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Abstract | VitaminD is a precursor of the steroid hormone calcitriol that is crucial for bone and
mineral metabolism. Both the high prevalence of vitaminD deficiency in the general population
and the identification of the vitaminD receptor in the heart and blood vessels raised interest
inthe potential cardiovascular effects of vitaminD. Experimental studies have demonstrated
various cardiovascular protective actions of vitaminD, but vitaminD intoxication in animals is
known to induce vascular calcification. In meta-analyses of epidemiological studies, vitaminD
deficiency is associated with an increased cardiovascular risk. Findings from Mendelian
randomization studies and randomized, controlled trials (RCTs) do not indicate significant effects
of a general vitaminD supplementation on cardiovascular outcomes. Previous RCTs, however,
were not adequately designed to address extraskeletal events, and did not focus on
vitaminD-deficient individuals. Therefore, currently available evidence does not support
cardiovascular benefits or harms of vitaminD supplementation with the commonly used doses,
and whether vitaminD has cardiovascular effects in individuals with overt vitaminD deficiency
remains to be evaluated. Here, we provide an update on clinical studies on vitaminD and
cardiovascular risk, discuss ongoing vitaminD research, and consider the management of
vitaminD deficiency from a cardiovascular health perspective.
Correspondence to S.P.
Department of Internal
Medicine, Division of
Endocrinology and
Diabetology, Medical
University of Graz,
Auenbruggerplatz15,
8036Graz, Austria.
stefan.pilz@chello.at
*These authors contributed
equally as first authors.
doi:10.1038/nrcardio.2016.73
Published online 6 May 2016
VitaminD metabolism
VitaminD, the fourth vitamin to be named, was first
described by McCollum as a factor that was able to
cure rickets, a disease that is characterized by impaired
bone mineralization and skeletal deformities1. Although
initially classified as a vitamin, vitaminD is now recog
nized as a precursor (a prohormone) of the steroid
hormone 1,25dihydroxyvitamin D (1,25(OH) 2D),
also called calcitriol. The major source for vitaminD
is endogenous synthesis in the skin (FIG.1). When the
skin is exposed to ultravioletB (UVB) or sunlight radiation, the liver-derived precursor 7dehydrocholesterol
is converted to pre-vitaminD, which in turn isomerizes
to vitaminD7. Food intake is usually only a minor source
ofvitaminD.The two main isoforms of vitaminD are
vitaminD3 (cholecalciferol), which is synthesized in
the skin and is contained in animal foods such as fish,
and vitaminD2 (ergocalciferol), which the human body
cannot synthesize and is contained in fungi (for example, yeast and mushrooms). VitaminD3 probably has
a higher bioavailability than that of vitaminD2, but in
this Review (unless otherwise stated), we do not distinguish between these two isoforms because they share the
same metabolism8. In the circulation, vitaminD sterols
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Key points
The vitaminD receptor (VDR) and enzymes for vitaminD metabolism are expressed
throughout the cardiovascular system
VDR and 1hydroxylase knockout mice have hypertension with myocardial
hypertrophy and increased activity of the reninangiotensinaldosterone system
The molecular effects of VDR activation indicate various antiatherosclerotic and
protective effects on the heart and on common cardiovascular risk factors
Observational studies have shown that low 25hydroxyvitaminD levels are associated
with an adverse cardiovascular risk profile and significantly increased risk of
cardiovascular events
Mendelian randomization studies and randomized clinical trials have not shown
significant effects of vitaminD on cardiovascular events, but these trials were not
designed to investigate cardiovascular outcomes in vitaminD-deficient individuals
VitaminD supplementation is currently not indicated for the purpose of
cardiovascular disease prevention, but treatment of vitaminD deficiency is critical
forskeletal health
are mainly transported by the vitaminDbinding protein (DBP), which is a serum glycoprotein secreted by
the liver 9. VitaminD itself is biologically inactive and
is hydroxylated to 25hydroxyvitaminD (25(OH)D) in
the liver (FIG.1). Serum 25(OH)D is measured to assess
vitaminD status, because this isoform is the major circulating vitaminD metabolite that best reflects vitaminD
intake from all sources6. Further 1hydroxylation
of 25(OH)D occurs mainly in the kidney, and results
in the formation of the active vitaminD hormone
1,25(OH)2D10. The endocrine production of 1,25(OH)2D
is tightly regulated by parameters of bone and mineral
metabolism. For example, 1,25(OH)2D production is
stimulated by the parathyroid hormone and inhibited by
fibroblast growth factor23 (FGF23), with the main aim
of maintaining an adequate serum calcium level through
the effects of 1,25(OH)2D on the kidney, intestine, and
bone10. Therefore, serum 1,25(OH)2D concentrations are
not a good measure of vitaminD supply orstatus.
