Vitamin D and heart disease

Vitamin D - An Overview
 A fat soluble vitamin.
 Not just a vitamin, a prehormone
 Also nonhormonal, intracrine, and paracrine actions of
1-hydroxylated vitamin D metabolites
 The major endogenous, synthetic source of vitamin D1
for humans is the epidermis.
 25OHD level in the serum is the best indicator of vitamin
D

 Vit D2 (ergocalciferol) – Plant Sources
 Vit D3 (cholecalciferol) – A product of UVB irradiaton of 7-
dehydrocholesterol synthesis in the skin, or from oily
fish, fortified foods or supplementation
 Vit D → 25- OH D → 1, 25 OH D
 Serum levels of 1, 25 OH D are not helpful in assessing
Vitamin D stores

Endocrine, paracrine and intracrine
functions of Vitamin D

Vitamin D & Heart Disease
 Vit D receptors are present in cardiomyocytes, beta cells,
vascular endothelial cells and osteoblasts.
 Vit D deficiency plays an important role in CV risk.
 Vit D deficiency is ass’d with DM, HTN, Metabolic
Syndrome, LVH, CHF and Vascular Inflammation and
calcification.

Forman JP et al.
Hypertension
2008 November ;
52(5): 828–832
Prospective case control study.
1,484 women aged 32-52 years who did not have hypertension at baseline.
matched cases and controls on age, race, and month of blood collection, and further
adjusted for BMI, physical activity, family history of hypertension, oral contraceptive
use, and plasma levels of parathyroid hormone, calcium, phosphorous, creatinine, and
uric acid.
Median plasma 25(OH)D levels were lower in the cases (25.6 ng/mL) than in the
controls (27.3 ng/mL, p<0.001). Women in the lowest compared to highest quartile of
plasma 25(OH)D had an adjusted OR for incident hypertension of 1.66 (1.11-2.48; p-
trend=0.01).
Compared to women with sufficient levels, those with vitamin D deficiency (<30
ng/mL, 65.7% of the study population) had a multivariable OR of 1.47 (1.10-1.97).
Plasma 25(OH)D levels are inversely and independently associated with risk of
developing hypertension.
Vit D Levels and Risk of Incident Hypertension

Measured serum 25-OH D and compared it to endothelial function
assessed by brachial artery flow-mediated dilation and and microvascular
function was assessed as digital reactive hyperemia index. Carotid-
femoral pulse wave velocity and radial tonometry-derived central
augmentation index and subendocardial viability ratio were measured to
assess arterial stiffness.
Vitamin D insufficiency was associated with increased arterial stiffness
and endothelial dysfunction in conductance and resistant blood vessels,
irrespective of traditional risk burden.
Mheid I.A. et al.
J Am Coll Cardiol
2011; 58: 186-
192
Vit D & Arterial stiffness

Mheid I.A. et al. J
Am Coll Cardiol
2011; 58: 186-192
Follow up of vit D deficient subjects after 6 mnths, 42/91 subjects had normalised vit
D levels(vit D>30ng/ml) and 49/91 remained deficient.
Subjects who had normalised levels of vit D, had significant increase in RHI and
SEVR, and a decrease in MAP.

In moderate hypertensive patients, levels of 25-OH D were
inversely associated with plethysmography derived calf
vascular resistance at rest and after 3 min of arterial
occlusion*.
The third National Health and Nutrition Examination Survey
found increased blood pressure, with vitamin D deficiency
.#
*Duprez D et al, Blood
Press 1994;3:389 –93.
#Martins D,
Arch Intern Med
2007;167:1159–65.

Renin–angiotensinsystemactivityin vitaminD deficient, obese individuals
with hypertension: An urban Indian study
SK kota et al.
Indian J Endocrinol
Metab. 2011
October; 15(Suppl4)
: S395–S401.
 Fifty newly detected hypertensive patients were screened.
 All the three blood pressure parameters [SBP, DBP and mean arterial pressure (MAP)] were
significantly higher among individuals with lower 25(OH)D levels.
 Increasing trends in PRA and PAC were noticed with lower 25(OH)D and higher BMI levels.

