Download Anabolic Deficiency in Men With Chronic Heart

Anabolic Deficiency in Men With Chronic Heart Failure
Prevalence and Detrimental Impact on Survival
Ewa A. Jankowska, MD, PhD; Bartosz Biel, MD; Jacek Majda, PhD; Alicja Szklarska, PhD;
Monika Lopuszanska, MSc; Marek Medras, MD, PhD; Stefan D. Anker, MD, PhD;
Waldemar Banasiak, MD, PhD; Philip A. Poole-Wilson, MD, FRCP; Piotr Ponikowski, MD, PhD
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Background—The age-related decline of circulating anabolic hormones in men is associated with increased morbidity and
mortality. We studied the prevalence and prognostic consequences of deficiencies in circulating total testosterone (TT)
and free testosterone, dehydroepiandrosterone sulfate (DHEAS), and insulin-like growth factor-1 (IGF-1) in men with
chronic heart failure (CHF).
Methods and Results—Serum levels of TT, DHEAS, and IGF-1 were measured with immunoassays in 208 men with CHF
(median age 63 years; median left ventricular ejection fraction 33%; New York Heart Association class I/II/III/IV,
19/102/70/17) and in 366 healthy men. Serum levels of free testosterone were estimated (eFT) from levels of TT and
sex hormone binding globulin. Deficiencies in DHEAS, TT, eFT, and IGF-1, defined as serum levels at or below the
10th percentile of healthy peers, were seen across all age categories in men with CHF. DHEAS, TT, and eFT were
inversely related to New York Heart Association class irrespective of cause (all P⬍0.01). DHEAS correlated positively
with left ventricular ejection fraction and inversely with N-terminal pro-brain natriuretic peptide (both P⬍0.01).
Circulating TT, eFT, DHEAS, and IGF-1 levels were prognostic markers in multivariable models when adjusted for
established prognostic factors (all P⬍0.05). Men with CHF and normal levels of all anabolic hormones had the best
3-year survival rate (83%, 95% CI 67% to 98%) compared with those with deficiencies in 1 (74% survival rate, 95%
CI 65% to 84%), 2 (55% survival rate, 95% CI 45% to 66%), or all 3 (27% survival rate, 95% CI 5% to 49%) anabolic
endocrine axes (P⬍0.0001).
Conclusions—In male CHF patients, anabolic hormone depletion is common, and a deficiency of each anabolic hormone
is an independent marker of poor prognosis. Deficiency of ⬎1 anabolic hormone identifies groups with a higher
mortality. (Circulation. 2006;114:1829-1837.)
Key Words: heart failure 䡲 anabolic hormones 䡲 prognosis
A
nabolic/catabolic imbalance, which favors catabolism, is
a key pathological feature of patients with severe
chronic heart failure (CHF). The imbalance is related to
activation of the neuroendocrine and inflammatory systems,
symptoms, exercise intolerance, and the occurrence of cardiac cachexia.1,2 Anabolic deficiency is an important component of the imbalance and has traditionally been expressed as
an impairment of the GH/IGF-1 (growth hormone/insulin-like
growth factor-1) axis.3– 6 But anabolic impairment is a multifaceted phenomenon and is related to abnormalities in at least
3 key anabolic endocrine axes: gonadal, adrenal, and somatotropic. The clinical significance of reduced activity in
multiple anabolic pathways in men with heart failure has not
been established.
Clinical Perspective p 1837
Patients with CHF develop GH resistance, which results in
depletion of IGF-1 in peripheral tissues, thereby promoting
skeletal muscle apoptosis.5,6 Reduced circulating IGF-1 identifies those patients in whom, despite the absence of classic
markers of disease severity, detrimental changes in body
composition and cytokine and neurohormonal activation are
present.4 Early studies reported androgen status in a small
number of patients with CHF but did not make a comparison
with age-matched reference values from a healthy male
population.1,2,7–9 In healthy men, such endocrine abnormalities constitute a crucial element of the normal aging process,
albeit with unfavorable health consequences, such as sexual
dysfunction, cognitive impairment, depression, visceral obe-
Received January 31, 2005; de novo received July 3, 2006; accepted August 11, 2006.
From Cardiology Department, Military Hospital (E.A.J., B.B., J.M., W.B., P.P.), Wroclaw, Poland; Institute of Anthropology, Polish Academy of
Sciences (E.A.J., A.S., M.L.), Wroclaw, Poland; Cardiac Medicine, Royal Brompton Hospital (E.A.J., S.D.A., P.A.P.-W.), National Heart and Lung
Institute, Imperial College London, London, United Kingdom; Endocrinology and Diabetology Department, Wroclaw Medical University (M.M.),
Wroclaw, Poland; and Division of Applied Cachexia Research, Department of Cardiology, Charité (S.D.A.), Berlin, Germany.
