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Impact of Thyroid Disease on Heart Failure

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DOI: 10.5772/66283

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 Chapter
Provisional chapter8

Impact of
Impact ofThyroid
ThyroidDisease
Diseaseonon
Heart Failure
Heart Failure

Adina Elena
Adina ElenaStanciu,
Stanciu,Adina
AdinaZamfir‐Chiru‐Anton,
Zamfir‐Chiru‐Anton,
Marcel Marian Stanciu and Dan Cristian Gheorghe
Marcel Marian Stanciu and Dan Cristian Gheorghe
Additional information is available at the end of the chapter
Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/66283

Abstract
The modern vision concerning the physiological actions and pathological relevance of
endocrine cardiac system is a very complex one. Decreased or increased action of
thyroid hormone (hypo‐ or hyperthyroidism) on different cellular and molecular
pathways in the heart plays an important role in the development and progression of
myocardial remodelling and heart failure. Cardiovascular signs and symptoms that
accompany both hyperthyroidism and hypothyroidism are presented, highlighting that
correction of thyroid dysfunction most often reverses the abnormal cardiovascular
hemodynamics.

Keywords: hyperthyroidism, hypothyroidism, heart failure, thyroid hormones, na‐

triuretic peptides

1. Introduction

The modern vision concerning the physiological actions and pathological relevance of endocrine
cardiac system is a very complex one. It is well‐known that thyroid hormones and endocrine
cardiac systems are strictly correlated in both physiological [1] and pathological conditions,
especially in patients with cardiac diseases [2, 3]. Thyroid disease is the second most common
endocrine disorder after diabetes mellitus, being present in 5–10% of the population. Current
estimates suggest that the incidence of thyroid disease in adult female population is higher than
in adult males, but with advancing age, especially beyond the eighth decade of life, the incidence
in males rises to be equal to that of females [4]. Thyroid hormone has a homeostatic role on the
cardiovascular system, especially in the presence of heart failure (HF). HF is a major public
health issue, being currently diagnosed in approximately 23 million patients worldwide [5].

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution
© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
medium, provided the original work is properly cited.
distribution, and reproduction in any medium, provided the original work is properly cited.
142 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

Many studies have recently confirmed that persistent subclinical thyroid dysfunction is
associated with the development of HF by changes in cardiac structure and function [6, 7]. The
term subclinical thyroid disease is used to define the state having an abnormal serum thyroid‐
stimulating hormone (TSH) concentration (below or above the statistically defined lower or
upper limit of the reference range: 0.45–4.50 mIU/L) in the presence of normal serum thyroid
hormones concentrations (free thyroxine and triiodothyronine within their reference ranges).
Subclinical thyroid disease may progress to overt thyroid disease. Overt thyroid dysfunction
is defined by an abnormality of both the TSH and thyroid hormones. Untreated overt hyper‐
thyroidism and hypothyroidism have been reported to be common causes of HF [8].
Unfortunately, the impact of thyroid disease on HF and, implicitly, the full potential of the
therapeutic use of thyroid hormones in treating and/or preventing HF, has not been adequately
studied. This chapter addresses the effects of thyroid hormones on cardiac function and the
clinical consequences of thyroid dysfunction.

2. Cellular and molecular mechanisms underlying the effects of thyroid

hormones on the cardiovascular system

The hypothalamic‐pituitary‐thyroid axis is responsible for the regulation of thyroid metabo‐

lism involving the following steps: (step 1) hypothalamus produces thyrotropin‐releasing
hormone (TRH), needed to monitor the thyroid hormone concentrations; (step 2) TRH
stimulates the pituitary to produce TSH; (step 3) under the action of TSH, thyroid gland
secretes 85–90% thyroxine (T4) and 10–15% triiodothyronine (T3), the primary circulating
thyroid hormones; (step 4) T4 is converted to T3 by the deiodinase system (D1–D3) in the liver,
kidney, and skeletal muscle; (step 5) thyroxine binding globulin (TBG) is responsible for
carrying T4 and T3 to the tissues.
Maintenance of thyroid hormone homeostasis is required for proper cardiovascular function
[9]. Actually, an altered thyroid hormone metabolism leads to cardiac parameters changes by
acting on some molecular pathways involved in cardiac hypertrophy and HF progression.
Thyroid hormone may act directly on transcription on specific and nonspecific cardiac genes
that include α and β myosin heavy chain (MHC‐α and MHC‐β, respectively), sarcoplasmic
reticulum Ca2+‐ATPase (SERCA), atrial natriuretic peptide, sodium‐potassium adenosine
triphosphatase (Na‐K‐ATPase), β‐adrenergic receptor and cardiac troponin I (genomic effect)
[10–12], or on plasma membrane, sarcoplasmic reticulum (a specialized type of smooth
endoplasmic reticulum that regulates the calcium ion concentration in the cytoplasm of striated
muscle cells) and mitochondria (nongenomic effect) [13].
Many invasive and noninvasive measurements have shown that T3 plays an important role in
modulating cardiac function [14]. T3 is the active form of thyroid hormone in the heart, because
no significant myocyte intracellular deiodinase activity takes place at heart level. In fact, there
is no experimental study to prove the conversion of T4 to T3 in cardiomyocytes. Due to their
lipophilic nature, T3 and T4 can easily diffuse through the cytoplasmic membrane of cardio‐
myocytes. Lipophilic T3 enters the nucleus and binds to inactive nuclear thyroid hormone
 Impact of Thyroid Disease on Heart Failure 143
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receptors, which are encoded by the c‐erbA proto‐oncogene families. Further, the complex
recognizes one of the several DNA consensus sequences and the thyroid response elements,
located in the enhancer region of target genes [15]. The subsequent binding of the T3‐receptor
complexes to DNA regulates the expression of genes, encoding for structural and functional
cardiac proteins (regulating calcium cycling in the cardiac myocyte) [16]. Thus, T3 modulates
heart rate, cardiac contractility and arterial peripheral resistance, being essential to preserve
both cardiac morphology and performance in adult life. In these circumstances, it is easy to
understand why an altered thyroid status in patients with cardiovascular disorders could
modify cardiac gene expression and contribute to impaired cardiac function.

