AHA thyroid and heart failure review 2011

A study in rats demon-strated that chronic hypothyroidism alone can eventually lead to HF.2Other studies suggest reduced cardiac tissue triiodo-thyronine T3 levels after myocardial infar

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Thyroid Replacement Therapy and Heart Failure

Anthony Martin Gerdes, PhD; Giorgio Iervasi, MD

Heart 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)

experi-mental 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.1Ventricular contractile function is also

influenced by changes in hemodynamic conditions secondary

to TH effects on peripheral vascular tone.1TH homeostasis

preserves positive ventricular-arterial coupling, leading to a

favorable balance for cardiac work A study in rats

demon-strated that chronic hypothyroidism alone can eventually lead

to HF.2Other studies suggest reduced cardiac tissue

triiodo-thyronine (T3) levels after myocardial infarction (MI) or with

development of hypertension by upregulating type 3

deio-dinase (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 T4.7Thus, 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 concen-tration of THs: type 1 (D1); type 2 (D2), and type 3 (D3).6D1

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 homeosta-sis is required for proper cardiovascular function Bioactive T3 is a powerful regulator of inotropic and lusitropic prop-erties of the heart through their effects on myosin isoforms and calcium handling proteins in particular.1,11 Hyperthyroid-ism and hypothyroidHyperthyroid-ism can lead to cardiovascular injury, including HF Development of TH assays permitted differen-tial 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 atherosclero-sis.13Hypothyroidism promotes myocardial fibrosis by stim-ulating fibroblasts, whereas the opposite is true of hyperthy-roidism.14,15 Chronic hypothyroidism in adult rats leads to loss of coronary arterioles, impaired blood flow, a maladap-tive 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 mgerdes@usd.edu

(Circulation 2010;122:385-393.)

Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIRCULATIONAHA.109.917922

385 by guest on January 18, 2015

http://circ.ahajournals.org/

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(FT3) serum concentrations.16,17 All cardiovascular

alter-ations that have been reported in the presence of overt

hypothyroidism have also been identified in scHypo,

differ-ing only in the extent of the alteration.16Clinical 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

prog-nosis 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.29Epidemiological data

also suggest that scHypo may be the only reversible cause of

left ventricular (LV) diastolic dysfunction with slowed

myo-cardial relaxation and impaired filling, particularly in subjects

with TSH ⬎10 ␮IU/mL.16,30 The Health, Aging, Body

Composition population-based study showed that participants

with TSH ⬎7 ␮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

⬎65 years of age with TSH ⬎10␮IU/mL.32Reports on the

prevalence of primary scHypo in the general population vary

widely.23,25The 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.18scHypo is an independent risk factor for

athero-sclerosis and MI in women24and 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.18A randomized crossover trial in patients

with scHypo showed beneficial effects of T4 on

cardiovas-cular 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

hypo-function and differently from other organs, the heart is

particularly vulnerable to reductions in biologically active T3

in plasma because cardiomyocytes have a negligible

capabil-ity 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

sec-ondary 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

administra-tion.11 Low-T3 syndrome is the central finding and defines

the illness in a variety of acute and chronic severe

nonthy-found in 20% to 30% of patients with dilated cardiomyopa-thy.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.36Low-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 car-diac remodeling, neurohumoral activation, and systemic de-rangement 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.37Accordingly, cardiac oxygen consumption, as measured by positron emission tomography

11C acetate, was reduced in hypothyroid patients, but cardiac work was compromised more severely than oxidative metab-olism 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 pres-ence 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 pharmacolog-ical 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.44Values for reverse T3 were increased but T4 remained normal In-hospital and postdischarge mortality was highest among patients

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with the most pronounced T3 depression and reverse T3

eleva-tion.19 Moreover, there is a worsening prognosis in post-MI

patients with persistently low plasma T3.44These observations,

together with recent evidence that mild TSH abnormalities are

associated not only with traditional coronary risk factors35but

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-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.

