Current Drug Targets, 2011, 12, 29-41 29
1389-4501/11 $58.00+.00 © 2011 Bentham Science Publishers Ltd.
Vitamin D Biology in Heart Failure: Molecular Mechanisms and
Laura M.G. Meems, P. van der Harst, W.H. van Gilst and R.A. de Boer*
Department of Cardiology, University Medical Center Groningen, University of Groningen, The Netherlands
Abstract: Vitamin D has recently been suggested as an important mediator of blood pressure and cardiovascular disease,
including heart failure. In patients with heart failure, low vitamin D levels are associated with adverse outcome and
correlate with established clinical correlates and biomarkers. Many precursor states of heart failure, such as hypertension,
atherosclerosis, and diabetes are more prevalent in subjects with low vitamin D levels. Recent experimental data have
provided clues how vitamin D might exert cardioprotective effects. The steroid hormone vitamin D regulates gene
expression of many genes that play a prominent role in the progression of heart failure, such as cytokines and hormones.
Specifically, vitamin D is a negative regulator of the hormone renin, the pivotal hormone of the renin-angiotensin system.
Mechanistic insights were gained by studying mice deficient for the vitamin D receptor, which develop hypertension and
adverse cardiac remodeling mediated via the renin-angiotensin system. Furthermore, vitamin D receptor is expressed in
the heart and regulated under pro-hypertrophic stimuli and vitamin D as receptor has been associated with the expression
of other hypertrophic genes such as natriuretic peptides.
So, epidemiological data and mechanistic studies have provided strong support for a potentially cardioprotective effect of
vitamin D. It remains unclear if vitamin D supplementation is beneficial in preventing heart failure or if it could be a
therapeutic addendum in the treatment of heart failure. This review summarizes current knowledge on vitamin D and its
biology in heart failure.
Keywords: Heart failure, hypertrophy, renin, renin-angiotensin system, vitamin D, vitamin D receptor.
Western world with an increasing incidence and prevalence
. Once HF has ensued, patients have to be hospitalized
often, thereby having a low quality of life score mainly due
to worsening HF, arrhythmias or (recurrent) myocardial
infarction. HF is a progressive condition involving activation
of regulatory systems like the sympathetic nervous system
(SNS) and the renin-angiotensin system (RAS). Initially
activation of these systems is adaptive, but when activation
becomes sustained, they contribute to pathological cardiac
remodeling and progression of HF . Treatment specifi-
cally targeting neurohormonal systems has reduced HF
associated morbidity and mortality considerably . How-
ever, despite optimal medical therapy, the prognosis remains
poor, with a 5 years mortality of approximately 50% .
Novel targets and treatments are urgently needed and
continuously sought after .
Heart failure (HF) is a major medical problem in the
physiology of HF includes influencing regulators of gene
transcription [4, 5]. A gene regulator that may be of parti-
cular importance for cardiovascular disease and HF is the
vitamin D receptor (VDR) . Insight was gained by study-
ing VDR-/- mice that were shown to develop hypertension
and cardiac remodeling. It has been suggested that treatment
with vitamin D may attenuate experimental cardiac remode-
One of the novel concepts in intervening in the patho-
*Address correspondence to this author at the Department of Cardiology,
Division of Experimental Cardiology, University Medical Center
Groningen, University of Groningen, P.O. Box 30.001, Groningen, 9700
RB, The Netherlands; Tel: +31 50 361 23 55; Fax: +31 50 361 13 47;
ling. Experimental data are supported by (older and recent)
epidemiological data, consistently showing that vitamin D
levels are substantially decreased in patients with HF com-
pared with healthy controls. In various cohorts it was
confirmed that higher vitamin D levels are associated with
favorable outcome in patients with HF. However, the exact
mechanism of these associations is unclear. This review will
describe the most important findings from epidemiological
studies and trials and discuss them in the light of recently
uncovered mechanistic clues. We will describe the metabo-
lism of vitamin D and the potential effects of vitamin D
signaling in HF. We have reviewed published data on the
effects of vitamin D deficiency in HF. Finally, the potential
role of vitamin D supplementation as a treatment in HF will
1. VITAMIN D METABOLISM
1A. Vitamin D Synthesis
allow better understanding why vitamin D levels could be
associated with development of HF. Vitamin D is an essen-
tial precursor of the active form of vitamin D: calcitriol,
1,25-hydroxivitamin-D3 (1,25(OH)2D3). The two major
forms of vitamin D are indicated as ergocalciferol (vitamin
D2) and cholecalciferol (vitamin D3). Dietary intake of
vitamin D provides 10-20% of the required supply ,
whereas most of the vitamin D is synthesized in the skin.
Through the absorbance of Ultraviolet-B (UVB) light by the
skin the first step in the regulatory cascade from lesser active
synthesized vitamin D to more biologically active forms
The basic metabolism of vitamin D is briefly discussed to
30 Current Drug Targets, 2011, Vol. 12, No. 1 Meems et al.
epidermis by solar UVB radiation produces previtamin D3,
which turns to vitamin D3 by thermal isomerization. Primary
hydroxylation of vitamin D3 in the liver results in 25-
hydroxivitamin D (25(OH)D), which transforms into the
highly biologically active calcitriol (1,25(OH)2D3) after sec-
ond hydroxylation in the kidney. Of note, there are several
other cell types with 1α-hydroxylase enzymatic activity, e.g.
vascular smooth muscle, monocytes and endothelial cells.
Although these cells are thought to be of great relevance for
local paracrine effects, they do not significantly contribute to
circulating 1,25(OH)D levels.
Specifically, photolysis of 7-dehydrocholesterol in the
1B. Definition of Vitamin D Deficiency
exists. Nevertheless, vitamin D deficiency is mostly defined
as a 25(OH)D level of less than 20 ng/mL (50 nmol/L) [8-
11]. A level of 25(OH)D of 21-29 ng/mL (52–72 nmol/L)
may be regarded as relative insufficiency, considering data
that shows an increased intestinal calcium transport by 45 to
65% in women when 25(OH)D levels were increased from
average of 20-32 ng/mL (50–80 nmol/L) . A level of 30
ng/mL or greater (>75 nmol/L) may be considered as
sufficient vitamin D levels .