A decrease in serum T3 needs to be analysed very carefully, because there are two possible
causes: (i) low levels of T3 associated with low levels of T4 and high levels of TSH suggest a
dysfunction of the thyroid gland itself (hypothyroidism), most often caused by an autoimmune
disease (Hashimoto's thyroiditis) and/or iodine deficiency; (ii) low levels of T3 or free T3 (FT3)
with normal T4 and low or normal TSH suggest a dysfunction which is unrelated to thyroid
gland. This particular pattern has three names as follows: euthyroid sick syndrome, non‐
thyroidal illness syndrome, or low T3 syndrome.

The exact cause of low T3 syndrome is not known, but it is assumed that it occurs as a result
of modified expression of the deiodinases (reduced enzyme activity of 5‐monodeiodinase
responsible for converting T4 into T3 in peripheral tissues) [17], modified entry of thyroid
hormone into tissue (damage membrane) [18], or altered signalling due to changes in thyroid
hormone receptors. Clinical and experimental evidence have shown that low T3 syndrome has
been found in about 30% of HF patients, being associated with HF New York Heart Association
(NYHA) functional class III–IV [19]. Furthermore, low T3 syndrome is considered a strong
prognostic predictor of death in patients with HF, contributing to the progressive deterioration
of cardiac function and myocardial remodelling in HF [17]. This might be explained by the fact
that HF develops as the result of the added stress of health conditions, and a single risk factor
may be sufficient to cause this syndrome.

Risk factors Inflammatory markers Cellular events Cardiac events

Thyroid dysfunction IL‐1 β, IL‐6, IL‐8, Fibroblast proliferation Cardiac failure

Diabetes TNF‐α, CRP Collagen synthesis

Viral infections Matrix metalloproteinases activation

High blood pressure Mechanical stress

Coronary artery disease Cardiomyocyte hypertrophy

Heart attack Cardiomyocyte apoptosis/necrosis

Congenital heart defects

Heart arrhythmias

Valvular heart disease

Table 1. Risk factors and mechanisms that are involved in the development of heart failure.
144 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

Actually, pathophysiological phenomena behind HF involve a compensatory activation of

hormonal, neurohumoral, immunological, and proinflammatory systems as can be seen from
Table 1.

Thyroid dysfunction triggers an inflammatory cascade. The balance between T‐helper type 1
(Th1) and type 2 (Th2) lymphocytes may determine the outcome of autoimmune thyroid
diseases. According to cytokine profiles, both Th1 and Th2 response have been supposed to
be involved in the pathogenesis of Hashimoto's thyroiditis (the most common cause of
hypothyroidism) and Graves’ disease (the most common cause of hyperthyroidism), but with
deviation toward Th1 pattern in Hashimoto's thyroiditis and toward Th2 pattern in Graves’
disease. Autoimmune thyroid diseases have serum antibodies reacting with thyroglobulin,
thyroid peroxidase, or TSH receptor and these antibodies might be cytotoxic. High antibodies
concentrations correlate with proinflammatory cytokines, including interleukin‐6 (IL‐6) and
tumour necrosis factor‐α (TNF‐α), responsible for oxidative stress, thyroid damage, and the
loss of thyroid function [20]. Furthermore, many studies have shown that proinflammatory
cytokines (IL‐6, IL‐1β, and TNF‐α) are cardiodepressant and play a pathogenic role in HF,
contributing to cardiac remodelling, which is a progressive process (Table 1). Also, it is known
that IL‐6 is a hallmark of the acute phase of low T3 syndrome [21]. Inflammatory biomarker
C‐reactive protein (CRP) is mainly produced in response to IL‐6 and plays many pathophy‐
siological roles in the inflammatory process in HF, in direct relation to deterioration of NYHA
functional class and cardiac performance. In patients with Hashimoto's thyroiditis, there was
a positive correlation between TgAb and hs‐CRP (r = 0.55, P = 0.01) [22], CRP being inversely
correlated with T3 and T3 levels, inversely correlated to the presence and severity of HF [23].

Plasma concentration of natriuretic peptides, including B‐type natriuretic peptide (BNP),

particularly its amino‐terminal fragment (NT‐proBNP) and A‐type natriuretic peptide (ANP),
and especially its amino‐terminal fragment (NT‐proANP) or mid‐regional fragment (MR‐
proANP), can be used as an initial diagnostic test of HF, especially in the non‐acute setting
when echocardiography is not immediately available [24]. NT‐proBNP, NT‐proANP, and MR‐
proANP have longer half‐lives, are more stable and, consequently, are more reliable analytes
of prolonged cardiac overload than are the biologically active peptides [25]. NT‐proBNP is
considered a prognostic determinant of HF progression, it levels paralleling the degree of left
ventricular dysfunction [26]. High NT‐proBNP concentrations predict cardiac‐related mortal‐
ity in HF patients.