Correspondence to Ewa A. Jankowska, MD, PhD, Cardiology Department, Military Hospital, ul. Weigla 5, 50-981 Wroclaw, Poland. E-mail
[email protected]
© 2006 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/CIRCULATIONAHA.106.649426
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October 24, 2006
sity, metabolic syndrome, and cardiovascular diseases.10 –13 In
the general male population, deficiencies in circulating dehydroepiandrosterone sulfate (DHEAS) and IGF-1 are related to
increased risk of all-cause and cardiovascular death,14 –16 and
reduced IGF-1 levels promote development of heart failure in
an elderly community.17 The purpose of the present study was
to evaluate prospectively the prevalence and prognostic
consequences of multiple anabolic hormone deficiencies in a
cohort of unselected men with CHF.
Methods
Study Population
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The study was conducted between October 2001 and November
2002 among male patients with CHF who were hospitalized or
attended the outpatient clinic. The criteria for study inclusion were as
follows: (1) a ⬎6 month documented history of CHF; (2) left
ventricular ejection fraction (LVEF) ⬍45% as assessed by echocardiography; and (3) clinical stability and unchanged medications for
at least 1 month preceding the study. Diagnosis of systolic CHF was
based on the following criteria recommended by the European
Society of Cardiology: (1) presence of CHF symptoms; (2) evidence
of left ventricle systolic dysfunction (as documented by LVEF
⬍45%); and (3) positive response to CHF-specific therapy.18 Exclusion criteria included (1) acute coronary syndrome or coronary
revascularization within the 6 months preceding the study, (2) any
acute/chronic illness that might influence hormonal metabolism, and
(3) any hormonal treatment, either at the time of the study or in the
past. We prospectively identified 208 patients who were suitable for
the study and who agreed to participate.
The reference population consisted of 366 healthy men aged 35 to
80 years living in the same area, who were examined in the year
2000 in the Silesian Centre for Preventive Medicine (DOLMED;
Wroclaw, Poland).19 These individuals had no history of any chronic
disease and no abnormalities on physical examination. These healthy
subjects were included to provide a reference for cutoffs and were
not pooled with those with CHF in any formal statistical analyses.
The study protocol was approved by the local ethics committee,
and all subjects gave written informed consent. The study was
conducted in accordance with the Helsinki Declaration.
Serum Levels of Anabolic Hormones and
Laboratory Measurements
In all patients and healthy men, venous blood samples were taken in
the morning after an overnight fast and after a supine rest of at least
15 minutes. After centrifugation, serum was collected and frozen at
⫺70°C until being analyzed. Serum levels of total testosterone (TT),
DHEAS, and IGF-1 were measured with immunoassays (Diagnostic
Products Corp, San Francisco, Calif) and expressed in nanograms per
milliliter. The interassay and intraassay variability coefficients were
12.0% and 6.8% for DHEAS, 9.8% and 7.4% for TT, and 6.2% and
3.1% for IGF-1, respectively.
Anabolic deficiency with regard to TT (gonadal androgen deficiency), DHEAS (adrenal androgen deficiency), and IGF-1 was
defined prospectively as a serum hormone level less than or equal to
the 10th percentile calculated for the equivalent age categories in the
cohort of healthy men, as described elsewhere.20,21 The 10th percentiles of assessed hormone levels for healthy men from the reference
population in the present study aged ⱕ45, 46 to 55, 56 to 65, and
ⱖ66 years, respectively, were 3.2, 3.0, 2.7, and 2.6 ng/mL for serum
TT; 1411, 1048, 709, and 310 ng/mL for serum DHEAS; and 258,
227, 216, and 168 ng/mL for serum IGF-1.
To estimate a circulating fraction of free testosterone, which may
express more accurately the biological activity of circulating testosterone,22,23 we also measured serum level of sex hormone binding
globulin (SHBG) in all subjects using an immunoassay (Diagnostic
Products Corp), and SHBG was expressed in nanomoles per liter.
The interassay and intraassay variability coefficients were 5.2% and
3.0%, respectively. Serum level of estimated free testosterone (eFT)
was calculated with the validated equation of Vermeulen et al.23
Gonadal androgen deficiency was defined as serum eFT level less
than or equal to the 10th percentile calculated for the equivalent age
categories in the cohort of healthy men. The 10th percentiles of eFT
for healthy men from the present reference population aged ⱕ45, 46
to 55, 56 to 65, and ⱖ66 years were 77, 64, 59, and 52 pg/mL,
respectively.
Plasma levels of N-terminal pro-brain natriuretic peptide (NTproBNP; pg/mL) were measured with immunoassay based on electrochemiluminescence on the Elecsys 1010/2010 System (Roche
Diagnostics GmbH, Mannheim, Germany). In our laboratory, the
upper limit of normal values of plasma NT-proBNP for male subjects
was 125 pg/mL. Renal function was assessed with the estimated
glomerular filtration rate (GFR; mL · min⫺1 · 1.73 m⫺2), calculated
from the Cockroft-Gault formula.24
Clinical Follow-Up
Patients were seen regularly by the study investigators in the
outpatient CHF clinic, with a follow-up duration of at least 3 years.
