AHA thyroid and heart failure review 2011

Contemporary Reviews in Cardiovascular Medicine
Thyroid Replacement Therapy and Heart Failure
Anthony Martin Gerdes, PhD; Giorgio Iervasi, MD

H

eart failure (HF) is a major public health and economic
problem in Western countries and is one of the most
common causes of hospitalization and death. Coronary artery
disease is the underlying cause in more than two thirds of
chronic HF patients. By 2020, the World Health Organization
projects that ischemic heart disease alone will be the most
important global cause of morbidity and mortality. The
estimated increases in HF-related morbidity and mortality
suggest that our understanding of the pathophysiological
mechanisms of this syndrome is inadequate.
Interest in the role of thyroid hormones (THs) in HF has
increased in recent years. The driving considerations can be
summarized as follows: (1) the known effects of THs on
contractile and relaxation properties of the heart; (2) experimental findings offering strong support for the hypothesis
that TH signaling is critical in preserving cardiac structure
and performance under normal conditions and after cardiac
injury; and (3) evidence that mildly altered TH function is
strongly associated with a worsening prognosis in cardiac
patients in general and in HF patients in particular.
Diastolic function and systolic function are clearly
influenced by THs.1 Ventricular contractile function is also
influenced by changes in hemodynamic conditions secondary
to TH effects on peripheral vascular tone.1 TH homeostasis
preserves positive ventricular-arterial coupling, leading to a
favorable balance for cardiac work. A study in rats demonstrated that chronic hypothyroidism alone can eventually lead

to HF.2 Other studies suggest reduced cardiac tissue triiodothyronine (T3) levels after myocardial infarction (MI) or with
development of hypertension by upregulating type 3 deiodinase (D3), which leads to deactivation of T3 and T4
(thyroxine).3– 6 This review highlights a growing body of
evidence from animal studies and small-scale clinical trials
suggesting that low cellular thyroid activity at the cardiac
tissue level may adversely affect HF progression and that
treatment may lead to improvement.

TH Metabolism
The human thyroid gland produces and releases hormones
mostly as the prohormone T4. In contrast, the thyroid gland
secretes just a small amount (4 to 6 ␮g/d) of T3; the major
portion (20 to 25 ␮g/d) of T3 derives from conversion of
precursor T4.7 Thus, deiodination of T4 in peripheral tissues
is the key element of TH metabolism and action because only

T3 is considered the biologically active form of the TH. Three
deiodinase enzymes regulate circulating and tissue concentration of THs: type 1 (D1); type 2 (D2), and type 3 (D3).6 D1
is considered the major peripheral source of circulating T3,8
whereas D2 plays a critical role in providing local conversion
to T3. D3 is involved mainly in the conversion of T4 to
reverse T3, which is considered an inactive form of TH, and
in degrading T3 to inactive diiodothyronine (T2). Cardiac
levels of active T3 are dynamically determined by a balance
between availability and destruction of T3. Reduced TH
function in the heart could arise from 1 or more of the
following mechanisms: (1) reduced T3 production and/or
increased T3 degradation resulting from inhibition of D1 and
D2 activity and/or increased activity of D3, (2) reduced TH
uptake and/or increased T3 degradation in the cardiac tissue,

(3) changes in TH membrane transporters,9 and (4) altered
signaling resulting from changes in TH nuclear receptors. TH
signaling in cardiac hypertrophy and HF was recently reviewed
by Dillmann.10

