(Circulation. 2001;103:72.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Aldosterone Production Is Activated in Failing Ventricle in Humans
From the Division of Cardiology (Y.M., H.Y.), Kumamoto Aging Research Institute; Department of Cardiovascular Medicine (M.Y., T.S., H.O., K.K., E.H., M.N., S.N., T.I., Y. Shimasaki), Kumamoto University School of Medicine, Kumamoto; and Department of Medicine and Clinical Science (Y. Saito, K.N.), Kyoto University Graduate School of Medicine, Kyoto, Japan.
Correspondence to Hirofumi Yasue, MD, PhD, Division of Cardiology, Kumamoto Aging Research Institute, 6-8-1 Yamamuro, Kumamoto City 860-8518, Japan. E-mail yasue{at}juryo.or.jp
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Abstract |
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Background—Recent reports have indicated that aldosterone is produced in extra-adrenal tissues in animals. The present study was designed to examine whether aldosterone is produced in human heart.
Methods and Results—Plasma levels of aldosterone, BNP, and angiotensin-converting enzyme were measured in anterior interventricular vein (AIV), coronary sinus (CS), and aortic root (Ao), respectively, in 20 patients with left ventricular systolic dysfunction (LVSD), 25 patients with LV diastolic dysfunction (LVDD), and 23 control subjects. Aldosterone levels were significantly higher in AIV and CS than Ao in LVSD (98±10 versus 72±9 pg/mL, P<0.001, and 97±11 versus 72±9 pg/mL, P<0.001, respectively) and LVDD (87±10 versus 71±9 pg/mL, P<0.01, and 84±10 versus 71±9 pg/mL, P<0.01, respectively) groups, but no differences were observed in levels for these sites in the control group. Levels of ACE activity and BNP also were higher in AIV than Ao in both LV dysfunction groups. The difference in aldosterone levels between AIV and Ao and those in BNP and angiotensin-converting enzyme had a significant positive correlation with LVEDP and a significant negative correlation with LV ejection fraction in the LVSD group.
Conclusions—Production of aldosterone, angiotensin-converting enzyme, and BNP are activated in failing human ventricle in proportion to severity.
Key Words: aldosterone • angiotensin-converting enzyme • angiotensin • B-type natriuretic peptide • ventricles
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Aldosterone plays an important role in the pathophysiology of heart failure.1 2 This substance promotes retention of sodium and loss of potassium, activates the sympathetic nervous system and myocardial and vascular fibrosis, and causes baroreceptor dysfunction.1 2 3 4 5 Traditionally, aldosterone has been thought to be produced solely by adrenal cortex in response to angiotensin II, making it an important component of the circulating renin-angiotensin-aldosterone system.1
Recently, some workers reported that aldosterone is produced also in extra-adrenal tissues, including heart and blood vessels, in animals.6 7 8 9 10 However, whether aldosterone is produced in human heart, particularly in failing heart, is unknown.
Coronary sinus drains blood from the heart as a whole, and the anterior interventricular vein (AIV), which lies in the anterior interventricular groove, drains blood from the anterior left ventricle (LV).11 Therefore, the difference in hormone level between AIV and aortic root reflects the level of hormone from the LV, and that between the coronary sinus and aortic root reflects hormone level from the whole heart. By the use of this method, we showed that production of A-type (ANP), and B-type (BNP) natriuretic peptides was activated in the LV in patients with heart failure.12 13 14 15 We also showed by use of this method that angiotensin-converting enzyme (ACE) activity from LV is increased in patients with LV dysfunction (LVD).15
The present study was designed to examine whether aldosterone is produced in addition to ACE and BNP in hearts of patients with LVD. We measured plasma levels of aldosterone together with those of BNP and serum ACE.
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Methods |
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Subjects
The study population consisted of 45 patients with LVD who underwent cardiac catheterization at our institution. Patients were divided into systolic dysfunction (20 patients; 14 men and 6 women; mean age, 56.0±3.0 years; and age range, 33 to 72 years) and isolated diastolic dysfunction (25 patients; 16 men and 9 women; mean age, 58.0±3.0 years; and age range, 20 to 83 years) groups. Underlying cardiac disorders were dilated cardiomyopathy in 12 patients, old myocardial infarction in 6, and hypertensive heart disease in 2 in the systolic dysfunction group and hypertrophic cardiomyopathy in 13, hypertensive heart disease in 5, mitral regurgitation in 5, and aortic valvular regurgitation in 2 in diastolic dysfunction group. We defined LV systolic dysfunction (LVSD) as LV ejection fraction (LVEF) <55% and isolated LV diastolic dysfunction (LVDD) as LV end-diastolic pressure (LVEDP) >12 mm Hg, with LVEF >55% in the present study. Patients with severe heart failure were excluded from the study. All medications, including ACE inhibitors, angiotensin II receptor antagonists, aldosterone receptor blockers, nitrates, Ca antagonists, adrenergic ß-antagonists, and diuretics, were withheld in all patients for
4 days before study. The control group comprised 23 patients (15 men and 8 women; mean age, 60.0±3.0 years; age range, 23 to 78 years) in whom diagnostic cardiac catheterization, including coronary angiography and left ventriculography, was performed. Twenty control patients had atypical chest pain with normal coronary angiograms, and 3 patients had stable angina pectoris. None had myocardial infarction, cardiac hypertrophy, other heart muscle diseases, electrolyte disturbance, renal impairment (serum creatinine >2.0 mg/mL), or hypertension.
