Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?
Piscaer et al. Respiratory Research
Vitamin K deficiency: the linking pin between COPD and cardiovascular diseases?
Ianthe Piscaer 0
Emiel F. M. Wouters 0 3
Cees Vermeer 2
Wim Janssens 5
Frits M. E. Franssen 0 3
Rob Janssen 4
0 Department of Respiratory Medicine, Maastricht University Medical Center
1 , Maastricht , The Netherlands
2 R&D Group VitaK, Maastricht University , Maastricht , The Netherlands
3 CIRO, Center of Expertise for Chronic Organ Failure , Horn , The Netherlands
4 Department of Pulmonary Medicine, Canisius-Wilhelmina Hospital , Nijmegen , The Netherlands
5 Department of Chronic Diseases, Metabolism and Ageing, Laboratory of Respiratory Disease, University of Leuven , Leuven , Belgium
Cardiovascular diseases are prevalent in patients with chronic obstructive pulmonary disease (COPD). Their coexistence implies that many COPD patients require anticoagulation therapy. Although more and more replaced by direct oral anticoagulants, vitamin K antagonists (VKAs) are still widely used. VKAs induce profound deficiency of vitamin K, a key activator in the coagulation pathway. It is recognized however that vitamin K is also an essential cofactor in the activation of other extrahepatic proteins, such as matrix Gla protein (MGP), a potent inhibitor of arterial calcification. No or insufficient MGP activation by the use of VKAs is associated with a rapid progression of vascular calcification, which may enhance the risk for overt cardiovascular disease. Vitamin K consumption, on the other hand, seems to have a protective effect on the mineralization of arteries. Furthermore, vascular calcification mutually relates to elastin degradation, which is accelerated in patients with COPD associating with impaired survival. In this commentary, we hypothesize that vitamin K is a critical determinant to the rate of elastin degradation. We speculate on the potential link between poor vitamin K status and crucial mechanisms of COPD pathogenesis and raise concerns about the use of VKAs in patients with this disease. Future intervention studies are needed to explore if vitamin K supplementation is able to reduce elastin degradation and vascular calcification in COPD patients.
COPD; Cardiovascular diseases; Desmosine; Elastin; Matrix Gla protein; Vascular calcification; Vitamin K; Vitamin K antagonists
Cardiovascular diseases are more prevalent in patients
with chronic obstructive pulmonary disease (COPD)
compared to age- and smoking-matched controls with
no lung disease [
]. Vascular calcification is a major risk
factor for cardiovascular morbidity and mortality. COPD
patients have on average more extensive coronary artery
calcification (CAC) than controls [
]. Furthermore, the
burden of emphysema is related to the thoracic aortic
calcification score [
]. The frequency of cardiac
arrhythmias is also high in patients with COPD [
], and an
inverse association has been identified between forced
expiratory volume in one second and incident atrial
]. Atrial fibrillation and pulmonary embolism
may be both cause and consequence of acute COPD
exacerbations, and often necessitate prolonged
anticoagulation therapy [
Although the use of direct oral anticoagulants
(DOACs) is rising, vitamin K antagonists (VKAs) are
still widely used as anticoagulant drugs. VKAs inhibit
vitamin K recycling thereby inducing functional vitamin
K deficiency [
]. Vitamin K is generally known as an
activator of coagulation proteins in the liver and
therefore often incorrectly regarded as a mono-functional
cofactor . It is much less acknowledged that vitamin
K is also essential in the activation of extrahepatic
]. Matrix Gla protein (MGP) is vitamin
K-dependent and a potent inhibitor of soft tissue
]. Furthermore, evidence suggests a potential
role for MGP in the protection of extracellular matrix
proteins from enzymatic degradation [
knockout mice die within two months after birth due to
vascular calcifications leading to large blood vessel
rupture, illustrating the importance of MGP [
research has mainly focused on its protective effects
against arterial pathologies [
], MGP is also extensively
expressed in the lungs [
Vitamin K status
Vitamin K cannot be produced endogenously and is
