Thyroid hormone and cardiac function in mice deficient in thyroid
hormone receptor-
or -
: an echocardiograph study
Roy E.
Weiss1,
Claudia
Korcarz1,
Olivier
Chassande3,
Kevin
Cua1,
Peter
M.
Sadow2,
Eugene
Koo1,
Jacques
Samarut3, and
Roberto
Lang1
Departments of 1 Medicine and
2 Pathology, University of Chicago, Chicago, Illinois
60637; and 3 Laboratoire de Biologie Moleculaire et
Cellulaire de l'Ecole Normale Supérieure de Lyon, 69364 Lyon, France
 |
ABSTRACT |
We investigated the effect of thyroid
hormone (TH) receptor (TR)
and -
isoforms in TH action in the
heart. Noninvasive echocardiographic measurements were made in mice
homozygous for disruption of TR
(TR
0/0) or TR
(TR
/
). Mice were studied at baseline, 4 wk after TH
deprivation (using a low-iodine diet containing propylthiouracil), and
after 4-wk treatment with TH. Baseline heart rates (HR) were similar in
wild-type (WT) and TR
0/0 mice but were greater in
TR
/
mice. With TH deprivation, HR decreased 49% in
WT and 37% in TR
/
mice and decreased only 5% in
TR
0/0 mice from baseline, whereas HR increased in all
genotypes with TH treatment. Cardiac output (CO) and cardiac index (CI)
in WT mice decreased (
31 and
32%, respectively) with TH
deprivation and increased (+69 and +35%, respectively) with TH
treatment. The effects of CO and CI were blunted with TH withdrawal in
both TR
0/0 (+8 and
2%, respectively) and
TR
/
mice (
17 and
18%, respectively). Treatment
with TH resulted in a 64% increase in LV mass in WT and a 44%
increase in TR
0/0 mice but only a 6% increase in
TR
/
mice (ANOVA P < 0.05). Taken
together, these data suggest that TR
and TR
play different roles
in the physiology of TH action on the heart.
left ventricular mass; thyrotropin; cardiac index; cardiac
output; shortening fraction
 |
INTRODUCTION |
THYROID HORMONE (TH)
exerts a profound effect on the chronotropic and ionotropic function of
the heart (25, 28). TH deficiency results in systolic and
diastolic dysfunction with reduction in heart rate and force of
contraction and an increase in cardiac relaxation (18,
23). The molecular basis for the negative ionotropic
consequences of hypothyroidism can be linked to decreased expression of
the sarcoplasmic reticulum Ca2+ ATPase gene
(42) and myosin heavy chain (MHC)
and increase in
MHC
(27, 42). The latter results in decreased speed of systolic contraction due to the increased expression of myosin V3,
which has a lower ATPase activity (2, 44). The
molecular basis for the ionotropic effect seen in hypothyroidism,
namely the bradycardia, is related to decreased expression of the
hyperpolarization-activated, cyclic nucleotide-gated genes 2 or 4, which are specific targets of the TH receptor (TR)
gene
(19).
TH action is mediated by its interaction with specific nuclear TRs
functioning as ligand-dependent transcription factors that modulate the
expression of target genes (30, 33). The two TR genes
TR
and TR
have substantial structural and
sequence similarities. Each generates multiple TR proteins by
alternative splicing (
1 and
2;
1,
2, and
3) or
alternative start sites (
1, 
2,
revErb). TR
2 binds to DNA, but, due to a sequence difference at the ligand-binding site, it does not bind TH and thus
does not function as a TR proper (35). The relative
expression of TR genes and the distribution of their products vary
among tissues and during different stages of development (20, 31, 46). Furthermore, an internal promoter, located within intron 7 of the TR
gene, is responsible for the expression, in
mice, of truncated isoforms of TR
1 and
TR
2, (TR
1 and TR
2)
containing the carboxy-terminal segment of the molecule. These
additional products of the TR
gene may play a role in
downregulation of transcriptional activity (5, 17, 40).
TR
1 and TR
2 are the major isoforms of TR
expressed in the heart (24). Although TR
1
is expressed at low levels (10), TR
2 is
also expressed (43). The use of mice with disruption of
either the TR
or TR
gene has led to the
conclusion that the effect of L-triiodothyronine (L-T3) on the heart is mediated predominantly
by TR
(19, 21, 22, 38, 48). These studies have
primarily examined the effect of TH deprivation and have not examined
the effect of long-term TH excess.