The study protocol was in agreement with the guidelines of the ethics committee at our institution, and written informed consent was obtained from each patient before study, including consent for withholding of medication.
Cardiac Catheterization Study
Cardiac catheterization was performed in the morning,
with patients in a fasting state. Hemodynamic measurements, including
pulmonary artery pressure, pulmonary capillary wedge pressure, right
atrial pressure, and cardiac output, were performed with a Swan-Ganz
catheter inserted into the femoral or subclavian vein. Cardiac output
was determined by use of the thermodilution technique in triplicate.
After right heart catheterization was completed, a 6F Goodale-Lubin
catheter was placed in the coronary sinus through a brachial
vein.
The catheter was then advanced into the AIV fluoroscopically by use of a guidewire.12 13 14 15 Position of catheter tip in AIV was confirmed by injection of contrast dye medium. Patients in whom at least the proximal half of the AIV was not visualized were excluded from study. A Judkins catheter was placed at the root of the aorta by way of the femoral artery. Blood was sampled within 2 minutes at the aortic root, AIV, and coronary sinus. Care was taken to draw blood samples slowly from the AIV. Initial parts of the sample, including those forcibly drawn, were discarded, because forcible drawing of blood from the AIV resulted in spurious levels of hormone, probably because backflow from the coronary sinus occurred and contaminated the AIV.11 12
Systemic arterial pressure, heart rate, and LVEDP were measured, and coronary arteriography and left ventriculography were performed. LVEF was determined by left ventriculograms.
Hormonal Analysis
Plasma levels of aldosterone were measured in
duplicate by commercially available radioimmunoassay kits (SPAC-S
aldosterone kit; Dainabot
Inc).16 The minimal
detectable quantity of aldosterone was 25 pg/mL. Intra-assay and
interassay coefficients of variation were 4.7% and 4.5%,
respectively. Serum ACE activity was measured in duplicate by
colorimetry using commercially available kits (ACE color; Fujirebio
Inc).17 Intra-assay and
interassay coefficients of variation by this method were 6.7% and
8.3%, respectively. Plasma levels of BNP were measured with a specific
immunoradiometric assay for human BNP (Shionoria BNP kit; Shionogi) as
reported previously.18
Minimal detectable quantity of human BNP is 4 pg/mL. Intra-assay and
interassay coefficients of variation were 5.3% and 5.9%,
respectively.
Statistical Analysis
All values are expressed as mean±SE. Statistical
significance was defined as a probability value <0.05. Unpaired
t test or 1-way ANOVA was used
to analyze results of hemodynamic or hormonal
measurements.19 Hormonal
levels at the aortic root, AIV, and coronary sinus within each group
were compared with 2-way ANOVA with repeated measurements followed by
Scheffé’s test. Correlation of plasma levels of aldosterone and BNP
as well as serum levels of ACE activity with hemodynamic parameters
were examined by use of linear regression
analysis.
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Results |
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Cardiac Catheterization Data
The Table
shows cardiac catheterization data for patients with LVSD and LVDD and
control subjects. LVEDP, LV end-diastolic volume index, and LV
end-systolic volume index were significantly increased, and mean
arterial blood pressure, cardiac index, and LVEF were significantly
decreased in patients with LVSD versus control subjects. Mean arterial
blood pressure and LVEDP were significantly higher in the LVDD group
than in the control group.
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Comparison of Hormonal Levels
Figure 1 shows plasma aldosterone levels, serum ACE
activity, and plasma BNP levels in aortic root, AIV, and coronary sinus
in LVSD and LVDD groups versus control subjects.
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In the LVSD group, plasma levels of aldosterone were significantly higher in AIV and coronary sinus than aortic root (98±10 versus 72±9 pg/mL, P<0.001, and 97±11 versus 72±9 pg/mL, P<0.001, respectively), whereas no difference existed in levels between AIV and coronary sinus. Plasma aldosterone levels in the LVSD group were significantly higher in AIV (98±10 versus 58±6 pg/mL; P<0.001) and coronary sinus (97±11 versus 62±7 pg/mL; P<0.01) than in the control group.
In the LVDD group, plasma levels of aldosterone were significantly higher in AIV and coronary sinus than aortic root (87±10 versus 71±9 pg/mL, P<0.01, and 84±10 versus 71±9 pg/mL, P<0.01, respectively), whereas levels were not different between AIV and coronary sinus. Plasma levels of aldosterone in the LVDD group were significantly higher in AIV (87±10 versus 58±6 pg/mL; P<0.01) and coronary sinus (84±10 versus 62±7 pg/mL; P<0.01) than in controls. On the other hand, no significant differences were seen in plasma aldosterone levels among aortic root, AIV, and coronary sinus (61±7, 58±6, and 62±7 pg/mL, respectively) in the control group.
