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Plasma 25-Hydroxyvitamin D and Mortality in Patients With Suspected Stable Angina Pectoris

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Context and objective Vitamin D status may affect cardiovascular disease (CVD) development and survival. We studied the relationship between concentrations of the circulating biomarker 25-hydroxyvitamin D (25OHD) and all-cause and cardiovascular mortality risk. Design, Setting, Participants and main Outcome Measures 25OHD, the sum of 25-hydroxyvitamin D3 and 25-hydroxyvitamin D2, was analysed in plasma samples from 4114 Caucasian patients with suspected stable angina pectoris, and adjusted for seasonal variation. Hazard ratios (HR) for all-cause and cardiovascular mortality were estimated using multivariable Cox models with 25OHD as main exposure variable, while adjusting for study site, age, gender, smoking, body mass index, estimated glomerular filtration rate, and systolic blood pressure. Results A total of 895 (21.8%) deaths including 407 (9.9%) from CVD causes occurred during a mean±SD follow-up of 11.9±3.0 years. Compared to the first quartile, HRs in the second, third and fourth 25OHD quartiles were 0.64 (0.54, 0.77), 0.56 (0.46, 0.67) and 0.56 (0.46, 0.67) for all-cause mortality and 0.70 (0.53, 0.91), 0.60 (0.45, 0.79) and 0.57 (0.43, 0.75) for cardiovascular mortality, respectively. Threshold analysis demonstrated increased all-cause and CVD mortality in patients with 25OHD concentrations below ∼42.5 nmol/l. Moreover, analysis suggested increased all-cause mortality at concentrations above 100 nmol/l. Conclusion Plasma 25OHD concentrations were inversely associated with cardiovascular mortality and non-linearly (U-shaped) associated with all-cause mortality.
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CLINICAL RESEARCH ARTICLE
Plasma 25-Hydroxyvitamin D and Mortality in Patients
With Suspected Stable Angina Pectoris
Eirik Degerud,
1
Ottar Nyg ˚ard,
2,3
Stefan de Vogel,
4
Rune Hoff,
5
Gard Frodahl Tveitev ˚ag Svingen,
2,3
Eva Ringdal Pedersen,
2,3
Dennis Winston Trygve Nilsen,
2,6
Jan Erik Nordrehaug,
2,3
Øivind Midttun,
7
Per Magne Ueland,
2,8
and Jutta Dierkes
1
1
Department of Clinical Medicine, University of Bergen, 5021 Bergen, Norway;
2
Department of Clinical
Science, University of Bergen, 5021 Bergen, Norway;
3
Department of Heart Disease, Haukeland University
Hospital, 5021 Bergen, Norway;
4
Department of Global Public Health and Primary Care, University of Bergen,
5018 Bergen, Norway;
5
Institute of Basic Medical Sciences, University of Oslo, 0372 Oslo, Norway;
6
Department of Cardiology, Stavanger University Hospital, 4069 Stavanger, Norway.;
7
Bevital AS, 5021,
Bergen,Norway; and
8
Laboratory of Clinical Biochemistry, Haukeland University Hospital,5021 Bergen, Norway
Context and Objective: Vitamin D status may affect cardiovascular disease (CVD) development
and survival. We studied the relationship between concentrations of the circulating biomarker
25-hydroxyvitamin D (25OHD) and all-cause and cardiovascular mortality risk.
Design, Setting, Participants, and Main Outcome Measures: 25OHD, the sum of 25-hydroxyvitamin
D3 and 25-hydroxyvitamin D2, was analyzed in plasma samples from 4114 white patients suspected
of having stable angina pectoris and was adjusted for seasonal variation. Hazard ratios (HRs) for all-
cause and cardiovascular mortality were estimated by using multivariable Cox models with 25OHD
as the main exposure variable, with adjustment for study site, age, sex, smoking, body mass index,
estimated glomerular filtration rate, and systolic blood pressure.
Results: A total of 895 (21.8%) deaths, including 407 (9.9%) from CVD causes, occurred during a
mean 6standard deviation follow-up of 11.9 63.0 years. Compared with the first 25OHD quartile,
HRs in the second, third, and fourth quartiles were 0.64 [95% confidence interval (CI), 0.54 to 0.77],
0.56 (95% CI, 0.46 to 0.67), and 0.56 (95% CI, 0.46 to 0.67) for all-cause mortality and 0.70 (95% CI,
0.53 to 0.91), 0.60 (95% CI, 0.45 to 0.79), and 0.57 (95% CI, 0.43 to 0.75) for cardiovascular mortality,
respectively. Threshold analysis demonstrated increased all-cause and CVD mortality in patients
with 25OHD concentrations below ;42.5 nmol/L. Moreover, analysis suggested increased all-cause
mortality at concentrations .100 nmol/L.
Conclusion: Plasma 25OHD concentrations were inversely associated with cardiovascular mortality
and nonlinearly (U-shaped) associated with all-cause mortality. (J Clin Endocrinol Metab 103:
11611170, 2018)
Plasma 25-hydroxyvitamin D (25OHD) is an in-
termediate metabolite in the conversion of acquired
and stored vitamin D to the active metabolite calcitriol. A
plasma concentration above 50 nmol/L is the target level
for dietary intake recommendations of vitamin D in
several countries (1, 2), based on differentiation between
optimal and suboptimal skeletal health (1).
Vitamin D activity is implicated in the etiology of
noncommunicable diseases (3), including cardiovascu-
lar diseases (CVDs), where calcitriol may regulate gene
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in USA
Copyright © 2018 Endocrine Society
This article has been published under the terms of the Creative Commons Attribution
License (CC BY; https://creativecommons.org/licenses/by/4.0/).
Received 23 October 2017. Accepted 4 January 2018.
First Published Online 8 January 2018
Abbreviations: 25OHD, 25-hydroxyvitamin D; CAD, coronary artery disease; CI,
confidence interval; CRP, C-reactive protein; CVD, cardiovascular disease; eGFR, esti-
mated glomerular filtration rate; HR, hazard ratio; ICD-10, International Classification of
Diseases, 10th revision; LURIC, Ludwigshafen Risk and Cardiovascular Health; SAP, stable
angina pectoris; SD, standard deviation; WENBIT, Western Norway B-Vitamin
Intervention Trial.
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expression in cells involved in atherosclerosis (4, 5).
Reduced vitamin D activity, as a result of dietary de-
ficiency (6), metabolic dysfunction (7), or reduced
availability of the vitamin D receptor (8), causes the
development of unfavorable cardiovascular phenotypes
in mice. These mechanistic studies demonstrate that
vitamin D activity is required for cardiovascular health,
which raises the question of whether physiologic vari-
ation in vitamin D status in humans may be implicated in
the etiology or progression of CVDs.
Meta-analyses of prospective observational studies
among predominantly healthy participants have in-
dicated an inverse relationship between 25OHD levels
and CVD mortality (9, 10). However, this relation is not
observed when genetic variants are used as instrumental
variables for 25OHD concentration (1114), and pub-
lished randomized controlled trials have not detected any
effect of vitamin D supplementation on incident CVD
(15, 16). Moreover, some prospective observational
studies reported that a very high vitamin D status could
be detrimental to CVD or all-cause mortality (1719).
In contrast to studies among healthy persons, pro-
spective observational studies in patients with stable CVD
have reported inconsistent results for the association
between 25OHD and the risk for CVD events (2022).
Additional studies could help determine whether the
association is similar or differs between patients with
CVD and healthy individuals. This is relevant to the
extent to which results from ongoing clinical trials in
healthy individuals may be generalized to patients. In the
current study, we contribute with data on the relationship
between circulating 25OHD concentration and the risk
for all-cause and CVD mortality in 4114 patients suspected
of having stable angina pectoris (SAP). An additional
objective was to identify potential threshold concentra-
tions associated with mortality, and stratified analyses
were conducted to assess for differences in groups of
statin treatment, disease status, and smoking status.
Patients and Methods
Study population
We used prospective observational data from 4164 adult and
mostly white patients who underwent elective coronary angi-
ography for suspicion of SAP at two university hospitals
(Haukeland University Hospital and Stavanger University
Hospital) in Norway (situated at 59 to 60 degrees North) (23).
Recruitment started 14 April 1999 and ended 26 April 2004.
We excluded 50 patients because of missing data and thus
included 4114 patients in the final statistical analyses. Of these
patients, 62% were also participants in the Western Norway
B-Vitamin Intervention Trial (WENBIT; ClinicalTrials.gov
identifier: NCT00354081) (24). WENBIT was a randomized
trial aiming to study the effects of folic acid + vitamin B12 and/
or vitamin B6 vs placebo on CVD and mortality outcomes,
with a median follow-up period of 38 months. The studies were
conducted according to the principles of the Declaration of
Helsinki and approved by the Regional Committee for Medical
and Health Research Ethics and the Norwegian Data Protection
Authority. Participants gave written informed consent.
Baseline data and biochemical analyses
Self-administered questionnaires provided information on
medical history, CVD risk factors, and medication. The data
were validated against medical records when available. Ques-
tionnaires also asked about vitamin D supplement consumption
and leisure time physical activity levels. Measurements of blood
pressure, anthropometry, and blood sampling were conducted
by trained study personnel. At Haukeland University Hospital,
nonfasting blood samples were drawn before angiography. At
Stavanger University Hospital, samples were taken from fasting
patients in conjunction with the angiographic procedure. Par-
ticipants who reported that they were current smokers or in-
dicated that they have quit smoking #90 days before blood
sampling, or those who had a measured plasma cotinine
concentration $85nmol/L, were defined as smokers. Plasma
cotinine was measured by liquid chromatography tandem mass
spectrometry (25) at Bevital AS (Bergen, Norway). In addition,
information was collected on the angiographic extent of clini-
cally significant ($50% diameter stenosis) coronary artery
disease (CAD), measurement of left ventricular ejection frac-
tion, C-reactive protein (CRP), apolipoprotein A1, and apoli-
poprotein B 100, as described previously (23). Estimated
glomerular filtration rate (eGFR) was calculated with the for-
mula suggested by the Chronic Kidney DiseaseEpidemiology
Collaboration (26). Diabetes mellitus was defined as a pre-
existing diagnosis of type 1 or 2 diabetes. Plasma 25OHD2
and 25OHD3 concentrations were analyzed by using liquid
chromatography tandem mass spectrometry (27) at Bevital AS.
