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The Relation of Thyroid Function and Ventricular Repolarization: Decreased Serum Thyrotropin Levels Are Associated with Short Rate-Adjusted QT Intervals

Department of Internal Medicine B (M.D., J.R., D.M.R., S.B.F.) and Institute of Epidemiology and Social Medicine (H.V.), Ernst Moritz Arndt University, D-17475 Greifswald, Germany; and Department of Medical Informatics (J.A.K.), Erasmus University Medical Center, 3000 CA Rotterdam, The Netherlands

Address all correspondence and requests for reprints to: Marcus Dörr, M.D., Department of Internal Medicine B, M. Ernst Moritz Arndt University, Friedrich Loeffler Strasse 23 a, D-17475 Greifswald, Germany. E-mail: mdoerr{at}uni-greifswald.de.

	Abstract

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Context: The linkage of thyroid dysfunction with ventricular repolarization properties has not been investigated extensively, although alterations might be associated with an increased ventricular vulnerability.

Objective: The objective of the study was to investigate whether there is an association between functional thyroid status and rate-adjusted QT intervals (QTc).

Design, Setting, and Participants: The population-based Study of Health in Pomerania included 4310 subjects aged 20–79 yr. Data of 3610 subjects (1862 women and 1748 men) without branch bundle blocks or pacemaker were available for the present analyzes.

Main Outcome Measures: QTc with respect to thyroid status. Short QTc was defined below the 25th percentile, and long QTc above the 75th percentile of the gender-specific distribution.

Results: TSH levels were positively associated with QTc independent from potential confounders in multivariable analyses (P for trend = 0.001). Subjects with decreased TSH levels had shorter QTc than those with normal TSH levels (426.4 ± 8.2 vs. 430.2 ± 8.2; P < 0.001). Adjusted odds ratios for short QTc in subjects with elevated, normal, and decreased TSH were 0.87 (95% confidence interval 0.58–1.31), 1.00 (reference), and 1.53 (95% confidence interval 1.16–2.03), respectively (P for trend = 0.008).

Conclusion: TSH levels were positively related to QTc in a population-based sample. Subjects with decreased serum TSH levels had an increased risk for short QTc. Whether these findings are of clinical significance has to be investigated by further studies.

	Introduction

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THYROID DYSFUNCTION MAY affect the cardiovascular system by several mechanisms, i.e. atrial fibrillation (1) and left ventricular hypertrophy (2). In contrast, the impact on ventricular repolarization properties has not been investigated very extensively, although such a relation is biologically plausible (3, 4). Ventricular repolarization is traditionally measured by the heart rate-corrected QT (QTc) interval. A prolonged QT interval is a risk factor for life-threatening ventricular arrhythmias and cardiovascular mortality in patients with habitual long-QT syndromes (5) and myocardial infarction (6) but also in healthy subjects (7, 8). Conversely, little is known about the significance of a shortened QT interval, although some data point to an association with an increased cardiovascular risk for congenital short-QT syndromes as well as the normal population (9).

A few small studies (4, 10, 11) investigated whether thyroid function influences ventricular repolarization as measured by QTc toward one of the above-mentioned directions. The aim of the present study was to analyze whether there was an association of thyroid function with the QTc interval in a large sample from the general population.

	Participants and Methods

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The Study of Health in Pomerania (SHIP)

SHIP is a population-based survey in a region of former iodine deficiency in northeast Germany. A representative sample from the population aged 20–79 yr was drawn. Of the total study population of 4310 subjects, electrocardiograms (ECGs) from 3719 subjects were available. Participants with pacemakers (n = 8) and left (n = 34) or right bundle branch block (n = 67) were excluded from analysis, resulting in a study population of 3610 subjects. The study protocol complied with the Declaration of Helsinki and was approved by the institutional review committee.

Participant characteristics

Sociodemographic and medical characteristics were assessed by computer-assisted personal interviews. Diabetes and myocardial infarction were defined as self-reported physician diagnoses. Study participants were classified as nonsmokers or current smokers and as physically active if they participated in physical training during summer or winter for at least 1 h/wk. Present medication was recorded by a computer-aided method using the anatomic, therapeutic, and chemical code.

Thyroid function and electrocardiography

Serum TSH was analyzed by immunochemiluminescent procedures (LIA-mat; Byk Sangtec Diagnostica GmbH, Frankfurt, Germany). The reference range that was recently established for the SHIP region was 0.25–2.12 mIU/liter (12). Twelve-lead ECGs were recorded (personal 120LD; Esaote, Genova, Italy) and processed by the modular ECG analysis system (13), which has been evaluated extensively (8, 13). QT intervals were rate adjusted as a linear function using the algorithm described by Hodges et al.: QTc = QT + 1.75 (heart rate – 60) (14).

