Curr Heart Fail Rep (2011) 8:123–130
DOI 10.1007/s11897-011-0048-6
Vitamin D in Chronic Heart Failure
Miles D. Witham
Published online: 17 February 2011
# Springer Science+Business Media, LLC 2011
Abstract Recent evidence suggests a number of mecha-
nisms whereby vitamin D may positively influence the
pathophysiology of heart failure. These include actions on
the renin-angiotensin system, calcium handling, reduction
of proinflammatory cytokines, and improvements in
endothelial function and blood pressure. Observational data
suggest that low vitamin D levels are common in patients
with heart failure and are associated with worse exercise
capacity and natriuretic peptide levels. Little interventional
data are currently available, but evidence to date does not
support vitamin D supplementation, even in patients with
low vitamin D levels. Further studies are needed to
establish whether larger doses of vitamin D given over a
longer period of time can reduce symptoms, hospitalization,
and mortality in heart failure.
Keywords Heart failure . Vitamin D . Cardiovascular
Introduction
Although vitamin D was discovered a century ago, our
knowledge of this ancient and ubiquitous molecule recently
has undergone a step change. For decades, its effects on
calcium absorption, role in bone health, and, more recently, its
effects on neuromuscular function were well appreciated.
Over the past 15 years, we have learned that vitamin D is
metabolized in tissues as diverse as macrophages and
placenta, has receptors in almost all bodily organs, and affects
M. D. Witham (*)
Section of Ageing and Health, Centre for Cardiovascular and
Lung Biology, Division of Medical Sciences, University of
Dundee, Ninewells Hospital,
Dundee DD1 9SY, Scotland, UK
e-mail: m.witham@dundee.ac.uk
the function of over 60 genes. This review highlights how
a number of strands of evidence, from recent insights into
the vascular effects of vitamin D (Fig. 1) and observations
linking heart failure and other vascular diseases with low
vitamin D levels, suggest that vitamin D may have a role to
play in the pathophysiology of chronic heart failure. This
review also critically reviews the evidence from interven-
tional studies to date, and summarizes the next steps for this
fascinating field.
Vitamin D Insufficiency
Vitamin D is predominantly formed in the skin by the
action of ultraviolet-B radiation, which transforms 7-
dehydrochlesterol into vitamin D3 (cholecalciferol). Small
amounts of vitamin D3 are ingested from the diet (via oily
fish and dairy products), as are small amounts of plant-
derived vitamin D2 (ergocalciferol), which is closely
related in structure to vitamin D3. These forms of vitamin
D are hydroxylated by cytochromes in the liver to form 25-
hydroxyvitamin D (25OHD), which forms a long-lived
circulating reservoir bound to vitamin D–binding protein. It
is for this reason that 25OHD is measured to determine
vitamin D status. Further hydroxylation then occurs to form
1,25 hydroxyvitamin D (1,25OHD), also known as calci-
triol. This step is carried out by the kidney, but also can be
carried out by a range of other tissues including macro-
phages and parathyroid tissue, making it likely that
1,25OHD has paracrine actions in these tissues [1, 2].
Most of the biological effects of vitamin D are thought to
be mediated by 1,25OHD, which binds to the vitamin D
receptor (VDR). This receptor then translocates to the cell
nucleus, heterodimerizes with the retinoic acid X receptor
[3], and binds to VDR response elements in the genome to
124
Fig. 1 Potential actions of vita-
min D in heart failure. BP—
blood pressure; PTH—parathy-
roid hormone; VEGF—vascular
endothelial growth factor
control DNA transcription. It is possible that 25OHD itself
mediates some actions of vitamin D, as it binds to a
cytoplasmic variant of the VDR as strongly as 1,25OHD
[4]. However, it is not clear what physiological actions are
mediated by this receptor. Levels of 25OHD levels in nmol/
L can be converted to ng/mL by dividing by 2.5; vitamin D
(D2 or D3) doses are given in international units (IU),
where 1 IU is equal to 0.025 μg of vitamin D.
No consensus exists regarding the optimum level of
25OHD required for human health, and it is possible that
different thresholds apply to different biological systems.
Levels above 25 nmol/L are required to prevent rickets and
osteomalacia [5]; boosting levels above 50 nmol/l previous-
ly was believed not to suppress parathyroid hormone (PTH)
levels further, thus denoting sufficiency, although more
recent data challenge this assumption [6, 7]. Levels of over
75 nmol/L have been suggested as being optimum for
health by some commentators, based on extrapolation from
observational studies in a range of disease states [8].
