Prognostic impact of subclinical thyroid dysfunction in heart failure

https://doi.org/10.1016/j.ijcard.2012.09.064Get rights and content

Abstract

Background

Therapeutic and prognostic implications of subclinical thyroid dysfunction in patients with heart failure (HF) are unclear. We compared the prognostic impact of euthyroidism, subclinical thyroid dysfunction, and euthyroid sick syndrome (ESS) in systolic HF.

Methods

We included 1032 patients hospitalized for systolic HF (left ventricular ejection fraction [LVEF] ≤ 40%) who participated in a randomized trial assessing the effects of a HF disease management program. Patients with incomplete thyroid function tests or thyrotropic medication were excluded. In the remaining 758 subjects, the risk of all-cause death was estimated based on TSH only, or full thyroid function profile. Changes of thyroid function after six months were assessed in 451 subjects.

Results

Subclinical thyroid dysfunction was present in 103 patients at baseline (14%). No differences were found between groups regarding NYHA class (P = 0.29), and LVEF (P = 0.60). After a median follow-up of three years patients with ESS (n = 13) had a 3-fold age-adjusted increased risk of death compared to euthyroid patients (P = 0.001). However, neither subclinical hyperthyroidism (HR 1.18, 95%CI:0.82–1.70) nor hypothyroidism (HR 1.07, 95%CI:0.58–1.98) were associated with increased age-adjusted mortality risk. Subclinical thyroid dysfunction had normalized spontaneously at follow-up in 77% of patients. However, persistent subclinical thyroid dysfunction was also not associated with worse outcome.

Conclusions

In this large well-characterized HF cohort, subclinical thyroid dysfunction did not predict an increased mortality risk. Thus, in patients with moderate to severe HF, further diagnostic and therapeutic procedures for subclinical thyroid dysfunction appear dispensable. ESS was an infrequent but important indicator of a poor prognosis in HF.

Clinical trial registration

URL: http://www.controlled-trials.com. Unique identifier: ISRCTN23325295.

Introduction

Heart failure is a frequent clinical syndrome representing the common final pathway of various heart diseases of different etiology [1], [2]. It has been acknowledged that comorbidities are important modifiers of disease progression and outcome in heart failure [3], [4]. Thyroid dysfunction represents a frequent comorbid condition exhibiting heterogeneous clinical manifestations [5], [6].

Both overt hyper- and hypothyroidism are known to profoundly impact on cardiac function. Tachycardia is the dominant clinical feature and pathophysiological force driving heart failure in patients with Grave's disease (autoimmune hyperthyroidism) and thyroid autonomy [7], [8], [9]. Low thyroid hormone levels were shown to reduce cardiac contractility and output by various mechanisms [5], [10]. Correspondingly, bradycardia and left ventricular heart failure are common in overt hypothyroidism [11]. The euthyroid sick syndrome (ESS) is defined by low levels of circulating triiodothyronine (T3) in patients with normal or slightly decreased thyroid stimulating hormone (TSH) and tetraiodothyronine (T4) concentrations and viewed as adaptive response to serious clinical impairment rather than genuine thyroid disease. Comorbid ESS in patients with heart failure has been reported to indicate a particularly grave prognosis [12].

Subclinical thyroid dysfunction is characterized by altered TSH but normal thyroid hormone levels. With a prevalence of up to 20% of the normal population aged 60–80 years it is much more frequent than overt thyroid dysfunction [13], [14]. There is an ongoing debate whether or not subclinical thyroid diseases are really clinically inapparent or whether they possess prognostic relevance [14], [15], [16], [17].

Several studies investigated the prognostic impact of subclinical thyroid dysfunction in heart disease. However, the data are inconclusive and partly conflicting [15], [18], [19]. One major limitation comparing studies on the association between thyroid function and clinical outcome in patients with cardiac disease is that selection of populations and definitions of thyroid disorders were heterogeneous, with several studies using only TSH as an indicator of thyroid dysfunction [4], [16], [17], [19], [20], [21]. It has, thus, remained unclear whether subclinical thyroid dysfunction is a clinically and prognostically relevant entity in heart failure requiring specific diagnostic and therapeutic measures.

We, therefore, investigated whether

  • (i)

    Subclinical thyroid dysfunction has an impact on overall survival in systolic heart failure;

  • (ii)

    The full thyroid profile including free T3 (fT3) and free T4 (fT4), in comparison to TSH only, confers better differential appraisal of thyroid function and, hence, incremental prognostic relevance;

  • (iii)

    Repeating thyroid function tests after 6 months improves the diagnostic and prognostic accuracy of these measurements.

Section snippets

Patients

Between March 2004 and December 2008, 1032 patients hospitalized for heart failure were included in the Interdisciplinary Network Heart Failure study (INH study). The original study investigated in 715 patients the effects of a telephone-based nurse intervention on clinical outcome and enrolled consecutive adults hospitalized for decompensated cardiac failure at nine hospitals in South Germany. Details of the study design have been reported elsewhere [22]. In brief, inclusion criteria were left

Baseline characteristics

Of the 1032 patients included in the INH study, 274 patients had to be excluded for incomplete (n = 176) or implausible (n = 9) results of thyroid tests or the intake of amiodarone, thyreostatic agents or corticosteroids (Fig. 1). Baseline characteristics of the remaining 758 patients (mean age 68 ± 12 years; range: 20–95 years; 29% female) are presented in Table 1. No differences were found regarding most baseline characteristics between patients with euthyroidism (n = 628), subclinical hyperthyroidism

Discussion

This prospective follow-up study in 758 well-characterized patients demonstrated that neither subclinical hyper- nor hypothyroidism are relevant prognostic factors in patients with systolic heart failure and ejection fraction ≤ 40%. Whereas in unadjusted analyses suppressed TSH alone and subclinical hyperthyroidism were associated with an increased risk of all-cause death by 35% and 44%, respectively, these associations were lost after adjustment for age. Using the full information on thyroid

Funding

This work was supported by:

Main sponsor: Federal Ministry of Education and Research, Germany [01GL0304].

Additional support: German Competence Network Heart Failure [01GI0205] and Comprehensive Heart Failure Center Würzburg [01EO1004].

None of the funding sources interfered with the collection, management, and interpretation of the data, nor requested review of the manuscript.

Acknowledgment

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.

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