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Departments of Cardiovascular Medicine (K.W., A.B., T.S., E.D.) and Endocrinology (B.C., P.D.), University Hospital Bern, and Department of Physiology (J.P.K.), University of Bern, CH-3010 Bern, Switzerland; and Division of Nephrology and Department of Medicine (A.Z.), Centre Hospitalier Universitaire Vaudois and University of Lausanne, CH-1011 Lausanne, Switzerland
Address all correspondence and requests for reprints to: Etienne Delacrétaz, M.D., F.E.S.C., Professor of Cardiology, Swiss Cardiovascular Center Bern, University Hospital, CH-3010 Bern, Switzerland. E-mail: etienne.delacretaz{at}insel.ch.
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Abstract |
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Objective: Our objective was to determine the activity of abnormal supraventricular electrical depolarizations in response to elevated thyroid hormones in patients without structural heart disease.
Patients and Design: Twenty-eight patients (25 females, three males, mean age 43±11 yr) with newly diagnosed and untreated hyperthyroidism were enrolled in a prospective trial after exclusion of heart disease. Patients were followed up for 16 ± 6 months and studied at baseline and 6 months after normalization of serum TSH levels.
Main Outcome Measures: The incidence of abnormal premature supraventricular depolarizations (SVPD) and the number of episodes of supraventricular tachycardia was defined as primary outcome measurements before the start of the study. In addition, heart rate oscillations (turbulence) after premature depolarizations and heart rate variability were compared at baseline and follow-up.
Results: SVPDs decreased from 59 ± 29 to 21 ± 8 per 24 h (P = 0.003), very early SVPDs (so called P on T) decreased from 36 ± 24 to 3 ± 1 per 24 h (P < 0.0001), respectively, and nonsustained supraventricular tachycardias decreased from 22 ± 11 to 0.5 ± 0.2 per 24 h (P = 0.01) after normalization of serum thyrotropin levels. The hyperthyroid phase was characterized by an increased heart rate (93 ± 14 vs. 79 ± 8 beats/min, P < 0.0001) and a decreased turbulence slope (3.6 vs. 9.2, P = 0.003), consistent with decreased vagal tone. This was confirmed by a significant decrease of heart rate variability.
Conclusion: Hyperthyroidism is associated with an increased supraventricular ectopic activity in patients with normal hearts. The activation of these arrhythmogenic foci by elevated thyroid hormones may be an important causal link between hyperthyroidism and atrial fibrillation.
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Introduction |
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The hypothesis of this study was that hyperthyroidism is associated with an increased activity of focal arrhythmogenic centers. Accordingly, potential triggers of AF were studied in patients diagnosed with hyperthyroidism before treatment and more than 6 months after normalization of thyroid-stimulating hormone levels. Because of the importance of parasympathetic tone in the pathophysiology of AF, the alterations in the sympathovagal balance were assessed by the analysis of heart rate variability (HRV) and heart rate turbulence (HRT) (7, 8, 9).
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Subjects and Methods |
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Twenty-eight patients with newly diagnosed and untreated hyperthyroidism were recruited from the outpatient clinic. Exclusion criteria were structural and ischemic heart disease, treatment with antiarrhythmic drugs, and a history of AF. The study protocol was approved by local ethics committee, and all participants gave written informed consent before entering the study.
Study protocol
Baseline clinical and laboratory were obtained at the time of enrollment. Structural heart disease was ruled out by echocardiography. Hyperthyroidism was defined as decreased serum TSH with increased serum-free T4 and/or free T3 concentrations. Twenty-six patients received carbimazole and two patients received propylthiouracil. Normal ranges for serum-free T4 and T3 and serum TSH concentrations were, respectively, of 9.5–25.0 pmol/liter, 2.9–6.5 pmol/liter, and 0.35–4.50 mU/liter. Patients underwent 24-h electrocardiogram (ECG) recordings before any medication was administered (hyperthyroid phase) and more than 6 months after normalization of the thyroid function (euthyroid phase). All patients underwent repeated clinical assessment and sequential determination of hormone levels until complete normalization of the thyroid function.
Twenty-four-hour ECG recordings
The 24-h ECG data were transferred to a computer and a commercially available interactive software was used to detect arrhythmias (CardioDay; Getemed, Teltow, Germany). In addition, all recordings were reviewed and edited by a well-trained technician blinded to the clinical data. All R-R interval sequences were labeled for normal R-R intervals (NN); premature atrial and ventricular complexes, both with prematurity (
80%); nonsustained supraventricular tachycardia; and AF.
