(Circulation. 1997;96:592-598.)
© 1997 American Heart Association, Inc.
Articles |
Effects of Thyroid Hormone on Cardiac ß-Adrenergic Responsiveness in Conscious Baboons
From the Division of Cardiology, University of Cincinnati (Ohio) Medical Center.
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Abstract |
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Background Many of the cardiovascular manifestations of thyroid hormone excess resemble those produced by sympathoadrenal stimulation. The objective of this study was to determine the effects of thyroid hormone excess on myocardial ß-adrenergic expression and responsiveness to infused agonists in the primate heart.
Methods and Results The responses of left
ventricular isovolumic contraction (dP/dtmax)
and relaxation (
) during graded dobutamine infusion were
studied both before and after 4 weeks of thyroid hormone administration
in 8 chronically instrumented baboons. At matched (atrially paced)
heart rates, thyroid hormone significantly increased resting
dP/dtmax (3073±1034 versus 2318±829 mm Hg/s,
P<.05) and decreased (24.0±5.5 versus 28.2±5.4 ms,
P<.05). The change from baseline for dP/dtmax
and in response to ß1-adrenergic stimulation was
significant at each dobutamine dose (2.5 to 10
µg·kg-1·min-1),
but when expressed as a percent change, it was similar before versus
after thyroid hormone. Similar changes were found when
ß2-adrenergic stimulation was produced by terbutaline
infusion in three additional baboons. ß-Adrenergic receptor (ßAR)
expression was higher in five thyroxine-treated than in five control
baboons (37.4±1.2 versus 15.7±3.2 fmol/mg, P<.001), and
this was due to a greater increase in the ß2AR (5.9±1.5
to 20.6±1.2 fmol/mg, P<.001) than the ß1AR
(9.7±1.7 to 16.8±0.1 fmol/mg, P<.01) subtype.
Conclusions In the primate heart, thyroid hormone produces positive inotropic and lusitropic effects in the resting state and upregulates both ß1AR and ß2AR, with the ß2AR increase predominating. At equivalent rates, however, thyroid hormone excess does not appear to enhance the sensitivity of left ventricular contractility and relaxation to either ß1- or ß2-adrenergic stimulation.
Key Words: thyroid • receptors, adrenergic, beta • contractility
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Many of the cardiovascular manifestations of thyroid hormone excess bear a striking resemblance to those produced by sympathoadrenal stimulation.1 Since plasma catecholamine levels and turnover rates are not increased in hyperthyroidism,2 3 4 it has been argued that the effects of thyroid hormone result partly from increased responsiveness to catecholamines. This hypothesis is supported by studies that indicate that ßAR number and sensitivity are increased in isolated hearts and cultured cells from experimental animals (most often the rat) treated with thyroid hormone.5 6 7 8 However, in vivo data are conflicting9 10 11 12 13 14 15 16 17 ; disparate results may be due to different preparations and study designs, the dose and duration of thyroid hormone administration, and the analytical methods used. In addition, responses to adrenergic stimulation may be age-, tissue-, and receptor subtype–specific.18 Importantly, there is convincing evidence that the effects of thyroid hormone are species-dependent.16 In contrast to small animals, there is a paucity of data supporting the hypothesis that cardiovascular sensitivity to adrenergic stimulation is increased in large animals (including humans) subjected to thyroid hormone excess. Moreover, few studies have coupled thyroid hormone–induced changes in the ßARs with an appropriate physiological response. Although increased numbers of right atrial ßARs and enhanced chronotropic sensitivity to isoproterenol in hyperthyroid pigs were demonstrated by Hammond et al,15 measures of ventricular function were not examined.
Accordingly, the objective of our study was to critically examine the
effects of thyroid hormone on LV systolic and
diastolic function and ßAR number and sensitivity in
nonhuman primates (baboons) using high-resolution techniques. We
previously showed that thyroid hormone increases velocity- but not
force-dependent indices of ventricular function in this
model.19 Because the influence of thyroid hormone–induced
increases in heart rate on velocity-dependent indices of
ventricular function confound previous data, which suggest
an increased inotropic sensitivity to catecholamines in
humans,12 we measured LV dP/dtmax and at
constant (atrially paced) heart rates both before and after thyroid
hormone administration.
