The association between vitamin D and inflammation with the 6-minute walk and frailty in patients with heart failure.

Abstract

To identify relationships between anabolic hormones, inflammatory markers, and physical function.
Cross-sectional.
Outpatient university heart failure program in Connecticut.
Sixty patients with an ejection fraction of 40% or less.
The 6-minute walk distance and frailty phenotype were measured. The relationship between physical measures of hormones and inflammatory mediators were examined. Linear and ordinal logistic regression analyses were performed for the physical measures.
Forty-three men (mean age 77 +/- 9) and 17 women (mean age 78 +/- 12) participated. Longer 6-minute walk distance was correlated with higher 25-hydroxyvitamin D (25OHD) level, and a shorter walk was correlated with higher cortisol: dehydroepiandrosterone sulphate (DHEAS) ratio, high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), and intact parathyroid hormone (PTH) (all P<.05). Percentage of free testosterone, DHEAS alone, and N-terminal pro-brain natriuretic peptide (NTpro-BNP) did not correlate with 6-minute walk distance. Higher frailty phenotype score (more frail) was correlated with higher high-sensitivity CRP, higher IL6, and lower 25OHD levels (all P<.05). Linear regression with the 6-minute walk distance as the dependent variable and independent variables of age, sex, percentage of free testosterone, DHEAS, 25OHD, intact PTH, hsCRP, IL6, cortisol/DHEAS ratio, and NTpro-BNP, revealed age, sex, 25OHD and hsCRP to be significant (coefficient of determination=53.5%). Ordinal logistic regression with the frailty phenotype and hormonal levels revealed that age, 25OHD, and hsCRP also predicted frailty status.
Twenty-five-hydroxyvitamin D and hsCRP levels may contribute to lower aerobic capacity and frailty in patients with heart failure. A longitudinal study will further define the role of 25OHD and hsCRP on muscle strength and functional decline.

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CLINICAL INVESTIGATIONS
The Association Between Vitamin D and Inflammation with the
6-Minute Walk and Frailty in Patients with Heart Failure
RebeccaS.Boxer,MD,?Deborah A.Dauser,MPH,wStephenJ. Walsh,ScD,zW.DavidHager,MD,§and
Anne M. Kenny, MDk
OBJECTIVES: To identify relationships between anabolic
hormones, inflammatory markers, and physical function.
DESIGN: Cross-sectional.
SETTING: Outpatient university heart failure program in
Connecticut.
PARTICIPANTS: Sixty patients with an ejection fraction
of 40% or less.
MEASUREMENTS: The 6-minute walk distance and
frailty phenotype were measured. The relationship between
physical measures of hormones and inflammatory media-
tors were examined. Linear and ordinal logistic regression
analyses were performed for the physical measures.
RESULTS: Forty-three men (mean age 77 ? 9) and 17
women (mean age 78 ? 12) participated. Longer 6-minute
walk distance was correlated with higher 25-hydroxy-
vitamin D (25OHD) level, and a shorter walk was
correlated with higher cortisol: dehydroepiandrosterone
sulphate (DHEAS) ratio, high-sensitivity C-reactive protein
(hsCRP), interleukin-6 (IL6), and intact parathyroid hor-
mone (PTH) (all Po.05). Percentage of free testosterone,
DHEAS alone, and N-terminal pro-brain natriuretic pep-
tide (NTpro-BNP) did not correlate with 6-minute walk
distance. Higher frailty phenotype score (more frail) was
correlated with higher high-sensitivity CRP, higher IL6, and
lower25OHDlevels(allPo.05).Linearregressionwiththe
6-minute walk distance as the dependent variable and in-
dependent variables of age, sex, percentage of free testos-
terone, DHEAS, 25OHD, intact PTH, hsCRP, IL6, cortisol/
DHEAS ratio, and NTpro-BNP, revealed age, sex, 25OHD
and hsCRP to be significant (coefficient of determina-
tion553.5%). Ordinal logistic regression with the frailty
phenotype and hormonal levels revealed that age, 25OHD,
and hsCRP also predicted frailty status.
CONCLUSION: Twenty-five-hydroxyvitaminDandhsCRP
levels may contribute to lower aerobic capacity and frailty in
patients with heart failure. A longitudinal study will further
define the role of 25OHD and hsCRP on muscle strength and
functional decline. J Am Geriatr Soc 2008.
