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Efectos de La Hormona Tiroidea en El Corazon - ElSevier 2014
Efectos de La Hormona Tiroidea en El Corazon - ElSevier 2014
2014;26(6):296---309
www.elsevier.es/arterio
REVIEW ARTICLE
a
Division of Endocrinology and Metabolism, Internal Medicine Department, University of Cauca, Popayán-Cauca, Colombia
b
Division of Basic Immunology and Biomedical Sciences, University of Valle, Cali-Valle, Colombia
c
Division of Genetic and Molecular Epidemiology, University of Cauca, Popayán-Cauca, Colombia
KEYWORDS Abstract Thyroid hormones have a significant impact on heart function, mediated by genomic
Cardiovascular; and non-genomic effects. Consequently, thyroid hormone deficiencies, as well as excesses,
Hyperthyroidism; are expected to result in profound changes in cardiac function regulation and cardiovascu-
Hypothyroidism; lar hemodynamics. Thyroid hormones upregulate the expression of the sarcoplasmic reticulum
Subclinical calcium-activated ATPase and downregulate the expression of phospholamban. Overall, hyper-
dysfunction; thyroidism is characterized by an increase in resting heart rate, blood volume, stroke volume,
Thyroid hormones; myocardial contractility, and ejection fraction. The development of ‘‘high-output heart fail-
Heart; ure’’ in hyperthyroidism may be due to ‘‘tachycardia-mediated cardiomyopathy’’. On the other
Atrial fibrillation; hand, in a hypothyroid state, thyroid hormone deficiency results in lower heart rate and weaken-
Thyrotoxicosis; ing of myocardial contraction and relaxation, with prolonged systolic and early diastolic times.
Mortality Cardiac preload is decreased due to impaired diastolic function. Cardiac afterload is increased,
and chronotropic and inotropic functions are reduced. Subclinical thyroid dysfunction is rela-
tively common in patients over 65 years of age. In general, subclinical hypothyroidism increases
the risk of coronary heart disease (CHD) mortality and CHD events, but not of total mortality.
The risk of CHD mortality and atrial fibrillation (but not other outcomes) in subclinical hyper-
thyroidism is higher among patients with very low levels of thyrotropin. Finally, medications
such as amiodarone may induce hypothyroidism (mediated by the Wolff---Chaikoff), as well as
hyperthyroidism (mediated by the Jod---Basedow effect). In both instances, the underlying cause
is the high concentration of iodine in this medication.
© 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España, S.L.U. All rights
reserved.
Abbreviations: AIH, amiodarone-induced hypothyroidism; AIT, amiodarone-induced thyrotoxicosis; AF, atrial fibrillation; ANP, atrial natri-
uretic peptide; CHD, coronary heart disease; T2, diiodothyronine; LV, left ventricular; RAAS, Renin---Angiotensin---Aldosterone system; rT3,
reverse T3; SHyper, subclinical hyperthyroidism; SHypo, subclinical hypothyroidism; SCTD, subclinical thyroid dysfunction; TMC, tachycardia-
mediated cardiomyopathy; TRs, thyroid hormone receptors; TREs, thyroid hormone response elements; TH, thyroid hormones; TSH, thyroid
stimulating hormone; TRH, thyrotropin-releasing hormone; T4, thyroxine; T3, triiodothyronine.
∗ Corresponding author.
http://dx.doi.org/10.1016/j.arteri.2014.07.003
0214-9168/© 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España, S.L.U. All rights reserved.