Recent attention has been drawn to the relation of thyroid hormone, inflammatory biomarkers,
such as IL‐6 and CRP, and natriuretic peptides. Many authors studied natriuretic peptides
levels in different thyroid function states and found that their serum levels were strongly
affected by thyroid function. Generally, natriuretic peptides are elevated in overt and subclin‐
ical hyperthyroidism and reduced in overt and subclinical hypothyroidism. Thus, Christ‐Crain
et al. [27] have found statistically significant higher serum NT‐proBNP and proANP concen‐
tration in hyperthyroid patients compared to hypothyroid and euthyroid subjects. Kato et al.
[28] measured ANP and BNP levels in 130 patients with thyrotoxicosis and correlated them
with HF severity and thyroid function. The levels of BNP and ANP were elevated in thyrotoxic
patients. After therapy, when euthyroidism was established, a normalization of their levels has
 Impact of Thyroid Disease on Heart Failure 145
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been noted. The authors concluded that the measurement of serum BNP levels in thyrotoxic
patients is useful for monitoring cardiovascular conditions of HF. Pakula et al. [29] assessed
echocardiographically diameters of cardiac cavities, left ventricular mass, left ventricular
ejection fraction, and NT‐proBNP in 101 patients with thyroid dysfunction, free from any
cardiovascular disease. They have shown that hyperthyroidism, in both its clinical and
subclinical forms, results in a significant increase in NT‐proBNP serum levels, their results
being in line to those obtained by Christ‐Crain et al. [27]. Moreover, they noted that despite
normalization of plasma levels of TSH, the treatment with levothyroxine (L‐T4) did not restore
a hyperthyroidism‐induced increase in plasma NT‐proBNP levels. These findings are in
accordance with Stanciu et al. [30], who investigated the effects of short‐term overt hypothyr‐
oidism and exogenous subclinical hyperthyroidism on NT‐proBNP and NT‐proANP, in
patients with differentiated thyroid cancer treated with radioactive iodine (131I—RAI). As
illustrated in Figures 1 and 2, serum levels of NT‐proBNP and NT‐proANP were significantly
higher in subclinical hyperthyroidism (t2) than in overt hypothyroidism (t1) (6185 ng/L, IQR:
1689–8778 ng/L vs. 21.6 ng/L, IQR: 13.9–203 ng/L and 674 ng/L, IQR: 529–858 ng/L vs. 309 
ng/L, IQR: 23.7–580 ng/L, respectively, P < 0.001). The authors have found that FT3 positively
regulates NT‐proANP production from cardiac myocytes, NT‐proANP more accurately
reflecting direct thyroid hormone effects, than NT‐proBNP. Stanciu et al. concluded that short‐
term acute hypothyroidism, due to L‐T4 withdrawal, and subclinical hyperthyroidism, due to
suppressive doses of L‐T4, induce deleterious effects on natriuretic peptides profiles during
RAI therapy.

Figure 1. Median NT‐proBNP levels in patients with differentiated thyroid cancer (DTC) compared with healthy eu‐
thyroid controls. DTC‐t1: short‐term overt hypothyroidism after levothyroxine withdrawal; DTC‐t2: subclinical hyper‐
thyroidism during suppressive levothyroxine therapy (P < 0.001 vs. DTC and healthy controls; P < 0.001 vs. DTC‐t1 and
DTC‐t2).
146 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

Figure 2. Median NT‐proANP levels in patients with differentiated thyroid cancer (DTC) compared with healthy eu‐
thyroid controls. DTC‐t1: short‐term overt hypothyroidism after levothyroxine withdrawal; DTC‐t2: subclinical hyper‐
thyroidism during suppressive levothyroxine therapy (P < 0.001 vs. DTC and healthy controls; P < 0.001 vs. DTC‐t1 and
DTC‐t2).

Brozaitiene et al. [31] studied the relationship and prognostic impact of thyroid hormones,
inflammatory biomarkers, and NT‐proBNP on long‐term outcomes in coronary artery disease
(CAD) patients with HF. Multivariate linear regression models, adjusted for age, gender, and
body mass index, revealed that (ln) NT‐proBNP was associated with hs‐CRP (β = 0.59, P < 
0.001), (ln) IL‐6 (β = 0.254, P < 0.001), free thyroxine (FT4) (β = 0.100, P = 0.011), and T4 (β = 0.112,
P = 0.019). Their results showed that thyroid hormones (i.e. FT4 level and FT3/FT4 ratio)
together with NT‐proBNP level may be valuable and simple predictors of long‐term outcomes
of CAD patients after experiencing acute coronary syndrome.
The question is: is this due to a compensatory mechanism, secondary to the thyroid hormone
changes, or is it due to a direct action of thyroid hormone on the secretion of natriuretic
peptides? The presented data have shown that natriuretic peptides are directly stimulated and
regulated by thyroid hormones and immunological factors. Thyroid dysfunction triggers
proinflammatory cytokines, known as stimulators of NT‐proANP and NT‐proBNP release. All
of these leads to the idea that the thyrometabolic state must be taken into account when NT‐
proBNP or NT‐proANP are assessed as markers of HF.

3. Impact of hyperthyroidism on heart failure

Endogenous hyperthyroidism (overproduction of thyroid hormone) and exogenous hyper‐

thyroidism (ingestion of excessive amounts of thyroid hormone, i.e. suppressive doses of L‐
T4 to treat thyroid cancer) are associated with palpitations, tachycardia, exercise intolerance,
 Impact of Thyroid Disease on Heart Failure 147
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dyspnea on exertion and increased heart rate. Patients with overt and subclinical hyperthyr‐
oidism are at increased risk of atrial arrhythmias and HF, because long‐term exposure to
thyroid hormone excess exerts unfavourable effects on cardiac morphology and function by
increasing left ventricular mass, arterial stiffness, and left atrial size [32]. More than that,
autoimmune hyperthyroidism (Graves’ disease) has been frequently linked to autoimmune
cardiovascular involvement (pulmonary arterial hypertension, myxomatous cardiac valve
disease, and autoimmune cardiomyopathy). The effects of thyroid hormones on the heart and
peripheral vasculature include decreased systemic vascular resistance (SVR) and diastolic
blood pressure and increased resting heart rate, left ventricular contractility and pulmonary
arterial pressure, as can be seen from Table 2. In overt hyperthyroidism, these combined effects
increase cardiac output by 50–300% more than in normal subjects [33], resulting in right
ventricular failure, as a consequence of immune‐mediated endothelial damage [34]. Also, in
patients with overt hyperthyroidism, a high prevalence of left ventricular hypertrophy and an
increase in the contractility of the left ventricle and ejection fraction have been reported [34].

Variables Hyperthyroidism Hypothyroidism

Thyroid hormones ↑ ↓

Oxidative metabolism ↑ ↓

Natriuretic peptides ↑ ↓

Lipids and lipoproteins ↓ ↑

Heart rate ↑ ↓

Systemic vascular resistance ↓ ↑

Cardiac output ↑ ↓

Cardiac contractility ↑ ↓

Note: ↑, increased; ↓, decreased.

Table 2. Cardiovascular effects of thyroid dysfunction.