The purpose of the present study was to examine the contribution that
both TR
and TR
make in the presence of TH withdrawal and TH
treatment on the chronotropic and ionotropic effect on the heart in
vivo as determined by echocardiographic parameters. Echocardiography
uniquely allows the study of sequential changes in TH action over time
in the same animals. We have confirmed that chronotropic effects of TH
on the heart are primarily TR
dependent. Furthermore, we have
demonstrated that in an intact animal the action of TH on the heart is
both TR
and TR
dependent.
 |
METHODS |
Mice.
Mice were weaned on the 4th wk after birth and fed a rodent diet (no.
5053; Lab Diet, Brentwood, MO) containing 0.53 ppm iodine and were
given tap water ad libitum. They were housed three to five mice per
cage in an environment of controlled 19°C temperature and 12-h
alternating dark-artificial light cycles. All animal experiments were
performed according to approved protocols at the University of Chicago
by the Institutional Animal Care and Use Committee.
Male mice were 50-90 days old at the time of initial blood
sampling. Three hundred microliters of blood were obtained by
retroorbital vein puncture under light methoxyflurane (Pitman Moore,
Mundelein, IL) anesthesia. Bleeding was generally done between 0900 and
1200. Serum was separated by centrifugation and stored at
20°C
until analyzed.
The TR
knockout mice were produced by insertion of the LacZ-NeoR
cassette downstream of the splice site in exon 4, eliminating the
expression of the DNA and ligand-binding domains of TR
1
and TR
2 (TR
/
) (16). The
TR
knockout mouse was produced by insertion of the LacZ-NeoR
cassette downstream of exon 3 and replacing exons 5-7, thus
effectively abolishing not only the generation of full TR
1 and TR
2 transcripts but also that of
TR
1 or TR
2 (TR
0/0)
by removal of the transcription start point at intron 7 (17). The gene sequence for rev-erbA-
protein
encoded by the opposite strands for the TR
(45) remains
intact. In both sets of mice, the recombinant ES cells were derived
from 129sv mice and were implanted into C57BL/6 recipient blastocysts.
C57BL/6 mice were mated to each chimeric mouse and then back-crossed
three to four times into the same strain, thereby diluting the 129sv
background. The TR
0/0 and TR
/
mice
were crossed for greater than five generations to select wild-type mice
that had similar backgrounds.
Induction of hypothyroidism and treatment with TH.
TH deficiency was induced in 10 male mice of each type (wild type,
TR
0/0, and TR
/
) with a low-iodine
diet containing 0.15% 5-propyl-2-thiouracil (PTU) for 4 wk.
Blood samples were obtained from the retroorbital vein after recording
of echocardiograms as described in Echocardiograms. The same
mice were then placed for 4 wk on L-thyroxine
(L-T4) contained in the drinking water (2 µg/ml). Mice drank ~5 ml/day, resulting in a total dose of 10 µg
L-T4 · day
1 · mouse
1.
Hormone measurements.
Serum total T4 was measured by coated-tube RIAs (DPC;
Diagnostic Products, Los Angeles, CA) with 25 µl of serum. The
sensitivity of this assay is 0.2 µg T4/dl (2.6 nmol/l).
The interassay coefficients of variation were 5.4, 4.2, and 3.6% at
3.8, 9.4, and 13.7 µg/dl T4, respectively.
Serum TSH was measured in 50 µl of serum by use of a sensitive,
heterologous, disequilibrium, double-antibody precipitation RIA, as
previously described (41). The sensitivity of this assay was 5-10 mU/l. The intra-assay and interassay coefficients of variation were, respectively, 16 and 27% at 20 mU/l, 6.3 and 8.2% at
200 mU/l, 5.4 and 9.8% at 850 mU/l, and 10 and 24% at 2,000 mU/l.
Samples containing >1,000 and >10,000 mU thyroid-stimulating hormone
(TSH)/l were diluted 10- to 100-fold, respectively, with zero TSH mouse
serum obtained from wild-type mice treated with a suppressive dose of
T4 (41).
Ventricular weight.
At the end of the 4 wk of L-T4 treatment and
after completion of the final echocardiographic recording, mice were
killed and their hearts excised. The left ventricles were separated and
carefully isolated by trimming the atria and the valves, blotted of
excess fluid, and were weighed on a Mettler Balance (model no. AG245) with an accuracy of ± 0.01 mg.
