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Original Studies |
Department of Cardiovascular Medicine, Kumamoto University School of Medicine, Kumamoto 860-8556; and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine (Y.S., K.Na.), Kyoto 606-8501, Japan
Address all correspondence and requests for reprints to: Hirofumi Yasue, M.D., Department of Cardiovascular Medicine, Kumamoto University School of Medicine, 1–1-1 Honjo, Kumamoto 860-8556, Japan. E-mail: yasue{at}gpo.kumamoto-u.ac.jp
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Abstract |
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Introduction |
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Heart failure is the final common pathway of most cardiovascular diseases, and the incidence of heart failure rises in the elderly population (10). Recently, Anker et al. reported that DHEA levels were decreased in male patients with chronic heart failure (CHF) (11). However, its mechanism and relation to the severity of heart failure have not been fully examined.
We and others have reported that plasma levels of A-type natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are sensitive biochemical markers of left ventricular dysfunction (12, 13, 14, 15, 16, 17, 18). In the present study, we examined the relation between plasma levels of DHEAS and severity of heart failure by using hemodynamic markers and plasma levels of ANP and BNP in male patients with left ventricular dysfunction. We examined also the relation between plasma levels of DHEAS and those of thiobarbituric acid-reactive substances (TBARS), a traditional marker of lipid peroxidation, in patients with CHF, as it has been reported that that oxidative stress is increased in patients with heart failure (19, 20).
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Subjects and Methods |
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To examine the relationship between age and plasma level of DHEAS or cortisol, we measured plasma levels of DHEAS and cortisol in 211 Japanese male subjects who underwent a health check-up at our institution (mean age, 57.5 ± 1.0 yr; range, 22–83). Blood samples were collected in the morning after fasting period of 12 h. After supine rest for at least 20 min, a polyethylene catheter was inserted into antecubital vein, and venous blood was drawn.
Forty-nine male patients with CHF (mean age, 60.7 ± 1.3 yr; range, 38–75) with left ventricular dysfunction (33 old myocardial infarction and 16 idiopathic dilated cardiomyopathy) were included in this study. Diagnostic cardiac catheterization was performed in all patients. At the time of investigation, all CHF patients were clinically stable. Patients with malignant disease, hemodynamically important valvular disease, severe lung disease, renal failure, or peripheral vascular disease were excluded. Patients with myocardial infarction within the previous 2 months were also excluded. Angiotensin-converting enzyme inhibitors were withdrawn from 3–5 days before the study in all 30 patients who had been taking these drugs. All other drugs were discontinued at least 1 day before the study.
We selected 32 controls (mean age, 60.2 ± 1.8 yr; range, 40–76) who were age matched with CHF patients without heart disease. All of the controls also underwent diagnostic cardiac catheterization for evaluation of the chest pain or electrocardiogram abnormality. They had no organic stenosis (>25%) in their coronary arteries angiographically and did not show coronary spasm after intracoronary injection of acetylcholine. All drugs were discontinued at least 1 week before the study. Written informed consent was obtained from all patients before the study. The study was in agreement with the guidelines approved by the ethics committee at our institution.
Cardiac catheterization
Cardiac catheterization was performed in patients with CHF and age-matched controls (n = 81) in the morning in the fasting state. Using a Swan-Gantz catheter inserted into the femoral vein, hemodynamic measurements, including pulmonary capillary wedge pressure (PCWP) and cardiac output, were made. Sampling of blood for ANP, BNP, cortisol, DHEAS, and TBARS was performed at the femoral vein. Systemic arterial pressure was then measured, and coronary angiography and left ventriculography were performed in each patient. Left ventricular ejection fraction (LVEF) was determined by left ventriculogram (n = 78) or echocardiogram (n = 3).
Measurements of plasma levels of ANP, BNP, DHEAS, and cortisol
All blood samples were withdrawn into chilled
plastic syringes and transferred to siliconized disposable tubes that
contained aprotinin (1.000 kallikrein inactivator units/mL; Ohkura
Pharmaceutical, Kyoto, Japan) and ethylenediamine tetraacetate (1
mg/mL), immediately placed on ice, and centrifuged at 4 C. An aliquot
of plasma was immediately frozen at -80 C and thawed only once at the
time of extraction. The plasma ANP concentration was measured with a
specific RIA for 
-human ANP (Shionoria ANP kit, Osaka, Japan) as
previously reported (14). The intra- and interassay coefficients of
variation were 4.7% and 5.8%, respectively. The cross-reactivity with
human BNP was less than 0.001% on a molar basis. The plasma BNP
concentration was measured with a specific RIA for human BNP as
previously reported (15). The intra- and interassay coefficients of
variation were 8.4% and 6.4%, respectively. The cross-reaction for
-human ANP was less than 0.001% on a molar bias.
