Vitamin K2 and Vascular Disease

I have been asked to talk about the role of Vitamin K (K2 specifically) in the pathogenesis of vascular disease.  This is a controversial topic as “mainline cardiology” has not yet embraced the data and the “jury” is not yet out as to the importance of vitamin K2 in preventing and treating cardiovascular disease.  The data I will summarise is extremely interesting and I believe we will be incorporating this knowledge into prevention and management of atherosclerotic vascular disease soon.



We have been conventionally taught that the role of vitamin K was solely ascribed to coagulation and coagulation was thought to be involved only in the venous system.

This view has dramatically changed with the recent (last decade) discovery of vitamin K-dependent proteins outside the coagulation cascade and the role of coagulation factors in the pathogenesis of atherosclerosis on the arterial side. Vitamin K-dependent proteins are involved in the regulation of vascular smooth muscle cell migration, apoptosis (programmed cell death), and vascular calcification.

Vascular calcification is a well recognised important independent predictor of cardiovascular disease and closely correlates cardiac morbidity and mortality. The involvement of vitamin K-dependent proteins such as matrix Gla-protein (MGP) in vascular calcification makes that calcification amendable for intervention with high intake of vitamin K2. 

Nutritional vitamin K consists of two forms:

  • vitamin K1 (a phylloquinone also known as phytonadione)
  • vitamin K2 (a menaquinone)

Vitamin K1 is found in leafy green vegetables (lettuce, spinach and broccoli)where it is tightly bound to the chloroplast membrane resulting in a poor absorption (poor bio-availability) of vitamin K1 from vegetables but it is still the dominant form making up about 90% of the vitamin K in a typical Western diet.


Vitamin K2 is found in fermented foods such as cheese, sauerkraut and the Japanese Natto (a foul-smelling sticky web of fermented soybeans typically served with a Japanese breakfast.derived from the bacterium Bacillus subtilis). The absorption of vitamin K2 is apparently much better as compared to vitamin K1 comprising 10% of our vitamin K consumption.  Vitamin K2 importantly can be synthesised in the colon by microflora. There are apparently 4 isoforms of vitamin K2 determined by the number of prenyl side chains (MK-4; MK-7; MK-8 & MK-9). MK-4 is found in meat whereas the MK-7 to 9 tend to come from the fermented foods.


Importantly the bioavailability of the isoforms differ with MK-4 demonstrating very poor bioavailability at a nutritional level dose compared to excellent bioavailability with MK-7.

After being absorbed in the intestine, vitamin K, as a fat soluble vitamin is transported by lipoproteins, as it has no specific carrier protein. The different lipophilicity (fat solubility) of K1 and K2 may result in substantial differences in plasma transport, half-life and delivery to target tissues (t1/2 for K1 ~ 3 hours; 1.5 hours for MK-4 and > 70 hours for MK-7; MK-8 & MK-9).

Vitamin K-dependent proteins:

Vitamin K-dependent proteins constitute a family of 16 known proteins with diverse functions, not only involved in the haemostatic coagulation pathway. The vitamin K dependent coagulation proteins (clotting factors II, VII, IX and X) are essential for the coagulation cascade and are γ-carboxylated in the liver to be functionally active. They are well-balanced by the anticoagulant factors protein C and protein S.

All these vitamin K-dependent proteins are mainly synthesized and γ-glutamylcarboxylated in the liver, with the exception of proteins S which is synthesized in part by endothelial cells.

Over the past decade an enormous amount of evidence has suggested that coagulation factors play an important role in (chronic) inflammation. Phagocytosis of apoptotic cells by macrophages is thought to limit the inflammatory response and Protein S has been identified as a factor responsible for stimulation of this phagocytosis. Additionally protein S regulates the expression and function of scavenger receptor A (SR-A) on macrophages resulting in diminished uptake of acetylated low density lipoprotein.