Information regarding survival (as of November 30, 2005) was
obtained directly from patients or their relatives, from the CHF clinic
database, or from the hospital system. No patient was lost to
follow-up. The primary end point for the analysis was all-cause
mortality.
Statistical Analysis
Most variables had a skewed distribution and were expressed as
medians with lower and upper quartiles. The intergroup differences
were tested with the Mann-Whitney U test, the ␹2 test, or the
Kruskal-Wallis ANOVA where appropriate. Correlations between
variables were assessed with Spearman rank test (r).
The associations between analyzed variables and survival were
assessed by Cox proportional hazards analysis (both single-predictor
and multivariable models). In the single-predictor analyses, we
included clinical parameters (age; New York Heart Association
[NYHA] class; LVEF; plasma NT-proBNP; CHF origin; major
comorbidities, ie, renal dysfunction, assessed with GFR, or anemia,
assessed with hemoglobin level; and presence of diabetes mellitus)
and serum levels of anabolic hormones (TT, DHEAS, IGF-1, and
eFT). We also considered a number of anabolic deficiencies as a
separate categorical variable to express information about the magnitude of anabolic deficiency within all 3 endocrine axes (ranging
from 0⫽no deficiency to 3⫽deficiency in all 3 axes). During the
construction of multivariable models, we included all variables that
had been shown to be significant predictors of survival in singlepredictor regression models. Forward and backward stepwise multivariable analyses were applied with P⫽0.20 used for both inclusion
and exclusion of variables into the model. The assumptions of
proportional hazard were tested for all the covariates.
To estimate the effect of severity of anabolic deficiency (expressed as the number of reduced anabolic hormones) on 3-year
mortality rates, Kaplan-Meier curves for cumulative survival were
constructed for CHF men with no anabolic deficiency or deficiency
in 1, 2, or all 3 anabolic axes, respectively. Differences in survival
rates were tested with the Cox-Mantel log-rank test. A value of
P⬍0.05 was considered statistically significant. Statistical analyses
were performed with StatView 5.0 for Windows (Abacus Concepts,
Berkley, Calif) and Stata 9.1 (College Station, Tex).
The authors had full access to the data and take full responsibility
for their integrity. All authors have read and agreed to the manuscript
as written.
Results
Prevalence of Anabolic Deficiency in Men
With CHF
The baseline clinical characteristics of 208 white men with
CHF are given in Table 1. The reference group consisted of
366 healthy men. Median age of the reference male population was 51 (44 to 58) years, and median body mass index
Jankowska et al
TABLE 1.
Baseline Characteristics of Men With CHF
Men With CHF
(n⫽208)
Variables
Age, y
63 (54–71)
BMI, kg/m2
26.5 (23.8–29.6)
Ischemic CHF cause, n (%)
NYHA class I/II/III/IV, n (%)
169 (81)
19/102/70/17 (9/49/34/8)
LVEF, %
33 (28–38)
Plasma NT-proBNP, pg/mL
1824 (729–4216)
GFR, mL · min⫺1 · 1.73 m⫺2
52.4 (42.7–65.6)
Diabetes mellitus, n (%)
58 (28)
Treatment, n (%)
ACE inhibitors or ARB
202 (97)
␤-Blockers
181 (87)
Diuretics
166 (80)
Digoxin
50 (24)
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Statin
166 (80)
Acetylsalicylic acid
129 (62)
BMI indicates body mass index; ACE, angiotensin-converting enzyme; and
ARB, angiotensin receptor blockers.
Values are presented as medians (with lower and upper quartiles) or n (%)
where appropriate.
was 26.9 (24.9 to 29.3) kg/m2 (median with lower and upper
quartiles; P⬍0.0001 and P⬎0.2, respectively, compared with
a group of men with CHF).
Reduced circulating levels of DHEAS and IGF-1 were
consistently seen across all age categories, whereas both eFT
and TT levels were reduced in men with CHF aged ⱕ45 years
and those aged ⱖ66 years (Table 2). When we applied
prospectively established criteria, the prevalence of anabolic
deficiencies in men with CHF differed across age categories.
Deficiency in circulating testosterone was most frequent in
the youngest and oldest groups of men with CHF, when
Anabolic Deficiency in Chronic Heart Failure
assessed with both TT (39% and 27%, respectively) and eFT
(62% and 36%, respectively), whereas marked deficiencies in
DHEAS and IGF-1 were present in all age groups among men
with CHF (Table 2). Figure 1 presents serum levels of
anabolic hormones of all individual men with CHF compared
with normal values (10th, 33rd, 50th, 66th, and 90th percentiles) of healthy men in the corresponding age categories.