The plasma DHEAS concentration was measured by RIA (Diagnostic Products, Los Angeles, CA). The intra- and interassay coefficients of variation were 7.2% and 8.3%, respectively. The plasma cortisol concentration was measured by RIA (INCSTAR Corp., Stillwater, MN). The intra- and interassay coefficients of variation were 5.0% and 8.7%, respectively.
Assays of plasma TBARS
The lipid peroxidation product in plasma samples, into which butylated hydroxytoluene at a final concentration of 20 nmol/mL was added, was measured in terms of TBARS (21). TBARS is expressed using malondialdehyde equivalents as a standard. The intra- and interassay coefficients of variation were 7.5% and 9.6%, respectively.
Statistical analysis
Comparisons between patients with CHF and age-matched controls
were made using the 
2 test or Student’s
t test, and comparisons among controls and subgroups with
each New York Heart Association (NYHA) class were made by one-way ANOVA
with factorial measurements, followed by Games-Howell test. To analyze
relationships between variables, linear regression and stepwise
regression analyses were performed. The presence or absence of coronary
risk factors (smoking and diabetes mellitus) was coded as a dummy
variable (i.e. absence = 0, presence = 1) in the
stepwise regression model. Statistical significance was defined as
P < 0.05.
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Results |
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Figure 1A
shows correlations
between age and plasma level of DHEAS or cortisol or the plasma
cortisol/DHEAS ratio in 211 subjects. There was a significantly inverse
correlation between plasma levels of DHEAS and age (r = -0.63;
P < 0.0001), whereas there was no correlation between
the plasma level of cortisol and age (r = 0.09; P
= NS). The plasma cortisol/DHEAS ratio was significantly and positively
correlated with age (r = 0.34; P < 0.0001).
Figure 1B shows correlations between ages and plasma levels of DHEAS
and cortisol and the plasma cortisol/DHEAS ratio in patients with CHF
and age-matched controls. There was a significant and inverse
correlation between age and plasma level of DHEAS in controls (r =
-0.60; P < 0.01), whereas this correlation was
not found in patients with CHF (r = -0.22; P =
NS). There was no correlation between plasma level of cortisol and age
in patients with CHF or age-matched controls. The plasma cortisol/DHEAS
ratio was also significantly correlated with age in controls (r =
0.50; P < 0.01.), whereas the correlation was not
found in patients with CHF (r = 0.01; P = NS)
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Clinical characteristics in patients with CHF and age-matched
controls are shown in Table 1. There was
no significant difference in age among controls and patients with NYHA
classes I–IV. There also were no significant differences in smoking
status, serum cholesterol levels, and body mass index among the four
groups. Patients with NYHA I had higher proportion of diabetic mellitus
than controls. The type of patients with diabetes mellitus were all
type 2 diabetes mellitus.
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Table 2 and Fig. 2 show plasma levels of ANP, BNP,
cortisol, and DHEAS in patients with CHF and age-matched controls.
Plasma levels of both ANP and BNP were increased in proportion to the
severity of the NYHA classification. Plasma levels of DHEAS were
significantly lower in patients with patients with all CHF than in
controls (79.0 ± 6.7 µg/dL in all CHF vs. 131.8
± 19.1 µg/dL in controls; P < 0.01). Moreover, the
levels of plasma DHEAS were significantly lower in patients with NYHA
classes III–IV than in patients with NYHA class I and controls
(53.0 ± 8.0 µg/dL in NYHA classes III–IV vs.
