Vitamin D and blood pressure connection: update on epidemiologic, clinical, and mechanistic evidence.

Abstract

Hypertension is an important risk factor for cardiovascular and kidney disease. High blood pressure is a growing public health problem that is expected to affect 1.6 billion people worldwide by the year 2025. In light of emerging evidence of a widespread global problem of vitamin D deficiency, there has been increasing interest concerning the role of vitamin D in chronic disease. The recent publication of several studies, highlighted in this brief review, supports an association between vitamin D status and blood pressure. It remains to be determined what level of vitamin D status needs to be achieved in different subpopulations to assure the maximum benefit of vitamin D status on blood pressure.

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goom-
Emerging Science
Vitamin D and blood pressure connection: update on
epidemiologic, clinical, and mechanistic evidence
Ligia A Martini and Richard J Wood
Hypertension is an important risk factor for cardiovascular and kidney disease. High
blood pressure is a growing public health problem that is expected to affect 1.6
billion people worldwide by the year 2025. In light of emerging evidence of a
widespread global problem of vitamin D deficiency, there has been increasing
interest concerning the role of vitamin Din chronic disease. The recent publication of
several studies, highlighted in this brief review, supports an association between
vitamin D status and blood pressure. It remains to be determined what level of
vitamin D status needs to be achieved in different sub populations to assure the
maximum benefit of vitamin D status on blood pressure.
© 2008 International Life Sciences Institute
INTRODUCTION
Hypertension (blood pressure ^! 140 systolic and 90 dias-
tolic) is quite prevalent in many countries and is expected
to affect 1.6 billion people worldwide by the year 2025. In
the United States, hypertension is currently estimated to
affect 67% of adults aged 60 years and older' and the
prevalence of this condition has been increasing. As a
major risk factor for heart and kidney disease and the
major risk factor for cerebrovascular disease (stroke),
hypertension is an important contributor to the burden
of chronic disease, disability, and death in the population.
High blood pressure can be treated with antihypertensive
medication and modulated by changing modifiable risk
factors, such as body weight, smoking and diet. Many
studies have investigated the association of these modifi-
able host risk factors on blood pressure and the risk of
hypertension. Regarding dietary approaches to reducing
blood pressure, most studies have investigated the role of
sodium,` consumption of iegetables and fruits,',' and
calcium.` Recently, the association of vitamin D status
with blood pressuè has also been reported.'-"
Vitamin ?
deficiency has been described world-
wide,"-" and its possible 'health consequence include
several conditions in addition to bone health; these
include increased risk of some types of cancer, immune
diseases, diabetes, and cardiovascular diseases.'5 Surpris-
ingly, in addition to concerns about vitamin D insuffi-
ciency developing in residents of higher latitudes due to
reduced UVB exposure, which lowers cutaneous vitamin
D synthesis, there has been increasing concern about
inadequate vitamin D status in more sunny climates. 11,17
Currently, vitamin D experts are recommending that the
optimal level of plasma 25-hydroxyvitamin D, a biomar-
ker of vitamin D status, for optimal bone health is
—30 ng/ml (75 nmol/L). This level of plasma
25-hydroxyvitamin D also appears necessary to reduce
the risk of some chronic diseases.'8
The chronic disease burden and the costs of health
complications associated with aging are expected to
increase dramatically in the coming decades in botheco-
nomically developed and many less well-developd coun-
tries around the globe. Considering that poor vitamin D
status is' widespread and is a readil'm ,odifiable nutri-
tionalisk factor that could help prent chronic diseases,
a better understanding of the role of vitamin D in various
hèàlth outcomes, including hype rtension,' 9 is needed to
help reduce the growing global burden of chronic disease.
Affiliations: LA Martini is with the Nutrition Department,'School of Public Health, Sao Paulo University, Sao Paulo, Brazil. Ri Wood is
Director of the Mineral Bioavailability Laboratory, Jean Mayer USDA Human Nutrition Research Center on 'Aging at Tufts University,
Boston; Massachussetts, USA.
Correspondence: Ri Wood, Director, Minral'Bioavailability Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at.