In experimental animal studies, vitamin D
 modulates endothelial cell function by decreasing expression of adhesion
molecules,
 providing protection against advanced glycation products,
 reduction in endothelium-dependent contractions and
 modulation of calcium influx .*
Vitamin D deficiency also
 activates the renin-angiotensin-aldosterone system,
 causes proliferation of vascular smooth muscle cells,
 activates macrophage invasion of the vascular wall,
 promotes calcification, and increases parathyroid hormone release.#
Finally, vitamin D might modulate adaptive immunity by reducing inflammatory
cytokine gene expression, alternating circulating subsets of T-cells, and reducing
inflammation.^
Possible mechanism:
* Wong MS et al.
Am J Physiol
Heart Circ Physiol
2008;295:H289–
96.
#Helming L et al.
Blood 2005;
106:4351– 8.
^Pittas AG et al.
J Clin Endocrinol
Metab 2007;
92:2017–29

Vit D and Coronary calcification
Watson KE et al.
Circulation.
1997;96:1755-1760
studied two human populations (173 subjects) at high and moderate risk for
coronary heart disease and assessed the relation between serum levels of
osteoregulatory molecules (Levels of osteocalcin, PTH, and 1,25-vitamin D)
and the extent of vascular calcification as detected by EBCT.
1,25-vitamin D levels are inversely correlated with the extent of vascular
calcification in both groups. No correlations were found between extent of
calcification and levels of osteocalcin or parathyroid hormone.
Negative relation between coronary calcification and serum 1,25-
vitamin D levels in subjects with a moderate risk of developing
CHD
Inverse relationships between coronarycalcification and
serum 1,25-vitamin D levels (A) and between total vascula
calcification (coronary plus aortic) and 1,25D levels (B) in
the FH group.

 strong inverse association between 25(OH)D concentrations and
prevalent CVD among type 2 diabetic outpatients.
 diabetic patients with hypovitaminosis D were more likely to be
women and had increased prevalence of higher values of A1C,
triglycerides, CRP, and fibrinogen than their vitamin D–sufficient
counterparts.
 1,25(OH)vitD has been shown to exert several protective effects on
atherogenesis and vascular calcification, and
in a case-control study 25(OH)D levels were significantly reduced in
patients with myocardial infarction *.
*Cigolini M, Diabetes
Care 2006.
29:722–724

recent data from 1739 Framingham Offspring Study participants
without cardiovascular disease at baseline showed that after a
follow-up time of 5.4 yr, in which 120 nonfatal and fatal
cardiovascular events occurred, low vitamin D levels were
independently associated with an increased risk of cardiovascular
events.*
Association between cardiovascular events and 25(OH)D levels was
confined to people with arterial hypertension .
*Wang TJ,
Circulation 2008.
117:503–511
Deficiency 25-(OH) D & CVD

 A community-based study among the elderly.
 report that higher circulating serum vitamin D levels were significantly associated with
decreased LV end-systolic diameter and increased measures of systolic function at
baseline in cross-sectional analyses
 The association persisted after adjusting for several potential confounders, including
cardiovascular risk factors as well as biomarkers from the calcium/vitamin D pathway
(calcium, phosphate, magnesium, and parathyroid hormone).
In longitudinal analyses, vitamin D levels at baseline were not significantly associated
with change in LV geometry and function after 5 years.
These observations argue against vitamin D levels being causally related to LV systolic
function and geometry;
Randomized clinical trials are needed to establish firmly or refute a causal relationship
between vitamin D levels and changes in LV geometry and function.
Relations of circulating vitaminD concentrations with left ventricular
geometry and function
Tove Fall et al.
European Journal
of Heart Failure
(2012) 14, 985–
991