Further laboratory parameters

Determination of serum magnesium was performed by atom-absorption spectroscopy (AAS 1100 B; Perkin-Elmer Inc., Boston, MA), calcium by a colorimetric assay, and potassium by ion-selective electrodes (Roche/Hitachi 911; Roche Diagnostics, Indianapolis, IN).

Statistical analysis

Continuous data are given as means and SD (or SE) and nominal data as absolute numbers or percentages. Comparisons between groups were made using linear ANOVA (continuous data) and ² test (nominal data). According to the serum TSH levels, three thyroid function groups were defined: 1) elevated TSH: serum TSH greater than 2.12 mIU/liter; 2) normal TSH: serum TSH within normal range; 3) decreased TSH: serum TSH less than 0.25 mIU/liter. All analyses were performed for men and women separately and afterward irrespective of gender. The relation of the TSH groups with QTc was tested by two different strategies. First, QTc was used as a continuous variable to calculate adjusted means using the ANOVA method. Thereafter, QTc was dichotomized and analyzed by logistic regression models. The 75th percentile of the gender-specific distribution of QTc (422.8 msec for men; 427.5 msec for women) was used to define long QTc and the 25th percentile of the gender-specific distribution of QTc (399.3 msec for men; 406.3 msec for women) to define short QTc. The adjusted odds ratio (OR) with its 95% confidence interval (CI) was calculated. For both strategies, ANOVA and logistic regression, various models were created stepwise by considering determinants of QTc. The full model controlled for age, body mass index (BMI), systolic and diastolic blood pressure, potassium, calcium, magnesium, history of myocardial infarction and diabetes, drugs (beta blockers, digitalis, sotalol, amiodarone, class I antiarrhythmics), smoking habits, and physical activity as well as for gender in the combined model. A value of P < 0.05 was considered statistically significant. Analyses were performed with SPSS software version 14.0 (SPSS Inc., Chicago, IL).

	Results

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Characteristics of participants

A total of 1748 men and 1862 women were included in the analyses (mean age 49.8 ± 16.2 yr). With regard to TSH, 157 subjects had increased (4.3%), 3168 normal (87.8%), and 285 decreased (7.9%) serum levels. Further baseline characteristics are presented in Table 1.

Serum TSH levels were positively correlated with the QTc interval in both men and women in the full multivariable model (P for linear trend = 0.014 and 0.032) (Table 2). This association was the strongest when models were analyzed in the whole study population (P for trend = 0.001) and remained statistically significant independent from the confounders that were included into the models (Table 2).

View larger version (8K): [in this window] [in a new window]   FIG. 1. Short rate-corrected QT intervals (A) and long rate-corrected QT intervals (B) with respect to serum TSH levels. Values are OR and 95% CIs for both genders with respect to serum TSH levels (logistic regression models). Short rate-corrected QT intervals defined under 25th gender-specific percentile (399.25 msec for men; 406.25 msec for women) and long QT rate-corrected QT intervals defined above 75th gender-specific percentile (422.75 msec for men; 427.50 msec for women). Final model 3: adjustment for age, BMI, systolic and diastolic blood pressure, serum potassium, serum calcium, serum magnesium, myocardial infarction, diabetes mellitus, drugs known to affect QT interval, current smoking, and physical activity. TSH elevated, Serum TSH greater than 2.12 mIU/liter; TSH normal, serum TSH 0.25–2.12 mIU/liter; TSH decreased, serum TSH less than 0.25 mIU/liter. *, P < 0.05; , P < 0.01 vs. euthyroidism (reference).

Application of other standard equations for calculation of heart rate-adjusted QT interval [formulas of Bazett, Fridericia, and Framingham (see Ref. 15)] as well as exclusion of subjects receiving drugs known to influence ventricular repolarization arrived at similar results. Likewise, different categorizations of the age variable (5-, 10-, and 20-yr age groups) did not substantially affect the major results. Moreover, sensitivity analyses were run by varying the cutoffs used for defining serum TSH levels. These analyses only marginally changed the main results. For example, when the lower limit of TSH was defined less than 0.3 mIU/liter and the upper limit more than 4.5 mIU/liter, there were 408 (11.3%) subjects with decreased, 3185 (88.2%) with normal, and 17 (0.5%) with elevated serum TSH levels. The mean QTc (± SE) for the fully adjusted model was then 427.2 ± 8.2 msec for subjects with decreased, 429.9 ± 8.2 msec for participants with normal, and 431.9 ± 9.1 msec for those with elevated serum TSH levels (P = 0.009 for the comparison between decreased vs. normal serum TSH levels).

