisms underlying VC process. MK4 could be a natural food supplement that inhibits vascular dysfunction.
Patntirapong S, Phupunporn P, Vanichtantiphong D, et al. Inhibition of macrophage viability by bound and free bisphosphonates. Acta Histochem. 2019;121:400-406.
Chen Z, Qureshi AR, Parini P, et al. Does statins promote vascular calcification in chronic kidney disease? Eur J Clin Invest. 2017;47:197-208.
Roumeliotis S, Dounousi E, Eleftheriadis T, Liakopoulos V. Association of the inactive circulating Matrix Gla Protein with vitamin K intake calcification, mortality, and cardiovascular disease: A review. Int J Mol Sci. 2019 Feb;20(3):DOI: 10.3390/ijms20030628.
Vascular calcification is not a passive, degenerative, untreatable disease, but an active process in which proteins and molecules are involved. MGP is the most powerful natural calcification inhibitor found in the human body, and is tightly associated with all types of calcification, mortality, and cardiovascular disease. Exogenous supplementation of vitamin K might upregulate its function, reduce calcification, and protect against mortality and cardiovascular disease.
Saputra WD, Aoyama N, Komai M, Shirakawa H. Menaquinone-4 suppresses lipopolysaccharide-induced inflammation in MG6 mouse microglia-derived cells by inhibiting the NF-kB signaling pathway. Int J Mol Sci. 2019 May;20(9):2317.
Increasing evidence shows that MK4 can attenuate inflammation. This study investigated the effect of MK4 on microglial activation and found that Mk4 suppressed the upregulation of inflammatory cytokines at the mRNA level. Inflammation was attentuated by inhibiting Nf-kB signaling.
Shikdar S, Bhattacharya PT StatPearls [Internet] StatPearls Publishing; Treasure Island, FL, USA: 2019. [(accessed on 12 December 2019)]. International Normalized Ratio (INR) [Updated 2019 Mar 25]
Tasfamariam B. Involvement of vitamin K-Dependent proteins in vascular calcification. J of Cardio Pharm & Thera. 2019;24(4):323-333.
This article overviews the involvement of systemically and locally expressed vitamin K-dependent proteins in vascular calcification and their potential as biomarkers of calcification. Vascular calcification results from an imbalance of promoters and inhibitors of mineralization in the vascular wall, culminating in the creation of an organized extracellular matrix deposition. The underlying initiators of dysregulated calcification maintenance are diverse. They range from the expression of bone-associated proteins, to the osteogenic trans-differentiation of smooth muscle cells, to the release of fragmented apoptotic bodies and mineralization competent extracellular vesicles by smooth muscle cells, which as act as a nucleation site. The process involves a complex interplay between vitamin K-dependent calcification inhibitory proteins and stimulatory mediators, such as osteocalcin. Vitamin K plays an important role. Drugs that inhibit vitamin K, result in the accumulation of uncarboxylated proteins that lack calcification-inhibitory capacity.
Van den Bergh G, Opdebeeck B, D'Haese PC, Verhulst A. The Vicious Cycle of Arterial Stiffness and Arterial Media Calcification. Trends Mol Med. 2019 25:1133-1146.
Wei F, Thijs L, Cauwenberghs N, Yang W, Zhang A, Yu C, et al. Central hemodynamics in relation to circulating Desphospho-uncarboxylated Matrix Gla Protein: A population study. J Am Heart Assoc. 2019;8:01 1960.
This study evaluated vitamin K status in Flemish individuals. They found that higher level of uncarboxylated Matrix Gla Protein (meaning deficient vitamin K intake) was associated with greater pulse wave velocity (PWV) and greater pulse waves. Stiffening and calcification of large arteries are forerunner of cardiovascular complications. They concluded that improving vitamin K status can preserve vascular integrity and prevent cardiovascular complications.