No consensus on optimal levels of (serum) 25(OH)D
1C. Vitamin D and Calcium and PTH
as maintenance of normal ionized calcium and phosphorus
concentrations and thereby as major regulator of the bone
mineralization. Although experimental data of the last years
strongly suggest that vitamin D exerts many effects in the
body, regulation of bone mineralization still remains its most
important function. Without vitamin D, only 10 to 15% of
dietary calcium and about 60% of phosphorus is absorbed
Traditionally, the role of vitamin D has been considered
plasma parathyroid hormone (PTH) levels and serum
calcium and phosphorus levels . Increased levels of PTH,
serum calcium and phosphorus lead to a decrease in
25(OH)D, so an inverse relationship exists. Presence of
1,25(OH)2D3 increases efficiency of the absorption of renal
calcium and of intestinal calcium and phosphorus.
1,25(OH)2D3 also induces the expression of the enzyme 25-
hydroxivitamin-D-24-hydroxylase (CYP24). This enzyme
catabolizes both 25(OH)D and 1,25(OH)2D3 into biologically
inactive, water-soluble calcitroic acid . Although
1,25(OH)2D3 is not the only modulator of PTH secretion, this
inverse relationship is of importance for the cardiovascular
Renal production of 1,25(OH)2D3 is tightly regulated by
2. VITAMIN D AND ITS RECEPTOR IN THE HEART
fically binds to 1,25(OH)2D3 and interacts with target-cell
nuclei to produce a variety of biologic effects .
The VDR is an intracellular hormone receptor that speci-
. A more recent study showed that immunoreactivity was
present for VDR in both neonatal rat cardiomyocytes and in
The VDR is expressed in rat  and human heart tissue
fibroblasts . As expected for a nuclear hormone receptor,
nuclei and not the cytoplasm were positively stained for
VDR. The VDR seems to be subcellular located, within or
adjacent to the T-Tubulus . Expression of the VDR is
under tight control , although cardiac transcriptional
regulation hitherto remains largely unknown. Chen et al.
showed that in cardiac hypertrophy, expression of the VDR
is increased .
2B. Function of VDR
phate homeostasis, to ensure the deposition of bone mineral.
Recently, the role of vitamin D as a steroid hormone
belonging to the steroid hormone nuclear receptor family
with important effects on gene transcription has been
elucidated . Many novel targets of the VDR have been
identified which appear to be important players in heart
disease. The potential importance of transcription factors as
modulators of cardiac hypertrophy and failure has been
appreciated recently  although initital enthusiasm has
The traditional action of vitamin D is calcium and phos-
3. VITAMIN D: EFFECTS ON PATHOPHYSIOLOGI-
CAL PATHWAYS OF HEART FAILURE (FIG. 1)
3A. Renin-Angiotensin System (RAS)
(BP) and volume homeostasis and plays an essential role in
the pathophysiology of HF. The RAS has been an important
drug target for therapeutic intervention: angiotensin convert-
ing enzyme inhibitors (ACEi), Angiotensin II Receptor Bloc-
kers (ARBs), and aldosterone receptor antagonists (ARAs)
reduce HF-related morbidity and mortality . PRA has
been identified as risk factor for worse outcome [26, 27].
Interestingly, in the presence of treatments aimed to inhibit
the RAS, sustained elevations of PRA still exert malicious
The RAS is a key regulatory system in blood pressure
3A-2. Epidemiological Data
and hypertensive subjects, 1,25OH2D3 serum levels are
inversely associated with BP [28-30] and also with PRA [30,
31]. This suggests a potentially causal relationship between
vitamin D and hypertension via renin regulation. Recent
evidence showed that nuclear hormone receptors (NHRs)
including VDR, liver X receptor (LXR) and peroxisome
proliferator-activated receptor (PPAR) importantly mediate
renin transcription regulation  via specific elements in the
renin promoter. VDR binds Retinoid X Receptor (RXR) and
forms a heterodimer, which may bind the Ec, Eb, or DR3
elements in the renin promoter and suppresses renin
transcription [5, 32, 33]. Data from Forman et al. 
showed a significant trend between 25(OH)D levels and
Angiotensin II (Ang II) concentration. Patients with the
lowest 25(OH)D levels had the highest levels of Ang II,
furthermore supporting the notion that the RAS is oversti-
mulated in absence of 25(OH)D. In other small scale clinical
studies, administration of 1,25(OH)2D3 also showed reduc-
Epidemiological data showed that in both normotensive
Vitamin D Biology in Heart Failure Current Drug Targets, 2011, Vol. 12, No. 1 31
tions in PRA, Ang II levels, BP and myocardial hypertrophy
ciation between vitamin D and hypertension, supplementa-
tion studies with vitamin D have yielded equivocal results.
The Women’s Health Initiative Calcium/Vitamin D trial 
could not establish a beneficial effect of long term supple-
mentation with vitamin D (combined with calcium) on BP
and cardiovascular events. Possibly, this could be explained
by the relative low dose (400 IU daily) of vitamin D in this
study. Further studies with well-defined amounts of vitamin
D intake and precise monitoring of BP are necessary to
corroborate a potential relationship between vitamin D status
3A-3. Data from VDR-/- Mice
Although epidemiological data clearly indicate an asso-
between vitamin D and renin has been provided by Li et al.