Among men with CHF, deficiencies in none, 1, 2, and 3
main anabolic axes were found in 23 (11%), 85 (41%), 85
(41%), and 15 (7%), respectively. In men with CHF, serum
TT weakly correlated with serum DHEAS (r⫽0.14, P⬍0.05),
whereas serum IGF-1 was related neither to DHEAS nor to
TT (both P⬎0.2). Serum eFT correlated with DHEAS
(r⫽0.22, P⬍0.01), IGF-1 (r⫽0.28, P⬍0.0001), and TT
(r⫽0.78, P⬍0.0001). In healthy men, serum IGF-1 correlated
with serum DHEAS (r⫽0.24, P⬍0.0001), whereas serum TT
was related neither to DHEAS nor to IGF-1 (both P⬎0.2).
Serum eFT was related to DHEAS (r⫽0.24, P⬍0.0001),
IGF-1 (r⫽0.11, P⬍0.05), and TT (r⫽0.77, P⬍0.0001). Age
was inversely related to DHEAS (r⫽⫺0.30, P⬍0.0001, and
r⫽⫺0.60, P⬍0.0001, respectively, for men with CHF and
healthy peers), IGF-1 (r⫽⫺0.18, P⬍0.01, and r⫽⫺0.38,
P⬍0.0001), TT (r⫽⫺0.20, P⬍0.01, and r⫽⫺0.10, P⫽0.07),
and eFT (r⫽⫺0.28, P⬍0.0001, and r⫽⫺0.35, P⬍0.0001).
Anabolic Deficiency and Clinical Indices in Men
With CHF
Serum TT, eFT, and DHEAS levels (but not IGF-1) in men
with CHF correlated inversely with NYHA class (TT
r⫽⫺0.31, P⬍0.0001; eFT r⫽⫺0.25, P⬍0.001; DHEAS
r⫽⫺0.32, P⬍0.0001; and IGF-1 r⫽⫺0.11, P⫽0.1). Results
of the Kruskal-Wallis ANOVA confirmed that the severity of
CHF expressed as NYHA class significantly differentiated
the variance of DHEAS, TT, and eFT levels (for DHEAS and
TT, P⬍0.0001; for eFT, P⬍0.01) but not IGF-1 (P⬎0.2;
Figure 2). There were no differences in anabolic status
TABLE 2. Serum Levels of Anabolic Hormones and the Prevalence of Anabolic Deficiencies in Men With
CHF and Healthy Male Subjects in Equivalent Age Categories
Men Aged ⱕ45 y
Healthy male subjects, n
Serum TT level, ng/mL
Serum eFT level, pg/mL
108
4.30 (3.60–5.10)
Men Aged 46 –55 y
138
4.20 (3.30–5.00)
Men Aged 56 – 65 y
81
4.10 (3.30–5.10)
Men Aged ⱖ66 y
39
4.10 (3.10–5.80)
90 (76–109)
81 (69–101)
Serum DHEAS level, ng/mL
2331 (1707–2986)
1625 (1188–2199)
991 (813–1430)
651 (342–1168)
Serum IGF-1 level, ng/mL
334 (279–383)
297 (256–344)
276 (242–321)
256 (182–299)
Men with CHF
Serum TT level, ng/mL
Prevalence of TT deficiency, %
Serum eFT level, pg/mL
Prevalence of eFT deficiency, %
Serum DHEAS level, ng/mL
Prevalence of DHEAS deficiency, %
Serum IGF-1 level, ng/mL
Prevalence of IGF-1 deficiency, %
103 (86–119)
13
3.60 (2.36–4.49)‡
39†
72 (64–108)‡
62*
1000 (553–1850)*
62*
204 (187–213)*
92*
1831
59
4.35 (3.37–5.27)
17
90 (68–126)
22‡
723 (398–1210)*
63*
193 (158–211)*
80*
46
4.42 (3.31–5.53)
13
92 (67–125)
17
420 (308–670)*
78*
185 (165–211)*
78*
Results are presented as median (with upper and lower quartiles) or % where appropriate.
*P⬍0.0001, †P⬍0.01, ‡P⬍0.05, men with CHF vs healthy male subjects in the same age categories.
81(63–99)
90
3.59 (2.56–4.55)‡
27‡
67 (45–91)‡
36†
328 (183–845)*
44†
173 (126–204)*
43†
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October 24, 2006
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Figure 1. Serum levels of anabolic hormones of men with CHF compared with normal reference values of healthy men in relation to
age (percentiles).
between male CHF patients with ischemic origins and those
with nonischemic origins of CHF (all P⬎0.2).
LVEF correlated positively with DHEAS (r⫽0.18,
P⬍0.01) but not with TT, eFT, or IGF-1 (all P⬎0.2). There
was an inverse correlation between elevated plasma NTproBNP level and reduced DHEAS (r⫽⫺0.19, P⬍0.01),
with no relationships with TT, eFT, or IGF-1 (all P⬎0.2).
Circulating levels of all hormones correlated with renal
function expressed as GFR (TT r⫽0.18, P⬍0.01; eFT
r⫽0.17, P⬍0.05; DHEAS r⫽0.23, P⬍0.001; and IGF-1
r⫽0.24, P⬍0.001). In men with CHF, body mass index was
not related to any anabolic hormone level (all r⬍0.1, P⬎0.2).