Key words: heart failure; walk; frailty; vitamin D; in-
flammation
A
in an aging population.1,2Often patients have multiple co-
morbidities, require multiple hospitalizations, and are in-
creasinglyfrail.Deteriorationto dependency,disability,and
development of frailty are particularly apparent in the older
population with HF.3
In the Cardiovascular Health Study, frailty was strong-
ly associated with a diagnosis of HF.3The cardiac cachexia
and fatigue seen in advanced HF may be associated
with skeletal myopathy, which enhances decline in func-
tion and furthers disability.4–6Skeletal muscle function
predicts exercise capacity independent of central hemody-
namics in patients with HF,7and the elderly population is
especially likely to have a decline in function when HF is
present.8
Muscular changes in HF are multifactorial and are un-
der investigation. Decreased peripheral muscle perfusion is
at the basis of many of these changes. Increased vasocon-
striction resulting from an overactive sympathetic nervous
system9and aberrant signals from ergoreceptors10contrib-
ute. Changes in muscle structure and metabolism occur and
include a decrease in type I muscle fibers (slow fibers that
are used in high-endurance exercise and are more resistant
tofatigue)andanincreaseintypeIImusclefibers(fastfibers
that are used for short bursts of activity and are more easily
fatigued).11–14Skeletal muscle metabolism represented
by reduced glycogen content has been linked to exertional
consequence of the successful treatment strategies
for heart disease is slow progressive heart failure (HF)
Address correspondence to Rebecca S. Boxer, MD, Departments of Family
and Internal Medicine, Case Western Medical Center, 11100 Euclid Ave,
Cleveland, OH 44106. E-mail: Rebecca.Boxer@uhhospitals.org
DOI: 10.1111/j.1532-5415.2007.01601.x
From the?Departments of Family Medicine and Internal Medicine, Case
Western University Hospital, Cleveland, Ohio;wGeneral Clinical Research
Center,zDivision of Epidemiology and Biostatistics, Department of Com-
munity Medicine and Health Care,§Division of Cardiology, Department of
Internal Medicine, andkCenter on Aging, Department of Internal Medicine,
University of Connecticut Health Center, Farmington, Connecticut.
JAGS
r 2008, Copyright the Authors
Journal compilation r 2008, The American Geriatrics Society
2008
0002-8614/08/$15.00

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fatigue in people with and without HF.15–17Levels of ox-
idative enzymes such as citrate synthase have also been
shown to be low18and inversely related to blood lactate
accumulation19in these patients.
It has also been theorized that high levels of markers of
catabolism such as cortisol and cytokines contribute to the
development of muscle loss.20,21Inflammatory mediators
such as tumor necrosis factor alpha, interleukin (IL)-1, and
IL-6 affect muscle catabolism and fatigue in HF as in other
disease, although the mechanism for this is unknown.22
Excess sympathetic stimulation, resulting in elevated levels
of epinephrine and norepinephrine often seen in HF may
affect skeletal muscle, resulting in local vasoconstriction,
poor perfusion, ischemia, and radical formation.9
Neurohormones, anabolic and catabolic hormones,
and inflammatory mediators have been identified as con-
tributors to the functional decline and frailty that occur in
patients with HF.20,23,24It was hypothesized that hormones
known to affect muscle health (testosterone, dehydroepi-
androsterone sulphate (DHEAS), cortisol, vitamin D) and
inflammatory markers (high-sensitivity C-reactive protein
(hsCRP), IL-6) would be associated with physical capacity
and frailty3,25in patients with HF.
METHODS
The institutional review board at the University of Con-
necticut Health Center reviewed and approved the study.
Patients aged 60 and older with an ejection fraction of 40%
or less participated in the study. Exclusion criteria included
metastatic, active, or advanced cancer or ongoing chemo-
therapy; systemic rheumatological or connective tissue dis-
orders; consumption of more than three alcoholic drinks
per day; use of androgen, estrogen, DHEAS, or hormone
receptor antagonists in the preceding year; or advanced
liver disease, renal disease requiring dialysis, Parkinson’s
disease, inability to ambulate, or myocardial infarction
within 3 months before the study. Medical history was re-
viewed, including the cause of HF and comorbidities. In
addition, serum N-terminal pro-brain natriuretic peptide
(NT-proBNP) level and New York Heart Association class
were determined at the study visit.