, who employed mice with genetic total disruption of the
gene encoding VDR (VDR-/- mice). In this model, the
mRNA renin in the kidney is three-fold higher than in wild
type mice and plasma Ang II is increased 2.5-fold. As the
angiotensinogen levels show no difference between the
VDR-/- and wild type mice, the increase of Ang II is attri-
buted to increased renin activation. VDR-/- mice exhibit LV
hypertrophy and increased cardiomyocyte size. Furthermore,
VDR-/- mice have a two-fold increased water intake and
urine output. Besides the cardiomyocytes, matricellular pro-
teins are also regulated in VDR-/- mice . The deve-
lopment of hypertension in VDR-/- mice can be corrected by
administration of ACEi and ARBs but only as long as
1,25(OH)2D3 levels are at sufficient levels . So, from this
Compelling experimental evidence for the interplay
model, it is strongly suggested that 1,25(OH)2D3 is not only
crucial for calcium homeostasis, but also for maintaining BP
3A-4. 1α-Hydroxylase Deficient Mice
been seen in another mouse strain with genetic intervention
in vitamin D homeostasis: the 1α-hydroxylase knockout
mice. These mice lack the 1α-hydroxylase enzyme and
develop abnormalities similar to those reported in VDR-/-
mice. Administration of 1,25(OH)2D3 to 1α-hydroxylase
deficient mice results in normalization of the cardiac
abnormalities and neutralizes RAS activity . A rescue
diet aimed at restoring the serum calcium D levels indeed
showed normalized serum calcium and phosphorus levels,
but the abnormalities in BP, cardiac structure and function
and RAS activation persist. As the increase in renin is not a
result of hypocalcaemia, but disrupted VDR signaling, it was
argued that 1,25(OH)2D3 suppresses renin in an exclusively
VDR-dependent manner . More recent studies in the
same mouse model confirmed that 1,25(OH)2D3 not only
regulates the renal RAS, but also the cardiac RAS in mice in
a calcium-independent and 1,25(OH)2D3 dependent manner
. This underscores the hypothesis that 1,25(OH)2D3
regulates cardiac function, at least partially, through the local
Interestingly, an increase in renin expression had also
evidence was obtained in experimental studies using the spe-
cific VDR agonist paricalcitol. In mice, paricalcitol suppres-
ses in a dose-dependent manner renin expression . The
potentially functional importance of this observation was
shown by Zhang and colleagues . In a model of diabetic
In experimental pharmacological studies, corroborative
Fig. (1). Effect of vitamin D on pathophysiological pathways of HF.
32 Current Drug Targets, 2011, Vol. 12, No. 1 Meems et al.
nephropathy, the ARB losartan decreased proteinuria, how-
ever, at the expense of an increased (compensatory) PRA.
Inhibition of this PRA with the VDR agonist paricalcitol
further decreased proteinuria. In another study from Bodyak
et al. in hypertensive rats, paricalcitol partially reversed
hypertension-induced LV remodeling .
tions of the VDR consistently show that vitamin D is a
negative regulator of renin.
Taken together, genetic and pharmacological perturba-
3B. Other Regulatory Effects of the Vitamin D Receptor
in Heart Failure
3B-1. Effects of Vitamin D on PTH
to increase BP and cardiac contractility, leading to cardio-
myocyte hypertrophy and interstitial fibrosis of the heart
, factors which are directly contributing to cardiovas-
cular disease. An inverse association of 25(OH)D and
1,25(OH)2D3 concentrations with PTH levels have been
reported in CHF patients, similar to the one in healthy adults
. The rate of coronary artery disease increases 1.7-fold in
subjects in the highest PTH quartile range (> 32pg/ml in
men) versus subjects in the lowest PTH quartile (<17.3
pg/ml in men). So, defective PTH regulation may contribute
to the association between abnormalities in vitamin D
homeostasis and heart failure.
Excess levels of parathyroid hormone (PTH) are known
3B-2. Effects of Vitamin D on ANP and BNP
function as part of a counter-regulatory system of the RAS
and are well-used biomarkers in HF. Their production is
stimulated by stretch applied to the cell , which makes
them serve as surrogate markers of hypertrophy [47, 48].
1,25(OH)2D3 lowers levels of immunoreactive ANP (irANP)
and endogenous ANP gene expression . Furthermore,
1,25(OH)2D3 leads to reduction in human BNP (hBNP)
promotor activity. A direct association between VDR with
the hBNP promotor has been indicated by Chen and
colleagues: when cardiac hypertrophy is induced by
isoproterenol administration, not only an increase in hBNP
promoter activity is found, but also in VDR expression .
These data indicate that some of the effects of 1,25(OH)2D3
are rather directly than indirectly operating at the level of the
target gene expression in suppressing the hypertrophic
Atrial and Brain Natriuretic Peptides (ANP, BNP)
3B-3. Effects of Vitamin D on Myotrophin
trophy, but also in normal cardiomyocyte development and
is considered as a potential compensatory mechanism in HF
. By treatment of cells with 1,25(OH)2D3 the level of
myotrophin expression increases  but it is unclear
whether this is cause or consequence of the phenotypic
response of the cardiomyocytes.
Myotrophin acts in the pathogenesis of cardiac hyper-
3B-4. Effect of Vitamin D on (Cardiac) Muscle
several genomic VDR-mediated effects and rapid nongeno-
mic effects of 1,25(OH)2D3 have been described in vitro
. Data from VDR-/- mice suggest that 1,25(OH)2D3 pro-
vides a late stage effect of muscle development, confirmed
Finally, as the VDR is also expressed in skeletal muscle,
by gene and protein expression analysis . So it could be
hypothesized that a direct effect of the VDR system may also
exist in the heart muscle or during heart development.
3B-5. Effects of Vitamin D on Contractility
expression, growth and differentiation in cardiomyocytes
. 1,25(OH)2D3 inhibits myocyte proliferation, induces
myocyte hypertrophy and regulates expression of fetal
myocyte specific genes . Induction of myocyte hyper-
trophy leads to an increase in VDR mRNA and protein
levels, suggesting the presence of a 1,25(OH)2D3-dependent
signaling system within the heart, which is amplified in
cardiac hypertrophy for his beneficial antihypertrophic
system . Thereby, 1,25(OH)2D3 enhances cardiac myo-
cyte contractility [21, 55] and facilitates relaxation through
both genomic and non-genomic pathways [21, 23]. Invol-
vement of 1,25(OH)2D3 in the genomic pathway leads to a
direct regulation of gene transcription, whereas the activation
of non-genomic pathways displays a wide variety of rapid
(seconds to minutes) and transient changes in transmem-
brane transport of ions (such as calcium and chloride) or
intracellular signaling pathways (such as cAMP, protein
kinase A, protein kinase C) . Whether these effects of
vitamin D have consequences for cardiomyocyte function on
the long term is unknown.