HRV
Series of R-R intervals were derived from the Holter data for the analysis of HRV according to the guidelines (7). HRV measures were computed on series of normal R-R (NN) intervals using the HRV analysis software developed by Niskanen et al. (10) (kindly provided by Dr. J. Niskanen and Dr. P. A. Karjalainen).
Time-domain analysis SD of all normal to normal R-R intervals (NN) during a 24-h period (SDNN; in milliseconds) reflects both long- and short-term NN interval variations. SD of 5-min average NN intervals (SD of all normal to normal NN intervals [SDANN], in milliseconds) evaluates long-term NN interval variations, whereas the SDNN index (mean of the SDs of all NN intervals for all 5 min segments in 24 h, in milliseconds) reflects short-term variations. Additionally, the percentage of intervals greater than 50 msec different from preceding interval (pNN50; in percent), reflecting the proportion of differences between successive intervals greater than 50 msec and thus the vagal modulation of heart rate, the root mean square successive difference of all NN intervals (RMSSD; in milliseconds), indicating vagally mediated variability were analyzed. Finally, HRV index, the total number of NN intervals divided by the height of the histogram of all NN intervals measured on a discrete scale with bins of 7.8125 msec, showing overall autonomic modulation, as well as baseline width of the minimum square difference triangular interpolation of the highest peak of the histogram of all NN intervals (TINN; in milliseconds) were computed (7).
Frequency-domain analysis Spectral analyses were conducted on 24-h R-R interval sequences devoid of ectopic beats and artifacts. Original R-R interval series were detrended using a second-degree polynomial. The HRV power spectrum was computed using parametric (autoregressive model with 12 coefficients) and nonparametric methods [Welch’s periodogram based on the fast Fourier transform (FFT)]. The following spectral HRV parameters were derived using both methods: high frequency (HF) power (0.15–0.5 Hz), low frequency (LF) power (0.04–0.15 Hz), and very low frequency (VLF) power (0–0.04 Hz). HF and LF power were expressed in normalized units (n.u.) as 100 x HF/(total power – VLF) and 100 x LF/(total power – VLF), respectively. Finally, the LF to HF ratio, reflecting the sympathovagal balance, was computed (7).
HRT
Turbulence onset (TO) and turbulence slope (TS) after supraventricular premature depolarization (SVPD) were derived according to the method of Schmidt et al. (8) using HRT View (version 1.11, Klinikum rechts der Isar, Munich, Germany).
A prerequisite for the determination of HRT parameters is the presence of a normal sinus rhythm free of ectopic beats and artifacts immediately 2 or more beats before and more than 16 beats after the considered SVPD. Because TO and TS must be averaged for several ectopic beats, their predictive power is low in the presence of only one SVPD. Therefore, we analyzed HRT in only 11 patients who had 2 or more SVPDs fulfilling the analysis criteria above.
Statistical analysis
Normally distributed data are presented as mean ± SD and as median for nonnormal distributions. Baseline and follow-up clinical data and HRV and HRT measurements were compared using the Wilcoxon signed rank test. Statistical significance was assumed for P < 0.05. All statistical analyses were performed with Stat View (version 4.5; Abacus Concepts, Berkeley, CA).
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Results |
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Twenty-eight patients (25 females, three males, mean age 43 ± 11 yr) with newly diagnosed and untreated hyperthyroidism were included in the study. Twenty-two patients were diagnosed with Graves’ disease, two patients had an autonomous adenoma, three patients presented a struma multinodosa or diffusa, and one patient was diagnosed with Hashimoto’s thyroiditis. Baseline and follow-up serum-free T4, T3, and serum TSH concentrations are presented in Table 1
. Echocardiographic and Doppler examinations at inclusion showed normal values for left ventricular function, left ventricular mass index (85 ± 22 g/m2), pulmonary pressure, and valvular function.