exclusively obtained exogenously. Different forms of
vitamin K can be discerned, including naturally
occurring vitamins K1 and K2 [
]. Vitamin K2 usually
comprises not more than about one-tenth of total vitamin K
consumption, but it holds a much larger share in the
activation of vitamin K-dependent proteins as vitamin K2
has higher bioavailability and longer half-life time than
]. Although there is no absolute tissue specificity,
vitamin K1 is preferentially used in the liver to activate
coagulation factors, whereas vitamin K2 has a more
prominent role in the activation of extrahepatic vitamin
K-dependent proteins, such as MGP [
Vitamin K1 levels can be reliably measured in the
circulation and reflect the intake of vitamin K1 [
Vitamin K2, however, usually cannot be detected in the
blood stream unless taken as supplements [
]. To date,
there is no gold standard for assessing total vitamin K
status, although measuring inactive levels of vitamin
K-dependent proteins in the circulation seems to be the
most appropriate method [
(dp-uc; i.e. inactive) MGP levels are often used as a surrogate
marker for vitamin K status. Dp-ucMGP levels are inversely
correlated with vitamin K status, which means that subjects
with high dp-ucMGP levels have low vitamin K status and
vice versa [
There are several potential reasons why vitamin K
status might be impaired (Fig. 1). Obviously, it can be the
result of low vitamin K consumption. Cheese is an
important source of vitamin K2 in many countries. In
relation to COPD, it is interesting that cheese consumption
was shown to be associated with better lung function
and less emphysema in a large observational study [
Differences in vitamin K metabolism due to the use of
VKAs or genetic variation are other causes of a lower
vitamin K status. The human body uses vitamin K very
economically given that it is reused about 2000 fold via
the so-called vitamin K cycle (Fig. 2). The two reduction
steps of this cycle are executed by the enzyme vitamin
K epoxide reductase (VKOR). VKAs are specific
inhibitors of VKOR [
], which is the explanation for the poor
vitamin K status found in subjects using these
anticoagulant drugs [
]. The VKOR activity is also
influenced by single nucleotide polymorphisms (SNPs) in the
VKOR complex subunit 1 (VKORC1) gene, which are in
linkage disequilibrium with each other [
SNPs that are associated with low vitamin K recycling
rates may be overrepresented in subjects with low vitamin
K status. The T-allele of the VKORC1 1173C > T SNP
associates with poor vitamin K recycling and a significantly
higher risk of aortic calcification [
]. We could further
speculate that the VKORC1 C1173T SNP might also
influence the susceptibility to COPD or specific phenotypes
such as emphysema. Genetic association studies are
needed to assess whether this hypothesis holds true
Finally, it is possible that subjects with enhanced rates
of elastin degradation have higher vitamin K expenditure
given that elastin degradation stimulates elastin
]. A rising calcium content in elastin fibers
stimulates MGP synthesis in an attempt to prevent further
calcium precipitation within the elastin fibers [
However, MGP first needs to be activated by vitamin K. This
increased vitamin K demand might induce a vitamin K
Elastin calcification and degradation
Vascular calcification usually starts in the elastin
fibers of the arterial medial wall [
]. Elastin is a
unique protein that provides elasticity, resilience and
deformability to dynamic tissues, such as arteries and
]. It is mainly produced in utero and early
childhood after which elastin synthesis is suppressed
at a posttranscriptional level [
]. During the aging
process, the elastic properties of elastin fibers can be
compromised by both calcification and degradation
]. Elastin has high affinity for calcium, and as a
result its calcium content increases during aging [
Arterial calcifications can be induced in rats via the
administration of VKAs to induce vitamin K
deficiency and thereby preventing vitamin K-dependent
MGP activation [
]. A similar mechanism has also
been demonstrated in humans in whom the use of
VKAs is associated with more vascular calcifications
]. This is of course highly undesirable in
calcification-prone COPD patients.