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Methods |
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Animal Instrumentation
The animals used in this study were maintained in accordance with the Guide for the Care and Use of Laboratory Animals. The experimental protocol was approved by the Institutional Animal Care and Use Committee at the University of Cincinnati.
A total of 12 adult male baboons (Papio anubis) weighing 21 to 30 kg were preinstrumented for physiological monitoring in the lightly anesthetized, sedated state by methods previously described.20 Some hemodynamic data from a subgroup of these animals were included as part of another study.19 Briefly, animals were preinstrumented with a Konigsburg micromanometer and a polyvinyl catheter in the LV apex, miniaturized sonomicrometer pairs (3 MHz, 6 mm) across the LV anteroposterior minor axis, a polyvinyl catheter in the right atrium for central venous access, and pacing wires on the right atrial appendage. Wires and tubes were tunneled subcutaneously into the interscapular area for later use. Postoperative pain was reduced by the use of Buprenex (0.01 mg/kg IM, q 6 hours), and postoperative antibiotic (Monocid 25 mg/kg) was administered for 5 days to reduce the risk of infection. Baseline hemodynamic studies were performed after a minimum of 1 week for postoperative recovery.
Animal Modeling
T4 tablets were crushed, concealed in fruit, and
given under direct supervision. The initial dose of T4 was
0.25
mg·kg-1·d-1
for 10 days, then 0.25 mg/kg every other day for a total of 26.8±2.7
days (range, 22 to 30 days).
Hemodynamic Data Acquisition and Analysis
The micromanometers and fluid-filled
catheters were calibrated with a mercury manometer. Zero drift of the
micromanometer was corrected by matching the LV
end-diastolic pressure measured simultaneously
through the LV catheter. The fluid-filled LV catheter was connected to
a precalibrated Statham 23 dB transducer with zero pressure at the
level of the mid right atrium. The transit time of ultrasound between
the ultrasonic dimension crystals was measured with a multichannel
sonomicrometer (Triton Technology, Inc) and converted to
distance assuming a constant velocity of sound in blood of 1.55
mm/ms.
The analog LV dP/dt signal was obtained on-line by electronic
differentiation of the high-fidelity LV pressure signal. was
derived from the high-fidelity LV pressure tracing by the method of
Weiss et al,21 which assumes a
monoexponential decay of LV pressure to a zero
asymptote and has been shown to be directionally equivalent to
other mathematical approaches for quantification of isovolumic pressure
decay.22 is equal to the time in milliseconds for LV
pressure to decay to 1/e; thus, decreases in reflect
improved isovolumic ventricular relaxation.
Fractional shortening of the LV minor axis was calculated as
(EDD-ESD)/EDD, where EDD is LV end-diastolic dimension and
ESD is LV end-systolic dimension. LV end diastole
was defined as the time in which LV dP/dtmax increased by
150 mm Hg/s for 50 ms, and LV end systole was defined as the
time of the maximum ratio of LV pressure to LV minor-axis
dimension.20 23 LV volumes were derived from minor-axis
diameter (D) measurements: LV volume=
/6(D)3.
Vcf was calculated as LV fractional shortening divided by LV ejection time; LV ejection time was defined as the time from peak positive to peak negative dP/dt.
Analog signals for high-fidelity and fluid-filled LV pressures, LV short-axis dimension, LV dP/dt, and the ECG were recorded on-line on a Gould multichannel recorder at 25 and 100 mm/s paper speed and digitized through an analog-to-digital board (Dual Control Systems) interfaced to an IBM AT computer at 500 Hz and stored on a floppy disk. Data were analyzed by use of an algorithm and software developed in our laboratory.23 Steady-state data were acquired over 5 to 10 seconds during spontaneous respiration and averaged.
Experimental Protocols
Hemodynamic studies were performed a minimum of
1 week after instrumentation and were repeated after 22 to 30
(26.8±2.7) days of T4 administration. Animals were
tranquilized with valium (1 to 5 mg) and ketamine (100 mg), and
cholinergic blockade was achieved with atropine (0.4 to 0.8 mg IV);
additional ketamine was administered as necessary, to a maximum
cumulative dose of 40 mg/kg. Animals were atrially paced at a rate 40%
to 50% greater than the control heart rate in order to obtain data at
matched heart rates after thyrotoxicosis was produced.