25OHD2 and 25OHD3 values below the lower limit of
quantification (6.6 nmol/L) were set to zero.
Follow-up and endpoints
Participants were followed until death or through 1 January
2013. Endpoints were defined according to the International
Classification of Diseases, 10th revision (ICD-10), and CVD
death included deaths ascribed to ICD-10 codes I00 and I99 in
addition to R96. Information on cause of death was obtained from
the Cause of Death Registry at Statistics Norway by linkage using
each patients unique personal identification number.
Statistical analyses
Each patients measured value of plasma 25OHD3 was
adjusted for the seasonal variation in the study sample by
using a cosinor model (28). The concentrations of 25OHD2 and
seasonally adjusted 25OHD3 were then summed to reflect total
25OHD. Baseline characteristics are presented as mean 6
standard deviation (SD) for continuous variables and numbers
(percentages) for categorical variables. Characteristics were
assessed and compared across plasma 25OHD quartiles by
linear regression for continuous variables and logistic regression
for categorical variables. Survival curves for all-cause and CVD
mortality according to 25OHD were calculated with the
Kaplan-Meier estimator and differences assessed by log-rank
testing. Hazard ratios (HRs) with 95% confidence intervals
(CIs) were assessed by using Cox proportional hazard models,
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and the assumption of proportional hazards was assessed by
checking the Schoenfeld residuals. Covariates in multivariable
models included study site, age, sex, smoking, body mass index,
systolic blood pressure, and eGFR.
The risk for all-cause and CVD mortality was first assessed
by modeling 25OHD as quartiles and thereafter as a continuous
variable per 10-nmol/L incremental increase of 25OHD. We
then visualized the association of 25OHD by adding penalized
smoothing splines to the multivariable Cox model. The re-
lationships were subsequently analyzed for possible thresholds.
Following steps described previously (29), we considered values
of 25OHD between 15 and 150 nmol/L with increments of 0.01
as a series of cutoff values that could be used to identify potential
thresholds. For all cutoff values, we created a dichotomous
exposure variable and included it in a Cox model while
adjusting for aforementioned covariates. We then extracted
Wald statistics for each model, which is closer to null when the
relationship between all explanatory variables and the outcome
is weaker and increases when the relationship is stronger. The
cutoff value of 25OHD resulting in the model with the highest
Wald statistic was considered as a potential threshold because it
provides the most optimal separation of participants with high
and low risk for the outcome (30). In addition, potential
thresholds were considered from a combined interpretation of
both the Wald statistics and the exposure-outcome relationship.
Furthermore, we used the potential thresholds to categorize
participants according to low, medium, and high 25OHD
concentration. These categories were subsequently described
and compared in terms of baseline characteristics, survival
curves, and HRs.
We also assessed the risk for all-cause and CVD mortality by
using threshold-derived categories of 25OHD concentrations in
subgroups of sex, smoking status, CAD, diabetes, chronic
kidney disease (eGFR #60 mL/min per 1.73 m
2
), statin treat-
ment, and WENBIT intervention groups receiving combina-
tions of B vitamins or placebo. In this analysis, non-WENBIT
participants were categorized as receiving placebo. To test
whether the risk differed by the subgroups, we tested for effect
modification on a multiplicative scale and present the results as
HRs with 95% CIs and Pvalues. Statistical analyses were
performed by using R statistical software (31). We included
additional analyses as part of the peer review process. The
association between vitamin D supplement use and the risk for
all-cause and CVD mortality were assessed in multivariable
models adjusting for the same covariates as in the analysis of
plasma 25OHD. We also described the participants with de-
tectable 25OHD2 concentrations in more detail to evaluate the
possibility of reverse causation.
Results
Baseline characteristics
Plasma 25OHD ranged from 8.4 to 197 nmol/L,
with a mean 6SD of 59.7 619.2 nmol/L. The distri-
bution of baseline characteristics across plasma 25OHD
quartiles showed a positive relationship with vitamin D
supplementation, physical activity, serum apolipoprotein
A1 concentrations, LVEF, and statin use after the baseline
visit and an inverse relationship with smoking, body mass
index, inflammation (CRP level), diabetes, kidney function
(eGFR), and serum triglyceride concentrations (Table 1).
The proportion of patients taking vitamin D supplements
regularly in each quartile were 20%, 30%, 40%, and 50%,
respectively. The uneven distribution of patients from each
study site indicated higher plasma 25OHD at one study site
(Haukeland University Hospital, Bergen; 60.6 619.8 nmol/L)
in comparison with the other site (Stavanger University
Hospital, Stavanger; 55.5 617.3 nmol/L).
Associations between plasma 25OHD and all-cause
and CVD mortality
Mean 6SD duration of follow-up was 11.9 63.0
years. A total of 895 (21.8%) deaths from all causes and
407 (9.9%) deaths from CVD occurred during follow-up.
In comparison with the lowest quartile, multivariable HRs
(95% CI) in the three upper quartiles of 25OHD concen-
tration were 0.64 (95% CI, 0.54 to 0.77), 0.56 (95% CI,
0.46 to 0.67), and 0.56 (95% CI, 0.46 to 0.67) for all-cause
mortality and 0.70 (95% CI, 0.53 to 0.91), 0.60 (95% CI,
0.45 to 0.79), and 0.57 (95% CI, 0.43 to 0.75) for CVD
mortality, respectively (Table 2). Plasma 25OHD was in-
versely associated with the risk for all-cause and CVD
mortality in multivariable models per 10-nmol/L incre-
mental increase of 25OHD, with HRs of 0.91 (95% CI,
0.88 to 0.95) and 0.90 (95% CI, 0.85 to 0.95), respectively.
Potential thresholds for relationship between
plasma 25OHD and all-cause and CVD mortality
The distribution of plasma 25OHD in the study
sample is shown in Fig. 1A. The exposure-outcome re-
lationships of plasma 25OHD with the risks for all-cause
mortality and CVD mortality are shown in Fig. 1B and
1C, respectively, and suggest nonlinear relationships.
Potential thresholds were identified at 42.5 nmol/L for
all-cause mortality (Fig. 1D) and at 40.9 nmol/L for CVD
mortality (Fig. 1E). A second potential threshold for both
endpoints at 100 nmol/L was indicated by the nonlinear
risk curves and threshold analyses.
Because the potential thresholds for all-cause and CVD
mortality were similar, we chose to categorize the patients
only according to the thresholds for all-cause mortality,
including low (,42.5 nmol/L; n = 779), medium (42.5 to
100 nmol/L; n = 3214), and high (.100nmol/L;n=121)
25OHD concentrations. Cross-sectional differences in
baseline characteristics according to these categories were
similar to the differences between quartiles (Supplemental
Table 1). Kaplan-Meier survival curves for all-cause and
CVD mortality are shown for participants with low,
medium, and high concentrations of 25OHD (Fig. 2). Log-
rank test indicated a difference in survival between the
groups for both endpoints (P,0.001). In comparison
with individuals with medium 25OHD concentrations,
multivariable HRs for all-cause and CVD mortality were
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1.94 (95% CI, 1.66 to 2.27) and 1.87 (95% CI, 1.49 to
2.36) among those with low concentrations and 1.79 (95%
CI, 1.31 to 2.46) and 1.44 (95% CI, 0.87 to 2.37) among
those with high concentrations, respectively (Table 3).
Subgroup analyses
The excess risk for all-cause and CVD mortality as-
sociated with plasma 25OHD ,42.5 nmol/L did not vary
substantially in subgroups of sex, smoking status, extent
of CAD, diabetes, kidney function, statin treatment, or
WENBIT study treatment, but trends toward differences
were observed for plasma 25OHD .100 nmol/L (Sup-
plemental Tables 2 and 3). The excess risk for all-cause
mortality for patients with 25OHD .100 nmol/L appeared
to be confined to patients with CAD and to statin users
(79% with CAD and 53% without CAD use statins),
whereas the excess risk for CVD mortality was confined
to statin users and participants without chronic kidney
Table 1. Descriptive Characteristics (n = 4114) According to Quartiles of Plasma 25OHD
Characteristic
Plasma 25OHD Quartiles
PValue for Trend1st (n = 1029) 2nd (n = 1028) 3rd (n = 1028) 4th (n = 1029)
25OHD (range) (nmol/L) 36.7 (8.446.2) 52.2 (46.358.1) 64.4 (58.171.4) 85.2 (71.4197)
Study site Bergen, n (%) 786 (76.4) 828 (80.5) 848 (82.5) 905 (88.0) ,0.001
Age (y) 60.0 611.0 61.8 610.4 62.3 610.3 62.9 69.7 ,0.001
Male sex, n (%) 706 (68.6) 737 (71.7) 767 (74.6) 749 (72.8) 0.014
Current smoker, n (%) 406 (39.5) 317 (30.8) 283 (27.5) 296 (28.8) ,0.001
Body mass index (kg/m
2
) 27.5 64.6 27.2 64.1 26.5 63.6 25.9 63.4 ,0.001
C-reactive protein (mg/L) 4.6 68.6 3.4 65.5 3.4 67.0 3.4 67.3 ,0.001
Physically active, n (%) 429 (59.4) 493 (65.5) 588 (73.3) 625 (76.0) ,0.001
Vitamin D supplements, n (%) 175 (20.0) 267 (30.0) 371 (40.5) 459 (50.2) ,0.001
Diabetes mellitus, n (%) 145 (14.1) 127 (12.4) 112 (10.9) 106 (10.3) 0.005
Hypertension, n (%) 488 (47.4) 475 (46.2) 470 (45.7) 494 (48.0) 0.856
Systolic blood pressure (mm Hg) 140 621 141 622 142 621 142 620 0.010
eGFR (mL/min per 1.73 m
2
)91617 88 617 87 616 85 618 ,0.001
Serum triglycerides (mmol/L) 1.98 61.69 1.81 61.01 1.67 60.96 1.66 61.03 ,0.001
Serum apolipoprotein B100 (g/L) 0.91 60.27 0.90 60.24 0.89 60.23 0.90 60.24 0.198
Serum apolipoprotein A1 (g/L) 1.27 60.28 1.30 60.26 1.33 60.27 1.37 60.26 ,0.001
Extent of coronary artery disease, n (%)
No stenotic vessel 261 (25.5) 252 (24.6) 255 (25.0) 261 (25.5) 0.952
1 stenotic vessel 233 (22.7) 229 (22.3) 235 (23.0) 250 (24.4) 0.339
$2 stenotic vessels 531 (51.8) 544 (53.1) 532 (52.1) 514 (50.1) 0.390
LVEF (%) 62.5 612.2 64.7 611.4 64.2 610.7 64.8 611.0 ,0.001
Statin use before baseline visit, n (%) 736 (71.5) 766 (74.5) 721 (70.1) 758 (73.7) 0.743
Statin use after baseline visit, n (%) 793 (77.1) 843 (82.0) 808 (78.6) 847 (82.3) 0.027
25OHD is the sum of 25-hydroxyvitamin D2 and D3 (nmol/L); "physically active" refers to physical activity for $2 h per week; "vitamin D supplements"
refers to regular use. Unless otherwise noted, values are presented as mean 6SD or number (percentage). Pvalues are unadjusted and derived from linear
and logistic regression as appropriate.