Little vitamin D is derived from diet; thus, sunlight is the
predominant source. At high latitudes (>40° north), there is
insufficient ultraviolet light reaching the Earth’s surface
between October and March to produce vitamin D. Levels
therefore decline over the winter, reaching a nadir in
March/April. In fact, it was the observation that cardiovas-
cular events are also more common in winter that led to the
current upsurge of interest in cardiovascular disease and
vitamin D.
Vitamin D insufficiency becomes more common with
age and in individuals with dark skin, due to reduced
efficiency of vitamin D production. The 2005 Health
Survey for England revealed that 50%–60% of people aged
65 years and over had 25OHD levels below 50 nmol/L,
with between 8% and 13% having 25OHD levels below
Curr Heart Fail Rep (2011) 8:123–130
25 nmol/L [9]. Patients of South Asian origin are at even
higher risk of insufficiency; 94% of a cohort of young
South Asian women from the United Kingdom had 25OHD
levels less than 37.5 nmol/L [10]. Similarly high preva-
lences of vitamin D insufficiency are found amongst the
nonwhite United States population; the National Health and
Nutrition Examination Survey showed that 4% of white
women, but 42% of black women, had 25OHD levels
below 37.5 nmol/L [11].
The optimum level of vitamin D needed for cardiovascular
health is unclear; the Framingham study suggested a
relationship between incident cardiovascular events and levels
below about 50 nmol/L, with no clear association above this
level [12•]. Most interventional studies have not boosted
25OHD levels to above 75 nmol/L, and there is concern that
excessive vitamin D levels may be associated with increased
vascular calcification [13]. The picture is even less clear for
patients with established heart failure, in whom few studies
have been performed. Vitamin D has a long half-life
(between 3 and 8 weeks) and can thus be given intermit-
tently; paradoxically, oral doses provide much better
pharmacokinetics than intramuscular doses [14].
Vascular Effects of Vitamin D
Renin-angiotensin System Function
Vitamin D–receptor knockout mice have marked overpro-
duction of renin [15], leading to hypertension, cardiac
enlargement, and elevation of natriuretic peptides. Recent
evidence suggests that a similar relationship between low
vitamin D levels and enhanced renin-angiotensin system
activity exists in patients without heart failure [16•, 17•].
Curr Heart Fail Rep (2011) 8:123–130
Whether vitamin D actually suppresses renin-angiotensin
system activity in humans is less clear; no suppression of
the renin-angiotensin system was seen in a trial of vitamin
D in older patients with heart failure [18•], but a study of
vitamin D supplementation in patients with type 2 diabetes
mellitus showed nonsignificant reductions in angiotensin II
and increases in renin, suggesting effects similar to
angiotensin-converting enzyme inhibitors [19].
Vascular Endothelial Growth Factor
Vascular endothelial growth factor (VEGF) has been postulat-
ed to play a role in maintaining myocardial blood supply and
function, especially diastolic function [20, 21]. Conversely,
blockade of VEGF by anti-VEGF antibody therapy for
malignancy appears to increase the risk of heart failure in
humans [22]. Vitamin D has been shown to upregulate VEGF
expression [23], suggesting another pathway through which
vitamin D may positively influence myocardial function.
Calcium Handling
Myocyte calcium handling is known to be deranged in heart
failure, and contributes to both disturbances of myocyte
contraction and relaxation. Vitamin D is now known to
influence calcium influx via nongenomic actions (e.g., by
opening L-type calcium channels in osteoblasts) [24], and it is
possible that related pathways may mediate effects of
vitamin D on myocyte calcium handling. Cardiac myocytes
possess the VDR and a calcitriol-dependent calcium-binding
protein [25]. They also may possess the ability independently
to produce calcitriol that can act in an autocrine or paracrine
fashion. Calcitriol can activate adenylate cyclase [26], thus
mimicking the effects of β-adrenergic stimulation on
myocardial contractility. Case reports of profound heart
failure in neonates with hypocalcemia caused by low vitamin
D levels [27] lend further weight to these mechanisms;
vitamin D replacement and normalization of serum calcium
can lead to recovery in such cases.