Dobutamine Group (n=8)
After hemodynamic stability was ensured and
baseline data were recorded, intravenous
dobutamine was infused at 5-minute intervals at upwardly
titrated rates of 2.5, 5.0, 7.5, and 10.0
µg·kg-1·min-1
to examine the effects of ß1-adrenergic stimulation. The
dose range of catecholamine for these studies was chosen to
alter inotropic and lusitropic states without causing an untoward
increase in heart rate. Steady-state hemodynamic
measurements were made during minutes 4 and 5 of each infusion period.
At each level, the pacemaker was briefly turned off to determine the
effect of dobutamine on the heart rate.
Four of the animals in this group were studied with incremental pacing
both before and after ß-adrenergic blockade with esmolol (0.3
mg·kg-1·min-1
IV). The pacing protocol and the results from a larger group of animals
studied before ß-adrenergic blockade were detailed in a previous
report.19 Briefly, atrial pacing was instituted at a rate
above the intrinsic heart rate to avoid competing rhythms and was
increased at 0.2-Hz increments until the critical heart rate was
achieved. The critical heart rate was defined as the rate at which
dP/dtmax and reached a maximum and minimum,
respectively, during progressive increases in heart rate. We showed
previously that hyperthyroidism significantly increases the critical
heart rates for both dP/dtmax and .19
The EC50 of dobutamine for LV dP/dtmax was determined by fitting log(dose)-transformed data to a sigmoidal relation with software from Graph Pad.
Terbutaline Group (n=4)
An additional four animals were chronically instrumented so that
we could examine the effects of ß2-adrenergic
stimulation. One animal died suddenly after receiving thyroid hormone
for 20 days. In the remaining three animals, the
ß2-adrenergic agonist terbutaline was infused both before
and after production of the hyperthyroid state. Incremental
doses of terbutaline (15 min/dose) were infused over a dosing range of
25 to 300
ng·kg-1·min-1.24
ßAR Binding Assays
ßAR radioligand binding was performed with ICYP by
methods previously described.25 Briefly, for determining
Bmax, membranes (
30 µg) were incubated with a
saturating concentration of ICYP (400 pmol/L) in the absence (total
binding) or presence (nonspecific binding) of 100 µmol/L
isoproterenol for 2 hours at 25°C. GTP (100 µmol/L) was
included in the incubations to eliminate any retained agonist binding.
Reactions were terminated by rapid vacuum filtration over glass fiber
filters (GF/C), which were subsequently washed three times with
ice-cold 10 mmol/L Tris buffer. Filters were counted in a gamma
counter at 70% efficiency. To assess the proportion of
ß1ARs versus ß2ARs present in baboon
ventricular myocardium, competition assays were
performed in duplicate with 15 concentrations
(10-3 to 10-10 mol/L)
of the relatively ß2AR-selective antagonist
ICI118551 in the presence of 60 pmol/L ICYP under reaction conditions
as described above.
Data from radioligand binding assays were analyzed by nonlinear iterative least-squares techniques. For ICI118551 competition curves, data were fitted to a two-site model, as given by the following equation26 : BmaxT={Bmaxß1/[L+kdß1·(1+I/kiß1)]}+{Bmaxß2/[L+kdß2·(1+I/kiß2)]}, where BmaxT is the total amount of radioligand bound, Bmaxß1 and Bmaxß2 are the densities of the ß1ARs and ß2ARs, L is the concentration of ICYP used, I is the concentration of competing ligand (such as (ICI118551), kdß1 and kdß2 are the dissociation constants for ICYP binding to ß1ARs and ß2ARs, and kiß1 and kiß2 are the dissociation constants for the inhibition of ICYP binding to ß1ARs and ß2ARs by the competing ligand. The twofold greater selectivity of ICYP for the ß2ARs compared with the ß1ARs was taken into account.25 The goodness of fit was assessed by the relative distance method, and R2 was >.950 for all curves. Receptor densities were normalized to protein, which was measured by the copper-bicinchoninic acid method.27
Thyroid Function Tests
Thyroid function tests were performed before the baseline
experiment in the euthyroid state and before the terminal experiment
(within 24 hours of the last dose of T4) in the
hyperthyroid state. The tests were performed at Cincinnati Veterinary
Laboratory, Inc, Cincinnati, Ohio. T3 radioimmunoassay,
T4, and free T4 levels were measured at each
state.
