CLINICAL STUDY: CONGESTIVE HEART FAILURE
Beneficial neurohormonal profile of spironolactone in severe congestive heart failure
Results from the RALES neurohormonal substudy
Michel F. Rousseau, MD, PhD, FACC*,*,
Olivier Gurné, MD, PhD*,
Daniel Duprez, MD, PhD, FACC ,
Walter Van Mieghem, MD, PhD ,
Annie Robert, PhD ,
Sylvie Ahn*,
Laurence Galanti, MD, PhD*,
Jean-Marie Ketelslegers, MD, PhD|| Belgian RALES Investigators
* Division of Cardiology, University of Louvain, Brussels, Belgium
School of Public Health, University of Louvain, Brussels, Belgium
|| Diabetes and Nutrition Unit, University of Louvain, Brussels, Belgium
Cardiovascular Division, University of Minnesota, Minneapolis, Minnesota, USA
Hartcentrum Limburg, Genk, Belgium
Manuscript received April 23, 2002;
revised manuscript received May 28, 2002,
accepted July 15, 2002.
* Reprint requests and correspondence: Dr. Michel F. Rousseau, Division of Cardiology, University of Louvain, Avenue Hippocrate 10/2800, B-1200 Brussels, Belgium.
rousseau{at}card.ucl.ac.be
 |
Abstract
|
|---|
OBJECTIVES: We sought to evaluate the effects of spironolactone on neurohormonal factors in patients with severe congestive heart failure (CHF).
BACKGROUND: In the Randomized ALdactone Evaluation Study (RALES), spironolactone, an aldosterone receptor antagonist, significantly reduced mortality in patients with severe CHF. However, the mechanism of action and neurohormonal impact of this therapy remain to be clarified.
METHODS: The effects of spironolactone (25 mg/day; n = 54) or placebo (n = 53) on plasma concentrations of the N-terminal portion of atrial natriuretic factor (N-proANF), brain natriuretic peptide (BNP), endothelin-1 (ET-1), norepinephrine (NE), angiotensin II (AII), and aldosterone were assessed in a subgroup of 107 patients (New York Heart Association functional class III to IV; mean ejection fraction 25%) at study entry and at three and six months.
RESULTS: Compared with the placebo group, plasma levels of BNP (–23% at 3 and 6 months; p = 0.004 and p = 0.05, respectively) and N-proANF (–19% at 3 months, p = 0.03; –16% at 6 months, p = 0.11) were decreased after spironolactone treatment. Over time, spironolactone did not modify the plasma levels of NE and ET-1. Angiotensin II increased significantly in the spironolactone group at three and six months (p = 0.003 and p = 0.001, respectively). As expected, a significant increase in aldosterone levels was observed over time in the spironolactone group (p = 0.001).
CONCLUSIONS: Spironolactone administration in patients with CHF has opposite effects on circulating levels of natriuretic peptides (which decrease) and aldosterone and AII (which increase). The reduction in natriuretic peptides might be related to changes in left ventricular diastolic filling pressure and/or compliance, whereas the increase in AII and aldosterone probably reflects activated feedback mechanisms. Further studies are needed to link these changes to the beneficial effects on survival and to determine whether the addition of an AII antagonist could be useful in this setting.