94.8 ± 11.2 µg/dL in NYHA class I, P < 0.05;
NYHA classes III–IV vs. controls, P <
0.01; Fig. 2A). There was no significant difference in plasma levels of
cortisol among the four groups (11.3 ± 0.7 µg/dL in controls,
12.3 ± 0.9 µg/dL in NYHA class I, 12.8 ± 1.0 µg/dL in
NYHA class II, and 12.2 ± 1.0 µg/dL in NYHA classes III—IV;
Fig. 2B). The plasma cortisol/DHEAS ratio and the plasma levels of
TBARS were significantly increased in patients with CHF compared with
controls [plasma cortisol/DHEAS ratio, 0.24 ± 0.03 in CHF
vs. 0.13 ± 0.01 in controls (P <
0.01); plasma TBARS, 8.6 ± 0.3 in CHF vs. 7.2 ±
0.3 in controls (P < 0.01)]. The plasma
cortisol/DHEAS ratio and the plasma TBARS level were significantly
higher in patients with NYHA classes III–IV than in controls (Table 2).
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Table 3 and Figs. 3 and 4
show correlations among the hemodynamic parameters (PCWP and LVEF) and
plasma levels of ANP, BNP, DHEAS, cortisol, and TBARS in patients with
CHF and age-matched controls. Plasma levels of ANP and BNP were
significantly and negatively correlated with LVEF and significantly and
positively correlated with PCWP (Fig. 3). Plasma levels of DHEAS were
significantly and positively correlated with LVEF, and inversely
correlated with plasma levels of ANP and BNP and PCWP (Fig. 4A and
Table 3). The plasma cortisol/DHEAS ratio was also significantly and
positively correlated with plasma levels of ANP and BNP and PCWP and
negatively correlated with LVEF (Fig. 4B and Table 3). The plasma
levels of cortisol were correlated with none of these parameters. The
plasma TBARS level was significantly and positively correlated with the
plasma BNP level (r = 0.24; P < 0.03) and
negatively correlated with LVEF (Table 3). Moreover, there was a
significant inverse correlation between the plasma level of DHEAS and
that of TBARS, and there was a positive correlation between the plasma
cortisol/DHEAS ratio and the plasma level of TBARS (Fig. 5). The plasma levels of ANP and BNP were
significantly and closely correlated with each other (r = 0.87;
P < 0.001).
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Tables 4 and 5 show stepwise regression analyses for
the determination of the plasma levels of DHEAS and the plasma
cortisol/DHEAS ratio in patients with CHF and age-matched controls.
Ages, current smoking status, diabetes mellitus, serum total
cholesterol level, body mass index, mean arterial pressure, LVEF, PCWP,
and the plasma levels of ANP, BNP, and TBARS were included in this
analysis as independent variables. The plasma levels of DHEAS were
significantly and independently correlated with age and the plasma
level of BNP (Table 4). The plasma cortisol/DHEAS ratio was
significantly and independently correlated with the plasma levels of
ANP and TBARS and age (Table 5).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We and others have shown that ANP is secreted from atria in normal adult humans and also from ventricles in proportion to the severity of left ventricular dysfunction in patients with CHF and that BNP is secreted and released mainly from the left ventricles in proportion to the severity of the left ventricular dysfunction in patients with CHF (12, 13, 14, 15, 16). Furthermore, whereas a high plasma level of ANP has been reported to be a sensitive marker of heart failure (12, 13), there is increasing evidence that BNP is a more sensitive marker of the severity of the heart failure (12, 13, 14, 15, 16, 17, 18). The present study also showed that plasma levels of ANP and BNP were closely correlated with left ventricular dysfunction, in agreement with our previous results (12, 13, 14). In the present study stepwise regression analysis showed that the plasma level of DHEAS and the plasma cortisol/DHEAS ratio were significantly correlated with plasma levels of BNP and ANP, respectively, independently of age and other clinical variables. These results indicate that the plasma level of DHEAS is decreased and the plasma cortisol/DHEAS ratio is increased in proportion to the severity of CHF independently of age. ANP and BNP as sensitive markers of left ventricular dysfunction may account for our finding that plasma levels of ANP and BNP are stronger predictors of the plasma cortisol/DHEAS ratio and the plasma DHEAS level than hemodynamic variables. Furthermore, because of the close correlation between plasma levels of ANP and BNP, when one was independently correlated with the plasma level of DHEAS or the plasma cortisol/DHEAS ratio in stepwise regression analysis, another was not. Recently, Anker et al. reported that levels of DHEA were decreased in patients with CHF (11). However, they compared the levels between controls and patients with CHF without adjusting for age and failed to show an association between the DHEA level and the severity of heart failure.