Statistics
Paired mean data were compared by Student's t test.
The effects of thyroid status, catecholamine dose, and
ß-blockade on hemodynamic and dimension variables
were examined with repeated-measures ANOVA (SuperAnova, Abacus
Concepts). When significant differences were found, group means were
compared with contrasts. A value of P<.05 was considered
significant. Unless specified, data are expressed as mean±SD.
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Results |
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Thyroid hormone supplementation produced a state characterized by clinical and laboratory evidence of thyrotoxicosis. In the hyperthyroid state, the thyroid function tests were >500 ng/dL for T3 radioimmunoassay, 20 µg/dL for T4, and 4.2 ng/dL for free T4.19 The normal values for baboons in our laboratory (n=11) are 105±49 ng/dL, 5.2±1.4 µg/dL, and 1.4±0.5 ng/dL for T3 radioimmunoassay, for T4, and for free T4, respectively. Body weight was significantly reduced after supplementation with T4 (26.4±2.9 versus 23.5±2.3 kg, P<.05).
Baseline Hemodynamics
The hemodynamic effects of chronic thyroid
administration in the conscious baboon were reported in a previous
publication19 and are summarized as follows. Thyroid
hormone significantly increased the baseline heart rate, LV
systolic and developed (systolic minus
end-diastolic) pressures, and the peak rate of LV pressure
development (dP/dtmax). Concomitantly, thyroid hormone
excess decreased and shortening fraction, whereas Vcf
and LV end-diastolic pressure and dimension were unchanged.
By contrast, at matched heart rates, thyroid hormone increased
Vcf and LV end-diastolic pressure and
dimension, whereas the augmentations of isovolumic contraction
(dP/dtmax) and especially LV relaxation and the decrease in
shortening fraction were less prominent.
Effects of ß1-Adrenergic
Stimulation
The effects of dobutamine infusion on heart rate, LV
dP/dtmax, and before and after thyroid hormone are
summarized in Figs 1 through 3
. At matched (atrially
paced) heart rates, dobutamine dose had a significant
positive effect on LV dP/dtmax by ANOVA; however, the
overall effect of thyroid hormone was not significant, because the
dobutamine dose-response relations before and after thyroid
hormone tended to converge. When expressed as a percent change from
baseline, LV dP/dtmax tended to increase more in
response to graded infusions of dobutamine before thyroid
hormone administration than after (137±39% versus 80±37%). By
contrast, the effects of both thyroid excess and dobutamine
dose on (at atrially paced rates) and intrinsic (ie, unpaced) heart
rates were significant by ANOVA; however, there were no significant
interactions between the two effects for either variable. Moreover,
when expressed as a percent change from baseline, the effects of
dobutamine on heart rate (36±17% versus 21±5%) and
(-32±11% versus -29±18%) were similar. Thus, by these
analyses, thyroid hormone excess did not enhance either the
lusitropic or chronotropic effects of dobutamine and
actually tended to attenuate its inotropic effect. The EC50
of dobutamine for LV dP/dtmax was similar
before and after thyroid hormone (4.2±1.0 versus 4.4±1.0
µg·min-1·mL-1).
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Effects of ß-Adrenergic Blockade
The effects of intravenous esmolol on
hemodynamic variables before and after thyroid
hormone administration are summarized in Table 1.
ß-Adrenergic blockade significantly decreased the intrinsic (unpaced)
heart rate, LV dP/dtmax, and the critical heart rates for
dP/dtmax and and significantly increased in both
the euthyroid and hyperthyroid states; the percent reduction of
hemodynamic parameters with ß-adrenergic
blockade was similar for heart rate (7.5±5.6% versus 9.0±3.7%), LV
dP/dtmax (17.7±10.2% versus 21.7±11.5%), and
(25.1±14.4% versus 37.3±10.4%). In contrast, the changes in both
critical heart rates owing to ß-adrenergic blockade were
significantly greater in hyperthyroid than euthyroid baboons
(29.4±7.8% versus 12.3±7.4% and 28.3±9.2% versus 7.6±15.6% for
the critical heart rates for LV dP/dtmax and ,
respectively).