|
Abbreviations and Acronyms
| | AII | | angiotensin II | | ACE | | angiotensin-converting enzyme | | BNP | | brain natriuretic peptide | | CHF | | congestive heart failure | | ET-1 | | endothelin-1 | | NE | | norepinephrine | | N-proANF | | N-terminal portion of pro-atrial natriuretic factor | | NYHA | | New York Heart Association | | RAAS | | renin-angiotensin-aldosterone system | | RALES | | Randomized ALdactone Evaluation Study |
|
Congestive heart failure (CHF) is characterized by the progressive activation of several endocrine systems (1). Increased levels of norepinephrine (NE) and natriuretic peptides, such as atrial natriuretic peptide and brain natriuretic peptide (BNP), as well as activation of the renin-angiotensin-aldosterone system (RAAS), have been described and associated with a poor prognosis (2,3). Aldosterone promotes the retention of sodium and the loss of potassium, activates the sympathetic nervous system, stimulates the development of myocardial and vascular fibrosis, and causes endothelial and baroreceptor dysfunction (4,5). Angiotensin II (AII), which increases sympathetic drive, aldosterone release, and cardiac remodeling, is known to exacerbate the progression of CHF (6). Despite progress achieved with angiotensin-converting enzyme (ACE) inhibitors and, more recently, with beta-blockers, mortality and morbidity remain high in patients with severe CHF (7). Pitt et al. (8) demonstrated that a low dose of spironolactone, an aldosterone receptor antagonist, significantly reduced the risk of morbidity and mortality in patients with severe CHF included in the Randomized ALdactone Evaluation Study (RALES). However, the mechanism(s) by which spironolactone affects survival remain(s) unclear. Recently, the beneficial effects of spironolactone on markers of tissue collagen turnover and fibrosis were reported in a substudy of RALES (9). The aim of the present substudy was to assess, in the Belgian cohort enrolled in the RALES trial, the effects of spironolactone on several neurohormonal markers of the severity of CHF—namely, natriuretic peptides, NE, endothelin-1 (ET-1), and AII.
|
Methods
|
|---|
Patients and study design.
Of the 130 patients from Belgian centers who were randomized into the RALES trial, we prospectively included 127 patients in the neurohormonal substudy. Patients with the following inclusion criteria were eligible for enrollment: a history of New York Heart Association (NYHA) functional class IV within the previous six months and class III or IV at the time of randomization; full treatment with ACE inhibitors and loop diuretics; and left ventricular ejection fraction <35%. Patients were randomized to receive placebo or spironolactone (25 mg/day). The mean survival follow-up period was 24 months. Neurohormonal plasma samples were obtained at baseline and after three and six months of treatment. Of the 127 patients with baseline neurohormonal data, 20 were excluded from the follow-up because of premature death (n = 8) or dropout (n = 12). Thus, data on 107 patients (Table 1) were available for analysis at baseline and at a minimum of one follow-up time point. The number of samples available in each treatment group at any time point is listed in Table 2. Each patient gave written, informed consent, and the protocol was approved by the local institutional Review Board.
Measurements of neurohormonal markers
Venous blood samples were obtained after 30 min of rest in the supine position. Blood samples were collected in chilled tubes containing 3 mmol/l EDTA and 9 mmol/l benzamidine and stored on wet ice until centrifugation. Plasma was carefully separated and frozen at –80°C. Briefly, 3 ml of unfrozen plasma mixed with 1 g of guanidine hydrochloride was extracted on SEP-PAK C18 cartridges (Waters, Milford, Massachusetts) and eluted with 0.1% trifluoroacetic acid/80% acetonitrile. Natriuretic peptides (N-terminal portion of atrial natriuretic factor [N-proANF] and BNP), ET-1, and AII were measured on the same extracts by radioimmunoassay, using specific antibodies and synthetic peptides from Peninsula (Belmont, California), as well as home-iodinated tracers purified by high-performance liquid chromatography (HPLC) (10). There was no significant cross reactivity between the assays; samples displaced tracer parallel to their respective standard curve. The percent cross reactivities of the antiserum for AII were 0.5% for AI and 100% for AIII. Recoveries, intra-assay and inter-assay coefficients of variation, and the median effective dose (ED50) were 70%, 7% and 10%, and 135 pg/ml for N-proANF; 84%, 7% and 6%, and 350 pg/ml for BNP; 68%, 12% and 16%, and 140 pg/ml for ET-1; and 95%, 2% and 4.5%, and 110 pg/ml for AII, respectively. To provide control values for natriuretic peptides and AII, blood samples were obtained in 24 healthy age-matched control subjects; normal values expressed as the geometric mean value (95% confidence interval [CI]) were 219 (105 to 453) pg/ml for N-proANF, 11 (5 to 25) pg/ml for BNP, and 9.3 (8 to 10.6) pg/ml for AII. Normal values for ET-1 were <3 pg/ml. Serum aldosterone was measured by a commercial radioimmunoassay (Abbott Diagnostics, Chicago, Illinois). Intra-assay and inter-assay coefficients of variation were 3.7% and 6.3%, and the ED50 was 0.78 nmol/ml. Normal values for aldosterone were <0.4 nmol/ml. Norepinephrine was measured by HPLC with intra-assay and inter-assay coefficients of variation of 7% and 12%, respectively. Normal values for NE in our laboratory ranged from 164 to 262 pg/ml, with a normal geometric mean value of 207 pg/ml.
