1 Centre for Human Drug Research and 2 Department of General Internal Medicine, Leiden University Medical Centre, 2333 CL Leiden; and 3 Department of Psychiatry, Erasmus University, 3015 GD Rotterdam, The Netherlands
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ABSTRACT |
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We assessed
sympathovagal balance in thyrotoxicosis. Fourteen patients with
Graves' hyperthyroidism were studied before and after 7 days of
treatment with propranolol (40 mg 3 times a day) and in the euthyroid
state. Data were compared with those obtained in a group of age-, sex-,
and weight-matched controls. Autonomic inputs to the heart were
assessed by power spectral analysis of heart rate variability. Systemic
exposure to sympathetic neurohormones was estimated on the basis of
24-h urinary catecholamine excretion. The spectral power in the
high-frequency domain was considerably reduced in hyperthyroid
patients, indicating diminished vagal inputs to the heart. Increased
heart rate and mid-frequency/high-frequency power ratio in the presence
of reduced total spectral power and increased urinary catecholamine
excretion strongly suggest enhanced sympathetic inputs in
thyrotoxicosis. All abnormal features of autonomic balance were
completely restored to normal in the euthyroid state. -Adrenoceptor
antagonism reduced heart rate in hyperthyroid patients but did not
significantly affect heart rate variability or catecholamine excretion.
This is in keeping with the concept of a joint disruption of
sympathetic and vagal inputs to the heart underlying changes in heart
rate variability. Thus thyrotoxicosis is characterized by profound
sympathovagal imbalance, brought about by increased sympathetic
activity in the presence of diminished vagal tone.
heart rate variability; catecholamines
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INTRODUCTION |
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HYPERTHYROIDISM
IS CHARACTERIZED by a variety of clinical features that closely
resemble those of catecholamine excess (i.e., tachycardia, sweating,
weight loss, diarrhea). Moreover, -adrenergic receptor antagonists
effectively dampen these symptoms. However, early studies examining
epinephrine and/or norepinephrine kinetics in hyperthyroid patients
revealed that plasma levels and turnover of catecholamines are reduced
in hyperthyroidism (6, 7). Subsequent experiments refuted
the suggestion that thyroid hormone excess is associated with increased
sensitivity to catecholamines (12). The blunted effect of
pharmacological inhibition of parasympathetic neurotransmission on
heart rate in hyperthyroid patients suggested that reduced vagal tone,
as opposed to increased sympathetic tone, determines autonomous
imbalance associated with hyperthyroidism (9).
Power spectrum analysis (PSA) of heart rate fluctuations is a sensitive, quantitative, and noninvasive measure of sympathovagal balance in humans (1). Recent studies employing PSA confirmed the hypothesis that thyroid hormone excess is associated with a reduction of parasympathetic tone (3, 10). However, although PSA allows rather accurate quantification of vagal inputs to the heart and also measures sympathovagal balance, it is less suitable for determination of absolute sympathetic tone in recumbent subjects. It is conceivable that reduced vagal activity and increased sympathetic tone perturb the autonomic balance in hyperthyroidism.
This study was performed to further elucidate the activities of the two
major components of the autonomous nervous system in hyperthyroidism.
We hypothesized that autonomic imbalance in hyperthyroid patients is
caused by the joint effects of reduced parasympathetic tone and
increased sympathetic activity. PSA was used to determine vagal inputs
to the heart in hyperthyroid patients. In addition, 24-h urinary
catecholamine excretion was used to estimate systemic exposure to
sympathetic neurohormones. The effect of -adrenergic receptor
blockade on sympathovagal balance was evaluated to further assess the
contribution of the sympathetic nervous system. Finally, autonomic
balance in response to reestablishment of euthyroidism was measured.
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SUBJECTS AND METHODS |
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Subjects. Newly diagnosed, untreated hyperthyroid patients were recruited from the outpatient clinic of the Department of Internal Medicine of Leiden University Medical Center. The diagnosis of Graves' disease was established on the basis of clinical, biochemical, and immunological data in all patients. Severe Graves' opthalmopathy, any serious concomitant disease, the use of medication (except oral contraceptives), or diet and pregnancy were exclusion criteria. The healthy control subjects, who were matched for gender, age (allowed limits ±5 yr), and body mass index (BMI; allowed limits ±2 kg/m2), were recruited using advertisements in local newspapers. The Ethics Committee of Leiden University Medical Center approved the study protocol, and all subjects gave written informed consent. The study was conducted according to the principles of the Helsinki Declaration.