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Effects of ß2-Adrenergic Stimulation
In view of the greater increase in ß2- than in
ß1-adrenergic receptors observed in
ventricular biopsy samples (see below), the effects of the
ß2AR agonist terbutaline were studied in three additional
animals with the same protocol as used in the larger study. At matched
(atrially paced) heart rates, both terbutaline dose and excess thyroid
hormone had significant positive effects on LV dP/dtmax
without any interactions by ANOVA (data not shown). The percent
increase in LV dP/dtmax tended to be greater before thyroid
administration than after (44±18% versus 15±17%). Terbutaline
caused nonsignificant decreases in both before and after thyroid
hormone was given. The percent increase in heart rate was similar
before and after thyroid hormone administration (25±8% versus
21±10%). Thus, thyroid hormone excess had no effect on the inotropic,
lusitropic, and chronotropic responses to terbutaline.
Characterization of Myocardial ßARs
The effects of thyroid hormone excess on myocardial ßARs are
summarized in Table 2. The total ßAR density was
significantly increased in LV samples from thyrotoxic compared with
control baboons. Although both ß1ARs and
ß2ARs increased significantly with thyroid hormone, the
percent of ß2ARs was significantly greater in
hyperthyroid than control animals (54.9±1.4% versus 36.8±3.1%,
P=.002).
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Discussion |
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The principal finding of our study is that thyroid hormone excess does not impart enhanced sensitivity to the inotropic and lusitropic responses of infused catecholamines. This result was demonstrated by four separate analyses. First, there was a lack of statistical interaction between the effects of catecholamine dose and thyroid hormone on either LV dP/dtmax or
; ie, the catecholamine
dose-response curves before and after 3 weeks of thyroid hormone
administration were parallel. Second, the percent change in
dP/dtmax and from baseline to peak
dobutamine dose were similar before and after thyroid
hormone was given. Third, the EC50 for LV
dP/dtmax, derived from log(dose)-transformed data, was not
changed by thyroid hormone. Finally, there was no statistical
interaction between the effects of thyroid hormone and ß-blockade on
dP/dtmax and . Although dP/dtmax is
dependent on preload, dobutamine infusion did not
differentially affect the end-diastolic volume in the
hyperthyroid baboons. Moreover, since dP/dt and are heart
rate–sensitive indices, measurements were made at the same atrially
paced rates before and after production of hyperthyroidism. The
concordance of these separate analyses, the precision of the
indices of LV contraction and relaxation, and the lack of confounding
heart rate effects strongly support the conclusion that thyroid hormone
excess does not enhance the inotropic and lusitropic responses to
catecholamines. We also examined changes in the intrinsic
heart rate in response to catecholamines and ß-adrenergic
blockade. The data support the additional conclusion that thyroid
hormone does not increase sensitivity to the chronotropic effects of
catecholamines, and taken together, these findings support
the concept, first proposed by Levey,28 that the
cardiovascular manifestations of hyperthyroidism are
not due to enhanced sensitivity to catecholamines. Although
we did not measure the release or serum concentrations of
catecholamines, others have shown normal or decreased
levels of catecholamines in hyperthyroid
subjects.2 3 4 Our findings are consistent with those of a study that found a significant increase in ßAR density in fat and muscle without an associated increase in either metabolic or hemodynamic (ie, heart rate or blood pressure) sensitivity to catecholamines in 10 healthy volunteers who received T3 for 10 days.13 Our results are also similar to those from a recent study in conscious dogs in which the slopes of the LV peak dP/dt versus log dobutamine and isoproterenol doses were similar before and after induction of the hyperthyroid state.16 In that study, however, ßAR density and basal and isoproterenol-stimulated adenylate cyclase activities were similar in euthyroid and hyperthyroid dogs.16 Although most investigators report increases in ßAR number, it should be recognized that an increase in ßARs is neither necessary nor sufficient to produce an enhanced physiological response18 and that cAMP levels and adenylate cyclase activities may not necessarily be predictive of in vivo catecholamine responsiveness.29 30 Moreover, the majority of studies that have examined cardiac ßAR numbers have been performed in the rat18 ; a study that demonstrated increased atrial ßAR number and heart rate sensitivity to isoproterenol in the hyperthyroid versus euthyroid pig15 and the aforementioned canine study16 are notable exceptions. It is likely that species and tissue differences and/or postreceptor modifications, such as changes in signal transduction mechanisms and receptor uncoupling, explain, at least in part, the different results reported in these studies.
