Vit k2 prof.kamal mohamed okasha

Role of Vitamin K2 in management of
Vascular Calcification
Kamal Mohamed Okasha MD
Prof Of Int Med & Head Division Of Nephrology.
Tanta University, Egypt.
Fellow Of Nephrology, Univeristy Of Saskatchewan,
Canada
Email: Okasha70@yahoo.Com
1/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

•Introduction and clinical significance
•Type of vascular calcification
•Molecular determinants and inducers
•Role of Vitamin K2.
•Role of Vit D.
•Conclusion
Key points:

Arterial Calcification (AC)
• “AC is an Independent Risk Factor for CV Morbidity and
Mortality.”
• “AC is an independent RF for atherosclerosis, MI, stroke, &
renal ds.”
• “Pts with manifest AC have an unfavorable prognosis
compared with patients with no or mild calcification.”
Rocha-Singh et al. 20141/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

Arterial Calcification- Prevalence
In a large cohort study (n=4,291), after a mean 7.8 y
• Calcification of the thoracic aorta, carotid, Iliac arteries
correlated with Total Mortality.
• Calcification of the coronary correlated with CV mortality
Hirsch et al, circulation 20061/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

Arterial Calcification- Prevalence
In an unselected cohort of asymptomatic pts presenting for preventive
care (n=650):
• 61% of pts displayed atherosclerotic calcification
• Calcification increased exponentially with age:
• >2/3 of pts > 70 y: calcifications in all vascular beds
Hirsch et al, circulation 20061/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

• 13% of ‘healthy’ patients without renal disease
• Increase prevalence as kidney function declines
• 40% of patients with CKD patients not on dialysis
• 57% of patients starting dialysis
• 83% of patients on long-term dialysis
Coronary Artery Calcification(CAC) Prevalence

Vascular Calcification – Contributing Factors
The Imbalance between
Promoters
Inhibitors

Vascular Calcification – Contributing Factors
Ott, S. M. Nat. Rev. Nephrol. 9, 681–692 (2013);1/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

Vascular Calcification – Medication Factor

Vascular Calcification – Warfarin

Conclusions:
VKA has negative effects on vascular and cardiac phenotypes of
subclinical cardiovascular disease, indicating a possible influence
on long‐term disease development.

Statins Promote Coronary Atheroma Calcification
1,545 patients received
high-intensity statin
therapy, low-intensity
statin therapy, and no-
statin therapy
Compared changes in
coronary atheroma
volume and calcium
indices

Vascular Calcification – Statins

2017
Vascular Calcification – Statins

Matrix Gla-protein
The Vitamin K-dependent Protein

Matrix Gla-protein (MGP)
o Vitamin K-dependent protein
o 84 amino acids (Mw ~11 kD)
o Gla-residues (required for activity)
o Serine-phosphorylation (function unknown)
Luo et al. Nature 1997

“Matrix Gla protein (MGP) is one of the strongest in vivo inhibitors of
AC, and its activity depends on vitamin K2.”

What is Vitamin K2?

Vitamin K
Vitamin K is a fat-soluble vitamin, important for the function of
numerous proteins within the body:
Coagulation factors (II, VII, IX, X and protein C and protein S),
Osteocalcin, matrix-Gla protein (MGP) (an anticalcification protein)
Vitamin K exists naturally as vitamin K1 (phylloquinone) and
vitamin K2 (menaquinone, MK-4 through MK-10).

Vitamin K Family
Vitamin K1
(phylloquinone)
Vitamin K2
(menaquinones)
MK-4
MK-7

Vitamin K1 vs. K2
K1 K2
Main function: Maintains blood clotting Removes calcium from arteries
and transports it to bones
Forms: Phylloquinone Menaquinone 4 (MK-4)
Menaquinone 7 (MK-7)
Primary sources: Green leafy vegetables Bacterial fermentation (natto,
cheeses, intestinal bacteria)
Half-life: 1.5 hrs ≥3 days (MK-7)

How does Vitamin K2 work?

Rapid clearance of
vitamin K1 by liverTransport of mainly higher
menaquinones to other
tissues

Mk-7 Maintain Calcium Hemeostasis
Out of arteries
MK-7
moves
calcium
Into bones

Vitamin K2 turns on osteocalcin, binding calcium to bone
stimulates VSMCs calcification

K2 Prevents AC
• Activates MGP to inhibit calcium from the
depositing in arteries and blood vessels.
• Reverse arterial stiffness, reducing risk of
cardiovascular disease1
• No known side effects or safety concerns2
1 Thrombosis and Haemostasis, May 2015; 113(5)1135-44.
2 Br J Nutr, Nov 2012; 14;108(9):1652-7.