In the LVSD group, serum ACE activity was significantly higher in AIV and coronary sinus than in aortic root (13.2±0.7 versus 11.9±0.6 pg/mL, P<0.001, and 13.1±0.7 versus 11.9±0.6 pg/mL, P<0.001, respectively), whereas levels were not significantly different between AIV and coronary sinus. ACE activity levels were significantly higher in AIV (13.2±0.7 versus 10.6±0.7 pg/mL; P<0.01) and coronary sinus (13.1±0.7 versus 10.8±0.8 pg/mL; P<0.01) compared with controls. In the LVDD group, serum ACE activities were not significantly different for every sampling point, and levels were not different from those of the control group. No significant difference existed in ACE activity among the aortic root, AIV, and coronary sinus (10.7±0.7, 10.6±0.7, and 10.8±0.8 pg/mL, respectively) in the control group.
In the LVSD group, plasma BNP levels were significantly higher in AIV and coronary sinus than aortic root (673±121 versus 232±58 pg/mL, P<0.001, and 694±127 versus 232±58 pg/mL, P<0.001), whereas levels were not different between AIV and the coronary sinus. Plasma BNP levels in the LVSD group were significantly higher in aortic root (232±58 versus 20±2 pg/mL, P<0.001), AIV (673±121 versus 74±13 pg/mL, P<0.001), and coronary sinus (694±127 versus 79±15 pg/mL, P<0.001) versus the control group. In the LVDD group, plasma levels of BNP were significantly higher in AIV and coronary sinus than aortic root (215±72 versus 78±9 pg/mL, P<0.001, and 200±65 versus 78±9 pg/mL, P<0.001, respectively), with levels not different between AIV and coronary sinus. Plasma levels of BNP in the LVDD group tended to be higher at every sampling point compared with those of the control group. In the control group, plasma levels of BNP were significantly higher in AIV and coronary sinus than aortic root (74±13 versus 20±2 pg/mL, P<0.001, and 79±15 versus 20±2 pg/mL, P<0.001), whereas levels were not different between AIV and coronary sinus.
Correlation of Cardiac Hormones With
Hemodynamic Parameters
The difference in plasma aldosterone levels between the
AIV and the aortic root (
Aldo [AIV-Ao], where Ao indicates aortic
root) had a significant negative correlation with LVEF and a
significant positive correlation with LVEDP in the LVSD group
(Figure 2, left). On the other hand, the Aldo (AIV-Ao) had
no significant correlation with either LVEF or LVEDP in the LVDD group
(Figure 3, left).
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indicates control subjects; •, patients with systolic dysfunction.
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The difference in serum ACE activity (ACE [AIV-Ao]) had
a significant negative correlation with LVEF and a significant positive
correlation with LVEDP in the LVSD group
(Figure 2
, center) but no correlation with either LVEF or
LVEDP in the LVDD group
(Figure 3, center).
The difference in plasma BNP levels (BNP [AIV-Ao]) had
a significant negative correlation with LVEF and a significant positive
correlation with LVEDP in the LVSD group
(Figure 2, right). In the LVDD group, BNP (AIV-Ao) had
only a weakly significant correlation with LVEDP
(Figure 3, right).
Correlations Among Cardiac Aldosterone, ACE
Activity, and BNP
In the LVSD group, Aldo (AIV-Ao) had a significant
positive correlation with ACE (AIV-Ao) but no correlation with
BNP (AIV-Ao)
(Figure 4A). A significant positive correlation occurred
between ACE (AIV-Ao) and BNP (AIV-Ao)
(Figure 4A).
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In the LVDD group, Aldo (AIV-Ao) had a significant
positive correlation with ACE (AIV-Ao), whereas it had no
correlation with BNP (AIV-Ao)
(Figure 4B) as in the LVSD group. A significant positive
correlation occurred between ACE (AIV-Ao) and BNP (AIV-Ao)
(Figure 4B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In the present study, plasma level of aldosterone was increased significantly between AIV and aortic root in failing human ventricle, particularly when failure was caused by systolic dysfunction. No significant difference occurred in plasma aldosterone level in controls, which indicates that aldosterone production is activated in failing human LV but not in normal human heart. However, the difference in aldosterone level between AIV and aortic root was modest, which suggests that the function of cardiac aldosterone may be mainly paracrine or autocrine. Aldosterone effects are mediated by binding of the hormone to its specific receptor, the mineralocorticoid receptor (MR), and both MR and MR-protecting 11ß-hydroxysteroid dehydrogenase (11-HSD) have been shown to be expressed in human heart.20 21
The present study also showed that levels of serum ACE activity were increased significantly between AIV and aortic root in failing hearts with systolic dysfunction but not significantly in failing hearts with diastolic dysfunction or control hearts. These results are in agreement with those of our previous studies15 and indicate that ACE production also was activated in failing ventricles of humans with systolic dysfunction. However, the absolute differences in ACE activity between AIV and aortic root were small, which indicates that the biological function of cardiac ACE is mainly autocrine, paracrine, or both.