Statistical analysis
Data are expressed as numbers for discrete data, as the mean value ± SD for normal continuous data, and as the geometric mean value (95% CI) for neurohormonal data due to a right-skewed distribution. The placebo and spironolactone groups were compared using the Fisher exact test for discrete data and the Student t test for continuous data. Neurohormonal data were log-transformed before statistical comparisons. Analysis of variance for repeated measures was used to analyze neurohormonal changes over time (11). Analysis of variance was computed using a grouping factor with two levels (spironolactone or placebo) and a repeated measurement factor with three levels (0, 3, and 6 months). Because only 89 patients were measured at baseline and three and six months, the degrees of freedom (df) were 2 and 174 for the interaction F test and for the time change F test. For the grouping effect F test, the df’s were 1 and 87. Because of significant interaction tests, changes over time were tested within each treatment group. Bonferroni-corrected p values were used, adjusting for four comparisons, because we considered only changes from baseline within each of the two groups. Time changes were expressed as ratios by taking the anti-log of differences at three (T3/T0) or six (T6/T0) months from baseline. All tests were two-tailed, and p < 0.05 was considered as statistically significant.
|
Results
|
|---|
Patient characteristics.
Of the original group of 127 patients, 11 had died in the placebo group and five in the spironolactone group at the six-month time point. After a mean follow-up period of 24 months, there were 46 deaths (35%) in the study group: four were non-cardiovascular deaths and 42 were attributed to cardiovascular causes (19 sudden deaths, 19 due to worsening heart failure, 2 due to stroke, and 2 due to other cardiovascular causes). Consistent with the main trial results, cardiac mortality was lower in the spironolactone group than in the placebo group (21% vs. 38%, p = 0.05). Considering the mode of deaths, we observed a significant decrease in sudden deaths in the spironolactone group compared with the placebo group (8% vs. 22%, p = 0.026).
As summarized in Table 1, no significant differences between the placebo and spironolactone groups were observed for the 107 patients for whom neurohormonal data were available at baseline and at a minimum of one follow-up time point, except that patients randomized in the spironolactone group were slightly older than those in the placebo group (71 vs. 66 years, p = 0.02) and received less beta-blockers (8% vs. 16%, p = 0.07). Seventy-one percent of our study population had ischemic cardiomyopathy, 25% had idiopathic dilated cardiomyopathy, and 4% had valvular disease. Seventy-nine percent were in NYHA class III. Patients were treated with loop diuretics and ACE inhibitors in 97% and 95% of cases, respectively.
Neurohormonal measurements
Table 2 shows the neurohormonal measurements at baseline and after three and six months of follow-up. The severity of left ventricular dysfunction is demonstrated by the high baseline levels of NE, ET-1, BNP, and N-proANF, compared with the normal values of each respective assay. No significant difference was observed between the two groups.
Natriuretic peptides
As shown in Figure 1, the BNP plasma concentration, expressed in time change ratios, decreased by 23% in the spironolactone group compared with the placebo group (0.99 vs. 0.77, p = 0.004 and 0.96 vs. 0.77, p = 0.05, respectively at 3 and 6 months). A significant decrease of 19% in N-proANF was observed at three months in the spironolactone group (1.0 vs. 0.81, p = 0.03) (Fig. 2) and a decrease of 16% at six months (0.99 vs. 0.84, p = 0.11).
View larger version (17K):
[in this window]
[in a new window]
|
Figure 1 Changes in plasma levels of brain natriuretic peptide (BNP) (expressed on a log scale) from baseline to three and six months in the placebo and spironolactone groups.
|
|
View larger version (17K):
[in this window]
[in a new window]
|
Figure 2 Changes in plasma levels of N-terminal portion of pro-atrial natriuretic factor (N-proANF) (expressed on a log scale) from baseline to three and six months in the placebo and spironolactone groups.
|
|
Plasma norepinephrine and endothelin-1
Compared with placebo, spironolactone did not significantly change the plasma levels of NE (0.98 vs. 1.03, p = 0.64; 0.96 vs. 1.07, p = 0.33) or ET-1 (1.03 vs. 0.94, p = 0.10; 1.11 vs. 1.03, p = 0.25) at three and six months, respectively.