Echocardiograms.
For animal preparation, 30 mice were studied, including 10 wild-type,
10 TR
/
, and 10 TR
0/0 mice, as described.
Before acquisition of cardiac ultrasound recordings, anesthesia was
induced by administering chloral hydrate (500 mg/5 ml; Pennex
Pharmaceutical) intraperitoneally in a 4% solution in PBS at a dose of
0.4 mg/g mouse. Animals were then secured to a custom-made waterbed in
a shallow left lateral decubitus position to facilitate imaging. The
bed was connected to a circulating water bath set at 40°C to prevent
hypothermia. The actual bed temperature was maintained at 38°C
throughout the experiment, and every effort was made to maintain
constant temperature, but the application of gel for echocardiography
was an unavoidable variable. Transthoracic echocardiography was
performed three times during the experiment. Baseline recordings were
obtained at 8 wk of age, after 4 wk with PTU treatment (as described,
at 12 wk of age), and after 4 wk of L-T4
treatment (as described, at 16 wk of age).
Data acquisition.
Cardiac ultrasound imaging was performed using a high-frequency 15-MHz
linear transducer (Sonos 5500; Agilent, Andover, MA) at a maximum frame
rate of 120 frames/s. Parasternal long- and short-axis views were
obtained after adjusting gain settings for optimal epicardial and
endocardial wall visualization. From the short-axis view, left
ventricular (LV) M-mode tracings were obtained. From an unconventional,
more superior parasternal long-axis view, ascending aortic
two-dimensionally targeted M-modes were recorded. Ascending aortic
pulse wave Doppler velocities were obtained from the suprasternal
window by means of a pediatric short focal length, 12-MHz phased array
transducer (Sonos 5500; Agilent Technologies). To improve image
quality, an acoustic coupling gel standoff was mounted to the probe.
This resulted in a 1- to 1.5-cm standoff between the transducer and the
chest wall, enabling the transducer to work at its ideal focal length.
To further improve quality by decreasing artifacts, the gel (Aquasonic
100; Parker, Orange, NJ) was centrifuged at 2,000 g to
remove air bubbles.
Echocardiographic loops of
20 cardiac cycles containing the
two-dimensional data, M-mode tracings, and Doppler velocity panels were
stored digitally on magneto-optical disk for off-line analysis.
Measurements.
From the short-axis view, epicardial and endocardial LV areas were
measured offline at end systole and end diastole. Images were
considered adequate for measurement when >75% of the epicardial and
endocardial contour could be adequately visualized. In accordance with
American Society of Echocardiography recommendations, the short-axis
endocardial border was traced on the innermost endocardial edge,
whereas the epicardial border was traced along the first bright pixel
immediately adjacent to the darker myocardium (Fig. 1B). The LV length, defined as
the distance between the apex and the midmitral annulus, was obtained
from the parasternal long-axis views in which the mitral annular plane
and the apex were well defined (Fig. 1A). LV measurements
were made from at least three cardiac cycles, at both end systole and
end diastole.

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Fig. 1.
Representative echocardiograms used for measurement of
left ventricular (LV) mass by use of the area-length method.
A: in the parasternal long-axis view, the ventricular length
(L) is measured from the endocardial apex to the mitral valve annulus
(MVA). B: in the short-axis view, the LV area is traced at
the level of the papillary muscles (arrow). The tip of the papillary
muscles was used as a landmark reference.
|
|
LV mass was calculated using the formula
where 1.05 is the specific gravity of muscle, A1 and
A2 are the epicardial and endocardial parasternal
short-axis area, respectively, L is the parasternal long-axis length,
and t is the wall thickness calculated from A1 and
A2 (Fig. 1).
Two-dimensionally targeted M-mode echocardiographic images were
obtained at the level of the papillary muscles from the parasternal short-axis view and recorded at a speed of 150 cm/s (Fig.
2). LV internal diameters and wall
thickness (leading edge to trailing edge) were obtained at end systole
and end diastole from cross-sectional short-axis views. Heart rate was
measured, and shortening fraction (SF), the echocardiographic
equivalent of ejection fraction, was calculated from these tracings by
using the formula
where LVedd and LVeds are the LV internal diameter at end
diastole and end systole, respectively.

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Fig. 2.