The effects of 1,25(OH)2D can be autocrine and para
crine because 25hydroxyvitaminD-1hydroxylase
(1hydroxylase) expression has been reported in several extrarenal cells, including cells of the cardiovascular
system10. This local tissue production of 1,25(OH)2D
seems to be mainly dependent on the availability of
circulating 25(OH)D, but 1,25(OH)2D production is also
regulated by other factors such as cytokines3,10. Finally,
1,25(OH)2D exerts its biological effects by binding to
the almost ubiquitously expressed VDR3,10. The tissue
and cell-type specific distribution of the VDR throughout the body is still not fully resolved, however, and not
all studies detected VDR expression in tissues such as
skeletal, cardiac, or smooth muscle11. After activation
of the cytosolic VDR by ligand binding and trans
location to the nucleus, the activated VDR interacts with
vitaminD response elements in the promoter region of
target genes and, thereby, regulates approximately 3%
ofthe genome3,10. Degradation of 1,25(OH)2D and other
vitaminD metabolites is initiated by 24hydroxylation
(FIG.1), an enzymatic process that is induced, for example,
by VDR activation itself, thereby preventing v itaminD
intoxication as part of an autoregulatoryloop.
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Nutritional vitamin D3,
vitamin D2 intake
Ultraviolet-B
7-dehydrocholesterol
Circulation
Pre-vitamin D3
Skin
80%
Vitamin D
20%
DBP
Vitamin D
Liver
25-hydroxylase
25-hydroxyvitamin D
FGF-23
PTH
1-hydroxylase
1,25-dihydroxyvitamin D
Endocrine eects
Particularly important for calcium
and phosphate homeostasis
24-hydroxylase
24,25-hydroxyvitamin D
1,24,25-hydroxyvitamin D
Calcitrioic
acid
Excretion
24-hydroxylase
Figure 1 | Human metabolism of vitaminD. After endogenous synthesis in the skin where 7dehydrocholesterol is
Nature Reviews
| Cardiology
converted to pre-vitaminD3 in response to ultravioletB exposure and then is isomerized to vitaminD
3 in the epidermal
basal layers or dietary intake of vitaminD2/D3, vitaminD binds to the vitaminDbinding protein (DBP) in the
bloodstream and is transported to the liver, where vitaminD is hydroxylated to 25hydroxyvitaminD8. Production of the
active secosteroid 1,25dihydroxyvitaminD upon 1hydroxylation in the kidney is tightly regulated, stimulated by the
parathyroid hormone (PTH) and inhibited by fibroblast growth factor23 (FGF23) and 1,25dihydroxyvitaminD itself10.
Therate-limiting step in catabolism is the degradation of 25hydroxyvitaminD and 1,25dihydroxyvitaminD to
24,25hydroxyvitaminD and 1,24,25dihydroxyvitaminD, respectively, which are consequently metabolized to calcitrioic
acid and excreted by the kidney. The biological effects of 1,25dihydroxyvitaminD are induced via binding to the almost
ubiquitously expressed vitaminD receptor3,10. Major endocrine actions include the regulation of calcium and phosphate
homeostasis10. In extrarenal tissues (for example, in cardiovascular tissues), 1,25dihydroxyvitaminD can also exert
autocrine and paracrine effects.