Table 2. Association Between Plasma 25OHD and Risk for All-Cause and CVD Mortality
Outcome
Continuous Plasma 25OHD:
per 10 nmol/L (n = 4114)
Plasma 25OHD Quartiles
1st (n = 1029) 2nd (n = 1028) 3rd (n = 1028) 4th (n = 1029)
All-cause mortality
Events (n) 895 271 217 198 209
Incidence rate 2.21 2.77 2.11 1.93 2.03
HR (95% CI)
Crude 0.96 (0.931.00) 1.00 0.75 (0.630.90) 0.69 (0.570.83) 0.73 (0.610.87)
Multivariable model
a
0.91 (0.880.95) 1.00 0.64 (0.540.77) 0.56 (0.460.67) 0.56 (0.460.67)
CVD mortality
Events, n407 118 103 93 93
Incidence rate 1.01 1.20 1.00 0.91 0.90
HR (95% CI)
Crude 0.95 (0.901.00) 1.00 0.82 (0.631.07) 0.74 (0.570.98) 0.74 (0.570.98)
Multivariable model
a
0.90 (0.850.95) 1.00 0.70 (0.530.91) 0.60 (0.450.79) 0.57 (0.430.75)
25OHD refers to sum of 25-hydroxyvitamin D2 and D3 (nmol/L). Incidence rate is per 100 person-years.
a
Multivariable model (n = 4109) includes study site, age, sex, smoking, body mass index, systolic blood pressure, and eGFR.
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disease. In comparison with patients with no regular
intake of cod liver oil or vitamin D supplements, HRs
among participants with regular intake were 0.92 (95%
CI, 0.79 to 1.07) for all-cause mortality and 0.75 (95%
CI, 0.60 to 0.95) for CVD mortality. The 80 individuals
with detectable levels of 25OHD2 constituted 1%, 2%, and
7% of the groups with low, medium, and high 25OHD
concentrations, respectively, and were collectively more
likely to die during follow-up (35%) than the sample as a
whole (22%).
Discussion
Principal findings
Plasma 25OHD demonstrated an inverse association
with CVD mortality and a nonlinear (U-shaped) association
Figure 1. The analyses were performed among 4114 participants suspected of having SAP. (A) Distribution of 25OHD. (B and C) The functional
relationships in parts B and C were analyzed by adding a penalized smoothing spline function to multivariable Cox models containing study site,
age, sex, smoking, body mass index, systolic blood pressure, and kidney function. (D and E) The stippled lines are suggested risk thresholds
derived from the analyses for potential thresholds, defined as most optimal differentiation of participants into groups with higher and lower risk
for all-cause or CVD mortality, respectively.
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with all-cause mortality. Analyses suggested that a thresh-
old around 42.5 nmol/L may best discriminate between
high- and low-risk groups for both endpoints and that a
threshold of 100 nmol/L might further discriminate between
low and high risk for all-cause mortality.
Previous observational studies
Previous observational studies of the relation between
25OHD and CVD risk were mostly conducted in pop-
ulations without CHD, most of which report inverse
relationships (32, 33); however, a few studies, such as the
large Danish Cop-D study, report nonlinear relationships
(19, 34). Among the studies performed in patients with
CHD, the most comparable to our study is the Ludwigshafen
Risk and Cardiovascular Health (LURIC) study (20),
which included 3258 white German patients referred
to coronary angiography for suspicion of SAP or acute
coronary syndrome. The prevalence of clinically signifi-
cant CAD (68%) at baseline was similar to that in our
study sample (75%). The authors observed an inverse
linear association with all-cause and CVD mortality
across quartiles of 25OHD, with no indications of a
U-shaped pattern when they compared the lowest and
highest 25OHD deciles. A lower mean total 25OHD
concentration (42.4 nmol/L in the LURIC study vs
59.7 nmol/L in the current study) may explain why an
increased risk at high concentrations (.100 nmol/L) was
not observed in the LURIC study. The higher observed
25OHD concentrations in this study may be the result of
high vitamin D supplement use in the sample (35%), as
well as in Norwegians in general, which is mostly in the
form of cod liver oil. When all confounders and potential
mediators were included, neither the German KAROLA
study (n = 1125; median 25OHD of 55 nmol/L) nor the
American Heart and Soul Study (n = 946; mean 25OHD
of 64.5 nmol/L) demonstrated an association with all-
cause or CVD mortality after 8 years of follow-up in
mostly white patients with stable coronary heart disease
Figure 2. Kaplan-Meier estimate of all-cause (left) and CVD (right) mortality for 4114 patients suspected of having SAP according to categories
of 25OHD concentrations.
Table 3. Risk for All-Cause and CVD Mortality According to Categories of Plasma 25OHD
Outcome
Categories of Plasma 25OHD
Low (<42.5 nmol/L)
(n = 779)
Medium (42.5100 nmol/L)
(n = 3214)
High (>100 nmol/L)
(n = 121)
All-cause mortality
Events (n) 227 625 43
Incidence rate 3.12 1.94 4.08
HR (95% CI)
Crude 1.64 (1.411.91) 1.00 2.18 (1.602.96)
Multivariable model
a
1.94 (1.662.27) 1.00 1.79 (1.312.46)
CVD mortality
Events (n) 101 289 17
Incidence rate 1.39 0.90 1.61
HR (95% CI)
Crude 1.57 (1.251.97) 1.00 1.84 (1.133.00)
Multivariable model
a
1.87 (1.492.36) 1.00 1.44 (0.872.37)
25OHD refers to sum of 25-hydroxyvitamin D2 and D3 (nmol/L). Incidence rate is per 100 person-years.
a
Multivariable model (n = 4109) includes study site, age, sex, smoking, body mass index, systolic blood pressure, and eGFR.
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(21, 22). In contrast, a U-shaped association between
serum 25OHD and the risk for in-hospital death and
12-month mortality was observed in German patients
undergoing cardiac surgery (18). And lastly, a recent clinical
trial in patients with heart failure found that patients who
were randomly assigned to vitamin D supplements, and
who thereby obtained a 25OHD level .100 nmol/L, had
greater need for mechanical circulatory support implan-
tation during 3 years of follow-up compared with those
receiving placebo (although they were not at increased risk
for mortality) (35).
Interpretation of current findings
In linear risk models, we observed an overall inverse
association of plasma 25OHD with all-cause and CVD
mortality, supporting a role for low vitamin D in CVD
risk. Categorical modeling in 25OHD quartiles indicated
that the difference in risk primarily was observed be-
tween the first and second quartiles, which matched with
potential thresholds at ;42.5 nmol/L. Vitamin D suf-
ficiency is currently defined by a 25OHD concentra-
tion of $50 nmol/L, with most patients differentiated
according to optimal and suboptimal skeletal health
(1, 2). Our findings suggest that a similar threshold may
also apply to CVD risk.
However, we also observed increased risk for all-cause
mortality at particularly high plasma 25OHD concen-
trations, indicating a U-shaped relationship. Risk esti-
mates were in the same direction for CVD mortality,
albeit numerically weaker and with wider CIs. A limited
number of patients (n = 121) had very high 25OHD, and
thus these findings should be interpreted with caution.
For example, this association could result from random
variation, residual confounding, or reverse causation.
Patients with higher CVD risk or vitamin D deficiency
could be more likely to take or be prescribed higher doses
of vitamin D supplements. However, we did not find
evidence that vitamin D supplement use per se, which was
common in our sample, was associated with a higher risk
for all-cause or CVD mortality. On the contrary, sup-
plement use was associated with a lower risk for CVD
mortality. There were also no indications that participants
with high 25OHD had more severe CAD at baseline. They
appeared healthier in terms of several risk factors despite
their older age, including the level of physical activity. One
notable difference, however, was the particularly low
eGFR in patients with very high 25OHD. Detectable
concentrations of 25OHD2 in patients with high total
25OHD could be especially indicative of vitamin D sup-
plementation because of prior deficiency and therefore
further indicate the possibility for reverse causation (36).
We found that patients with detectable 25OHD2 con-
centrations were more likely to die during follow-up and
also to be slightly overrepresented in the group with
25OHD .100 nmol/L. However, it does not fully account
for the higher risk for mortality in this group.
