Published online before print March 19, 2007, doi: 10.1161/CIRCULATIONAHA.106.653964
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(Circulation. 2007;115:1754-1761.)
© 2007 American Heart Association, Inc.
Heart Failure |
Complementary and Incremental Mortality Risk Prediction by Cortisol and Aldosterone in Chronic Heart Failure
From the Department of Internal Medicine I, Center for Cardiovascular Medicine, University of Würzburg, Würzburg, Germany.
Correspondence to Dr Stefan Störk, MD, PhD, University of Würzburg, Department of Internal Medicine I, Center for Cardiovascular Medicine, Klinikstrasse 6–8, D-97070 Würzburg, Germany. E-mail stoerk_s{at}klinik.uni-wuerzburg.de
Received July 24, 2006; accepted January 19, 2007.
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Abstract |
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Background— In patients with systolic heart failure, high levels of circulating aldosterone are associated with an adverse prognosis, and mineralocorticoid receptor blockade improves survival. The prognostic significance of cortisol that may also bind and activate the mineralocorticoid receptor in chronic heart failure is unknown.
Methods and Results— Serum levels of cortisol and aldosterone were quantified in a prospective cohort study of 294 consecutive patients with chronic heart failure [48% were in New York Heart Association functional class III or IV; 58% had systolic heart failure]. During a median follow-up of 803 days (interquartile range, 314 to 1098), 79 patients died (27.3% mortality rate). Cortisol and aldosterone were independent predictors of increased mortality risk in Cox regression analyses adjusted for age, sex, New York Heart Association functional class, C-reactive protein, N-terminal pro-brain natriuretic peptide, sodium, and hypercholesterolemia. The hazard ratio for highest versus lowest tertile of cortisol was 2.72 [95% confidence interval [CI], 1.38 to 5.36; P=0.004], and the hazard ratio for aldosterone was 2.19 (95% CI, 1.23 to 3.93; P=0.008). Patients with both cortisol and aldosterone levels above the respective medians had a 3.4-fold higher mortality risk compared with subjects with both corticosteroids below the median (95% CI, 1.54 to 7.46; P=0.0001). Addition of cortisol and aldosterone levels to the fully adjusted model significantly improved the discriminatory power [increase in Harrell’s C-statistic from 0.80 (95% CI, 0.70 to 0.90) to 0.86 (95% CI, 0.79 to 0.94; P<0.001 for change].
Conclusions— In patients with chronic heart failure, higher serum levels of both cortisol and aldosterone were independent predictors of increased mortality risk that conferred complementary and incremental prognostic value.
Key Words: aldosterone • cortisol • heart failure • hormones • prognosis
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Introduction |
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Progression of chronic heart failure is mediated largely via persistent activation of various neuroendocrine systems.1 Inhibition of the sympathoadrenergic system by ß-blockers and of the renin-angiotensin-aldosterone system by angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and mineralocorticoid receptor (MR) antagonists is responsible for the marked prognostic improvement of patients with chronic heart failure over the last 2 decades.2,3 Despite the combined administration of different neurohumoral antagonists, neuroendocrine activation remains incompletely blocked in many patients.4,5 Higher serum aldosterone concentrations in patients on diuretics treated with or without angiotensin-converting enzyme inhibitor/angiotensin II receptor blockers were associated with increased mortality and rehospitalization rates.5–8 Nevertheless, these studies were restricted to patients in New York Heart Association (NYHA) functional classes III and IV with systolic heart failure after myocardial infarction.7 So far, no data exist on the prognostic value of aldosterone in nonsystolic chronic heart failure.
Clinical Perspective p 1761
Over the past several years, evidence has accumulated that cortisol may also contribute to the progression of cardiac damage in chronic heart failure. Because cardiomyocytes lack 11ß-hydroxysteroid dehydrogenase type II, MRs are normally occupied by cortisol in a tonic inhibitory fashion.9–11 However, in the context of tissue damage and generation of reactive oxygen species, this inhibitory role of cortisol is transformed by the altered intracellular redox state, and cortisol may act as a MR agonist that mimics the physiological and pathophysiological effects of aldosterone.11–13 Up to now, the prognostic value of cortisol levels in chronic heart failure, additive or complementary to aldosterone levels, has not been determined.
The present study investigated the independent and incremental association of serum cortisol and aldosterone concentrations with all-cause mortality risk in a consecutive cohort of patients across all NYHA classes with systolic as well as nonsystolic heart failure.