Tufts University;71 1 Washington Street, Boston, MA 02111, USA. E-mail: richard.wood@tufts.edu, Phone: +1-617-556-3192, Fax:
+1-617:556-3344
Key words: angiotensin, blood pressure, cholecalciferol, hypertension, renin
doi:10.1 11 1/j.1753-4887.2008.00035.x
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III -
VITAMIN D STATUS AND BLOOD PRESSURE? risk factors, including hypertension, in US adults. The
mean level of serum 25-hydroxyvitamin D in the overall
Recent epidemiologic evidence?
sample was 30 ng/mL (75 nmol/L), which is similar to
the current recommendations for optimal vitamin D sta-
tus.'5 Mean serum 25-hydroxyvitamin D concentrations
were lower in women, elderly persons (^60 years),
racial/ethnic minorities, and participants with obesity,
hypertension, and diabetes mellitus. Martins et al.'°
found that the adjusted prevalence of hypertension in
adults in the United States was 30% higher in the lowest
compared to the highest quartile of serum 25-
hydroxyvitamin D.
On the other hand, in a recently reported
non-?
population-based cohort study of 1205 elderly subjects
participating in the Longitudinal Aging Study Amster-
dam in the Netherlands, no association was found
between vitamin D status and the risk of having hyper-
tension". This observation held even when subjects
taking hypertensive medication were excluded from the
analysis. However, it should be pointed out that in this
elderly population, most (80%) of the participants had
hypertension and one-third of the subjects were taking
anti-hypertensive medications.
It is also of interest to know whether poor vitamin D
status is a risk factor for the development of hyperten-
sion. The question was recently addressed in a report by
Forman et al.," who used prospective data on incident
hypertension and baseline serum concentrations of
25-hydroxyvitamin D for a subset of men in the Health
Professionals Follow-up Study (n = 613) and for a subset
of women from the Nurses' Health Study (n = 1198). The
prospective follow-up in the analyzed cohort was 4-8
years. In men, there were 61 incident eases of hyperten-
sion at 4-year follow-up and 133 incident cases at 8-year
follow-up. In women, there were 129 incident cases of
hypertension at 4-year follow-up and 274 cases at 8-year
follow up. These subjects represent a subgroup of the
larger cohorts of men and women participating in these
prospective studies because they were the individuals
for whom baseline serum measurements of 25-
hydroxyvitamin D were available.
•. ...........?
rnortality.,Interestingly, this analysis also suggested that?
the impact of vitamin D status on blood Oressure.,may,be?
greater in the elderly. After adjusting for gender, ethnicity,?
and leisure time physical activity, their regression model?
predicted that an increase in serum 25 hydroxyvitamin D?
from 20 to 100 nmol/L in people aged <50 years or ^:50?
years would cause respective decreases in systolic blood --,4 ered sufficient, 29-.15 ng/mL(74-37.5 nmol/L) was insuf-
pressure of 1.8 and 4.6 mm Hg.?
Analysis of the NHANES III data set also indicates?
that poor vitaminD status is associated with a higher - ity, and race. In addition, other possible confounders,
risk of having hypertension. Martins et al.'° evaluated?
the cross-sectional association between serum 25-?
hydroxyvitamin D and selected cardiovascular disease?
New evidence from three epidemiologic studies supports?
the view that higher vitamin D status, measured as serum?
25-hydroxyvitamin D concentration, is associated with?
lower mean blood pressure and reduced prevalence of?
hypertension.9"°" 2 Scragg et al.' recently reported on their?
evaluation of the cross-sectional relationship between?
serum 25-hydroxyvitamin D concentration and blood?
pressure in the third National Health and Nutrition?
Examination Survey (NI-lANES III), a nationally repre-?
sentative?
cross-sectional?
survey?
of the?
institutionalized population in the United States carried?
out during 1988-1994. In this analysis of 12,644 people?
aged ^20 years (people on hypertensive medications?
were excluded), a modest, but significant, inverse associa-?
tion between serum 25-hydroxyvitamin D concentration?
and blood pressure was evident even when vitamin D?
status was adjusted for age, gender, ethnicity, and physical?
activity, each of which were found to be significantly asso-?
ciated with vitamin D status. Grouping subjects into?
25-hydroxyvitamin D quintile groups, Scragg et al.'?
found that mean systolic blood pressure was 3.0 mmHg?
lower and diastolic BP was 1.6 mmHg lower in the?
highest (serum 25-hydroxyvitamin D ^85.7 nmol/L)?
compared with the lowest (serum 25-hydroxyvitamin?
D 40 nmol/L) quintile of vitamin D status. Moreover,?
since the level of body fat can influence serum?
