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Original Investigation |

Association Between Serum Free Thyroxine Concentration and Atrial Fibrillation FREE

M. D. Gammage, MD, FRCP; J. V. Parle, MD, FRCGP; R. L. Holder, BSc; L. M. Roberts, PhD; F. D. R. Hobbs, FRCP, FRCGP; S. Wilson, PhD; M. C. Sheppard, PhD, FRCP; J. A. Franklyn, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Cardiovascular Medicine (Dr Gammage) and Medicine (Drs Sheppard and Franklyn), Division of Medical Sciences and Department of General Practice (Drs Parle, Roberts, Hobbs, and Wilson and Mr Holder), Division of Primary Care, Public, and Occupational Health, University of Birmingham, Birmingham, England.


Arch Intern Med. 2007;167(9):928-934. doi:10.1001/archinte.167.9.928.
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Background  Previous studies have suggested that minor changes in thyroid function are associated with risk of atrial fibrillation (AF). Our objective was to determine the relationship between thyroid function and presence of atrial fibrillation (AF) in older subjects.

Methods  A population-based study of 5860 subjects 65 years and older, which excluded those being treated for thyroid dysfunction and those with previous hyperthyroidism. Main outcome measures included tests of thyroid function (serum free thyroxine [T4] and thyrotropin [TSH]) and the presence of AF on resting electrocardiogram.

Results  Fourteen subjects (0.2%) had previously undiagnosed overt hyperthyroidism and 126 (2.2%), subclinical hyperthyroidism; 5519 (94.4%) were euthyroid; and 167 (2.9%) had subclinical hypothyroidism and 23 (0.4%), overt hypothyroidism. The prevalence of AF in the whole cohort was 6.6% in men and 3.1% in women (odds ratio, 2.23; P<.001). After adjusting for sex, logistic regression showed a higher prevalence of AF in those with subclinical hyperthyroidism compared with euthyroid subjects (9.5% vs 4.7%; adjusted odds ratio, 2.27; P = .01). Median serum free T4 concentration was higher in those with AF than in those without (1.14 ng/dL; interquartile range [IQR], 1.05-1.27 ng/dL [14.7 pmol/L; IQR, 13.5-16.4 pmol/L] vs 1.10 ng/dL; IQR, 1.00-1.22 ng/dL [14.2 pmol/L; IQR, 12.9-15.7 pmol/L]; P<.001), and higher in those with AF when analysis was limited to euthyroid subjects (1.13 ng/dL; IQR, 1.05-1.26 ng/dL [14.6 pmol/L; IQR, 13.5-16.2 pmol/L] vs 1.10 ng/dL; IQR, 1.01-1.21 ng/dL [14.2 pmol/L; IQR, 13.0-15.6 pmol/L]; P = .001). Logistic regression showed serum free T4 concentration, increasing category of age, and male sex all to be independently associated with AF. Similar independent associations were observed when analysis was confined to euthyroid subjects with normal TSH values.

Conclusions  The biochemical finding of subclinical hyperthyroidism is associated with AF on resting electrocardiogram. Even in euthyroid subjects with normal serum TSH levels, serum free T4 concentration is independently associated with AF.

Figures in this Article

Thyroid dysfunction is common in the general population, with increasing prevalence of overt thyroid disease with increasing age.1 Subclinical thyroid dysfunction, indicated biochemically by abnormal serum thyrotropin (TSH) values in association with normal thyroid hormone values, is also common, with a prevalence among adults of up to 12% and increasing with age.24

The pathophysiological consequences of mild thyroid dysfunction remain unclear. Several studies have shown an effect of subclinical hyperthyroidism on cardiac function or morphology.5 Importantly, there is evidence from 2 large prospective cohort studies6,7 and a cross-sectional study8 of an association between subclinical hyperthyroidism and atrial fibrillation (AF). Atrial fibrillation is an important dysrhythmia representing an independent risk factor for cardiovascular events and stroke.9 We have previously reported from a cohort study of 1191 subjects 60 years or older that a single low serum TSH measurement predicts increased all-cause mortality during 10 years of follow-up, an excess mortality specifically reflecting increased deaths from circulatory disorders,10 although another study has not replicated this.6 Subclinical hypothyroidism may also have pathophysiological consequences relevant to the cardiovascular system, with associations described with hyperlipidemia and left ventricular dysfunction11,12 and evidence for reversal of these changes with thyroxine (T4) replacement therapy.13 There is conflicting evidence whether these findings translate into cardiovascular morbidity or mortality,6,1419 but a recent meta-analysis suggests that subclinical hypothyroidism is associated with increased coronary heart disease risk.20

Overall, evidence of an association of subclinical thyroid dysfunction with morbidity or mortality has been considered insufficient, at least to direct strategies for screening or therapeutic intervention.21 Since AF is one of the most important chronic disorders linked to subclinical thyroid dysfunction that might warrant screening or treatment, we have examined the relationship between thyroid status and the presence of AF on electrocardiogram (ECG) in a large community-based cohort of subjects 65 years or older.