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Methods |
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Study Design and Subjects
A total of 300 patients who presented consecutively between June 2002 and July 2003 with either impaired left ventricular function [echocardiographic fractional shortening (FS) <24%] or typical heart failure symptoms with preserved left ventricular function (FS
24%) were enrolled if they were not on current corticosteroid therapy. Patients were eligible regardless of heart failure severity and mode of admission. In 6 patients, blood analyses on hormones were not feasible because of storage failure; therefore, the current report refers to 294 subjects. All patients underwent a detailed standardized clinical examination, and FS was measured according to standard recommendations. The study was approved by the Ethics Committee of the Medical Faculty of Würzburg University, and all patients provided written informed consent.
Hormone Analysis and Laboratory Measurements
Serum samples for aldosterone and cortisol measurements were collected at study start between 8 and 11 AM after 30 minutes of rest. Cortisol was measured with an automated immunoassay (Immulite 2000, DPC Biermann, Bad Nauheim, Germany). Aldosterone was measured by radioimmunoassay with commercially available reagents (DPC Biermann, Bad Nauheim, Germany). All other laboratory parameters such as C-reactive protein (Roche Diagnostics GmbH, Basel, Switzerland) and N-terminal pro-brain natriuretic peptide (NT-proBNP; Roche Diagnostics GmbH) were measured as part of the clinical routine in the central laboratory of the University Hospital. For all assays, the intra- and interassay coefficients of variation were <8% and <12%, respectively.
Outcome Ascertainment
Patient status (dead or alive) was ascertained between June and August 2005 by communication with the patient’s general practitioner or by review of hospital discharge letters. Follow-up was 100% complete. The median follow-up time for survivors was 803 days.
Data Analysis
Group comparisons between systolic (FS24%) and nonsystolic (FS<24%) heart failure were made with Fisher exact test and the Mann-Whitney U-test, as appropriate. Comparisons within groups were made with the Kruskal-Wallis test. Univariate and multivariate determinants of naturally log-transformed aldosterone and cortisol levels were determined with linear backstep regression (P value for exclusion was 0.05). Age and sex were forced into all regression models. The association of aldosterone and cortisol levels with all-cause mortality was determined by Cox proportional hazards regression with the corticosteroids as log-normalized continuous or categorized variables (tertiles, or dichotomized at the median). Univariately predictive variables (P<0.05) were backward eliminated in multivariable models with the likelihood ratio criterion, and hazard ratios (HRs) with 95% confidence intervals (CIs) were reported. Four multivariable Cox models were constructed: model 0 included all predictors except the corticosteroids; models 1 and 2, in addition to model 0, included information on cortisol or aldosterone, respectively; model 3 included combined information on both corticosteroids in addition to model 0. Interaction was assessed by the introduction of a product term. To assess the incremental prognostic value of the corticosteroids on top of variables included in model 0, Harrell’s C-statistic was computed (comparable to the area under the receiver-operating characteristic curve).14 To compare the difference between the C-statistics of models 0 and 3, a bootstrap procedure was used with 2000 repetitions. The empirical 1-sided P value was calculated as the number of differences <0. Statistical analysis was performed with SPSS 13.0.1 (SPSS Inc, Chicago, Ill) and S-plus software (Version 2000, Math-Soft Inc, Seattle, Wash).15
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Patient Characteristics
Table 1 summarizes the baseline characteristics of all subjects and subgroups according to systolic (58%) and nonsystolic (42%) heart failure. Women comprised 34% of the study population and were on average 5 years older than men. The distribution of NYHA classes was similar between groups. As expected, women were more frequently in the group with nonsystolic heart failure (28% versus 44%).16
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Hormone Concentrations and Inflammatory Markers
The median cortisol and aldosterone serum levels are shown in Table 2 together with levels of C-reactive protein and NT-proBNP. Levels of cortisol (P=0.036) and NT-proBNP (P<0.001) were higher in systolic heart failure, whereas levels of aldosterone and C-reactive protein were not different between groups. Table 3 summarizes the statistically significant univariate and multivariate associations of cortisol and aldosterone levels selected from the parameters listed in Tables 1 and 2
. In multivariate analysis, the independent determinants of cortisol were body mass index, renal insufficiency, and atrial fibrillation; for aldosterone, the respective determinants were renal insufficiency, use of MR antagonists, and use of diuretics.