1,25(OH)2D3 plays an important role in regulating gene
4. VITAMIN D LEVELS ARE ASSOCIATED TO RISK
FACTORS FOR DEVELOPMENT OF HF
that pointed towards a causal role of vitamin D and its
receptor in HF from early states on. Several risk factors, that
are crucially involved in HF development, are, at least in
part, associated with changes in vitamin D regulation.
Well over 30 years ago, the first observations were made
have demonstrated an inverse relationship between serum
levels of 1,25(OH)2D3, BP [28, 29] and PRA [31, 30] in nor-
motensive and hypertensive subjects. HF that is preceded by
hypertension is about 70% of all patients [1, 3], rendering
hypertension as one of the main causes of HF.
Clinical and epidemiologic studies over the past decades
the leading cause of HF: about 70% of all patients have
ischemic HF. As vitamin D regulates the levels of calcium in
the blood, by increasing the absorption in the intestine, a role
for vitamin D in atherosclerosis is expected. Indeed, low
levels of vitamin D are predictive for increased incidence of
myocardial infarction .
1,25(OH)2D3 are inversely correlated with the extent of
vascular calcification, not only in high risk patients, but also
in patients with low risk of developing HF .
Atherosclerosis with or without myocardial infarction is
Low serum levels of
HF . As the VDR is expressed by pancreatic β-cells and
cells of the immune system, a role for vitamin D has been
Diabetes is increasingly recognized as important cause of
Vitamin D Biology in Heart Failure Current Drug Targets, 2011, Vol. 12, No. 1 33
suggested in diabetes mellitus (DM). Previous data shows
that vitamin D deficiency leads to impaired secretion of
insulin, in both animal and human models, and induces glu-
cose intolerance [57, 58]. And, indeed vitamin D deficient
individuals are at increased risk for developing type 2 DM
[59, 60]. Rectification of the glucose intolerance is observed
after supplementation with vitamin D [61, 62].
4D. Other Risk Factors
ficant positive correlation between serum concentrations of
25(OH)D and lipid profiles, such as apolipoprotein A-1 and
high density lipoprotein (HDL)-cholesterol [63, 64]. Accu-
mulating epidemiological data are linking a low vitamin D
status to the development of autoimmune diseases and chro-
nic infections, like chronic obstructive pulmonary disease,
allergy/asthma, multiple sclerosis, and rheumatoid arthritis
. The VDR is required for the cellular and humoral
immune response [65, 66]. In vitro studies suggest that
vitamin D suppresses pro-inflammatory cytokines  and
upregulates anti-inflammatory cytokines [66-68], leading to
a possible inhibitory pathway in worsening of HF .
Several studies showed an independent and highly signi-
5. VITAMIN D LEVELS AND THE CLINICAL HEART
FAILURE SYNDROME: A SYSTEMATIC REVIEW
5A. Methodology of Systematic Review
MESH terms “heart failure”, “cardiomyopathy”, and “vita-
min D”. This yielded 139 references. We excluded case
reports, case series, review articles, articles in other lang-
uages than English and articles describing experiments in
laboratory animals or cells. This left us with 27 articles,
We performed a search in Pubmed (April 2010), using
which are discussed in the text and categorized in Tables 1
and 2. In Table 1, articles are presented with data on vitamin
D levels and development and/or outcome in HF. Table 2
shows articles that describe the effects of vitamin D
supplementation on HF development or outcome.
5B. The Cause of Vitamin D Deficiency in HF is
multifactorial. First, in the general population, serum
1,25(OH)2D3 decreases with age . The average HF
patient tends to be older (>70 years), so already prone to low
vitamin D levels. Secondly, limited mobility is a hallmark of
HF [71, 72]. Patients with HF have an increased risk of
developing vitamin D insufficiency, simply because of their
sedentary life-style . Interestingly recent data indicated
that HF patients, compared to healthy controls, already had a
lower vitamin D status in the period of their lives when they
were still free from HF .
Vitamin D deficiency in patients with HF is likely to be
ciency is not only due to variation in environment; also
genotype is a determinant factor in the development of vita-
min D deficiency. As an example serves the gene CYP27B1
which decodes the rate limiting enzyme for bioactivation of
1,25OH2D3, and therefore involved in vitamin D metabolism
. A SNP (Rs4646537) situated in the eight intron of the
gene encoding CYP27B1 has been associated with hyper-
tension and chronic HF. The homozygote rs4646537 carrier
status is associated with increased risk for chronic HF in
hypertensive patients, whereas the heterozygote carrier status
demonstrates protective effects against development of
Thereby, this multifactorial character of vitamin D defi-
Table 1. Vitamin D Levels and Development and/or Outcome in HF
HF and Vit. D
N Race Age (Years)
% Deficient Key Findings
Bolland et al.  Post MPW 1481 C 50.0%
Serum 25(OH)D <50
736 74.5±4.4 37.7±8.5 nmol/L
Serum 25(OH)D >50
735 73.6±4.0 65.4±13.0 nmol/L -
Risk for congestive HF, p=NS (p=0.97). Risk for
MI, p=NS (p=0.52).
Pilz et al.  CHF pt 3257 C - 89.7%
Lowest quartile of serum 25(OH)D is associated
with a higher number of deaths due to HF. NT-
proBNP and 1,25(OH)2D are significantly
Zittermann et al.  CHF pt 88 C 61.3%
CHF patients < 50 years 20 38.9±7.9 9.5 ng/mL
CHF patients ≥ 50 years 34 64.1±6.4 11.5 ng/mL
Controls ≥ 50 years 34 68.9±5.2 17 ng/mL
Significant reduced 25(OH)D and 1,25(OH)2D
levels in chronic HF pt (p<0.001). Significant
inverse relationship between NT-proANP and
serum 25(OH)D (p<0.001).
34 Current Drug Targets, 2011, Vol. 12, No. 1 Meems et al.
(Table 1) Contd…..