25-hydroxyvitamin D concentration, it was noteworthy?
that these investigators still found a signifcant, although?
attenuated, difference when controlling for this potential?
confounder between vitamin D status and mean systolic?
blood pressure (-1.8 mmHg) between the lowest and?
highest quintile groups. As pointed out by the authors,?
even this small difference in systolic blood pressure on a?
population basis can have important public health impli-?
cations because it has been estimated that a 2-3 mmHg?
decrease .in systolic blood pressure would be associated?
with a .10-15% decline in cardiovascular disease-related?
It. .....'? t,jr4 :.,?
'
For statistical analysis, subjects were assigned to one
of three categories of vitamin status based on their level
of serum 25-hydroxyvitarninD measured at baseline. The
vitamin 1D status categories were based on the follow
ing concentrations of, 11serurn 25 hydroxyvitamin D
^30 ng/ml (^-_75 nmol/L, reference goup) was consid-
•-?• ' .ficient, and <is ng/mL (<37.5 nmol/L) was deficient.'. 5 All
of the analyses were adjusted for age, BMI,physicl activ-
:. such as famil)i historyof hypertension smoking status,
menopausal status, season, and intakes of vitain D,
alcohol, folate,sodium; potassium, calcium, and magne-
292?
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sium were tested individually; they were only kept in the
predictive model if their inclusion changed the relative
risk for vitamin D status as a predictor of incident hyper-
tension by at least 10%. Of these variables, only meno-
pausal status had a marked enough effect to be included
in the final model.
Compared to the reference group of men that were
vitamin D sufficient (^30 ng/ml/75 nmol/L), the relative
risk at 4-year follow up for incident hypertension in men
considered vitamin D deficient (<15 nglml/37.5 nmol/L)
was 6.13 (95% Cl 1.00-37.8); at 8-year follow-up, the
multivariable relative risk was 3.53(95% Cl 1.02-12.3) for
the same group. In a similar analysis in women, the
adjusted relative risk was 2.67 (95% Cl 1.05-6.97) at 4
years and 1.7 (95% Cl 0.92-3.16) at 8 years.
To confirm their findings, Forman et al.' 2 analyzed a
larger data set (38,388 men and 77,531 women) from
the Health Professionals Follow-up Study and the
Nurses' Health Study. However, they had to use pre-
dicted, instead of measured, serum 25-hydroxyvitamin
D concentrations. This approach afforded them a much
larger cohort and a longer follow-up period of 16-18
years to accrue more cases of incident hypertension
(9029 cases in men and 26,525 in women). The correla-
tion coefficient between measured and predicted
25-hydroxyvitamin D concentrations in a cohort subset
was r=-0.5.
Using predicted levels of serum 25-hydroxyvitamin
D, the relative risk of incident hypertension was evaluated
in subjects categorized into deciles of predicted
25-hydroxyvitamin D. For men, comparison of the lowest
decile of predicted vitamin D status to the highest decile
group in an adjusted multivariable logistic regression
model resulted in a relative risk of incident hypertension
of 2.31 (95% CI 2.03-2.63). In women, this comparison
of lowest and highest decile groups indicated a relative
risk of incident hypertension of 1.57 (95% Cl 1.44-1.72).
These findings provide important support for the exist-
ence of an association between poor vitamin D status and
increased risk for incident hypertension, independent of
age, BMI, physical activity, race, menopausal status, and
other important covariates.
Collectively, the preponderance of evidence from
these recent epidemiologic findings supports the conjec-
ture made a' decade ago by Rostand20 of. an , association
between blodd.pressure and vitamin D status; this was
based on the finding of-the INTERSALT' study oft an
association between geographic latitude distant from the
equator and rise in blood • pressure and prevalence of
hypertension. In addition, these new findings suggest that
the apparent impact of poor vitamin D status on blood
pressure and hypertension risk are of sufficient. magni-
tude ,to have a 'potentially important. impact. on . cardio-
vascular mortality. ......-,?
L J? I.