Aerobic Capacity
The 6-minute walktest (6MW)was performed according to
the previously published protocol as a measure of aerobic
capacity.26Participants were permitted to use an assistive
device such as a walker or cane if needed.
Frailty Definition
Frailty status was determined using the frailty phenotype
(FP) evaluation adapted from previous work.27The char-
acteristics of the phenotype included self-reported weight
loss of more than 10 pounds in the preceding year, grip
strength measured using handheld Jamar dynamometer,
sense of exhaustion as evaluated according to two questions
from the Center of Epidemiologic Studies Depression
Scale,28walking speed during an 8-foot walk, and level of
physical activity reported in kcal/wk from the Physical Ac-
tivity Scale in the Elderly (PASE).29Two aspects of this
phenotype were modified to maintain consistency within
the research program as well as familiarity with the mea-
sures. Walk time was modified from 15 feet to 8 feet as
measured by the Established Populations for Epidemiologic
Research in the Elderly battery.30Previous studies have
demonstrated correlations of 0.97 between 8-ft walk and
4-m walk.31Based on this, the cutpoints for classification of
frailty were extrapolated and were as follows: walk time
longer than 3.73 seconds for subjects 173cm tall or shorter
and longer than 3.1 seconds for those taller than 173cm.
The PASE was used instead of the Minnesota Leisure Time
Activity Questionnaire, but the same kcal cutpoints for men
and women were used. Frailty status was recorded as non-
frail for zero of five characteristics, intermediate frailty for
one or two of five characteristics, and frail for three to five
of five characteristics.
Biochemical Measurements
Serum was divided into 0.5-mL aliquots and stored at
?701C. Biochemical analysis of anabolic hormones testos-
terone, free testosterone, and percentage of free testoster-
one were measured by an outside laboratory, as described
elsewhere.32DHEAS was measured using immunoassay
(Immulite 1000, Diagnostic Products Corporation, Los An-
geles, CA) with an intra-assay coefficient of variation (CV)
of less than 5.2%. Catabolic hormones and markers of
inflammation included cortisol, cortisol/dehydroepiandros-
terone (DHEA) ratio, IL6, and high-sensitivity C-reactive
protein (hsCRP). Cortisol was measured using immunoas-
say (Immulite 1000, Diagnostic Products Corporation)
with an intra-assay CV of 4.9%L, IL-6 with an intra-assay
CV of 3.4%, CRP with an intra-assay variation of 3.3%.
Calcitropic hormones included 25-hydroxyvitamin D
(25OHD) measurements measured using enzyme immuno-
assay (Immunodiagnostic Systems Inc., Fountain Hills,
AZ), with an intra-assay CV of less than 6.6% and intact
parathyroid hormone (PTH) measured using immunoassay
(Immulite 1000, Diagnostic Products Corporation) with an
average intra-assay variability of 3.2%. The NT-proBNP
was measured using enzyme-linked immunosorbent assay
(Alpco Diagnsostics, Windham, NH) with an intra-assay
CV of 5.3%. Blood urea nitrogen, creatinine, and hemo-
globin were measured in the clinical laboratory of the
University of Connecticut Heath Center, Farmington, Con-
necticut.
Statistical Methods
Summary statistics included means ? standard deviations
for continuous variables and proportions for categorical
variables. Values across groups were compared using the
two-sample t-test or Pearson chi-square, as appropriate.
Continuous variables were examined for normality. Non-
normally distributed variables were transformed with
square root or natural log transformations.
Associations between the 6MW variable and the hor-
monal measures and inflammatory markers were evaluated
using Pearson correlation coefficients. Multivariate linear
regression was applied to determine which of the markers
were associated with 6MW performance while controlling
for possible confounding by other markers or by demo-
graphic covariates. In the multivariate analyses, a forward
variable selection method was employed, with the inclusion
criterion set at 0.05. Independent variables on continuous
2
BOXER ET AL.
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Page 3

scales were examined for evidence of nonlinear relation-
ships with the 6MW.