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Box 1 | Classification of vitaminD status
VitaminD status is classified according to the serum levels of 25hydroxyvitaminD
(25(OH)D). Several cut-off targets and reference ranges have been proposed. The
guidelines from the Institute of Medicine of the National Academies (USA)12 (see the
figure) conclude that 25(OH)D serum levels of 50nmol/l (20ng/ml) are sufficient to
meet the vitaminD requirements in 97.5% of the general population. When sunlight
exposure is low or absent, the recommended dietary allowance for vitaminD
(cholecalciferol or ergocalciferol) is 600international units (IU) per day for ages
170years and 800IU/day for ages 71years. VitaminD deficiency is defined by serum
25(OH)D levels <30nmol/l. By contrast, the Endocrine Society Practice Guidelines28
define vitaminD deficiency as serum 25(OH)D levels <50nmol/l, insufficiency as
52.572.5nmol/l, and sufficiency as >75nmol/l.
<30
Deciency
30 <50
50 75
>75 125
Inadequacy
Suciency
Not consistently
associated with
increased benet
>125
Reason for
concern
by approximately 25nmol/l (10ng/ml). Another possibility is to treat patients with vitaminD deficiency with
active vitaminD, that is, with calcitriol or its a nalogues
(such as paricalcitol). However, active vitaminD treatment has a narrow therapeutic window with risk of
hypercalcaemia and hyperphosphataemia; therefore, this
treatment is mainly restricted to patients with chronic
kidney disease or hypoparathyroidism. In this Review,
we focus on the literature on vitaminD (cholecalciferol or
ergocalciferol) supplementation and 25(OH)D concentrations, and provide only a few examples of studies on
active vitaminD treatment or 1,25(OH)2D levels.
Mechanistic studies
From a cardiovascular perspective, mice with a systemic
knockout of the Vdr or 1hydroxylase (Cyp27b1) genes
are characterized by myocardial hypertrophy with overexpression of the reninangiotensinaldosterone system
(RAAS), hypertension, increased thrombogenicity, and
progression of atherosclerosis3,10. Various molecular
effects of vitaminD with relevance to the cardiovascular
system have been described, which we have summarized
according to the effects on cardiovascular risk factors,
blood vessels, and the heart (FIG.2).
Cardiovascular risk factors. Apart from modulating
mineral metabolism, VDR activation also has a suppressive effect on parathyroid hormone synthesis3,10. High
parathyroid hormone serum concentrations are associ
ated with cardiovascular risk factors such as chronic
kidney disease and obesity, and with increased risk of
cardiovascular events40. Experimental studies indicate
that parathyroid hormone exerts various effects on
the cardiovascular system, including the promotion of
intracellular calcium overloading of cardiomyocytes,
generation of oxidative stress, proarrhythmic actions,
and induction of myocardial hypertrophy, endothelial
dysfunction, and aldosterone secretion4143.
The proposed antihypertensive properties of vitamin D might be mediated by suppression of the
RAAS4446. VDR activation suppresses the transcription of the renin gene by blocking the activity of the
cAMP response element in the renin gene promoter 44.
Experimental studies suggest that, besides low calcium
and high parathyroid hormone levels, vitaminD deficiency can also contribute to arterial hypertension by
increasing vascular resistance and vasoconstriction46.
Various molecular effects of VDR activation suggest
antidiabetic properties of vitaminD, including increases
in insulin secretion and insulin sensitivity as well as protection against cytokine induced cell dysfunction and
cell death47,48. VitaminD might also prevent type1
diabetes mellitus through anti-inflammatory actions
and by increasing regulatory Tcells that protect against
autoimmune diseases (and atherosclerosis)48.