Table 1 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 7.3 ⫾6.6‡ mo FT3 index/rT3 ratio ⬎4:

survival 100% FT3 index/rT3 ratio ⱕ4: survival 37% Opasich

et al, 39 1996

Ischemic and

nonischemic

HF

Low TT3: survival 52% Kozdag

et al, 40 2005

Ischemic and

non ischemic

DCM

111 76 62 ⫾12‡ III–IV FT3/FT4 Ratio 12 ⫾8‡ mo FT3/FT4 ratio ⬎1.7: survival

specificity 71% FT3/FT4 ratio ⱕ1.7: survival sensitivity 100% Pingitore

et al, 20 2005

Ischemic and

non ischemic

DCM

⬎20%: survival 90% Normal TT3 and LVEF

⬍20%: survival 83% Low TT3 and LVEF ⬎20%: survival 73% Low TT3 and LVEF ⬍20%: survival 61% Passino

et al, 41 2009

Ischemic and

nonischemic

HF

(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.

‡Mean ⫾SD.

§Mean ⫾SE.

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treatment of rats with MI led to a modest improvement in

heart function Henderson et al48demonstrated 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.49T3 can also prevent remodeling by reducing

apoptosis at the early phase of ischemia/reperfusion.50

Up-regulation of D3 may be a generalized response to cardiac

injury since Wassen et al4have 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

transcrip-tion.5It 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

ani-mal studies on the effects of THs on the heart, particularly

during ischemia or MI They have shown that short- and

long-term T3⫹T4 treatment of rats with MI leads to

im-proved LV function and remodeling.53,54However,

remodel-ing 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

inter-esting to note that T3 and/or T4 replacement therapy has

never been tested in humans after MI despite a clear

associ-ation 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

T3⫹T4 from 4 to 6 months of age prevented progression of

reduced in both 4- and 6-month-old TO2 hamsters T3⫹T4 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.57It 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 car-diac 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 pa-tients 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 dem-onstrated 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), pro-gression to dilated failure is associated with only cell length-ening from series addition of sarcomeres This is the case in dilation of the noninfarcted myocardium after MI,63,64 idio-pathic dilated cardiomyopathy,62and hypertension associated with dilated failure (Figure 2).65Cumulatively, our remodel-ing 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,66,67a pattern similar to that of normal physiological growth.68 Hypothy-roidism induced by propylthiouracil in rats leads to cardiac atrophy caused by a reduction in myocyte CSA initially.69

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However, long-term hypothyroidism leads to induction of cell

lengthening from series sarcomere formation.2Series 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

mechan-ical unloading

We investigated the effects of T3⫹T4 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

cham-ber 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

im-proved 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,74however, 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.75A

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 cos-tameric region of cardiac myocytes.76,77Melusin is upregu-lated in early hypertension (CSA growth period) and down-regulated with progression to dilated HF (cell-lengthening phase).77Melusin knockout mice showed excessive dilatation and impaired growth of myocyte CSA after aortic constric-tion, whereas melusin overexpression promoted wall thick-ening 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.79These 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 – 86A 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,87,88with all abnor-malities 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

Figure 2 Changes in myocyte shape with

with permission of the publisher Copyright

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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(2⫹) 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

implanta-tion).89Tissue-engineered heart muscle (also called cardioids)

is a fascinating alternative treatment modality for end-stage

congestive HF T3 stimulation is able to promote the

self-organization of primary neonatal cardiac cells into a

contrac-tile 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,

phos-pholamban, 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

Inde-pendently 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.93Importantly, the benefit of T3 infusion on cardiac function paralleled deactivation of the neuroendocrine profile In the above-mentioned 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 Ther-apy 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

Moruzzi

et al, 85

1994

Randomized (1:1),

placebo controlled

Nonischemic HF 10 47–78 II–III 27 ⫾8 T4 100 ␮g/d for 1

wk OS

2 SVR (dobutamine test), 1 CO (dobutamine test),

1 O 2 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 29 ⫾6 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 22⫾1 T3 cumulative dose

0.15–2.7 ␮g/kg bolus⫹continuous 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

bolus ⫹continuous infusion (36 h)

1 CI, 1 PCWP and MAP

Unchanged No

Iervasi et

al, 86

2001

Uncontrolled Ischemic,

nonischemic HF

6 64⫾8 III–IV 24⫾3 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 65.6 ⫾11 (T) 67.3⫾10.3 (P)

II–IV 28 ⫾6.8 (T) 28⫾6 (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 mean ⫹SD.

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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䡲heart failure䡲myocardial infarction䡲remodeling

䡲thyroid hormones

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