Elastin degradation is enhanced in patients with
COPD due to an imbalance between the protective
effects of antiproteases and the destructive properties of
proteases. In COPD patients, elastinolysis is not only
accelerated in lungs but also in other elastin-rich tissues
]. The severity of emphysema is correlated with
arterial stiffness and skin wrinkling, indicating that a process
of “systemic elastin degradation” may occur in COPD
]. Desmosine and isodesmosine (DES) are two amino
acids that are only present in crosslinked elastin fibers,
and plasma DES levels therefore reflect the rate of
elastin degradation. The COPD Biomarker Qualification
Consortium regards DES as biomarkers with great
]. In a uniform cohort of COPD patients
with alpha-1 antitrypsin (AAT) deficiency, plasma DES
was related to emphysema progression [
]. Plasma DES
levels were not associated with emphysema in a cohort
of patients with a variety of COPD endotypes and
]. However, they were correlated with arterial
stiffness and cardiovascular comorbidity in these
heterogeneous COPD patients [
], which probably indicates
that the vascular compartment is the main contributor
of elastin degradation products in the blood stream of
most AAT sufficient COPD patients. Remarkably, plasma
DES levels were also associated with the CAC score,
illustrating the close relationship between elastinolysis
and vascular calcification [
Elastin calcification and degradation are two pathogenic
mechanisms that stimulate each other [
of calcium chloride (CaCl2) in rat aortas induced both
elastin calcification and degradation [
]. Inhibiting elastin
degradation, prior to CaCl2 administration, also reduced
elastin calcification [
]. The calcification promoting
actions of elastases are probably based on the higher affinity
of degraded elastin for calcium than intact elastin probably
due to increased polarity of the former [
calcification, on the other hand, induces an upregulation of
matrix metalloproteinase (MMP) gene expression leading
to an acceleration of elastin degradation [
]. In an animal
model, it has been demonstrated that VKAs not only
induced elastin mineralization but also promoted elastin
]. MMP-9 activity even preceded
macroscopic elastin calcification [
]. The interrelationships
between elastin calcification, elastin degradation and the
actions of MGP could potentially be a pathomechanistic
explanation for the observed link between COPD and
Osteoporosis and vascular calcification
Remarkably, demineralization of bone tissue and
mineralization of arteries often coexist in individual
patients with COPD [
]. The mechanism behind
this apparently paradoxical link has yet to be established.
We speculate that insufficient activation of the vitamin
K-dependent proteins osteocalcin (OCN) and MGP
might be involved. Whereas activated OCN is regarded
as a regulator of mineralization in bone tissue, MGP
protects extra-osseous tissues from calcification. This
concept is supported by a randomized-controlled trial in
postmenopausal women demonstrating that vitamin K2
supplementation ameliorated both bone loss and arterial
]. Future studies in well-characterized
cohorts have to reveal whether vitamin K deficiency is
indeed the linking pin between osteoporosis and
vascular calcifications in COPD.
Vitamin K supplementation
Preliminary data of our group suggest that vitamin K
status is reduced in patients with COPD compared to
]. We also found an inverse association
between vitamin K status and plasma DES levels; i.e.
lower vitamin K status related to accelerated elastin
The rate of elastin degradation seems to be a strong
independent predictor of mortality in COPD [
Decelerating elastin degradation might therefore be an
attractive therapeutic target in COPD. A recent trial, in
which AAT augmentation therapy reduced plasma DES
levels in COPD patients with AAT deficiency, serves as
a convincing proof-of-principle for this intriguing
]. Since vitamin K supplementation can be
hypothesized as an alternative therapeutic strategy, an
intervention trial should be conducted to assess whether
vitamin K supplementation does indeed decelerate
elastin degradation in patients with COPD.