TH Imbalance and Heart Disease
An argument suggesting a link between heart disease and
thyroid state is founded on evidence of a relationship between
the presence of an altered thyroid state and the occurrence and
progression of cardiac disease. Maintenance of TH homeostasis is required for proper cardiovascular function. Bioactive
T3 is a powerful regulator of inotropic and lusitropic properties of the heart through their effects on myosin isoforms
and calcium handling proteins in particular.1,11 Hyperthyroidism and hypothyroidism can lead to cardiovascular injury,
including HF. Development of TH assays permitted differential diagnosis of hypothyroidism from HF in that these
diseases share dyspnea, edema, pleural effusions, T-wave
changes, a decrease in contractility, decreased cardiac output,
and a grossly dilated, flabby heart.12 Hypothyroidism may
lead to increased blood cholesterol levels and atherosclerosis.13 Hypothyroidism promotes myocardial fibrosis by stimulating fibroblasts, whereas the opposite is true of hyperthyroidism.14,15 Chronic hypothyroidism in adult rats leads to
loss of coronary arterioles, impaired blood flow, a maladaptive change in myocyte shape, and development of HF.2
Changes in cardiac structure and function resulting from
hypothyroidism depend only on the severity of TH deficiency
and regress with T4 replacement treatment. Subclinical (mild)

From the Cardiovascular Health Research Center, Sanford Research/University of South Dakota, Sioux Falls (A.M.G.), and Clinical Physiology
Institute, CNR/Fondazione G. Monasterio CNR–Regione Toscana, Pisa e Massa, Italy (G.I.).
Correspondence to A. Martin Gerdes, PhD, Cardiovascular Health Research Center, 1100 E 21st St, Suite 700, Sioux Falls, SD 57105. E-mail

(Circulation. 2010;122:385-393.)
© 2010 American Heart Association, Inc.
Circulation is available at

DOI: 10.1161/CIRCULATIONAHA.109.917922

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primary thyroid hypofunction (scHypo or mild hypothyroidism) is defined by elevated values of thyrotropin (TSH) in the
presence of normal free T4 (FT4) and total (TT3) or free T3
(FT3) serum concentrations.16,17 All cardiovascular alterations that have been reported in the presence of overt
hypothyroidism have also been identified in scHypo, differing only in the extent of the alteration.16 Clinical observations
suggest a strong link between scHypo and poor outcome in
patients with and without heart disease.18 –24 In particular,
many reports suggest that scHypo is a risk factor in heart
disease.18,21,25–27 In a recent prospective study of euthyroid
HF patients subsequently developing scHypo, a poorer prognosis and increased hospitalization were observed in scHypo
patients compared with those with persistent euthyroidism.28
In addition, in chronic HF patients, TSH levels even slightly
above normal range are independently associated with a
greater likelihood of HF progression.29 Epidemiological data
also suggest that scHypo may be the only reversible cause of
left ventricular (LV) diastolic dysfunction with slowed myocardial relaxation and impaired filling, particularly in subjects
with TSH Ͼ10 ␮IU/mL.16,30 The Health, Aging, Body
Composition population-based study showed that participants
with TSH Ͼ7 ␮IU/mL had 3-times-higher HF events than

euthyroid patients.31 The Cardiovascular Health Study also
showed a greater incidence of HF events among participants
Ͼ65 years of age with TSH Ͼ10 ␮IU/mL.32 Reports on the
prevalence of primary scHypo in the general population vary
widely.23,25 The National Health and Nutrition Examination
Survey III trial reported that 4.3% of the US population has
scHypo, with higher rates in the elderly and women.33 In
patients with cardiac diseases, however, the prevalence of
primary scHypo is similar to that reported in the general
population.18 scHypo is an independent risk factor for atherosclerosis and MI in women24 and is associated with coronary
artery disease and increased all-cause mortality in men.25,34
Evidence indicates that patients with clinically stable heart
diseases and scHypo have a greater rate of cardiac death than
euthyroid patients.18 A randomized crossover trial in patients
with scHypo showed beneficial effects of T4 on cardiovascular risk factors and quality of life.26 Results from the
Nord-Trøndelag Health Study showed that coronary artery
disease mortality in women and unfavorable serum lipids for
patients increased at higher TSH levels within the normal
range.27,35
Independently from the presence of primary thyroid hypofunction and differently from other organs, the heart is
particularly vulnerable to reductions in biologically active T3
in plasma because cardiomyocytes have a negligible capability to generate T3 from locally converted precursor T4.
Consequently, when circulating T3 is low, the myocardium
may become relatively hypothyroid. In animals, a low-T3
state resulting from altered peripheral TH metabolism secondary to caloric restriction is associated with impaired
cardiac contractility and changes in cardiac gene expression,
similar to those observed during chronic hypothyroidism.
Importantly, these alterations are reversible after restoration
of normal T3 plasma levels by exogenous T3 administration.11 Low-T3 syndrome is the central finding and defines
the illness in a variety of acute and chronic severe nonthy-