On the other hand, differences in BNP levels between AIV and aortic root were highly significant in failing ventricles with systolic dysfunction as well as failing ventricles with diastolic dysfunction and control hearts. This indicates that the heart is the main source of BNP production and the endocrine organ for circulating BNP. These results are in agreement with those of our previous studies.13 14 15 22
The exact mechanism for induction of aldosterone into the failing heart is not clear. Aldosterone synthesis is mainly stimulated by angiotensin II, the active peptide of renin-angiotensin system, but its production is also controlled by potassium, adrenocorticotropic hormone, and natriuretic peptides, including ANP and BNP.23 24 25 26 27 28 In the present study, levels of aldosterone had a highly significant positive correlation with levels of ACE activity in failing ventricles. This result suggests that increased activity of local ACE, causing conversion of angiotensin I to angiotensin II, may stimulate production of aldosterone in failing hearts in a paracrine or autocrine manner. Indeed, Silvestre and coworkers10 recently showed that cardiac aldosterone is activated in rat heart with myocardial infarction and that this is mediated primarily by cardiac angiotensin II. They further showed that aldosterone synthase mRNA was elevated in infarcted rat ventricles.10
Cardiac aldosterone, ACE, and BNP had significant positive correlations with LVEDP and significant negative correlations with LVEF in patients with LVSD. These results are in agreement with those of our previous studies13 14 15 22 and suggest that increased wall tension or stretch in the dilated ventricles may be a main stimulus for activation of cardiac aldosterone as well as ACE and BNP production in ventricles with systolic dysfunction. On the other hand, no significant correlation was found between cardiac hormones and LVEDP except cardiac BNP, which had a weak correlation with LVEDP in patients with isolated LVDD. The results indicate that systolic dysfunction is more important than diastolic dysfunction for activation of cardiac aldosterone as well as ACE and BNP in failing hearts.
No significant correlation existed between levels of aldosterone and BNP in failing ventricles. This result probably is due to the fact that aldosterone production is stimulated by angiotensin II but suppressed by natriuretic peptides (ANP and BNP) in failing hearts.23 24 25 26 27 28 We and others have shown that ANP and BNP directly suppress aldosterone production.25 26 27 28
Clinical Implications
Aldosterone was originally thought to be important in
the pathophysiology of heart failure only because of its ability to
increase sodium retention and potassium loss. However, Weber et
al4 and Young et
al5 have shown that
aldosterone promotes myocardial and vascular fibrosis independent of
the hemodynamic effects. Aldosterone also causes direct vascular damage
and baroreceptor dysfunction and prevents uptake of norepinephrine by
the
myocardium.4 29 30
Recently, Pitt and
coworkers31 showed that
blocking aldosterone with a low dose of spironolactone substantially
reduced the risks of morbidity and mortality among patients with severe
heart failure (RALES trial). Efficacy of an aldosterone blockade in
their trial does not appear to be due entirely to prevention of
sodium retention or potassium loss.
The present study shows that aldosterone production is activated in failing ventricles of humans. Concentration of aldosterone within the heart is reported to greatly exceed circulating concentrations.9 Thus, cardiac aldosterone may play an important role in the pathophysiology of heart failure, and aldosterone receptor antagonists may ameliorate heart failure by blocking the action of locally produced aldosterone in failing heart.
Conclusions
We conclude that the production of aldosterone, in
addition to ACE and BNP, is activated in failing human ventricles in
proportion to severity, particularly of systolic
dysfunction.
Received June 14, 2000; revision received August 7, 2000; accepted August 17, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. 1. Laragh JH. Hormones in the pathogenesis of congestive heart failure: vasopressin, aldosterone, angiotensin II. Circulation. 1962;25:1015–1023.
2. Dzau VJ. Circulating versus local renin-angiotensin system in cardiovascular homeostasis. Circulation. 1988;77(suppl I):I-4–I-13.
3.
Swedberg K,
Eneroth P, Kjekshus J, et al. Hormones regulating cardiovascular
function in patients with severe congestive heart failure and their
relation to mortality: CONSENSUS trial study group.
Circulation. 1990;82:1730–1736.
4.
Weber KT, Brilla
CG. Pathological hypertrophy and cardiac interstitium: fibrosis and
renin-angiotensin-aldosterone system.
Circulation. 1991;83:1849–1865.
5. Young M, Fullerton M, Dilley R, et al. Mineralocorticoids, hypertension, and cardiac fibrosis. J Clin Invest. 1994;93:2578–2583.
6.
Mukai K, Imai M,
Shimada H, et al. Isolation and characterization of rat CYP11B genes
involved in late steps of mineralo- and glucocorticoid syntheses.
J Biol Chem. 1993;268:9130–9137.
7.
Hatakeyama H,
Miyamori I, Fujita T, et al. Vascular aldosterone: biosynthesis and a
link to angiotensin II-induced hypertrophy of vascular smooth muscle
cells. J Biol Chem. 1994;269:24316–24320.
8.
Gomez-Sanchez CE,
Zhou MY, Cozza EN, et al. Aldosterone biosynthesis in the rat brain.
Endocrinology. 1997;138:3369–3373.
9.
Silvestre JS,
Robert V, Heymes C, et al. Myocardial production of aldosterone and
corticosterone in the rat: physiological regulation.
J Biol Chem. 1998;273:4883–4891.
10.
Silvestre JS,
Heymes C, Oubenaissa A, et al. Activation of cardiac aldosterone
production in rat myocardial infarction: effect of angiotensin II
receptor blockade and role in cardiac fibrosis.
Circulation. 1999;99:2694–2701.
11. Roberts DL, Nakazawa HK, Klocke FJ. Origin of great cardiac vein and coronary sinus drainage within the left ventricle. Am J Physiol. 1976;230:486–492.