Four ordinal frailty groups were created by classifying
study participants into the following categories: 0, 1, 2,
and 3 to 5. Frailty scores of 3, 4, and 5 were collapsed
into a single group because of small numbers of subjects in
these individual categories. Associations between frailty
status and anabolic hormones and inflammation markers
wereinvestigatedusingSpearman
coefficients. Relationships between individual components
of the frailty scale and the hormones and markers were
measured using Pearson or point biserial correlations, as
appropriate.
To assess the effects of anabolic hormones and inflam-
matory markers on frailty while controlling for possible
confounding by other hormones and markers or by demo-
graphic characteristics, multivariate ordinal logistic regres-
sion modeling was used. The proportional odds assumption
underlying the ordinal logistic models was checked at each
step of the modeling process. The final model was chosen
througha forwardstepwise variableselectionstrategy using
a 5% criterion.
The final multivariate ordinal logistic regression model
revealed significant associations between frailty and two
hormones or markersFvitamin D and hsCRP. To better
understand the relationship between the ordinal scale for
frailty and these variables, the model was used to calculate
predicted probabilities for each frailty category relative to a
wide range of vitamin D and hsCRP values. By graphing the
predicted probabilities, it was possible to illustrate the in-
dividual effects of vitamin D and hsCRP on frailty status
while adjusting for the other marker and for age.
Analyses were performed using SAS statistical soft-
ware, version 9.0 (SAS Institute, Cary, NC) or SPSS soft-
ware, version 12.0.2 (SPSS Inc., Chicago, IL).
rank correlation
RESULTS
One hundred sixty-nine patients (68 women and 101 men)
withHFtreatedintheoutpatientHFclinicvolunteeredforthe
study. Eighty-six were eligible, and 60 (43 men, mean age
77 ? 9; 17 women, mean age 78 ? 12) agreed to participate;
58% wereNewYork
I and II and 42% were Classes III and IV. Seventy-five per-
cent of participants were taking 400IU of vitamin D or
less, 23% were taking no vitamin D, and one participant was
taking 50,000IU a month. The mean EF was 29 ? 8%. The
mean 6MW distance was 309 ? 121m. According to the
frailty phenotype criteria, 17 (28%) were not frail (0 frailty
characteristics), 12 (20%) had one of five frailty characteris-
tics, 15 (25%) had two of five characteristics, and 16 (25%)
had three to five of five characteristics. Hormone levels in the
60 patients revealed that 48% of the group had a free tes-
tosterone levelbelownormal,77%hada DHEASlevel below
normal, and 30% had vitamin D levels below normal. PTH
was above normal in 78% of the patients, and NTpro-BNP
was above normal in 98%. Demographic data and hormone
levels are listed in Table 1.
Correlations between hormones and inflammatory
markers and 6MW distance are listed in Table 2, along
with total frailty score and frailty score components. Over-
all, longer 6MW distance correlated with higher vitamin D
HeartAssociationClasses
Table 1. Demographics and Hormone Levels (N560)
Characteristic Value
Age, mean ? SD
Male/female, %
Body mass index, kg/m2, mean ? SD
Cause of HF: ischemic/non-ischemic, %
New York Heart Association Class: I and II/III and IV, %
Years with heart failure, mean ? SD
Creatinine clearance, mL/min, mean ? SD
Hemoglobin, g/dL, mean ? SD
Diabetes mellitus, %
Claudication, %
High cholesterol, %
Hypertension, %
Stroke, %
Arthritis, %
History of Cancer, %
Chronic obstructive pulmonary disease
or emphysema, %
Angina pectoris, %
Current smoker, %
Frailty: 0/1/2/3–5, %?