roidal illnesses with cardiac origin, including MI, HF, and
surgically treated cardiac disease.1 Low circulating levels of
T3 in the absence of primary thyroid hypofunction have been
found in 20% to 30% of patients with dilated cardiomyopathy.18 Moreover, FT3 levels were inversely correlated to
coronary artery disease, and low T3 levels conferred an
adverse prognosis, even after adjustment for coronary risk
factors in patients with coronary artery disease, normal LV
function, and no history of MI.36 Low-T3 syndrome could be
a mere marker of poor health. More intriguing, and to the
contrary, is the hypothesis that a progressive T3 decrease is
part of the vicious pathophysiological circle sustaining cardiac remodeling, neurohumoral activation, and systemic derangement in HF, thus leading to an increase in global and
cardiac mortality. Consistent with the regulation of many
structural and functional genes by T3, a low-T3 state in
cardiac tissue may cause impaired diastolic and systolic
function, prolongation of action potential, and increased
susceptibility to arrhythmias. In addition, hypothyroid hearts
show poor substrate use such as glucose, lactate, and free
fatty acids by mitochondria.37 Accordingly, cardiac oxygen
consumption, as measured by positron emission tomography
11
C acetate, was reduced in hypothyroid patients, but cardiac
work was compromised more severely than oxidative metabolism. This led to decreased cardiac energetic efficiency of
the hypothyroid human heart.38 Because of well-known
multiple and systemic actions, THs may also interact with
other hormone/organ systems and with all the hemodynamic
and metabolic variables involved in HF that modulate the
development and progression of HF (Figure 1). At present,
the concept that altered TH metabolism may contribute to
human HF progression is supported mainly by several clinical

observational studies showing the important role of a low-T3
state in the prognostic stratification of patients with HF
(Table 120,22,39 – 41). Independently of the parameter used, all
of these studies showed that impaired T4-to-T3 conversion is
associated with a high incidence of fatal events consisting of
cardiac or cumulative death or of heart transplantation.
Impairment of T4-to-T3 conversion was also found to be
proportional to the clinical severity of HF as assessed by the
New York Heart Association functional classification.21,42
Furthermore, T3 levels in plasma strongly correlated with
exercise capacity and oxygen consumption in HF patients.43
In summary, clinical observations seem to indicate the presence of a close pathophysiological link between primary scHypo
or impaired T4 to T3 conversion and evolution of HF. It is
important that clinicians and scientists evaluate the evidence
fairly and objectively before making a decision on the potential
for therapeutic TH treatment of heart disease. This is particularly
true because there have been few promising new pharmacological treatment options for HF in recent years.

TH Metabolism During the Early
Post-MI Phase
Human and animal studies suggest that low TH levels contribute
to worsening outcome after MI. There is rapid decline in T3 and
TSH during the first week after an acute MI in patients.44 Values
for reverse T3 were increased but T4 remained normal. Inhospital and postdischarge mortality was highest among patients

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Thyroid Treatment of Heart Failure

387

Figure 1. Thyroid function and HF progression: the
vicious pathophysiological circle. GFR indicates
glomerular filtration rate; GTB, glomerular tubular
balance; NE, neuroendocrine; and NP, natriuretic
peptides.

with the most pronounced T3 depression and reverse T3 elevation.19 Moreover, there is a worsening prognosis in post-MI
patients with persistently low plasma T3.44 These observations,
together with recent evidence that mild TSH abnormalities are
associated not only with traditional coronary risk factors35 but
Table 1.