Effects of thyroid hormones 297
Mechanisms of TH action on the T3, the active form of TH, exerts many of its actions
cardiovascular system through its TRs: TR␣1, TR␣2, TR1, and TR2. TRs, with the
exception of TR2, are expressed in all tissues and the pat-
tern of expression varies in different types of tissues. TR␣1
TH play a key role in energy homeostasis. The set point
is predominantly expressed in the myocardium and regulates
for TH production and secretion by the thyroid gland is
important genes related to cell differentiation and growth,
regulated by the hypothalamic thyrotropin-releasing hor-
contractile function, pacemaker activity, and conduction.
mone (TRH), determining the equilibrium between serum
The three major TRs isoforms, TR␣1, TR1, and TR2, are
thyroid stimulating hormone (TSH) and TH concentrations.1,2
expressed in a tissue-specific fashion and regulate a spec-
The major form of TH produced by the thyroid is the pro-
trum of metabolic and developmental functions; moreover,
hormone thyroxine (T4) which can be converted into the
TRs are members of the nuclear receptor superfamily and
biologically active tri-iodothyronine (T3) mediated by the
function as T3-inducible transcription factors.7,8
removal of an iodide by deiodinases (the iodothyronine
The TRs are highly homologous transcription factors
deiodinases constitute a family of selenoenzymes that selec-
which transduce signals of active forms of TH (especially
tively remove iodide from thyroxine and its derivatives,
T3). Like other nuclear receptors, TRs bind TREs comprised
thus activating or inactivating these hormones which have a
of degenerate repeats of the sequence AGGTCA, usually as
tissue-specific distribution). All deiodinases are membrane-
heterodimers with retinoid X receptors (RXRs). From these
anchored proteins of 29---33 kDa that share substantial
locations, the TRs recruit co-regulator complexes that influ-
sequence homology, catalytic properties and contain seleno-
ence gene expression, and T3 modulates transcription by
cysteine as the key residue within their catalytic centers;
inducing conformational changes in the receptor C-terminal
they catalyze and sequentially remove stereo-specific iodine
ligand binding domain which, in turn, alters the complement
atoms from T4, generating active and inactive isomers of
of TR associated co-regulators.
both T3 and diiodothyronine (T2). The deiodination of T4,
The selective actions of TRs are influenced by local ligand
T3, and other iodothyronines is an integral component of TH
availability, by transport of TH into the cell by related
homeostasis.3,4 There are three deiodinases: Type 1 (D1),
transporters, by the relative expression and distribution of
localized to the plasma membrane and expressed in liver,
the TR isoforms and nuclear receptor co-repressors and co-
thyroid and kidney, it catalyzes removal of inner or outer
activators; and, finally, by the sequence, arrangement, and
ring iodine atoms in equimolar proportions to generate T3,
promoter context of the TREs.
reverse T3 (rT3), or T2, depending on the substrate. Most
TH binds to serum transport proteins that help ensure
of the circulating T3 is derived from conversion of T4 to
even delivery of hormone to all tissues, cell type-specific
T3 by the actions of D1. Type 2 (D2), which is consider-
membrane transporters, cytoplasmic interacting proteins,
ably more efficient than D1, catalyzes only the removal of
enzymes that variously activate pro-hormones or inactivate
an outer ring iodine atom from T4, generating the active
active hormones, and the TRs themselves. TH interacting
product T3. The major role of D2 is to control the intra-
proteins regulate important steps that dictate hormone
cellular T3 concentration, its availability to the nucleus,
availability for the intracellular receptor, so it is very impor-
and the saturation of the nuclear T3 receptor in target
tant to understand structure activity relationships of TH in
tissues; it is mainly active in brain, pituitary, and skele-
the context of both the receptor and the proteins that com-
tal muscle. And Type 3 (D3), which is expressed in the
prise the entire signaling system.
brain and other tissues; it irreversibly inactivates T3, or
TH acts in large part by binding to nuclear TRs. Binding
prevents activation of T4 by catalyzing removal of an inner
of the T3 ligand to the TRs results, for a great majority of
ring iodine atom to generate T2 or rT3, respectively. Thus,
genes, in their increased transcription. In the absence of the
inactivating D3 prevents TH access to specific tissues at crit-
T3 ligand, TRs can repress the expression of genes leading
ical times and reduces TH receptors (TRs) saturation. Given
to gene silencing. The communication between the TH and
these functions, D3 is considered the major physiological
the basal transcription machinery occurs through a complex
inactivator and terminator of TH action at the peripheral
set of co-activators and co-repressors.9,10
level.5,6
The ligand-activated TRs recruit co-activators, which
TH signaling is a local phenomenon, with target cells
have a positive stimulatory interaction with the basic
playing a major role through restricted expression of the
transcriptional machinery. In contrast, recruitment of TH-
activating or inactivating deiodinases. This local role played
related co-repressors leads to decreased transcription of
by the deiodinases in customizing TH signaling is the main
TH-responsive genes.