Cytokines
A number of derangements of cytokine production are
found in chronic heart failure, notably enhanced production
of interleukin (IL)-1, IL-6, and tumor necrosis factor–α
(TNF-α) and reduced levels of IL-10. This proinflamma-
tory state not only is thought to contribute to the
pathophysiology of cardiac dysfunction and endothelial
dysfunction, but also may underlie the skeletal myopathy
and cachexia seen in heart failure. Vitamin D has long been
used in dermatology as an immunologically active therapy
(e.g., for psoriasis). Vitamin D and related compounds
reduce IL-6 production by endothelial cells [28], and in
125
patients with heart failure, vitamin D supplementation has
been shown to reduce TNF-α and increase IL-10 levels in
one study [29]. Interestingly, high TNF-α levels can inhibit
conversion of 25OHD to 1,25OHD by endothelial cells
[30], which is likely to lead to a vicious circle of
inflammation and suppression of vitamin D activation.
Parathyroid Hormone
PTH often is elevated in vitamin D insufficiency, partly in
response to low vitamin D levels, but also to low serum
calcium levels. PTH is thought to be vasculotoxic in its
own right, and has been shown to be involved in
myocardial fibrosis and left ventricular hypertrophy [31].
Parathyroidectomy for primary hyperparathyroidism
improves left ventricular ejection fraction in some studies
[32] (although low calcium levels postsurgery can in fact
worsen cardiac function in some cases) and elevated PTH
levels independently predict heart failure hospitalization in
patients with established chronic heart failure [33].
Endothelial Function
Derangement of endothelial function is seen in heart failure,
and is thought to be an early pathophysiological lesion
underpinning a wide range of vascular diseases. Several
therapies that are used in heart failure (e.g., angiotensin-
converting enzyme inhibitors and spironolactone) improve
endothelial function. Low vitamin D levels are associated with
deranged endothelial function in patients without heart failure
[34], and vitamin D supplementation has been shown to
improve endothelial function in patients with type 2 diabetes
[19] and in healthy adults with low vitamin D levels [34].
Blood Pressure
Evidence from interventional trials suggests that in selected
patients, vitamin D may be able to reduce blood pressure
[35]. The mechanism of action underlying this effect is
unclear, but if vitamin D acts as a vasodilator, this could
reduce afterload, with potentially beneficial effects on
ventricular stress and remodeling.
Skeletal Myopathy
Heart failure is accompanied by a profound skeletal
myopathy, characterized by reduced numbers and function
of type I muscle fibers [36]. It is this myopathy that
underlies much of the exercise intolerance seen in heart
failure. Vitamin D is known to improve muscle strength in
vitamin D–deficient patients [37]; it is possible that vitamin
D insufficiency could therefore be a contributory factor to
the myopathy seen in heart failure.
126
Evidence from Observational Studies
A growing number of studies now link low vitamin D
levels with chronic heart failure; some key studies are
summarized in Table 1. Patients with heart failure have
lower vitamin D levels than age-matched control patients,
and in some (but not all) studies, lower vitamin D levels are
linked to worse exercise capacity and worse ejection
fraction. In patients without symptomatic heart failure,
low vitamin D levels predict future occurrence of heart
failure. In patients referred for coronary angiography, those
with the lowest vitamin D levels have the highest risk of
future cardiovascular events, including death from heart
failure. However, it is unclear whether low vitamin D levels
in patients with established heart failure are an independent
risk factor for future hospitalization and death.
Although the above evidence is interesting, and is
strengthened by longitudinal association, it still is possible
that reverse causality is operating to explain these observed
associations. Patients with more comorbid disease, those
who are more obese, and those who are less physically
active will tend to have lower vitamin D levels, their
opportunities for sun exposure will be lower, and obesity
appears to lower circulating 25OHD levels directly, perhaps
due to adipose tissue acting as a reservoir for this
Table 1 Observational studies of vitamin D and heart failure
Study Population
Shane et al. [43] 101 NYHA III/IV HF patients;
mean age: 54 years
Zittermann 54 patients (20 with HF with any
et al. [44] ejection fraction, 34 control patients);
mean age: 55 years
Pilz et al. [45•] 3,299 patients referred for coronary
angiography (predominantly non-CHF);
mean age: 64 years
Boxer et al. [46] 60 HF patients with LVSD; mean age:
77 years
Anderson et al. [47•] 23,793 (population database with 25OHD
measurements); mean age: 55 years
Boxer et al. [48] 40 patients with HF with any ejection
fraction; mean age: 68 years
Pilz et al. [49] 641 (population-based cohort
[non-HF]); mean age: 69 years
Ameri et al. [50] 90 patients with stable HF with any
ejection fraction; mean age: 78 years
25OHD—25-hydroxyvitamin D; BNP—B-type natriuretic peptide; CHF—chronic heart failure; HF—heart failure; LV—left ventricle; LVSD—
left ventricular systolic dysfunction; NYHA: New York Heart Association; NT-proANP—N-terminal atrial natriuretic peptide; NT-proBNP—N-
terminal B-type natriuretic peptide; VO2 max—peak oxygen uptake
Curr Heart Fail Rep (2011) 8:123–130
hydrophobic molecule. Thus, it is possible that low vitamin
D levels in patients with heart failure merely reflect the
burden of preexisting disease, and that patients with
preexisting risk factors (inactivity, obesity, comorbid
disease) are more likely to develop heart failure, with low
vitamin D levels being an epiphenomenon. Of course, this
issue can be resolved only via randomized controlled
interventional studies.
