Clinical Investigation
Prognostic Value of Aldosterone and Cortisol in Patients Hospitalized for Acutely Decompensated Chronic Heart Failure With and Without Mineralocorticoid Receptor Antagonism

https://doi.org/10.1016/j.cardfail.2014.12.011Get rights and content

Highlights

  • We model the prognostic value of aldosterone and cortisol in systolic heart failure (HF)

  • Analyses were stratified according to mineralocorticoid receptor blocker (MRA) intake

  • In MRA-naïve patients, high levels of both aldosterone and cortisol predicted death

  • In patients on MRA, only aldosterone, but not cortisol, levels predicted death

  • The prognosis-mediating effect of MRA supports a causal role of cortisol in HF

Abstract

Background

Serum aldosterone and cortisol independently predict an increased mortality risk in heart failure (HF), and mineralocorticoid receptor antagonism (MRA) improves survival. The prognostic relevance of aldosterone and cortisol with MRA is unclear.

Methods and Results

In this post hoc analysis of a prospective cohort, study serum levels of aldosterone and cortisol were measured at baseline in 842 patients with systolic HF. The mean age was 68 ± 12 years (27% female, 45% in New York Heart Association functional class III/IV, 43% with MRA; median follow-up 38 months [interquartile range 30–43 mo]). Crude mortality in the total cohort was 43% (patients with vs without MRA: 34% vs 41%; P = .052). In MRA-naïve patients, higher levels of both aldosterone and cortisol were predictive of increased mortality risk in multivariable Cox regression: hazard ratio (HR) with 95% confidence interval of highest vs lowest tertile for aldosterone: 1.51 [1.02–2.24] (P = .040); and for cortisol: 1.94 [1.28–2.93] (P = .002). In MRA-treated patients, aldosterone (highest vs lowest tertile: HR 1.65 [1.01–2.71]; P = .048) but not cortisol (HR 0.77 [0.44–1.27]; P = .33) was associated with all-cause mortality. Further subgroup analysis revealed that particularly patients with low cortisol and high aldosterone levels had the worst prognosis (HR 5.01 [2.22–11.3]; P < .001), compared with the reference of low cortisol and low aldosterone. Subjects with this profile had larger ventricles and more often coronary artery disease.

Conclusions

In systolic HF, the prognostic value of aldosterone and cortisol levels differs in dependency of MRA intake. The pathophysiologic link between low cortisol, high aldosterone, and increased mortality risk in patients with MRA needs to be clarified.

Section snippets

Study Design and Population

For the present analysis we made use of the dataset of the Extended Interdisciplinary Network Heart Failure study, a randomized, 2-armed, multicenter trial investigating a nurse-based disease management program for patients with acutely decompensated chronic heart failure. Details of the study design have been reported previously.11 In brief, inclusion criteria comprised age ≥18 years, informed written consent, ability to understand the purpose of the study and to participate in the telephone

Baseline Characteristics

Out of 842 patients, 360 (43%) were using MRAs at baseline (82% spironolactone, 18% eplerenone). The mean daily dose was slightly higher in patients receiving spironolactone compared with eplerenone (30 ± 15 mg vs 26 ± 6 mg; P = .010). Patients on MRAs were younger, had better renal function and lower hs-CRP, and were more often treated with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs; Table 1). In these patients, however, NYHA functional class was

Discussion

In MRA-naïve patients, higher levels of both aldosterone and cortisol were predictive of an increased mortality risk after comprehensive multivariable adjustment for potential confounders in the present study, thus confirming previously published data.8 Furthermore, in patients treated with MRAs, only higher levels of aldosterone, but not of cortisol, were predictive for all-cause death, questioning a mere associative role of the stress hormone cortisol in this context and strengthening the

Conclusion

High levels of both aldosterone and cortisol were predictive of an increased all-cause mortality risk in MRA-naïve patients with acutely decompensated chronic heart failure. In patients taking MRAs, in contrast, only aldosterone levels were associated with an adverse prognosis. Although the observational design of the present study does not allow any mechanistic conclusions about the impact of cortisol regarding MR activation, the differential prognostic value of cortisol in patients with and

Disclosures

None.

Acknowledgments

The authors thank all patients participating in the INH study and all nurses of the Clinical Study Unit of the Comprehensive Heart Failure Center, Würzburg.

References (43)

  • M.J. Young et al.

    Mineralocorticoid receptor activation and cardiac fibrosis

    Clin Sci (Lond)

    (2007)
  • B. Pitt et al.

    The effect of spironolactone on morbidity and mortality in patients with severe heart failure

    N Engl J Med

    (1999)
  • B. Pitt et al.

    Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction

    N Engl J Med

    (2003)
  • F. Zannad et al.

    Eplerenone in patients with systolic heart failure and mild symptoms

    N Engl J Med

    (2011)
  • J.J. McMurray et al.

    ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC

    Eur Heart J

    (2012)
  • A.S. Mihailidou et al.

    Glucocorticoids activate cardiac mineralocorticoid receptors during experimental myocardial infarction

    Hypertension

    (2009)
  • G. Guder et al.

    Complementary and incremental mortality risk prediction by cortisol and aldosterone in chronic heart failure

    Circulation

    (2007)
  • M. Yamaji et al.

    Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: the impact of oxidative stress

    Circ Heart Fail

    (2009)
  • P. Galuppo et al.

    Mineralocorticoid receptor activation in myocardial infarction and failure: recent advances

    Eur J Clin Invest

    (2012)
  • C.E. Angermann et al.

    Mode of action and effects of standardized collaborative disease management on mortality and morbidity in patients with systolic heart failure: the Interdisciplinary Network for Heart Failure (INH) study

    Circ Heart Fail

    (2012)
  • C. Drechsler et al.

    Aldosterone and cortisol affect the risk of sudden cardiac death in haemodialysis patients

    Eur Heart J

    (2013)
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    Funding: Grants from the German Ministry of Education and Research (BMBF), Berlin, Germany [BMBF 01GL0304 to Competence Network Heart Failure Germany; BMBF 01GI0205 and BMBF 01EO1004 to Comprehensive Heart Failure Center Würzburg]. GG was supported by a fellowship grant from the Medical Faculty of the University of Würzburg (Habilitationsstipendium).

    See page 215 for disclosure information.

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