also with mortality for coronary artery disease,35 support the
hypothesis that even a mild reduction in TH levels plays an
important role in the myocardial response to acute ischemia.
Induction of MI in severely hypothyroid dogs led to a
dramatic increase in infarct size.45 Ojamaa et al46 demon-

Observational Studies Showing Relationship Between Thyroid Function and Outcome in HF Patients

Author/Year

Population*

Patients, n

Male, n

Age, y

NYHA Class

Adopted Parameter

Follow-Up

Outcome

Hamilton
et al,22 1990

Ischemic and
nonischemic
congestive
advanced HF

84

70

17–71†

Not reported

FT3 index/rT3 ratio

7.3Ϯ6.6‡ mo

FT3 index/rT3 ratio Ͼ4:
survival 100%

Opasich
et al,39 1996

Ischemic and
nonischemic
HF

199

Kozdag
et al,40 2005

Ischemic and
non ischemic
DCM

111

Ischemic and
non ischemic
DCM

281

Pingitore

et al,20 2005

FT3 index/rT3 ratio Յ4:
survival 37%
171

51.6Ϯ0.6§

I–IV

TT3

417Ϯ259§ d

Normal TT3: survival 79%
Low TT3: survival 52%

76

62Ϯ12‡

III–IV

FT3/FT4 Ratio

12Ϯ8‡ mo

FT3/FT4 ratio Ͼ1.7: survival
specificity 71%
FT3/FT4 ratio Յ1.7: survival

sensitivity 100%

207

70Ϯ10‡

I–IV

TT3 FT3 LVEF

12Ϯ7‡ mo

Normal TT3 and LVEF
Ͼ20%: survival 90%
Normal TT3 and LVEF
Ͻ20%: survival 83%
Low TT3 and LVEF Ͼ20%:
survival 73%
Low TT3 and LVEF Ͻ20%:
survival 61%

Passino
et al,41 2009

Ischemic and
nonischemic
HF

442

331

65Ϯ12‡

I–IV

FT3/BNP

36 mo
(median)

Low BNP/normal FT3:
survival 84%
Low FT3/low BNP: survival
69%
High BNP/normal FT3:
survival 60%
High BNP/low FT3: survival
28%

NYHA indicates New York Heart Association; rT3, reverse T3; DCM, dilated cardiomyopathy; LVEF, LV ejection fraction; and BNP, brain natriuretic peptide.
*As defined by author.
†Range.
‡MeanϮSD.
§MeanϮSE.

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strated the presence of low-T3 syndrome in rats after MI. T3
treatment improved ejection fraction and normalized some of
the changes in gene expression. In another study,47 T4
treatment of rats with MI led to a modest improvement in
heart function. Henderson et al48 demonstrated normal serum
T4 levels but a sustained reduction in serum T3 levels 1 to 5
weeks after MI in rats. T3 treatment resulted in improved
systolic function and a trend for improved diastolic function.
A study by Olivares et al3 provided more insight into TH
impairment in MI. After MI was produced in rats, there was
a pronounced upregulation of D3. Serum T3 levels did not
normalize for 2 months. Combined with reduced muscle D2
activity, this may provide an additional mechanism for the
reduction of plasma T3 levels that is typically seen after MI.
T3 treatment of rats with MI led to a decrease in DNA
laddering and terminal deoxynucleotidyl transferase dUTP
nick-end labeling in the border zone, suggesting a potential
protective role.49 T3 can also prevent remodeling by reducing
apoptosis at the early phase of ischemia/reperfusion.50 Upregulation of D3 may be a generalized response to cardiac
injury since Wassen et al4 have also shown D3 activation in
pulmonary hypertension. The increase in D3 was specific to
the overloaded right ventricle and associated with a reduction
of both local T3 content and T3-dependent gene transcription.5 It is likely that reexpression of the fetal gene program
in the overloaded ventricle, a common feature of cardiac
disease, is enhanced by low tissue TH levels.

