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or -
: an echocardiograph study
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
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 (TR0/0) 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 TR0/0 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
TR0/0 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 TR0/0 (+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 TR0/0 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
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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). TR2 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 TR1 and
TR2, (TR1 and TR2)
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).
TR1 and TR2 are the major isoforms of TR
expressed in the heart (24). Although TR1
is expressed at low levels (10), TR2 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.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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 at20°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 TR1
and TR2 (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 TR1 and TR2 transcripts but also that of
TR1 or TR2 (TR0/0)
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 TR0/0 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,
TR0/0, 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 · day1 · mouse1.
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 TR0/0 mice, as described.
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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![=[1.05 (5/6 A<SUB>1</SUB>(L + t) − 5/6 A<SUB>2</SUB>L]](/content/vol283/issue3/fulltext/E428/img002.gif)
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![%SF = [(LVedd − LVeds)/LVedd)] × 100](/content/vol283/issue3/fulltext/E428/img003.gif)
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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).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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, TR0/0, 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 TR0/0 mice,
TR/ mice had slightly higher concentrations.
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/ 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 TR0/0 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 TR0/0 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, TR0/0, 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 TR0/0 mice (407 ± 10), likely reflective of the higher baseline T4 levels
in these mice. The difference in basal heart rate between wild-type and
TR0/0 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 TR0/0 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 TR0/0
(21 ± 6%) compared with wild-type mice (Fig.
4).
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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
TR0/0 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
TR0/0 mice had a response in CO or CI to TH deprivation,
and although the TR0/0 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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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
TR0/0 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 TR0/0 mice.)
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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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
TR1 and TR2 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 TR0/0 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 TR0/0 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 TR0/0 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.
TR1 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 TR0/0 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 TR0/0 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.
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ACKNOWLEDGEMENTS |
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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).
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FOOTNOTES |
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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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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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difference from PTU treatment, same genotype. BPM,
beats/min.