Evidence from Interventional Studies
Randomized Controlled Trials of Vitamin D in Chronic
Heart Failure
The first randomized controlled trial of vitamin D supple-
mentation [29] compared 2,000 IU of oral vitamin D3 with
placebo, given over a 9-month period to patients with heart
failure due to impaired systolic function. Despite a large
increase in mean 25OHD levels in the treatment arm (from
36 nmol/L to 103 nmol/L), most outcomes, including
ejection fraction, maximal exercise capacity, and B-type
natriuretic peptide levels, failed to improve in this study.
The exception was TNF-α, where a significant decrease
was observed in the treatment arm. Vitamin D was well
Study type Findings
Cross-sectional Association between 25OHD levels and VO2 max
Cross-sectional 25OHD levels lower in CHF patients than in similarly
aged patients without CHF; inverse relationship
between 25OHD levels and NT-proANP
Prospective Inverse association between 25OHD level and both
NT-proBNP level and NYHA class; association
between 25OHD level and LV function. 2.6x risk of
death from HF in those with 25OHD <25 nmol/L
compared to those with 25OHD >75 nmol/L after
adjustment
Cross-sectional Association between 25OHD levels and both
six-minute walk distance and frailty score
Prospective Risk of HF 2.01 times higher if 25OHD level
<37.5 nmol/L compared to 25OHD level >75 nmol/L
(after adjustment for cardiovascular risk factors)
Cross-sectional Association between VO2 max and 25OHD levels,
but not between 25OHD levels and muscle strength
Cross-sectional No relationship between 25OHD level and LV ejection
fraction or LV dimensions after adjustment
Cross-sectional Inverse association between 25OHD level and LV
dimensions & fractional shortening; no relationship
between 25OHD and either NT-proBNP or NYHA
class.
Curr Heart Fail Rep (2011) 8:123–130 127

tolerated in this study, with no excess of adverse events in
the treatment arm.
A randomized controlled trial from Scotland, UK studied
the effect of 100,000 IU of oral vitamin D2 every 10 weeks
compared to placebo on physical function and quality of
life in older patients with CHF and impaired systolic
function [18•]. Again, despite a doubling of 25OHD levels
(from 20 nmol/L to 40 nmol/L) in the treatment arm, there
was no improvement in the six-minute walk distance,
quality of life, or markers of muscle strength. No improve-
ments in TNF-α levels were seen in this study, but B-type
natriuretic peptide levels did fall significantly in the
treatment arm by 20 weeks. No changes in aldosterone or
renin levels were noted.
In this study, 25OHD levels failed to reach the level of
75 nmol/L that some commentators believe is optimal for
health across a wide range of disease states [8]. Whether
such levels are necessary for benefits to be seen in heart
failure and other vascular diseases is not known; the
recommendation was derived from observational studies.
Nevertheless, it is possible that larger doses of vitamin D,
taken for longer periods of time, are required to gain benefit
in established heart failure. It also is possible that vitamin D
still may reduce death and hospitalization in heart failure,
but the weak and inconsistent effects seen to date on
surrogate markers are not encouraging.
Other Studies
Witte et al. [38] tested the effect of a multivitamin
supplement in older patients with heart failure, and found
significant improvements in ejection fraction and quality of
life compared to placebo, but did not find an improvement
in six-minute walk distance. However, the daily dose of
vitamin D3 was only 400 IU, which is unlikely to have
caused a significant increase in 25OHD levels. It is possible
that another ingredient of the multivitamin (e.g., coenzyme
Q10) was responsible for the benefit, or perhaps synergies
between components of the multivitamin caused the
improvement.