Vitamin D supplementation and blood pressure
The demonstration of a salutary effect of vitamin D
supplementation on blood pressure in well-designed
clinical trials would be an important piece of evidence to
support the argument that changes in vitamin D status
affect blood pressure. However, clinical trials performed
to date have provided little support for a positive effect of
vitamin D supplementation on blood pressure. Our
review of the published literature indicates that very few
studies of vitamin D supplementation have included
blood pressure as an important study endpoint. More-
over, many of the studies focused on the effects of
1,25-dihydroxyvitamin D or similar active vitamin D
analogs" .23 rather than on the parent compound
cholecalciferol.2427 In these studies, interpretation of the
observed effects of active hormonal forms of vitamin D
on blood pressure is not necessarily straightforward in
the nutritional context because of the possible pharma-
cologic effects of these powerful compounds. Additional
issues of concern in some investigations include the fol-
lowing: limited number of subjects; lack of selection of
vitamin D-deficient subjects; combination treatments
with vitamin D and calcium; treatment of subjects with a
single large bolus dose of vitamin D; exclusion of hyper-
tensive subjects; or selection of study subjects on the
basis of particular abnormal conditions, such as primary
hyperparathyroidism and hypercalcemia or impaired
glucose tolerance.
The positive association between vitamin D status
and blood pressure or the risk of hypertension, as shown
in the recently published large cross-sectional surveys of
the US population or in large prospective cohort studies,
support a role for vitamin D in blood pressure regulation;
however, they also suggest that the mean difference in
systolic blood pressure in vitamin D-deficient subjects is
probably quite moderate (-3 mm Hg) and the effects of
vitamin D on diastolic blood pressure are even less.
Therefore, it will be difficult to ascertain what effect an
improvement in vitamin D status has on blood pressure
in small vitamin D supplementation trials and in studies
that do not include a sufficient number of vitamin
D-deficient subjects; in many of these studies, a negative
finding will likely be favored. Thus; it is.imperativethat
future supplementation trials that are focused on the rela-
tionship between vitamin D status and blood pressure.or
the risk of hypertension be appropriately designed. and
sufficiently powered. . ..?
,1.. ',.?.'?
' VITAMIN D AND BLOOD PRESSURE CONNECTION:
- ..'?A BIOLOGICAL-PLAUSIBILITY??r I
..
'?
-?
.( .11. I
IiI
Although the findings of recent epidmiologic studies
and some earlier clinical trials support a role of vitamin-D
Nutrition Reviews Vol. 66(5):291-297?
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status in blood pressure regulation, it is also important
that a plausible biological mechanism exist by which dif-
ferences in vitamin D status could affect blood pressure
and the risk of hypertension. The effect of vitamin D
status on cellular function is brought about by the actions
of the vitamin D hormone 1,25-dihydroxyvitamin D,
operating through the vitamin D receptor, to influence
gene expression. Effects of 1,25-dihydroxyvitamin D on
gene transcription are mediated by formation of a het-
erodimer between the vitamin D receptor and the retin-
oid X receptor. The heterodimer binds to the vitamin D
response element in the promoter region of vitamin
D-dependent genes to positively or negatively influence
gene transcription. In the laboratory of YC Li at the Uni-
versity of Chicago, Yuan et al .2' recently documented an
interesting mechanism by which the vitamin D ligand-
activated vitamin D receptor could suppress expression
of the renin gene.
Renin-angiotensin cascade and blood
pressure regulation
The regulation of blood pressure is mainly controlled by
the renin-angiotensin system, which affects blood vessel
tone, extracellular fluid volume, and electrolyte homeo-
stasis. Inappropriate activation of the renin-angiotensin
system can lead to hypertension. As illustrated in
Figure 1, the first and rate-limiting component of the
renin-angiotensin system cascade is production of
renin, a protease synthesized and secreted by the juxta-
glomerular (JG) cells of the kidney. The main function
of renin is to cleave the peptide angiotensin I from cir-
culating angiotensinogen, which is produced in the liver.
The released angiotensin I is then converted to angio-
tensin II by angiotensin-converting enzyme, found
mainly in the lungs. Angiotensin II is the central bio-
logical effector of the renin-angiotensin system and
influences renal electrolyte handling, extracellular fluid
volume, and blood vessel tone to regulate blood pres-
sure.29'3° Angiotensin II acts directly on blood vessel
smooth muscle cells to cause vasoconstriction; stimu-
lates the hypothalamus to produce a sensation of thirst
to increase fluid intake; stimulates the production of
vasopressin, the antidiuretic hormone, in the posterior
lobe of the pituitary gland, which increases renal water
resorption in the distal tubule by affecting the activity of
aquaporin water channels; and stimulates synthesis and
secretion in the adrenal cortex of the steroid hormone
aldosterone, which affects renal sodium channels to
enhance renal sodium reabsorption. Therefore, activa-
tion of renin.-angiotensin-vasopressin-aldosterone axis
leads to an increase in extracellular volume and blood
pressure.
