EDITORIAL COMMENT

Vitamin D and
Cardiovascular Disease
Time for Large Randomized Trials*
Carlos A. Camargo, JR, MD, DRPH
Boston, Massachusetts
Vitamin D is a hormone of critical importance to calcium
homeostasis and bone health (1). Although widely regarded
as a vitamin, a more accurate term is conditional vitamin,
in that vitamin D is required in the diet only when the skin
does not make enough through the action of ultraviolet B
radiation from the sun. At higher latitudes (e.g., most of the
United States, all of Canada and Europe, southern Austra-
lia, and all of New Zealand), ultraviolet B exposure drops
dramatically during autumn and winter (2). Although it is
certainly possible to produce and store sufcient vitamin D
after abundant sunlight exposure in spring and summer,
indoor life-styles and sun avoidance campaigns have de-
creased such exposure and led many to require ingestion of
this unique hormone/vitamin.
See page 1433
Over the past decade, a growing body of evidence
suggests that the health effects of vitamin D extend beyond
rickets and bone health (2). Although it would be preferable
to know local (even intracellular) levels of the active hor-
mone (i.e., 1,25-dihydroxyvitamin D), circulating levels of
the precursor, 25-hydroxyvitamin D (25-OHD), remain the
best available method of measuring overall vitamin D status.
The recommended level of serum 25-OHD is highly
controversial, with some recommending a level of 20 ng/ml
or higher (3) while others recommend a level of at least 30
ng/ml (4,5) or much higher (6). However, using either the
20 or 30 ng/ml threshold, national studies clearly document
low serum 25-OHD levels for a substantial segment of the
U.S. population, particularly among racial and ethnic mi-
norities (7).
Of particular interest to cardiovascular researchers and
clinicians is growing evidence of a link between low vitamin
D and increased risk for cardiovascular disease (CVD) (8).
Although this may seem like a recent development, the
origins of this hypothesis actually go back a few decades. In
1981 Scragg (9) drew on ecological studies of variations in
CVD by season, latitude, and altitude and published a
hypothesis that sunlight and vitamin D may protect against
CVD. In 1990, Scragg et al. (10) reported a population-
based case-control study from New Zealand that found a
strong inverse association between plasma 25-OHD level
and risk for myocardial infarction (10). Over the past 5
years, there has been renewed interest in this hypothesis,
with supportive evidence from several large prospective
cohort studies (11), including analyses that focused on older
adults (12). Indeed, the original hypothesis about myocar-
dial infarction has now expanded to include atherosclerosis,
heart failure, stroke, and several cardiometabolic disorders
(e.g., hypertension, diabetes). Although an explanation for
these diverse effects remains unclear, it undoubtedly in-
volves multiple mechanisms. The growing enthusiasm for
vitamin D deciency as an important, common, and easily
treatable CVD risk factor (8) has been offset recently by
skepticism about vitamin D as a panacea, a view reected in
a 2011 report from the Institute of Medicine (3). In brief,
skeptics wonder if vitamin D status is simply a marker of
general health. In other words, do healthier people tend to
spend more time outside, resulting in more ultraviolet B
exposure and thus higher 25-OHD levels? In such a
scenario, confounding by better baseline health (or outdoor
activity) would account for the positive ndings in recent
epidemiologic studies. If the association between vitamin D
and CVD is truly confounded in this manner, the initiation
of vitamin D supplements might yield little (if any) impact
on CVD risk.
In this issue of the Journal, Kestenbaum et al. (13)
examine the associations of 25-OHD, parathyroid hormone
(PTH), and incident CVD in the Cardiovascular Health
Study. In 2,312 older adults who were free of CVD at
baseline, 17% had baseline 25-OHD levels 15 ng/ml, and
25% had baseline PTH levels 65 pg/ml. In brief, the
investigators found that baseline levels of 25-OHD were
inversely associated with risk for myocardial infarction and
all-cause mortality, while PTH excess was associated with
heart failure. Although statistical power was limited, they
found no evidence of an interaction between 25-OHD and
PTH levels and cardiovascular events. These ndings sup-
port those who believe that low vitamin D is a modiable
risk factor for at least some types of CVD, such as
myocardial infarction, and also raise the possibility that
vitamin D and PTH might inuence CVD risk through
divergent pathways, at least in this population of older
adults without baseline CVD and 1% baseline use of
vitamin D supplements.
With regard to the confounding, the investigators had
data on all of the traditional CVD risk factors, including
physical activity, and multivariate analyses adjusted for these
*Editorials published in the Journal of the American College of Cardiology reect the
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology.
From Massachusetts General Hospital, Harvard Medical School, Boston,
Massachusetts. Dr. Camargo is supported in part by the Massachusetts General
Hospital Center for D-Receptor Activation Research.
Journal of the American College of Cardiology Vol. 58, No. 14, 2011
2011 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2011.06.037
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factors. Although it remains possible that residual con-
founding is responsible for the observed associations, it is
also possible that an observed association is both causal and
confounded. In other words, even a demonstrably con-
founded association might be true. Although multivariate
analysis would begin to address confounding, other meth-
odologic limitations (e.g., the use of a single measure to look
at 14-year outcomes) probably obscured real associations.