Study design.
Hyperthyroid patients were studied on three occasions in this open
study. The first occasion took place at the time of diagnosis. Subsequently, treatment with propranolol (1- and
2-adrenergic receptor blockade, 40 mg orally 4 times a
day) was initiated. The second occasion took place after 1 wk of
propranolol treatment. Thereafter, the subjects started using thiamazol
(Strumazol; 10 mg orally 3 times a day) to completely suppress thyroid
function. L-Thyroxine (Thyrax; 100 µg starting dose,
progressing to 2 µg/kg body wt) was added to establish clinical and
biochemical euthyroidism. Propranolol treatment was continued for
several weeks until most clinical symptoms had vanished. The third
occasion, which was required to be
1 mo after the last dose of
propranolol, took place with the subject in a stable euthyroid state.
An average period of ~5 mo (median; range 3-10 mo) elapsed
between the second and third occasions. The control subjects were
studied only once.
Procedures. At all occasions identical studies were performed. After an overnight fast, the subjects were admitted to the clinical research unit, where they handed in the urine collected over the previous 24 h. After a brief medical history and physical examination, an intravenous cannula was inserted in a forearm vein, and blood samples to assess the thyroid hormone status were taken. Approximately 15-20 min after the cannulation, a 1-lead electrocardiogram (ECG) registration recorded 600 subsequent beats while the subject was in supine position. The subjects were instructed to relax, to breathe regularly, not to speak, and to stay awake.
Assessment of heart rate variability. Variations in R-R intervals present during resting conditions reflect a fine tuning of beat-to-beat control mechanisms. Fluctuations of efferent sympathetic and vagal inputs to the heart are characterized by oscillatory patterns that generate rhythmic changes of R-R interval times. PSA of heart rate fluctuations quantifies cyclical changes in heart rate, which are the result of these alterations in autonomic tone. Fluctuations of autonomic inputs in the high-frequency (HF) domain typically oscillate in the 0.15- to 0.5-Hz frequency range. The power (i.e., variance) of R-R interval length in this frequency domain is almost completely determined by vagal (parasympathetic) input. R-R interval fluctuations that occur at a lower frequency [mid-frequency (MF) domain, typically 0.07-0.14 Hz] are governed by mixed vagal-sympathetic inputs. These neural inputs are modulated by a variety of central and peripheral factors [i.e., respiratory movements, vasomotor centers, (thyroid) hormones] that ultimately cause changes of R-R interval length and power in associated specific frequency domains. For example, marked increase of power in the HF domain reflects strong vagal inputs to the heart. For a complete description of methods and biological significance of heart rate variation analysis, we refer the reader to Ref. 16.
In this study, ECG signals were sampled at a rate of 500 Hz, digitized using a customized laboratory interface (model 1401, Cambridge Electronic Design, Cambridge, UK), and analyzed with software supplied with the interface. Each registration was screened for artifacts and subsequently analyzed for heart rate variability parameters in the time domain [mean, the coefficient of variation (CV), and the standard deviation (SD) of differences between subsequent R-R intervals] by use of Poincaré plots (11). The first 5-min period of the interbeat interval (IBI) time series of each registration was analyzed by PSA. The time series of IBIs were scrutinized for stationarity, artifacts, and frequency of occurrence of supraventricular extra beats by visual inspection. A linear interpolation correction procedure was applied to correct for isolated artifacts, R-wave detection errors, or isolated extra beats. If >5% of a 5-min time segment needed correction, the segment was discarded from further analysis. The IBI time series were subjected to a discrete Fourier transform, based on nonequidistant sampling of the R-wave incidences (CARSPAN program) (14, 21), to yield power spectra of rhythmic oscillations over a frequency range of 0.02-0.50 Hz, with a resolution of 0.01 Hz. For each 5-min time segment, the power was calculated for the total band (TP: 0.02-0.50 Hz), low-frequency band (LF: 0.02-0.06 Hz), MF band (0.07-0.14 Hz), and HF band (0.15-0.50 Hz). In this study, spectral power for each selected frequency band was expressed in relative terms, i.e., as a fraction of the mean value of the considered signal (squared modulation index; MI2). If this measure is computed for the whole spectrum, it is directly comparable to the squared CV (20).Assays. Thyroid hormones, thyroid-stimulating hormone (TSH), and urinary creatinine concentrations were determined using standardized routine methodology. Free thyroxine (T4) was measured on an IMx (Abbott, Abbott Park, IL; interassay CVs: 3.8-7.1% at different levels). Total T4 was determined on the TDx (Abbott; interassay CVs: 2.4-5.9%). Triiodothyronine (T3) was measured by RIABEAD of the same company (interassay CVs of 2.0-4.4%). TSH was determined with an immunofluorometric assay (Wallac, Turku, Finland, interassay CVs: 2.4-5.9%). Epinephrine (Epi), norepinephrine (NE), dopamine (D), and vanillylmandelic acid (VMA) were determined by routine HPLC methodology. All assays were performed at the clinical chemistry laboratories of Leiden University Medical Center.