410 pounds weight loss, %
Grip strength, kg, mean ? SD
Exhausted, %
8-foot walk speed, seconds, mean ? SD
Physical Activity Scale in the Elderly, kCal/wk,
mean ? SD
6-minute walk distance, m, mean ? SD
Total testosterone, ng/dL, mean ? SDw
77 ? 10
72/28
27.8 ? 5.2
83/17
58/42
5.9 ? 5.4
57 ? 25
13.2 ? 1.3
32
5
77
73
15
15
23
7
7
5
28/20/25/25
16.7
25 ? 10.4
31.7
3.1 ? 1.5
860.3 ? 1,058.6
309 ? 121
195 ? 175;
50 below, 15 above
28 ? 27;
48 below, 20 above
1.72 ? 0.99
N/A
42 ? 33;
77 below, 0 above
10.7 ? 3.5;
none out of range
6.5 ? 5.6;
none out of range
1.1 ? 2.3;
0 below, 19 above
26.7 ? 12.5;
30 below, 3 above
130 ? 94
0; below, 78 above
1,097 ? 660;
0 below, 98 above
Free testosterone, pg/mL, mean ? SD
Percentage of free testosterone, mean ? SD
Dehydroepiandrosterone sulfate, mg/dL,
mean ? SDz
Cortisol, mg/dL, mean ? SD§
Interleukin-6, mg/dL, mean ? SD
High-sensitivity C-reactive protein, mg/dL,
mean ? SDk
Vitamin 25OH D, ng/mL, mean ? SD#
Parathyroid hormone, pg/mL, mean ? SD??
N-terminal pro-brain natriuretic peptide,
fmol/mL, mean ? SDww
?Four ordinal frailty groups were created by classifying study participants
according to how many of five frailty characteristics they had. Frailty scores
of 3, 4, and 5 were collapsed into a single group because of small numbers of
subjects in individual categories.
Normal values:
wmale 241–463 ng/dL; female 19.8–25ng/dL.
zmale 80–560mg/dL; female 35–430mg/dL.
§5–25mg/dL.
k0.14–1.1mg/dL.
#11–67pg/mL.
??19–57.6ng/mL.
wwo350fmol/mL.
SD5standard deviation.
HEART FAILURE, VITAMIN D, INFLAMMATION
3JAGS2008

Page 4

level; lower cortisol:DHEAS ratio; and lower hsCRP, IL-6,
and intact PTH levels but not with the percentage of free
testosterone or DHEAS or with NTpro-BNP level. No
differences in correlations were found between the sexes for
6MW and vitamin D (P5.30) and between 6MW and
hsCRP (P5.39). A higher frailty phenotype score (more
impaired) correlated with higher hsCRP and IL6 levels and
lower vitamin D level. The components of the frailty score
had similar correlations to the overall score, although
exhaustion and weight loss were less consistent than the
measures of physical function.
Contributions that the hormonal and inflammatory
measures made to the 6MW and frailty score were evalu-
ated. Linear regression with the 6MW distance as the de-
pendent variable revealed independent variables remaining
after forward selection to be age (slope5 ?4.20, standard
error (SE)51.18, P5.001), male sex (slope558.01;
SE525.6; P5.03), vitamin D (slope53.04; SE50.93;
P5.002) and natural log of hsCRP (slope5 ?34.60;
SE58.67;Po.001)(coefficient
tion553.5%). The relationship between vitamin D and
the 6MW distance (unadjusted and adjusted for age, sex,
and hsCRP) is shown in Figure 1A. The relationship be-
tween hsCRP and 6MW distance (unadjusted and adjusted
for age, sex, and vitamin D) is shown in Figure 1B.
For ordinal regression analysis, the frailty phenotype
was divided into four domains (0 characteristics5
non-frail, 1 or 2 characteristics as separate domains5in-
termediate or prefrail, and ?3 characteristics5frail). In-
dependent variables used were age, sex, percentage of free
testosterone, DHEAS, 25OHD, intact PTH, CRP, IL-6,
cortisol:DHEAS ratio, and NTpro-BNP. Variables remain-
ingafterforward selection
(OR)51.14, 95% confidence interval (CI)51.07–1.22;
P5.001), vitamin D (OR50.95, 95% CI50.90–0.99;
P5.02), and hsCRP (OR51.66, 95% CI51.10–2.51;
of determina-
wereage (oddsratio
Table 2. Correlations Between Hormones and Physical Performance Measures
Physical Performance
Hormone
Percentage Free
Testosteronew
DHEASz
Cortisol/
DHEAS
Ratiow
High-Sensitivity
C-Reactive
Proteinz
Interleukin-
6w
Vitamin
Dz
Parathyroid
Hormonew
Brain Natriuretic
Peptidez
6-minute walk distance, m
Frailty score§
Handgrip strength, kg
Physical Activity Scale in
the Elderly, kcal/wk
8-foot walk time, secondsz
Weight loss, poundsw
Exhaustionk
?0.06
?0.00
?0.02
0.06
0.14
?0.26??