	Discussion

Top Abstract Introduction Participants and Methods Results Discussion References

 
This population-based study demonstrated an association between serum TSH levels and ventricular repolarization, independent from further determinants. The duration of the QTc interval was positively related to serum TSH levels. Moreover, subjects with decreased serum TSH levels had an increased risk of short QTc intervals, compared with those with normal serum TSH levels.

Thyroid function and ventricular repolarization

Thyroid hormones affect ventricular conduction characteristics and duration of ventricular repolarization, but data differ with respect to the direction of these alterations. Electrophysiological studies and animal trials revealed both prolongation (16) and acceleration of ventricular repolarization (3, 17). Inconsistent findings were also found in humans: on the one hand, hyperthyroidism was associated with prolonged QTc intervals (4, 10); on the other hand, a prolongation was shown in hypothyroidism (11). These apparently contradictory findings might be explained mainly by the low statistical power due to small numbers of patients included in these studies (4, 10, 11).

Physiological mechanisms and plausibility

From the pathophysiological view, our finding of a direct association between serum TSH levels and duration of QTc intervals appears to be plausible. Increased thyroid function is related to several factors that shorten the ventricular repolarization such as hyperthermia, hypercalcemia, and modification of the autonomic tone. Experimental studies have shown that thyroid hormones alter conduction properties of myocardial cells by affecting the sodium pump density and enhancement of Na+ and K+ permeability (18). In contrast, an inverse relation of thyroid function and repolarization properties has been proposed by a previous investigation (10). In this small study, the QTc intervals of 32 subclinical hyperthyroid subjects were significantly longer, compared with euthyroid controls. The different findings might be mainly explained by the very small number of patients but also may be due to differences of definition criteria used.

Interpretation of findings

For the first time, the physiological mechanism of an accelerated ventricular repolarization velocity has been demonstrated by using data of a population-based sample. This might be understood as a proof of physiological principle. The interpretation with respect to clinical significance and prognostic meaning of this relation, however, is complex. With the present data, we were not able to explain the biological and prognostic meaning of the demonstrated associations. Because the demonstrated QTc differences related to decreased serum TSH levels were rather small and thus probably far from biological relevance, our data might not argue for an arrhythmogenic influence of subclinical hyperthyroidism. However, prognostic longitudinal data are currently lacking, and further studies are needed to confirm an association of short QTc intervals and (subclinical) hyperthyroid state and investigate whether this might be related to increased cardiovascular risk and mortality, which might be of relevance, particularly in the presence of coexisting traditional risk factors that are related to thyroid overfunction such as atrial fibrillation (1) and left ventricular hypertrophy (2).

Study limitations and strengths

Due to the cross-sectional design of our study, we were not able to interpret the data with respect to causality between thyroid function and ventricular repolarization. Although we carefully controlled our analyses for imbalances in confounding factors, including age and cardiovascular risk factors among the exposure groups, we cannot fully rule out residual confounding by some of these factors. The large sample size, availability of data on key risk factors, wide range of age of participants, and consistence of our findings over a number of sensitivity analyses are strengths of our study. Because a reliable measurement of QT duration in general may be difficult, we used an automatic ECG analysis system (modular ECG analysis system), which has been validated in large epidemiological studies extensively (8, 13).

Conclusions

Our data demonstrated an association between thyroid function and ventricular repolarization. Serum TSH levels were related to the duration of rate-adjusted QT intervals. In particular, subjects with decreased serum TSH levels had an increased risk of short QTc intervals. Whether these findings are of clinical and prognostic significance has to be investigated by further studies.

	Acknowledgments

 
The contribution to data collection made by field workers, technicians, interviewers, and computer assistants is gratefully acknowledged.

	Footnotes

 
The work is part of the Community Medicine Research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (Grant ZZ9603), the Ministry of Cultural Affairs, and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from the population-based Study of Health in Pomerania (SHIP; http://www.medizin.uni-greifswald.de/cm).

Disclosure statement: The authors have nothing to disclose.

First Published Online September 12, 2006

Abbreviations: BMI, Body mass index; CI, confidence interval; ECG, electrocardiogram; OR, odds ratio; QTc, heart rate-corrected QT; SHIP, Study of Health in Pomerania.

Received May 11, 2006.

Accepted September 5, 2006.

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