Possible mechanisms:
 Vitamin D has been hypothesized to play an important role
in reduction of LV hypertrophy and function partly through
modulation of the renin–angiotensin system (RAS), which plays
a key role in the regulation of volume and blood pressure
homeostasis.*
 Vitamin D functions as an endocrine suppressor of renin
biosynthesis, and the subsequent genetic disruption of the
vitamin D receptor (VDR) could result in overstimulation of
the RAS, leading to high blood pressure and cardiac
hypertrophy#.
 Also, vitamin D deficiency has been observed to induce
myocardial hypertrophy and extracellular matrix production
and deposition in myocardial tissue of rats.
 Mediated by matrix metalloproteinase, extracellular matrix
remodelling may be involved in progressive LV remodelling,
dilatation, and heart failure#.
 In a healthy Indo-Asian population, plasma
metalloproteinase levels were inversely related to vitamin D
status^.Furthermore, after 1 year treatment with vitamin D,
mean plasma metalloproteinase levels were decreased
significantly.
*Covic A et al,
Nephron Clin Pract
2010;116:c187–
c195.
#Artaza JN et
al.Am Soc Nephrol
2009;4:1515–1522.
^Timms PM et al.
QJM 2002;95:787–
796

Cardiac myocytes express the vitamin D receptor (VDR)
and 1-hydroxylase and 24-hydroxylase, the enzymes
required for the conversion of 1,25-dihydroxyvitamin D
[1,25(OH)2D] from 25(OH)D and its subsequent
breakdown. Treatment with 1,25(OH)2D leads to
increased expression and nuclear localization of the VDR,
increased expression of myotrophin, and decreased
expression of atrial natriuretic peptide, c-myc and
human B-type natriuretic peptide#.
The induction of myocyte hypertrophy either in vitro or
in vivo leads to an increase in VDR mRNA and protein
levels, suggesting that the vitamin D system may act as
an antihypertrophic system in cardiac muscle.
A strong inverse correlation has been observed between
circulating 1,25(OH)2D levels and plasma renin activity in
patients with essential hypertension^.
#Chen S et al.
Hypertension 2008;
52:1106–1112.
^Resnick LM et al,
Ann Intern Med 1986;
105:649–654

Association of Vitamin D Deficiency withHeart Failure and Sudden Cardiac Death
Stefan Pilz et al. J
Clin Endocrinol
Metab, October
2008,
93(10):3927–3935
 Vit D levels were negatively correlated with Nt-proBNP and were inversely associated with
higher NYHA classes and impaired left ventricular function.
 During a median follow-up time of 7.7 yr, low levels of vit D were a significant risk factor for
mortality due to heart failure and for SCDs.
After adjustment for cardiovascular risk factors, the hazard ratios (with 95% CI) for death due
to heart failure and for SCD were 2.84 (1.20 – 6.74) and 5.05 (2.13–11.97), respectively, when
comparing patients with severe vitamin D deficiency [25(OH)D 25 nmol/liter (10 ng/ml)] with
persons in the optimal range [25(OH)D 75 nmol/liter (30 ng/ml)].
 individuals with low vitamin D levels were about three times more likely to die of heart failure
and five times more likely to die of sudden cardiac death, compared with individuals with
25(OH)D levels of at least 75 nmol/liter (30 ng/ml).
 The risk for the combined endpoint of death due to heart failure and sudden cardiac death was
higher in patients without CAD than those with CAD, suggesting a closer relationship between
vitamin D deficiency and nonischemic diseases than with ischemic heart disease.