12. Yasue H, Obata K, Okumura K, et al. Increased secretion of atrial natriuretic polypeptide from the left ventricle in patients with dilated cardiomyopathy. J Clin Invest. 1989;83:46–51.
13. Mukoyama M, Nakao K, Saito Y, et al. Brain natriuretic peptide (BNP) as a novel cardiac hormone in humans: evidence for an exquisite dual natriuretic peptide system, ANP and BNP. J Clin Invest. 1991;87:1402–1412.
14.
Yasue H,
Yoshimura M, Sumida H, et al. Localization and mechanism of secretion
of B-type natriuretic peptides in comparison with those of A-type
natriuretic peptide in normal subjects and patients with heart failure.
Circulation. 1994;90:195–203.
15. Sumida H, Yasue H, Matsuyama K, et al. Cardiac angiotensin-converting enzyme activity in myocardial infarction. Am J Cardiol. 1999;84:774–778.[Medline] [Order article via Infotrieve]
16. Shionoiri H, Minamizawa K, Sugimoto K, et al. Fundamental and clinical studies on SPAC-S Aldosterone RIA Kit. Jpn J Med Pharm Sci. 1989;21:293–302.
17.
Kasahara Y,
Ashihara Y. Colorimetry of angiotensin-I converting enzyme activity in
serum. Clin Chem. 1981;27:1922–1925.
18. Kono M, Yamauchi A, Tsuji T, et al. An immunoradiometric assay for brain natriuretic peptide in human plasma. Kaku Igaku. 1993;13:2–7.
19. Zar JH. Biostatistical Analysis. 2nd ed. Englewood Cliffs, NJ: Prentice-Hall International; 1984:162–184.
20.
Lombes M, Alfaidy
N, Eugene E, et al. Prerequisite for cardiac aldosterone action:
mineralocorticoid receptor and 11 ß-hydroxysteroid dehydrogenase in
the human heart. Circulation. 1995;92:175–182.
21.
Funder JW, Pearce
PT, Smith R, et al. Mineralocorticoid action: target tissue specificity
is enzyme, not receptor, mediated.
Science. 1988;242:583–585.
22.
Yoshimura M,
Yasue H, Okumura K, et al. Different secretion patterns of atrial
natriuretic peptide and brain natriuretic peptide in patients with
congestive heart failure.
Circulation. 1993;87:464–469.
23. Quinn SJ, Williams GH. Regulation of aldosterone secretion. Annu Rev Physiol. 1988;50:409–426.[Medline] [Order article via Infotrieve]
24.
Clyne CD, Zhang
Y, Slutsker L, et al. Angiotensin II and potassium regulate human
CYP11B2 transcription through common cis-elements.
Mol Endocrinol. 1997;11:638–649.
25. Kudo T, Baird A. Inhibition of aldosterone production in the adrenal glomerulosa by atrial natriuretic factor. Nature. 1984;312:756–757.[Medline] [Order article via Infotrieve]
26.
Atarashi K,
Mulrow PJ, Franco-Saenz R, et al. Inhibition of aldosterone production
by an atrial extract. Science. 1984;224:992–994.
27.
Saito Y, Nakao K,
Nishimura K, et al. Clinical application of atrial natriuretic
polypeptide in patients with congestive heart failure: beneficial
effects on left ventricular function.
Circulation. 1987;76:115–124.
28.
Yoshimura M,
Yasue H, Morita E, et al. Hemodynamic, renal, and hormonal responses to
brain natriuretic peptide infusion in patients with congestive heart
failure. Circulation. 1991;84:1581–1588.
29.
Wang W. Chronic
administration of aldosterone depresses baroreceptor reflex function in
the dog. Hypertension. 1994;24:571–575.
30. Barr CS, Lang CC, Hanson J, et al. Effects of adding spironolactone to an angiotensin-converting enzyme inhibitor in chronic congestive heart failure secondary to coronary artery disease. Am J Cardiol. 1995;76:1259–1265.[Medline] [Order article via Infotrieve]
31.
Pitt B, Zannad F,
Remme WJ, et al. The effect of spironolactone on morbidity and
mortality in patients with severe heart failure: Randomized Aldactone
Evaluation Study Investigators. N
Engl J Med. 1999;341:709–717.