way in which TH exert its metabolic effects. Although the
The mediation of nuclear T3 receptor-based TH action is
thyroid gland produces predominantly T4, the primary bio-
a complex process which is influenced by TH concentration
logically active form of the hormone is T3, which binds
and the level and type of the TR alpha and beta isoforms;
to, and activates, the TRs. TRs homodimerize or interact
the configuration of the TREs also influences TH action.
with other nuclear receptors such as the retinoic X recep-
The important role of interactions with co-repressors and
tor and control essential functions in growth, development
co-activators, and the interactions with cell type-specific
and metabolism, and are important for normal functioning
factors, lead to changes in the histone acetylation status of
of almost all tissues.
chromatin.
TRs are transcription factors that bind to thyroid hor-
Besides the well-characterized genomic action (nuclear)
mone response elements (TREs) in the regulatory regions
of TH, mediated by TRs, the non-genomic action of TH is
of target genes. TRs are encoded by two genes, THRA and
often related to activation of signaling pathways. The clas-
THRB, located on chromosomes 17 and 3, respectively.
sical genomic actions of T3 are mediated by high-affinity
Effects of thyroid hormones 299
Regulation of specific
gene expression.
nuclear receptors that regulate gene expression directly. respectively. Some abnormalities of cardiac function in
This process begins with the entry of T3 into the car- patients with thyroid dysfunction directly reflect the effects
diomyocyte through specific transport proteins located of TH on calcium-activated ATPase and phospholamban,
within the cell membrane; once in the cardiomyocyte, T3 which are involved primarily in the regulation of systodi-
enters the nucleus and interacts with specific transcrip- astolic calcium concentrations in cardiomyocytes. Calcium
tional co-activators or with co-repressors. Occupancy of re-uptake is dependent on the action of sarcoplasmic
these receptors by T3, in combination with recruited co- Ca2+ -ATPase, which is normally inhibited by phospho-
factors, allows the TR complex to bind or release specific lamban. Phosphorylation of phospholamban inhibits the
DNA sequences (TREs). action of phospholamban and results in increased affin-
In contrast, the non-genomic effects of TH occur rapidly ity of the Ca2+ -ATPase for calcium, increased calcium
and are unaffected by transcription inhibitors and protein uptake, and diastolic relaxation. Sarcoplasmic reticulum
synthesis. The genomic actions of TH have an established calcium-activated ATPase is responsible for the rate of
role in the development, differentiation and homeostatic calcium reuptake into the lumen of the sarcoplasmic
maintenance of target tissues.11,12 reticulum during diastole, which is in turn a major deter-
T3 exerts its effects by two mechanisms: genomic actions minant of the velocity of myocardial relaxation after
consisting of T3 link to nuclear receptors that bind respon- contraction.13,14
sive elements in the promoter of target genes, and the Finally, TH upregulate expression of the sarcoplas-
extranuclear nongenomic activities on the cardiac myocyte mic reticulum calcium-activated ATPase and downregulates
and on the systemic vasculature can occur rapidly and do phospholamban expression, thereby enhancing myocardial
not involve TREs-mediated transcriptional events (Fig. 1). relaxation. Moreover, the improved calcium reuptake during
These activities include rapid effects on the plasma mem- diastole may have a favorable effect on myocardial con-
brane and cytoplasmic organelles. Many of the rapid effects tractility. Actually, the greater end-diastolic reduction in
mediated by these hormones are not changed by the use cytoplasmic concentration of calcium increases the mag-
of transcription and translation inhibitors; however, these nitude of the systolic transient of calcium that, in turn,
T3-mediated effects include changes in various membrane augments its availability for activation of tropo-myosin
sodium, potassium, and calcium ion channels, effects on units. TH lower systemic vascular resistance, increase blood
actin polymerization, and on the intracellular signaling path- volume, and have inotropic and chronotropic effects on car-
ways in the heart and vascular smooth muscle cells. Both the diac function; these changes on both the circulation and the
non-genomic and genomic effects of T3 act in concert to heart itself result in increased cardiac output.
