Vitamin D and the
Cardiovascular System: Hype
or Hope?
• A Grassroots Health Consortium of
Scientists, Institutions and Individuals
Committed to Solving the Worldwide
Vitamin D Deficiency Epidemic
• Support efforts to “… raise people’s
vitamin D blood levels to the healthy
range of 40-60 ng/ml (100-150
nmol/L) and maintain them in that
range year around.”
“In view of our findings, there is little justification for prescribing
vitamin D supplements to prevent myocardial infarction, or ischaemic
heart disease, cancer, or fractures, or to reduce the risk of death in
unselected community-dwelling individuals.
Bolland MJ et al The effect of vitamin
D supplementation on skeletal, vascular,
or cancer outcomes: a trial sequential
meta-analysis. Lancet Diabetes
Endocrinol 2:307, 2014
“In view of our findings, there is little justification for prescribing
vitamin D supplements to prevent myocardial infarction, or ischaemic
heart disease, cancer, or fractures, or to reduce the risk of death in
unselected community-dwelling individuals. Individuals and funding
bodies should consider the probable futility of undertaking similar trials
of vitamin D to investigate any of these endpoints.”
Bolland MJ et al The effect of vitamin
D supplementation on skeletal, vascular,
or cancer outcomes: a trial sequential
meta-analysis. Lancet Diabetes
Endocrinol 2:307, 2014
Calcium-PTH-Vitamin D Axis
NON-CLASSICAL TARGETS OF
VITAMIN D
Cardiovascular
Cardiac myocytes
Fibroblasts
Endothelial Cells
Vascular Smooth Muscle Cells
Immune
Dendritic Cells
Macrophage
Lymphocytes
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
VDR IN CARDIAC CELLS
DAPI
a actinin
VDR
MERGE
DAPI
vimentin
VDR
MERGE
Myocyte
Fibroblast
Chen, S, Glenn, D et al Hypertension 52: 1106, 2008
VDR IN
CARDIAC
CELLS
Chen, S, Glenn, D et al Hypertension 52: 1106, 2008
VDR IN RAT HEART
Chen, S, Glenn, D et
al Hypertension, 52:
1106, 2008
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
• Vitamin D inhibits hypertrophy and hypertrophydependent gene expression in cultured neonatal rat
myocytes
EFFECT OF VD ON MYOCYTE SIZE
SAMPLE
RELATIVE CELL SIZE
CONTROL
100 +/- 12
VITAMIN D (10-8 M)
98 +/- 8
ENDOTHELIN (10-7 M) 270 +/- 30*
VITAMIN D (10-8 M) + 120 +/- 14**
ENDOTHELIN (10-7 M)
Wu, J. et al JCI 97: 1577, 1996
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
• Vitamin D inhibits hypertrophy and hypertrophydependent gene expression in cultured neonatal rat
myocytes
• VDR activators have been shown to inhibit
hypertrophy in a number of rodent models
EFFECT OF PARICALCITOL ON ANG IIDEPENDENT MYOCYTE HYPERTROPHY
AII+PC
AII
6
LVW/BW (mg/g)
C
C
300
150
100
50
0
C
AII
AII+PC
LVW/BW (mg/g)
)
2
Area (uM
**
##
**
3
2
1
C
6
##
200
4
0
**
250
**
5
AII
**
5
AII+PC
**
4
3
2
1
0
C
AII
AII+PC
Chen S and Gardner DG
J Steroid Biochem Mol Biol 136:150,2013
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
• Vitamin D inhibits hypertrophy and hypertrophydependent gene expression in cultured neonatal rat
myocytes
• VDR activators have been shown to inhibit
hypertrophy in a number of rodent models
• Vitamin D deficiency is associated with
hypertension and cardiac hypertrophy in rats
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
• Vitamin D inhibits hypertrophy and hypertrophydependent gene expression in cultured neonatal rat
myocytes
• VDR activators have been shown to inhibit
hypertrophy in a number of rodent models
• Vitamin D deficiency is associated with hypertension
and cardiac hypertrophy in rats