Vitamin D has also been shown to reduce the activation
of the systemic and cardiac renin-angiotensin system,
which contributes to hypertension and cardiac
hypertrophy in animal studies.
In a double-blind, randomised, placebo controlled trial,
1,25(OH)2D may be cardioprotective by its
antiinflammatory Effects in heart failure patients *.
Myocardial calcium homeostasis, which is crucial for the
contractility and electrophysiology of the heart, is also
partially regulated by 1,25(OH)2D, mediated by its
influence on ion channels and enzymatic reactions. #
The precise mechanisms remain to be clarified further,
but it appears that sufficient vitamin D status is
important to prevent myocardial hypercontractility and
to maintain diastolic function.
* Schleithoff SS et al.
Am J Clin Nutr 2006;
83:754–759.
# Green JJ et al. C. J
Mol Cell Cardiol 2006;
41:350–359

Kim DH et al,
Prevalence
of hypovitaminosis D in
cardiovascular diseases
(from the
National Health and
Nutrition Examination
Survey 2001 to 2004).
Am J Cardiol 2008;
102:1540–1544
The NHANES III database clearly shows:
 an increase in adjusted all-cause mortality
as the serum 25OHD level falls to less than
30 ng/ml, especially in women; and
 peak protection from death with a 25OHD
level in the 35–40 ng/ml range.
 Most of the increase in all-cause mortality
can be attributed to cardiovascular disease
deaths in this population.
 The prevalence of coronary artery disease,
heart failure, and peripheral artery disease
is significantly increased in a stepwise
fashion as the serum 25OHD level drops to
less than 30 and then 20 ng/ml.
Vit D & All-cause and cardiovascularMortality

 Thus, a significant inverse association between
vitamin D status and all-cause mortality.
The mechanisms by which vitamin D could decrease
all-cause mortality are not clear, but it has been
suggested that vitamin D could reduce aggressiveness
of cancerous processes and expansion of
atheromatous lesions.
Melamed et al. found significant associations
between vitamin D status and CVD mortality.#
Wang et al. found an inverse association between
vitamin D status and incident CVD in participants
with
Hypertension. *
Hosseinpanah et al. found an inverse association
between vitamin D status and CVD in a nested case–
control study.**
#M.L. Melamed et
al. Arch. Intern.
Med. 168, 1629–
1637 (2008)
*T.J. Wang et al.
Circulation 117,
503–511 (2008)
**F. Hosseinpanah et
al, Atherosclerosis
218, 238–242
(2011)

Vit D & Metabolic Syndrome
 After adjustments for known risk factors, odd of metabolic
syndrome decreased progressively across increasing
concentrations of 25(OH)D
 Relative risk compared with bottom quintile of vitamin D
level:
 2nd quintile – 0.85
 3rd quintile – 0.75
 4th quintile – 0.62
 5th quintile – 0.46
Ford, et al.,
2005

Kim DH et al,
Prevalence of
hypovitaminosis D in
cardiovascular diseases
(from the National
Health and Nutrition
Examination Survey
2001 to 2004).
Am J Cardiol 2008;
102:1540–1544
striking inverse correlation of the25OHDlevel to all components of
metabolic syndrome:

 the only age-adjusted trend in the NHANES
population that matches the magnitude of the rate of
decrease in the serum 25OHD level over time is the rate
of increase in the BMI in that period (National Center
for Health Statistics, 2009).
YetleyEA et al.
Am J Clin Nutr
2008; 88:558S–
564S

Hye Yin Park et
al. J Korean
Med Sci 2012;
27: 653-660
Inverse association was demonstrated between serum OHVD levels and
insulin resistance(P = 0.004), triglyceride (P = 0.023) and blood pressure
(systolic blood pressure: P = 0.002; diastolic blood pressure: P < 0.001).
Vitamin D deficiency was found to increase risk of
‘hypertriglyceridemia’ category of metabolic syndrome (odds ratio: 1.73, 95%
confidence interval: 1.13-2.66).