Protein C deficiency is associated with severe coagulation response to endotoxin and this Protein C also plays a significant role in the inflammatory response with activate Protein C inhibiting endotoxin-induced production of important cytokines like TNF-alpha, IL-1, IL-6 and Il-8 by momocytes/macrophages.

Extrahepatic vitamin K-dependent proteins:

Within the arterial vessel wall vitamin K-dependent proteins are synthesized with functions not related to blood coagulation.

Growth arrest specific gene 6 protein (Gas-6) is a vitamin K-dependent protein produced by vascular smooth muscle cells (VSMCs). Gas-6 seems to protects VSMCs from calcification by inhibiting apoptosis as the cell death may act as a nidus for calcification.

The vitamin K-dependent matrix Gla-protein (MGP) is regarded as the strongest inhibitor of vascular calcification (VC) and produced by many cells, including VSMCs. Rescue experiments in MGP null mice demonstrated that MGP acts locally in the vascular tissue as restoration of MGP expression in arteries completely rescued the arterial mineralization phenotype, whereas hepatic MGP expression, resulting in high systemic MGP levels, did not.

Vascular calcification as a marker of atherosclerosis risk stratifies into high risk outcome:

Vascular calcification (VC) is associated with increased cardiovascular mortality and morbidity, and is recognised as a strong and independent risk factor for cardiovascular death. The amount of VC, as measured and quantified by multidetector computed tomography (CT-coronary angiography) is an important predictor of:

  • all-cause mortality
  • vascular complications
  • myocardial infarction and stroke

Patients with higher coronary artery calcification scores have approximately ten times more chance to have a cardiac event in the next 3–5 years. Patients with a calcification-progression over 15% per year had a 17.2 fold increased risk of myocardial infarction compared to patients without significant progression.

Vascular calcification is an even stronger predictor than the Framingham Risk Score (FRS) which is currently used to score 10-year risk prediction for cardiovascular events.

Clinically,VC causes stiffening of the vascular arteries via elastic fiber and VSMC calcification resulting in:

  • decreased arterial compliance with the development of chronic systemic hypertension
  • development of left ventricular hypertrophy leading to diastolic heart failure
  • decreased coronary perfusion 

In spite of this data, calcification of arteries has been generally neglected and considered to be clinically unmodifiable, often regarded as an end stage passive process not amenable to therapeutic intervention.  Recent data however suggests that punctated and spotty calcification in the atherosclerotic plaque influence stability negatively and render the plaque vulnerable to rupture thus potentiating the progression of atherosclerosis and vascular events.

As VC is a complex and actively regulated process involving cells and vitamin K dependent proteins acting as catalysts and inhibitors. Recruitment of macrophages in the atherosclerotic plaque and consequently their secretion of inflammatory cytokines may serve as a signal for intimal calcification.  When VSMCs phagocytose calcium crystals it seemingly destabilize atherosclerotic plaques by initiating inflammation and by causing SMC death. Vascular calcification

Circulating biomarkers (MGP) for detecting vascular calcification:

This is an attractive concept to screen for and perhaps regulate mechanisms of VC.  Vitamin K-dependent proteins have been associated with the earliest calcification areas in the plaque. Uncarboxylated MGP seemingly strongly correlates with both medial and intimal calcification. By measuring circulating MGP isoforms it has been shown that the majority of the healthy population have sub-optimal levels of vascular vitamin K. Preliminary data suggest that some MGP conformations are associated with aspects of cardiovascular disease for instance patients with high VC scores display high levels of inactive MGP, especially dialysis patients.

This creates possibilities for targeting VC with vitamin K therapy. Indeed high intake of vitamin K has been shown to regress preformed medial calcification in a rat model and the first data is available in dialysis patients showing that vitamin K supplementation markedly reduced the level of plasma uncarboxylated prothrombin, uncarboxylated osteocalcin and inactive MGP.


Effort must be directed towards retarding or reversing the development of calcification in the vasculature, especially in those patients prone to vascular calcification (chronic kidney disease, diabetes, atherosclerotic cardiovascular disease). In these patients the treatment with vitamin K antagonists should be reconsidered perhaps with a view to used specific Thrombin inhibitors in cases where anticoagulation is required.