• VDR gene deletion in mice leads to hyper-reninemic
hypertension and cardiac hypertrophy
VDR-/- Mice Develop Hypertension
WT (white bars) vs. VDR–/– (black bars)
Li, YC et al, JCI. 2002
Hearts in VDR-/- Mice Are
Hypertrophied
Xiang W et al. AJP. 2005
STRATEGY FOR CARDIAC-SPECIFIC DELETION
loxP
loxP
exon4
FRT
FRT
NeoR
exon5
Germline
Excise NeoR with Flpe
VDRloxP/+
Sox2-Cre
VDRloxP/loxP
VDR+/-
Sox2-Cre
VDR-/-
VDRloxP/- × MLC-Cre
Cardiac-specific VDR deletion
HISTOLOGY OF CONTROL AND CARDIAC SELECTIVE
VDR KO MICE INFUSED WITH ISOPROTERENOL
Control
Control
+ Isoproterenol
Myocyte(-/-)
Myocyte(-/-)
+ Isoproterenol
1.25× Magnification
20× Magnification
Chen S et al Circulation 124: 1838, 2011
CARDIAC MYOCYTE SPECIFIC VDR DELETION
CAUSES CARDIAC HYPERTROPHY
Chen S et al Circulation 124: 1838,
2011
INCREASED MYOCYTE AREA IN CARDIAC
SELECTIVE VDR GENE KNOCKOUT
Chen S et al
Circulation 124:
1838, 2011
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
• Vitamin D inhibits hypertrophy and hypertrophydependent gene expression in cultured neonatal rat
myocytes
• VDR activators have been shown to inhibit
hypertrophy in a number of rodent models
• Vitamin D deficiency is associated with
hypertension and cardiac hypertrophy in rats
• VDR gene deletion in mice leads to hyper-reninemic
hypertension and cardiac hypertrophy
• Cardiac myocyte-specific deletion of the VDR gene
leads to myocyte hypertrophy without cardiac
fibrosis.
VITAMIN D – CLINICAL
EPIDEMIOLOGY
CLINICAL CONDITIONS ASSOCIATED
WITH LOW CIRCULATING 25-OH
VITAMIN D LEVELS
•
•
•
•
•
Hypertension
Ischemic Heart Disease
Myocardial Infarction
Heart Failure
Diabetes Mellitus
RELATIONSHIP OF MEAN BP AND DISTANCE NORTH OR
SOUTH OF THE EQUATOR
Rostand S G Hypertension. 1997;30:150156
Copyright © American Heart Association, Inc. All rights reserved.
PREVALENCE OF HBP AND DISTANCE NORTH OR SOUTH OF
EQUATOR
Rostand S G Hypertension. 1997;30:150-156
Copyright © American Heart Association, Inc. All rights reserved.
BLOOD 25-HYDROXYVITAMIN D CONCENTRATION
AND HYPERTENSION: A META-ANALYSIS
Burgaz A et al J Hypertension 29:636, 2011
© 2011 Lippincott Williams & Wilkins, Inc. Published by Lippincott Williams & Wilkins, Inc.
2
PLASMA 25 OH VITAMIN D LEVELS
RELATED TO INCIDENT HBP
•
•
•
•
Nurses Health Study 2
Nested Case Control Study
Design
1484 Women Aged 32-52
Highest vs. Lowest Quartile Adj
Odds Ratio = 1.66 for Incident
HBP
Forman JP et al Hypertension 52:828, 2008.
NHANES 2001-04: PREVALENCE OF
HYPOVITAMINOSIS D IN CV DISEASE
Kim DH et al Am J Cardiol 102:1540, 2008
25-Hydroxyvitamin D and Symptomatic
Ischemic Stroke
• Danish general population –
Copenhagen City Heart Study
• 10,170 subjects
• Followed 21 years
Brondum-Jacobsen P, Ann Neurol 73: 38, 2012
VITAMIN D LEVELS ARE LOW
IN CHF
Zittermann A et al JACC 41: 105, 2003
VITAMIN D LEVELS ARE LOW
IN CHF
Zittermann A et al JACC 41: 105, 2003
25 OH Vitamin D Levels Post MI
Lee J et al Am J Card 107: 1636, 2011
25-OH Vitamin D Levels in CHF
• HMO Israel
• Controls n = 46825 vs HF n = 3009
Gotsman I, Euro J Heart Failure
14:357, 2014
VITAMIN D LEVELS CORRELATE
WITH SURVIVAL
Gotsman I, Euro J Heart Failure 14:357, 2014
“The fact that most major organ systems and a wide variety of pathological
processes (infection, inflammation, neoplasia, psychiatric illness, metabolic
disease, developmental abnormalities, and trauma) are implicated makes an
etiologic role for vitamin D in each of them both implausible and without
precedent.