Link between vit D and Metabolic syndrome– Vit D: Fat axis
???
low 25OHD levels observed in association with obesity
may be due to:
1) the increased volume of distribution of lipid soluble
vitamin D, to fat as it leaves the general circulation
after being synthesized in the skin or obtained through
the diet; and
2) preferential retention of vitamin D in those fat
stores. *
*de Luis DA et al.
Ann Nutr Metab
2008. 53:234–
239
#Matsunuma A et
al, Arch Biochem
Biophys 2007.
463:118–127
linking of low serum 25D levels and
secondary hyper-parathyroidism with 1,25D
driven fat accumulation amplifying the
state of vitamin D depletion, while at the
same time generating an increase in the
serum leptin concentration, which exerts
feedback inhibition on the synthesis of
1,25D. #

Animal studies indicate that:
1) vitamin D deficiency, in and of itself,
increases body weight (Hewison, M.,
unpublished data);
2) null mutations in the VDR or the CYP27B1-
hydroxylase have the opposite effect to
prevent abdominal fat mass accumulation
and weight gain in mice.
3) It is hypothesized that this increase in body
fat mass acts in a “feed-forward” fashion to
further increase the volume of distribution
for vitaminD, deepen the state of vitamin D
deficiency, and amplify the consequences of
secondary hyperparathyroidism on the
skeleton and body fat.
Wong KE et al,
Am J Physiol
Endocrinol
Metab 2009.
296:E820–E828

Potential Mechanisms for CV Toxicity &
Vit D Deficiency
Vitamin D Deficiency
↑ PTH
↑ Inflammation
↑ Atherosclerosis
↑ CVD
Insulin Resistance
+
Beta Cell Dysfunction
Diabetes &
Metabolic Syndrome
↑ RAAS
HTN /
Hypertrophy

Trials of Vit D
Supplementation

treatment of hemodialysis patients
with activated vitaminD(calcitriol), was associated with
regression of cardiac hypertrophy and a reduction of QTc
dispersion, a risk factor for sudden cardiac death;
these changes were not seen in a similar group of
untreated patients *
*Kim HW et al.
Nephron Clin
Pract 2006;
102:c21–c29

 A Double-blind, parallel group, placebo-controlled randomized trial,
 where a single large dose of oral vitamin D2 was administered to
patients with Type 2 diabetes and vitamin D insufficiency.
 Vitamin D supplementation increased 25-hydroxyvitamin D levels by
15.3 nmol/l relative to placebo and
 significantly improved endothelial function by improving flow
mediated vasodilatation (FMD) of the brachial artery by 2.3%.
 The improvement in FMD remained significant after adjusting for
changes in blood pressure.
 Vitamin D supplementation significantly decreased systolic blood
pressure by 14 mmHg compared with placebo; this did not correlate with
change in FMD.
Sugden JA et al.
Diabet Med 2008
Mar;25(3):320-5

Tarcin O et al. J
Clin Endocrinol
Metab.2009
Oct;94(10):4023-
30
 25(OH)D deficiency is associated with endothelial dysfunction and
increased lipid peroxidation. Vitamin D deficiency can be seen as an
independent risk factor of atherosclerosis.
 Replacement of vitamin D has favorable effects on endothelial function
 endothelial function by brachial artery flow mediated
dilatation measurements were significantly lower in 25(OH)D-deficient
subjects than controls (P = 0.001)
 and improved after replacement therapy (P = 0.002).
 Posttreatment values of TBARS (thiobarbituric acid reactive substances) as
measures of lipid peroxidation were significantly lower than pretreatment
levels (P < 0.001).
 There was a significant increase in leptin levels after therapy, and the leptin
levels were positively correlated with 25(OH)D levels (r = 0.45; P < 0.05).