A number of small studies in patients with end-stage
kidney disease have suggested that vitamin D supple-
mentation may be able to regress left ventricular
hypertrophy, and in selected patients, to improve ejection
fraction [39, 40]. However, none of these studies used a
control group, and they did not set out to study patients
with the clinical syndrome of heart failure; thus, the
relevance of these findings to patients with overt heart
failure remains unclear.
Prevention of Chronic Heart Failure
No randomized controlled trials have directly tested
whether vitamin D supplementation can prevent heart
failure. However, a growing body of evidence suggests
that in selected populations (e.g., those with hypertension),
high-dose vitamin D2 or D3 supplementation may reduce
blood pressure [35]. Meta-analyses of vitamin D supple-
mentation trials in patients with osteoporosis have sug-
gested that vitamin D may reduce rates of cardiovascular
death modestly [41•]. It is likely that myocardial infarction
rates are a major contributor to this reduction [42], and if

Table 2 Planned and ongoing vitamin D trials relevant to heart failure

Database number Population Intervention Main outcomes

NCT 01125436 64 HF patients aged >50 years with any Vitamin D3, 50,000 VO2 max and muscle strength at 6 months
ejection fraction; NYHA II–IV; 25OHD IU/wk vs placebo
<94 nmol/L
NCT 01230307 100 HF patients with LVSD and 25OHD Vitamin D3, 100,000 IU Biomarkers of HF at 6 months; exercise capacity
>25 nmol/L and <62.5 nmol/L loading dose, then 2,000 and quality of life
IU/day vs placebo
NCT 01092130 100 HF patients with LVSD; NYHA II–IV Vitamin D3, 2,000 IU/d Plasma renin activity at 6 weeks; ejection
fraction; angiotensin II; collagen and matrix
degradation markers
NCT 01005303 112 HF patients with LVSD; NYHA II/III Multivitamin supplement plus Ejection fraction at 1 year; physical function;
vitamin D, 2,000 IU/d vs quality of life; heart failure biomarkers;
placebo oxidative stress
NCT 00497900 40 HF patients with LVSD; NYHA II–IV; Calcium and vitamin D vs Ejection fraction at 6 months
25OHD <50 nmol/L placebo
NCT 01169259 20,000 healthy participants aged >60 years Vitamin D3, 2,000 IU vs 5-year risk of cancer and cardiovascular disease
(VITAL) placebo for 5 years
ISRCTN17873085 100 HF patients with LVSD; NYHA II/III; Vitamin D3, 4,000 IU vs LV function; endothelial function; symptoms;
25OHD <50 nmol/L placebo for 12 months quality of life; exercise capacity

25OHD—25-hydroxyvitamin D; HF—heart failure; LV—left ventricle; LVSD—left ventricular systolic dysfunction; NYHA: New York Heart
Association; VO2 max—peak oxygen uptake
128
these effects are borne out in large multicenter randomized
controlled trials, it is possible that vitamin D supplementation
may be able to reduce the occurrence of heart failure secondary
to reducing hypertension and myocardial infarction.
Planned Studies
A search of the major clinical trials databases reveals
several randomized controlled trials of vitamin D in heart
failure that are either planned or ongoing. These trials are
summarized in Table 2. No large study that is adequately
powered to detect differences in death rates in patients with
heart failure appears to be ongoing. The large Vitamin D
and Omega-3 Trial (VITAL) aims to recruit 20,000 patients
to examine the effect of both vitamin D3 and omega-3 fatty
acids on cardiovascular events and deaths; although this
study is not recruiting patients with heart failure at baseline,
it may provide useful information on whether vitamin D
can prevent new-onset heart failure.
Questions to Be Answered
Several important questions need to be answered by future
research. What dose and duration of vitamin D therapy is
needed to improve hemodynamic, neurohormonal, and
functional markers in patients with heart failure? Is there a
subset (e.g., those with preserved systolic function) that would
benefit more? Are the benefits confined only to those with
renal impairment, those with very low vitamin D levels, or
those unable to tolerate renin-angiotensin system blockers?
Most importantly of all, does long-term vitamin D supple-
mentation reduce death and hospitalization from heart failure,
and could supplementation in those with hypertension,
diabetes, or ischemic heart disease delay or prevent progres-
sion to the clinical syndrome of heart failure?