Recent studies with transgenic mice overexpressing ßARs are
consistent with the concept that increased expression of ßARs
alone is not the sole basis for enhanced basal heart rate and
contractile parameters observed in the thyrotoxic state. We
recently expressed the ß2ARs in a cardiac-specific manner
to 45-fold above endogenous ßAR levels in the FVB/N
mouse29 ; resting heart rates in these animals were
increased only 20% despite this substantial increase in
ß2AR expression. Moreover, in another study, transgenic
mice with a 5- to 10-fold overexpression of the ß1ARs
over background did not exhibit increased heart rates compared with
wild-type controls.31 In the present study, the
increase in resting heart rate of the thyrotoxic animals (60%) was
associated with a relatively small (2- to 3-fold) increase in ßAR
expression. The observation that ß-blockade in thyroid-treated
animals failed to normalize either heart rate or dP/dtmax
to their pretreatment levels implicates other mechanisms. The lack of a
leftward shift in the dose-response curve (ie, increase in sensitivity
to agonist) in the thyrotoxic baboons is also consistent with
results from our transgenic animals30 ; with the extensive
overexpression of ß2ARs, we found an 3-fold decrease
in the EC50 in both in vitro and in vivo
parameters. Thus, it is unlikely that we could detect a
shift, given the much smaller increases in ßAR expression we observed
in thyrotoxic baboons.
There are several potential explanations other than changes in postreceptor signal transduction for the lack of increased adrenergic responsiveness in hyperthyroid baboons despite increased LV ßAR density. First, the primary increase in receptor subtype was the ß2ARs, whose physiological response would not have been observed during dobutamine infusion. Therefore, graded catecholamine infusions were repeated in a separate group of animals with the ß2AR agonist terbutaline. In those animals, however, the slopes of the terbutaline dose-response curves were similar in the euthyroid and hyperthyroid states. Moreover, ß2ARs were preferentially but not exclusively upregulated in the hyperthyroid baboon (ie, there was a significant, 73% increase in the ß1AR subtype). Second, as alluded to earlier, it is possible that the magnitude of the increase in ßAR number was insufficient to produce a detectable physiological response. However, the purpose of our study was to investigate the effects of thyrotoxicosis on ßAR function, and the state we induced by T4 reproduced that found in humans. Finally, it has been suggested that a constant infusion of agonist may acutely blunt the dose-response relation because of receptor desensitization.15 However, this is not likely to have significantly influenced our results, because the same graded catecholamine infusions were given both before and after production of hyperthyroidism.
The influence of thyroid hormone on adrenergic responsiveness is particularly controversial in large animals and humans.9 10 11 12 13 14 17 Human studies have been criticized justifiably for their use of (1) ß-adrenergic blockade, which precludes analysis of the adrenergic dose-response relation; (2) nonselective adrenergic agonists (epinephrine, norepinephrine); (3) inadequate measurements of LV function; and (4) patients with spontaneous (versus experimental) hyperthyroidism.12 In response to these criticisms, Martin and coworkers12 administered T3 to eight healthy volunteers for 2 weeks and found increased ßAR density (skeletal muscle) and increased responsiveness of the heart rate and LV ejection time (and as a direct result, Vcf) to graded isoproterenol infusions. In that study, heart rates were not controlled, and isoproterenol, which produces profound heart rate and hemodynamic effects, was used; when Vcf was corrected for heart rate, the enhanced responsiveness was much less prominent. The present investigation was designed to eliminate many of the confounding variables and limitations of previous human and animal studies. We examined healthy primates serially with invasive, high-resolution measurements of LV pressure and dimension, used specific ß-adrenergic agonists, and controlled for the severity and duration of the hyperthyroid state. Animals were sedated with diazepam and the dissociative anesthetic ketamine, thereby obviating difficulties owing to alterations in sympathetic tone that complicate the use of open-chest, anesthetized animals. Finally, we also assessed the response to ßAR blockade. A constant infusion of a clinically relevant, weight-adjusted dose of a rapidly acting ß-blocker was administered until a steady hemodynamic state was produced; the modest fall in heart rate and the changes in contraction and relaxation indices were consistent with earlier reports of esmolol.32 33