Subclinical hyperthyroidism can contribute to HF by increasing of heart rate and left ventric‐
ular mass, by worsening diastolic function and by predisposing to atrial fibrillation (AF) [35].
AF occurs in 10–25% of patients with hyperthyroidism (subclinical hyperthyroidism: RR = 1.31;
95% CI: 1.19–1.44 and overt hyperthyroidism RR = 1.42; 95% CI: 1.22–1.63) [36]. Actually,
hyperthyroidism alters cardiac ion channel expression and function, increases heart rate and
shortens atrial effective refractory period (ERP). The main cellular mechanisms of atrial
contractile dysfunction are downregulation of the Ca2+ inward current and impaired release
of Ca2+. In fact, downregulation of the L‐type Ca2+ inward current and upregulation of inward
rectifier K+ currents lead to shortening of action potential duration and atrial EPR, providing
a substrate for AF. High levels of thyroid hormones can increase automaticity and enhance
148 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

triggered activity in cardiomyocytes from pulmonary veins, resulting in atrial tachyarrhyth‐

mias.

In the last few years, many authors have attempted to show that exogenous subclinical
hyperthyroidism, due to suppressive doses of L‐T4, exerts many significant effects on the
cardiovascular system, resulting in cardiovascular dysfunction [34–39]. A population‐based
prospective study was conducted in Denmark [38]. A total of 609 subjects from general practice,
aged 50 years or above, with normal left ventricular function, were examined during a median
of 5 years of follow‐up. The incidence of stroke was increased among subjects with subclinical
hyperthyroidism, HR = 3.39 (95% CI: 1.15–10.00, P = 0.027) after adjusting for sex, age, and AF.
The authors concluded that subclinical hyperthyroidism seems to be a risk factor of developing
major cardiovascular events, especially stroke in older adults from the general population with
normal left ventricular function.

Collet et al. [39] performed another large analysis of prospective cohort studies. Individual
data on 52,674 participants were pooled from 10 cohorts. Coronary heart disease events were
analysed in 22,437 participants from 6 cohorts with available data, and the incidence of AF was
analysed in 8711 participants from 5 cohorts. The study results showed that endogenous
subclinical hyperthyroidism is associated with an increased risk of coronary heart disease
mortality, and incident AF, with highest risks of coronary heart disease mortality, AF and HF
when TSH level is lower than 0.10 mIU/L.

However, all these alterations may be reversible or may improve with the achievement of
euthyroidism, because an excess of thyroid hormone does not induce cardiac fibrosis. Actually,
the goal of thyroid dysfunction treatment is to restore the euthyroid state and avoid potential
side effects.

Figure 3. Algorithm for the treatment of hyperthyroidism in patients with atrial fibrillation and/or heart failure. TSH:
thyroid‐stimulating hormone; GD: Graves’ disease; TA: toxic adenoma; TMNG: toxic multinodular goitre; ATDs: anti‐
thyroid drugs; RAI: radioactive iodine.

An algorithm for the treatment of hyperthyroidism in patients with AF and/or HF is present‐

ed in Figure 3. The first‐line therapy in patients older than 65 years of age with hyperthyroid‐
 Impact of Thyroid Disease on Heart Failure 149
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ism, due to Graves’ disease, should be the treatment with anti‐thyroid drugs (carbimazole or
its metabolite methimazole) in order to obtain spontaneous conversion to sinus rhythm.
Ablative therapy (surgery or RAI) is the best treatment option in patients with hyperthyroid‐
ism, due to toxic adenoma (TA) or toxic multinodular goitre (TMNG), and concomitant heart
disease, as can be seen in Figure 3. RAI therapy is much safer than it sounds and has no
associated complications [40]. Also, ablative therapy may be recommended for patients with
Graves’ disease if the treatment with anti‐thyroid drugs fails [32]. Nevertheless, HF may
become irreversible in some cases of autoimmune hyperthyroid cardiomyopathy with a low
ejection fraction [41].

4. Impact of hypothyroidism on heart failure

As shown in Table 2, in hypothyroidism, cardiovascular effects are diametrically opposed to

hyperthyroidism and cardiac output declines by 30–50% [33]. Hypothyroidism is associated
with bradycardia, reduced pulse pressure, cold intolerance, mild diastolic hypertension, and
fatigue.
Significant changes in cardiac structure and function have been reported in patients with
hypothyroidism, with a severity depending on the degree and length of thyroid hormone
deficiency [42–48]. Overt hypothyroidism affects approximately 3% of the adult female
population. Overt and subclinical hypothyroidism results in an increased SVR with a reduced
cardiac output, a reduction in heart rate, an increased prevalence of hypertension, changes in
cardiac natriuretic hormones, changes in lipid profile, accelerated atherosclerosis, damage of
the physical and intellectual capacities, and an impaired quality of life. Hypothyroidism is a
risk factor of HF in the general population. Several similarities have been observed between
acute hypothyroidism and HF, including: decreased cardiac output; decreased cardiac
contractility and an altered gene expression profile (alteration in myosin heavy chain isoform
expression and alterations in the activity of the sarcoplasmic reticulum Ca2+ pump that are
induced by its interactions with phospholamban, a reversible inhibitor). In most cases, these
changes are the result of reduced T3 level (<3.1  pmol/L), the physiological T3 therapy im‐
proving cardiac function.
A systematic review and meta‐analysis to clarify the association of hypothyroidism and all‐
cause mortality, as well as cardiac death and/or hospitalization in patients with HF, was
conducted by Ning et al. [49]. They included 13 articles that reported relative risks estimates
and 95% confidence intervals for hypothyroidism with outcomes in patients with HF. The
authors found hypothyroidism associated with increased all‐cause mortality as well as cardiac
death and/or hospitalization in patients with HF.
Multiple cardiac effects of hypothyroidism have been reviewed by Biondi and Cooper [50].
Left ventricular diastolic dysfunction was found at rest and exercise in subclinical hyperthyr‐
oidism by Doppler echocardiography and radionuclide ventriculography. The isovolumetric
relaxation time is prolonged and filling rate is impaired compared with controls. Actually, the
most common cardiac abnormality in subclinical hypothyroidism is left ventricular diastolic
150 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

dysfunction, characterized by slowed myocardial relaxation, and impaired ventricular filling.