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 A. Goette, K. Jentsch-Ullrich, M. Hammwohner, S. Trautmann, A. Franke, H. U. Klein, and A. Auricchio Cardiac uptake of progenitor cells in patients with moderate-to-severe left ventricular failure scheduled for cardiac resynchronization therapy. Europace, March 1, 2006; 8(3): 157 - 160. [Abstract] [Full Text] [PDF]
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 A. M. Deschamps and F. G. Spinale Pathways of matrix metalloproteinase induction in heart failure: Bioactive molecules and transcriptional regulation Cardiovasc Res, February 15, 2006; 69(3): 666 - 676. [Abstract] [Full Text] [PDF]
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P. Ye, C. J. Kenyon, S. M. MacKenzie, A. S. Jong, C. Miller, G. A. Gray, A. Wallace, A. S. Ryding, J. J. Mullins, M. W. McBride, et al. The Aldosterone Synthase (CYP11B2) and 11{beta}-Hydroxylase (CYP11B1) Genes Are Not Expressed in the Rat Heart Endocrinology, December 1, 2005; 146(12): 5287 - 5293. [Abstract] [Full Text] [PDF]
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 S. Nattel Aldosterone antagonism and atrial fibrillation: time for clinical assessment? Eur. Heart J., October 2, 2005; 26(20): 2079 - 2080. [Full Text] [PDF]
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T. Karram, A. Abbasi, S. Keidar, E. Golomb, I. Hochberg, J. Winaver, A. Hoffman, and Z. Abassi Effects of spironolactone and eprosartan on cardiac remodeling and angiotensin-converting enzyme isoforms in rats with experimental heart failure Am J Physiol Heart Circ Physiol, October 1, 2005; 289(4): H1351 - H1358. [Abstract] [Full Text] [PDF]
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 J. M C Connell and E. Davies The new biology of aldosterone J. Endocrinol., July 1, 2005; 186(1): 1 - 20. [Abstract] [Full Text] [PDF]
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D. Fraccarollo, P. Galuppo, I. Schmidt, G. Ertl, and J. Bauersachs Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction Cardiovasc Res, July 1, 2005; 67(1): 97 - 105. [Abstract] [Full Text] [PDF]
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A. Fiebeler, J. Nussberger, E. Shagdarsuren, S. Rong, G. Hilfenhaus, N. Al-Saadi, R. Dechend, M. Wellner, S. Meiners, C. Maser-Gluth, et al. Aldosterone Synthase Inhibitor Ameliorates Angiotensin II-Induced Organ Damage Circulation, June 14, 2005; 111(23): 3087 - 3094. [Abstract] [Full Text] [PDF]
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J. Katada, T. Meguro, H. Saito, A. Ohashi, T. Anzai, S. Ogawa, and T. Yoshikawa Persistent Cardiac Aldosterone Synthesis in Angiotensin II Type 1A Receptor-Knockout Mice After Myocardial Infarction Circulation, May 3, 2005; 111(17): 2157 - 2164. [Abstract] [Full Text] [PDF]
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 S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Effects of candesartan on cardiac sympathetic nerve activity in patients with congestive heart failure and preserved left ventricular ejection fraction J. Am. Coll. Cardiol., March 1, 2005; 45(5): 661 - 667. [Abstract] [Full Text] [PDF]
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G. M. Kuster, E. Kotlyar, M. K. Rude, D. A. Siwik, R. Liao, W. S. Colucci, and F. Sam Mineralocorticoid Receptor Inhibition Ameliorates the Transition to Myocardial Failure and Decreases Oxidative Stress and Inflammation in Mice With Chronic Pressure Overload Circulation, February 1, 2005; 111(4): 420 - 427. [Abstract] [Full Text] [PDF]
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 J. P. Goetze, J. F. Rehfeld, R. Videbaek, L. Friis-Hansen, and J. Kastrup B-type natriuretic peptide and its precursor in cardiac venous blood from failing hearts Eur J Heart Fail, January 1, 2005; 7(1): 69 - 74. [Abstract] [Full Text] [PDF]
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A. Lal, J. P. Veinot, and F. H.H. Leenen Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats Cardiovasc Res, December 1, 2004; 64(3): 437 - 447. [Abstract] [Full Text] [PDF]
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J. W. Funder Cardiac Synthesis of Aldosterone: Going, Going, Gone... ? Endocrinology, November 1, 2004; 145(11): 4793 - 4795. [Full Text] [PDF]
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E. P. Gomez-Sanchez, N. Ahmad, D. G. Romero, and C. E. Gomez-Sanchez Origin of Aldosterone in the Rat Heart Endocrinology, November 1, 2004; 145(11): 4796 - 4802. [Abstract] [Full Text] [PDF]
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S. Nakamura, M. Yoshimura, M. Nakayama, T. Ito, Y. Mizuno, E. Harada, T. Sakamoto, Y. Saito, K. Nakao, H. Yasue, et al. Possible Association of Heart Failure Status With Synthetic Balance Between Aldosterone and Dehydroepiandrosterone in Human Heart Circulation, September 28, 2004; 110(13): 1787 - 1793. [Abstract] [Full Text] [PDF]
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A. Garnier, J. K. Bendall, S. Fuchs, B. Escoubet, F. Rochais, J. Hoerter, J. Nehme, M.-L. Ambroisine, N. De Angelis, G. Morineau, et al. Cardiac Specific Increase in Aldosterone Production Induces Coronary Dysfunction in Aldosterone Synthase-Transgenic Mice Circulation, September 28, 2004; 110(13): 1819 - 1825. [Abstract] [Full Text] [PDF]