Vitamin K has an excellent safety profile, and no
toxicity has been observed even with very high-doses [
Vitamin K is obligatory to maturate clotting factors in
the liver, however, it is also necessary for the activation
of anticlotting factors (i.e. protein C and S). Whereas
protein C is solely produced in the liver, about 50% of
protein S is synthesized hepatically and the other half in
the vascular wall [
]. Protein S production in the
vascular system seems to be of key importance in local
thrombosis prevention [
]. The triage theory posits that in
case of scarcity, nature will provide nutrients first to
places in the body where shortage leads to an immediate
treat to short-term survival at the expense of places
where shortage only has long-term consequences (Fig. 3)
]. Regarding vitamin K deficiency, increased bleeding
tendency is the biggest short-term threat for survival,
and the limited supply of vitamin K will therefore be
preferentially used for the synthesis of clotting factors
with the sacrifice of protein S maturation in the vascular
]. Therefore, counterintuitively, vitamin K
supplementation does not increase the risk of
thromboembolism and might even decrease it by fully activating
the anti-thrombosis activity [
]. The triage theory also
Fig. 3 Triage theory. The triage theory implies that in case of mild
vitamin K deficiency the coagulation factors are still activated by
vitamin K, however, the anticoagulation protein S in the vascular
wall and matrix Gla protein are insufficiently activated. This will lead
to both increased thrombosis risk and elastin calcification. Elastin
calcification causes elastin degradation and vice versa. Elastin
degradation in the lungs leads to lung emphysema. Vascular
calcification begins at the elastin fibers in the vascular walls. Only in
case of severe vitamin K deficiency, coagulation factors are also
insufficiently activated leading to increased bleeding tendency
implies that MGP activation in VKA-users is more
severely compromised than the activation of coagulation
], which might have deleterious effects on
vascular calcifications, elastin degradation and survival in
patients with COPD.
Vitamin K1 and K2 in cardiovascular diseases
Whether vitamin K2 alone or both vitamin K1 and K2
have beneficial effects on vascular calcification remains
partially elusive. Data from observational studies suggest
that vitamin K2 rather than vitamin K1 has protective
properties against cardiovascular morbidity and
]. Participants in the non-interventional
Rotterdam study were categorized based on the
estimated consumption of vitamin K1 and K2 . Subjects
from the upper vitamin K2 intake tertile had 0.57 lower
relative risk of cardiovascular mortality than those from
the lowest one [
]. The presence of severe aortic
calcification in the highest tertile for vitamin K2 intake was
also less than 50% compared to that in the lowest tertile
]. Vitamin K1 was not related to either mortality or
aortic calcification in the Rotterdam study [
suggestion of a protective effect of vitamin K2 consumption and
an indifferent effect of vitamin K1 on vascular calcification
was corroborated in the observational Prospect-EPIC study
]. More than 16,000 women were followed for on
average 8 years, and, unlike higher vitamin K1 intake, higher
intake of vitamin K2 was associated with reduced incidence
of coronary heart disease [
Intervention trials, on the other hand, suggest a
favorable effect of both vitamin K1 and K2 on cardiovascular
pathology. A randomized-controlled trial assessed the
effect of one year vitamin K1 supplementation on aortic
valve calcification, which turned out to progress
significantly slower in the active arm [
]. In another
interventional trial, postmenopausal women were supplemented
with vitamin K2 or placebo for three years [
K2 improved arterial compliance, especially in those
women with high stiffness at baseline [
stiffness is a strong independent predictor of cardiovascular
], which is for a large part caused by the
pathophysiological processes elastinolysis and elastocalcinosis
]. COPD patients have increased stiffening of their
arteries compared to controls [
]. Whether vitamin K
supplementation has favorable effects on arterial
stiffness in COPD is currently unknown. Future studies are
needed to assess whether vitamin K could help to
prevent cardiovascular diseases in patients with COPD.
In a rat model, equivalent doses of vitamin K1 and K2
were equally effective in reversing vascular calcifications
]. Inactivation of MGP by the administration of VKAs
led to rapid calcification of arteries in these animals [
Subsequently, both high-dose vitamin K1 and K2
supplementation reduced the calcium content in the rats’
arteries by some 50% [
It might be that the differences between the effects of
vitamin K1 and K2 supplementation are dose-dependent.
Given the lower vitamin K1 bioavailability and shorter
half-life compared to that of K2, it is conceivable that
higher doses of vitamin K1 are needed to achieve the same
results on cardiovascular endpoints than with vitamin K2.
