Cardiovascular mechanisms of thyroid hormones and heart failure: Current knowledge and perspectives

Abstract

A multiple hormonal imbalance that accompanies heart failure (HF) may have a significant impact on the clinical course in such patients. The non-thyroidal illness syndrome (NTIS), also referred to as euthyroid sick syndrome or low triiodothyronine syndrome, can be found in about 30% of patients with HF. NTIS represents a systemic adaptation to chronic illness that is associated with increased cardiac and overall mortality in patients with HF. While conclusions on thyroid-stimulating hormone, free triiodothyronine, total and free thyroxine are currently unresolved, serum total triiodothyronine levels and the ratio of free triiodothyronine to free thyroxine seem to provide the best correlates to the echocardiographic, laboratory and clinical parameters of disease severity. HF patients with either hyper- or hypothyroidism should be treated according to the appropriate guidelines, but the therapeutic approach to NTIS, with or without HF, is still a matter of debate. Possible treatment options include better individual titration of levothyroxine therapy, combined triiodothyronine plus thyroxine therapy and natural measures to increase triiodothyronine. Future research should further examine the cellular and tissue mechanisms of NTIS as well as new therapeutic avenues in patients with HF.

Key Words: Heart failure, Non-thyroidal illness syndrome, Low triiodothyronine syndrome, Therapy, Thyroxine, Triiodothyronine

Core Tip: The non-thyroidal illness syndrome, also referred to as euthyroid sick syndrome or low triiodothyronine syndrome, can be found in about 30% of patients with heart failure (HF). Serum total triiodothyronine levels and the ratio of free triiodothyronine to free thyroxine seem to correlate the best with the echocardiographic, laboratory and clinical parameters of the severity of HF. Future research should further explore cellular and tissue mechanisms of this syndrome as well as possible therapeutic options in patients with HF.

INTRODUCTION

The cardinal symptoms of heart failure (HF) are fatigue and shortness of breath, which in more severe cases may be accompanied by signs such as peripheral edema, pulmonary crackles and elevated jugular venous pressure[1]. HF is caused by a structural and/or functional abnormality of the heart producing increased ventricular filling pressures and/or impaired cardiac output. According to the left ventricular ejection fraction (LVEF), HF is divided into the 3 subgroups: HF with preserved ejection fraction and LVEF ≥ 50%, HF with mildly reduced ejection fraction in those with LVEF between 41% and 49%, and HF with reduced ejection fraction and LVEF ≤ 40%[1]. In developed countries, primarily due to population ageing and significant advances in the management of cardiovascular diseases, the overall incidence of HF is continuously and substantially increasing[2,3].

HF: MULTIPLE HORMONAL IMBALANCE SYNDROME

A body of evidence suggests that HF is accompanied by a multiple hormonal imbalance which may affect the clinical course of such patients[4]. In older men with HF, a lower endogenous testosterone level contributes to the occurrence of HF[5] due to a lack of testosterone’s favorable cardiac and peripheral effects[6], particularly on diastolic function[7]. Since estrogen’s cardiovascular effects somewhat protect against HF, estrogen stimulation in postmenopausal women may be useful for improving cardiac functioning in this disease[8,9]. However, in men with HF, circulating levels of estradiol are also inversely associated with diastolic dysfunction independently of circulating testosterone levels and other clinical variables[10], whereas both low and high levels of estradiol are predictors of a poorer prognosis[11]. The multiple hormonal deficiency syndrome associated with HF also encompasses down-regulation of anabolic axes of growth hormone, its tissue effector insulin-like growth factor-1, and insulin signaling[4]. Finally, we now realize that alterations in the serum level, tissue concentration and metabolism of thyroid hormones (TH) are common hormone disturbances which accompany HF.

TH METABOLISM, NON-THYROIDAL ILLNESS SYNDROME AND HF

By stimulating TH receptors present in the heart and vascular endothelial tissue, TH directly regulate the dynamics of the cardiovascular system and may modulate cardiovascular risk factors, primarily arterial hypertension, hyperlipidemia and thrombogenesis. Fluctuation of the TH concentration in both peripheral tissues and circulation substantially affect cardiovascular function, whereas both hyperthyroidism and hypothyroidism may induce HF. Untreated hyperthyroidism may lead to a hyperdynamic state with increased cardiac output caused by increased myocardial contractility and heart rate coupled with increased cardiac preload due to reduced systemic vascular resistance[12]. The long-term consequences of hyperthyroidism include cardiac hypertrophy, chronically increased preload and development of cardiac arrhythmias, all of which may lead to HF[13]. In contrast, hypothyroidism is associated with reduced myocardial contractility, heart rate and cardiac output, and increased peripheral vascular resistance[14]. Both overt[15] and subclinical[16,17] hypothyroidism may be associated with systolic dysfunction of the left ventricle (LV).