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Heart rate, arrhythmias, and HRT in the hyperthyroid phase and the euthyroid state are shown in Table 1
. New-onset symptomatic paroxysmal AF was observed in two patients. SVPD and short-coupled SVPD (P on T) as well as nonsustained supraventricular tachycardia were significantly more frequent in baseline 24-h-ECG than in follow-up recordings (Table 1). Figure 1 shows SVPD and nonsustained supraventricular tachycardias in a 46-yr-old female who had AF after inclusion in the study. Her 24-hr ECG recording showed 41 short-coupled SVPDs (P on T) and 51 SVPDs, and the control 24-h ECG after normalization of TSH showed only seven SVPDs. The median number of ventricular premature depolarizations was 2 (range 0–174) in the hyperthyroid phase vs. 0 (0–444) after normalization of thyroid function (p 0.6). TS and TO after SVPD were altered during the hyperthyroid phase and restored in the euthyroid state, consistent with decreased vagal outflow in the presence of hyperthyroidism.
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Results from the HRV time-domain analysis are reported in Table 1. RMSSD, pNN50, and the HRV index were significantly decreased in the hyperthyroid phase, demonstrating a reduced vagal outflow.
The spectral power of HF, LF, and VLF were significantly diminished in the hyperthyroid phase in both analyses (Table 1). When HF and LF spectra were expressed in normalized units, the HF spectrum obtained with the AR model was significantly decreased in the hyperthyroid phase, compared with the follow-up data, demonstrating a decreased parasympathetic activity, whereas in the FFT spectrum, the HF in normalized units showed a trend only for the same effect. When compared between baseline and follow-up, LF in normalized units tended to decrease in the FFT spectrum after normalization of thyroid function, whereas no changes were seen with the AR model. Finally, in both analyses, the LF to HF ratio clearly tended to be higher during the hyperthyroid phase when compared with follow-up data.
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Discussion |
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The shortening of the atrial refractory period was considered to be the main factor favoring AF (3). However, the onset and maintenance of AF requires events (triggers) that repeatedly initiates the arrhythmia and the presence of a predisposing substrate that perpetuates it (11). The presence of repetitive triggers has been associated with the risk of developing AF in different patient populations (12, 13, 14). Most of these triggers were shown to originate from the pulmonary veins and their junction with the posterior left atrium (4, 5, 11). The increased activity of AF triggers in hyperthyroidism may be due to a direct effect of thyroid hormones or to an effect mediated by the alteration of sympathovagal balance associated with hyperthyroidism (15).
Our clinical results correlate with recent experimental studies by Chen et al. (16) and Sun et al. (17). In isolated rabbit atrial and pulmonary vein cells, they showed an increased automaticity and enhanced triggered activity in response to elevated T4 levels. Our clinical data support the concept that abnormal local spon-taneous depolarizations act as a trigger of AF during hyperthyroidism.
In euthyroid patients, vagal stimulation shortens refractory period, modifies atrial substrate, and has an import role in the genesis of AF, together with the arrhythmogenic triggers (18, 19). In addition, vagal denervation has a beneficial effect in controlling AF (19). During the hyperthyroid phase, our patients had a markedly decreased vagal tone, in accordance to previous studies. This was shown by both alterations in HRV (time domain and frequency domain measurements) and the analysis of cardiac turbulence, showing blunted oscillations of sinus rhythm after SVPD (8, 9, 20).
Not all patients had an increase of abnormal electrical activity during the hyperthyroid phase. Reasonably, those more susceptible to the arrhythmogenic properties of thyroid hormones may be those at higher risk of developing AF later in life.
The low incidence of AF in our population is due to the exclusion of patients with structural heart disease to eliminate other causes of AF. As a consequence, many elderly patients were excluded. Nevertheless, the abnormal activity of arrhythmogenic centers were demonstrated in these young patients without heart disease.
In conclusion, elevated thyroid hormones increase abnormal electrical atrial activity in young patients without heart disease. In euthyroid patients, such arrhythmogenic activity can trigger AF. Activation of arrhythmogenic foci in hyperthyroidism plays an important role in the pathogenesis of AF. Further studies are needed to determine whether patients who have the most abnormal atrial depolarizations during hyperthyroidism are at risk of AF later in life.
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Footnotes |
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First Published Online March 18, 2008
Abbreviations: AF, Atrial fibrillation; ECG, electrocardiogram; FFT, fourier transform; HF, high frequency; HRT, heart rate turbulence; HRV, heart rate variability; LF, low frequency; NN, normal R-R interval; n.u., normalized units; pNN50, percentage of intervals greater than 50 msec different from preceding interval; RMSSD, root mean square successive difference of all NN intervals; SDNN, SD of all normal to normal NN intervals; SVPD, supraventricular premature depolarization; TO, turbulence onset; TS, turbulence slope; VLF, very low frequency.
Received January 14, 2008.
Accepted March 7, 2008.
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References |
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