Effect of vitamin K antagonists on elastin degradation
Since the rate of elastinolysis is related to mortality in
], we speculate that the stimulating effect of
VKAs on elastin degradation might contribute to disease
progression and mortality in patients with COPD. VKAs
cause vitamin K deficiency leading to inadequate levels
of active MGP to protect elastin fibers from calcification.
MGP is virtually the only protein that is able to inhibit
elastin calcification given other anti-calcifying proteins,
such as fetuin, are too large to penetrate into the interior
of the elastin fibers [
]. Microscopic elastin
calcification induces an increase of MMP synthesis leading to
accelerated elastin degradation . Preliminary data of
our group suggest that VKAs have an accelerating effect
on elastin degradation [
]. Plasma DES levels were
higher in VKA-users compared to subjects not using
these anticoagulant drugs [
]. However, additional
studies are still required to unequivocally establish that
VKAs enhance elastin breakdown.
Alternative anticoagulant drugs in COPD
The use of VKAs has reduced in recent years following
the introduction of DOACs. Contrary to VKAs, DOACs
work directly on coagulation factors thrombin or factor
Xa without interrupting the vitamin K cycle and the
activation of MGP. It is therefore not to be expected that
DOACs promote vascular calcification and/or elastin
degradation. A variety of studies are currently registered
on ClinicalTrials.gov comparing the effects of VKAs and
DOACs on progression of vascular calcification [
Our group intends to conduct a trial assessing the
differential effects of both anticoagulant drugs on elastolysis.
These clinical studies are needed to unequivocally
establish the effects of VKAs and DOACs on central
mechanisms of COPD pathogenesis. With the current state of
scientific evidence, however, it might already be argued
that VKAs are better to be avoided in COPD patients
given the established adverse effect of VKAs on arterial
mineralization and the high prevalence of cardiovascular
diseases in COPD [
1, 23, 24
Future studies assessing the role of vitamin K in COPD pathogenesis
Additional animal and human studies are needed to fully
unravel the role of vitamin K on the development and
progression of COPD.
A variant of the smoking mouse model, previously
applied to study the effects of vitamin D status on
emphysema formation [
], could be used to assess the effects
of high and low vitamin K status on lung destruction.
Analogously to a rat model of vascular calcification,
vitamin K deficiency is probably best induced in these
experiments by combining high-dose VKAs to prevent
vitamin K-dependent MGP activation with vitamin K1 to
prevent hemorrhage [
Furthermore, large human cohort studies are needed
to see if vitamin K deficiency is a significant factor for
pulmonary disease progression in COPD. Intervention
trials in patients with COPD are necessary to assess
whether vitamin K administration may decelerate
pulmonary elastin degradation and emphysema progression.
Abundant circumstantial evidence, both from human
observational studies and from animal intervention
studies, points to a link between low vitamin K levels, elastin
degradation and cardiovascular pathology in COPD
patients. As VKAs are still widely used in this particular
population concerns may rise on their long-term safety
profile. Vitamin K intervention studies are warranted to
reveal if vitamin K supplementation may play a role in
the management of patients with COPD.
AAT: Alpha-1 antitrypsin; CAC: Coronary artery calcification; CaCl2: Calcium
chloride; COPD: Chronic obstructive pulmonary disease; DES: Desmosine and
isodesmosine; dp-uc: Desphospho-uncarboxylated (i.e. inactive); KH2: Vitamin
K hydroquinone; KO: Vitamin K epoxide; MGP: Matrix Gla protein;
MMP: Matrix metalloproteinase; OCN: Osteocalcin; SNP: Single nucleotide
polymorphism; VKA: Vitamin K antagonist; VKOR: Vitamin K epoxide
reductase; VKORC1: VKOR complex subunit 1
We would like to thank Mrs. Ilse Voornhout-Brouwer for creating the
Availability of data and materials
IP and RJ wrote the first draft of the manuscript, and EFMW, CV, WJ and
FMEF revised the manuscript. All authors read and approved the final
Ethics approval and consent to participate
Consent for publication
CV is an employee of R&D Group VitaK. WJ is a senior clinical investigator of
the Flemish Research Funds (FWO). None declared (IP, EFMW, FMEF and RJ).
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