Angiotensin II and aldosterone
Compared with placebo, AII increased significantly at three and six months in the spironolactone group (8.4 vs. 13.9 pg/ml, p = 0.02 and 7.9 vs. 13.2 pg/ml, p = 0.02). Furthermore, the AII ratios of 3 months/baseline and 6 months/baseline also rose markedly (0.78 vs. 1.41, p = 0.003 and 0.66 vs. 1.41, p = 0.001) (Fig. 3). As expected (Fig. 4), a significant increase in aldosterone levels was observed in the spironolactone group, both in absolute values and in the ratios of 3 months/baseline (0.92 vs. 1.75, p = 0.001) and 6 months/baseline (0.92 vs. 2.03, p = 0.001).
View larger version (17K):
[in this window]
[in a new window]
|
Figure 3 Changes in plasma levels of angiotensin II (AII) (expressed on a log scale) from baseline to three and six months in the placebo and spironolactone groups.
|
|
View larger version (18K):
[in this window]
[in a new window]
|
Figure 4 Changes in plasma levels of aldosterone (expressed on a log scale) from baseline to three and six months in the placebo and spironolactone groups.
|
|
|
Discussion
|
|---|
Our study demonstrated that the administration of spironolactone, an aldosterone receptor antagonist, significantly reduced the plasma levels of BNP and, to a lesser extent, N-proANF in patients with severe CHF, whereas AII and aldosterone levels increased and NE and ET-1 levels remained essentially unchanged.
Circulating plasma levels of cardiac natriuretic peptides are inversely related to the severity of left ventricular dysfunction and have been found to be prognostic predictors (10,12). More specifically, the plasma BNP level is directly correlated to changes in ventricular wall stress (13). Furthermore, natriuretic peptides have several biologic functions, including vasodilation, increased compliance in large vessels, enhanced baroreceptor sensitivity, and renal effects, particularly sodium excretion (14). Spironolactone can influence the progression of left ventricular remodeling by a reduction in interstitial fibrosis and reorganization of the collagen matrix (15–17). Thus, the reduction of BNP and N-proANF levels could be related to an improvement of left ventricular diastolic properties and/or filling pressures. Spironolactone may prevent myocardial fibrosis by blocking the aldosterone effects on collagen formation, as suggested by decreased levels of collagen markers such as the procollagen type III aminoterminal peptide (9,13). Our data are also consistent with the results of Tsutamato et al. (13), who showed, after four months of spironolactone therapy (25 mg/day), a significant decrease in BNP and ANF levels in a small group of patients with mild to moderate non-ischemic cardiomyopathy.
Levels of NE and ET-1 also identify a CHF population with a poor prognosis (18,19). The high-risk profile of our population is confirmed by the marked NE and ET-1 levels at baseline. We did not observe a decrease in NE and ET-1, and these well-established neuroendocrine prognostic markers failed to predict the beneficial survival effect, suggesting that the effects of spironolactone on mortality are related to mechanisms independent of adrenergic and endothelin systems. Similarly, the plasma levels of NE and ET-1 were not changed after spironolactone therapy in the study performed by Tsutamoto et al. (13). The role of aldosterone in sympathetic modulation is controversial, as indicated in the study of Yee et al. (20), where whole-body NE clearance and spillover did not appear to be significantly affected by spironolactone therapy compared with placebo. In that study, spironolactone reduced the heart rate and improved heart rate variability and QT dispersion in patients with CHF, and these beneficial effects seem to be related to the modulation of parasympathetic tone. Moreover, an antagonizing aldosterone effect could improve baroreflex function, which is an important determinant of sudden cardiac death. Therefore, spironolactone could possess properties able to reduce life-threatening arrhythmias (21,22).