regulate cardiac function and cardiovascular hemodynam- A high output circulation state has been described in
ics. hyperthyroidism, whereas hypothyroid patients have low
Moreover, myocardial contraction and relaxation are cardiac output, decreased stroke volume, decreased vas-
mediated through the release and re-uptake of calcium, cular volume, and increased systemic vascular resistance.
300 H. Vargas-Uricoechea et al.
These alterations in cardiac function mediated by TH depend formation inside the heart, with embolism and stroke
ultimately on the regulation of target genes within the if there is clot dislodgment.17,18 The AF is usually per-
heart and on indirect effects resulting from hemodynamic sistent rather than paroxysmal, and is more probable
changes. Moreover, TH play an important role in blood in older patients --- perhaps reflecting a reduction in
pressure (BP) control but may exert other effects on the the threshold for this arrhythmia with age. Pulse pres-
cardiovascular system; both hypo and hyperthyroidism may sure is widened, cardiac output and sympathetic tone
cause cardiovascular dysfunction, increase the response of are increased, and a hyperkinetic apex beat and a loud
tissues to the action of the sympathetic system, and this may first heart sound are described; in addition, an accen-
be a mechanism by which they regulate BP. However, TH can tuated pulmonic component of the second sound can
also activate the RAAS without involving the sympathetic be noticed frequently. The increase in chronotropism
nervous system. and batmotropism is probably caused by imbalanced
A number of cardiovascular changes have been described sympathovagal tone due to a relative rather than an
in thyroid dysfunction, and the right treatment for the absolute adrenergic overdrive. Alterations in the pulse
condition has shown to be of great benefit. The heart is a and heart sounds are common, as is also the case with
major target for TH action, and thyroid dysfunction has pro- the Means---Lerman ‘‘scratch’’ (mid-systolic and end-
found effects on the heart and cardiovascular system, i.e., tidal murmur heard at the left upper sternal border
changes in cardiac gene expression in the contractile appa- thought to occur from rubbing of the pericardium against
ratus, the sarcoplasmic reticulum, and the outer myocytic the pleura, which may sound like a pericardial friction
cell membrane. The positive inotropic, dromotropic, and rub as seen in pericarditis). Left ventricular (LV) systolic
chronotropic heart rates are also increased by TH, and these function is consistently increased at rest and the rate
effects are associated with greater sensitivity of adren- of LV chamber relaxation and LV filling is increased.19,20
ergic and cardiac receptors, as well as increased myosin Additionally, systolic arterial pressure is increased and
synthesis.15,16 diastolic arterial pressure is decreased, so that pulse
pressure is particularly wider and mean arterial pres-
A. In the hyperthyroid state, TH modulate every com- sure is usually decreased, with a remarkable increase
ponent of the cardiovascular system necessary for in cardiac output and a notable reduction in periph-
normal cardiovascular development and function. Excess eral vascular resistance. However, hyperthyroidism has
TH have pronounced cardiovascular manifestations only minor effects on mean arterial blood pressure,
(Table 1). Overall, hyperthyroidism is characterized by because of increases in systolic pressure --- caused by
an increase in resting heart rate (at least half the increased stroke volume --- and decreases in diastolic
patients with hyperthyroidism have sinus tachycardia pressure due to peripheral vasodilatation. The periph-
exceeding 100 beats/min) blood volume, stroke volume, eral vascular effects result from a TH-mediated decrease
myocardial contractility and ejection fraction, and an in systemic peripheral resistance, induced by dilating
improvement in diastolic relaxation. An increase in TH arterioles and by increased metabolic rate in peripheral
level induces resting tachycardia, palpitations are one tissues. As a rule, the total peripheral vascular resis-