Vitamin D and renin expression
A series of studies have been performed with cell culture
and VDR knockout mice to support the hypothesis that
vitamin D status may control blood pressure by regulat-
ing the activity of the renin-angiotensin system.28'3135
Vitamin D receptor knockout mice, which lack vitamin
D-mediated cell signaling, have increased blood pressure
and elevated renin levels. The studies performed in Li's
laboratory also support the idea that administration of
1,25-hydroxyvitamin D decreases renin gene expression.
It is known that expression of the renin gene is regulated
at the renin promoter region by a number of factors,
including different steroid hormone receptors (LXR and
RAR) and various other transcription factors, including
CREB, a cyclic AMP response element (CRE) binding
protein. However, it was not known how 1,25-
dihydroxyvitamin D treatment brought about a reduction
in renin transcription, or whether there was a vitamin D
response element in the renin promoter. Recently, Li's
laboratory has provided an important mechanistic
insight into this process by suggesting that 1,25-
dihydroxyvitamin D does not influence renin transcrip-
tion through a vitamin D response element, but rather
that 1,25-dihydroxyvitamin D suppresses gene transcrip-
tion by activating the vitamin D receptor, which then
binds to CREB and blocks cyclic AMP response element-
mediated activation of the renin gene promoter
(Figure 2).
Cyclic AMP is a major intracellular signal stimulat-
ing renin gene expression in juxtaglomerular cells of the
kidney. Cyclic AMP stimulates renin gene expression by
binding to the regulatory subunit on protein kinase A
(PKA), which causes the release of a catalytic subunit
from PKA. The PKA catalytic subunit then enters the
nucleus to affect phosphorylation and activation of
CREB. Activation of CREB allows it to bind to the cyclic
AMP response element in the renin gene promoter and
recruit CBPIp300 (CREB binding protein) to promote
gene transcription.
Yuan et al.28 have provided new evidence that the
mechanism of the inhibitory effect of the vitamin D
hormone on renin gene transcription lies in the binding
of the liganded vitamin D receptor to the nuclear CREB
transcription factor, thereby interfering with the forma-
tion of the CRE-CREB-CBP complex on the renin pro-
moter and the initiation of transcription.
CONCLUSION
Given the primary importance of renin-mediated regula-
tion of blood pressure, this system obviously still operates
regardless of the vitamin D status of the host. Presumably,
then, vitamin D deficiency, or altered vitamin D receptor
294?
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VITAMIN D AND BLOOD PRESSURE
^
CREHPOLII
VDR
EBO8
C R E?RENIN GENE?
C R E?RENIN GENE
- 1.25-DIHYDROXYVITAMIN D
• Absence of Vitamin D signal
prevents VDR activation
• Deactivated VDR can not bind
to CREB
• Binding of CREB to CRE
leads to assembly of renin
gene transcriptional complex
• Renin production increases
+ 1,25-DIHYDROXYVITAMIN D
• Presence of Vitamin 0 signal
promotes VDR activation
-Activated VDR binds CREB
-Loss of CREB binding to CRE
prevents assembly of renin gene
transcriptional complex
•Renin production decreases
Blood pressure increases? Blood pressure decreases
Figure 2 Proposed role of 1 ,25-dihydroxyvitamin D in renin expression. This model is based on the work performed at YC
Li's laboratory, as discussed in the text.
function, must interfere with a vitamin D-mediated tonic
brake on basal renin synthesis, thereby leading to relative
hyperreninemia and increased blood pressure.
The recent publication of several studies highlighted
above support a moderate, but potentially important,
association between vitamin D status and blood pressure.
This is one additional reason, among many, why it is
important for individuals to maintain an adequate
vitamin D status. However, additional research is war-
ranted to better determine to what extent the blood
pressure-related effects of vitamin D may be of additional
clinical importance in certain population subgroups (e.g.,
high-renin versus low-renin hypertensives and the
elderly). Moreover, it remains to be determined what level
of vitamin D status needs to be achieved in these different
subpopulations to assure the maximum benefit of
vitamin D on blood pressure.
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