Therefore, it is of importance to identify patients with vascular disease and to evaluate different strategies that are more effective in the prevention of hypercoagulability as well as vascular calcification.

Here lies the real interest in high dose vitamin K2 replacement to minimise and reverse vascular calcification as part of general prevention and management of atherosclerotic vascular disease.

This is consistent with separate research also showing superior health benefits from vitamin K2, including:

  • The Rotterdam Study the first study demonstrating the beneficial effect of vitamin K2, showed that people who consume 45 μg/d of K2 daily live seven years longer than people getting 12 μg/d
  • Data from the Prospect EPIC Cohort published in
    Nutrition, Metabolism & Cardiovascular Diseases
    Gast Volume 18, Issue 7 Pages 504-510, September 2009
    suggested a high menaquinone intake reduces the incidence of coronary heart disease (CHD). 16,057 women, enrolled between 1993 and 1997 and aged 49–70 years, who were free of cardiovascular diseases at baseline. Intake of vitamin K and other nutrients was estimated with a food frequency questionnaire. After a mean follow-up of 8.1±1.6 years, with 480 incident cases of CHD. Mean vitamin K1 intake was 211.7±100.3 μg/d and vitamin K2 intake was 29.1±12.8 μg/d.After adjustment for traditional risk factors and dietary factors, the authors observed an inverse association between vitamin K2 and risk of CHD with a Hazard Ratio (HR) of 0.91 [95% CI 0.85–1.00] per 10 μg/d vitamin K2 intake. This association was mainly due to vitamin K2 subtypes MK-7, MK-8 and MK-9. Vitamin K1 intake was not significantly related to CHD


Um food for thought….

Blessings Cardiologydoc

Atherosclerosis hope in 2013

Dr PBM tradepic

The prevalence of coronary atherosclerosis among deployed USA service members who died during the past decade is 8.5%, which is markedly lower than rates observed in soldiers who served in the Korean and Vietnam wars. 

This prevalence demonstrates a steep decline from the rates of 77% noted in the Korean War and 45% in the Vietnam War — researchers wrote in the Journal of the American Medical Association in December 2012.

JAMA 2012; 308:2624-2625.

Bryant J. Webber, MD, of the Uniformed Services University of the Health Sciences in Bethesda, Md., and colleagues conducted a study of 3,832 (mean age, 25.9 years; 98.3% men) members of the armed forces with available autopsy reports who died from combat-related or unintentional injuries in support of Operation Enduring Freedom and Operation Iraqi Freedom/New Dawn between 2001 and 2011.

Coronary atherosclerosis was classified as minimal (fatty streaking only), moderate (10% to 49% luminal narrowing of ≥1 vessel) and severe (≥50% narrowing of ≥1 vessel).

Prevalence of any coronary atherosclerosis was 8.5% (95% CI, 7.6-9.4); severe coronary atherosclerosis, 2.3% (95% CI, 1.8-2.7); moderate, 4.7% (95% CI, 4-5.3); and minimal, 1.5% (95% CI, 1.1-1.9). The researchers found that age was most strongly associated with prevalence of atherosclerosis. Service members with atherosclerosis were older than those without (30.5 years vs. 25.3 years; P<.001). Further, prevalence of atherosclerosis appeared to be approximately seven times higher in those aged at least 40 years vs. those aged 24 years or younger (45.9% vs. 6.6%).

Data also indicated that, compared with service members without conventional cardiovascular risk factors (11.1%), prevalence of atherosclerosis was greater among those with a diagnosis of dyslipidemia (50%), hypertension (43.6%) or obesity (22.3%). 

In an accompanying editorial from the National Heart, Lung, and Blood Institute, highlighted these issues but also indicated these autopsy studies again show that coronary disease begins at a young age and even in a better risk controlled population group almost 1 in 2 soldiers over 40 have significant coronary atherosclerosis.  Once again aggressive primary prevention is key.