The nal odds ratio reects a complex mixture of causality,
bias and confounding. Notwithstanding these familiar epi-
demiologic challenges, the ndings are generally consistent
with those of prior studies. For example, the all-cause
mortality nding (a 9% increase for every 10 ng/ml decrease
in 25-OHD) matches a meta-analysis of bone health
randomized controlled trials (RCTs) comparing vitamin D
with placebo, in which vitamin D supplementation yielded
a 7% reduction in all-cause mortality (14).
The investigators suggestion that vitamin D and PTH
may affect CVD risk through divergent pathways requires
further study. Although it is likely that these hormones have
more (or less) impact on specic outcomes, PTH represents
an endogenous biologic marker of inadequate vitamin D; it
seems highly likely that there would be some overlap.
Although it is tempting to conclude that PTH is uniquely
associated with heart failure, other studies suggest that
vitamin D plays an important role in the pathogenesis and
clinical course of heart failure (15,16). It is possible that
PTH plays a predominant role in some populations, but I
doubt that this is an all-or-none phenomenon. Further
epidemiologic studies are needed to clarify this issue.
More important, the eld needs insights from 2 other
types of research: 1) translational research to improve
understanding of potential mechanisms for the emerging
epidemiologic associations; and 2) large, population-based
RCTs to formally test causality in humans. Already, 2 such
trials are under way (Table 1): the ViDA (Vitamin D
Assessment) trial in New Zealand and the VITAL (Vitamin
D and Omega-3 Trial) in the United States. The 2 RCTs
are sufciently different that they should provide comple-
mentary answers to the major question, Does the initiation
of vitamin D supplementation prevent CVD? The design
and implementation of additional population-based RCTs
would help address the impact of other vitamin D regimens
in different populations.
Unfortunately, these trials will take several years to
complete. In the meantime, in the absence of RCT evi-
dence, it is difcult to draw conclusions about the cardio-
vascular benets of vitamin D supplementation (3). Even
for those at lower 25-OHD levels, there is controversy
about the 25-OHD target for optimal general health, with
several discordant recommendations in the published re-
search (36). On the basis of my review of the available
data, I believe that the optimal 25-OHD level for most
health problems will be around 40 ng/ml (100 nmol/l), with
relatively small differences found in the range of 35 to 50
ng/ml. I also submit that it will be easier to demonstrate
benet by elevating a persons 25-OHD from, for example,
10 to 20 ng/ml, compared to elevating another persons
25-OHD from 40 to 50 ng/ml; baseline levels of 25-OHD
have to matter. Although this may seem like a common-
sense observation, the role of baseline vitamin status in
RCTs continues to receive inadequate attention in scientic
circles (17). Last, given the many factors that affect vitamin
D status (e.g., latitude, season, sunlight exposure, skin color,
obesity, genetics), the search for a one-size-ts-all regi-
men seems misguided. Although RCTs need to test specic
doses because of the ethical challenge of testing baseline
25-OHD and then assigning someone with established
(albeit asymptomatic) vitamin D deciency to placebo, it is
unclear why supplementation of individual patients should
be restricted to a xed regimen.
In summary, for those who believe that the inverse
association between vitamin D and CVD risk is probably
causal, and that the association will prove modiable, the
next steps are clear: widespread serum 25-OHD testing and
vitamin D supplementation to achieve a specic 25-OHD
target. For those who are more skeptical of epidemiologic
associations, who have concerns about adding unjustied
costs to an already burdened health system, or who worry
that supplementation may cause unintended harmas has
happened with antioxidant interventions (18)the next
steps are equally clear: the imperative of completing large
Large, Population-Based, Randomized, Double-Blind, Placebo-Controlled Trials on the Health Effects of Vitamin D Supplementation (as of August 2011)
Table 1
Large, Population-Based, Randomized, Double-Blind, Placebo-Controlled Trials
on the Health Effects of Vitamin D Supplementation (as of August 2011)
ViDA VITAL
Country New Zealand United States
Principal investigator(s) Scragg and Camargo Manson and Buring
Target sample size 5,100 20,000
Age range 5084 yrs (both men and women) Men: 50 yrs; women: 55 yrs
Vitamin D
3
intervention 100,000 IU/month (about 3,300 IU/day); subjects also are given
an extra 100,000 IU at the start of the trial and every autumn
2,000 IU/day; part of a 2 2 factorial trial in which the other intervention
is 1 g/day of specic omega-3 fatty acids
Primary outcomes CVD, infection, fractures Cancer, CVD
Year enrollment started 2011 2011
Expected year of results 2017 2017
Trial registration ACTRN12611000402943 NCT01169259
CVD cardiovascular disease; ViDA Vitamin D Assessment trial; VITAL Vitamin D and Omega-3 Trial.
1443 JACC Vol. 58, No. 14, 2011 Camargo, Jr
September 27, 2011:14424 Vitamin D and CVD
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RCTs to justify changes in clinical practice and health
policy. In a few years, ViDA and VITAL will begin to shed
a light on this important and controversial issue.
Reprint requests and correspondence: Dr. Carlos A. Camargo,
Massachusetts General Hospital, 326 Cambridge Street, Suite 410,
Boston, Massachusetts 02114. E-mail: ccamargo@partners.org.
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Key Words: heart failure y mineral metabolism y myocardial infarction
y parathyroid hormone y vitamin D.
1444 Camargo, Jr JACC Vol. 58, No. 14, 2011
Vitamin D and CVD September 27, 2011:14424
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