of the most-common symptoms associated with overt tance decreases in thyrotoxicosis, and these alterations
hyperthyroidism, and about 20% of hyperthyroid patients may be mediated by changes in non-thyroid hormones
overall have AF. Since symptoms of hyperthyroidism are which affect the vasculature.21,22 Even though in thyro-
often non-specific and develop slowly, the latter may toxicosis plasma catecholamines are unchanged or low,
be the first clinical manifestation of thyroid dysfunc- the -adrenergic receptor density is altered in a time-
tion; and this arrhythmia increases the risk of blood clot and tissue-dependent manner, raising tissue sensitivity
Effects of thyroid hormones 301
to catecholamines. The rapid use of oxygen, increased an autoimmune process associated with endothelial
production of metabolic end-products, and relaxation damage or dysfunction, increased cardiac output and
of arterial smooth muscle fibers by TH cause peripheral increased metabolism of intrinsic pulmonary vasodilating
vasodilatation, leading to a reduction in peripheral vas- substances, all these with normal pulmonary artery resis-
cular resistance, and contributing to a further increase tance. Although the mechanism is uncertain, the reversal
in heart rate; concomitantly there is a selective blood of pulmonary artery hypertension following restoration
flow increase in some sites such as the skin, skeletal to a euthyroidism state supports a causal relationship. A
muscles and heart, and a fall in diastolic pressure with possible explanation includes an influence of TH, which
a simultaneous widening of pulse pressure. The vaso- affects growth and maturation of vascular cells, and
dilatation present and the lack of an increase in renal enhanced catecholamine sensitivity, causing pulmonary
blood flow generate a reduction in renal perfusion pres- vasoconstriction. Therefore, pulmonary artery hyperten-
sure, with activation of the RAAS, which increases sodium sion should be considered in hyperthyroid patients with
retention and blood volume. These changes result in dyspnea.
preload increase and afterload reduction, leading to a B. In the hypothyroid state, a deficiency in TH compro-
significant increase in stroke volume.23,24 A higher car- mises the function of the cardiac muscle by decreasing
diac preload may trigger secretion of atrial natriuretic the activity of enzymes involved in the regulation of cal-
peptide (ANP); however, it is suggested that TH-induced cium uptake and the expression of several contractile
myocardial ANP secretion in healthy subjects is not the proteins in cardiomyocytes, resulting in lower heart rate
result of a direct action on the myocardium, but rather and weakening of myocardial contraction and relaxation.
the result of an indirect modification in cardiovascular The most obvious effect of TH deficiency on the heart is
hemodynamic leading to increased atrial stretch. There- a prolongation of both systolic and early diastolic time
fore, hyperthyroidism is characterized by a high cardiac characteristics.25,26 In the hypothyroid heart, in contrast
output state with a remarkable increase in heart rate to congestive heart failure, pulmonary pressure is not
and cardiac preload and a reduction in peripheral vas- increased; hypothyroid patients have reduced cardiac
cular resistance, resulting in hyperdynamic circulation output, stroke volume and plasma volume. Even though
(Fig. 2). Moreover, increased pressure in the left atrium hypothyroidism causes fewer cardiovascular symptoms
increases pressure in the pulmonary veins, and this in and signs, it is associated with bradycardia, increased
turn causes reflex contraction of the arterioles in the vascular resistance, narrow pulse pressure and mild
lesser circulation (Kitaev’s reflex) due to stimulation of hypertension. Circulation time is prolonged, but right
baroreceptors. Spasm in the arterioles produces a signif- and left heart filling pressures are usually within normal
icant increase in pulmonary artery pressure to intensify limits, unless they are elevated by pericardial effusion.