The effects of vitaminD on lipid metabolism are
largely unclear and might be harmful or beneficial4951.
VDR activation suppresses apolipoproteinAI (APOA1)
expression the major constituent of HDL cholesterol
and might indirectly increase fat absorption in the
gut because the increased calcium absorption induced
by vitaminD might reduce the formation of the calcium-
fatty acid soaps that are excreted in the faeces4951. By
contrast, another hypothesis is that the increases in
calcium absorption induced by vitaminD might even
reduce serum triglyceride levels by decreasing hepatic
triglyceride formation or secretion through an effect
on hepatocellular calcium49,52. Other potentially beneficial vitaminD effects on blood lipids might be mediated by lowering parathyroid hormone levels (which
suppresses lipolysis) or by increasing insulin secretion
andsensitivity 49,50.
Several other cardiovascular, protective, molecu
lar effects of VDR activation have been described.
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Forexample, VDR activation regulates inflammation
by blocking nuclear factorB (NFB) activation, might
prevent kidney diseases through protective effects on
podocytes and other antiproteinuric actions such as
increased expression of LRP2 (which encodes megalin)
and anaemia (for example, through suppression of
inflammation and hepcidin production, and by increasing erythropoiesis), regulates coagulation, and reduces
oxidative stress3,10,33,3739,53.
Vasculature. The molecular effects of vitaminD on
blood vessel cells have been extensively reviewed53.
Experimental studies suggest that vitaminD can protect
against atherosclerosis by inhibiting the transformation
of macrophages to foam cells and by increasing cholesterol efflux 54,55. Endothelial repair might be promoted by
1,25(OH)2D-induced production of vascular endothelial
growth factor (VEGF) in vascular smooth muscle cells53.
Upregulation of endothelin receptor typeB (EDNRB)
Plasma membrane
Activation of VDR
Gene
Co-activators transcription
VDR RXR
RNA
Pol II
Nucleus
Heart
b
Blood vessels
Cardiovascular
risk factors
Parathyroid hormone
Suppressed parathyroid
hormone synthesis in
parathyroid glands
Diabetes
Increased insulin secretion
Increased insulin sensitivity
Protection against -cell
dysfunction and death
Anti-inammatory actions
Increase of regulatory T cells
Lipid metabolism
Reduced expression
of apolipoprotein A-I
(APOA1)
Kidney disease
Anti-proteinuric
eects by protective
eects on podocytes
and increased
megalin (LRP2)
expression
Protection against
renal anaemia
Hypertension
Supression of the
reninangiotensin
aldosterone system
Anti-inammatory
Antioxidative
Antimicrobial
Nature Reviews
| Cardiology
findings from experimental studies, the effects
of vitaminD
can be
categorized into effects on the blood vessels, the heart, and
oncardiovascular risk factors. While most studies indicate beneficial
cardiovascular effects of vitaminD receptor activation, the effects of
vitaminD on lipid metabolism and vascular calcification are unclear and
might be harmful or beneficial. LRP2, low-density lipoprotein receptorrelated protein 2; MCIP1, modulatory calcineurin inhibitory protein1;
RNA PolII, RNA polymeraseII; VSMC, vascular smooth muscle cell.
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The effects of vitaminD on vascular calcification are
a double-edged sword, with both deficiency and excess of
vitaminD (in particular in the setting of end-stage renal
disease) causing vascular calcification and transformation
of vascular smooth muscle cells towards an osteoblastic
phenotype53. Phosphate overload, which stimulates
vitaminD degradation by increasing 24hydroxylase
expression, is a pivotal component for vascular calcification33. VDR activation increases phosphate absorption
and phosphate levels, which in turn stimulate FGF23
secretion by osteocytes. FGF23 is a master regulator of
phosphate homeostasis and increases renal phosphate
excretion. The expression of klotho, which is encoded by
the KL gene and is a coreceptor for FGF23, is increased
by VDR activation53. This coreceptor has been shown to
protect against vascular calcification, indicating that the
interactions between vitaminD, klotho, and FGF23 are
critically involved in vascularcalcification53.