0.16
?0.21
?0.18
0.26?
0.03
0.16
?0.50??
0.32??
?0.26?
?0.32??
0.36??
0.18
0.22?
?0.46??
0.32??
?0.25?
?0.28??
0.37??
0.20
0.13
0.42??
?0.30??
0.25?
0.24?
?0.31??
0.20
?0.20
?0.03
?0.11
0.06
?0.04
?0.04
?0.10
0.22?
0.06
0.10
?0.16
0.01
0.02
?0.39??
?0.10
?0.19?
0.140.07
?0.04
?0.04
?0.05
0.05
?0.02
?0.02
?Po.10.
??Po.05.
wSquare root transformation applied.
zNatural log transformation applied.
§Spearman correlation coefficient.
kPoint Biserial correlation coefficient.
Correlation coefficients of physical performance measures with hormone levels. Frailty Score adapted from the Frailty Phenotype, Exhaustion measured
according to two questions from the Center of Epidemiologic Studies Depression Scale.
DHEAS5dehydroepiandrosterone sulfate
100
200
300
400
500
A
B
Distance Walked in 6 Minutes (meters)
Distance Walked in 6 Minutes (meters)
0
20 4060 80
Vitamin D
100
200
300
400
500
−4
−2024
LN Transformation of hsCRP
Figure 1. (A) Distance walked in 6 minutes,
age, sex, and high-sensitivity C-reactive protein (hsCRP), - - - -
unadjusted. (B) Distance walked in 6 minutes,
age, sex, and vitamin D, - - - - unadjusted.
adjusted for
adjusted for
4
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Page 5

P5.02), indicating that they were able to predict frailty
status.
Probabilities of frailty for a hypothetical combination
of vitamin D, age, and hsCRP were estimated using
the ordinal logistic regression model. Figures 2 and 3
demonstrate two hypothetical examples. In Figure 2, age
and hsCRP are held constant at averages for this population
(age 77, hsCRP 0.43mg/dL) to examine the relationship
between vitamin D levels and frailty. At high levels of vi-
tamin D,such as 70ng/mL, theprobabilityof notbeingfrail
is approximately70%. Ifvitamin Dlevelswere to decline to
50ng/mL, the probability of not being frail would decrease
to approximately 40%, and the probability of having one
frailty characteristic would be approximately 35%. At vi-
tamin D levels considered inadequate for bone metabolism,
such as 20ng/dL, the probability of being without frailty
characteristics is only 10%, and the probability of having
three or more frailty characteristics is near 40%. Figure 3
presents similar prediction models for hsCRP, with age and
25OHD levels held constant at the population average. At
the lowest hsCRP level, the probability of having no frailty
characteristics was 45% but dropped to 30% with an in-
crease to 0.10mg/dL. Similar prediction models were per-
formed for age with vitamin D and hsCRP held constant
and showed that, for an increase of 10 years, from age 60 to
70, the probability of no frailty characteristics dropped
from 70% to 35% (data not shown).
DISCUSSION
In this study of 60 older patients with systolic HF, older age,
lower vitamin D, and higher CRP levels predicted poorer
performance on the 6MW test and a higher frailty pheno-
type score. Other studies have found vitamin D to be as-
sociated with poor physical performance and frailty,
including studies of patients with and without HF,33–35as
well as a greater risk of nursing home admission.36An ep-
idemiological study of community-dwelling elderly people
found lower vitamin D to be associated with lower grip
strength.37Furthermore, repletion of vitamin D improved
muscle strength, walking distance,38and balance and body
sway39,40and decreased fall frequency.35,41In addition to
poor physical performance, vitamin D deficiency has been
noted in patients with HF. One study of 101 patients with
moderate to severe HF found that vitamin D levels were in
the deficient range (o9pg/mL) in 17% of individuals, and
similarly low 1,25-dihydroxyvitamin D3 (1,25OH2D) lev-
els (o15pg/mL) were found in 26%. In this group, an as-
sociation was described between vitamin D levels and
exercise tolerance, with peak maximal rate of oxygen con-
sumption lower in individuals with low serum 25OHD
(6.7 ? 1.2 vs 11.5 ? 1.1mL/kg per minute, P5.01) and
low serum 1,25(OH)2D (7.4 ? 1.3 vs 10.8 ? 1.2mL/kg per
minute, P5.09).42
AlthoughtherelationshipbetweenlowvitaminDlevels
and poor physical performance has been well described, the
relationship between vitamin D deficiency and cardiovas-
cular disease and risk of cardiovascular events is still being
defined. The information that is available includes an in-
verse relationship between vitamin D and blood pres-
sure,43,44and administration of vitamin D results in
reduction in blood pressure and heart rate in older wom-
en.45Similarly, vitamin D levels are inversely associated
with coronary calcification46and myocardial infarction,47
and a role in general vascular health has been suggested.48
Finally, treatment of patients undergoing hemodialysis with
intravenous active vitamin D decreases left ventricular mass
and vasoactive hormones.49
The mechanisms by which vitamin D affects the car-
diovascular system are unknown. HF is a known compli-
cation of severe vitamin D deficiency (rickets) in children.