Declines in cardiovascular disease risk factors in these military personnel have almost certainly contributed to the observed reductions in prevalence of subclinical atherosclerosis, incidence of clinical atherosclerotic disease, and deaths from heart disease. Although age-adjusted heart disease death rates have declined by 72% since their peak during the Vietnam War years, cardiovascular disease still remains the leading cause of death in the United States. The national battle against heart disease is not over; increasing rates of obesity and diabetes signal a need to engage earlier and with greater intensity in a campaign of pre-emption and prevention.

It is important to note that rates of obesity, smoking, hypertension, dyslipidemia, and impaired fasting glucose are markedly lower in USA military service members than in men and women of the same age in the civilian US population–making it possible to understand the high rate of poor general health in USA and high degree of sub clinical disease in “healthy” US individuals. While primary and secondary prevention have likely contributed equally to national declines in heart disease deaths, advances in primary, but not secondary, prevention most likely explain the declines in coronary atherosclerosis across the three autopsy studies.

Heart attack concept

Some great advances in primordial and primary prevention of atherosclerotic vascular disease have taken place over the past decade.  In my next blog I will highlight some of the novel new approaches to prevent and minimise the clinical effects of atherosclerosis.

Blessings Cardiologydoc


South African Dyslipidaemia Guideline Concensus Statement 2012

Published recently in the South African Medical Journal 2012; 102: 177-188 are the consensus guidelines for the management of dyslipidaemia. I have taken extracts directly from this paper to highlight the 2012 guidelines.


South Africa is a multi-ethnic society, with a large range of cultures and lifestyles at different stages of epidemiological transition. In all sub-populations, cardiovascular disease is a major cause of morbidity and mortality. Every day, approximately 80 people die of myocardial infarction or heart failure, while another 60 die due to stroke.

The INTERHEART Africa study indicated that more premature acute myocardial infarctions occur in sub-Saharan Africa than in any other of the 52 countries participating in the INTERHEART study.

This statistic reflects a lack of prevention, early detection and effective management of cardiovascular risk factors in the countries of this region.In particular in the black population increasing urbanisation and adoption of an unhealthy lifestyle, the prevalence of cardiovascular disease (CVD) and the incidence of premature death are likely to continue to increase.

Consequently, the timely institution of lifestyle modification, early diagnosis and effective management of CVD risk factors are essential to curb the epidemic of cardiac disease that has been seen in other countries.

In 2003, the South African Heart Association (SA Heart) and the Lipid and Atherosclerosis Society of Southern Africa (LASSA) officially adopted the European Guidelines for the Prevention of Cardiovascular Disease to replace the SA Lipid guidelines published in 2000.

The European document has recently been updated with the publication of the European Society of Cardiology (ESC)/European Society of Atherosclerosis (EAS) Guideline for the Management of Dyslipidaemias in 2011.

This Consensus Statement promotes current best management of dyslipidaemia and should be adopted by all health care professionals in South Africa.

Using a cardiovascular risk stratification score:

High risk for CVD

Individuals who are considered to be at very high risk of cardiovascular events (>30% risk of a suffering a cardiovascular event over next 10 years) are listed in Table 1. Patients in this group DO NOT require cardiovascular risk scoring, because the risk score will be an underestimate in these settings.

Risk scoring using well-documented key risk factors is appropriate to estimate the total cardiovascular risk in asymptomatic adults. This risk scoring is especially important in individuals with the following:

  • Those with hypertension and or on antihypertensive medication
  • Those who smoke any form of tobacco product
  • BMI ≥30 kg/m2 or waist circumference > 94 cm for men, >80 cm for women
  • People with “metabolic syndrome”
  • Family history for premature cardiovascular disease (in males < 55 years and female before 60 years)
  • Auto-immune chronic inflammatory disease such as rheumatoid arthritis, systemic lupus erythematosus, psoriasis

When to start screening for CVD (when to risk stratify):

In South Africa, because the prevalence of familial hypercholesterolaemia is as high as 1 in 100 in some communities, each individual should be tested, preferably with a full lipogram or at least TC/LDL-C, at least once in young adulthood (from 20 years of age). Particular attention should be paid to individuals with other risk factors for CVD (list above).