HF and Vit. D
N Race Age (Years)
% Deficient Key Findings
Alsafwah et al. 
CHF pt, HD-
NHF pt, controls
86 AA - 84-96%
Mild hypovitaminosis D
20 - 30 ng/mL
Mod. hypovitaminosis D
10 - 19 ng/mL
Severe hypovitaminosis D
Hypovitaminosis D is quite prevalent in AA,
irrespective of the season. As well in individuals
with either decompensated or compensated HF,
and those with HD-NHF and healthy volunteers.
Nevertheless, most and most severe
hypovitaminosis D is seen in HF patients
compared to the other groups.
Zittermann et al.  CHF pt 383 C
Electively listed patients 325 55.8±0.6 35.0±3.0 nmol/L 50.2%
Urgent/high urgent listed
58 52.6±1.7 23.3±2.0 nmol/L 56.9%
Low circulating 1,25(OH)2D levels are more
often found in urgent/high urgent candidates for
cardiac transplantation than in elective
candidates. 1-year survival in those patients with
lower 1,25(OH)2D levels vs. higher levels (p
<0.001). An association between lower
1,25(OH)2D levels and higher risk of adverse
events such as death and the need for cardiac
transplantation was observed (p<0.001).
Watson et al. 
113 C -
Low risk group for
100 >45 years 40.1 ± 13.0 pg/mL
High risk group for
13 >45 years 34.5 ± 9.9 pg/mL
Serum levels of 1,25(OH)2D levels are inversely
correlated with the extent of vascular calcification
in low risk group (p= 0.24). Serum levels of
1,25(OH)2D levels are inversely correlated with
the extent of vascular calcification in high risk
group (p= 0.05).
Wang et al.  HD pt 1739 C 19.7 ng/mL 28.0%
Vitamin D sufficient
1258 59 ± 9
Vitamin D deficient
481 59 ± 9
Low serum 25(OH)D levels are associated with
increased cardiovascular events (p=0.01) above
and beyond established cardiovascular risk
Forman et al.  184 C & AA - 79.9%
Optimal ≥30 ng/mL 37 42.2 (9.5)
108 40.0 (12.2)
Deficient <15 ng/mL 39 38.2 (13.5)
Plasma 25(OH)D levels are not significantly
related to PRA (p-trend= 0.40). Plasma 25(OH)D
levels are inversely related to Ang II
concentration (p-trend= 0.03). Lower 25(OH)D
levels are associated with a blunted RPF response
to exogenous Ang II infusion (p-trend= 0.009).
Abou-Raya et al.  CHF pt, controls 137 C
CHF patients 83 69.9±4.5 24.1±1.1 pg/mL
Controls 54 70.1±3.9 34.7±1.7 pg/mL
1,25(OH)2D levels are significantly lower in CHF
patients than in healthy controls (p= 0.005). An
association between chronic HF severity (expressed
by lower LVEF (p=0.001) or higher NYHA class)
and BMD measurements was found.
Ameri et al.  CHF pt, controls 121 C
All CHF patients 90 78.41±7.74
CHF patients with echo 52 76.85±8.33
Control subjects 31 72.13±7.73
25(OH)D and 1,25(OH)2D concentrations are
significantly lower in CHF patients than in controls
(p= not available) . Vitamin D deficiency is
associated with LV dilation; LV EDD and ESD
were significantly longer in vitamin D deficient
patients (p<0.05 for both). LV EDV and ESV were
significantly higher in patients with 25(OH)D <25
nmol/L (p<0.05 for both). FS was significantly
lower in severely vitamin D deficient patients
(p<0.05). NT-proBNP and 1,25(OH)2D are
negatively associated. Vitamin D supplementation
is ineffective in reducing NT-proBNP levels in
chronic HF patients.
Boxer et al.  CHF pt 60 - 77 ± 10 26.7 ± 12.5 ng/mL 30.0%
Lower vitamin D levels were associated with
poor aerobic capacity and greater frailty (p=0.02).
Arroyo et al.  CHF pt, controls 49 AA
Compensated HF patients 10 52±3 37±7 ng/mL 80.0%
15 56±3 14±1 ng/mL 100.0%
15 50±3 17±4 ng/mL 80.0%
Control group 9 36 (24-58) 18±4 ng/mL 0.0%
Hypovitaminosis is present in AA patients who
were either hospitalized with decompensated HF
or asymptomatic outpatients. Serum 25(OH)D
levels of <30 ng/mL are associated with
elevations in serum PTH (HF patients vs.
Vitamin D Biology in Heart Failure Current Drug Targets, 2011, Vol. 12, No. 1 35
(Table 1) Contd…..
HF and Vit. D
N Race Age (Years)
% Deficient Key Findings
Fiscella et al. 
43.64 29.64 ng/mL -
<25th quartile 25(OH)D
levels (<18 ng/mL)
45.55 13.90 ng/mL
25(OH)D levels (18-24.9
45.83 21.60 ng/mL
44.53 28.44 ng/mL
40.89 41.63 ng/mL
Low 25(OH)D levels independently predict
cardiovascular mortality, with an apparent
threshold effect around the 25th percentile
(p<0.01). The low 25(OH)D levels substantially
accounted for the higher age- and sex-adjusted
cardiovascular mortality among blacks.
Kenny et al. 
CHF 59 76.9±9.9 26.6±12.6 ng/mL
Control 23 77.4±9.3 32.4±9.6 ng/mL
The HF group showed significantly lower
25(OH)D levels (p=0.01). Individuals with HF
are at increased risk of bone loss; a significant
percentage of HF patients met the criteria for
frailty, whereas none of the control subjects did
Kim et al. 
8351 24.3 ng/mL 74.0%
White ≥20 26.2 ng/mL 68.0%
Black ≥20 14.9 ng/mL 97.0%
Hispanic ≥20 21.2 ng/mL 88.0%
Mean 25(OH)D decreases with older age
(p=0.001) and by black and Hispanic race
(p<0.001), but not by gender (p=0.115). 25(OH)D
levels of 20-29 ng/mL are not significantly
associated with increased prevalence of CVD.