There are vitamin D receptors throughout the cardiovas-
cular system, and animal and clinical studies suggest that
vitamin D downregulates the renin-angiotensin system, re-
sulting in lower renin gene expression,50angiotensin II
synthesis,51,52and renin synthesis.49–51Vitamin D receptor
Figure 2. Age and high-sensitivity C-reactive protein (hsCRP)
are held constant at averages for this population (aged 77,
hsCRP 0.43mg/dL). For example, at high levels of vitamin
25OH D, such as 70ng/mL, the probability of not being frail is
approximately70%.IfvitaminDlevelsweretodeclineto50ng/mL,
the probability of not being frail would decrease to approxi-
mately 40% while the probability of having one frailty charac-
teristic would be approximately 35%. At vitamin D levels of
20ng/dL, the probability of being without frailty characteristics
is only 10%, and the probability of having three or more frailty
characteristics is near 40%.
Figure 3. Age and vitamin D are held constant at averages for
this population (aged 77, C-reactive protein (CRP) 0.43mg/dL).
For example, at the lowest CRP level, the probability of having
no frailty characteristics was 45% but dropped to 30% with an
increase to 0.10mg/dL.
HEART FAILURE, VITAMIN D, INFLAMMATION
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knockout mice that cannot be influenced by vitamin D
develop hypertension and cardiac hypertrophy.50,52
In addition to the association between vitamin D and
frailty, it was also found that greater levels of inflammation
correlated with poor aerobic performance and frailty. In-
flammation is a factor in physical decline and mortality in
populations without HF.53–55Higher levels of CRP have
been associated with frailty in cross-sectional56and longi-
tudinal studies in populations without HF57and with lower
skeletal muscle protein synthesis, greater skeletal muscle
breakdown, and loss of skeletal muscle in a variety of dis-
ease states, including cancer and acquired immune defi-
ciencysyndrome.22
High
cardiovascular events in older adults without cardiovascu-
lar disease.58Inflammation, muscle health, and cachexia
may be linked in patients with HF, in whom oxidative stress
resulting from underperfusion results in muscle tissue is-
chemia and is a trigger for proinflammatory mediators.59,20
High CRP is frequently found in people with HF60and is
linked to prognosis.61–63IL-6, often high in people with HF,
was high in the population in the current study. CRP and
IL-6arecloselycorrelatedandwerepracticallyinterchange-
able measures, which is not surprising, in that IL-6 stim-
ulates production of CRP, both identifying the same
inflammatory process. In the final analysis, it was CRP that
remained significantly associated with the dependent vari-
able when both measures were left in the analysis. Because
vitamin D and CRP were independent contributors to
6MW performance and to frailty in the model, an impor-
tant question is whether vitamin D supplementation im-
proves aerobic capacity and reduces inflammation in
patients with HF. In a randomized, controlled trial of vi-
tamin D supplementation (2,000IU/d for 9 months) in men
with HF, tumor necrosis factor alpha was suppressed, and
IL-10 (an antiinflammatory cytokine) increased, although
there were no changes in CRP.64In another study under-
taken to address bone loss in critically ill patients, supple-
mentation with 500IU/d of vitamin D decreased CRP
levels.65
The probability models constructed from the data in
this study envisage marked changes in functional ability
with modest changes in vitamin D and CRP levels. There are
multiple reasons that may account for vitamin D deficiency
in patients with HF. Poor appetite reduces dietary intake of
vitamin D, bowel edema reduces absorption, congested he-
patocytes decrease the synthesis of 25OHD, and inactivity
due to poor exercise tolerance and depression results in in-
adequate exposure to sunlight. In addition, chronic kidney
disease may also affect the synthesis of 1,25OH2D (active
vitamin D).42,66,67These probability models cannot address
the effect of interventions to improve vitamin D and CRP
levels, but they suggest that using serum levels of vitamin D
and CRP may be helpful in monitoring clinical progress.