Wei FF, Trenson S, Verhamme P, Vermeer C, Staessen JA. Vitamin K-dependent matrix Gla protein as multifaceted protector of vascular and tissue integrity. Hypertension. 2019 Jun; 73(6):1160-1169.
Aging is one of the greatest social and economic challenges worldwide. In the FLEMENGHO study, it appears that vitamin K supplementation before irreversible organ damage sets in, might be important to prevent a wide range of disabling diseases. In aged people and folks with kidney disease, diabetes, or cardiac disease, levels of Matrix Gla Protein might be measured over time to track the risk of chronic disease.
Zhang S, Guo L, Bu C. Vitamin K status and cardiovascular events or mortality: A meta-analysis. Eur J Prev Cardiol 2019 Mar;26(5):549-553.
This study was a systematic review and meta-analysis of cohort studies to quantify the association between desphospho-uncarboxylated MGP (dp-ucMGP) and desphospho-carboxylated MGP (dp-cMGP) levels and cardiovascular risk. They concluded that folks with high levels of dp-ucMGP) or vitamin K deficiency have a significantly higher CVD and total mortality risk.
Ikari Y, Saito F, Kiyooka T, et al. Switching from warfarin to rivaroxaban induces sufficiency of vitamin K and reduction of arterial stiffness in patients with atrial fibrillation. Heart Vessels. 2020;35:1727-1733.
Use of chronic vitamin K antagonist (VKA) induces a long-term deficiency of vitamin K, which may cause arterial stiffness and bone-related disease. Switching from VKA to rivaroxaban could induce rapid sufficiency of vitamin K and improvement of arterial stiffness. The K2 SUMMIT-3 study is a multicenter, open-label, prospective, and randomized design. Patients with atrial fibrillation who have been taking VKA for more than 6 months but less than 10 years were randomly assigned to two groups; those switching from VKA to rivaroxaban and those continuing with VKA medication. Switching from VKA to rivaroxaban resulted in rapid sufficiency of vitamin K and reduction of arterial stiffness in 3 months.
Karsli-Ceppioglu S,Yazar S, Keskin Y, et al. Association of Genetic Polymorphisms in the Matrix Gla Protein (MGP) Gene with Coronary Artery Disease and Serum MGP Levels. Balkan J Med Genet. 2019;22:43–50.
Silaghi CN, Fodor D, Gheorghe SR, Cracium AM. Serum total matrix Gla protein: reference interval in healthy adults and variations in patients with vascular and osteoarticular diseases. Clinica Chimia Acta:Int J Clinic Chem. 2019 Mar;490:128-134.
Matrix Gla protein (MGP) species are inhibitors of ectopic calcification in vascular diseases (VD) and osteoarticular diseases (OD). This study aimed to establish the reference interval for serum total MGP (tMGP) in healthy adults, the variation in patients with VD and OD and the associations with common cardiovascular risk factors. They found that total MGP decreases in healthy individuals over age 40. Found that serum levels of tMGP were significantly higher in patients with VD and OD compared to a healthy population. Established the reference interval for tMGP as 6-108 ug/L. Also serum tMGP levels were increased in smokers vs non-smokers. Concluded that total MGP was suitable to discriminate between the healthy population and patients with VD and OD. Higher tMGP levels could identify patients with VD and OD, being also associated with smoking in healthy adults.
Vermeer C, Hogne V. Effect of Menaquinone-7 (vitamin k2) on vascular elasticity in healthy subjects: results from a one-year study. Vasc Dis Ther. 2020;5:1-4.
3-year intervention studies in the general population have shown that increased vitamin K intake may decrease arterial stiffening, but the difference with placebo became only significant in the third year of treatment. In the present trial we have investigated whether in a pre-selected group of vitamin K-insufficient subjects (men and women) an effect of vitamin K-supplementation may be demonstrated within one year. Treatment was performed with either vitamin K (menaquinone-7, MK-7) or placebo for one year. In the total study group, MK-7 induced a significant decrease of both dp-ucMGP and cfPulse Wave Velocity. After subdividing by gender, it appeared that the effects were only seen in women, in whom we also found beneficial effects in other vascular characteristics as well as in body weight and BMI. High vitamin K intake decreased age-related vascular stiffening. The effects were most obvious in women with poor vitamin K status and were statistically significant after one year of treatment.