Vitamin K2 Builds Strong Bones
VITAMIN K2
Osteoporos Int. 2013 Sep;24(9):2499-5071/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

K2 is an Important Cofactor for
Cardiovascular Health
Observational studies show dietary intake of Vitamin K2 is
associated with a reduced risk of coronary heart disease
K2 is an Important Cofactor for Cardiovascular Health
The ucMGP assay seems to be suited to assess vascular
vitamin K status, and may therefore contribute to
cardiovascular risk assessment

UcMGP a Biomarker of Calcification
J. Clin. Invest. Volume 65 February 1980 563-5661/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

Uncarboxylated MGP: survival marker
Aortic stenosis Chronic kidney disease
Vermeer C. Food Nutr Res. 2012; 56: 5329-5335. Schlieper et al. Kidney Int. 2008; 74:1582-1587
UCR: Uncarboxylated/carboxylated ratio

Clarck et al Circulation 2008; Shroff et al Circulation 2008
In Normal patients
cMGP is more
Expressed than
ucMGP
Vessel Calcification & ucMGP

In Pre-dialysis patients
cMGP and ucMGP
Are expressed the same

In dialysis patients
ucMGP is more
Expressed than
cMGP

The Landmark Rotterdam Study
4500 elderly Dutch people followed for 10 years
Dietary K1 had no effect on cardiovascular health
Dietary K2 significantly reduced:
Aortic calcification; Myocardial infarction; Cardiovascular mortality
Overall mortality
J Nutr. 2004 Nov;134(11):3100-5

Prospect-EPIC Utrecht Cohort
• Analyzed the diets of 16,057 European W.49-70 y, free of CVD at
baseline:
• Vitamin K1 intake not related to CHD
• Inverse association between vitamin K2 and CHD risk
10 μ/d vitamin K2 intake reduced CHD risk by 9%
Effect attributed to menaquinones MK-7, MK-8, and MK-9
Nutr Metab Cardiovasc Dis. 2009 Sep;19(7):504-10

Inactive MGP levels can be decreased markedly by daily vitamin K2 supplementation.
Our study provides the rationale for intervention trials aimed at decreasing vascular
calcification in hemodialysis patients by vitamin K supplementation.
Am J Kidney Dis. 59(2):186-195. © 2012 by the National Kidney
Foundation, Inc
The National Kidney Foundation
Published in the American Journal of Kidney Disease
2012

3-Year Intervention Trial
Healthy postmenopausal women (n=244) received either placebo or
180 µg MK-7 daily for 3 y
• Improved arterial stiffness, especially in women with high arterial
stiffness
• Positive effects on bone strength, mineral density, and mineral
content
Thrombosis and Haemostasis, 19;113(5) (2015); Osteoporos Int. 2013 Sep;24(9):2499-507

3-Year Intervention Trial
Thrombosis and Haemostasis, 19;113(5) (2015); Osteoporos Int. 2013 Sep;24(9):2499-507

Vitamin K-antagonist aggravate CKD induced intimal
hyperplasia and calcification in arterialized Veins:
Potential role for vitamin K2 to prevent AVF failure
The clinical Problem
63 %
patency rate in autologous fistula

Warfarin
A
A
V
V
V
Vitamin K2
100µm
b c
21 days 42 days 84 days
a
Zaragetski et al. Kidney Int 2015 Accepted
VKA treatment has detrimental effects on AVF remodeling. Vitamin K2
supplementation reduced NIH and calcification indicating vasoprotective
effects.
Vitamin K2 should be considered as therapeutic approach to prevent
NIH and calcification.

The synergistic effect between
Vitamin K2 and Vitamin D3

Role of Vit D3
Ca

Role of Vit D3
Osteocalcin
INACTIVE
[Formation]
D3 Osteocalcin
ACTIVEK2 bone
FormationCa

Role of Vit D3
MGP (Inactive)
[formation]
MGP (Active)
Inhibits Ca Deposition in
vascular walls
K2
D3

Dose of Vit K2
“80 % of Americans do not get enough K2 to activate their MGP
proteins, which is similar to the deficiency rate of vit. D.”
“Most recent clinical trials used at least 200μg/of K2.”
• Difficult to get enough K2 from dietary sources
• MK-7 has longer half-life than other forms of K2
• Extremely safe Low dose (45 μg) unlikely to interfere with OACs
• 240 μg/day MenaQ7 effective dose in clinical trial
Dr. Kate Rheaume-Bleue. Vitamin K2 and the Calcium Paradox: How a Little Known Vitamin Could Save Your Life. Collins ; June 25, 20131/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

Effect of K2 on Biomarkers
Schurgers Ljet al. Clin J Am Soc Nephrol 2010; 5: 56875.
Effect of K2 on Biomarkers

Dose of Vit K2
• “For the average person, around 200 to 280μg of K2 will
activate vit K2 dependent proteins.”.
• Hence the optimal dose of K2 needed to activate ALL vit K2
dependent proteins would be 240 μg
Dr. Kate Rheaume-Bleue. Vitamin K2 and the Calcium Paradox: How a Little Known Vitamin Could Save Your Life. Collins ; June 25, 2013

Vit K2 Safety
• “K2 has no toxicity. No toxic effects have ever been
demonstrated in the medical literature.”
• "The reason why K2 doesn't have potential toxic effect is that
all other vit Ks does, is activate vit K2 dependent proteins.
Dr. Kate Rheaume-Bleue. Vitamin K2 and the Calcium Paradox: How a Little Known Vitamin Could Save Your Life. Collins ; June 25, 20131/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

Ethics and dissemination
There are no reported adverse effects associated with the use of MK-7.
The protocol is approved by the Regional Scientific Ethical Committee
for Southern Denmark and the Data Protection Agency.

Overall, the available observational population-based
evidence, based on dietary intake measures, suggests
menaquinone intake may be more likely to protect against
vascular calcification.1/7/2019 vit k2 in managament of vc Mansoura DNG. K okasha

“Decalcify your arteries; Calcify your bones.”

Vit k2 prof.kamal mohamed okasha

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