Pantos and colleagues51–55 have published numerous animal studies on the effects of THs on the heart, particularly
during ischemia or MI. They have shown that short- and
long-term T3ϩT4 treatment of rats with MI leads to improved LV function and remodeling.53,54 However, remodeling data were limited to echocardiographs and measurement
of infarct size with no tissue structure analyses of spared
myocardium. Importantly, the Pantos group has not observed
any TH treatment–related changes in infarct scar remodeling.
Because interventions affecting post-MI scar remodeling may
lead to cardiac aneurism or rupture and THs are known to
have antifibrotic effects, it is reassuring to know that TH
treatment is not likely to promote such changes. It is interesting to note that T3 and/or T4 replacement therapy has
never been tested in humans after MI despite a clear association between low thyroid function and poor prognosis after
MI and many animal studies showing similar changes and
improvement with TH treatment. At present, the issue of
using T3, T4, or their combination has not been completely
resolved but may depend on specific clinical situations. For
instance, it seems logical that T4 treatment may work better
in the presence of primary hypothyroidism but not in the
presence of impaired peripheral conversion of T4 to T3, when
T3 seems to be more useful.
When considering the large number of patients with
primary scHypo and the number of patients with heart
disease, it is remarkable that only a few animal studies have
investigated the combined effects of these conditions. We
confirmed the presence of scHypo (increased TSH, normal
T3 and T4) in BIO-TO2 cardiomyopathic hamsters.56,57
Treatment of TO2 hamsters with a therapeutic dose of
T3ϩT4 from 4 to 6 months of age prevented progression of

fibronecrosis and further loss of cardiac myocytes and attenuated progressive LV dilatation and dysfunction. Resting and
maximum (adenosine) coronary blood flow was significantly

reduced in both 4- and 6-month-old TO2 hamsters. T3ϩT4
treatment of TO2 hamsters normalized resting and maximum
blood flow. This was the first study to demonstrate potential
benefits of TH treatment of scHypo in an animal model of
HF.57 It is not known at present if long-term TH treatment of
TO2 hamsters will reduce mortality. Our studies with TO2
hamsters raise the possibility that patients with similar cardiac conditions may benefit from TH treatment. A recent rat
study also demonstrated that serum TH levels may be normal
when cardiac tissue levels are significantly depressed.58
Cardiac tissue TH levels were a more reliable indicator of LV
function than serum hormone levels. This raises an important
question: How much ventricular dysfunction in cardiac patients who are diagnosed as “euthyroid” is actually due to low
tissue hormone levels? Thyroid dysfunction at the tissue level
may be exacerbated by downregulation of thyroid nuclear
receptors, known to occur in HF.59

Cardiac Remodeling and the Effect of THs
Although much of the work on HF has focused largely on
improving contractility and relaxation without inducing an
increase in heart rate, new evidence suggests that beneficial
effects on myocardial tissue remodeling could be a more
important target. To understand and fully appreciate the
effects of THs on myocyte remodeling, a brief overview of
myocyte remodeling is helpful. Because changes in wall
stress are directly proportional to chamber diameter and
inversely proportional to wall thickness, it seems plausible
that changes in myocyte length and width are likely to play a
key role in pathological alterations in chamber diameter and
wall thickness, respectively. After extensively characterizing
and implementing a precise method to measure myocyte

size,60 we subsequently documented patterns of myocyte
remodeling in many mammalian species during physiological
and pathological cardiac growth (see reviews61,62). We demonstrated that pressure overload leads to an increase in
myocyte cross-sectional area (CSA) and volume overload
leads to proportional growth of myocyte length and width
(Figure 261,62). Regardless of the starting point (normal CSA
or increased CSA with the presence of hypertension), progression to dilated failure is associated with only cell lengthening from series addition of sarcomeres. This is the case in
dilation of the noninfarcted myocardium after MI,63,64 idiopathic dilated cardiomyopathy,62 and hypertension associated
with dilated failure (Figure 2).65 Cumulatively, our remodeling data suggest that the cellular defect in progression to
dilated failure is related to the inability of the myocytes to
properly regulate CSA. The absence of an increase in CSA as
myocytes lengthen leads to a vicious cycle of progressively
increasing wall stress, impaired coronary blood flow, and
increased stiffness from collagen accumulation in HF.
Induction of hyperthyroidism in normal rats leads to
balanced growth of myocyte length and width,66,67 a pattern
similar to that of normal physiological growth.68 Hypothyroidism induced by propylthiouracil in rats leads to cardiac
atrophy caused by a reduction in myocyte CSA initially.69