the load on the right ventricle, which needs contact with Venous pressure is normal, but peripheral resistance
a greater force in order to eject blood into the pulmonary is increased; there is a redistribution of blood flow
trunk, leading to the increase of pulmonary resistance with marked reduction in cerebral, renal and cuta-
and pulmonary hypertension. Several mechanisms have neous flow. Cardiac oxygen consumption is reduced even
been suggested in the pathogenesis of pulmonary artery further than what is anticipated from the decreased
hypertension in patients with hyperthyroidism, including work load, making for an energy-efficient state of
302 H. Vargas-Uricoechea et al.
cardiac contraction. However, congestive heart failure ventricular arrhythmias and sudden death are uncom-
has been described in severely hypothyroid patients mon in hypothyroidism, despite the marked prolongation
without underlying heart disease. Measurements of iso- of the QT interval. However, increased QT dispersion
volumetric relaxation time reveal a prolongation of in hypothyroidism may facilitate ventricular arrhythmias
this interval.27,28 In addition, there is prolongation of with hypokalemia, hypomagnesemia, long QT syndrome,
the pre-ejection period and an increased pre-ejection and sudden cardiac death.
period to LV ejection time ratio (Table 2). Myocar- Other findings are: incomplete or complete right bun-
dial work efficiency is lower in normal subjects than dle branch block, decreased p wave amplitude, diffuse
other sick persons. Angina pectoris, diastolic hyper- flattening or inversion of T waves together with a gen-
tension, atrioventricular blocks, and pericarditis are eralized low voltage of all the complexes. The T wave is
major cardiovascular complications in a hypothyroid dome-shaped and partially obliterates the ST segment
state. Diastolic dysfunction both at rest and on exer- (‘‘the mosque sign’’). Isolated myxedema may cause
tion is the most uniformly found cardiac abnormality heart failure, pericardial effusion (PE) and pericardial
in patients with hypothyroidism; LV diastolic function tamponade (PT), especially in subjects with profound
is altered, with a slowed myocardial relaxation and T4 deprivation; PE in hypothyroidism is common and the
impaired early ventricular filling. This is frequently mechanisms of myxedematous PE are increased perme-
associated with a fluctuating impairment in LV systolic ability of capillaries with subsequent leakage of protein
function even at a very early stage. LV asynchrony is rich fluid into the interstitial space, impaired lymphatic
defined as deterioration of the simultaneous contrac- drainage, and salt and water retention; nevertheless, an
tion of corresponding cardiac segments; as a result, effusion which causes cardiac tamponade is rarely seen.
delayed activation of some ventricular segments leads PT in hypothyroid patients with PE is attributed to the
to uncoordinated contraction. LV asynchrony may affect slow accumulation of fluid and the remarkable compli-
diastolic and systolic functions, exercise capacity, prog- ance of the pericardium.
nosis, quality of life, and symptoms of heart failure, The heart in overt myxedema is often flabby, and
worsening the heart failure. LV systolic function is grossly dilated. Classic findings of overt myxedema are:
marginally subnormal, with slightly lower ejection frac- cardiac enlargement, dilatation, significant bradycardia,
tion and stroke volume values.29,30 Preload is reduced, weak arterial pulses, hypotension, distant heart sounds,
with a subnormal cardiac output. High cholesterol lev- low EKG voltage, non-pitting edema and evidence of con-
els are an additional risk for the development of gestive heart failure.
atherosclerosis. Alterations in the pulse and peripheral There is a relationship between hypothyroidism and
vasoconstriction may be observed, such as prolonga- coronary artery disease, either because of the pres-
tion of the QRS complex and the QT interval (the ence of a negative chronotropic and inotropic state or
QT interval reflects traditional electrocardiographic the presence of hypercholesterolemia and hypertension,
parameter of the duration of ventricular repolariza- with an increased risk of atherogenesis; but otherwise,
tion) with an increased risk of developing ventricular thyroid hormones are powerful regulators of vascula-
tachyarrhythmias. QT dispersion is the inter-lead vari- ture in the adult myocardium; therefore, a low free T3
ability of the QT interval on surface electrocardiogram, state would inhibit neovascularization in cardiac tissue
reflecting regional variations in myocardial repolariza- after acute myocardial infarction, which would accel-
tion. Increased QT dispersion has been linked to the erate cardiac pathologic remodeling and heart failure,
occurrence of malignant ventricular arrhythmias and leading to short-term and long-term adverse cardiac
sudden cardiac death; clinical observations show that events.31,32
Effects of thyroid hormones 303
Decreased effective
Table 3 Characteristics that define ‘‘high-output heart arterial filling volume
failure’’ in hyperthyroidism.