Representative echocardiogram used for calculation of
shortening fraction (%SF). This is an LV 2-dimensionally targeted
M-mode tracing at midcavity level, where LV end-diastolic (LVedd) and
end-systolic (LVesd) dimensions are measured and used for calculating
%SF.
|
|
For both two-dimensional and M-mode calculations, LV
end-diastolic measurements were obtained at the peak of the R wave,
whereas end-systolic measurements were obtained at the time of minimal chamber area.
Aortic stroke volume (SVao) was calculated from pulse wave
aortic Doppler recordings and measurements of the proximal ascending aortic diameter (Fig. 3). Because of the
pulsatile nature of the cardiovascular system, velocities are not
constant throughout the cardiac cycle, thereby requiring temporal
integration of the Doppler velocities known as the time velocity
integral (TVI). The cross-sectional area of the aorta
(CSAao) was calculated assuming a constant circular orifice
throughout the cardiac systole by use of the formula
where CO is cardiac output, CI is cardiac index, and HR is heart
rate.

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Fig. 3.
Two-dimensionally targeted M-mode tracing of proximal
ascending aorta (A) and aortic Doppler velocity profile
(B). AO, aorta; LA, left atrium.
|
|
Data analysis.
Values are reported as means ± SD. P values were
calculated by two-way ANOVA when mice of different genotypes and
treatment were compared and by the Student's t-test when
comparisons were made within the same genotype with the Statview 5.0 program (SAS Institute, Cary, NC).
 |
RESULTS |
Thyroid function tests and body weights.
The thyroid function tests before and after treatment with PTU and
L-T4 are shown in Table
1. Determination of the effect of TH on
heart physiology could not be done with baseline measurements alone,
because the mice had different serum concentrations of T4
and TSH. Therefore, mice of all genotypes were made deficient in TH by
PTU treatment for 4 wk. This treatment normalized the serum
T4 levels to <0.02 µg/dl in all groups, whereas the TSH concentration increased 340-, 48-, and 149-fold in the wild-type, TR
0/0, and TR
/
mice, respectively.
L-T4 treatment suppressed the TSH in all genotypes to <20 mU/l, whereas serum T4 levels were
similar in wild-type and TR
0/0 mice,
TR
/
mice had slightly higher concentrations.
At baseline, TR
/
mice had markedly elevated serum
T4 and TSH, consistent with their state of resistance to
TH. Four-week treatment with PTU resulted in a decrease of serum
T4 levels below the limit of detection with a concomitant
increase in TSH. In the TR
0/0 mice, the serum TSH did
not reach the level attained in the wild-type or TR
/
mice. Treatment with L-T4 suppressed the TSH in
all mice, and although the serum T4 concentration attained
in the TR
/
mice was not different from that in
wild-type mice, it was slightly higher in the TR
0/0 mice
(P < 0.05). There were no significant differences in
body weight at baseline for any of the three genotypes. Mice treated with PTU for 4 wk did not gain weight during this time. However, after
4 wk of L-T4 treatment, body weight increased
by 26, 13, and 32% in wild-type, TR
0/0, and
TR
/
mice, respectively, compared with baseline weights.
Effect of TH on heart rate.
Heart rate in these mice determined during the echocardiograph analysis
demonstrated resting tachycardia in untreated TR
/
mice (415 ± 10 beats/min) relative to the untreated wild-type mice (372 ± 10 beats/min) and TR
0/0 mice (407 ± 10), likely reflective of the higher baseline T4 levels
in these mice. The difference in basal heart rate between wild-type and
TR
0/0 mice was not significant. During TH deprivation,
heart rates significantly decreased in both wild-type (49 ± 6%)
and TR
/
(39 ± 6%) mice and changed only a
small amount in the TR
0/0 mice (5 ± 6%). Although
TH treatment resulted in an increase in the wild-type mice (43 ± 6%), there was only minimal change in the TR
/
(5 ± 2%), yet a moderate increase in the TR
0/0
(21 ± 6%) compared with wild-type mice (Fig.
4).

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Fig. 4.
Heart rate (HR) in wild-type mice, mice homozygous for
disruption of thyroid hormone receptor- (TR / ) and
mice homozygous for disruption of TR (TR0/0) at baseline
(filled bar), with TH deprivation [5-propyl-2-thiouracil (PTU); gray
bar], and with L-thyroxine (L-T4)
treatment (open bar). A: HR; B: %difference in
HR. Statistical significance, P <0.05: * difference
between baseline values, same genotype; difference from wild-type,
same treatment; difference from PTU treatment, same genotype. BPM,
beats/min.
|
|
Echocardiographic analyses.