There are concerns that statin treatment and vitamin D
status may interact, and several mechanisms in opposite
directions have been proposed (3739). In particular, the
safety and efficacy of bolus vitamin D supplementation
have been investigated [reviewed by Glueck et al. (40)]
as a treatment of statin-associated muscle symptoms, and
it was concluded that further studies are warranted. In
our study, we did not observe that the excess risk for all-
cause or CVD mortality associated with low plasma
25OHD differed substantially by statin treatment or
other covariates. The association with plasma 25OHD .
100 nmol/L, however, differed in the sense that we ob-
served higher risk for all-cause and CVD mortality only
among statin-treated patients, although the number of
CVD deaths among patients not treated with statins was
very low. Nonetheless, the observed heterogeneity is
interesting and potentially important, but we acknowl-
edge that because this was a secondary analysis not
adjusted for multiple comparison, it may be spurious or
result from reverse causation.
Potential mechanisms
The current study supports that vitamin D status is
associated with the risk for all-cause and CVD mortality.
Vitamin D activity may affect endothelial function, fi-
brosis, and inflammation, which are processes relevant to
stenosis progression and atheromatous plaque stability
(3). However, in a previous study from the same cohort,
which was restricted to patients who underwent repeated
coronary angiography, we did not observe an association
of 25OHD with stenosis progression during ~1 year of
follow-up (41). Hence, results from the current study may
point to a mechanistic role for vitamin D status in plaque
stability rather than volume.
The current study also suggests that high vitamin D
level may be associated with excess all-cause mortality,
potentially mediated in part by increased CVD mortality
risk. Vitamin D status is relevant to the regulation of
many genes, but the main function is to maintain systemic
calcium concentrations. Genetically elevated serum cal-
cium levels were recently shown to increase the risk for
CAD and myocardial infarction (42), and vitamin D
status could play a modifying role by lowering the
threshold for safe intake of dietary calcium. An extreme
example is patients with elevated vitamin D activity due
to rare genetic mutations that reduce vitamin D catab-
olism; these patients must limit dietary intake of calcium
and vitamin D to prevent elevated calcium concentra-
tions, soft tissue calcification, and chronic kidney disease
(43). Accordingly, it is important to assess whether there
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are common genetic variants of vitamin D and calcium
metabolism that may interact with vitamin D status and
calcium intake over the life course to influence CVD risk.
A recent trial found that plasma calcium was increased in
patients with heart failure randomly assigned to vitamin
D supplementation and that they had greater need for
mechanical circulatory support implantation during
follow-up than did the placebo group (35). Although the
trial did not find an increased risk for mortality from
vitamin D supplementation, the combined results from
that trial, our study, and other observational studies
warrant concern regarding high 25OHD values in pa-
tients with pre-existing CVD. The findings remind us that
it is important to thoroughly assess the safety of long-
term vitamin D supplementation in ongoing clinical
trials.
Methodological considerations
The study design was prospective, the follow-up pe-
riod long, and the study sample large and clearly con-
fined to patients with stable SAP. We have previously
observed that patients with acute coronary syndrome
have lower concentrations of 25OHD (210 nmol/L) and
more systemic inflammation as defined by higher CRP
(.10 mg/L) than patients suspected of having SAP (41).
The inverse relationship between inflammation and
25OHD is well documented, and a CRP .20 mg/L may
render 25OHD measurements unreliable as biomarker of
vitamin D status (44). Hence, we argue that plasma
25OHD in this cohort may better reflect vitamin D status
than in cohorts with higher levels of inflammation. A
current area of investigation is the role of the different
circulating fractions of 25OHD. Free or albumin-bound
25OHD could be more easily transported through the
membrane of target cells and correlate more strongly with
vitamin D activity, and their relation to the risk for CVD
differs from the relation to total 25OHD or the fraction
bound to vitamin D binding protein (45). Given that this
is the case, the findings for total 25OHD in this study of
mostly white men might not be detected in populations
for which the fraction of protein bound 25OHD is different
(45, 46). The thresholds reported in the current study were
identified by applying a statistically reproducible method
that was previously used for the same purpose (29).
We were able to control for several potential con-
founders, but information on socioeconomic position
was not available, and physical activity was based on self-
report and was not available for all patients. We also did
not have data on the concentrations of parathyroid
hormone, which could be a mediator of vitamin D activity
in relation to CVD (22). Inability to fully include these
characteristics in statistical analyses is a limitation of
the study. Given that Mendelian randomization studies
(1114) and randomized clinical trials (15, 16) have not
found an association between 25OHD and a lower risk
for CVD, the findings in this study and similar pro-
spective observational studies might be biased because
of residual confounding or reverse causation. Another
limitation is that patient characteristics were based on
single measurements because their validity may decrease
with longer follow-up. The Norwegian Cause of Death
Registry provided data on all-cause and CVD mortality
for all participants. Information on the cause of death in
the registry is almost exclusively based on certificates
filled out by onsite medical doctors (47). In cases where
autopsies were performed, 32% of the causes of deaths
were reclassified from one ICD-10 chapter to another;
this is a source of inaccuracy and a limitation regarding
CVD-related mortality, but not all-cause mortality (47).
Conclusions
In this observational study of white patients suspected of
having SAP, we observed an inverse association between
plasma 25OHD and the risk for CVD mortality and a
nonlinear (U-shaped) association with the risk for all-cause
mortality. Our data suggest that a potential threshold
of ~42.5 nmol/L may best discriminate between groups
with low and high risk for both outcomes, and that all-
cause mortality is also higher in the small group of patients
with concentrations .100 nmol/L.
Acknowledgments
We thank all the participants and coworkers at Haukeland
University Hospital, Stavanger University Hospital, and Bevital
A/S, Bergen.
Financial Support: The work was funded by the Norwe-
gian Foundation for Health and Rehabilitation (O.N.); the
Norwegian Heart and Lung Patient Organization (O.N.); the
Norwegian Ministry of Health and Care Services; the Western
Norway Regional Health Authority; the Department of Heart
Disease at Haukeland University Hospital, Bergen (O.N.), the
Foundation to Promote Research Into Functional Vitamin B12
Deficiency (O.N.), Bergen; and Alpharma Inc. (O.N.), Copenha-
gen, Denmark.
Clinical Trial Information: Western Norway B-Vitamin
Intervention Trial. ClinicalTrials.gov Identifier: NCT00354081
(registered 20 July 2006).
Correspondence and Reprint Requests: Eirik Degerud,
PhD, Norwegian Institute of Public Health, P.O. Box 4404,
Oslo N-0403, Norway. E-mail: eide@fhi.no.
Disclosure Summary: The authors have nothing to disclose.
References
1. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. Institute of
Medicine Committee to Review Dietary Reference Intakes for
1168 Degerud et al 25OHD and Mortality in Stable Angina Pectoris J Clin Endocrinol Metab, March 2018, 103(3):11611170
Downloaded from https://academic.oup.com/jcem/article-abstract/103/3/1161/4794886
by guest
on 19 March 2018
Vitamin D and Calcium. Dietary reference intakes: calcium, vita-
min D. Washington, DC: National Academies Press; 2011. xv, 536,
1115.
2. Lamberg-Allardt C, Brustad M, Meyer HE, Steingrimsdottir L.
Vitamin D - a systematic literature review for the 5th edition of the
Nordic Nutrition Recommendations. Food Nutr Res. 2013;57.
3. Bouillon R, Carmeliet G, Verlinden L, van Etten E, Verstuyf A,
Luderer HF, Lieben L, Mathieu C, Demay M. Vitamin D and
human health: lessons from vitamin D receptor null mice. Endocr
Rev. 2008;29(6):726776.
4. OConnell TD, Berry JE, Jarvis AK, Somerman MJ, Simpson RU.
1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte pro-
liferation and hypertrophy. Am J Physiol. 1997;272(4 Pt 2):
H1751H1758.
5. Mitsuhashi T, Morris RC Jr, Ives HE. 1,25-dihydroxyvitamin D3
modulates growth of vascular smooth muscle cells. J Clin Invest.
1991;87(6):18891895.
6. Weishaar RE, Simpson RU. Vitamin D3 and cardiovascular
function in rats. J Clin Invest. 1987;79(6):17061712.
7. Zhou C, Lu F, Cao K, Xu D, Goltzman D, Miao D. Calcium-
independent and 1,25(OH)2D3-dependent regulation of the renin-
angiotensin system in 1alpha-hydroxylase knockout mice. Kidney
Int. 2008;74(2):170179.
8. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP. 1,25-Dihy-
droxyvitamin D(3) is a negative endocrine regulator of the renin-
angiotensin system. J Clin Invest. 2002;110(2):229238.
9. Zhang R, Li B, Gao X, Tian R, Pan Y, Jiang Y, Gu H, Wang Y,
Wang Y, Liu G. Serum 25-hydroxyvitamin D and the risk of
cardiovascular disease: dose-response meta-analysis of prospective
studies. Am J Clin Nutr. 2017;105(4):810819.
10. Gaksch M, Jorde R, Grimnes G, Joakimsen R, Schirmer H,
Wilsgaard T, Mathiesen EB, Njølstad I, Løchen ML, M¨arz W,
KleberME,TomaschitzA,Gubler M, Eiriksdottir G, G udmundsson
EF, Harris TB, Cotch MF, Aspelund T, Gudnason V, Rutters F,
Beulens JW, van t Riet E, Nijpels G, Dekker JM, Grove-Laugesen D,
Rejnmark L, Busch MA, Mensink GB, Scheidt-Nave C, Thamm M,
Swart KM, Brouwer IA, Lips P, van Schoor NM, Sempos CT,
Durazo-Arvizu RA, ˇ
Skrab´akov´a Z, Dowling KG, Cashman KD,
Kiely M, Pilz S. Vitamin D and mortality: individual participant data
meta-analysis of standardized 25-hydroxyvitamin D in 26916 in-
dividuals from a European consortium. PLoS One.2017;12(2):
e0170791.