Persistent tachycardia Decrease in peripheral
Increased renal sodium
vascular resistance
reabsorption and blood
Increase in cardiac preload Increase in ventricular
filling pressure
Increase in pulmonary Increase in total blood Increased cardiac inotropy
arterial pressure volume and chronotropy
Absence of underlying heart Increase in activity of the
disease sympatho-adrenal system
and increase in cardiac Increased cardiac
output
tissue responsiveness to
catecholamines
Figure 3 Increase in cardiac output mediated by TH excess.
304 H. Vargas-Uricoechea et al.
Diastolic and systolic Impaired left ventricular Moreover, ‘‘right ventricular heart failure’’ may result
dysfunction diastolic filling from right ventricular volume overload, due to the increased
blood volume and venous return. It is characterized by
right ventricular dilation, enlargement of the tricuspid valve
Low cardiac Decreased cardiac
annulus and tricuspid insufficiency, and is frequently associ-
performance preload
ated with pulmonary hypertension.39,40
Hyperthyroidism
LV hypertrophy
Diastolic dysfunction
Heart failure
Table 4 Components leading to heart failure in Table 5 Risk factors for AF in patients with
hypothyroidism. hyperthyroidism.
Bradycardia Impaired systolic function Classic factors Novel factors
Decreased cardiac preload Impaired diastolic function
Age >60 years Obesity
Increased systemic vascular Impaired left ventricular
Ischemic heart disease Chronic kidney disease
resistance diastolic filling
Congestive heart failure Proteinuria
Increase in left ventricular Pericardial effusion
Male sex Elevated transaminase
mass
concentrations
Cardiac valve disease Elevated sensitive C reactive
protein
function slows down, just like the contraction velocity dur- TSH levels <0.1 mIU/L Serum free T4 concentration
ing systole, and there is chamber dilatation and impaired Female sex
myocardial blood flow (Fig. 4). Cardiac frequency
Dilated cardiomyopathy (DCM) is a heart muscle disorder >80 beats/min
defined by the presence of a dilated and poorly functioning
left ventricle in the absence of abnormal loading condi-
tions (hypertension, valve disease) or ischemic heart disease increased fibrinogen levels, and increased factor VIII and
sufficient to cause global systolic impairment; in hypothy- factor X activity in patients in sinus rhythm with thyrotoxi-
roidism, although cardiac output is reduced, heart failure cosis; even so, the best evidence-based study did not find a
is relatively rare because there is a lower oxygen demand trend toward increased embolic risk.
in the periphery. The improvement of the cardiac func- AF alters atrial electrical and structural properties in a
tion after hormonal treatment is an important argument in way that promotes its own maintenance; this increases the
favor of the implication of hypothyroidism in the genesis of risk of recurrence and may alter the response to antiar-
DCM.43,44 rhythmic drugs. The risk factors for AF in patients with
hyperthyroidism are similar to those in the general popula-
tion (age, ischemic heart disease, congestive heart failure,
Atrial fibrillation and thyroid male sex and valvular heart disease). However, other factors
have been associated with the presence of AF in hyperthy-
AF is the most common cardiac complication of hyperthy- roidism (Table 5) including obesity, chronic kidney disease
roidism, occurring in an estimated 10% to 25% of overtly (which is a powerful predictor of new-onset AF in hyperten-
hyperthyroid patients; in comparison 0.4% of the general sive patients, independently of LV hypertrophy and left atrial
population has AF, representing an independent risk factor dilatation), proteinuria, female sex, serum free T4 concen-
for cardiovascular events. tration, and elevated transaminase concentrations.49,50
Prevalence increases with age; so much so that 25% of Moreover, it has been suggested that high sensitive C
hyperthyroid patients older than 60 years had AF compared reactive protein, an indicator of inflammation, free T4, and
to 5% in patients less than 60 years of age, indicating that left atrial diameter are associated with the development of
age is a major factor in the onset of AF. AF in patients with hyperthyroidism.