Interventions aimed at raising vitamin D and lowering
CRP levels in patients with HF are possible. Understanding
the causes of altered vitamin D status and CRP levels and
the potential mediators of these levels warrants further in-
vestigation. It remains unclear whether vitamin D therapy
has a role in the management of elderly patients with HF.
If vitamin D therapy improves physical performance and
modulatesthe inflammatoryresponse,thiscouldbecome an
attractive therapy for patients with HF.
CRPis associatedwith
No relationship was found between testosterone or
DHEAS and frailty or physical performance; whether this is
because of a lack of relationship or small sample size is
uncertain. Lower levels of testosterone and DHEAS have
previously been indicators of poor prognosis and severity of
HF.68,69The mechanism for the association is unclear but
maybeamarkerforprognosisratherthenfunctionalstatus.
Additionally, testosterone supplementation improved exer-
cise capacity in one small study of 20 men with HF.70To the
authors’ knowledge, DHEA supplementation has not oc-
curred in patients with HF, and DHEA supplementation in
older adults was not beneficial.71NT-pro-BNP, used as a
marker of HF severity at the time of the study, was high in
most of the population, suggesting that their HF was not
adequately treated. NTpro-BNP was not significantly cor-
related with physical performance measures or hormonal
measurements.
PTH levels were high in this cohort but were less
strongly correlated with 6MW distance than vitamin D
levels, and PTH did not correlate with any of the frailty
measures. The reason for this is unclear but suggests that
vitamin D is more closely related to physical performance
and inflammation than PTH.
The limitations of this study are the small sample size
and cross-sectional design. Although the sample size is
small, it includes a large percentage of frail patients (25%),
which is higher then the 7% seen in a community sample.27
ThisemphasizestheassociationbetweenfrailtyandHFthat
has been previously reported.56Although this study is only
able to draw associations between physical function and
vitamin D levels and inflammatory markers, it provides an
important base for future study.
CONCLUSION
In this study of older subjects with mild to moderate HF,
lower vitamin D levels and higher CRP levels were associ-
ated with poor aerobic capacity and greater frailty, whereas
no significant role for other hormones such as testosterone,
DHEA, or cortisol was found. Further studies are required
to examine whether altering vitamin D intake and inflam-
mation status in patients with HF will improve functional
and aerobic capacity.
ACKNOWLEDGMENTS
This work has been supported by grant MO1-RR06192
from the General Clinical Research Center (GCRC). We
wish to thank the staff at the University of Connecticut
GCRC, including Paula Gendreau, RN, for data collection
and David Lazuk and Alison Kleppinger for data manage-
ment. We also thank the University of Connecticut Heart
FailureCenterstaff,includingMaryBethBarry,APRN,and
Laura Kearney, RN, for patient recruitment and data col-
lection, and the University of Connecticut Division of Ge-
riatrics.
Conflict of Interest: The editor in chief has reviewed the
conflictof interestchecklistsprovided bytheauthor andhas
determined that none of the authors have any financial or
any other kind of personal conflicts with this manuscript.
Author Contributions: R.S. Boxer: study concept and
design, acquisition of subjects and data, analysis and inter-
pretationofdata,andpreparationofmanuscript.D.Dauser,
6
BOXER ET AL.
2008JAGS

Page 7

S. Walsh: analysis and interpretation of data, and prepara-
tion of manuscript. W.D. Hager: study concept and design,
acquisition of subjects and preparation of manuscript. A.M.
Kenny: study concept and design, data, analysis and inter-
pretation of data, and preparation of manuscript.
Sponsor’s Role: None.
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