Qi Sun et al. Am J
Clin Nutr
2011;94:534–42
 Prospective study
 In the Nurses’ Health Study (1984–2006) and the Health
Professionals Follow-Up Study (1986–2006)—consisting of 74,272 women and
44,592 men, respectively, who were free of CVD and cancer at baseline—were
prospectively examined, to assess the association between vitamin D intake and
incident CVD.
 Over a total of 2,280,324 person-years of follow-up, identiﬁed 9886 incident cases of
coronary heart disease and stroke.
 the relative risks (95% CIs) for a comparison of participants who met the Dietary
Reference Intake of vitamin D (600 IU/d) with participants whose vitamin D intake
was ,100 IU/d were 0.84 (0.72, 0.97; P for trend = 0.009) for men and 1.02 (0.89, 1.17; P
for trend = 0.12) for women
 These observations suggest that a higher intake of vitamin D is associated with a
lower risk of CVD in men but not in women

vitamin D supplementation with no effect on
CVD.
In the Women’s Health Initiative, there was
no effect of vitamin D and calcium
supplementation on coronary or
cerebrovascular risk in postmenopausal
women over a 7-year use period.#
Likewise, Trivedi et al. found no significant
effect of vitamin D supplementation on CVD
or total mortality after 5 years of follow-up
in a randomised double blind trial. *
#J. Hsia et al.
Circulation 115,
846–854 (2007)
*D.P. Trivedi et al.
BMJ 326, 469
(2003)

 RCT of vitamin D + calcium vs. placebo + calcium x 9 months
in subjects with CHF
 93 subjects completed study
 Anti-inflammatory cytokine interleukin 10 significantly higher
 Suppressed release of TNF-α
 No difference in survival but blood levels not optimized
Schleithoff,
et al., 2006

Vitamin D & Statin Myopathy
20 30 40 50 60 70
Distribution
Density
25-(OH) D ng/mL
80 90
ASym = 493 (34.2 +/- 13.8 ng/mL
Myalgia n = 128 (vit D=28.6 +/- 13.2),
Ahmed et al,
Translational
Research
2009; 153:11-
16
10
621 statin-treated patients, which consisted of 128 patients with myalgia at entry and 493 asymptomatic
patients.
excluded subjects who took corticosteroids or supplemental vitamin D.
P < 0.0001

At FU n Initial Vit D (ng/mL) FU Vit D Level (ng/mL) P value
Asymptomatic 35 20 +/- 7 48 +/- 17 <.0001
Myalgia 3 20 +/- 8 49 +/- 30 - - -
All 38 20 +/-7 48 +/-18 <.0001
Of the 82 vitamin-D-deficient, myalgic patients, while continuing
statins, 38 were given vitamin D (50,000 units/week for 12 weeks),
with a resultant increase in serum vitamin D from 20.4 +/- 7.3 to 48.2
+/- 17.9 ng/mL (P < 0.0001) and resolution of myalgia in 35 (92%).
Ahmed et al,
Translational
Research
2009; 153:11-
16

Although cause-and-effect data from human studies are still lacking, there is sound rationale for avoiding
vitamin D depletion.
Before vit D supplementation, establish degree of secondary hyperparathyroidism if present, and second, rule
out underlying hypercalcemia, hypercalciuria, and primary hyperparathyroidism.
Replacement: Oral vit D 50,000 IU / wk for 6 -8 wks.
Maintainance: 800 IU / day (100 µg / day)
The serum 25OHD is monitored annually to ensure sufficiency.
The serum iPTH is also redetermined at this interval to ensure that it has not increased from baseline, which
may be indicative of coexistent primary hyper-parathyroidism, a not uncommon occurrence.
If the 25OHD does not normalize at the 10- to 12-wk mark, the replacement and monitoring regimen is
repeated. If the serum 25OHD is still subnormal after two rounds of vitamin D replacement and compliance
with the treatment regimen is documented, then a search for and treatment of intestinal fat malabsorption is
undertaken.
RDA of vit D: 0 – 50 yrs : 5 µg / day
50 – 70 yrs: 10 µg / day
> 70 yrs : 15 µg / day

 Vit D levels correlate with CV Disease
 Supplementation possibly may improve CV Outcomes
but trials are needed
 Vit D levels should be obtained in CV patients and
supplementation considered, especially if treated
with Statins
To Summarize:

Vitamin D and heart disease

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