The propensity to develop AF may be due to the short- Moreover, hypothyroidism is associated with bradycardia,
ened refractory period of atrial cells and a greater delay in decreased variability in heart rate, and has been asso-
the rectifier potassium current increases between the right ciated with a lower risk of AF compared with euthyroid
atrium and the left atrium, creating a substrate for AF.45,46 patients.51,52
Furthermore, TH potentiate the effect of the adrener-
gic system on the heart, and while catecholamine levels
are either normal or decreased in hyperthyroidism, cate- Subclinical thyroid dysfunction (SCTD) and
cholamine action occurs through increased tissue sensitivity cardiovascular disease and mortality
due to upregulated transcription of beta-adrenergic recep-
tors and differences in autonomic innervations between Although it is recognized that patients with SCTD may have
atria and ventricles. It is also possible that the sensitivity subtle symptoms of thyroid dysfunction, the definition is
of atrial or ventricular myocardial cells to TH is different. purely a biochemical one: SCTD is defined as serum free T4
Generally, the onset of AF occurs with premature com- and total or free T3 levels within their respective reference
plexes originating from the pulmonary veins, and the ranges in the presence of abnormal serum TSH levels. Serum
persistence of AF requires re-entry; premature complexes TSH is undetectable or low in subclinical hyperthyroidism
occur secondary to automaticity or triggered activity. Hyper- (SHyper), and it is increased in subclinical hypothyroidism
thyroidism is associated with reduced vagal activity and (SHypo). It is a common finding in the growing population of
reduced heart rate variability; the rapid and irregular elderly patients, occurring in 10---15% among those aged 65
heartbeat produced by AF increases the risk of blood clot and older.53,54
formation inside the heart.47,48 Controversy persists about whether screening and treat-
These clots may eventually become dislodged, causing ing subclinical thyroid dysfunction is warranted.
embolism. Moreover, TH have various effects on coagula- SHypo has been associated with elevated cholesterol
tion, TH excess is associated with coagulation abnormalities, levels and increased risk for atherosclerosis. SHyper has
such as shortened activated partial thromboplastin time, been associated with cardiovascular and total mortality. The
306 H. Vargas-Uricoechea et al.
Amiodarone and thyroid Table 6 Amiodarone and its effects on the thyroid gland.
Amiodarone is a potent class III anti-arrhythmic drug used Intrinsic effects of Iodine-induced effects of
in clinical practice for the prophylaxis and treatment of amiodarone amiodarone
many cardiac rhythm disturbances, ranging from paroxysmal Direct thyroid cytotoxicity Iodine-mediated
AF to life-threatening ventricular tachyarrhythmias. Amio- potentiation of thyroid
darone often causes changes in thyroid function tests mainly autoimmunity
related to the inhibition of 5 -deiodinase activity resulting in Blockade of TH entry into Inability to escape from
a decrease in the generation of T3 from T4, with a resulting cells Wolff---Chaikoff effect
increase in rT3 production and a decrease in its clearance. Inhibition of type I and type Unregulated hormone
However, the use of amiodarone is associated with several II 5 -deiodinase synthesis (Jod---Basedow
side effects owing to its marked lipid affinity. It is highly effect)
concentrated in tissues and is linked to a number of adverse Decreased T3 binding to its Increased intrathyroid
effects including photosensitivity, corneal microdeposits, TRs iodine stores
pulmonary toxicity, hepatotoxicity, peripheral neuropathy,
Effects of thyroid hormones 307
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