11. K ¨uhn T, Kaaks R, Teucher B, Hirche F, Dierkes J, Weikert C,
Katzke V, Boeing H, Stangl GI, Buijsse B. Plasma 25-hydroxy-
vitamin D and its genetic determinants in relation to incident
myocardial infarction and stroke in the European prospective in-
vestigation into cancer and nutrition (EPIC)-Germany study. PLoS
One. 2013;8(7):e69080.
12. Trummer O, Pilz S, Hoffmann MM, Winkelmann BR, Boehm BO,
arz W, Pieber TR, Obermayer-Pietsch B, Renner W. Vitamin D
and mortality: a Mendelian randomization study. Clin Chem.
2013;59(5):793797.
13. Brøndum-Jacobsen P, Benn M, Afzal S, Nordestgaard BG. No
evidence that genetically reduced 25-hydroxyvitamin D is associ-
ated with increased risk of ischaemic heart disease or myocardial
infarction: a Mendelian randomization study. Int J Epidemiol.
2015;44(2):651661.
14. Manousaki D, Mokry LE, Ross S, Goltzman D, Richards JB.
Mendelian randomization studies do not support a role for vitamin
D in coronary artery disease. Circ Cardiovasc Genet. 2016;9(4):
349356.
15. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D
supplementation on skeletal, vascular, or cancer outcomes: a trial
sequential meta-analysis. Lancet Diabetes Endocrinol. 2014;2(4):
307320.
16. Scragg R, Stewart AW, Waayer D, Lawes CMM, Toop L, Sluyter J,
Murphy J, Khaw KT, Camargo CA Jr. Effect of monthly high-dose
vitamin D supplementation on cardiovascular disease in the
Vitamin D Assessment Study: a randomized clinical trial. JAMA
Cardiol. 2017;2(6):608616.
17. Dror Y, Giveon SM, Hoshen M, Feldhamer I, Balicer RD, Feldman
BS. Vitamin D levels for preventing acute coronary syndrome and
mortality: evidence of a nonlinear association. J Clin Endocrinol
Metab. 2013;98(5):21602167.
18. Zittermann A, Kuhn J, Dreier J, Knabbe C, Gummert JF,
orgermann J. Vitamin D status and the risk of major adverse
cardiac and cerebrovascular events in cardiac surgery. Eur Heart J.
2013;34(18):13581364.
19. Durup D, Jørgensen HL, Christensen J, Tjønneland A, Olsen A,
Halkjær J, Lind B, Heegaard AM, Schwarz P. A Reverse J-shaped
association between serum 25-hydroxyvitamin D and cardiovas-
cular disease mortality: the CopD Study. J Clin Endocrinol Metab.
2015;100(6):23392346.
20. Dobnig H, Pilz S, Scharnagl H, Renner W, Seelhorst U, Wellnitz B,
Kinkeldei J, Boehm BO, Weihrauch G, Maerz W. Independent
association of low serum 25-hydroxyvitamin d and 1,25-dihy-
droxyvitamin D levels with all-cause and cardiovascular mortality.
Arch Intern Med. 2008;168(12):13401349.
21. Grandi NC, Breitling LP, Vossen CY, Hahmann H, W¨usten B,
arz W, Rothenbacher D, Brenner H. Serum vitamin D and risk
of secondary cardiovascular disease events in patients with
stable coronary heart disease. Am Heart J. 2010;159(6):
10441051.
22. Welles CC, Whooley MA, Karumanchi SA, Hod T, Thadhani R,
Berg AH, Ix JH, Mukamal KJ. Vitamin D deficiency and cardio-
vascular events in patients with coronary heart disease: data from
the Heart and Soul Study. Am J Epidemiol. 2014;179(11):
12791287.
23. Svingen GF, Ueland PM, Pedersen EK, Schartum-Hansen H, Seifert
R, Ebbing M, Løland KH, Tell GS, Nyg˚ard O. Plasma dimethyl-
glycine and risk of incident acute myocardial infarction in patients
with stable angina pectoris. Arterioscler Thromb Vasc Biol. 2013;
33(8):20412048.
24. Ebbing M, Bleie Ø, Ueland PM, Nordrehaug JE, Nilsen DW,
Vollset SE, Refsum H, Pedersen EK, Nyg˚ard O. Mortality and
cardiovascular events in patients treated with homocysteine-
lowering B vitamins after coronary angiography: a randomized
controlled trial. JAMA. 2008;300(7):795804.
25. Midttun Ø, Hustad S, Ueland PM. Quantitative profiling of bio-
markers related to B-vitamin status, tryptophan metabolism and
inflammation in human plasma by liquid chromatography/tandem
mass spectrometry. Rapid Commun Mass Spectrom. 2009;23(9):
13711379.
26. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF III,
Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J;
CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration).
A new equation to estimate glomerular filtration rate. Ann Intern
Med. 2009;150(9):604612.
27. Midttun Ø, Ueland PM. Determination of vitamins A, D and E in a
small volume of human plasma by a high-throughput method based
on liquid chromatography/tandem mass spectrometry. Rapid
Commun Mass Spectrom. 2011;25(14):19421948.
28. Degerud E, Hoff R, Nygard O, Strand E, Nilsen DW, Nordrehaug
JE, Midttun Ø, Ueland PM, de Vogel S, Dierkes J. Cosinor mod-
elling of seasonal variation in 25-hydroxyvitamin D concentrations
in cardiovascular patients in Norway. Eur J Clin Nutr. 2016;70(4):
517522.
29. de Boer IH, Levin G, Robinson-Cohen C, Biggs ML, Hoofnagle
AN, Siscovick DS, Kestenbaum B. Serum 25-hydroxyvitamin D
concentration and risk for major clinical disease events in a
community-based population of older adults: a cohort study. Ann
Intern Med. 2012;156(9):627634.
30. Williams B, Mandrekar JN, Mandrekar SJ, Cha SS, Furth AF.
Finding optimal cutpoints for continuous covariates with binary
and time-to-event outcomes. Technical Report #79. Rochester,
MN: Division of Biostatistics, Mayo Clinic; 2006.
doi: 10.1210/jc.2017-02328 https://academic.oup.com/jcem 1169
Downloaded from https://academic.oup.com/jcem/article-abstract/103/3/1161/4794886
by guest
on 19 March 2018
31. R Development Core Team. R: A language and environment for
statistical computing. Vienna, Austria: R Foundation for Statistical
Computing; 2008.
32. Wang L, Song Y, Manson JE, Pilz S, M¨arz W, Micha¨elsson K,
Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB,
May HT, Anderson JL, Sesso HD. Circulating 25-hydroxy-vitamin
D and risk of cardiovascular disease: a meta-analysis of prospective
studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819829.
33. Sch ¨ottker B, Jorde R, Peasey A, Thorand B, Jansen EH, Groot L,
Streppel M, Gardiner J, Ord ´o~
nez-Mena JM, Perna L, Wilsgaard T,
Rathmann W, Feskens E, Kampman E, Siganos G, Njølstad I,
Mathiesen EB, Kub´
ınov´aR,Paja
˛k A, Topor-Madry R, Tamosiunas A,
Hughes M, Kee F, Bobak M, Trichopoulou A, Boffetta P, Brenner H;
Consortium on Health and Ageing: Network of Cohorts in Europe and
the United States. Vitamin D and mortality: meta-analysis of individual
participant data from a large consortium of cohort studies from Europe
and the United States. BMJ. 2014;348(jun17 16):g3656.
34. Durup D, Jørgensen HL, Christensen J, Schwarz P, Heegaard AM,
Lind B. A reverse J-shaped association of all-cause mortality with
serum 25-hydroxyvitamin D in general practice: the CopD study.
J Clin Endocrinol Metab. 2012;97(8):26442652.
35. Zittermann A, Ernst JB, Prokop S, Fuchs U, Dreier J, Kuhn J,
Knabbe C, Birschmann I, Schulz U, Berthold HK, Pilz S, Gouni-
Berthold I, Gummert JF, Dittrich M, B ¨orgermann J. Effect of vi-
tamin D on all-cause mortality in heart failure (EVITA): a 3-year
randomized clinical trial with 4000 IU vitamin D daily. Eur Heart J.
2017;38(29):22792286.
36. Kroll MH, Bi C, Garber CC, KaufmanHW,LiuD,Caston-Balderrama
A, Zhang K, Clarke N, Xie M, Reitz RE, Suffin SC, Holick MF.
Temporal relationship between vitamin D status and parathyroid
hormone in the United States. PLoS One. 2015;10(3):e0118108.
37. Taylor BA, Lorson L, White CM, Thompson PD. Low vitamin D
does not predict statin associated muscle symptoms but is associ-
ated with transient increases in muscle damage and pain. Ath-
erosclerosis. 2017;256:100104.
38. Mazidi M, Rezaie P, Vatanparast H, Kengne AP. Effect of statins on
serum vitamin D concentrations: a systematic review and meta-
analysis. Eur J Clin Invest. 2017;47(1):93101.
39. Verdoia M, Pergolini P, Rolla R, Nardin M, Schaffer A, Barbieri L,
Daffara V, Marino P, Bellomo G, Suryapranata H, De Luca G;
Novara Atherosclerosis Study Group (NAS). Impact of high-dose
statins on vitamin D levels and platelet function in patients with
coronary artery disease. Thromb Res. 2017;150:9095.
40. Glueck CJ, Lee K, Prince M, Milgrom A, Makadia F, Wang P. Low
serum vitamin D, statin associated muscle symptoms, vitamin D
supplementation. Atherosclerosis. 2017;256:125127.
41. Degerud E, Loland KH, Nygard O, Midttun O, Ueland PM, Seifert
R, Strand E, Bleie Ø, Dierkes J. Vitamin D status was not associated
with one-yearprogression of coronary artery disease, assessed by
coronary angiography in statin-treated patients. Eur J Prev Cardiol.
2015;22(5):594602.
42. Larsson SC, Burgess S, Micha¨elsson K. Association of genetic vari-
ants related to serum calcium levels with coronary artery disease and
myocardial infarction. JAMA.2017;318(4):371380.