Much work needs to be done before the above questions
can be answered, and although initial interventional results
do not show promise, it is probably premature to abandon
research on vitamin D. Vitamin D is inexpensive, easy to
take (as it can be taken intermittently), and thus, could form
an important addition to heart failure treatment if the correct
target population and dose can be found.
Conclusions
The observational evidence for an association between low
vitamin D levels, cardiovascular disease in general, and
heart failure specifically, is strong. These observations are
rendered biologically plausible by the discovery of several
potential mechanisms whereby vitamin D may interact with
pathophysiological features of the heart failure syndrome.
Curr Heart Fail Rep (2011) 8:123–130
Although little interventional data is available at present, the
existing data do not support a large effect on either pathophys-
iological or functional outcomes. Nevertheless, further work is
needed to test whether larger doses, given for longer, to
particular subsets of patients with heart failure may be able to
improve exercise capacity and quality of life, and to reduce
death and hospitalization. Until such trial evidence is available,
there is insufficient current evidence to recommend either
measuring or replacing vitamin D in patients with heart failure.
Disclosure Dr. Miles D. Witham has received funding from the Chief
Scientist Office, Scottish Government; Diabetes UK; Chest Heart and
Stroke Scotland; Heart Research UK; and ME Research UK for research
into vitamin D and cardiovascular disease. Dr. Witham also is funded by a
Chief Scientist Office (Scottish Government) Clinician Scientist award.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
1. Norman AW. From vitamin D to hormone D: fundamentals of the
vitamin D endocrine system essential for good health. Am J Clin
Nutr. 2008;88:491S–9S.
2. Hewison M, Burke F, Evans KN, et al. Extra-renal 25-
hydroxyvitamin D3-1alpha-hydroxylase in human health and
disease. J Steroid Biochem Mol Biol. 2007;103:316–21.
3. Jones G, Strugnell SA, DeLuca HF. Current understanding of the
molecular actions of vitamin D. Physiol Rev. 1998;78:1193–231.
4. Norman AW, Okamura WH, Bishop JE, Henry HL. Update on
biological actions of 1alpha, 25(OH)2-vitamin D3 (rapid effects) and
24R, 25(OH)2-vitamin D3. Mol Cell Endocrinol. 2002;197:1–13.
5. Preece MA, Tomlinson S, Ribot CA, et al. Studies of vitamin D
deficiency in man. Q J Med. 1975;44:575–89.
6. Adami S, Viapiana O, Gatti D, et al. Relationship between serum
parathyroid hormone, vitamin D sufficiency, age, and calcium
intake. Bone. 2008;42:267–70.
7. Bjorkman M, Sorva A, Tilvis R. Responses of parathyroid
hormone to vitamin D supplementation: a systematic review of
clinical trials. Arch Gerontol Geriatr. 2009;48:160–6.
8. Bischoff-Ferrari HA, Giovannucci E, Willett WC, et al. Estima-
tion of optimal serum concentrations of 25-hydroxyvitamin D for
multiple health outcomes. Am J Clin Nutr. 2006;84:18–28.
9. Hirani V, Tull K, Ali A, Mindell J. Urgent action needed to
improve vitamin D status among older people in England! Age
Ageing. 2010;39:62–8.
10. Roy DK, Berry JL, Pye SR, et al. Vitamin D status and bone mass
in UK South Asian women. Bone. 2007;40:200–4.
11. Nesby-O’Dell S, Scanlon KS, Cogswell ME, et al. Hypovitaminosis
D prevalence and determinants among African American and white
women of reproductive age: third National Health and Nutrition
Examination Survey, 1988–1994. Am J Clin Nutr. 2002;76:187–92.
12. • Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and
risk of cardiovascular disease. Circulation. 2008;117:503–11. This
large prospective study of healthy adults showed that low vitamin D
levels predict future cardiovascular events. Effects were more
pronounced in those with elevated blood pressure at baseline.
Curr Heart Fail Rep (2011) 8:123–130
13. Norman PE, Powell JT. Vitamin D, shedding light on the
development of disease in peripheral arteries. Arterioscler Thromb
Vasc Biol. 2005;25:39–46.
14. Romagnoli E, Mascia ML, Cipriani C, et al. Short and long-term
variations in serum calciotropic hormones after a single very large
dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin
D3) in the elderly. J Clin Endocrinol Metab. 2008;93:3015–20.
15. Li YC, Kong J, Wei M, et al. 1, 25-Dihydroxyvitamin D(3) is a
negative endocrine regulator of the renin-angiotensin system. J
Clin Invest. 2002;110:229–38.