In our study, we observed direct evidence that spironolactone therapy activated the RAAS. Spironolactone significantly increased the plasma levels of AII (and/or its metabolite AIII, as cross-reactivity existed in our assay) and aldosterone during the follow-up period. This observation raises two additional questions: first, regarding the physiologic impact of this rise in AII, and second, the mechanisms by which AII is further increased in the presence of an ACE inhibitor. One can only speculate about the physiologic consequences of the increase in angiotensin in the presence of a decrease in BNP, as well as the likely blockade of the effects of aldosterone at the cellular level. There were no obvious changes in blood pressure, plasma creatinine, or potassium levels. Furthermore, two other markers of vasoconstrictor activity—NE and ET-1—were also unchanged. Admittedly, this rise is modest, and the statistical significance is also driven by the fact that the values decreased slightly in the placebo group. However, AII can stimulate left ventricular hypertrophy and perhaps cardiac myocyte apoptosis. Accordingly, and despite the fact that the changes remained essentially within a normal range, it would be tempting to assess the changes in cardiac mass during follow-up in these patients or to determine the effects of an AII antagonist. Some benefit of an AII antagonist has been recently reported in patients already treated with an ACE inhibitor in the Valsartan Heart Failure Trial (Val-HeFT) (23). However, because only 5% of the Val-HeFT patients were receiving spironolactone, no conclusion can be drawn yet regarding the safety and efficacy of a combination of an ACE inhibitor/AII receptor blocker and spironolactone (23). With respect to the mechanism underlying the AII and aldosterone escape, this probably reflects activated feedback mechanisms on the RAAS (24). The possibility also exists that renin or ACE expression in the failing heart could contribute to this enhanced production of AII. Sun et al. (25) demonstrated that after myocardial infarction in the rat, cardiac renin production was induced and contributed to local AII generation. Mizuno et al. (26) also showed in failing ventricles that the levels of aldosterone had a highly significant positive correlation with levels of ACE activity, suggesting that increased activity of local ACE, causing conversion of AI to AII, may stimulate production of aldosterone in heart failure. Silvestre et al. (27) recently showed that cardiac aldosterone is activated in the rat heart with myocardial infarction, and that this is mediated primarily by cardiac AII. Thus, cardiac aldosterone may play a major role in the progression of heart failure, and spironolactone, an aldosterone receptor antagonist, may improve heart failure by blocking the action of locally produced aldosterone in the failing heart.
Study limitations.
One potential limitation of this study could be a bias introduced by the unbalanced attrition of the placebo and spironolactone-treated groups and by the small imbalances noted for age and use of beta blockers at baseline. However, the numbers of deaths, dropouts, and missing samples at six months were relatively well balanced, and the baseline characteristics of the two subsets of patients, in whom six-month data were available, were not only similar but also comparable to those of the whole study group. Furthermore, differences in age and use of beta-blockers would have tended to underestimate the benefit of spironolactone and were therefore unlikely to affect the conclusions. Another potential limitation of the study relates to the specificity of the AII assay. The anti-serum used for the AII assay cross reacted with AIII, another peptide known to produce vasoconstriction and stimulate aldosterone production. Thus, because AIII is also a biologically active peptide, with effects qualitatively similar to those of AII, the high concentration detected by the anti-serum used indicates an abnormal activation of the RAAS (24). Because of the disparity of baseline BNP levels in our study compared with other studies, the specificity of the BNP assay should also be considered. The higher baseline BNP values observed in other laboratories likely resulted from utilization of commercially available assays with technical differences in the extraction procedure, standardization, and antibody affinity for various circulating forms of BNP (28). In our RALES cohort, we observed a sevenfold increase in baseline BNP levels, compared with control values, and these levels appeared consistent with severe CHF. Therefore, variability in normal values related to the type of assay used is unlikely to qualitatively affect our conclusions.