43. Jacobs TP, Kaufman M, Jones G, Kumar R, Schlingmann KP,
Shapses S, Bilezikian JP. A lifetime of hypercalcemia and hyper-
calciuria, finally explained. J Clin Endocrinol Metab. 2014;99(3):
708712.
44. Duncan A, Talwar D, McMillan DC, Stefanowicz F, OReilly DS.
Quantitative data on the magnitude of the systemic inflammatory
response and its effect on micronutrient status based on plasma
measurements. Am J Clin Nutr. 2012;95(1):6471.
45. Brown AJ, Coyne DW. Bioavailable vitamin D in chronic kidney
disease. Kidney Int. 2012;82(1):57.
46. Pilz S, Hahn A, Sch ¨on C, Wilhelm M, Obeid R. Effect of two
different multimicronutrient supplements on vitamin D status in
women of childbearing age: a randomized trial. Nutrients. 2017;
9(1):E30.
47. Alfsen GC, Mæhlen J. The value of autopsies for determining the
cause of death. Tidsskr Nor Laegeforen. 2012;132(2):147151.
1170 Degerud et al 25OHD and Mortality in Stable Angina Pectoris J Clin Endocrinol Metab, March 2018, 103(3):11611170
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... Vitamin D deficiency or insufficiency is prevalent in patients with CAD (6)(7)(8). Low blood 25-hydroxyvitamin D level is emerging as a predictive biomarker for patients with CAD (9)(10)(11)(12)(13). However, inconsistent findings (14)(15)(16)(17) have been recorded on the predictive value of Vitamin D deficiency in these patients. ...
... All articles adopted the prospective designs. Four studies (10,11,17,21) included patients with ACS, one study (22) enrolled patients with post-acute myocardial infarction (AMI), one study (13) included stable angina patients, and others did not report the specific type of CAD. Sample sizes ranged from 252 to 4,114, with a total of 17,892 patients with CAD. ...
... Six studies (9,13,16,17,20,23) evaluated the value of 25hydroxyvitamin D level in predicting cardiovascular mortality. Figure 3 shows a pooling risk estimate of the association between 25-hydroxyvitamin D level and cardiovascular mortality. ...
Article
Full-text available
Background A consensus has not been made about the predictive value of blood vitamin D level in patients with coronary artery disease (CAD). This meta-analysis aimed to assess the association between blood 25-hydroxyvitamin D level and adverse outcomes in patients with CAD. Methods Two independent authors searched the articles indexed in PubMed and Embase databases until June 28, 2022. Cohort studies or post-hoc analysis randomized trials evaluating the value of 25-hydroxyvitamin D level in predicting cardiovascular or all-cause mortality, and major adverse cardiovascular events ([MACEs] including death, non-fatal myocardial infarction, heart failure, revascularization, stroke, etc.) were included. Results The literature search identified 13 eligible studies for our analysis, including 17,892 patients with CAD. Meta-analysis showed that the pooled adjusted risk ratio (RR) was 1.60 (95% confidence intervals [CI] 1.35–1.89) for all-cause mortality, 1.48 (95% CI 1.28–1.71) for cardiovascular mortality, and 1.33 (95% CI 1.18–1.49) for MACEs. Leave-out one study sensitivity analysis suggested that the predictive values of blood 25-hydroxyvitamin D level were reliable. Conclusions Low blood 25-hydroxyvitamin D level is possibly an independent predictor of cardiovascular or all-cause mortality and MACEs in patients with CAD. Baseline 25-hydroxyvitamin D level may provide useful information in CAD patients.
... Evidence from observational studies is limited and inconsistent in this regard (20)(21)(22)(23)(24)(25)(26)(27). Prior cohort studies among patients with CVD (20), HF (21)(22)(23), suspected coronary artery disease (24), or suspected stable angina pectoris (25) found that plasma 25(OH)D concentrations are inversely associated with all-cause and cardiovascular mortality. ...
... Evidence from observational studies is limited and inconsistent in this regard (20)(21)(22)(23)(24)(25)(26)(27). Prior cohort studies among patients with CVD (20), HF (21)(22)(23), suspected coronary artery disease (24), or suspected stable angina pectoris (25) found that plasma 25(OH)D concentrations are inversely associated with all-cause and cardiovascular mortality. However, two cohort studies did not find a significant association between vitamin D levels and all-cause mortality or secondary cardiovascular event incidence (26,27). ...
... Although numerous observational studies have examined the association of vitamin D with all-cause and cause-specific mortality, most studies focused on the general population and deliberately excluded patients with known CVD (37). Existing evidence for the long-term association between vitamin D status and adverse outcomes in CVD patients is inconsistent and insufficient (20)(21)(22)(23)(24)(25)(26)(27). One cohort study including 1,125 German patients with stable CHD found no significant association of serum 25 (OH)D levels with secondary cardiovascular event incidence and all-cause mortality (27). ...
Article
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Background: Vitamin D insufficiency and deficiency are common in patients with cardiovascular disease (CVD). We aimed to prospectively examine the associations of serum 25-hydroxyvitamin D [25(OH)D] concentrations with all-cause and cause-specific mortality among adult patients with existing CVD. Methods: We included 37,079 patients with CVD from the UK Biobank study, a prospective cohort of half a million participants aged 40–69 years. We defined patients with CVD as those who suffered coronary heart disease, atrial fibrillation, heart failure, or stroke. The associations of serum 25(OH)D concentration with all-cause and cause-specific mortality were examined by using multivariable Cox regression models and competing risk analyses. Results: Among 37,079 patients with CVD at baseline, 57.5% were subjected to vitamin D deficiency (i.e., 25[OH]D <50 nmol/L). During a median follow-up of 11.7 years, 6,319 total deaths occurred, including 2,161 deaths from CVD, 2,230 deaths from cancer, 623 deaths from respiratory disease, and 1,305 other-cause deaths. We observed non-linear inverse associations for all-cause, cancer, respiratory disease, and other-cause mortality ( P -non-linearity <0.01) and approximately linear inverse associations for CVD mortality ( P -non-linearity = 0.074). Among CVD patients with vitamin D deficiency, per 10 nmol/L increment in serum 25(OH)D concentrations was associated with an 12% reduced risk for all-cause mortality and 9% reduced risk for CVD mortality. Conclusion: Among patients with existing CVD, increasing levels in serum 25(OH)D were independently associated with a decreased risk of all-cause and cause-specific mortality. These findings suggest that elevated serum 25(OH)D concentration benefits CVD patients with vitamin D deficiency.
... Lower circulating concentrations of 25(OH)D have also been associated with an increased risk of mortality [4][5][6][7]. Results from a recent individual participant meta-analysis of standardised circulating 25(OH)D concentrations showed that mortality was raised among participants with 25(OH)D lower than 50 nmol/L [5]. Despite the consistent finding of an inverse association of 25(OH)D and risk of CVD and mortality in observational studies, meta-analyses of randomised controlled trials of vitamin D supplementation and CVD and mortality have generally been mixed [8,9]. ...
... Therefore, the totality of the evidence would suggest that lower circulating concentrations of 25(OH)D are associated with a greater risk of heart failure. The finding of an increased mortality in patients with low 25(OH)D is consistent with results from other individual participant meta-analyses [5,29], tabular meta-analyses [4,30], and other cohort studies not included in these meta-analyses [6,7]. While these studies showed no evidence of a major difference in risk among participants with a longer follow-up time, the findings reported herein suggest that the association between 25(OH)D and mortality was only apparent during the first three years of follow-up which has also been reported in another individual study [31]. ...
... These results also showed that patients with 25(OH)D that was 100 nmol/L or higher also had a greater risk of dying which has also been reported in another study [6] but not in the individual participant meta-analyses [5,29] and likewise may be due to patients with ill health starting to take high-dose vitamin D supplements [33]. ...
Article
Background: There is increasing evidence that vitamin D supplementation may only be beneficial in people with vitamin D deficiency, and the lack of sufficient people with very low vitamin D levels could explain the lack of protection against cardiovascular disease (CVD) reported in recent clinical trials of vitamin D supplementation. The aim of this study was to assess associations of low to moderate circulating concentrations of 25-hydroxyvitamin D (25(OH)D with risk of incident CVD and all-cause mortality, as well as the risk of ischaemic heart disease (IHD), cerebrovascular disease, and heart failure separately. Methods and results: Longitudinal analysis of electronic health records in The Health Improvement Network (THIN), a UK primary care database. The analysis included 180,263 patients age 18 years and older without a history of CVD and with circulating concentrations of 25(OH)D. After a mean follow-up of 2.2 (SD 1.7) years, there were 3,747 patients diagnosed with CVD and 3,912 patients died. Compared to patients in the highest quintile of 25(OHD) (≥ 67.5 nmol/L), those in the lowest 25(OH)D quintile (<23.1 nmol/L) had a hazard ratio (HR) of 1.24 (95% CI 1.12-1.38, P < 0.001) for CVD and 1.71 (1.55-1.88, P < 0.001) for mortality. The HR for both outcomes associated with 25(OH)D concentration was non-linear, being significantly increased in patients with 25(OH)D <35 nmol/L, and highest in those with 25(OH)D <25 nmol/L, although increased for mortality at 25(OH)D ≥100 nmol/L. The increased CVD HR in the lowest 25(OH)D quintile was more from IHD (1.35, 95% CI 1.13-1.60) and heart failure (1.38, 95% CI 1.08-1.77), than from cerebrovascular disease (1.13, 95% CI 0.97-1.31). Conclusion: Low 25(OH)D are associated with highest risk of CVD and mortality, and are consistent with accumulating evidence that increased risk of these diseases occurs primarily in people with vitamin D deficiency.