Shane et al.  CHF patients 101
Low 25(OH)D levels
(≤ 9 ng/mL)
Normal 25(OH)D levels
Men: 54 (25-70)
Pre MPW: 37
Post MPW: 54
Low serum 25(OH)D levels are associated with
diminished exercise tolerance: peak VO2 is lower
(p=0.01) in patients with low serum 25(OH)D
low serum 1,25(OH)2D is also associated with a
lower peak VO2 (p=0.09). Higher serum PTH is
associated with better cardiovascular function:
LVEF was slightly, but significantly, higher in
patients with elevated serum PTH (p=0.05).
Kilkkinen et al. 
Men: 43.4 ± 19.7
Women: 41.5 ± 18.9
First quintile 25(OH)D
1258 53.9 (15.1)
Men: 23.0 (5.0-
Second quintile 25(OH)D
1202 48.9 (13.8)
Men: 33.0 (29.0 -
Women: 30.0 (26.0-
Third quintile 25(OH)D
1284 48.4 (13.1)
Men: 42.0 (38.0-
Women: 38.0 (34.0-
Fourth quintile 25(OH)D
1222 48.8 (12.8)
Men: 54.0 (48.0-
Women: 49.0 (44.0-
Fifth quintile 25(OH)D
1253 47.0 (12.2)
Men: 72.0 (62.0-
Women: 67.0 (56.0-
A significant inverse association between serum
25(OH)D level and total CVD mortality had been
seen when results were adjusted for age and sex
(highest quintile vs. lowest quintile; P for trend
< 0.001). This inverse association was found
between serum 25(OH)D level and the risk of
CVD death (highest quintile vs. lowest; P for
trend = 0.0037). After adjustment for potential
confounders, p= NS (P for trend = 0.20).
Statistically more total CVD death in multivariate
model of low vitamin D category (<50 nmol/L)
vs. high vitamin D category (>50 nmol/L); (P for
Zittermann et al. 
300 C 23-89 - -
cHF patients 150
Significant reduce of 25(OH)D levels in CHF
patients, compared to healthy controls (p<0.001).
Life style factors associated with low 25(OH)D
levels (like low physical activity, residence in large
towns and low frequency of summer holidays) are
more common in HF patients than in healthy
36 Current Drug Targets, 2011, Vol. 12, No. 1 Meems et al.
(Table 1) Contd…..
HF and vit. D
N Race Age (Years)
% Deficient Key Findings
Zittermann et al. 
Pt with CHF,
CHD, DM, RD
510 C -
First quintile 25(OH)D
102 54.7 (11.8)
First quintile calcitriol
Second quintile 25(OH)D
102 54.7 (10.1)
Second quintile calcitriol
21.3 (2.4) ng/L
Third quintile 25(OH)D
102 54.0 (9.9)
Third quintile calcitriol
Fourth quintile 25(OH)D
102 52.3 (10.3)
Fourth quintile calcitriol
Fifth quintile 25(OH)D
102 52.5 (10.8)
Fifth quintile calcitriol
Circulating calcitriol is related to 25(OH)D
(p<0.001). Low calcitriol concentrations should
be regarded as a non classic risk factor for total
mortality. Calcitriol concentration <25 ng/mL are
linked to excess midterm mortality. 1-year
survival curves are significantly related to serum
levels 25(OH)D and calcitriol. 25(OH)D first
quintile: 79.8% vs. 25(OH)D fifth quintile: 92.0
%. Calcitriol first quintile: 66.2 % vs. fifth
quintile: 96.1%. Serum calcitriol levels < 25ng/L
are significantly related to higher mortality risks
Wilke et al. 
CHF pt, controls
Controls 206 58.5±20.5
Hypertensive patients 206 59.4±13.8
Hypertension + CHF 205 60.2±13.0
The gene product for CYP27B1 (25(OHD 1α-
hydroxylase) is the rate-limiting enzyme for bio-
activation of 1.25(OH)2D. The homozygote
rs4646537 carrier status (a SNP in the eight
intron of CYP27B1) is associated with increased
risk for CHF in hypertensive patients (p<0.05).
The heterozygote carrier status of rs4646537
demonstrates protective effects against
development of hypertension (p<0.05).
Pilz et al.  Pt with CVD 614 C -
No significant associations of 25(OH)D levels with
echocardiographic measures of LV geometry and
systolic function. Prevalence of diastolic
dysfunction was significantly higher in the first vs.
the fourth season specific 25(OH)D quartile, but
attenuated towards a non-significant trend after
adjustment for age and cardiovascular risk factors.
Table 2. Effects of Vitamin D Supplementation on HF Development or Outcome
HF and Vitamin D
N = Race Age
Witham et al. 
100 000 U vitamin D2 at
baseline and 10 weeks
No improvement of physical function (p=0.8)
Treatment group 53
Placebo Group 52
Schleithoff et al.
2000 IU vitamin D3 daily
and 500 mg calcium (both
groups) for period of 9
IL-10 was significantly reduced (p=0.042). TNF-α remained
unchanged in treatment, but increased significantly in
placebo group (p=0.006). Other parameters did not show any
significant changes: LVEF (p=0.643), SBP (p=0.865), DBP
(9.2 - 35.1)
Control group (D-) 62 54 (50.62) 3.6 (-2.8- 8.5)
Vitamin D Biology in Heart Failure Current Drug Targets, 2011, Vol. 12, No. 1 37
(Table 2) Contd…..
HF and Vitamin D
N = Race Age
Saadi et al. 
Vitamin D2 2000 IU daily
or 60 000 IU monthly
Significant decline in NT-proBNP levels (p<0.001) and PRA
(p=0.06), no significant changes in SBP (p=0.2) and DBP
(p=0.2) (however, study did lack a placebo group).
Nulliparous women 63 24 ± 0.6 19.0 ± 1.4
Lactating women 53
26.6 ± 1.9
Park et al.  25 HD pt Asian
Treatment of 2 µg calcitriol
2x weekly intravenously for
Significant decrease of IVST (p=0.01), PW thickness
(p=<0.05), WMSI (p=0.01). No significant changes in CO
and BP (p=NS). Significant decrease in PRA (p<0.001), Ang
II (p<0.001) and ANP (p<0.05).