Conclusions
The present study indicates that spironolactone has the opposite effects on BNP and N-proANF, which are lowered during treatment, and AII and aldosterone, which are increased. The lack of a decrease in the neuroendocrine prognostic markers, NE and ET-1, suggests that the beneficial effects of spironolactone are mainly related to mechanisms independent of the adrenergic and endothelin systems. The escape of AII and aldosterone, probably reflecting activated feedback mechanisms, confirms the specific activity of spironolactone on the RAAS system and supports the hypothesis that the beneficial effects of spironolactone on the progression of heart failure are mediated by the blockade of aldosterone receptors.
|
Footnotes
|
|---|
This study was supported in part by a grant from Pharmacia, Brussels, Belgium. With respect to a potential conflict of interest, Dr. Ketelslegers received a grant from Pharmacia Belgium for the biochemical assays.
|
References
|
|---|
1. Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circulation. 1990;82:1724–1729[Abstract/Free Full Text]
2. Rouleau JL, Packer M, Moye L, et al. Prognostic value of neurohumoral activation in patients with an acute myocardial infarction: effect of captopril. J Am Coll Cardiol. 1994;24:583–591[Abstract]
3. Omland T, Aakvaag A, Bonarjee VSS, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation. 1996;93:1963–1969[Abstract/Free Full Text]
4. Duprez D, De Bruynere M, Rietzschel ER, et al. Aldosterone and vascular damage. Curr Hypertens Rep. 2000;2:327–334[Medline]
5. Farquharson CA, Struthers AD. Spironolactone increases nitric oxyde bioactivity, improves endothelial vasodilation dysfunction and suppresses vascular angiotensin I/angiotensin II conversion in patients with chronic heart failure. Circulation. 2000;101:594–597[Abstract/Free Full Text]
6. Swedberg K, Eneroth P, Kjekshus J, et al. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation. 1990;82:1730–1736[Abstract/Free Full Text]
7. Carvedilol Prospective Randomized Cumulative Survival Study GroupPacker M, Coats AJS, Fowler MB, et al. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med. 2001;344:1651–1658[Abstract/Free Full Text]
8. Pitt B, Zannad F, Remme J, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med. 1999;341:709–717[Abstract/Free Full Text]
9. Zannad F, Alla F, Dousset B, et al. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure. Circulation. 2000;102:2700–2706[Abstract/Free Full Text]
10. Selvais PL, Robert A, Ahn S, et al. Direct comparison between endothelin-1, N-terminal proatrial natriuretic factor, and brain natriuretic peptide as prognostic markers of survival in congestive heart failure. J Card Failure. 2000;6:201–207[CrossRef][Medline]
11. Glantz S, Slinker B. Applied Regression and Analysis of Variance. New York, NY: McGraw Hill; 2001. 949
12. Hall C, Rouleau JL, Moye L, et al. N-terminal proatrial natriuretic factor: an independent predictor of long-term prognosis after myocardial infarction. Circulation. 1994;89:1934–1942[Abstract/Free Full Text]
13. Tsutamato T, Wada A, Maeda K, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001;37:1228–1233[Abstract/Free Full Text]
14. Levin ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med. 1998;339:321–328[Free Full Text]
15. Weber KT, Brilla CG. Pathological hypertrophy and cardiac interstitium: fibrosis and renin-angiotensin-aldosterone system. Circulation. 1991;83:1849–1865[Abstract/Free Full Text]
16. Brilla CG, Matsubara LS, Weber KT. Anti-aldosterone treatment and the prevention of myocardial fibrosis in primary and secondary hyperaldosteronism. J Moll Cell Cardiol. 1993;25:563–575[CrossRef][Medline]
17. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001;345:1689–1697[Free Full Text]
18. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation. 1996;94:690–697[Abstract/Free Full Text]
19. Sakai S, Miyauchi T, Kobyashi M, et al. Inhibition of myocardial endothelin pathways improves long-term survival in heart failure. Nature. 1996;384:353–355[CrossRef][Medline]
20. Yee K-M, Pringle SD, Struthers AD. Circadian variation in the effects of aldosterone blockade on heart rate variability and QT dispersion in congestive heart failure. J Am Coll Cardiol. 2001;37:1800–1807[Abstract/Free Full Text]