... 12,13 No entanto, recentemente, a SBPC/ML, em conjunto com a SBEM, emitiu um novo posicionamento, no qual se discute a mudança dos critérios para diagnóstico, estabelecendo que para indivíduos "saudáveis" os níveis ideais seriam > 20 ng/mL; e o intervalo de 30 a 60 ng/mL é considerado para grupos de risco, a saber: indivíduos com quedas ou fraturas recorrentes, > 60 anos, gestantes e lactantes, com sarcopenia, raquitismo, osteomalácia, osteoporose e hiperparatireoidismo secundário, candidatos à cirurgia bariátrica, com doença inflamatória, autoimune e renal, obesidade, diabetes e câncer. 11 Os autores desse posicionamento consideraram ainda que apenas em níveis de 25(OH)D < 10 ng/mL ou de 10 a 20 ng/mL haveria maior risco de remodelação óssea, promovendo maior risco de osteoporose, quedas e fraturas, justificando então a suplementação de vitamina D. Em contrapartida, um estudo brasileiro com 132 pacientes em Minas Gerais encontrou 42% dos indivíduos "saudáveis," insuficientes em 25(OH)D e com elevação significativa de níveis de telopeptídeo C-terminal (CTx) sérico, indicando intensa remodelação óssea mesmo com níveis de vitamina D entre 20 e 30 ng/mL (r ¼ -0,29; p ¼ 0,038), 14 corroborado pelo estudo de Tangpricha et al. 15 Estudo recente de mortalidade cardiovascular, envolvendo 4.000 indivíduos, evidenciou redução de mortes para níveis de 25(OH) D > 40 ng/mL em comparação a níveis inferiores a 17 ng/mL, 16 em um seguimento médio de 12 anos. ...
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Resumo Objetivo Estabelecer um posicionamento a fim de padronizar as recomendações da Associação Brasileira de Nutrologia quanto ao manejo da deficiência de vitamina D na prática clínica, em relação aos critérios de investigação, diagnóstico, tratamento e prevenção. Métodos Foi realizada revisão da literatura nas bases de dados PubMed, Lilacs e SciELO, até julho de 2019. Resultados Considerando-se as novas informações obtidas da literatura em relação aos guidelines americanos e brasileiros já conhecidos, os autores redigiram o presente posicionamento que foi aprovado pela diretoria da Associação Brasileira de Nutrologia. Conclusões Após extensa análise crítica da literatura recente, foi apresentada uma atualização científica sobre a hipovitaminose D, que resultou no presente posicionamento e recomendações da Associação Brasileira de Nutrologia sobre o manejo da deficiência de vitamina D no Brasil.
... Recently Degerud et al. [146] examined the association between 25(OH)D levels and CVD mortality in 4,114 white patients with suspected stable angina pectoris followed for a mean of 11.9 years. They could show that plasma 25(OH)D levels were inversely associated with CVD mortality. ...
Article
Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Vitamin D deficiency has been identified as a potential risk factor for a number of diseases unrelated to the classical skeletal pathophysiology, such as cancer and CVD, but the effects of vitamin D supplementation are less clear. Purpose of this narrative review is to discuss the evidence suggesting an association between vitamin D status and CVD as well as the results of supplementation studies. Vitamin D deficiency has been associated with CVD risk factors such as hypertension, dyslipidemia and diabetes mellitus as well as with cardiovascular events such as myocardial infarction, stroke and heart failure. While vitamin D deficiency might contribute to the development of CVD through its association with risk factors, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells. Moreover, vitamin D has been shown to affect inflammation, cell proliferation and differentiation. While observational studies support an association between low plasma vitamin D levels and increased risk of CVD, Mendelian randomization studies do not support a causal association between the two. At present, high quality randomized trials do not find evidence of significant effects on CVD endpoints and do not support supplementation of vitamin D to decrease CVD events.
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Socioeconomic status (SES), defined as the ability to access desired resources, is associated with behaviors that may affect vitamin D status. Most studies of the effect of vitamin D status on outcomes do not account for individual-level SES. The ability to adjust for SES in epidemiologic studies, when data on conventional SES measures have not been obtained, would be advantageous. We identified all serum 25(OH)D measurements in adults age 18 years and older residing in Olmsted County, MN, a mixed urban-rural setting, between January 1, 2005 and December 31, 2011, through the Rochester Epidemiology Project. The first 25(OH)D measurement was considered the index measurement for each subject. SES was determined for each subject by the HOUsing-based SocioEconomic Status (HOUSES) index, derived from real property data. The HOUSES index is an aggregated z-score of assessed housing value, area of living space, number of bedrooms, and number of bathrooms, with higher scores indicating higher SES. Multivariable analyses were adjusted for age, BMI, sex, race, season of 25(OH)D measurement, and Charlson comorbidity index. HOUSES was matched for 10,378 of 11,002 subjects (94%) with 25(OH)D measurements available. The mean (SD) age was 54.3 (17.1) years with 26.9% ≥65 years; 77.3% were women, and 12.1% were non-white. The mean 25(OH)D concentration was 30.0 (12.9) ng/mL, and 598 (5.8%) had a 25(OH)D value <12 ng/mL. The mean (SD) HOUSES was -1.55 (3.09),-0.97 (3.34), 0.14 (3.52), 0.24 (3.51) for serum 25(OH)D categories of <12, 12-19, 20-50, and >50 ng/mL, respectively (P = 0.12 for trend). 25(OH)D increased by 0.43 (95% CI 0.36-0.50) ng/mL for each unit increase in HOUSES in univariate analysis and by 0.28 (0.21-0.35; P < 0.001) ng/mL in multivariable analysis. This represents a change of 4 ng/mL across the entire range of observed HOUSES, an effect similar in magnitude to the seasonal variation of 25(OH)D values. SES was independently associated with serum 25(OH)D concentrations in a dose-response manner after adjustment for important covariates. HOUSES is a useful tool to assess the role of individual-level SES in health outcomes when other SES measures are unavailable and to control for confounding by SES in examining the effect of 25(OH)D on clinical and metabolic outcomes.
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The negative influence of comorbidities on the quality of life of people with multiple sclerosis is evident and the problem is increasingly acknowledged by numerous international studies in long-term care. One therapeutic option would be an add-on therapy with vitamin D (VD), with the aim of achieving a therapeutically effective dose. The individually required VD dose must be tested, since the response to a certain dose is subject to variations between individuals. A possible toxicity with increased 1.25(OH)D3 (active VD metabolite) is largely prevented by increased activity of 24-hydroxylase (CYP24A1). Monitoring of serum VD levels as well as serum calcium and phosphate levels (optional Ca excretion in 24-hour urine, Ca creatinine ratio in urine) provides safety and is necessary because possible mutations on the (catabolic) CYP24A1 gene can lead to a partial or total loss of 24-hydroxylase activity and provoke hypercalcemia/hyperphosphatemia. The main therapeutic objective is to maintain functional and social independence by using drugs with a high safety profile. The prevention and optimal management of comorbidities can influence the quality of life of patients with MS (PwMS) when included in patient care. Adequate measures can reduce the burden of MS only if the risk of comorbidity is reduced through targeted monitoring, early detection and diagnosis. Such a strategy will contribute to influencing the premature mortality of patients with MS. If VD is recognized as a "multipurpose steroid hormone", it could also be used to maintain cognitive function and prevent premature possible dementia, especially as there is evidence that VD deficiency correlates with brain atrophy (hippocampus). At present, MS therapy is still a balancing act between therapeutically efficient action and the management of unexpected side effects, with VD add-on therapy being almost unproblematic and most likely to be accepted by PwMS.
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Introduction Vitamin D deficiency is a recognized pandemic. Even in a tropical country like India, where there is plentiful sunshine, vitamin D deficiency is widely prevalent. Adult females, particularly those above the age of 40, are mostly affected because vitamin D determines the pattern of post-menopausal bone loss and age-related osteoporosis. Methods A community-based cross-sectional study was conducted from April–December 2017 among 194 women aged 40 years and above residing in the village of Singur, West Bengal. For this study, multistage random sampling method was used. Each respondent was interviewed using a structured schedule to collect data on sociodemographic characteristics, dietary pattern, their daily sun exposure, tobacco use, and morbidity profile. Individuals with 25OH vitamin D <30ng/ml were said to have vitamin D insufficiency (VDI). Data entry and analysis was done using SPSS version 16.0. Results Out of 194 participants, 70.6% had VDI (Vitamin D deficient-19.6%, Vitamin D insufficient-51.0%). Mean (SD) age of the participant was 56.9 (8.9) years. Mean (SD) duration of daily sun exposure was 138.5 (59.2) minutes. 74 (38.1%) had overweight/obesity. Only 73 (37.6%) had adequate diet. Test results revealed low SES, decreasing duration of daily sun exposure, diabetes, overweight/obesity, and inadequate diet as significant predictors of VDI, explaining 39.3% of the variance with model fit. Conclusion The study has identified factors associated with VDI among the study participants. Emphasis on promoting consumption of vitamin D rich food and with vitamin D supplements, outdoor activities to increase sun exposure, maintaining optimum body weight, and strictly adhering to diabetes control will help alleviate the problem at large.
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Cardiovascular disease is the prevalent cause of morbidity and mortality in the world, affecting many millions of individuals every year. Atherosclerosis, a chronic inflammatory condition that involves different cell types, several cytokines and adhesion molecules, is the underlying cause of cardiovascular disease. Vitamin D is known to control skeletal patho/physiology, regulating calcium and phosphorus and bone remodeling along with other calcium-regulating hormones. However, several active metabolites of vitamin D can exert both direct action, mainly via vitamin D3 receptor trans-activation and indirect actions on several other tissues by an endocrine, autocrine and paracrine manners. With regard to cardiovascular disease, vitamin D deficiency has been associated with activation of the pro-inflammatory mechanism, promoting atherogenesis. There are several large-scale clinical studies, as well as meta-analyses that support this finding. However, it is still unclear whether the plasma 25-hydroxyvitamin D level can be used as a biomarker for future cardiovascular disease. Herein we review the studies reporting a causative role for vitamin D in cardiovascular disease.