Statistical analysis. The effects of different conditions on outcome variables were compared within and between patients and matched control subjects by use of paired Student's t-tests, where matches were treated as paired data. No correction for multiple comparisons was implemented, because our primary purpose was to estimate the magnitude of the difference between the distinct thyroid states in the patients. Statistical analysis of frequency domain heart rate variability was performed on log-transformed data. All parameters are reported as means ± SD. The level of statistical significance was set at 5%, and differences are presented with the corresponding 95% confidence intervals (95% CI). For the log-transformed data, differences are presented as percentage change with the 95% CIs. The calculations were performed using SPSS for Windows (SPSS, Chicago, IL).
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RESULTS |
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Fifteen hyperthyroid patients and 15 control subjects were included. The data from two subjects were not used in the analysis. One patient completed only the first occasion, and one control subject experienced a severe headache attack. Another patient withdrew from the study before the third occasion. The available data from this subject were used in the analysis. Thus the data represent 14 patients (13 F/1 M) and 14 matched controls. At inclusion, the patients were 38.9 ± 9.7 (mean ± SD; range: 21-56) yr old and had a BMI of 23.1 ± 4.4 kg/m2 (range: 16.2-30.0 kg/m2). The control subjects were 39.5 ± 10.3 yr (range: 21-56 yr) and had a BMI of 23.7 ± 4.7 kg/m2 (range: 14.0-30.8). The patients were in a hyperdynamic circulatory state, because systolic blood pressure (16 mmHg; CI: +4, +28 mmHg), pulse pressure (11 mmHg; CI: +4, +19 mmHg), and heart rate (39 beats/min; CI: +26, +51 beats/min) were all significantly higher than values in controls.
Thyroid hormone levels.
Thyroid hormone levels are summarized in Table
1. TSH and free T4
(FT4) concentrations were frequently lower and higher, respectively, than the limit of detection in untreated patients and
propranolol-treated patients. In these cases the limit of detection for
TSH (0.06 mU/l) or the valid upper-range value for FT4
(77.2 pmol/l) was used. FT4 concentrations exceeded the
valid upper range value in so many cases for the untreated (8 cases) and propranolol-treated (10 cases) patients that statistical analysis on these parameters was not performed. Propranolol had no major influence on TSH and T4 levels but reduced T3
levels by 0.74 nmol/l (CI: 0.39-1.10 nmol/l; P < 0.001). As a consequence, the T3-to-T4 ratio
also decreased (P < 0.001). The euthyroid state was
adequately established by the use of thiamazol and
L-thyroxine in all patients. Plasma levels of
T3 and T4 were significantly lower in the
patients when euthyroid than in controls.
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Urinary catecholamine excretion.
Urinary catecholamine excretion values are summarized in Table
2. Excretion of Epi was below the limit
of detection (0.01 µmol/l) in several subjects and was therefore not
analyzed. The excretions of NE, D, and VMA, normalized for creatinine
excretion, were considerably increased in the hyperthyroid patients
compared with controls. -Blockade did not significantly influence
urinary catecholamine excretion. Catecholamine excretion in the
euthyroid state was greatly reduced and not different from excretion in control subjects.
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Heart rate variability during supine rest.