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Predictors of All-Cause Mortality
During a median follow-up of 803 days (interquartile range, 314 to 1098 days), 79 patients died (27.3% mortality rate). The crude mortality rate per aldosterone tertile was 19.4%, 21.2%, and 40.6% (from low to high; P for trend was 0.001). The association of all-cause death with cortisol tertiles was in the same direction and of similar strength, with a risk of death of 14.0%, 25.8% and 42.1%, respectively (from low to high; P for trend <0.001). Both corticosteroids were positively associated with all-cause mortality risk in univariate analysis (Figure 1) with a HR of 3.41 (95% CI, 1.85 to 6.29) for highest versus lowest tertile of cortisol and of 2.48 (95% CI, 1.43 to 4.30) for highest versus lowest tertile of aldosterone. Further univariate predictors of increased all-cause mortality risk were age, NYHA class, high C-reactive protein, low sodium, high potassium, absence of hypercholesterolemia, high NT-proBNP, reduced FS, hypotension, atrial fibrillation, renal insufficiency, and intake of angiotensin-converting enzyme inhibitors, ß-blockers, and diuretics. Tables 4 and 5 shows the results of the multivariate Cox analysis after backward selection of univariate predictors other than the corticosteroids (model 0). To assess whether the protective effect of hypercholesterolemia was carried by intake of statins, we forced use of statins into the model and found an unchanged HR for hypercholesterolemia (HR, 0.36; 95% CI, 0.18 to 0.72; P=0.004) and no effect for statin use (HR, 0.73; 95% CI, 0.21 to 2.59; P=0.627). The corresponding test on multiplicative interaction was also negative (change in –2 log-likelihood 0.229, P=0.624).
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Complementary and Incremental Prognostic Value of Corticosteroids
To further elucidate the added value conferred by the corticosteroid hormones, we included cortisol and aldosterone separately (Tables 4 and 5
, models 1 and 2) and in combination (Tables 4 and 5, model 3) into multivariable Cox models adjusted for the variables of model 0. The highest tertiles of both cortisol and aldosterone were associated with an increased mortality risk of 2.72 (95% CI, 1.38 to 5.36; model 1) and 2.19 (95% CI, 1.23 to 3.93; model 2), respectively. To assess the influence of NYHA class we performed subanalyses in strata of NYHA classes I–II and III–IV. For cortisol, the highest-versus-lowest tertile in NYHA class I–II was associated with a HR of 5.00 (95% CI, 1.31 to 13.89; P=0.020), and in NYHA III–IV with a HR of 2.44 (95% CI, 1.27 to 4.62; P=0.034). The corresponding HRs for aldosterone were 4.20 (95% CI, 1.34 to 12.11; P=0.011) for NYHA I–II, and 1.82 (95% CI, 1.13 to 3.20; P=0.042) for NYHA III–IV. Further subanalyses were performed in groups with systolic and nonsystolic heart failure. For cortisol, the highest-versus-lowest tertile in patients with systolic heart failure was associated with a HR of 2.29 (95% CI, 1.15 to 4.92; P=0.032), and in nonsystolic heart failure with a HR of 7.19 (95% CI, 1.47 to 15.23; P=0.015). The corresponding HRs for aldosterone were 2.02 (95% CI, 1.12 to 4.02; P=0.034) for systolic and 2.40 (95% CI, 1.28 to 7.83; P=0.022) for nonsystolic heart failure.
If both corticosteroids were added to model 0, the highest tertiles of both cortisol and aldosterone remained independently predictive, with only small reductions in their respective HRs (model 3). The test on multiplicative interaction was not statistically significant, but showed a trend: change in -2 log likelihood 3.62 (P=0.092).
To examine whether use of the information on corticosteroids allows identification of a high-risk subgroup, cortisol and aldosterone were entered into model 0 with levels dichotomized at their median (see Table 2 for median levels). Compared with subjects who had low levels of both cortisol and aldosterone, patients with high levels of both corticosteroids had a 4.5-fold higher mortality risk in unadjusted analysis (HR, 4.48; 95% CI, 1.81 to 6.77; P<0.0001) (Figure 2) and a 3.4-fold higher mortality risk (HR, 3.37; 95% CI, 1.54 to 7.46; P=0.0001) in multivariable analysis. All analyses were rerun with log-normalized instead of trichotomized values and yielded very similar results (Table 5).
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To estimate the incremental prognostic value of corticosteroids, we compared the C-statistics of models 0 and 3 with both approaches (ie, trichotomized and log-normalized variables as detailed in Tables 4 and 5). For the trichotomized approach, we found that in model 0, C=0.80 (95% CI, 0.70 to 0.90), whereas in model 3, C=0.86 (95% CI, 0.79 to 0.94), for a difference between the 2 models of 0.057 (95% CI, 0.029 to 0.083); P<0.001. For the log-normalized approach, we found that in model 0, C=0.80 (95% CI, 0.70 to 0.90), whereas in model 3, C=0.85 (95% CI, 0.78 to 0.93), for a difference between the 2 models of 0.050 (95% CI, 0.020 to 0.081); P=0.004.