Heart. VDR expression has been detected in cardiac
myocytes and fibroblasts, and cardiomyocyte-specific
knock out of the Vdr gene in mice is associated with
myocardial hypertrophy 58,59. These knockout mice
display activation of the fetal gene programme in
cardiomyocytes that is, increased atrial natriuretic
peptide (Nppa) and actin, 1skeletal muscle (Acta1)
gene expression and increased expression of Rcan1,
which encodes MCIP1(modulatory calcineurin inhib
itory protein1, also known as calcipressin1), a downstream target of calcineurin/nuclear factor of activated
Tcells (NFAT) signalling 60. Given that 1,25(OH)2D
treatment reduced Rcan1 expression in neonatal
cardiomyocytes, the antihypertrophic effects of VDR
activation have been hypothesized to be mediated by
suppression of the calcineurin/NFAT/RCAN1 pathways60. Accordingly, rats with vitaminD deficiency
also develop cardiac hypertrophy along with interstitial
fibrosis58. Interestingly, myocardial hypertrophy in rats
is accompanied by increased VDR gene and protein
expression in the heart 58,59. In experimental studies,
VDR activation in the myocardium regulates extra
cellular matrix turnover by modulating the expression
of matrix metalloproteinases and tissue inhibitors of
metalloproteinases 58,59. Moreover, VDR activation
modulates myocardial contractility, probably by regulating calcium flux 58,59. Mice with a systemic knockout of
1hydroxylase have reduced systolic function that can
be restored by 1,25(OH)2D treatment 58,59. The effects of
vitaminD on myocardial contractility are still puzzling,
but the capacity of 1,25(OH)2D to induce accelerated
relaxation of cardiomyocytes might indicate that VDR
activation can be relevant to diastolic function58,59.
Observational studies
Many studies have reported on the associations between
vitaminD status best reflected by serum 25(OH)D
levels and cardiovascular risk4,5,33,3739. However,
despite careful adjustments, these epidemiological studies can be limited by residual confounding and reverse
causation. 25(OH)D levels are reduced, for example,
by limited physical mobility and the subsequently
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Table 1 | Meta-analyses on the association between vitaminD and cardiovascular events and mortality
Study (year)
Number
of
studies
Participants/
events
Metric
Pooled risk
(95%CI)
Tests for
heterogeneity
Egger
test,
Pvalue
23,081/1,886
NR
24,387/2,007
NR
NR
NR
1.42 (1.191.71) NR
NR
29
0.96
2*
35,334/3,194
NR
23,481/2,265
0.331
12
42,565/4,632
0.79 (0.720.87) NR
NR
Cardiovascular mortality
90
5,253/756
27,620/2,530
NR
19
65,994/6,123
0.11
82,982/8,376
0.12
10,170/1,625
1.83 (1.302.57) NR
NR
58,384/2,644
0.008
39,095/1,214
NR
47,809/926
0.7
NR
NR
1.64 (1.272.10) NR
NR
86
84
Myocardial infarction
Stroke
113
84
Heterogeneity was assessed by the CochranQ or I2. Probability of publication bias was expressed by Egger test. All meta-analyses used study-level data as source
data, except for Schttker etal. (2014), Afzal etal. (2014), and Brondum-Jacobsen etal. (2015), which used individual patient data. NR, not reported; Q, quartile;
Q5,quintile; RR, relative risk; T, tertile. *Meta-analyses by Afzal etal. (2014) and Brondum-Jacobsen etal. (2015) were not based on a systematic literature search.
Brndum-Jacobsen etal. (2012) used a composite outcome of myocardial infarction and ischaemic heart disease.
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0
0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
vitaminDmetabolism, for example, in vitaminD transport by DBP (GC) and 24hydroxylation (CYP24A1)131135.