Anabolic Deficiency and Prognosis in Men
With CHF
At the end of follow-up (mean follow-up duration 930⫾434
days; median 1144 days, limits 12 to 1370 days; ⬎3 years in
all who survived), there were 75 deaths (36%). All deaths
were cardiovascular. The cumulative survival of all patients
was 83%, 72%, and 64% at 1, 2, and 3 years, respectively.
The proportionality assumption and the assumption of a
log-linear relationship between the prognosticators and the
hazard function were fulfilled for all tested variables.
Single-Predictor Analyses
In single-predictor Cox proportional hazards models, the
following variables were related to increased mortality in
men with CHF: age (per 1 year: hazard ratio [HR]⫽1.04, 95%
CI 1.01 to 1.06, P⫽0.002), NYHA class (per NYHA class,
with NYHA I as a reference group: HR⫽2.83, 95% CI 2.08
to 3.85, P⬍0.0001), LVEF (per 1%: HR⫽0.92, 95% CI 0.89
to 0.95, P⬍0.0001), plasma NT-proBNP (per 500 pg/mL:
HR⫽1.05, 95% CI 1.03 to 1.06, P⬍0.0001), GFR (per 5
mL · min⫺1 · 1.73 m⫺2: HR⫽0.83, 95% CI 0.77 to 0.90,
P⬍0.0001), and hemoglobin level (per 1 g/dL: HR⫽0.81,
95% CI 0.71 to 0.92, P⫽0.001) but neither the cause of CHF
nor the presence of diabetes mellitus (both P⬎0.2; Table 3).
In single-predictor analyses, reduced serum levels of TT,
eFT, DHEAS, and IGF-1 were predictors of poor outcome in
men with CHF (TT [per 1 ng/mL]: HR⫽0.72, 95% CI 0.62 to
0.84, P⬍0.0001; eFT [per 10 pg/mL]: HR⫽0.89, 95% CI
0.84 to 0.95, P⫽0.0002; DHEAS [per 100 ng/mL]:
HR⫽0.87, 95% CI 0.81 to 0.93, P⬍0.0001; and IGF-1 [per
10 ng/mL]: HR⫽0.94, 95% CI 0.90 to 0.98, P⫽0.002). In
addition, a number of anabolic deficiencies predicted survival
(per each additional deficiency: HR⫽1.73, 95% CI 1.31 to
2.27, P⫽0.0001; Table 3).
Multivariable Analyses
In trivariable models, reduced serum levels of TT, DHEAS, and
IGF-1, independently of each other, were related to increased
risk of death in men with CHF (TT [per 1 ng/mL]: HR⫽0.75,
Jankowska et al
Anabolic Deficiency in Chronic Heart Failure
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Figure 2. Serum levels of anabolic hormones (medians with lower and upper quartiles) in men with CHF by NYHA class.
95% CI 0.65 to 0.86, P⬍0.0001; DHEAS [per 100 ng/mL]:
HR⫽0.88, 95% CI 0.83 to 0.94, P⫽0.0001; and IGF-1 [per 10
ng/mL]: HR⫽0.94, 95% CI 0.90 to 0.98, P⫽0.005; ␹2 of the
trivariable model⫽41.32, P⬍0.0001). Similar results were obtained when in an analogous trivariable model, serum TT was
replaced by serum eFT (eFT [per 10 pg/mL]: HR⫽0.92, 95% CI
0.87 to 0.97, P⫽0.004; DHEAS [per 100 ng/mL]: HR⫽0.88,
95% CI 0.83 to 0.94, P⫽0.0001; and IGF-1 [per 10 ng/mL]:
HR⫽0.96, 95% CI 0.92 to 1.00, P⫽0.08; ␹2 of the trivariable
model⫽32.38, P⬍0.0001).
In multivariable models of Cox proportional hazard, we
included all variables that were significantly related to sur-
TABLE 3. Single-Predictor Models of Cox Proportional Hazard Analyses in Men
With CHF
Variables
Age
Units
HR
95% CI
P
1y
1.04
1.01–1.06
0.002
⬍0.0001
NYHA class
I/II/III/IV
2.83
2.08–3.85
CHF origin
CAD/non-CAD
1.40
0.73–2.65
0.31
1%
0.92
0.89–0.95
⬍0.0001
1.05
1.03–1.06
⬍0.0001
LVEF
Plasma NT-proBNP
500 pg/mL
⫺1
⫺2
0.83
0.77–0.90
⬍0.0001
Hemoglobin
1 g/dL
0.81
0.71–0.92
0.001
Presence of diabetes mellitus
Yes/no
1.03
0.62–1.70
0.91
1 ng/mL
0.72
0.62–0.84
⬍0.0001
Serum eFT
10 pg/mL
0.89
0.84–0.95
0.0002
Serum DHEAS
100 ng/mL
0.87
0.81–0.93
⬍0.0001
Serum IGF-1
10 ng/mL
0.94
0.90–0.98
0.002
0/1/2/3
1.73
1.31–2.27
0.0001
GFR
5 mL · min
Serum TT
No. of anabolic deficiencies
CAD indicates coronary artery disease.