Reid, IR and Bolland MJ. Skeletal
and nonskeletal effects of vitamin D a
tonic for bone and other tissues.
Osteoporos Int, 2014
“The fact that most major organ systems and a wide variety of pathological
processes (infection, inflammation, neoplasia, psychiatric illness, metabolic
disease, developmental abnormalities, and trauma) are implicated makes an
etiologic role for vitamin D in each of them both implausible and without
precedent. Journal editors should consider whether the amount of space
devoted to these studies is justifiable.”
Reid, IR and Bolland MJ. Skeletal
and nonskeletal effects of vitamin D a
tonic for bone and other tissues.
Osteoporos Int, 2014
POTENTIAL RESIDUAL
CONFOUNDERS/QUESTIONS
• CHRONICALLY ILL MAY BE LESS PRONE TO
TAKE VITAMIN D SUPPLEMENTS, TO INGEST A
VITAMIN D RICH DIET OR TO SPEND MUCH
TIME EXPOSED TO THE ULTRAVIOLET
RADIATION OF THE SUN
• WHAT IS THE ROLE OF PARATHYROID
HORMONE IN CONTRIBUTING TO
PATHOGENESIS OF CV DYSFUNCTION?
• WHAT IS THE ROLE OF INFLAMMATION IN
CONTRIBUTING TO LOW VITAMIN D LEVELS?
ROLE OF INFLAMMATION IN
CONTRIBUTING TO LOW 25-OH VITAMIN
D LEVELS
• VITAMIN D LEVELS DROP ACUTELY WITH
ACUTE PANCREATITIS, KNEE REPLACEMENTS
AND CONGESTIVE HEART FAILURE
• LEVELS OF CYTOKINES IN BLOOD TEND TO
CORRELATE INVERSELY WITH VITAMIN D
LEVELS
• RECOVERY STUDIES DEMONSTRATING
INCREASED VITAMIN D LEVELS WITH
RESOLUTION OF INFLAMMATION HAVE NOT
BEEN FORTHCOMING
VITAMIN D –
INTERVENTIONAL STUDIES
KAPLAN-MEIER SURVIVAL CURVES AS A
FUNCTION AND VITAMIN D STATUS AND
SUPPLEMENTATION
• HMO Israel
• Controls n = 46825 vs HF n = 3009
• Survival improved with treatment in VitD<25 group – 4%
higher survival to 518 days in treated group (8001000 IU vit D/day); Hazard Ratio = 0.68
Gotsman I, Euro J Heart Failure 14:357, 2014
EFFECT IF Ca/VITAMIN D SUPPLEMENTS
ON CARDIOVASCULAR EVENTS
MI or Coronary Death
•
•
•
WHI – 36282 post-menopausal women
Ca Carbonate 500 mg + vitamin D 200 IU bid vs. placebo
7 years of followup
Stroke
Hsia J et al Circ 115: 846,
2007
VITAMIN D SUPPLEMENTATION AND
HYPERTENSION: A META-ANALYSIS
Witham MD et al J Hypertens 27: 1948, 2009
VITAMIN D SUPPLEMENTATION AND
HYPERTENSION: A META-ANALYSIS
Pittas AG et al Ann
Int Med 152:307,
2010.
EFFECT OF VITAMIN D REPLETION
ON ALL CAUSE MORTALITY
• 18 Randomized Controlled Trials wih 57,311
participants and 4777 deaths from any
cause
• Daily vitamin D supplemented from 3002000 IU
• Summary RR = 0.93 (0.87-0.99)
Autier P and Gandini S Arch
Intern Med 167: 1730, 2007
VITAMIN D AND CARDIOVASCULAR
OUTCOMES
•
•
51 Randomized Trials
Outcomes: Mortality, MI, CVA
Elamin MB et al JCEM 96: 1931, 2011
DAILY REQUIREMENTS FOR
VITAMIN D INTAKE
Hossein-nezhad A and Holick MF
Mayo Clin Proc 88: 720, 2013.