21. Macfadyen RJ, Barr CS, Struthers AD. Aldosterone blockade reduces vascular collagen turnover, improves heart rate variability and reduces early morning rise in heart rate in heart failure patients. Cardiovasc Res. 1997;35:30–34[Abstract/Free Full Text]
22. Yee K-M, Struthers AD. Aldosterone blunts the baroreflex response in man. Clin Sci. 1998;95:687–692[Medline]
23. Valsartan Heart Failure Trial InvestigatorsCohn JN, Tognoni G. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667–1675[Abstract/Free Full Text]
24. Rousseau MF, Konstam MA, Benedict CR, et al. Progression of left ventricular dysfunction secondary to coronary artery disease, sustained neurohormonal activation and effects of ibopamine therapy during long-term therapy with angiotensin-converting enzyme inhibitor. Am J Cardiol. 1994;73:488–493[CrossRef][Medline]
25. Sun Y, Zhang J, Zhang JQ, Weber KT. Renin expression at sites of repair in the infarcted rat heart. J Mol Cell Cardiol. 2001;33:995–1003[CrossRef][Medline]
26. Mizuno Y, Yoshimura M, Yasue H, et al. Aldosterone production is activated in failing ventricle in humans. Circulation. 2001;103:72–77[Abstract/Free Full Text]
27. 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[Abstract/Free Full Text]
28. Fischer Y, Filzmaier K, Stieger H, et al. Evaluation of a new, rapid bedside test for quantitative determination of B-type natriuretic peptide. Clin Chem. 2001;47:591–594[Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
C. A. Lemarie, S. M.C. Simeone, A. Nikonova, T. Ebrahimian, M.-E. Deschenes, T. M. Coffman, P. Paradis, and E. L. Schiffrin
Aldosterone-Induced Activation of Signaling Pathways Requires Activity of Angiotensin Type 1a Receptors
Circ. Res.,
October 23, 2009;
105(9):
852 - 859.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. S. De Silva, R. M. Wilson, C. Hutchinson, P. C. Ip, A. G. Garcia, S. Lancel, M. Ito, D. R. Pimentel, and F. Sam
Fenofibrate inhibits aldosterone-induced apoptosis in adult rat ventricular myocytes via stress-activated kinase-dependent mechanisms
Am J Physiol Heart Circ Physiol,
June 1, 2009;
296(6):
H1983 - H1993.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Mulder, V. Mellin, J. Favre, M. Vercauteren, I. Remy-Jouet, C. Monteil, V. Richard, S. Renet, J. P. Henry, A. Y. Jeng, et al.
Aldosterone synthase inhibition improves cardiovascular function and structure in rats with heart failure: a comparison with spironolactone
Eur. Heart J.,
September 1, 2008;
29(17):
2171 - 2179.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. T. Mathew, H. Patni, A. N. Chaudhary, W. Liang, A. Gupta, P. N. Chander, G. Ding, and P. C. Singhal
Aldosterone induces mesangial cell apoptosis both in vivo and in vitro
Am J Physiol Renal Physiol,
July 1, 2008;
295(1):
F73 - F81.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J.V. McMurray, B. Pitt, R. Latini, A. P. Maggioni, S. D. Solomon, D. L. Keefe, J. Ford, A. Verma, J. Lewsey, and for the Aliskiren Observation of Heart Failure Tre
Effects of the Oral Direct Renin Inhibitor Aliskiren in Patients With Symptomatic Heart Failure
Circ Heart Fail,
May 1, 2008;
1(1):
17 - 24.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Kurzyna and A. Torbicki
Neurohormonal modulation in right ventricular failure
Eur. Heart J. Suppl.,
December 1, 2007;
9(suppl_H):
H35 - H40.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Damgaard, J. P. Goetze, P. Norsk, and N. Gadsboll
Altered sodium intake affects plasma concentrations of BNP but not proBNP in healthy individuals and patients with compensated heart failure
Eur. Heart J.,
November 2, 2007;
28(22):
2726 - 2731.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Patni, J. T. Mathew, L. Luan, N. Franki, P. N. Chander, and P. C. Singhal
Aldosterone promotes proximal tubular cell apoptosis: role of oxidative stress
Am J Physiol Renal Physiol,
October 1, 2007;
293(4):
F1065 - F1071.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W.H. Wilson Tang, G. S. Francis, D. A. Morrow, L. K. Newby, C. P. Cannon, R. L. Jesse, A. B. Storrow, R. H. Christenson, COMMITTEE MEMBERS, R. H. Christenson, et al.