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Aims: Circulating 25-hydroxyvitamin D (25OHD) levels <75 nmol/L are associated with a nonlinear increase in mortality risk. Such 25OHD levels are common in heart failure (HF). We therefore examined whether oral vitamin D supplementation reduces mortality in patients with advanced HF. Methods and results: Four hundred HF patients with 25OHD levels <75 nmol/L were randomized to receive 4000 IU vitamin D daily or matching placebo for 3 years. Primary endpoint was all-cause mortality. Key secondary outcome measures included hospitalization, resuscitation, mechanical circulatory support (MCS) implant, high urgent listing for heart transplantation, heart transplantation, and hypercalcaemia. Initial 25OHD levels were on average <40 nmol/L, remained around 40 nmol/L in patients assigned to placebo and plateaued around 100 nmol/L in patients assigned to vitamin D. Mortality was not different in patients receiving vitamin D (19.6%; n = 39) or placebo (17.9%; n = 36) with a hazard ratio (HR) of 1.09 [95% confidence interval (CI): 0.69-1.71; P = 0.726]. The need for MCS implant was however greater in patients assigned to vitamin D (15.4%, n = 28) vs. placebo [9.0%, n = 15; HR: 1.96 (95% CI: 1.04-3.66); P = 0.031]. Other secondary clinical endpoints were similar between groups. The incidence of hypercalcaemia was 6.2% (n = 10) and 3.1% (n = 5) in patients receiving vitamin D or placebo (P = 0.192). Conclusion: A daily vitamin D dose of 4000 IU did not reduce mortality in patients with advanced HF but was associated with a greater need for MCS implants. Data indicate caution regarding long-term supplementation with moderately high vitamin D doses. Trial registration information: clinicaltrials.gov Idenitfier: NCT01326650.
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Background: During the past decade, an increasing number of prospective studies have focused on the association between vitamin D and cardiovascular disease (CVD). However, the evidence on the relation between serum 25-hydroxyvitamin D [25(OH)D] and the risk of overt CVD is inconclusive.Objective: We performed a dose-response meta-analysis to summarize and prospectively quantify the RR of low serum 25(OH)D concentration and total CVD (events and mortality).Design: We identified relevant studies by searching PubMed and EMBASE up to December 2015 and by hand-searching reference lists. Prospective studies based on the general population and reported RRs and 95% CIs were included. A random-effects model was used to calculate the pooled RRs. Nonlinear association was assessed by using restricted cubic spline analyses.Results: A total of 34 publications with 180,667 participants were eligible for the meta-analysis. We included 32 publications (27 independent studies) for total CVD events and 17 publications (17 independent studies) for CVD mortality. We observed an inverse association between serum 25(OH)D and total CVD events and CVD mortality, and the pooled RRs per 10-ng/mL increment were 0.90 (95% CI: 0.86, 0.94) for total CVD events and 0.88 (95% CI: 0.80, 0.96) for CVD mortality. A nonlinear association was detected for total CVD events (P-nonlinear < 0.001) and CVD mortality (P-nonlinear = 0.022).Conclusion: Serum 25(OH)D concentration was inversely associated with total CVD events and CVD mortality from the observed studies.
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Background Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. Methods In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. Findings We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths.
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The German Nutrition Society raised in 2012 the recommended daily vitamin D intake from 200 to 800 international units (IU) to achieve 25-hydroxyvitamin D (25(OH)D) levels of at least 50 nmol/L, even when endogenous vitamin D synthesis is minimal such as in winter. We aimed to evaluate this recommendation in women of childbearing age. This is a single-center, randomized, open trial conducted from 8 January to 9 May 2016 in Esslingen, Germany. We randomized 201 apparently healthy women to receive for 8 weeks a daily multimicronutrient supplement containing either 200 IU (n = 100) or 800 IU vitamin D3 (n = 101). Primary outcome measure was serum 25(OH)D. 196 participants completed the trial. Increases in 25(OH)D (median with interquartile range) from baseline to study end were 13.2 (5.9 to 20.7) nmol/L in the 200 IU group, and 35.8 (18.2 to 52.8) nmol/L in the 800 IU group (p < 0.001 for the between group difference). At study end, levels of ≥50 nmol/L were present in 70.4% of the 200 IU group and in 99% of the 800 IU group. Participants on hormonal contraceptives had higher baseline levels and a stronger increase in 25(OH)D. In conclusion, daily supplementation of 800 IU vitamin D3 during wintertime in Germany is sufficient to achieve a 25(OH)D level of at least 50 nmol/L in almost all women of childbearing age, whereas 200 IU are insufficient.
Article
Importance: Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction. Objective: To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization. Design, Setting, and Participants: The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis. Exposures: Genetic risk score based on genetic variants related to elevated serum calcium levels. Main Outcomes and Measures: Co-primary outcomes were the odds of CAD and myocardial infarction. Results: Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction. Conclusions and Relevance: A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
Article
Importance Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction. Objective To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization. Design, Setting, and Participants The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium’s 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD and myocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD and myocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis. Exposures Genetic risk score based on genetic variants related to elevated serum calcium levels. Main Outcomes and Measures Co-primary outcomes were the odds of CAD and myocardial infarction. Results Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction. Conclusions and Relevance A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD and myocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
Article
Importance: Cohort studies have reported increased incidence of cardiovascular disease (CVD) among individuals with low vitamin D status. To date, randomized clinical trials of vitamin D supplementation have not found an effect, possibly because of using too low a dose of vitamin D. Objective: To examine whether monthly high-dose vitamin D supplementation prevents CVD in the general population. Design, setting, and participants: The Vitamin D Assessment Study is a randomized, double-blind, placebo-controlled trial that recruited participants mostly from family practices in Auckland, New Zealand, from April 5, 2011, through November 6, 2012, with follow-up until July 2015. Participants were community-resident adults aged 50 to 84 years. Of 47 905 adults invited from family practices and 163 from community groups, 5110 participants were randomized to receive vitamin D3 (n = 2558) or placebo (n = 2552). Two participants retracted consent, and all others (n = 5108) were included in the primary analysis. Interventions: Oral vitamin D3 in an initial dose of 200 000 IU, followed a month later by monthly doses of 100 000 IU, or placebo for a median of 3.3 years (range, 2.5-4.2 years). Main outcomes and measures: The primary outcome was the number of participants with incident CVD and death, including a prespecified subgroup analysis in participants with vitamin D deficiency (baseline deseasonalized 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Secondary outcomes were myocardial infarction, angina, heart failure, hypertension, arrhythmias, arteriosclerosis, stroke, and venous thrombosis. Results: Of the 5108 participants included in the analysis, the mean (SD) age was 65.9 (8.3) years, 2969 (58.1%) were male, and 4253 (83.3%) were of European or other ethnicity, with the remainder being Polynesian or South Asian. Mean (SD) baseline deseasonalized 25(OH)D concentration was 26.5 (9.0) ng/mL, with 1270 participants (24.9%) being vitamin D deficient. In a random sample of 438 participants, the mean follow-up 25(OH)D level was greater than 20 ng/mL higher in the vitamin D group than in the placebo group. The primary outcome of CVD occurred in 303 participants (11.8%) in the vitamin D group and 293 participants (11.5%) in the placebo group, yielding an adjusted hazard ratio of 1.02 (95% CI, 0.87-1.20). Similar results were seen for participants with baseline vitamin D deficiency and for secondary outcomes. Conclusions and relevance: Monthly high-dose vitamin D supplementation does not prevent CVD. This result does not support the use of monthly vitamin D supplementation for this purpose. The effects of daily or weekly dosing require further study. Trial registration: clinicaltrials.gov Identifier: ACTRN12611000402943.
Article
Background: Statins represent a pivotal treatment in coronary artery disease, offering a reduction in cardiovascular risk even beyond their lipid-lowering action. However, the mechanism of these "pleiotropic" benefits of statins is poorly understood. Vitamin D has been suggested as a potential mediator of the anti-inflammatory, anti-thrombotic and vascular protecting effects of statins. Aim of present study was to assess the impact of a high-intensity statin therapy on vitamin D levels and platelet function in patients with coronary artery disease. Methods: Patients discharged on dual antiplatelet therapy and high-intensity statins after an ACS or elective PCI were scheduled for main chemistry and vitamin D levels assessment at 30-90days post-discharge. Vitamin D (25-OHD) dosing was performed by chemiluminescence method through the LIAISON® Vitamin D assay (Diasorin Inc). Platelet function was assessed by Multiplate® (multiple platelet function analyser; Roche Diagnostics AG). Results: Among 246 patients included, 142 were discharged on a new statin therapy or with an increase in previous dose (Inc-S), while 104 were already receiving a high-dose statin at admission, that remained unchanged (Eq-S). Median follow-up was 75.5days. Patients in the Inc-S group were younger (p=0.01), smokers (p<0.001), with a less frequent history of hypercholesterolemia (p=0.05), diabetes (p=0.03), hypertension (p=0.02), or previous cardiovascular events (p<0.001). They were more often admitted for an acute coronary syndrome (p<0.001) and used less anti-hypertensive drugs or nitrates. Higher total circulating calcium was observed in the Inc-S group (p=0.004), while baseline vitamin D levels were similar in the 2 groups (p=0.30). A significant reduction in the circulating low-density lipoprotein (LDL) cholesterol was observed in the Inc-S group. Vitamin D levels increased in the Inc-S patients but not in the Eq-S group (delta-25OHD: 23.2±20.5% vs 3.1±4.7%, p=0.003), with a linear relationship between the magnitude of vitamin D elevation and the reduction of LDL cholesterol (r=-0.17, p=0.01). Platelet reactivity was significantly lower in the Inc-S patients, when evaluating aggregation with different platelet activating stimuli (arachidonic acid, p=0.02, collagen, p=0.004, thrombin-activating peptide, p=0.07, ADP, p=0.002). Conclusions: In patients with coronary artery disease, the addition of a high-intensity statin treatment, besides the lipid-lowering effects, is associated to a significant increase in vitamin D levels and lower platelet reactivity, potentially providing explanation of the "pleiotropic" benefits of statins therapy in cardiovascular disease.