Impaired left ventricular systolic function is not commonly reported, but was identified using
more sensitive techniques [50]. Cardiac effects due to subclinical hypothyroidism are less
serious but somewhat similar to those seen in overt hypothyroidism, suggesting a continuum
in the impact of thyroid hormone on the heart. Overt hypothyroidism is usually associated
with grade I diastolic dysfunction, but grade II diastolic dysfunction, called “pseudonormal
filling dynamics”, can also be found [51].

There are also data showing that hypothyroidism results in an increased AF susceptibility
(HR = 1.23; 95% CI: 0.77–1.97) [36], quite similar to hyperthyroidism, but affecting other atrial
electrophysiological parameters than hyperthyroidism. Hypothyroidism alters cardiac ion
channel expression and function, decreases heart rate, and prolongs sinus node recovery time
and atrial ERP. In hypothyroid patients, increased atrial interstitial collagen may contribute to
longer atrial ERP and lead to increased conduction heterogeneity, thus favouring re‐entry
formation and AF vulnerability. On the other hand, ion channel remodelling and dispersion
may enhance AF arrhythmogenesis.

L‐T4 replacement therapy reduces myocyte apoptosis and is able to improve cardiovascular
performance and ventricular remodelling in hypothyroidism [52, 53]. It is important to rec‐
ognize that normal cardiovascular hemodynamic restoration can take place without a signif‐
icant increase in resting heart rate in the treatment of hypothyroidism. Treatment and
management of subclinical and overt hypothyroidism should be tailored to each patient. L‐
T4 dose varies according to age, weight, severity, and duration of hypothyroidism and car‐
diac condition of the patient. Treatment of subclinical and overt hypothyroidism with
appropriate doses of L‐T4 has shown benefits in restoring of normal TSH values (after 6–12 
months of substitution therapy). In hypothyroidism, systolic and diastolic functions (left
ventricular predominantly) are affected. For patients with systolic and diastolic HF and in
the elderly (>70 years), a small dose of L‐T4 should be started, 25 or 50 mcg daily. The dose
of L‐T4 should be increased by 25 mcg/day every three to four weeks until a full replace‐
ment dosage is reached. This treatment should be individualized and permanently moni‐
tored, the aim being to reach a stable serum TSH around 1–5 mIU/L. A special attention
should be given to the oldest old subjects (>80–85 years) with elevated serum TSH ≤ 10 
mIU/L. These patients should be carefully followed with a wait‐and‐see strategy, generally
avoiding hormonal treatment [54].

5. Perspectives and conclusions

Thyroid dysfunction is a common clinical problem that has key role in regulating the cardi‐
ovascular system and may contribute to the clinical course of CAD, HF, and arrhythmic
events. Actually, interrelations between thyroid function and cardiovascular system are
manifold. Changes in euthyroid status may induce cardiovascular abnormalities and vari‐
ous cardiovascular pathologies may alter thyroid function. Also, cardiac medication can un‐
balance or impair thyroid function. These things have to be taken into account in the
 Impact of Thyroid Disease on Heart Failure 151
http://dx.doi.org/10.5772/66283

assessment and treatment of cardiovascular disease. Thus, thyroid function tests are needed
in patients receiving amiodarone and when thyroid dysfunction is considered a possible or
concomitant cause of HF.

Secondary cardiovascular events require an early diagnosis to prevent complications and

establish a therapeutic conduct, with restoration of euthyroid status. An echocardiogram is
necessary to detect ventricular, valvular, and atrial disease. The use of Doppler echocardiog‐
raphy is mandatory to assess cardiac function, pulmonary pressure, valve disease, and pleural
or pericardial effusion in symptomatic patients with thyroid dysfunction. It is desirable to use
newer echocardiographic methods such as 3D echocardiography or speckle tracking echocar‐
diography for a more accurate assessment of myocardial function, offering a comprehensive
approach and a better assessment in the early stages of cardiac dysfunction in patients with
impaired thyroid.

Many authors have reported that thyroid dysfunction correction spontaneously converts AF
to sinus rhythm in up to two‐thirds of patients [36]. Unfortunately, one‐third of patients remain
in AF despite euthyroid state restoration, radiofrequency (RF) catheter ablation being the only
therapeutic option. Normalization of thyroid function prior to the RF ablation reduces the risk
of recurrence. Also, recommendations for antithrombotic prophylaxis are the same as for
patients without thyroid disease. If thyroid dysfunction persists (i.e. thyrotoxicosis), despite
an appropriate treatment, administration of a β‐blocker (i.e. β‐blockers are useful in cases of
thyroid storm) is recommended to control the rate of ventricular response. The β‐blocker will
be replaced by a non‐dihydropyridine calcium channel antagonist (diltiazem or verapamil) if
contraindications exist.

The management of thyroid dysfunction in patients who receive left ventricular assist device
(LVAD) or cardiac transplantation has not been directly addressed by recent guidelines.
Thyroid disease is not a contraindication to transplantation, but is a risk factor. That is why,
restoration of the euthyroid state should be the first‐step prior LVAD or cardiac transplantation.
Unfortunately, drugs administration such as amiodarone and anti‐coagulants presents a
management dilemma.

In conclusion, correction of thyroid dysfunction should be the first procedure in patients with
coexisting cardiac impairment, in order to improve cardiac hemodynamics [24]. Despite
message currently taught, thyroid hormones are too dangerous to treat patients, in the last few
years, clinical and experimental evidence suggests that thyroid may be a target for HF
treatment, thyroid hormone therapy improving clinical outcomes in HF [55–59]. It has been
proven that thyroid hormones have anti‐apoptotic, anti–inflammatory, anti‐fibrotic and anti‐
remodelling effects, promoting angiogenesis and regeneration [57]. L‐T4, L‐T3, or thyroid
hormone analogue diiodothyropropionic acid (DITPA) have been tested in patients with HF,
but unfortunately, the protocols used for thyroid hormones administration were much
different, affecting the results. However, preliminary data suggest that thyroid hormone
therapy in patients with HF is safe, the benefits being substantial. Further studies are necessary
to confirm, highlight, and explore the full potential of the therapeutic use of thyroid hormones
in treating and/or preventing HF.
152 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