Calcitriol supp. 15
No calcitriol supp. 10
Bodyak et al.  21 HD pt C - -
Paricalcitol for 12 months.
Level of paricalcitol was
left up to discretion of
Significant decrease of E/A ratio (p<0.01), LV septal
thickness (p< 0.05), PW thickness (p<0.05). No significant
difference in LVEF (p=NS).
Control Group 6
Hsia et al. 
Twice a day, 200 IU
vitamin D3 calcium +
calcium carbonate 500 mg
Calcium/vitamin D supplementation neither increased nor
decreased the risk for CHD in healthy post MPW (p=0.34).
Neither total calcium intake nor total vitamin D intake at
baseline affected cardiovascular risk with calcium/vitamin D
supplementation in post MPW (p=0.66).
HF = heart failure, vit. D = vitamin D, NS = non significant, C = Caucasian, AA = African American, MI = myocardial infarction, CHF pt = chronic heart failure patients, NT-
proBNP = N-terminal-pro brain natriuretic peptide, NT-proANP= N-terminal-pro atrial natriuretic peptide, 25(OH)D = 25-hydroxyvitamin D, 1,25(OH)2D = 1,25-dihydroxyvitamin
D, HD-NHF = Heart Disease- Non Heart Failure, PRA = plasma renin activity, Ang II = angiotensin II, HD pt =hemodialysis patients, RPF = renal plasma flow, LVEF = left
ventricular ejection fraction, NYHA = New York Heart Association, BMD = bone mass density, LV = left ventricle, EDD = end diastolic diameter, ESD = end systolic diameter,
ESV= end systolic volume, EDV= end diastolic volume, FS = fractional shortening, PTH = parathyroidhormone, MPW = menopausal women, CVD = cardiovascular disease,
DM = diabetes mellitus, CHD= coronary heart disease, RD = renal disease, IL-10 = interleukin-10, TNF-a = tumor necrosis factor-a, SBP = systolic blood pressure, DBP = diastolic
blood pressure, UAE = United Arab Emirates, IVST = interventricular septum thickness, PW = posterior wall, WMSI = wall motion score index, CO = cardiac output, BP = blood
pressure, ANP = atrial natriuretic peptide, IU= International Unit.
different factors, both environmental and genetic factors.
Therefore, it is difficult to pinpoint the causes of widespread
vitamin D deficiency in HF.
In conclusion, vitamin D deficiency seems to depend on
5C. Vitamin D Deficiency and HF Outcome (Table 1)
vational study in 101 HF patients, (men and women) of
multi-ethnical origin. They linked low serum 25(OH)D
levels to a diminished exercise tolerance, resulting in lower
peak VO2 in patients with low serum 25(OH)D and
1,25(OH)2D3 levels . It took 16 years before another
large study was reported that confirmed the relationship
between low 25(OH)D and 1,25(OH)2D3 levels and HF
characteristics. In a study of 88 Caucasian patients from
Zittermann et al., patients were divided into three groups:
chronic HF patients <50 years, chronic HF patients >50
years and a control group (patients >50 years). It was shown
that HF patients, regardless whether < 50 or >50 years of
age, have significantly lower levels of 25(OH)D and
1,25(OH)2D3 compared to the (elderly) healthy controls .
Thereby, this study also brought the first evidence that NT-
proANP (N-terminal pro-artrial natriuretic peptide) levels are
Already in 1997, Shane and colleagues reported an obser-
associated with serum 25(OH)D , and by this the
hypothesis was fueled that vitamin D levels might directly
relate to HF outcome.
1,25(OH)2D3 have been associated with LV dysfunction:
patients with a poor LV function showed decreased
25(OH)D and 1,25(OH)2D3 levels . Myocardial markers
like the NT-proANP and N-terminal pro-brain natriuretic
peptide (NT-proBNP) show significant and independent
correlations with 25(OH)D levels . A recent study even
considered low serum 25(OH)D levels as a new risk factor
above and beyond established cardiovascular risk factors, for
cardiovascular events .
Subsequent studies demonstrated that 25(OH)D and
5D. Vitamin D levels and Mortality in Chronic HF
Patients (Table 1)
et al.  show that significant lower levels of 25(OH)D and
1,25(OH)2D3 are found in chronic HF patients. The latter
study showed that with reduce of serum 25(OH)D levels the
prevalence of HF patients increases. Fiscella and Franks
reported that 1,25(OH)2D3 levels function as independent,
Epidemiological studies from Pilz et al.  and Kim
38 Current Drug Targets, 2011, Vol. 12, No. 1 Meems et al.
predictor of mortality in HF patients . Zittermann et al.
showed that one-year-survival is significantly related to
serum levels 25(OH)D and 1,25(OH)2D3; the number of
survivors increases with 12% when the lowest quintile of
serum 25(OH)D levels are compared with the highest
quintile of serum 25(OH)D levels . The effect of
1,25(OH)2D3 levels on the survival-curve of HF patients
even seemed to be of more importance: a one-year-survival
rate of 66.2% in the first quintile (lowest serum levels)
versus a one-year-survival rate of 96.1% in the fifth quintile
(highest serum levels) . Kilkinnen and his group
demonstrated that an inverse association between serum
25(OH)D levels and cardiovascular disease is present when
results are adjusted for age and sex. On the other hand, the
risk for coronary heart disease is not significantly related to
25(OH)D levels when they are adjusted for potential con-
founders . Nevertheless, low vitamin D levels statisti-
cally increased total cardiovascular disease mortality in a
multivariate model .