Hariri E, Kassis N, et al. Vitamin K2 – a neglected player in cardiovascular health: A narrative review. Open Heart. 2021;8:3001715.
Vitamin K2 serves an important role in cardiovascular health through regulation of calcium homeostasis. Its effects on the cardiovascular system are mediated through activation of the anti-calcific protein known as matrix Gla protein. In its inactive form, this protein is associated with various markers of cardiovascular disease including increased arterial stiffness, vascular and valvular calcification, insulin resistance and heart failure indices which ultimately increase cardiovascular mortality. Supplementation of vitamin K2 has been strongly associated with improved cardiovascular outcomes through its modification of systemic calcification and arterial stiffness. Strengthened by its affordability and Food and Drug Adminstration (FDA)-proven safety, vitamin K2 supplementation is a viable and promising option to improve cardiovascular outcomes.
Haugsgjerd TF, Egeland GM, Nygard OK, Vinknes KJ, Sulo G, Lysne V, et al. Association of dietary vitamin K and risk of coronary heart disease in middle-age adults: the Hordaland Health Study Cohort. BMJ Open. 2020 May 21;1085):e035953.
Participants in the community-based Hordaland Health Study in Norway from 1997-1999 through 2009 were followed to evaluated associations between intake of vitamin K and new onset of CHD. They found that a higher intake of vitamin K2 was associated with lower risk of CHD, while there was no association between the intake of vitamin K2 and CHD.
Jaminon AMG, Da L, Qureshi AR, Evenepoel P, Ripsweden J, Söderberg M, Witasp A, et al. Matric Gla protein is an independent predictor of both intimal and medial vascular calcification in chronic kidney disease. Scientific Reports. 2020;10:6586.
Lee SJ, Lee I-K, Jeon J-H. Vascular calcification – new insights into its mechanism. Int J Mol Sci. 2020 April;21:2685.
The past few decades have seen extensive research into vascular calcification, revealing that the mechanism occurs via delicate and well-organized biologic processes, including an imbalance between osteochondrogenic signaling and anti0calcific events. That work has shown that beyond a high-phosphate environment, several key proteins, related to VC pathophysiology, have been identified To provide understanding, this is a review of updated molecular mechanism of vascular calcification. As a consequence, therapeutic strategies targeting inflammation or inflammatory immune cells are anticipated to reduce unmet clinical needs in VC.
Shioi A, Morioka T, Shoji T, Emoto M. The inhibitory roles of vitamin K in progression of vascular calcification. Nutrients. 2020 Feb;12(2):583.
Vitamin K exerts anti-inflammatory effects which may prevent vascular calcification. Vascular calcification is a chronic inflammatory process in which activated macrophages promote osteoblastic differentiation of vascular smooth muscle cells (VSMCs) through the production of proinflammatory cytokines such as IL-1β, IL-6, TNF-α, and oncostatin M (OSM) in both intimal and medial layers of arterial walls. This process may be mainly mediated through NF-κB signaling pathway. Vitamin K has been demonstrated to exert anti-inflammatory effects through antagonizing NF-κB signaling in both in vitro and in vivo studies, suggesting that vitamin K may prevent vascular calcification via anti-inflammatory mechanisms. Vitamin K enhances the activity of MGP which also inhibits vascular calcification. Of the species of MGP, dephospho-uncarboxylated MGP (dp-ucMGP) may be regarded as the most useful biomarker of vitamin K deficiency and vascular calcification.
Van Gorp RH, Baaten CCFMJ, Habibi A, Jaminon AMG, Peeters FECM, et al. Vitamin K antagonist use induces calcification and atherosclerotic plaque progression resulting in increased hypercoagulability. European Heart Journel Open. 2020:00:1-11.