Author details

Adina Elena Stanciu1*, Adina Zamfir‐Chiru‐Anton2, Marcel Marian Stanciu3 and

Dan Cristian Gheorghe4

*Address all correspondence to: adinaelenastanciu@yahoo.com

1 Department of Carcinogenesis and Molecular Biology, Institute of Oncology Bucharest,

Bucharest, Romania

2 ENT Department, Grigore Alexandrescu Children's Emergency Hospital, Bucharest, Ro‐

mania

3 Electrical Engineering Faculty, University Politehnica of Bucharest, Bucharest, Romania

4 ENT Department, Maria Sklodowska Curie Children's Emergency Hospital, Bucharest, Ro‐
mania

References

[1] Clerico A, Giannoni A, Vittorini S, Passino C: Thirty years of the heart as an endocrine
organ: physiological role and clinical utility of cardiac natriuretic hormones. Am J
Physiol Heart Circ Physiol. 2011;301:H12–H20. doi:10.1152/ajpheart.00226.2011
[2] Cerillo AG, Storti S, Kallushi E, Haxhiademi D, Miceli A, Murzi M, Berti S, Glauber M,
Clerico A, Iervasi G: The low triiodothyronine syndrome: a strong predictor of low
cardiac output and death in patients undergoing coronary artery bypass grafting. Ann
Thorac Surg. 2014;97:2089–2095. doi:10.1016/j.athoracsur.2014.01.049
[3] Del Ry S, Cabiati M, Clerico A: Recent advances on natriuretic peptide system: new
promising therapeutic targets for the treatment of heart failure. Pharmacol Res.
2013;76:190–198. doi:10.1016/j.phrs.2013.08.006
[4] Canaris GJ, Manowitz NR, Mayor G, Ridgway EC: The Colorado thyroid disease
prevalence study. Arch Intern Med. 2000;160:526–530. PMID: 10695693
[5] World Heart Federation Available from: http://www.world‐heart‐federation.org/
cardiovascular‐health/global‐facts‐map/. [Accessed: 26.08.2016]
[6] Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, Ladenson PW,
Vittinghoff E, Gottdiener JS, Newman AB: Subclinical thyroid dysfunction, cardiac
function, and the risk of heart failure. The Cardiovascular Health Study. J Am Coll
Cardiol. 2008;52:1152–1159. doi:10.1016/j.jacc.2008.07.009
[7] Nanchen D, Gussekloo J, Westendorp RG, Stott DJ, Jukema JW, Trompet S, Ford I, Welsh
P, Sattar N, Macfarlane PW, Mooijaart SP, Rodondi N, de Craen AJ, PROSPER Group:
 Impact of Thyroid Disease on Heart Failure 153
http://dx.doi.org/10.5772/66283

Subclinical thyroid dysfunction and the risk of heart failure in older persons at high
cardiovascular risk. J Clin Endocrinol Metab. 2012;97:852–861. doi:10.1210/jc.2011‐1978

[8] Galli E, Pingitore A, Iervasi G: The role of thyroid hormone in the pathophysiology of
heart failure: clinical evidence. Heart Fail Rev. 2010;15:155–169. doi:10.1007/s10741‐008‐
9126‐6.

[9] Gerdes AM, Iervasi G. Thyroid replacement therapy and heart failure. Circulation.
2010;122:385–393. doi:10.1161/CIRCULATIONAHA.109.917922

[10] Fullerton MJ, Stuchbury S, Krozowski SZ, Funder JW. Altered thyroidal status and the
in vivo synthesis of atrial natriuretic peptide in the rat heart. Mol Cell Endocrinol.
1990;69:227–233. PMID: 2139421

[11] Averyhart‐Fullard V, Fraker LD, Murphy AM, Solaro RJ: Differential regulation
of slow‐skeletal and cardiac troponin I mRNA during development and by
thyroid hormone in rat heart. J Mol Cell Cardiol. 1994;26:609–616. doi:10.1006/
jmcc.1994.1073

[12] Tsai MJ, O'Malley BW: Molecular mechanisms of action of steroid/thyroid receptor
superfamily members. Annu Rev Biochem. 1994;63:451–486. doi:10.1146/annurev.bi.
63.070194.002315

[13] Davis PJ, Davis FB: Nongenomic actions of thyroid hormone. Thyroid. 1996;6:497–504.
doi:10.1089/thy.1996.6.497

[14] Klein I, Ojamaa K: Thyroid hormone and the cardiovascular system. N Engl J Med.
2001;344:501–509. doi:10.1056/NEJM200102153440707

[15] Ribeiro RCJ, Apriletti JW, West BL, Wagner RL, Fletterick RJ, Schaufele F, Baxter JD:
The molecular biology of thyroid hormone action. Ann N Y Acad Sci. 1995;758:366–389.
PMID: 7625705

[16] Biondi B: Mechanisms in endocrinology: Heart failure and thyroid dysfunction. Eur J
Endocrinol. 2012;167:609–618. doi:10.1530/EJE‐12‐0627

[17] Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate

A, Donato L: Low‐T3 syndrome: a strong prognostic predictor of death in
patients with heart disease. Circulation. 2003;107:708–713. doi:10.1161/01.CIR.
0000048124.64204.3F

[18] Brenta G, Thierer J, Sutton M, Acosta A, Vainstein N, Brites F, Boero L,

Gómez Rosso L, Anker S: Low plasma triiodothyronine levels in heart failure
are associated with a reduced anabolic state and membrane damage. Eur J
Endocrinol. 2011;164:937–942. doi:10.1530/EJE‐11‐0094.