· 1.73 m
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October 24, 2006
TABLE 4.
Multivariable Stepwise Models of Cox Proportional Hazard Analyses in Men With CHF
Model With Serum Levels of 3 Anabolic Hormones
Model With a Number of Anabolic Deficiencies
Variables
Units
HR
95% CI
P
Variables
Units
HR
95% CI
P
Serum TT
1 ng/mL
0.84
0.72–0.97
0.02
No. of anabolic deficiencies
0/1/2/3
1.78
1.29–2.45
0.0004
Age
1 year
1.04
1.01–1.07
0.02
NYHA class
I/II/III/IV
1.59
1.09–2.33
0.02
0.002
Serum DHEAS
100 ng/mL
0.92
0.87–0.99
0.02
Serum IGF-1
10 ng/mL
0.95
0.91–0.99
0.03
I/II/III/IV
1.60
1.11–2.33
0.01
NYHA class
LVEF
1%
0.95
0.92–0.99
0.007
LVEF
1%
0.94
0.91–0.98
500 pg/mL
1.03
1.01–1.04
0.008
Plasma NT-proBNP
500 pg/mL
1.02
0.99–1.04
0.12
5 mL · min⫺1 · 1.73 m⫺2
0.91
0.84–0.98
0.02
GFR
5 mL · min⫺1 · 1.73 m⫺2
0.93
0.85–1.01
0.09
-
Hemoglobin
1 g/dL
0.88
0.77–1.01
0.07
vival in single-predictor analyses. In the stepwise analyses,
both when forward and backward approaches were applied,
the final model consisted of 7 significant independent predictors (listed in order of decreasing predictive power), namely:
LVEF (per 1%: HR⫽0.95, 95% CI 0.92 to 0.99, P⫽0.007),
plasma NT-proBNP (per 500 pg/mL: HR⫽1.03, 95% CI 1.01
to 1.04, P⫽0.008), NYHA class (per NYHA class, with
NYHA I as a reference group: HR⫽1.60, 95% CI 1.11 to
2.33, P⫽0.01), GFR (per 5 mL · min⫺1 · 1.73 m⫺2: HR⫽0.91,
95% CI 0.84 to 0.98, P⫽0.02), serum DHEAS (per 100
ng/mL: HR⫽0.92, 95% CI 0.87 to 0.99, P⫽0.02), serum TT
(per 1 ng/mL: HR⫽0.84, 95% CI 0.72 to 0.97, P⫽0.02), and
serum IGF-1 (per 10 ng/mL: HR⫽0.95, 95% CI 0.91 to 0.99,
P⫽0.03; ␹2 of the 7-variable model⫽90.74, P⬍0.0001; Table
4). Similar results were obtained when, during a construction
of the best-fitted multivariable model, serum TT was replaced
by serum eFT. Similar to serum TT, in a multivariable model,
serum eFT remained an independent predictor of survival
(per 10 pg/mL: HR⫽0.94, 95% CI 0.89 to 0.99, P⫽0.01).
Once the number of anabolic deficiencies was put in the
best-fitted model instead of levels of 3 anabolic hormones,
this variable remained an independent predictor of survival in
men with CHF (per each additional deficiency: HR⫽1.78,
95%CI 1.29 to 2.45, P⫽0.0004; Table 4).
Taking into consideration the significance of age itself as a
general predictor of survival, we constructed a multivariable
model in which age was included as a potential prognosticator. The following HRs for subsequent variables were calculated: plasma NT-proBNP (per 500 pg/mL: HR⫽1.03, 95%
CI 1.01 to 1.04, P⫽0.008), LVEF (per 1%: HR⫽0.95, 95%
CI 0.92 to 0.99, P⫽0.008), NYHA class (per NYHA class,
with NYHA I as a reference group: HR⫽1.59, 95% CI 1.10
to 2.32, P⫽0.02), serum DHEAS (per 100 ng/mL: HR⫽0.93,
95% CI 0.87 to 0.99, P⫽0.02), serum TT (per 1 ng/mL:
HR⫽0.84, 95% CI 0.72 to 0.98, P⫽0.02), serum IGF-1 (per
10 ng/mL: HR⫽0.95, 95% CI 0.91 to 0.99, P⫽0.03), GFR
(per 5 mL · min⫺1 · 1.73 m⫺2: HR⫽0.92, 95% CI 0.84 to 0.99,
P⫽0.04), and age (per 1 year: HR⫽1.01, 95% CI 0.98 to
1.03, P⫽0.75; ␹2 of the 8-variable model⫽91.05, P⬍0.0001).
Similar results were obtained when, during a construction of
a multivariable model that included age, serum TT was
replaced by serum eFT. Similar to serum TT in such a
multivariable model, serum eFT remained an independent
predictor of survival (per 10 pg/mL: HR⫽0.94, 95% CI 0.89
to 0.99, P⫽0.01).