Vitamin K antagonists (VKA) are widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis, and are also associated with increased vascular calcification progression. This study treated mice with warfarin for 18 measures and measured plaque burden, calcification, and coagulation. The results showed that the VKA aggravated vascular calcification and atherosclerosis
Vossen LM, Kroon AA, Schurgers LJ, de Leeuw PW. Pharmacological and nutritional modulation of vascular calcification. Nutrients. 2020 Jan;12(1):100.
Vascular calcification is an independent predictor of cardiovascular disease, and therefore, inhibition or regression of this process is of clinical importance. The standard care regarding prevention and treatment of cardiovascular disease at this moment mainly depends on drug therapy. Although statin therapy has a proven role in the prevention and treatment of cardiovascular morbidity and mortality, it is associated with both regression and acceleration of the vascular calcification process. Recently, nutritional supplements have been recognized as a potential tool to reduce calcification. This is particularly true for vitamin K, which acts as an inhibitor of vascular calcification. In this narrative review, we discuss the current state of knowledge regarding the pharmacological and nutritional possibilities to prevent the development and progression of vascular calcification.
Vik CVaH. Effect of menaquinone-7 (vitamin k2) on vascular elasticity in healthy subjects: Results from a one-year study. Vasc Dis Therapeut. 2020; 5:1–4.
Wessinger C, Hafer-Macko C, Ryan AS. Vitamin K intake in chronic stroke: Implications for dietary recommendations. Nutrients. 2020 Oct 6;12(10):3059.
Sufficient vitamin K intake is associated with cardiometabolic disease. Monitoring vitamin K intake could be an important tool for individuals with cardiovascular disease. 60 chronic stroke survivors completed food records, and 82% did not meet the Daily Recommended Intake for vitamin K.
Bellinge JW, Dalgaard F, Murray K, Connolly E, Blekkenhorst LC, Bondonno CP, et al. Vitamin K intake and atherosclerotic cardiovascular disease in the Danish Diet Cancer and Health Study. J Am Heart Assoc. 2021 Aug 17;10(16):e020551.
Studies linking vitamin K intake with incident ASCVD are limited. This study aimed to determine the relationship between dietary vitamin K intake and ASCVD hospitalizations. In this prospective cohort study, participants from the Danish Diet, Cancer, and Health Study, with no prior ASCVD, completed a food-frequency questionnaire at baseline and were followed up for hospital admissions of ASCVD; ischemic heart disease, ischemic stroke, or peripheral artery disease. Intakes of vitamin K1 and vitamin K2 were estimated from the food-frequency questionnaire, and their relationship with ASCVD hospitalizations was determined. Among 53 372 Danish citizens with a median (interquartile range) age of 56 (52-60) years, 8726 individuals were hospitalized for any ASCVD during 21 (17-22) years of follow-up. Compared with participants with the lowest vitamin K1 intakes, participants with the highest intakes had a 21% lower risk of an ASCVD-related hospitalization (hazard ratio, 0.79; 95% CI: 0.74-0.84), after multivariable adjustments for relevant demographic covariates. Likewise for vitamin K2, the risk of an ASCVD-related hospitalization for participants with the highest intakes was 14% lower than participants with the lowest vitamin K2 intake (hazard ratio, 0.86; 95% CI, 0.81-0.91). They concluded that risk of ASCVD was inversely associated with diets high in vitamin K1 or K2. The similar inverse associations with both vitamin K1 and K2, despite very different dietary sources, highlight the potential importance of vitamin K for ASCVD prevention.
Florea A, Kooi ME, Mess W, Schurgers LJ, Bucerius J, Mottaghy FM. Effects of combined vitamin K2 and vitamin D33 supplementation on Na[18F]F PET/MRI in patients with carotid artery disease: the INTRICATW rationale and trial design. Nutrients. 2021;18:994.