Effect of Spironolactone
Intake of spironolactone was strongly associated with aldosterone levels and weakly with cortisol levels (Table 3) but was not a predictor of mortality risk. When use of spironolactone was forced into models 1 to 3, the HR and CI values for aldosterone and cortisol did not change materially (data not shown).
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Discussion |
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The present study identified higher serum levels of cortisol and aldosterone as independent, complementary, and incremental predictors of all-cause mortality risk in consecutively enrolled patients with chronic heart failure of any cause and severity.
We demonstrated for the first time the independent prognostic utility of serum cortisol in unselected patients with heart failure. Cortisol is known to unfavorably affect classic cardiovascular risk factors such as hypertension and insulin resistance, which in turn adversely influence survival.17,18 However, there is increasing evidence that cortisol may also interfere directly with the pathological processes that lead to heart failure progression by binding to and activating cardiac MRs.11,19 According to a hypothesis proposed by J.W. Funder, cortisol may be the dominant agonist that activates cardiac and vascular MRs under conditions of chronic heart failure.12,20 Blockade of the MR was effective in the reduction of cardiovascular damage in experimental models with low aldosterone and renin levels and also in patients with low to normal aldosterone levels.13,21,22 Cortisol and aldosterone exhibit a similar affinity to the MR, and free cortisol circulates at systemic concentrations 2 orders of magnitude higher than aldosterone, which suggests that the beneficial effect of MR blockade in these studies may result from inhibition of cortisol binding to the MR. Under physiological conditions, specific intracellular inhibitory systems counteract cortisol-mediated activation of the MR.
In typical aldosterone targets such as renal, tubular, or vascular smooth muscle cells, 11ß-hydroxysteroid dehydrogenase type II inactivates cortisol to cortisone and thus mediates specificity of the MR for aldosterone. In contrast, in several nonepithelial cells such as cardiomyocytes, expression of 11ß-hydroxysteroid dehydrogenase type II is negligibly low. Hence, under physiological conditions most MR are presumably occupied by cortisol.12 In situations of inflammation and hypoxia, generation of reactive oxygen species and changes in the intracellular redox state may interfere with the cortisol–MR complex and trigger cortisol-mediated activation of the MR.11 However, despite the powerful prognostic value of cortisol in the present study, it remains uncertain whether the observed increases in cortisol concentration significantly alter cardiac MR activation.
Activation of the hypothalamus-pituitary-adrenal axis is often considered to be a nonspecific indicator of stress or systemic inflammation, which calls into question any causative role of cortisol as a mediator of poor prognosis in cardiac failure. Higher cortisol concentrations have been reported in acute heart failure, cardiac cachexia, and systemic inflammation.23–25 However, no such increase in cortisol levels has been found in chronic heart failure. Inclusion of catabolic markers such as low cholesterol in our models did not alter the strength and direction of the observed associations, and no difference existed in cortisol concentrations between NYHA classes. Finally, in our data, C-reactive protein was not a determinant of cortisol levels, neither in crude nor in sex- and age-adjusted analyses. This suggests that the observed association is not merely an indicator of disease severity, cardiac cachexia, or a general inflammatory response. Of note, serum cortisol levels were well within the normal range and were comparable to morning cortisol concentrations in samples of healthy subjects.26 Thus, no major activation of the hypothalamus-pituitary-adrenal axis during morning hours was evident in our study, a finding that supports the concept that normal circulating cortisol concentrations are sufficient to predominantly activate cardiac MRs in heart failure.
Furthermore, we report a complementary prognostic value of cortisol and aldosterone levels. In contrast to cortisol, the prognostic and pathophysiological role of aldosterone in systolic heart failure is well characterized. Aldosterone participates in numerous detrimental procedures that lead to heart failure progression such as cardiovascular inflammation and fibrosis, endothelial dysfunction, hypertension, and arrhythmia.27–29 Elevated aldosterone levels serve as a prognostic marker in systolic heart failure and acute ST-elevation myocardial infarction and also correlate inversely with survival.6,30 In the present study, the prognostic value of both higher aldosterone and cortisol levels remained robust even after multivariable adjustment (Tables 4 and 5). As shown in Figure 2, the combined information on high concentrations of both corticosteroids had an intriguing impact on mortality risk prediction. Moreover, the concurrence of high cortisol and high aldosterone serum levels was an independent prognostic marker for all-cause mortality and increased the HRs of each of the individual corticosteroid hormones. Addition of both corticosteroids to a model that comprised the main multivariate predictors significantly improved the C-statistic, which also implies an incremental prognostic utility of corticosteroids. Hence, it is tempting to speculate that both aldosterone and cortisol play an important role in heart failure progression.