[19] Pingitore A, Landi P, Taddei MC, Ripoli A, L'Abbate A, Iervasi G: Triiodo‐

thyronine levels for risk stratification of patients with chronic heart failure.
Am J Med. 2005;118:132–136. doi:10.1016/j.amjmed.2004.07.052
154 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

[20] Nielsen CH, Brix TH, Leslie GQ: A role for autoantibodies in enhancement of pro‐
inflammatory cytokine responses to a self‐antigen, thyroid peroxidase. Clin Immunol.
2009;133:218–227. doi:10.1016/j.clim.2009.07.014

[21] Wajner SM, Goemann IM, Bueno AL, Larsen PR, Maia AL: IL‐6 promotes
nonthyroidal illness syndrome by blocking thyroxine activation while promoting
thyroid hormone inactivation in human cells. J Clin Invest. 2011;121:1834–
1845. doi:10.1172/JCI44678

[22] Stanciu AE, Serdarevic N, Hurduc AE, Stanciu MM: IL‐4, IL‐10 and high
sensitivity‐CRP as potential serum biomarkers of persistent/recurrent disease
in papillary thyroid carcinoma with/without Hashimoto's thyroiditis. Scand J
Clin Lab Invest. 2015;75:539–548. doi:10.3109/00365513.2015.1057895

[23] Lubrano V, Pingitore A, Carpi A, Iervasi G: Relationship between triiodothyronine and

proinflammatory cytokines in chronic heart failure. Biomed Pharmacother.
2010;64:165–169. doi:10.1016/j.biopha.2009.09.001

[24] Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González‐
Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P,
Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van
der Meer P: Authors/Task Force Members; Document Reviewers: 2016 ESC Guidelines
for the diagnosis and treatment of acute and chronic heart failure: The Task Force for
the diagnosis and treatment of acute and chronic heart failure of the European Society
of Cardiology (ESC). Developed with the special contribution of the Heart Failure
Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891–975. doi:10.1002/ejhf.592

[25] Luers C, Sutcliffe A, Binder L, Irle S, Pieske B: NT‐proANP and NT‐proBNP as prog‐
nostic markers in patients with acute decompensated heart failure of different etiolo‐
gies. Clin Biochem. 2013;46:1013–1019. doi:10.1016/j.clinbiochem.2013.03.014

[26] Stanciu AE, Vatasescu RG, Stanciu MM, Iorgulescu C, Vasile AI, Dorobantu M: Cardiac
resynchronization therapy in patients with chronic heart failure is associated with anti‐
inflammatory and anti‐remodelling effects. Clin Biochem. 2013;46:230–234. doi:
10.1016/j.clinbiochem.2012.11.002.

[27] Christ‐Crain M, Morgenthaler NG, Meier C, Muller C, Nussbaumer C, Bergmann A,

Staub JJ, Muller B: Pro‐A‐type and N‐terminal pro‐B‐type natriuretic peptides in
different thyroid function states. Swiss Med Wkly. 2005;135:549–554. doi:2005/37/smw‐
11119

[28] Kato K, Murakami H, Isozaki O, Tsushima T, Takano K: Serum concentrations of ANP

and BNP in patients with thyrotoxicosis. Endocr J. 2009;56:17–27. PMID: 18827406

[29] Pakula D, Marek B, Kajdaniuk D, Krysiak R, Kos‐Kudla B, Pakula P, Gatnar A, Borgiel‐

Marek H, Nowak M, Sieminska L, Glogowska‐Szeląg J, Ostrowska Z: Plasma levels of
NT‐pro‐brain natriuretic peptide in patients with overt and subclinical hyperthyroid‐
ism and hypothyroidism. Endokrynol Pol. 2011;62:523–528. PMID: 22144219
 Impact of Thyroid Disease on Heart Failure 155
http://dx.doi.org/10.5772/66283

[30] Stanciu AE, Hurduc AE, Stanciu MM: Effects of thyroid hormone withdrawal on
natriuretic peptides during radioactive iodine therapy in female patients with differ‐
entiated thyroid cancer. Scand J Clin Lab Invest. 2016. doi:
10.1080/00365513.2016.1230883

[31] Brozaitiene J, Mickuviene N, Podlipskyte A, Burkauskas J, Bunevicius R: Relationship

and prognostic importance of thyroid hormone and N‐terminal pro‐B‐Type natriuretic
peptide for patients after acute coronary syndromes: a longitudinal observational
study. BMC Cardiovasc Disord. 2016;16:45. doi:10.1186/s12872‐016‐0226‐2

[32] Biondi B, Bartalena L, Cooper DS, Hegedus L, Laurberg P, Kahaly GJ: The 2015
European Thyroid Association Guidelines on diagnosis and treatment of endogenous
subclinical hyperthyroidism. Eur Thyroid J. 2015;4:149–163. doi:10.1159/000438750

[33] Danzi S, Klein I: Thyroid hormone and the cardiovascular system. Minerva Endocrinol.
2004;29:139–150. PMID: 15282446

[34] Biondi B, Kahaly GJ: Cardiovascular involvement in patients with different causes of
hyperthyroidism. Nat Rev Endocrinol. 2010;6:431–443. doi:10.1038/nrendo.2010.105

[35] Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Sacca L, Filetti S, Lombardi G,
Perticone F: Endogenous subclinical hyperthyroidism affects quality of life and cardiac
morphology and function in young and middle‐aged patients. J Clin Endocrinol Metab.
2000;85:4702–4705. doi:10.1210/jcem.85.12.7085

[36] Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener HC,
Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten
U, Van Putte B, Vardas P: Authors/Task Force Members; Document Reviewers. 2016
ESC Guidelines for the management of atrial fibrillation developed in collaboration
with EACTS: The Task Force for the management of atrial fibrillation of the European
Society of Cardiology (ESC) Developed with the special contribution of the European
Heart Rhythm Association (EHRA) of the ESC Endorsed by the European Stroke
Organisation (ESO). Europace. 2016;pii:euw295. doi:10.1093/europace/euw295

[37] Cini G, Carpi A, Mechanick J, Cini L, Camici M, Galetta F, Giardino R, Russo MA, Iervasi
G: Thyroid hormones and the cardiovascular system: pathophysiology and interven‐
tions. Biomed Pharmacother 2009;63:742–753. doi:10.1016/j.biopha.2009.08.003

[38] Schultz M, Kistorp C, Raymond I, Dimsits J, Tuxen C, Hildebrandt P, Faber J: Cardio‐

vascular events in thyroid disease: a population based, prospective study. Horm Metab
Res 2011;43:653–659. doi:10.1055/s‐0031‐1283162