Myocardial contraction and relaxation are mediated, respectively,
through the release and resequestration of calcium by the SR
Ca2+-ATPase. Dephosphorylated phospholamban
decreases the affinity of the SR Ca2+-ATPase for calcium,
and phosphorylation of phospholamban by
catecholamine-mediated stimulation of cAMP-dependent
protein kinase A relieves this inhibition and facilitates reuptake of
calcium by the SR.34 35 Identification of
thyroid-responsive elements in the promoter region of the 
-myosin
heavy chain and SR Ca2+-ATPase genes indicates that thyroid
hormone transcriptionally regulates the expression of critical genes
involved in contraction and relaxation of the
cardiomyocyte.36 37 Experimental thyroid
hormone administration results in increased rates of tension
development and decline, which are associated with coordinate increases
in expression of ryanodine receptor and SR Ca2+-ATPase
mRNA.38 39 40 We recently showed that thyroid hormone
increases SR Ca2+-ATPase, decreases phospholamban, and
produces the de novo expression of -myosin heavy chain proteins in
the baboon19 ; similar results have been shown in the
rat.40 Taken together, these data suggest that the
cardiovascular manifestations of excess thyroid hormone
are largely due to direct myocardial effects.
The interaction between the sympathetic nervous system and the changes
in the SR calcium-cycling proteins is highlighted by the marked
inhibitory effects of ß-adrenergic blockade on the
critical heart rates for dP/dtmax and in hyperthyroid
baboons. The relation between dobutamine dose and
dP/dtmax in our study suggests that adrenergic
responsiveness may, in fact, be attenuated by thyroid hormone excess.
It is interesting in this regard that we recently demonstrated a 40%
decrease in the ratio of phospholamban to SR Ca2+-ATPase in
hyperthyroid baboons40 and attenuated responses to
ß-adrenergic stimulation in mice with targeted ablation of
phospholamban41 ; in both of these models, there is less
substrate for cAMP-mediated phosphorylation of
phospholamban. However, we cannot exclude the possibility that the
inotropic response to dobutamine was near maximum in the
basal state and was limited by downstream effector mechanisms.
Clinical Implications
Experimental limitations notwithstanding, our data strongly
suggest that the cardiac mechanical effects of hyperthyroidism cannot
be explained by enhanced sensitivity to catecholamines.
Despite significant increases in basal heart rate and rates of LV
contraction and relaxation, the response to ß-adrenergic agonists was
not increased in hyperthyroid baboons. Increased basal indices of LV
contraction and relaxation in this model are more clearly related to
changes in myosin heavy chain isoform expression and the relative
abundance of the SR calcium pumps (SR Ca2+-ATPase) and its
phosphoprotein inhibitor phospholamban, although other
thyroid hormone–mediated effects, such as those reported for L-type
calcium channels and Na+/K+-ATPase pumps,
cannot be excluded.19 42 43
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by National Institutes of Health grant HL-33579, SCOR in Heart Failure P-50-HL-52318, and American Heart Association Fellowship Grant SW-94-34-F. The authors gratefully acknowledge Norma Burns for her expert secretarial assistance.
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Footnotes |
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Reprint requests to Brian D. Hoit, MD, Division of Cardiology, University of Cincinnati Medical Center, PO Box 670542, Cincinnati, OH 45267-0542.
Received October 31, 1996; revision received December 13, 1996; accepted January 15, 1997.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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1. Levey GS, Klein I. Catecholamine-thyroid hormone interactions and the cardiovascular manifestations of hyperthyroidism. Am J Med. 1990;88:642-646.[Medline]
2. Coulombe P, Dussault JH, LeTarte J, Simard SJ. Catecholamine metabolism in thyroid diseases, I: epinephrine secretion rate in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab. 1976;42:125-130.[Abstract]
3. Coulombe P, Dussault JH, Walker P. Catecholamine metabolism in thyroid disease, II: norepinephrine secretion rate in hyperthyroidism and hypothyroidism. J Clin Endocrinol Metab. 1977;44:1185-1189.[Abstract]
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