These SNPs can be used to perform Mendelian ran
domization studies and evaluate whether the genetically
determined variation in 25(OH)D levels is associated
with cardiovascular risk136. However, these studies might
be limited because <5% of the variation in 25(OH)D
serum levels can be explained by the above mentioned
SNPs. Conversely, Mendelian randomization studies are
considered to have a high-evidence level because the
genetically determined variation in 25(OH)D serum concentration is, in general, not associated with confounding factors and indicates a lifelong exposure. By contrast,
RCTs are performed for only a short period oftime.
In relation to cardiovascular risk factors, Mendelian
randomization studies do not support a causal relationship between 25(OH)D serum levels and obesity and
Creactive protein concentration137139. AMendelian randomization study reported that genetic variants associ
ated with low serum concentrations of 25(OH)D are
associated with an increased risk of type2 diabetes140,
but this finding could not be replicated in another publication141. Similarly, another Mendelian randomization
study suggested an association between high 25(OH)D
levels and a favourable lipid profile142, but a larger study
did not confirm a causal association between genetically
determined 25(OH)D serum concentrations and HDL
or LDL cholesterol143. In the context of hypertension, one
Mendelian randomization study did not find an association between 25(OH)D levels and mean arterial blood
pressure138. However, a large consortium reported that a
10% increase in genetically determined 25(OH)D concentration was associated with a change of 0.29mmHg in
diastolic blood pressure (95%CI 0.52to0.07), achange
of 0.37mmHg in systolic blood pressure (95%CI
0.730to0.003), and 8.1% decreased risk of hypertension (OR0.92, 95%CI 0.870.97)144. Moreover, a fairly
small (n<10,000) Mendelian randomization study indicated that high serum concentrations of 25(OH)D might
be causally related to high serum adiponectin, which is
considered to protect against cardiovasculardiseases145.
Importantly, Mendelian randomization studies
have not demonstrated that genetically determined
25(OH)D serum concentration is associated with coro
nary artery disease, myocardial infarction, stroke, or
cardiovascular mortality 138,146148. In a large, Mendelian
randomization study, a 20nmol/l (8ng/ml) reduction in
25(OH)D plasma concentration was associated with an
increased risk of cardiovascular death (OR1.13, 95%CI
1.031.24), but genetically determined 25(OH)D was
not associated with cardiovascular mortality (OR0.77,
95% CI 0.551.08) 148. Therefore, Mendelian ran
domization studies confirm that measured plasma
25(OH)D is inversely associated with risk of cardio
vascular diseases, but genetically determined (and
likewise unconfounded) 25(OH)D isnot.
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RCTs have suggested blood-pressure-lowering effects
of vitaminD149,150. However, a meta-analysis published
in 2015 that included 4,541 participants reported no
significant effect of vitaminD supplementation on
systolic and diastolic blood pressure151. These data
have been confirmed in an RCT of 200patients with
hypertension that also showed no significant effect of
vitaminD supplementation on ambulatory blood pressure152. Notably, one small meta-analysis in adults with
obesity indicated that vitaminD supplementation was
associated with a slight, but significant, increase in systolic blood pressure153. However, this meta-analysis was
limited by the small number of studies included and by
a high heterogeneity between the trials153.
In a meta-analysis of RCTs including a total of
43,407 participants, vitaminD supplementation had
no significant effect on parameters of glucose homeostasis (insulin resistance, insulin secretion, and HbA1c)
or diabetes prevention154. Similar results have been
reported by meta-analyses in specific patient groups and
pregnantwomen155157.
VitaminD supplementation had no effect on measures of obesity in meta-analyses of RCTs158,159. The vast
majority of RCTs reported no relevant effect of vitaminD supplementation on blood lipids153,160,161. A slight
increase in LDL-cholesterol level was noted in two
meta-analyses, but these findings should be interpreted
with caution when considering the small samples sizes
and the high heterogeneity between the studies153,160,161.