Popa D-S, Bigman G, Rusu ME. The role of vitamin K in humans: Implication in aging and age-associated diseases. Antioxidants. 2021 Apr 6;10(4):566.
As human life expectancy is rising, the incidence of age-associated diseases will also increase. Scientific evidence has revealed that healthy diets, including good fats, vitamins, minerals, or polyphenolics, could have antioxidant and anti-inflammatory activities, with anti-aging effects. Recent studies demonstrated that vitamin K is a vital cofactor in activating several proteins, which act against age-related syndromes. Their Our review aimed to present the latest scientific evidence about vitamin K and its role in preventing age-associated diseases and/or improving the effectiveness of medical treatments in mature adults ˃50 years old.
Moran M. Reversing coronary artery calcium using a functional medicine protocol. J Cardiol Curr Res. 2021;14(2):38-41.
Coronary artery calcium, scored with a CT scan, is a reliable metric to predict future myocardial events. Standard CAD medications do not reverse coronary artery calcification. This study used a functional medicine approach, without any prescription meds, applied over 12 months. The interventions used diet – no refined carbs or grains or dairy, a quarterly fast, exercise, stress control, and supplements, including MK4 and MK7 and vitamin D among others, and infrared sauna. A repeat CT scan showed a significant improvement.
Bellinge JW, Dalgaard F, Murray K, Connolly E, Biekkenhorst LC, Bondonno CP, et c. Vitamin K intake and atherosclerotic cardiovascular disease in the Danish diet cancer and health study. J Am Heart Assoc. 2021;10:e020551. https://doi.org/10.1161/JAHA.120.020551.
They studied the relationship between dietary vitamin K intake and atherosclerotic cardiovascular disease in a cohort study from the Danish Diet, Cancer and Health Study, using a food-frequency questionnaire monitored over four years. They found that the risk of cardiovascular disease was higher in people who had diets low in vitamin K1 or K2. Folks with the highest vitamin K1 intake had a 14%, 17%, and 34% lower risk of a cardiac related hospitalization. Vitamin K2 intake was inversely associated with a 14% lower risk of cardiac hospitalizations. The data support an independent protective effect for both subtypes of vitamin K.
Beulens JW, Dal Canto E, Stehouwer CDA, Rennenberg RJMW, Elders PJM, van Ballegooijen ADJ. High vitamin K status is prospectively associated with decreased left ventricular mass in women: the Hoorn Study. Nutrition Journal. 2021;20:85.
The relationship of vitamin K intake or status with cardiac structure and function is largely unknown. This study aimed to investigate the prospective association of vitamin K status and intake with echocardiographic measures. The Dutch participants living in the Hoorn area were followed 7.6 years. The results showed that a high vitamin K status was associated with decreased left ventricular mass index (LVMI) only in women. These results are in line with earlier studies showing that a low vitamin K status was associated with reduced LV systolic function or a higher prevalence of LV diastolic dysfunction.
Bilalic A, Kurir TT, Kumric M, Borovac JA, Matetic A, Supe-Domic D, et al. Circulating levels of dephosphorylated-uncarboxylated matrix Gla protein in patients with acute coronary syndrome. Molecules. 2021;26:1108.
Matrix gla fractions, such as dephosphorylated-uncarboxylated MGP (dp-ucMGP), lack post-translational modifications and are less efficient in vascular calcification inhibition. This study compared dp-ucMGP levels between patients with acute coronary syndrome. They found that higher dp-ucMGP levels likely reflect higher calcification burden on coronary patients and might aid in the identification of patients at increased risk of in-hospital mortality.
Florea A, Morgenroth A, Bucerius J, Schurgers LJ, Mottaghy FM. Locking and loading the bullet against micro-calcification. Euro J Preventive Cardiology. 2021;28:1370-75.