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Thyroid Treatment of Heart Failure

389

Figure 2. Changes in myocyte shape with
pressure and volume overload (reprinted

from Gerdes61 with permission of the
publisher. Copyright © 1992, Elsevier) and
progression to HF (reprinted from Gerdes62
with permission of the publisher. Copyright
© 2002, Elsevier). CSA indicates crosssectional area; L, myocyte length; and W,
myocyte width.

However, long-term hypothyroidism leads to induction of cell
lengthening from series sarcomere formation.2 Series addition
of sarcomeres is a unique feature of dilated HF and is
reversed in myocytes from HF patients after unloading as a
result of implantation of a LV assist device.70 So, LV
unloading caused by hypothyroidism leads to an unexpected
change in myocyte shape typical of HF rather than mechanical unloading.
We investigated the effects of T3ϩT4 on LV chamber and
myocyte remodeling in aging spontaneously hypertensive
heart failure rats approaching dilated HF.71 There was a
dose-related improvement in the ratio of chamber diameter to
wall thickness that normalized systolic wall stress despite the
presence of sustained hypertension. This alteration in chamber anatomy resulted from a specific change in myocyte
shape, namely a reduction in myocyte major diameter (axis
runs in a circumferential direction correlating with chamber
dimension) and an increase in myocyte minor diameter (axis
runs in a transmural or wall thickening dimension).71,72
Preliminary results from T3-treated rats after MI also suggest
beneficial changes in myocyte shape (A.M.G., unpublished
observation, 2010). Cumulatively, our studies showing improved myocyte shape with TH treatment of various animal
models of HF suggest that TH plays an important role in the
regulation of myocyte shape in heart disease. In particular,
THs appear to play a key role in the proper regulation of

myocyte transverse shape and hence wall stress. It is possible
that impaired transverse growth during progression to dilated
HF is due to low thyroid function at the tissue level.
Our knowledge of the molecular regulation of cardiac
myocyte shape is slowly evolving. Of note, a vast array of
complex protein interactions in mechanical stress sensors has
been found in many regions of cardiac myocytes, including
costameres, intercalated disks, and caveolae-like domains.73
To the best of our knowledge, insertion of series sarcomeres
has never been observed in adult heart. In vitro work by Yu
and Russell,74 however, suggests that new series sarcomeres
are formed throughout the cell length. Very little is known
about the regulation of myocyte CSA. Of interest is the
transmission of lateral force during myocyte contraction via
cytoskeletal linkage from the sarcolemma to the nucleus.75 A
complex array of structural and signaling proteins is located
in this transverse network involving the sarcolemma, cos-

tameres, and Z disks. It is possible that this lateral network is
a key regulator of myocyte CSA. This was suggested by
studies showing a critical role for the cytoskeletal protein
melusin, which interacts with the ␤1-integrin in the costameric region of cardiac myocytes.76,77 Melusin is upregulated in early hypertension (CSA growth period) and downregulated with progression to dilated HF (cell-lengthening
phase).77 Melusin knockout mice showed excessive dilatation
and impaired growth of myocyte CSA after aortic constriction, whereas melusin overexpression promoted wall thickening and prevented dilated HF after aortic constriction.76,77
Like THs, melusin protects from fibrosis and apoptosis and
stimulates Akt signaling. THs increase NO expression, and
NO is known to increase expression of costameric proteins.78
T3 has also been shown to trigger Akt-dependent changes in
titin isoform transitions.79 These examples are given simply
to show how THs could affect mechanosensors and myocyte

shape. Clearly, more work is needed to demonstrate specific
mechanisms and causality.