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A. Mano, T. Tatsumi, J. Shiraishi, N. Keira, T. Nomura, M. Takeda, S. Nishikawa, S. Yamanaka, S. Matoba, M. Kobara, et al. Aldosterone Directly Induces Myocyte Apoptosis Through Calcineurin-Dependent Pathways Circulation, July 20, 2004; 110(3): 317 - 323. [Abstract] [Full Text] [PDF]
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S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, T. Ishikawa, S. Ichikawa, T. Suzuki, and M. Kurabayashi Effects of Intravenous Atrial Natriuretic Peptide on Cardiac Sympathetic Nerve Activity in Patients with Decompensated Congestive Heart Failure J. Nucl. Med., July 1, 2004; 45(7): 1108 - 1113. [Abstract] [Full Text] [PDF]
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 F. C. Luft Cardiac Angiotensin Is Upregulated in the Hearts of Unstable Angina Patients Circ. Res., June 25, 2004; 94(12): 1530 - 1532. [Full Text] [PDF]
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 R. S. Vasan, J. C. Evans, E. J. Benjamin, D. Levy, M. G. Larson, J. Sundstrom, J. M. Murabito, F. Sam, W. S. Colucci, and P. W. F. Wilson Relations of Serum Aldosterone to Cardiac Structure: Gender-Related Differences in the Framingham Heart Study Hypertension, May 1, 2004; 43(5): 957 - 962. [Abstract] [Full Text] [PDF]
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J. Fletcher, A. N. Buch, H. C. Routledge, S. Chowdhary, J. H. Coote, and J. N. Townend Acute aldosterone antagonism improves cardiac vagal control in humans J. Am. Coll. Cardiol., April 7, 2004; 43(7): 1270 - 1275. [Abstract] [Full Text] [PDF]
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N. Tsybouleva, L. Zhang, S. Chen, R. Patel, S. Lutucuta, S. Nemoto, G. DeFreitas, M. Entman, B. A. Carabello, R. Roberts, et al. Aldosterone, Through Novel Signaling Proteins, Is a Fundamental Molecular Bridge Between the Genetic Defect and the Cardiac Phenotype of Hypertrophic Cardiomyopathy Circulation, March 16, 2004; 109(10): 1284 - 1291. [Abstract] [Full Text] [PDF]
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 F. K Shieh, E. Kotlyar, and F. Sam Aldosterone and cardiovascular remodelling: focus on myocardial failure Journal of Renin-Angiotensin-Aldosterone System, March 1, 2004; 5(1): 3 - 13. [Abstract] [PDF]
|
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|
|
|
A. D Struthers and T. M MacDonald Review of aldosterone- and angiotensin II-induced target organ damage and prevention Cardiovasc Res, March 1, 2004; 61(4): 663 - 670. [Abstract] [Full Text] [PDF]
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D. Fraccarollo, P. Galuppo, S. Hildemann, M. Christ, G. Ertl, and J. Bauersachs Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction J. Am. Coll. Cardiol., November 5, 2003; 42(9): 1666 - 1673. [Abstract] [Full Text] [PDF]
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J. N. Cohn, I. S. Anand, R. Latini, S. Masson, Y.-T. Chiang, and R. Glazer Sustained Reduction of Aldosterone in Response to the Angiotensin Receptor Blocker Valsartan in Patients With Chronic Heart Failure: Results From the Valsartan Heart Failure Trial Circulation, September 16, 2003; 108(11): 1306 - 1309. [Abstract] [Full Text] [PDF]
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K. T Weber, Yao Sun, L. A Wodi, A. Munir, E. Jahangir, R. A Ahokas, I. C Gerling, A. E Postlethwaite, and K. J Warrington Toward a broader understanding of aldosterone in congestive heart failure Journal of Renin-Angiotensin-Aldosterone System, September 1, 2003; 4(3): 155 - 163. [Abstract] [PDF]
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|
 T. H. Hostetter and H. N. Ibrahim Aldosterone in Chronic Kidney and Cardiac Disease J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2395 - 2401. [Abstract] [Full Text] [PDF]
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W. Qin, A. E. Rudolph, B. R. Bond, R. Rocha, E. A.G. Blomme, J. J. Goellner, J. W. Funder, and E. G. McMahon Transgenic Model of Aldosterone-Driven Cardiac Hypertrophy and Heart Failure Circ. Res., July 11, 2003; 93(1): 69 - 76. [Abstract] [Full Text] [PDF]
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 P. C. White Aldosterone: Direct Effects on and Production by the Heart J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2376 - 2383. [Full Text] [PDF]
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|
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S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Addition of Valsartan to an Angiotensin-Converting Enzyme Inhibitor Improves Cardiac Sympathetic Nerve Activity and Left Ventricular Function in Patients with Congestive Heart Failure J. Nucl. Med., June 1, 2003; 44(6): 884 - 890. [Abstract] [Full Text] [PDF]
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N. J. Brown Eplerenone: Cardiovascular Protection Circulation, May 20, 2003; 107(19): 2512 - 2518. [Abstract] [Full Text] [PDF]
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A. J. Casal, J.-S. Silvestre, C. Delcayre, and A. M. Capponi Expression and Modulation of Steroidogenic Acute Regulatory Protein Messenger Ribonucleic Acid in Rat Cardiocytes and after Myocardial Infarction Endocrinology, May 1, 2003; 144(5): 1861 - 1868. [Abstract] [Full Text] [PDF]