Besides hyper- or hypothyroidism, the non-thyroidal illness syndrome (NTIS), also referred to as euthyroid sick syndrome or low triiodothyronine (T₃) syndrome, can be found in about 30% of patients with HF[18,19]. NTIS is not an isolated pathophysiological condition; it is rather a systemic adaptation to chronic illness. NTIS affects the pathophysiology of TH at the level of the hypothalamic-pituitary-thyroid axis, including organ and tissue levels[20]. This syndrome is characterized by a decrease in serum T₃ levels, an increase in reverse T₃ and a reduction in serum thyroxine (T₄). Absent is the expected rise in the serum levels of thyroid-stimulating hormone (TSH)[20]. Changes in serum TH levels have been suggested as an independent predictor of cardiac and overall mortality associated with NTIS[18,21,22]. This is not surprising since TH have important cardioprotective effects against HF at the level of the myocytes, the interstitium and the vasculature, with a strong antiapoptotic effect on myocytes, and reduction of interstitial fibrosis[19]. At the same time, increased reverse T₃, the inactive TH metabolite, is an important predictor of both acute- and long-term mortality[19].

CURRENT KNOWLEDGE AND UNANSWERED QUESTIONS

Given the body of evidence linking NTIS with poor prognosis in HF, three clinically relevant questions remain unanswered: (1) Which TH are most associated with the cardiovascular parameters and should be measured to identify those who should be treated; (2) when and how such patients should be treated; and (3) what parameters should be monitored to assess the efficacy of the therapy (Table 1).

Table 1 The chief areas of future research of non-thyroidal illness syndrome in heart failure.

Area of research	Clinical parameters
Best correlations of TH with clinical, echocardiographic and laboratory parameters of HF	Total serum T3 (LVEF, LVDD, NT-proBNP)
	Free T3/free T4 ratio (cardiac chamber diameters, LVEF, NYHA class)
	Reverse T3 (predictor of mortality)
Possible treatment options	Better individual titration of levothyroxine therapy
	Combined T3 + T4 therapy
	Natural measures to increase T3
Parameters of clinical status/improvement monitoring	LVEF
	LVDD
	NT-proBNP
	HF cardinal symptom attenuation/alleviation
	HF signs attenuation/alleviation

HF: Heart failure; TH: Thyroid hormones; LVEF: Left ventricular ejection fraction; LVDD: Left ventricular diastolic dysfunction; NT-proBNP: N-terminal pro-B-type natriuretic peptide; T₃: Triiodothyronine; T₄: Thyroxine.

Clinical research has provided some insight into the correlation of particular TH with the clinical parameters of HF. In general, the findings regarding TSH[23-25], free T₃ (fT₃)[25,26], total T₄ and free T₄ (fT₄)[25,27] are, at best, inconclusive. On the other hand, findings on two other TH indicators, although also relatively scarce, seem less contradictory. It has been suggested that total T₃ is closely associated with LVEF[25], LV diastolic dysfunction (LVDD)[25,27] and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels[25,28]. The role of T₃ as the most important TH in HF was strongly supported by a 2008 study by Pingitore et al[26]. This study showed that intravenous T₃ administered to patients with chronic HF due to dilated cardiomyopathy produced a significantly improved neuroendocrine profile and ventricular performance expressed through LV end-diastolic volume. Moreover, the stroke volume was increased without change in external and intra-cardiac workload, and was probably mediated through inodilating properties, i.e., positive inotropic effect and a favorable effect of T₃ on diastolic dysfunction and vascular resistance[26]. Additionally, it has been suggested that fT₃/fT₄ ratio is associated with cardiac chamber sizes, LVEF and NYHA class[23,29]. Therefore, it seems that total T₃ and fT₃/fT₄ ratio may serve as the best correlates to cardiac function, clinical status and progression of HF.

TREATMENT POSSIBILITIES

HF patients with either hyper- or hypo-thyroidism should be treated according to the appropriate guidelines. However, the therapeutic approach to NTIS, with or without HF, is still a matter of debate. In the case of persistent symptoms despite previous substitutional levothyroxine therapy and serum TSH values within the reference range, the T₄ plus T₃ combination has been suggested as a treatment option by the European Thyroid Association[30] regardless of reported contradictory findings[31,32]. Perhaps natural measures to raise T₃, such as lowering stress levels, having a healthy diet, along with emphasis on regular exercise[33] and selenium intake[34], may achieve clinically relevant improvement through changes in TH levels in HF patients.

Obviously, it is difficult to distinguish persistent hypothyroid symptoms despite achieved normal TSH from the typical HF symptoms. In this light, the whole concept of NTIS, more commonly called low T₃ syndrome when associated with HF, should be additionally explored in better-designed randomized clinical trials with rigorous selection criteria. The effect of any explored therapeutic option could be assessed by a change in LVEF, LVDD and NT-proBNP levels or through HF symptom alleviation, and correlated with TH improvement. Still, although these suggested therapeutic interventions appear useful and logical, we must be prepared for disappointment, as demonstrated by testosterone supplementation in HF within the physiologic range[35] after several decades of seemingly promising results[36].

CONCLUSION

TH are among the chief regulators of the cardiovascular system. At present, it seems that serum total T₃ levels and a fT₃/fT₄ ratio show the best correlation to echocardiographic, laboratory and clinical parameters of the severity of HF. Future research should further explore the role of hormonal changes in HF, particularly cellular and tissue mechanisms of NTIS as well as possible therapeutic options.

ACKNOWLEDGEMENTS

The author thanks Mary Louise Stover for editing the manuscript.