16. • Forman JP, Williams JS, Fisher ND. Plasma 25-hydroxyvitamin D
and regulation of the renin-angiotensin system in humans. Hyper-
tension. 2010;55:1283–8. This carefully conducted study showed
that the renin-angiotensin system is more active in patients with low
25OHD levels in humans, corroborating previous animal studies.
17. • Tomaschitz A, Pilz S, Ritz E, et al. Independent association
between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the
renin-angiotensin system: The Ludwigshafen Risk and Cardio-
vascular Health (LURIC) study. Clin Chim Acta. 2010;411:1354–
60. This article provides evidence, from a large prospective study,
that low vitamin D levels are related to renin-angiotensin system
activation in humans.
18. • Witham MD, Crighton LJ, Gillespie ND, et al. The effects of
vitamin D supplementation on physical function and quality of life
in older heart failure patients: a randomised controlled trial. Circ
Heart Fail. 2010;3:195–201. This was the first published random-
ized controlled trial of vitamin D in typical older heart failure
patients. No effect was seen on exercise capacity, quality of life, or
TNF-α levels despite doubling of 25OHD levels. However,
natriuretic peptides did fall in the intervention group.
19. Sugden JA, Davies JI, Witham MD, et al. Vitamin D improves
endothelial function in patients with type 2 diabetes mellitus and
low vitamin D levels. Diabet Med. 2008;25:320–5.
20. Hoenig MR, Bianchi C, Rosenzweig A, Sellke FW. The cardiac
microvasculature in hypertension, cardiac hypertrophy and dia-
stolic heart failure. Curr Vasc Pharmacol. 2008;6:292–300.
21. Westenbrink BD, Ruifrok WP, Voors AA, et al. Vascular endothelial
growth factor is crucial for erythropoietin-induced improvement of
cardiac function in heart failure. Cardiovasc Res. 2010;87:30–9.
22. Schutz FA, Je Y, Azzi GR, Choueiri TK. Risk of congestive heart
failure with VEGF-targeted therapy: a systematic review and
meta-analysis of clinical trials. J Clin Oncol. 2010;28(15S):4602.
23. Cardus A, Panizo S, Encinas M, et al. 1, 25-dihydroxyvitamin D3
regulates VEGF production through a vitamin D response element
in the VEGF promoter. Atherosclerosis. 2009;204:85–9.
24. Zanello LP, Norman AW. 1 alpha, 25(OH)2 vitamin D3-mediated
stimulation of outward anionic currents in osteoblast-like ROS 17/
2.8 cells. Biochem Biophys Res Commun. 1996;225:551–6.
25. Simpson RU, Weishaar RE. Involvement of 1, 25-dihydroxyvitamin
D3 in regulating myocardial calcium metabolism: physiological and
pathological actions. Cell Calcium. 1988;9:285–92.
26. Santillan GE, Vazquez G, Boland RL. Activation of a beta-
adrenergic-sensitive signal transduction pathway by the secoste-
roid hormone 1, 25-(OH)2-vitamin D3 in chick heart. J Mol Cell
Cardiol. 1999;31:1095–104.
27. Maiya S, Sullivan I, Allgrove J, et al. Hypocalcaemia and vitamin
D deficiency: an important, but preventable, cause of life-
threatening infant heart failure. Heart. 2008;94:581–4.
28. Hettmannsperger U, Detmar M, Owsianowski M, et al. Cytokine-
stimulated human dermal microvascular endothelial cells produce
interleukin 6–inhibition by hydrocortisone, dexamethasone, and
calcitriol. J Invest Dermatol. 1992;99:531–6.
29. Schleithoff SS, Zittermann A, Tenderich G, et al. Vitamin D
supplementation improves cytokine profiles in patients with
congestive heart failure: a double-blind, randomized, placebo-
controlled trial. Am J Clin Nutr. 2006;83:754–9.
129
30. Zehnder D, Bland R, Chana RS, et al. Synthesis of 1, 25-
dihydroxyvitamin D(3) by human endothelial cells is regulated by
inflammatory cytokines: a novel autocrine determinant of vascular
cell adhesion. J Am Soc Nephrol. 2002;13:621–9.
31. Stefenelli T, Abela C, Frank H, et al. Cardiac abnormalities in
patients with primary hyperparathyroidism: implications for
follow-up. J Clin Endocrinol Metab. 1997;82:106–12.
32. Drueke T, Fauchet M, Fleury J, et al. Effect of parathyroidectomy
on left-ventricular function in haemodialysis patients. Lancet.