5E. Vitamin D Deficiency in African Americans and
Hispanics (Table 1)
in the liver and kidney, a dark skin with more pigmentation
is a disadvantage. Mean 25(OH)D decreases with older age,
but also by black and Hispanic race . Arroyo and his
group demonstrated that hypovitaminosis is present in
African American (AA) patients independently if they where
hospitalized with decompensated heart failure or were
asymptomatic outpatients . A recent study from Forman
and colleagues indicated that plasma 25(OH)D levels are
inversely related to Angiotensin II concentration , which
may eventually lead to hypertension. As hypertension is a
chief risk factor for development of chronic HF, AA and
Hispanics may be at higher risk of developing HF due to
there pigmentated skin and diminished synthesis of vitamin
As vitamin D is absorbed by the skin and than converted
adverse outcome in HF. Published reports generally are
small and comprise of maximum several hundred of patients
with limited follow-up and low even rate. Clearly, larger
cohort (multiple hundreds or thousands of patients), with
meticulous characterization and systematic follow-up are
warranted to value the usefulness of vitamin D deficiency as
a prognostic marker in HF. Furthermore, we would like to
point out that as with any novel biomarker of HF, (publica-
tion) bias may overestimate the actual importance of vitamin
D in HF. Some negative reports are available: Bolland et al.
showed that neither the risk for MI significantly increases
when vitamin D deficiency is present, nor the risk for HF
In summary, low levels of vitamin D are associated with
5F. Intervention with Vitamin D and Analogues in HF
lation did not change the risk for development of coronary
heart disease . However, in dialysis patients, treatment
with a VDR agonist leads to decreased PRA, Ang II and
ANP levels , although the systolic blood pressure (SBP)
nor diastolic blood pressure (DBP) did not show significant
Daily Vitamin D3 supplementation in the general popu-
changes [36, 86, 87]. Echocardiographic markers for cardiac
hypertrophy decrease when vitamin D3 is supplemented, but
this decrease does not result in significant changes in cardiac
contractility [36, 87]. Furthermore, inflammatory markers
like IL-10 en TNF-α did show significant changes in favor of
a less inflammatory profile in HF patients .
vitamin D supplementation could be of benefit in HF
patients [86, 88]. Schleithoff et al. included 123 patients and
randomized them to receive daily 2000 U cholecalciferol
(plus calcium) or placebo, and followed the patients for up to
9 months. Various surrogate parameters, such as BP, exer-
cise capacity, left ventricular ejection fraction and NT-
proBNP did not differ between groups. Patients randomized
to vitamin D had a lesser pro-inflammatory cytokine profile
(lower TNF-α and higher IL-10) . Witham et al. inc-
luded 105 elderly patients with low vitamin D levels and
randomized them to 100,000 U vitamin D2 or placebo (given
at baseline and after 10 weeks). After 20 weeks, vitamin D
levels significantly increased in the patients allocated to
vitamin D treatment. Outcome parameters included exercise
capacity and quality of life measures and were not improved
by vitamin D supplementation .
To date, only a few publications specifically addressed if
dence suggests that Vitamin D supplementation could be of
benefit in HF patients. However, no adequately sized studies
have been conducted to prove this hypothesis. It is well
known that experimental data and clinical data are not
always in concert. For instance, PPAR-γ is a transcriptional
regulator of renin in vitro , but in humans, no effects on
renin levels were observed in a trial with a PPAR-γ agonist
. This underscores that the mechanisms are complex and
future trials should be carefully designed and have adequate
In conclusion, strong experimental and observational evi-
nized as mediators of HF. Low vitamin D status is associated
with an increased prevalence of risk factors for HF and may
also contribute to the development of the HF syndrome
itself. Once HF has developed, a low vitamin D status is
observed in patients with worse functional class and other
clinical and biochemical correlates of poor outcome. This
has been connected to increased inflammatory status, more
advanced age, and immobility. From experimental data it has
become clear that the VDR functions as a pivotal transcrip-
tional regulator, amongst others of several neurohormonal
systems, most prominently the RAS, and other crucial sys-
tems involved in HF. Therefore, vitamin D and its receptor
may represent a novel target for therapy in the devastating
HF syndrome. Future studies with vitamin D or VDR
receptor angonists should elucidate if this is a feasible option
for patients with HF.
Vitamin D and its receptor, VDR, are increasingly recog-
CONFLICT OF INTEREST
Abbott for the study of the effects of paricalcitol in expe-
rimental heart failure.
R.A.d.B. received an unrestricted research grant from
Vitamin D Biology in Heart Failure Current Drug Targets, 2011, Vol. 12, No. 1 39
Foundation (grant 2007T046 to R.A.d.B.) and the
Innovational Research Incentives Scheme program of the
Netherlands Organization for Scientific Research (NWO
VENI, grant 016.106.117 to R.A.d.B.).
This work was supported by the Netherlands Heart
= 1,25-dihydroxy-vitamin D
= 25-hydroxy-vitamin D
AA = African American
= Angiotensin converting enzyme
ANP = Atrial natriuretic peptide
ARB = Angiotensin II type 1 receptor blocker
BNP = Brain natriuretic peptide
BP = Blood pressure
CHD = Coronary heart disease
Cholecalciferol = Vitamin D3
CO = Cardiac output
CVD = Cardiovascular disease
CYP24 = 25-hydroxyvitamin-D-24-hydroxylase
DBP = Diastolic blood pressure
DM = Diabetes mellitus
EF = Ejection fraction
Ergocalciferol = Vitamin D2
= High density lipoprotein HDL
HF = Heart failure
HR = Heart rate
IL = Interleukin
IVST = Inter ventricular septal thickness
IU = International units
LV = Left ventricle
LVMi = Left ventricular mass index
LVPWT = Left ventricular posterior wall thickness
LXR = Liver X receptor
MI = Myocardial infarction
NHR = Nuclear hormone receptor
NT-proANP = N-terminal pro-atrial natriuretic peptide
NT-proBNP = N-terminal pro-brain natriuretic peptide
= Peroxisome proliferator-activated
PRA = Plasma renin activity
PTH = Parathyroidhormone
RAS = Renin-angiotensin system
RXR = Retinoid X receptor
SBP = Systolic blood pressure
SNS = Sympathetic nervous system
TNF-α = Tumor necrosis factor-α
VDR = Vitamin D receptor
VDR-/- = Vitamin D receptor deficient mice
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Received: May 01, 2010
Revised: May 18, 2010 Accepted: June 04, 2010