How to use the risk scoring system:

The European guidelines use the Systematic Coronary Risk Estimation(SCORE) system to estimate cardiovascular risk. Because this scoring system is based on an exclusively European population, it may not accurately reflect coronary risk in South Africa. While it is recognised that it would be impossible to accurately estimate risk in all South African subpopulations with a single data set, the Adult Treatment Panel (ATP) III Framingham risk tables provide and estimate of the 10-year risk of any cardiac event have been validated in white and black populations in the USA and are transportable to other culturally diverse populations. Consequently, we considered this approach to be more appropriate for South Africa. Nevertheless, these risk tables are likely to underestimate risk in South African black and Indian patients. The Framingham CHD tables may also underestimate total CVD risk in middle-aged and older women, whose risk of stroke and heart failure is typically higher than that of CHD. 

Consequently, more recent Framingham equations predict 10-year total CVD risk (including CHD, stroke, transient ischaemic attack and heart failure).The updated Framingham CVD risk tables for men and women and an algorithm for management and cholesterol goals have been incorporated into these recommendations (Appendix 1). Appendix 1a

Appendix 1b

Appendix 1c

Appendix 1d

The points are added to calculate the 10 year risk for men and women.

Points men

Points women

The risk is defined as the following:

Points risk

The goals of treatment follow the risk:

Treatment goals

In all cases of dyslipidaemia it is important to exclude and manage any secondary cause of abnormal lipids:

Secondary causes dyslipidaemia

The use of Statins:

Statins have demonstrated effectiveness in both primary and secondary prevention. The effect is dependent on the extent to which LDL-C is lowered and not on the type of statin used. At their maximum doses, the various statins differ in their capacity to lower LDL-C.

For every mmol/l reduction in LDL-C there is a:

  • 10% reduction in total mortality
  • 20% reduction in all-cause mortality
  • 23% recudtion in major cardiac events
  • 17% reduction in stroke

The effect of statin therapy is similar in all patient subgroups and becomes significant after 1 year, increasing progressively thereafter.

The scheme for introducing Statin therapy:

  • First evaluate the risk
  • Involve the patient in CV risk management and decisions
  • Identify the LDL-C target based on the risk
  • Calculate the % reduction in LDL-C required to reach target
  • Choose the Statin (and dose) most appropriate to achieve the desired reduction

Other Cholesterol lowering agents:

The cholesterol absorption inhibitor ezetimibe (Ezetrol) in combination with simvastatin (Inegy) was shown to reduce major atherosclerotic events in patients with advanced chronic kidney disease. Although no other outcome studies have been completed, ezetimibe is recommended:

  • As second-line treatment in combination with a statin when the LDL-C target is not reached at the highest tolerated statin dose.
  • When there is intolerance to statins (or high dose statin).
  • Bile acid sequestrants and nicotinic acid have cholesterol lowering properties. They may occasionally be useful alone or in combination with statin therapy. However, their side-effects limit wider application.

Finally the South African Heart Association/LASSA guidelines for lifestyle modification for patients with dyslipidaemia are summarized in Appendix 2:

Appendix 2

In summary:

Management 2

Additional tests:

The Consensus Statement also discusses the use of novel biomarkers of CVD (e.g. hs or us-CRP) and imaging technologies (e.g. coronary calcium scoring, carotid intima-media thickness) whilst is not recommended routinely these should be reserved to refine risk assessment in patients considered to be at moderate risk where there is uncertainty about whether to initiate drug therapy.

Measuring Lipoprotein – a (Lp-a) is appropriate in defining HIGH CVD risk subjects and/or when there is a family history of premature cardiovascular disease. 

Blessings for 2013

CardiolodydocWorld in your hands