An example of the R-R intervals obtained for one patient and her
control subject counterpart, plotted as a Poincaré plot, is given
in Fig. 1, which demonstrates the
increased heart rate and reduced R-R interval variability in all
frequency domains in the hyperthyroid condition, the reduction of heart
rate by -adrenergic receptor blockade, and the normalization of R-R
interval variability in response to treatment with thiamazol and
L-thyroxine. Figure 2 shows
the power spectrum in various frequency domains in the same
hyperthyroid patient and in her control subject counterpart.
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DISCUSSION |
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This study reveals profound changes of autonomic inputs to the
heart in hyperthyroidism. The spectral power in both frequency domains
was considerably reduced in hyperthyroid patients. In addition, their
24-h urinary catecholamine excretion was increased. Nonselective
antagonism of -adrenoreceptors reduced heart rate in hyperthyroid
patients, but it did not significantly affect heart rate variability.
Reestablishment of euthyroidism by thiamazol and
L-thyroxine treatment completely restored heart rate
variability power spectra and catecholamine excretion to normal.
The reduction of spectral power in the HF domain in hyperthyroid patients indicates withdrawal of vagal inputs to the heart (11, 18). This finding is in keeping with several previous observations (3, 9, 10). It is more difficult to draw definite conclusions concerning activity of the sympathetic nervous system on the basis of PSA. Although sympathetic inputs primarily affect heart rate variability in the MF domain (1, 18), MF spectral power in supine, resting subjects is also determined by vagal tone (18). However, several observations suggest that sympathetic activity was increased in our hyperthyroid patients. First, 24-h urinary D, NE, and VMA excretion was almost twice as high as that in euthyroid conditions and in normal control subjects. Urinary excretion of catecholamines and their metabolites reflects their average plasma concentrations and whole body turnover in plasma (8, 19). Second, heart rate and the MF/HF were increased and total spectral power was decreased in hyperthyroid subjects compared with values in the euthyroid state. All these features of heart rate variability are typical of enhanced sympathetic inputs to the heart (13, 18). The fact that sympathetic tone appears to be increased in hyperthyroidism is in apparent contrast to earlier studies reporting normal or even reduced sympathetic activity in hyperthyroidism (4, 6, 7, 17). However, these reports are generally based on plasma NE concentrations in single samples of venous forearm blood (4, 17) or whole body catecholamine turnover rates calculated from specific activities of radiolabeled catecholamines in venous plasma (6, 7). It is now known that catecholamine levels are more appropriately determined in arterial(ized) blood, inasmuch as extraction from venous circulation occurs across various organs (2, 8). Because hormone clearance critically depends on blood flow (8), this phenomenon may be of particular relevance in hyperthyroidism in view of the hyperdynamic circulatory state associated with this disease.
Although nonselective -adrenoceptor antagonism reduced heart rate in
hyperthyroid subjects, it did not fully restore heart rate to normal
values. Also, it did not significantly affect heart rate fluctuations.
These findings are in agreement with earlier observations indicating a
lack of effect of
-blockade on heart rate variability in healthy
volunteers (5, 15). Once euthyroidism was established,
heart rate and heart rate variability were similar in patients and
controls. These observations support the concept that sympathetic
inputs alone cannot explain the cardiac symptoms in hyperthyroidism.
Reduced vagal tone contributes to diminished heart rate variability and
increased heart rate. In addition, thyroid hormones may have a direct
chronotropic effect on the heart (16). Propranolol
significantly reduced the T3 concentrations in the
patients, which is a well known effect of this drug that is probably
responsible for some of the clinical effects of propranolol in
thyrotoxicosis (22).
In conclusion, hyperthyroidism is associated with a profoundly altered balance of the autonomous nervous system. It appears that the sympathetic component prevails over the parasympathetic as a result of enhanced sympathetic activity in the presence of diminished parasympathetic tone. The observed changes at least partly explain many of the clinical signs and symptoms of thyrotoxicosis and underscore the rationale for use of propranolol as a drug to reduce these symptoms.
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FOOTNOTES |
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Address for reprint requests and other correspondence: J. Burggraaf, Centre for Human Drug Research, Zernikedreef 10, 2333 CL Leiden, The Netherlands (E-mail: kb{at}chdr.nl).
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.
Received 20 September 2000; accepted in final form 16 March 2001.
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