The SF, equivalent to the ejection fraction, was significantly reduced
in the hypothyroid wild-type mice (25.6 ± 2.3%) compared with
pretreatment baseline (38.4 ± 2.3). Although there was a trend
toward having decreased SF in TR
/
and
TR
0/0 mice, it was not significantly different from that
of wild-type mice (Fig. 5,
A-C). There were no significant changes in SF with L-T4 treatment in the different groups compared
with baseline or compared with the hypothyroid state. Preload CO (Fig.
5, D-F) and CI (Fig. 5, G-I) decreased by 31 ± 8% and 33 ± 10%, respectively, in hypothyroid mice and
increased by 69 ± 10% and 35 ± 8%, respectively, in
hyperthyroid wild-type mice. Neither the TR
/
nor the
TR
0/0 mice had a response in CO or CI to TH deprivation,
and although the TR
0/0 mice had a slight increase in CI
and CO in response to TH treatment, it was not as robust as that seen
in the wild-type mice (Fig. 5).

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Fig. 5.
SF (A-C), cardiac output (CO; D-F),
and cardiac index (CI; G-I) in wild-type,
TR / , and TR 0/0 mice at baseline
(filled bar), with TH deprivation (PTU; gray bar), and with
L-T4 treatment (open bar). Top
(A, D, G): absolute values; middle (B, E,
H): %difference from untreated; bottom (C, F,
I): %difference between hypothyroid and hyperthyroid. Statistical
significance, P < 0.05: * difference between
baseline values, same genotype; difference from wild type, same
treatment; difference from PTU treatment, same genotype.
|
|
Effect of TH on LV mass.
LV mass was determined by area- to length-based estimates via
transthoracic echocardiographic measurements in diastole (ALd) and
systole (ALs). Although there was no significant difference in LV mass
between baseline and hypothyroid mice in any genotype, L-T4
treatment resulted in an increase in the ALd of wild-type (0.079 ± 0.001 to 0.126 ± 0.016 g, P < 0.05) and
TR
0/0 mice (0.079 ± 0.012 to 0.114 ± 0.021 g, P < 0.05) but less so in the TR
/
mice (0.085 ± 0.011 to 0.089 ± 0.009 g, P > 0.05) (Fig. 6). Similar changes were
seen in ALs and in ALs index and ALd index when corrected for body
weight. At autopsy, upon completion of the L-T4 treatment arm of the experiment the LV weight (mg) per gram of mouse correlated with the echocardiographic measurements (3.9 vs. 4.2 mg/g,
respectively, for the wild-type mice; 3.4 vs. 3.5 mg/g, respectively,
for the TR
/
mice; and 4.0 vs. 4.0 mg/g,
respectively, for the TR
0/0 mice.)

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Fig. 6.
LV mass measured by echocardiography. A:
absolute mass (g) during diastole (ALd). * P < 0.05 compared with baseline in same genotype. B: %difference
from baseline. * P < 0.05 compared with difference
from wild type; , %difference between TR / and
TR 0/0.
|
|
 |
DISCUSSION |
The effect of TH on the heart is both intrinsic and extrinsic.
Studies demonstrating effects of TH on isolated cardiac muscle (19, 34) or perfused intact hearts (37) give
insight into the intrinsic effects of TH on cardiac function, but
noninvasive assessment of cardiovascular function has not been well
reported in vivo. Technological advances, such as smaller probes and
the creation of high-frequency linear transducers, have allowed
accurate echocardiographic analysis of small mice and enabled one to
obtain in vivo measurements of cardiac function (8, 11,
13-15, 36). Echocardiographic measurements can accurately
determine dynamic changes in LV mass (8). Furthermore,
studies using mice with deletion of either of the TRs allows one to
delineate their contribution to TH action. This study demonstrates the
role that TR
and TR
play in TH action in the heart. Whereas
TR
1 and TR
2 are the major TR isoforms
expressed in the heart, it is not surprising that wild-type and
TR
/
mice had a decreased heart rate in response to
TH deprivation, whereas the TR
0/0 mice were unresponsive
(32, 48). Whereas all three genotypes demonstrated an
increase in heart rate in response to TH treatment, there was a blunted
response in both the TR
0/0 and TR
/
mice, indicating that TR
also plays a role in the increase in heart
rate associated with TH treatment. This study does not indicate whether
the TR
responsiveness is a direct effect on the heart or an indirect
effect on sympathomimetic factors, which, in turn, increase heart rate.