In the present study there was no significant correlation between plasma levels of cortisol and ages. Recently, it was reported that 24-h mean and nocturnal nadir levels of cortisol were significantly and positively correlated with age, whereas morning acrophase levels of cortisol were not in men (4, 5). However, our samples were drawn in the morning. Thus, our data are not inconsistent with these findings.
Possible mechanisms
In the present study plasma levels of DHEAS were decreased in
patients with CHF compared to those in controls, whereas plasma levels
of cortisol did not differ between the two groups. This suggests that
adrenal androgen secretion is selectively suppressed in patients with
CHF. DHEA(S) is synthesized by the enzyme cytochrome
P450C17 that catalyzes both the hydroxylation of the
C17 pregnenolone (17-hydroxylase activity) and
cleavage of the residual two-carbon side-chain at
C17 (17,20-lyase activity) in the adrenal zona
reticularis in humans (22, 23, 24). The dual function of this enzyme allows
direction of the steroid precursors along several different pathways:
17-hydroxylated substrates with the side-chain intact are
glucocorticoid precursors, whereas generation of
C19 steroids by both 17-hydroxylase and
17,20-lyase activities directs substrate toward androgen and estrogen
synthesis (22, 23, 24). It is suggested that inhibition of the electron
transport from NADPH-P450 reductase to cytochrome P450C17 selectively
interferes with 17,20-lyase activity (24, 25).
Oxidative stress has been suggested to be increased in patients with heart failure (19, 20). Recently, it was reported that glutathione, an antioxidant, increases the affinity between cytochrome P450 and NADPH-P450 reductase and enhances cytochrome P450 3A4 activity (26). The present study also showed that plasma levels of TBARS, a marker of oxidative stress, were increased in patients with CHF and negatively correlated with those of DHEAS. These findings suggest that increased oxidative stress may disturb the electron transport to cytochrome P450C17 and selectively suppress 17,20-lyase activity in patients with CHF.
It was reported that infusion of ANP significantly suppressed plasma levels of cortisol, but not those of DHEA (27). In in vitro experiments, ANP and BNP were reported to inhibit the secretion of both cortisol and DHEA (28). On the other hand, in the present study plasma levels of DHEAS were decreased, whereas plasma levels of cortisol were not, in patients with CHF. These results indicate that the decrease in DHEAS in patients with CHF was related to the severity of heart failure and was not caused by direct effects of ANP or BNP on the adrenal. We and others have shown that the renin-angiotensin system is activated in patients with CHF (29, 30, 31). Angiotensin II, an effector of the renin-angiotensin system, has been reported to stimulate the secretion of DHEA(S) and cortisol in an in vitro study (32, 33). However, plasma levels of DHEAS were decreased in patients with heart failure in the present study. Thus, the decrease in DHEAS in patients with CHF may not have been caused by direct effects of an activated renin-angiotensin system on adrenals.
In the present study, patients with CHF had a higher proportion of diabetes mellitus than controls. Diabetes mellitus is established as a risk factor for myocardial infarction (34), and a high degree of insulin resistance and hyperinsulinemia has been reported in patients with coronary artery disease (35) and CHF (36). Thus, our data are in agreement with these findings. Because hyperinsulinemia is reported to inhibit DHEAS production (37), we cannot exclude the possibility that the presence of diabetes influenced the decreased level of DHEAS in patients with CHF. However, in the present study, multivariate analyses showed that plasma levels of DHEAS were significantly and negatively correlated with plasma levels of BNP independently of the presence of diabetes mellitus. These data indicate that plasma levels of DHEAS are decreased in proportion to the severity of CHF despite the presence or absence of diabetes mellitus.
In conclusion, we demonstrated that plasma levels of DHEAS were decreased in patients with CHF in proportion to its severity. Increased oxidative stress may play a role in the decreased plasma levels of DHEAS in patients with CHF.
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Footnotes |
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Received September 29, 1999.
Revised December 29, 1999.
Accepted January 12, 2000.
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References |
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in pericardial fluid of patients with heart failure.
A potential role for in vivo oxidant stress in
ventricular dilatation and progression to heart failure. Circulation. 97:1536–1539.-atrial natriuretic polypeptide
on adrenocortical function in man. J Endocrinol. 110:287–292.[Abstract]
-hydroxylase and 3ß-hydroxysteroid
dehydrogenase expression in human adrenocortical H295R cells. J
Clin Endocrinol Metab. 81:2171–2178.[Abstract]
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