Plasma NT-proBNP
GFR
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Graded Relation Between Severity of Anabolic
Deficiency and Survival
There was a relationship between deficiencies of multiple
anabolic hormones and mortality in men with CHF
(␹2⫽26.12, P⬍0.0001). Men with CHF and normal circulating levels of all anabolic hormones had the best 3-year
survival rate (83%, 95% CI 67% to 98%) compared with
those with deficiencies in 1 (74%, 95% CI 65% to 84%), 2
(55%, 95% CI 45% to 66%), or 3 (27%, 95% CI 5% to 49%)
anabolic endocrine axes (Figure 3).
Discussion
The present study presents 2 major findings. In an unselected
cohort of men with CHF, we have demonstrated a high
prevalence of reduced serum concentrations of anabolic
hormones. The 3 hormones studied reflect the major anabolic
endocrine axes, namely, gonadal, adrenal, and somatotropic.
We have also found that reduced levels of multiple serum
anabolic hormones (TT, DHEAS, and IGF-1) constitute
strong markers of a poor prognosis independent of conventional risk predictors.
Published data on anabolic status in male patients with
CHF, assessed on the basis of serum concentrations of TT,
DHEA, or IGF-1, are sparse and equivocal. Some reports
have shown deficiencies of testosterone,8 DHEAS,1,2,9 and
IGF-1,3,4,8 whereas others have not.1,2,7,8 We have found
marked endocrine deficiencies in all 3 main anabolic hormonal axes reflected in measurements of serum concentrations of TT, DHEAS, and IGF-1. A major problem in making
comparisons between studies is the definition of hormonal
deficiency. We prospectively defined an anabolic hormone
deficiency as below or equal to the 10th percentile calculated
separately for TT, DHEAS, and IGF-1 levels in age groups
from a large population of 366 healthy male subjects. Because age is the major determinant of anabolic hormone
levels in men,10,12,13 a definition of anabolic deficiency should
not be based on threshold values that are constant across the
entire age spectrum.
Testosterone deficiency was most evident in the youngest
group of men with CHF (ⱕ45 years old) regardless of
Jankowska et al
Anabolic Deficiency in Chronic Heart Failure
1835
Figure 3. Graded relationship between
the number of impaired anabolic endocrine axes and survival in men with CHF.
Kaplan-Meier survival plot and HRs are
shown. *P⬍0.05 and ***P⬍0.001 vs men
with no anabolic deficiency.
Downloaded from http://circ.ahajournals.org/ by guest on April 22, 2017
whether testosteronemia was expressed as TT or as eFT (39%
or 62%, respectively, of CHF men demonstrated a testosterone level below the 10th percentile of their healthy peers). In
this age group, testosterone deficiency is of particular clinical
significance because androgen deficiency significantly affects patients’ quality of life. Testosterone deficiency was
also found in approximately one third of men aged ⱖ66
years, an age group in which heart failure is more common.
Deficiencies in DHEAS and IGF-1 were present in the
majority of CHF patients in all age groups ⱕ65 years, with a
lower prevalence in the oldest group. Endocrine activity of
somatotropic and adrenal axes was deranged, predominantly
in younger and middle-aged men with CHF.
Anabolic hormone deficiency in men with CHF is not a
simple surrogate of disease severity. The only meaningful
association was a decrease in TT, eFT, and DHEAS levels in
patients with more advanced CHF symptoms, as assessed by
NYHA class; however, these relationships, although statistically significant, were rather weak in magnitude. IGF-1 levels
remained low regardless of NYHA class. The underlying
cause of CHF did not determine anabolic status. Neither TT,
eFT, nor IGF-1 levels correlated with echocardiographic
(LVEF) or humoral (NT-proBNP) indices of left ventricle
function. LVEF and plasma NT-proBNP were only related to
circulating DHEAS levels, which confirms a previous report.9
Again, all of these correlations for DHEAS were not strong.
Impaired anabolic metabolism may be a generalized phenomenon seen in the course of CHF that begins at an early stage
of disease and accelerates the endocrine changes that normally occur in the course of male aging.
We have shown that the presence of multiple hormone
deficiencies in men with CHF carries a worse prognosis.
DHEAS deficiency is an independent risk factor of ischemic
heart disease25 and a predictor of increased all-cause and
cardiovascular mortality in a general male population.14
There are no data on the relationship between TT level and
mortality in men. Reduced circulating IGF-1 levels are
related to increased total16 and cardiovascular15 mortality in
men and to an increased incidence of heart failure in
community settings.17 In the present study, reduced levels of
TT, eFT, DHEAS, and IGF-1 were related to an unfavorable
outcome in men with CHF, even when adjusted for conventional clinical prognostic markers, such as plasma NTproBNP. Additionally, we showed a progressive association
between the number of impaired anabolic axes and all-cause
3-year mortality. Patients with multiple insufficiency that
affected at least 2 endocrine anabolic axes had the worst
survival, ie, 3-year mortality rates of approximately 50% and
75% in those with 2 and 3 impaired anabolic axes, respectively. The present findings demonstrate the clinical utility of
the evaluation of all 3 anabolic axes for the assessment of
long-term prognosis in men with CHF in addition to such
parameters as NYHA class, ejection fraction, NT-proBNP,
and renal function.