Contrary to the heart rate data presented in this paper, two previous
reports, including one from our laboratory (19, 32), have
demonstrated baseline bradycardia in the TR
0/0 mice.
Variables that may account for this discrepancy include 1)
the method of anesthesia, 2) the number of mice analyzed,
and 3) the body temperature of the animal at the time of
analyses. Although Gloss et al. (19) used a
ketamine-xylazine cocktail, Macchia et al. (32) used
chloral hydrate as we did in the present report. Although Gloss et al.
analyzed six animals and reported a difference in heart rate, Macchia
et al. required 43 wild-type mice to show significant differences, due
to the variability in heart rate. Furthermore, our measurement of heart
rate was done during simultaneous echocardiograph analysis, and
although every effort was attempted to maintain euthermia in the mice,
there may have been differences in body temperature to account for the differences in heart rate at baseline.
TR
1 knockout mice had an average heart rate 20% lower
than that of wild-type mice, with prolonged QRS and QT durations at baseline and with TH treatment, suggesting that TR
can also affect heart rate (49). Transgenic mice with myocardium-specific
expression of a mutant TR
(
377T) demonstrated heart failure in
vitro but not in vivo, suggesting that diminished performance in these
mice may be compensated for by other mechanisms in vivo
(38).
Change in %SF was limited to the wild-type mice. Although there was a
trend toward the TR
/
mice having decreased %SF with
TH deprivation and an increase with TH treatment, this did not reach
significance. Furthermore, CO and CI were increased in response to
TH treatment and were decreased in response to TH withdrawal in the
wild-type mice, and these changes were blunted in the both the
TR
/
and TR
0/0 mice. Therefore,
whereas TR
seems to be more important than TR
for the
chronotropic effects of TH on cardiac function, both TR
and TR
are necessary for the ionotropic effects. In humans, hyperthyroidism
results in an increase in echocardiograhic indexes of myocardial
contractility (12, 39). Whereas normal CO in humans is
4.0-6.0 l/min, it is >7.0 and <4.0 l/min in hyperthyroid and
hypothyroid humans, respectively.
Hyperthyroidism has been reported to result in increased cardiac mass
in both humans (7) and mice (4, 26). The
mechanism of increased cardiac mass may be related to the local
activation of the renin-angiotensin system in the heart in response to
TH that can be reversed with angiotensin-converting enzyme inhibitors (1, 3, 29). In addition, the TH-induced increase in heart size may be due, in part, to coordinated capillary and
myocardial growth that is TH dependent (6, 9, 47). The
absence of TR
prevented the TH-mediated increase in cardiac mass,
whereas the absence of TR
did not. TR
may be the important TR for
the generation of tissue angiotensin-converting enzyme. In our mice, the absolute T4 concentrations were higher in the
TR
/
mice compared with the TR
0/0 mice
only. This difference may partially account for the increase in LV mass
seen in TR
/
mice but cannot explain the difference
compared with wild-type mice.
TR
is the predominant isoform in the heart. We have shown that TR
is required for the changes in heart rate seen with TH deprivation or
treatment. However, the TH-induced increase in cardiac mass is TR
dependent. Taken together, these data suggest that TR
and TR
play
different roles in the physiology of TH action on the heart.
Furthermore, TR
may play a more important role in indirect effect of
TH on the heart.
 |
ACKNOWLEDGEMENTS |
This study was supported in part by Grant DK-58258 (to R. E. Weiss) from the National Institute of Diabetes and Digestive and Kidney
Diseases and by the Seymour J. Abrams Thyroid Research Fund and the
Ministry of Research ACI 283 (to J. Samarut).
 |
FOOTNOTES |
Address for reprint requests and other correspondence:
R. E. Weiss, Dept. of Medicine, MC 3090, Univ. of Chicago,
5841 S. Maryland Ave., Chicago, IL 60637 (E-mail:
rweiss{at}medicine.bsd.uchicago.edu).
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpendo.00019.2002
Received 18 January 2002; accepted in final form 16 April 2002.
 |
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