U-SHAPED CURVE RELATING INCIDENT
CARDIOVASCULAR DISEASE TO VITAMIN D
LEVELS
Wang, TJ et al
Circ 117:503,
2008
U-SHAPED CURVE RELATING ADJUSTED
ALL-CAUSE MORTALITY TO VITAMIN D
LEVELS
Melamed ML et al Arch Int Med 168: 1629,
2008
VITAMIN D
SUPPLEMETATION TRIALS
SUMMARY AND
RECOMMENDATIONS
•
•
•
•
•
•
Abundance of pre-clinical data indicating that vitamin D exerts
potentially beneficial effects in CV system
A variety of CV diseases are associated with low circulating 25 OH
vitamin D levels –non-specific?
Interventional studies have failed to demonstrate a clearcut benefit
of normalizing 25 OH vitamin D levels
One can make a reasonable argument for repleting vitamin D levels
to support skeletal health (25 OH vitamin D > 20 ng/ml) – there is,
as yet, no compelling evidence to increase levels further to support
cardiovascular health
Recommendations from the IOM and TES provide a reasonable
framework for providing supplementation
Final recommendations will ultimately depend on the outcomes from
clinical trials which are now in progress
QUESTIONS?
Figure 2. Kaplan-Meier estimates of cumulative hazard rates for CHD (myocardial infarction or
coronary death; left) and for stroke (right).
Hsia J et al. Circulation. 2007;115:846-854
Copyright © American Heart Association, Inc. All rights reserved.
Figure 2 Prevalence and adjusted ORs of hypovitaminosis D in subjects with various CVDs in NHANES 2001 to 2004.
*Hypovitaminosis D defined as serum 25(OH)D &lt;30 ng/ml (&lt;75 nmol/L); peripheral arterial disease was not included because
ankle-brachial in...
Dae Hyun Kim , Siamak Sabour , Utpal N. Sagar , Suzanne Adams , David J. Whellan
Prevalence of Hypovitaminosis D in Cardiovascular Diseases (from the National Health and Nutrition Examination Survey
2001 to 2004)
The American Journal of Cardiology, Volume 102, Issue 11, 2008, 1540 - 1544
http://dx.doi.org/10.1016/j.amjcard.2008.06.067
Wasson and shimbo
EFFECT OF VD ON PROTEIN
SYNTHESIS IN MYOCYTES
Wu, J. et al JCI 97: 1577, 1996
Cardiac Myocyte Selective VDR Knockout Mice
Display Significantly Lower VDR mRNA Levels
ABSENCE OF FIBROSIS IN MYOCYTE
SELECTIVE VDR GENE KNOCKOUT
ECHOCARDIOGRAPHY OF
CARDIAC-SELECTIVE VDR GENE
KNOCKOUT MICE
VITAMIN D AND THE HEART
AND VASCULATURE
• Vitamin D receptors present in both myocytes and
fibroblasts in the heart
• Vitamin D inhibits hypertrophy and hypertrophydependent gene expression in cultured neonatal rat
myocytes
• VDR activators have been shown to inhibit
hypertrophy in a number of rodent models
• Vitamin D deficiency is associated with
hypertension and cardiac hypertrophy in rats
• VDR gene deletion in mice leads to hyper-reninemic
hypertension and cardiac hypertrophy
Pittas
EFFECT OF CARDIAC SELECTIVE VDR KNOCKOUT
ON ANP AND SKELETAL ACTIN EXPRESSION
Chen S et al Circulation
124: 1838, 2011
PUTATIVE MECHANISMS LINKING VITAMIN D
DEFICIENCY TO CARDIOVASCULAR EVENTS
ASSOCIATION BETWEEN PTH LEVELS AND
CARDIOVASCULAR MORTALITY
Hagström E et al. Circulation.
2009;119:2765-2771
Copyright © American Heart Association, Inc. All rights reserved.
CUMULATIVE INCIDENCE OF ISCHEMIC HEART
DISEASE AS A FUNCTION OF VITAMIN D LEVELS
WOMEN’S HEALTH
INITIATIVE
36,282 POST-MENOPAUSAL WOMEN
INTERVENTION = Ca + VIT D SUPPLEMENT
FOLLOWED 7 YEARS WITH INTERVENTION +
4.9 YEARS POST-INTERVENTION
Cauley, J et al J Women’s Health 22:915, 2013
U-SHAPED CURVE RELATING ADJUSTED ALLCAUSE MORTALITY TO VITAMIN D LEVELS
Melamed ML et al Arch Int
Med 168: 1629, 2008