Despite recent advances, cardiovascular disease remains the leading cause of death worldwide. This review assesses state-of-the-art meta-analysis and clinical studies of possible treatment options and the concept of vitamin K supplementation to preserve vascular (loading the bullet).
Gheorge SR, Vermeer C, Olteanu G, Silaghi CN, Cracium AM. The active isoforms of MGP are expressed in healthy and varicose veins without calcification. J Clin Med. 2021;10:5896.
MGP is associated with vascular calcification. Depending on the carboxylation and phosphorylation status, MGP has active conformations, cMGP, pMGP, and inactive conformations ucMGP and dpMGP. This study assessed the presence of all MGP conformation in healthy veins and varicose veins. They found that the veins without calcification had both cMGP and pMGP, affirming their anti-calcifying role in veins.
Rapp N, Brandenburg VM, Kaesler N, Bakker SJL, Stohr R, Schuh A, et al. Hepatic and vascular vitamin K status in patients with high cardiovascular risk. Nutrients. 2021;13:3490.
Vitamin K deficiency results in inactive VKDP and is strongly linked to vascular calcification, one of the major risk factors for cardiovascular morbidity and mortality. This study investigated how two vitamin K markers, dp-ucMGP and PIVKA-II reflect vitamin K status in patients on hemodialysis or with calcific uremic arteriolapathy and patients with afib or aortic valve stenosis. They found that VKA therapy is associated with 8.5 fold higher PIVKA-ii and 3 fold higher dp-ucMPG levels. VKA use exacerbated vitamin K deficiency across all etiologies, while vitamin K supplementation results in vascular VKDP status better than that of the general population.
Zhelyazkova-Savova MD, Yotov YT, Nikolova MN, Nazifova-Tasinova NF, Vankova DG, Atanasov AA, et a. Stains, vascular calcification, and vitamin K-dependent proteins: is there a relation? Kaohsiung J Med Sci. 2021;1-8.
The cross-sectional study examined the connection between statin exposure, coronary artery calcification and vitamin K dependent proteins in patients with cardiovascular conditions. Among all participants, CACS weas more pronounced in statin users compared to non-users: The same was found among the CVD patients and among the controls. While the levels of ucMGP and GRP did not different between the groups, ucOC and ucOC were significantly evlevated in statin users, indicating vitamin K deficiency. Statins also had an impact on the international normalized ratio (INR). It appears that stains enhance calcium accumulation in the arterial wall, by inhibition of vitamin K dependent proteins and functions involved in vascular protection.
Kosciusek ND, Kalts D, Singh M, Savinova OV. Vitamin K antagonists and cardiovascular calcification: a systematic review and meta-analysis. Frontiers in Cardiovascular Medicine. 2022 Aug. Many patients treated with Vitamin K antagonists (VKA) for anticoagulation have concomitant vascular or valvular calcification. This meta-analysis aimed to evaluate a hypothesis that vascular and valvular calcification is a side-effect of VKA treatment. We conducted a systematic literature search to identify studies that reported vascular or valvular calcification in patients treated with VKA. They found a strong association between VKA use and vascular calcification and aortic valve calcification.
Liu C, Liu H, Xie T. Impact of Fetuin-A, Lp(a), matrix gla protein and macrophage density on calcific aortic valve disease: a clinical study. Lipids in Health and disease. 2022;21:14.
This study looked at the clinical characteristics of patients and occurrence of calcific aortic valve disease. They found that Fetuin-A and Lp(a) were positively correlated with progression of the disease, while MGP and macrophage density were negatively correlated with it. They concluded that Fetuin-A, MPG and Lp(a) may be potential predictors for diagnosis of the disease.
Malhotra R, Nicholson CJ, Wang D, Bhambhani V, Paniagua S, Slocum C. Matrix Gla protein levels are associated with arterial stiffness and incident heart failure with preserved ejection fraction. Arteri, Thromb & Vasc Biol. 2022;42(2): e61–e73.
Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp+/− mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation.
Written by RPT, 1/2/13
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