1980;1:112–4.
33. Hagstrom E, Ingelsson E, Sundstrom J, et al. Plasma parathyroid
hormone and risk of congestive heart failure in the community.
Eur J Heart Fail. 2010;12:1186–92.
34. Tarcin O, Yavuz DG, Ozben B, et al. Effect of vitamin D
deficiency and replacement on endothelial function in asymp-
tomatic subjects. J Clin Endocrinol Metab. 2009;94:4023–
30.
35. Witham MD, Nadir MA, Struthers AD. Effect of vitamin D on
blood pressure—a systematic review and meta-analysis. J Hyper-
tens. 2009;27:1948–54.
36. Coats AJ. The “muscle hypothesis” of chronic heart failure. J Mol
Cell Cardiol. 1996;28:2255–62.
37. Stockton KA, Mengersen K, Paratz JD, et al. Effect of vitamin D
supplementation on muscle strength: a systematic review and
meta-analysis. Osteoporos Int. 2010, [Epub ahead of print;
doi:10.1007/s00198-010-1407-y.
38. Witte KK, Nikitin NP, Parker AC, et al. The effect of
micronutrient supplementation on quality-of-life and left ventric-
ular function in elderly patients with chronic heart failure. Eur
Heart J. 2005;26:2238–44.
39. Park CW, Oh YS, Shin YS, et al. Intravenous calcitriol regresses
myocardial hypertrophy in hemodialysis patients with secondary
hyperparathyroidism. Am J Kidney Dis. 1999;33:73–81.
40. Lemmila S, Saha H, Virtanen V, et al. Effect of intravenous
calcitriol on cardiac systolic and diastolic function in patients on
hemodialysis. Am J Nephrol. 1998;18:404–10.
41. • Wang L, Manson JE, Song Y, Sesso HD. Systematic review:
vitamin D and calcium supplementation in prevention of
cardiovascular events. Ann Intern Med. 2010;152:315–23. This
systematic review of interventional trials showed a nonsignificant
(but potentially clinically important) reduction in cardiovascular
events with vitamin D supplementation, but a potential increase
with calcium supplementation.
42. Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin
D3 (cholecalciferol) supplementation on fractures and mortality in
men and women living in the community: randomised double
blind controlled trial. BMJ. 2003;326:469–74.
43. Shane E, Mancini D, Aaronson K, et al. Bone mass, vitamin D
deficiency, and hyperparathyroidism in congestive heart failure.
Am J Med. 1997;103:197–207.
44. Zittermann A, Schleithoff SS, Tenderich G, et al. Low vitamin D
status: a contributing factor in the pathogenesis of congestive
heart failure? J Am Coll Cardiol. 2003;41:105–12.
45. • Pilz S, Marz W, Wellnitz B, et al. Association of vitamin D
deficiency with heart failure and sudden cardiac death in a large
cross-sectional study of patients referred for coronary angiogra-
phy. J Clin Endocrinol Metab. 2008;93:3927–35. This large
prospective study showed a 2.6-times increase in the risk of death
from heart failure in angiography patients with the lowest vitamin
D levels.
46. Boxer RS, Dauser DA, Walsh SJ, et al. The association between
vitamin D and inflammation with the 6-minute walk and frailty in
patients with heart failure. J Am Geriatr Soc. 2008;56:454–61.
47. • Anderson JL, May HT, Horne BD, et al. Relation of
vitamin D deficiency to cardiovascular risk factors, disease
status, and incident events in a general healthcare population.
130
Am J Cardiol. 2010;106:963–8. This large population-based
cohort study showed a doubling in risk of new-onset heart
failure if any previous 25OHD level had been low.
48. Boxer RS, Kenny AM, Cheruvu VK, et al. Serum 25-
hydroxyvitamin D concentration is associated with functional
capacity in older adults with heart failure. Am Heart J.
2010;160:893–9.
Curr Heart Fail Rep (2011) 8:123–130
49. Pilz S, Henry RM, Snijder MB, et al. Vitamin D deficiency and
myocardial structure and function in older men and women: the
Hoorn study. J Endocrinol Investig. 2010;33:612–7.
50. Ameri P, Ronco D, Casu M, et al. High prevalence of vitamin D
deficiency and its association with left ventricular dilation: an
echocardiography study in elderly patients with chronic heart
failure. Nutr Metab Cardiovasc Dis. 2010;20:633–40.