Our results are in line with previously published data and show that the highest tertile of aldosterone is associated with an adverse outcome. In the Randomized Aldactone Evaluation Study (RALES), the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS), and the 4E Left Ventricular Hypertrophy study,22,31,32 the beneficial effects of aldosterone blockade were observed despite normal plasma levels of aldosterone, a finding that supports the concept that other ligands also activate the MR under pathological conditions. Cortisol is considered the ideal candidate because it binds to the MR, activates it under certain circumstances, and exceeds plasma aldosterone concentrations by several orders of magnitude. In our study, only patients in the highest aldosterone tertile (ie, plasma levels at a median concentration of 244 pg/mL) showed an association with mortality risk. Thus, the benefit of MR blockade in the trials mentioned above may indeed have resulted from blockade of both cortisol and aldosterone.
Current treatment guidelines emphasize the role of MR blockers in patients with severe chronic systolic heart failure or in patients after myocardial infarction with impaired ejection fraction.2 We found that the association between higher aldosterone serum levels and all-cause mortality was also observed in subjects with nonsystolic heart failure to a similar degree. This may support the use of MR antagonists in patients with nonsystolic heart failure.33 For a firm recommendation, however, we look forward to the results of the randomized, double-blind, placebo-controlled TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) and ALDO-DHF (MR Blockade in Diastolic Heart Failure) trials. TOPCAT will recruit 4500 subjects with left ventricular ejection fraction 45%. The primary end point is a composite of cardiovascular mortality, aborted cardiac arrest, or hospitalization for heart failure. ALDO-DHF will recruit 420 subjects with ejection fraction 50%. The primary end points are the changes in maximum exercise capacity (spiroergometry) and diastolic dysfunction.
Other significant predictors of mortality in our analysis were older age, increasing NYHA class, high amino-terminal pro-brain natriuretic protein and C-reactive protein levels, and low sodium and low cholesterol levels, all of which have consistently been related to worse outcome in patients with heart failure.34–38 In multivariable models, intake of medication was not predictive. In particular, the protective effect of higher cholesterol levels (total cholesterol levels 240 mg/dL) was not modified by statin intake.
Certain limitations need to be considered in the interpretation of the present findings. We investigated a consecutive heterogeneous cohort of patients with chronic heart failure across all NYHA classes who exhibited preserved as well as reduced ejection fraction and who were treated with various drug therapies. In addition, the modest sample size may limit the power of the analyses performed in subgroups. Serum levels of both cortisol and aldosterone were determined only once at baseline. Although the blood samples were drawn in a standardized manner during morning hours, a single sample may inadequately reflect the average adrenal hormone release. However, the determinants of corticosteroid levels as well as the main predictors of mortality risk found in this study were consistent with previous reports.21, 34–36, 38–40 The investigated cohort represents a typical real-world heart failure population. Our findings may thus be applicable to the heart failure population in general. It remains to be determined whether our study extends to other end points of clinical relevance in chronic heart failure such as sudden cardiac death, cardiovascular death, or rehospitalization rate. Obviously, conclusions about a specific role of cortisol cannot be drawn on the basis of the present study. Such a role needs to be defined in further studies.
In conclusion, serum levels of both cortisol and aldosterone appeared to be equally strong independent predictors of all-cause mortality risk in patients with systolic and nonsystolic chronic heart failure of any cause. The highest serum concentrations of both cortisol and aldosterone identified a subgroup of chronic heart failure patients with a particularly high mortality risk.
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Acknowledgments |
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We thank Prof Dr Ewout Steyerberg, Department of Public Health, Erasmus Medical Center Rotterdam, the Netherlands, for calculation of the C statistics and the bootstrap results.
Sources of Funding
This study was supported by the Ernst and Berta Grimmke Foundation and by an educational grant from Merck. The project received further support from a grant provided by the German Ministry for Education and Research and by a research grant from the Bavarian Ministry for Education and Research dedicated specifically to supporting the careers of young women scientists (Dr Güder).
Disclosures
None.
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