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S. Kasama, T. Toyama, H. Kumakura, Y. Takayama, S. Ichikawa, T. Suzuki, and M. Kurabayashi Effect of spironolactone on cardiacsympathetic nerve activity and left ventricular remodeling in patients with dilated cardiomyopathy J. Am. Coll. Cardiol., February 19, 2003; 41(4): 574 - 581. [Abstract] [Full Text] [PDF]
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T. Ito, M. Yoshimura, S. Nakamura, M. Nakayama, Y. Shimasaki, E. Harada, Y. Mizuno, M. Yamamuro, M. Harada, Y. Saito, et al. Inhibitory Effect of Natriuretic Peptides on Aldosterone Synthase Gene Expression in Cultured Neonatal Rat Cardiocytes Circulation, February 18, 2003; 107(6): 807 - 810. [Abstract] [Full Text] [PDF]
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S. I. McFarlane and J. R. Sowers Aldosterone Function in Diabetes Mellitus: Effects on Cardiovascular and Renal Disease J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 516 - 523. [Full Text] [PDF]
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S. M MacKenzie, R. Fraser, J. M. Connell, and E. Davies Local renin-angiotensin systems and their interactions with extra-adrenal corticosteroid production Journal of Renin-Angiotensin-Aldosterone System, December 1, 2002; 3(4): 214 - 221. [Abstract] [PDF]
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M. F. Rousseau, O. Gurne, D. Duprez, W. Van Mieghem, A. Robert, S. Ahn, L. Galanti, J.-M. Ketelslegers, and Belgian RALES Investigators Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: Results from the RALES neurohormonal substudy J. Am. Coll. Cardiol., November 6, 2002; 40(9): 1596 - 1601. [Abstract] [Full Text] [PDF]
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J. Davies and A. Struthers Review: The potential benefits of aldosterone antagonism in Type 2 diabetes mellitus Journal of Renin-Angiotensin-Aldosterone System, September 1, 2002; 3(3): 150 - 155. [Abstract] [PDF]
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|
|
M. Yoshimura, S. Nakamura, T. Ito, M. Nakayama, E. Harada, Y. Mizuno, T. Sakamoto, M. Yamamuro, Y. Saito, K. Nakao, et al. Expression of Aldosterone Synthase Gene in Failing Human Heart: Quantitative Analysis Using Modified Real-Time Polymerase Chain Reaction J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3936 - 3940. [Abstract] [Full Text] [PDF]
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M. Cicoira, L. Zanolla, A. Rossi, G. Golia, L. Franceschini, G. Brighetti, P. Marino, and P. Zardini Long-term, dose-dependent effects of spironolactone on left ventricular function and exercise tolerance in patients with chronic heart failure J. Am. Coll. Cardiol., July 17, 2002; 40(2): 304 - 310. [Abstract] [Full Text] [PDF]
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N. Yamamoto, H. Yasue, Y. Mizuno, M. Yoshimura, H. Fujii, M. Nakayama, E. Harada, S. Nakamura, T. Ito, and H. Ogawa Aldosterone Is Produced From Ventricles in Patients With Essential Hypertension Hypertension, May 1, 2002; 39(5): 958 - 962. [Abstract] [Full Text] [PDF]
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A. Goette, U. Lendeckel, and H. U Klein Signal transduction systems and atrial fibrillation Cardiovasc Res, May 1, 2002; 54(2): 247 - 258. [Abstract] [Full Text] [PDF]
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S. Neumann, K. Huse, R. Semrau, A. Diegeler, R. Gebhardt, G. H. Buniatian, and G. H. Scholz Aldosterone and D-Glucose Stimulate the Proliferation of Human Cardiac Myofibroblasts In Vitro Hypertension, March 1, 2002; 39(3): 756 - 760. [Abstract] [Full Text] [PDF]
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B. A. Groenning, J. C. Nilsson, L. Sondergaard, A. Kjaer, H. B.W. Larsson, and P. R. Hildebrandt Evaluation of impaired left ventricular ejection fraction and increased dimensions by multiple neurohumoral plasma concentrations Eur J Heart Fail, December 1, 2001; 3(6): 699 - 708. [Abstract] [Full Text] [PDF]
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 J.-P. Benitah, E. Perrier, A. M. Gomez, and G. Vassort Effects of aldosterone on transient outward K+ current density in rat ventricular myocytes J. Physiol., November 15, 2001; 537(1): 151 - 160. [Abstract] [Full Text] [PDF]
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C. E. Gomez-Sanchez and E. P. Gomez-Sanchez Cardiac Steroidogenesis--New Sites of Synthesis, or Much Ado About Nothing? J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5118 - 5120. [Full Text] [PDF]
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M. J. Young, C. D. Clyne, T. J. Cole, and J. W. Funder Cardiac Steroidogenesis in the Normal and Failing Heart J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5121 - 5126. [Abstract] [Full Text] [PDF]
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F. Zannad, B. Dousset, and F. Alla Treatment of Congestive Heart Failure: Interfering the Aldosterone-Cardiac Extracellular Matrix Relationship Hypertension, November 1, 2001; 38(5): 1227 - 1232. [Abstract] [Full Text] [PDF]
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E. Harada, M. Yoshimura, H. Yasue, O. Nakagawa, M. Nakagawa, M. Harada, Y. Mizuno, M. Nakayama, Y. Shimasaki, T. Ito, et al. Aldosterone Induces Angiotensin-Converting-Enzyme Gene Expression in Cultured Neonatal Rat Cardiocytes Circulation, July 10, 2001; 104(2): 137 - 139. [Abstract] [Full Text] [PDF]
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