Importantly, the largest meta-analysis on this topic
reported no effect of vitaminD supplementation on
total cholesterol, triglycerides, and LDL-cholesterol or
HDL-cholesterol levels162. The conclusion of a systematic review was that the relationship between vitaminD
and blood lipids is a topic that has not been adequately
investigated and reliable evidence does not yet exist 160.
With reference to inflammation, meta-analyses of
vitaminD RCTs have reported inconsistent results,
indicating either no effect or, for example, a decrease
in Creactive protein and tumour necrosis factor concentrations after vitamin D supplementation 163165.
Some RCTs indicate that vitaminD can exert immuno
modulatory effects, for instance, by increasing regulatory Tcells, but further studies are warranted to address
this topic166. Summarizing currently available RCT data
on vitaminD supplementation and cardiovascular risk
factors, we conclude that, apart from a well-established
effect on parathyroid hormone concentrations, no consistent and significant effects on other cardiovascular
risk factors have beendemonstrated92,167.
Cardiovascular diseases. Meta-analyses of RCTs of
vitaminD supplementation have shown no signifi
cant effects on endothelial dysfunction 168170. In a
meta-analysis including eight studies with a total of
529participants, vitaminD treatment had no overall
effect on flow-mediated dilatation (a method used to
estimate endothelial function), but the heterogeneity
between the included RCTs was very high168. Another
meta-analysis showed that vitaminD supplementation had no significant effect on pulse wave velocity
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Table 2 | Meta-analyses of RCTs on vitaminD effects on cardiovascular events and cardiovascular mortality
Meta-analysis (year)
Number
of RCTs
Participants/
events
Followup
(years)
Interventions
Metric
Pooled effect
(95%CI)
I2
(%)
10
47,267/1,957
0.316.20
RR
0.98 (0.901.07)
Cardiovascular mortality
Bjelakovic etal. (2014)172
36,473/985
17
RR
1.04 (0.921.18)
NR
NR
NR/NR
NR
NR
OR
0.94 (0.811.08)
8,189/148
1.08.2
HR
0.82 (0.581.15)
NR
NR
NR/NR
NR
NR
OR
0.86 (0.541.37)
NR
11
11,717/654
1.08.2
HR
0.96 (0.831.10)
NR
162
39,879/1,353
17
RR
1.02 (0.931.13)
48,647/1,489
17
RR
1.02 (0.931.13)
NR
NR/NR
NR
NR
OR
1.09 (0.871.37)
11
11,841/477
1.08.2
HR
1.07 (0.911.29)
NR
39,739/1,006
17
RR
1.05 (0.881.25)
15
46,431/1,213
17
RR
1.01 (0.901.13)
Cardiac failure
Ford etal. (2014)173
Myocardial infarction*
Stroke*
173
22
Direction of comparison is vitaminD versus control. Only meta-analyses of RCTs testing vitamin D3 (D3) or vitamin D2 (D2); or D3, D2, or active vitaminD (mixed)
areshown. Pooled effect estimate and 95%CI were calculated using random effects models. Heterogeneity was assessed by I2. NR, not reported; RCT,
randomizedcontrolled trial; RR, relative risk. *Bolland etal. (2014) investigated the effects on myocardial and ischaemic heart disease as well as on stroke
andcerebrovascular disease.
Future perspectives
Current classifications of vitaminD status are based on
total serum 25(OH)D concentrations, where approximately 90% of 25(OH)D is bound to DBP. However,
accumulating evidence suggests that free (unbound)
25(OH)D or bioavailable 25(OH)D (free plus albumin-
bound 25(OH)D) could be of relevance, in particular in
conditions with low DBP concentrations (such as liver
cirrhosis or nephritic syndrome) or high DBP concentrations (such as in pregnancy)177. Investigations on this
topic, as well as on the underlying reasons for the ethnic
differences in the association between vitaminD status
and cardiovascular diseases, are warranted178181.