[39] Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, Iervasi G,
Asvold BO, Sgarbi JA, Volzke H, Gencer B, Maciel RM, Molinaro S, Bremner A, Luben
RN, Maisonneuve P, Cornuz J, Newman AB, Khaw KT, Westendorp RG, Franklyn JA,
Vittinghoff E, Walsh JP, Rodondi N: Thyroid Studies Collaboration: Subclinical
hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med
2012;172:799–809. doi:10.1001/archinternmed.2012.402
156 The Role of the Clinical Cardiac Electrophysiologist in the Management of Congestive Heart Failure

[40] Stanciu AE. Synthesis and applications of alpha/beta emitter‐labelled nanoparticles. In:
Llop J, Gomez‐Vallejo V, editors. Isotopes in Nanoparticles: Fundamentals and Appli‐
cations. Pan Stanford; 2016. pp. 383–427. doi:10.1201/b19950‐16

[41] Siu CW, Yeung CY, Lau CP, Kung AW, Tse HF: Incidence, clinical characteristics and
outcome of congestive heart failure as the initial presentation in patients with primary
hyperthyroidism. Heart. 2007;93:483–487. doi:10.1136/hrt.2006.100628

[42] Biondi B, Klein I. Hypothyroidism as a risk factor for cardiovascular disease. Endocrine
2004;24:1–13. doi:10.1385/ENDO:24:1:001

[43] Biondi B, Palmieri EA, Lombardi G, Fazio S: Subclinical hypothyroidism and cardiac
function. Thyroid. 2002;12:505–510. doi:10.1089/105072502760143890

[44] Biondi B: Cardiovascular effects of mild hypothyroidism. Thyroid. 2007;17:625–630.

doi:10.1089/thy.2007.0158

[45] Klein I, Danzi S: Thyroid disease and the heart. Circulation. 2007;116:1725–1735. doi:
10.1161/CIRCULATIONAHA.106.678326

[46] Chaker L, Baumgartner C, den Elzen WP, Ikram MA, Blum MR, Collet TH, Bakker SJ,
Dehghan A, Drechsler C, Luben RN, Hofman A, Portegies ML, Medici M, Iervasi G,
Stott DJ, Ford I, Bremner A, Wanner C, Ferrucci L, Newman AB, Dullaart RP, Sgarbi
JA, Ceresini G, Maciel RM, Westendorp RG, Jukema JW, Imaizumi M, Franklyn JA,
Bauer DC, Walsh JP, Razvi S, Khaw KT, Cappola AR, Völzke H, Franco OH, Gussekloo
J, Rodondi N, Peeters RP: Thyroid studies collaboration: Subclinical hypothyroidism
and the risk of stroke events and fatal stroke: An individual participant data analysis.
J Clin Endocrinol Metab. 2015;100:2181–2191. doi:10.1210/jc.2015‐1438

[47] Brenta G, Mutti LA, Schnitman M, Fretes O, Perrone A, Matute ML: Assessment of left
ventricular diastolic function by radionuclide ventriculography at rest and exercise in
subclinical hypothyroidism, and its response to L‐thyroxine therapy. Am J Cardiol.
2003;91:1327–1330. PMID: 12767425

[48] Ripoli A, Pingitore A, Favilli B, Bottoni A, Turchi S, Osman NF, De Marchi D, Lombardi
M, L'Abbate A, Iervasi G: Does subclinical hypothyroidism affect cardiac pump
performance? Evidence from a magnetic resonance imaging study. J Am Coll Cardiol.
2005;45:439–445. doi:10.1016/j.jacc.2004.10.044

[49] Ning N, Gao D, Triggiani V, Iacoviello M, Mitchell JE, Ma R, Zhang Y, Kou H: Prognostic
role of hypothyroidism in heart failure: a meta‐analysis. Medicine (Baltimore).
2015;94:e1159. doi:10.1097/MD.0000000000001159

[50] Biondi B, Cooper DS: The clinical significance of subclinical thyroid dysfunction.
Endocr Rev. 2008;29:76–131. doi:10.1210/er.2006‐0043

[51] Tiryakioglu SK, Tiryakioglu O, Ari H, Basel MC, Ozkan H, Bozat T: Left ventricular
longitudinal myocardial function in overt hypothyroidism: a tissue Doppler echocar‐
 Impact of Thyroid Disease on Heart Failure 157
http://dx.doi.org/10.5772/66283

diographic study. Echocardiography. 2010;27:505–511. doi:10.1111/j.1540‐

8175.2009.01043.x
[52] Cooper DS, Biondi B: Subclinical thyroid disease. Lancet. 2012;379:1142–1154. doi:
10.1016/S0140‐6736(11)60276‐6

[53] Ravzi S, Ingoe L, Keeka G, Oates C, McMillan C, Weaver JU: The beneficial effect of L‐
thyroxine on cardiovascular risk factors, endothelial function and quality of life in
subclinical hypothyroidism: randomized, crossover trial. J Clin Endocrinol Metab.
2007;92:1715–1723. doi:10.1210/jc.2006‐1869

[54] Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, Wemeau JL. 2013
ETA Guideline: Management of Subclinical Hypothyroidism. Eur Thyroid J.
2013;2:215–228. doi:10.1159/000356507

[55] Gerdes A: Restoration of thyroid hormone balance: a game changer in the treatment of
heart failure? Am J Physiol Heart Circ Physiol. 2015;308:H1–10. doi:10.1152/ajpheart.
00704.2014

[56] Rajagopalan V, Gerdes AM: Role of thyroid hormones in ventricular remodeling. Curr
Heart Fail Rep. 2015;12:141–149. doi:10.1007/s11897‐014‐0246‐0

[57] Cokkinos DV, Chryssanthopoulos S: Thyroid hormones and cardiac remodeling. Heart
Fail Rev. 2016;21:365–372. doi:10.1007/s10741‐016‐9554‐7

[58] Martinez F: Thyroid hormones and heart failure. Heart Fail Rev. 2016;21:361–364. doi:
10.1007/s10741‐016‐9556‐5

[59] Pingitore A, Nicolini G, Kusmic C, Iervasi G, Grigolini P, Forini F: Cardioprotection and

thyroid hormones. Heart Fail Rev. 2016; 21:391–399. doi:10.1007/s10741‐016‐9545‐8
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