TH Treatment in HF
A prolonged controversy has developed over the issue of TH
treatment in cardiac patients, with data limited to only a few
studies.80 – 86 A strong argument in favor of TH treatment in
HF is that the failing heart has alterations in gene expression
similar to that found in hypothyroidism,87,88 with all abnormalities being reversible with TH substitutive treatment. An
unresolved question, however, is related to the meaning of
low FT3 in the background of normal levels of TSH and FT4,
which is observed in the majority of nonthyroidal illness
patients. Under these circumstances, TH action in peripheral
target tissues such as the heart is poorly understood. A major
limitation involves the assessment of tissue TH status in
peripheral tissues based on hormonal blood-borne data only.
Aside from the central issue of dosage, timing for initiating
and discontinuing TH treatment in scHypo patients with HF
is not clear. A good biomarker of intracardiac TH signaling
would be helpful but has not been identified. In the absence
of such a marker, a rational, cautious therapeutic approach
might be to restore and maintain over time biochemical
euthyroidism as documented by normal circulating levels of
TSH, FT4, and FT3.

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Table 2.

TH and TH Analog DITPA Treatment in Patients With HF

Author/
Year

Study Design

Population

Patients,
n

Age*, y

NYHA

LVEF, %

Intervention

Main Findings

Heart Rate

Side Effects

Moruzzi
et al,85
1994

Randomized (1:1),
placebo controlled

Nonischemic HF

10

47–78

II–III

27Ϯ8

T4 100 ␮g/d for 1
wk OS

2 SVR (dobutamine
test), 1 CO
(dobutamine test),
1 O2 consumption,
1 exercise
tolerance, 1 resting
LVEF

Unchanged

No

Moruzzi
et al,91
1996

Randomized (1:1),
placebo controlled

Nonischemic HF

10

51–70

II–IV

29Ϯ6

T4 100 ␮g/d for 3
mo OS

1 Cardiac
performance at rest,
exercise, and
dobutamine test; 2
LVEDD; 2 SVR

Unchanged

No

Hamilton
et al,84
1998

Uncontrolled

Ischemic,
nonischemic HF

23

50

III–IV

22Ϯ1

T3 cumulative dose
0.15–2.7 ␮g/kg
bolusϩcontinuous
infusion (6–12 h)

2 SVR, 1 CO

Unchanged

No

Malik et
al,92
1999

Uncontrolled

Systolic HF
(cardiogenic
shock)

10

37–65

Not available

T4 20 ␮g/h
bolusϩcontinuous
infusion (36 h)

1 CI, 1 PCWP and
MAP

Unchanged

No

Iervasi et

al,86
2001

Uncontrolled

Ischemic,
nonischemic HF

6

64Ϯ8

III–IV

24Ϯ3

T3 initial dose 20
␮g/m2bs per d,
continuous infusion
(4 d)

2 SVR, 1 CO, 1
UO

Unchanged

No

Pingitore
et al,93

2008

Randomized (1:1),
placebo controlled

Ischemic,
nonischemic HF

20

64–77

I–III

25 18–32

T3 initial dose 20
␮g/m2bs per day,
continuous infusion
(3 d)

1 LFSV, 1 LVEDV,
2 NT–proBNP, 2
noradrenaline, 2
aldosterone

Reduced

No

Goldman
et al,94
2009

Randomized (2:1),
placebo-controlled

Ischemic,
nonischemic HF

86

65.6Ϯ11 (T)
67.3Ϯ10.3 (P)

II–IV

28Ϯ6.8 (T)
28Ϯ6 (P)