National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure
Circulation,
July 31, 2007;
116(5):
e99 - e109.
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Najem, P. Unger, N. Preumont, J.-L. Jansens, A. Houssiere, A. Pathak, O. Xhaet, L. Gabriel, A. Friart, L. De Roy, et al.
Sympathetic control after cardiac resynchronization therapy: responders versus nonresponders
Am J Physiol Heart Circ Physiol,
December 1, 2006;
291(6):
H2647 - H2652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Sun, R. A. Ahokas, S. K. Bhattacharya, I. C. Gerling, L. D. Carbone, and K. T. Weber
Oxidative stress in aldosteronism
Cardiovasc Res,
July 15, 2006;
71(2):
300 - 309.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
C. Passino, R. Poletti, F. Bramanti, C. Prontera, A. Clerico, and M. Emdin
Neuro-hormonal activation predicts ventilatory response to exercise and functional capacity in patients with heart failure
Eur J Heart Fail,
January 1, 2006;
8(1):
46 - 53.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. H. W. Tang, A. C. Parameswaran, A. P. Maroo, and G. S. Francis
Aldosterone Receptor Antagonists in the Medical Management of Chronic Heart Failure
Mayo Clin. Proc.,
December 1, 2005;
80(12):
1623 - 1630.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. M.A. van de Wal, D. J. van Veldhuisen, W. H. van Gilst, and A. A. Voors
Addition of an angiotensin receptor blocker to full-dose ACE-inhibition: controversial or common sense?
Eur. Heart J.,
November 2, 2005;
26(22):
2361 - 2367.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Sugiyama, T. Yoshimoto, K. Tsuchiya, N. Gochou, Y. Hirono, T. Tateno, N. Fukai, M. Shichiri, and Y. Hirata
Aldosterone Induces Angiotensin Converting Enzyme Gene Expression via a JAK2-Dependent Pathway in Rat Endothelial Cells
Endocrinology,
September 1, 2005;
146(9):
3900 - 3906.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Saha, G. J. Eckert, W. T. Ambrosius, T.-Y. Chun, M. A. Wagner, Q. Zhao, and J. H. Pratt
Improvement in Blood Pressure With Inhibition of the Epithelial Sodium Channel in Blacks With Hypertension
Hypertension,
September 1, 2005;
46(3):
481 - 487.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M U Braun, T Rauwolf, T Zerm, M Schulze, A Schnabel, and R H Strasser
Long term biventricular resynchronisation therapy in advanced heart failure: effect on neurohormones
Heart,
May 1, 2005;
91(5):
601 - 605.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Bruins, M. R. Fokkema, J. W.P. Romer, M. J.L. DeJongste, F. P.L. van der Dijs, J. M.W. van den Ouweland, and F. A.J. Muskiet
High Intraindividual Variation of B-Type Natriuretic Peptide (BNP) and Amino-Terminal proBNP in Patients with Stable Chronic Heart Failure
Clin. Chem.,
November 1, 2004;
50(11):
2052 - 2058.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Bettencourt, A. Azevedo, J. Pimenta, F. Frioes, S. Ferreira, and A. Ferreira
N-Terminal-Pro-Brain Natriuretic Peptide Predicts Outcome After Hospital Discharge in Heart Failure Patients
Circulation,
October 12, 2004;
110(15):
2168 - 2174.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Okajima, R. Parent, E. Thorin, and M. Lavallee
Pathophysiological plasma ET-1 levels antagonize {beta}-adrenergic dilation of coronary resistance vessels in conscious dogs
Am J Physiol Heart Circ Physiol,
October 1, 2004;
287(4):
H1476 - H1483.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
S. de Denus, C. Pharand, and D. R. Williamson
Brain Natriuretic Peptide in the Management of Heart Failure: The Versatile Neurohormone
Chest,
February 1, 2004;
125(2):
652 - 668.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
H. Ruskoaho
Cardiac Hormones as Diagnostic Tools in Heart Failure
Endocr. Rev.,
June 1, 2003;
24(3):
341 - 356.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Abstract
Methods