Studies performed in groups of elderly men with testosterone or dehydroepiandrosterone deficiency suggest that pharmacological augmentation of anabolic drive can result in
favorable changes in the body composition, sexual function,
and psychological status of aging men.26,27 Recently, Malkin
et al28 showed that a 12-month testosterone replacement
therapy regimen in men with CHF was followed by improvement in NYHA class and functional capacity, as assessed by
an incremental shuttle walk test. There is no evidence that
gonadal or adrenal androgen supplementation can improve
survival.
Study Limitations
The observational character of the present study needs to be
acknowledged. The study was not designed to elucidate the
underlying mechanisms of anabolic deficiency in CHF. The
origin of the age-related decline in anabolic hormones in
aging men remains uncertain.12 One hypothesis is that male
1836
Circulation
October 24, 2006
Downloaded from http://circ.ahajournals.org/ by guest on April 22, 2017
aging is accompanied by a steady exacerbation of inflammatory processes, with elevated circulating proinflammatory
cytokines, which inhibit the secretion of sex steroids by
gonadal and adrenal glands.29,30 Reported relationships between high cytokine and reduced anabolic hormone levels1,4
might suggest the existence of an analogous phenomenon in
CHF. It is presumed that reduced DHEA secretion in CHF, at
least, may be due to insulin resistance and hyperinsulinemia,
because it is a frequent metabolic derangement found in CHF
patients.31 Insulin is a physiological inhibitor of DHEA
secretion in healthy subjects.32
The evaluation of testosterone deficiency in men with CHF
was based on serum levels of TT with appropriate reference
limits. This approach, although recommended for clinical
practice in some guidelines,33,34 may have potential disadvantages. There is no consensus regarding which fraction of
circulating testosterone should be routinely measured. Free
testosterone reflects the most active fraction of circulating
gonadal androgen, which reflects direct biological effects on
target tissues. Nevertheless, a preferable measurement is the
assessment of free testosterone by equilibrium dialysis.22,23
This technique is complex, time-consuming, and available
only in specialized centers.
To overcome these problems, we measured SHBG levels in
all subjects so as to be able to estimate serum levels of free
testosterone using a well-established and validated equation
published by Vermeulen et al and recommended for clinical
use by the International Society for the Study of the Aging
Male.23 We have confirmed that eFT predicted survival in
CHF men in both single-predictor and multivariable models,
and the replacement of TT by eFT in constructed multivariable models did not significantly influence the clinical meaning of the results.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Conclusions
The present study demonstrates that in an unselected cohort
of male CHF patients, multiple anabolic deficiencies occur
frequently and predict long-term outcome. Whether pharmacological correction of anabolic deficiencies might constitute
a therapeutic approach in men with CHF remains a subject for
further clinical investigation.
Sources of Funding
This research was financially supported by the State Committee for
Scientific Research (Poland) grants No. 4P05B 06517 and
6P04C04820. Dr Jankowska was supported by a postdoctoral research fellowship from the Foundation of Polish Science.
16.
17.
18.
Disclosures
None.
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CLINICAL PERSPECTIVE
Deficiency in anabolic hormones strongly predicts high morbidity and mortality in a general male population. In chronic
heart failure (CHF), strong evidence indicates that the balance between anabolic and catabolic processes is severely
disturbed, which constitutes a key pathophysiological feature of this syndrome. Until now, however, in CHF, this
imbalance has been investigated only selectively in the context of augmented catabolic drive. The present study
demonstrates that multiple anabolic depletion, defined as reduced serum levels of key anabolic hormones (testosterone,
dehydroepiandrosterone sulfate, and insulin-like growth factor-1), identifies CHF patients with high long-term mortality.
The higher the number of deficient anabolic hormones, the worse the prognosis. Further studies should elucidate the
mechanisms responsible for the protective role of anabolic signaling in this group of patients. Our results constitute
premises for the selective supplementation of deficient anabolic hormones, which may become a novel therapeutic
approach in CHF. Its safety and effectiveness need to be verified in future clinical trials.
Anabolic Deficiency in Men With Chronic Heart Failure: Prevalence and Detrimental
Impact on Survival
Ewa A. Jankowska, Bartosz Biel, Jacek Majda, Alicja Szklarska, Monika Lopuszanska, Marek
Medras, Stefan D. Anker, Waldemar Banasiak, Philip A. Poole-Wilson and Piotr Ponikowski
Downloaded from http://circ.ahajournals.org/ by guest on April 22, 2017
Circulation. 2006;114:1829-1837; originally published online October 9, 2006;
doi: 10.1161/CIRCULATIONAHA.106.649426
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2006 American Heart Association, Inc. All rights reserved.
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