DITPA twice daily,
90-mg increments
(every 2 wk) to
maximum 360 mg

1 CI, 2 SVR, 2
lipoproteins and
cholesterol

Increased

Poorly tolerated,
weight loss,
fatigue, GI
complaints

NYHA indicates New York Heart Association; DCM, dilated cardiomyopathy; LVEF, LV ejection fraction; SVR, systemic vascular resistances; CO, cardiac output; CI,
cardiac index; UO, urinary output; LVEDD, LV end-diastolic diameter; PCWP, pulmonary capillary wedge pressure; MAP, mean arterial pressure; LVSV, LV stroke
volume; NT-pro-BNP, N-terminal pro-brain natriuretic peptide; T, Treated; P, Placebo; GI, gastrointestinal; m2bs, m2 body surface; and OS, oral administration.
*Age reported as range, mean, or meanϩSD.

TH-based novel therapeutic options could find suitable
application not only at early but also at end stages of HF.
Treatment with physiological doses of T3 is able to restore
the expression of Ca(2ϩ) cycling and handling proteins and
contractile function of cardiac myocytes in an animal model
of chronic cardiac unloading (a condition similar to that in
patients with end-stage HF after LV assist device implantation).89 Tissue-engineered heart muscle (also called cardioids)
is a fascinating alternative treatment modality for end-stage
congestive HF. T3 stimulation is able to promote the selforganization of primary neonatal cardiac cells into a contractile tissue construct. An increased rate of contraction and
relaxation in response to T3 stimulation is observed with
parallel changes in the gene expression of SERCA2, phospholamban, and myosin heavy chains.90
A number of preclinical studies have tested L-T4, L-T3, or
TH analog diiodothyropropionic acid (DITPA) replacement
therapy in patients with HF (Table 284 – 86,91–94). Synthetic
L-T3 or L-T4 improved LV function consisting of enhanced
resting cardiac output and exercise capacity and reduced
systemic vascular resistance. However, the protocols used for
T3 administration in HF patients were much different. Independently of the adopted L-T3 regimen and different from
DITPA, T3 was well tolerated, and undesirable effects

consisting of arrhythmias, myocardial ischemia, or hemody-

namic instability were not documented. In a clinical study
from our group, improvement in cardiac performance induced
by T3 did not correspond to increased myocardial oxygen
consumption as indirectly estimated by calculation of the
rate-pressure product and total cardiac work.93 Importantly,
the benefit of T3 infusion on cardiac function paralleled
deactivation of the neuroendocrine profile. In the abovementioned study,93,95 the effects of TH replacement therapy
on cardiac function and morphology were assessed by cardiac
magnetic resonance, a noninvasive and nonionizing technique
currently considered the gold standard approach to assess LV
volumes and regional global function. The high quality of
imaging and the 3-dimensional approach of cardiac magnetic
resonance allow assessment of LV postischemic remodeling
accurately with high reproducibility, enabling smaller sample
sizes to reach statistical significance.96,97
It is worth noting here that a phase II, randomized,
double-blind, placebo-controlled clinical trial investigating
the effects of T3 treatment in patients with MI was recently
initiated by Dr Iervasi (Thyroid Hormone Replacement Therapy in ST Elevation MI [THiRST]).

Conclusions
A growing body of evidence suggests that TH dysfunction
may play an important role in the progression to dilated HF.

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Gerdes and Iervasi

Therapeutic use of THs in HF has not been adequately
studied. Until now, most studies have targeted improvement
in LV function. THs also produce remarkable improvements
in remodeling, including beneficial changes in myocyte
shape, microcirculation, and collagen. Clearly, more studies
are needed to explore the full potential of the therapeutic use
of THs in treating and/or preventing HF.

Disclosures
None.

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KEY WORDS: angiogenesis
Ⅲ thyroid hormones

Ⅲ heart failure Ⅲ myocardial infarction Ⅲ remodeling

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Thyroid Replacement Therapy and Heart Failure
Anthony Martin Gerdes and Giorgio Iervasi
Circulation. 2010;122:385-393
doi: 10.1161/CIRCULATIONAHA.109.917922
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