Several large RCTs to address whether vitaminD
supplementation has an effect on cardiovascular outcomes are currently ongoing 182186 (TABLE3). However,
these RCTs are limited by the inclusion of participants
regardless of their vitaminD status. This lack of restriction in baseline vitaminD status is of concern because
even subgroup analyses with the vitaminD-deficient
individuals included in these RCTs who should be
the target population for vitaminD treatment will
not change the general conclusions based on neutral
trial results. This concern is well exemplified by a recent
RCT involving patients in the intensive care unit that
showed no overall effect on all-cause mortality, but a
significantly reduced risk of death with vitaminD supplementation in patients with 25(OH)D concentrations
<30nmol/l (12ng/ml)187.
Apart from the RCTs on hard clinical end points,
several ongoing projects, such as the European Union
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Table 3 | Large, randomized, placebo-controlled trials on vitaminD treatment effect on cardiovascular outcomes
Randomized,
controlled trial
Intervention
doses
Cardiovascular end
points
VITAL*
(Pradhanetal.183,202)
USA
25,875/
completed
2017#
50years (men),
55years (women)
Cardiovascular disease
ViDa
(Scraggetal.184,203)
New
Zealand
5,110/
completed
2016
5084years
100,000IU per
month
Cardiovascular disease
FIND*
(Tuomainenetal.204)
Finland
2,500||/
completed
2018
60years (men),
65years (women)
Cardiovascular disease
DHealth
(Nealeetal.205)
Australia
25,000/
completed
2019
6079years
60,000IU per
month
Cardiovascular events
DOHEALTH*
(Bischoff-Ferrari etal.206)
Western
Europe
2,152/
completed
2017
70years
Cardiovascular events,
cardiovascular mortality
UK
1,600/
completed
2017
6584years
100,000IU per
month
Cause-specific mortality
EVITA*
(Zittermannetal.208)
Germany
400/
completed
2016
Event-free survival
Only trials with n400patients are shown and only the cardiovascular end points are provided. Study end was approximated from data available at the respective
clinical trial registry. 25(OH)D, 25hydroxyvitaminD; IU, international units. *Registered at ClinicalTrials.gov. Registered at Australian New Zealand Clinical Trials
Registry. Registered at ISRCTN registry. ||Sample size was reduced from 18,000 to 2,500, according to clinical trial registry. Events are defined as cardiac
transplantation, high urgent listing for cardiac transplantation, resuscitation, hospitalization, and ventricular assist device implantation. #The VITAL trial might end
later than 2017 because randomization was completed in March 2014.
Conclusions
Currently available evidence does not support significant benefits or harms of vitaminD supplementation
with the commonly used doses on cardiovascular
risk. The main knowledge gaps that remain to be
investigated in future trials are the potential cardio
vascular effects of vitaminD treatment in patients with
overt vitaminDdeficiency and to elucidate the adequate
vitaminD doses and 25(OH)D concentrations that are
associated with a risk of adverse or even toxic effects196.
From a public-health perspective, underscoring the
cardiovascular safety of vitaminD with the commonly
used doses is of great importance when considering
the efforts to improve vitaminD status in the general
population in order to meet the vitaminD requirements
for skeletal health. Public-health authorities are responsible for ensuring the recommended daily vitaminD
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Author contributions
Review criteria
References for this Review were retrieved from a PubMedMEDLINE literature search up to 30January2016 using the
search terms vitaminD plus cardiovascular, heart,
Mendelian randomization, randomized controlled trial, or
meta-analysis. Articles were limited to the English language,
and references from selected papers were used to expand the
search. All retrieved manuscripts were considered for
inclusion in this Review. Some articles were not cited because
of space restrictions.
FURTHER INFORMATION
Project ODIN: http://www.odin-vitd.eu/
ALL LINKS ARE ACTIVE IN THE ONLINE PDF
www.nature.com/nrcardio
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