PARTICIPANTS AND DATA RECORDED

The cohort comprised 5860 subjects 65 years or older and excluded those currently being treated for thyroid dysfunction and those with a history of hyperthyroidism. Subjects were identified and investigated in primary care with tests of thyroid function and resting 12-lead ECG digitally recorded onto a personal digital assistant, transferred to a personal computer, and displayed for analysis using Cardioview Software (MicroMedical Industries Ltd, Sydney, Australia). All ECGs were analyzed for the presence of AF by a single cardiologist (M.D.G.) blinded to thyroid status and patient details.

All current drug therapies were recorded, as were major risk factors for AF previously defined in the Framingham population (smoking, diabetes mellitus, hypertension, heart failure, and ischemic heart disease) and used in similar studies.7 Initial recording was based on patient reporting, with validation by inspection of primary care records as previously described.22 The sensitivity and positive predictive value of computerized information regarding major medical diagnoses recorded in family practice in the United Kingdom has been shown to exceed 90%.23,24 All subjects gave written informed consent for the study, which was approved by the multicenter research ethics committee.

TESTS OF THYROID FUNCTION AND CLASSIFICATION BY THYROID STATUS

Serum samples were stored at −80ºC. Serum free T4, free triiodothyronine (T3), and TSH were measured by chemiluminescent immunoassay (Advia Centaur; Bayer Diagnostics, Newbury, England). The laboratory reference range for free T4 was 0.70 to 1.55 ng/dL (9.0-20.0 pmol/L), with an interassay coefficient of variation of 8.2% to 9.8% over the range of 0.64 to 4.27 ng/dL (8.2-54.9 pmol/L). Serum TSH concentration had a reference range of 0.4-5.5 mU/L, with an interassay coefficient of variation of 4.4% to 10.9% over the range of 0.41 to 24.5 mU/L. The lower limit of reporting for the TSH assay was 0.1 mU/L, with a mean functional sensitivity 0.02 mU/L. Free T4 and TSH concentrations were determined in all; in those with serum TSH concentrations below the reference range, serum free T3 (reference range, 227.3-422.1 pg/dL [3.5-6.5 pmol/L], interassay coefficient of variation of 4.2%-6.9% over the range of 259.7-1039.0 pg/dL [4.0-16.0 pmol/L]) was additionally measured. The reference ranges used for free T4, TSH, and free T3 were those recommended by the manufacturer and used in other studies of this cohort and studies from our unit.22,25 Subjects were classified according to measurements of serum free thyroid hormone and TSH concentrations as follows:

  • Overt hyperthyroidism: raised free T4 and free T3 or raised free T3 alone (T3toxicosis) with serum TSH lower than 0.4 mU/L;

  • Subclinical hyperthyroidism: normal free T4 and free T3 with serum TSH lower than 0.4 mU/L;

  • Euthyroid: normal serum TSH;

  • Subclinical hypothyroidism: normal free T4 and TSH higher than 5.5 mU/L;

  • Overt hypothyroidism: low free T4 and TSH higher than 5.5 mU/L.

STATISTICAL ANALYSIS

Data were summarized using medians, interquartile ranges (IQRs), proportions, and associated 95% confidence intervals (CIs). The Kolmogorov-Smirnov test was used to assess normality of free T4, free T3, and TSH values. The comparison of median concentrations of free T4 and TSH used Mann-Whitney and Kruskal-Wallis nonparametric tests. The comparison of proportions was achieved using Pearson χ2 and Fisher exact tests, as appropriate. The analysis of factors associated with the prevalence of AF was conducted using a logistic regression model. Backward stepwise elimination was used to produce a parsimonious logistic regression model, and the possibility of nonlinearity and interaction effects was also investigated.

PREVALENCE OF THYROID DYSFUNCTION

The cohort comprised 5860 subjects. The median age of the cohort was 72 years (range, 65-98 years; 50.9% female and 49.1% male). Overall distributions of age and free T4, free T3, and TSH values were significantly different from normal (P<.01); nonparametric statistics were therefore used to summarize and analyze these parameters. Fourteen subjects (0.2%) were found to have previously undiagnosed overt hyperthyroidism (median free T4, 1.93 ng/dL [24.8 pmol/L], IQR, 1.40-2.28 ng/dL [18.0-29.3 pmol/L]; free T3, 506.5 pg/dL [7.8 pmol/L], IQR, 474.0-571.4 pg/dL [7.3-8.8 pmol/L]; and TSH, <0.1 mU/L in all). Of the 5860 subjects, 126 (2.2%) had subclinical hyperthyroidism (median free T4, 1.20 ng/dL [15.5 pmol/L], IQR, 1.06-1.31 ng/dL [13.6-16.9 pmol/L]; and free T3, 311.7 pg/dL [4.8 pmol/L], IQR, 285.7-344.2 pg/dL [4.4-5.3 pmol/L]). Of these 126 subjects, serum TSH was undetectable (<0.1 mU/L) in 27; TSH concentration was reported as 0.1 mU/L in 11 and was low but detectable (0.2-0.3 mU/L) in the remaining 88. Of the 5860 subjects, 5519 (94.4%) were euthyroid (median free T4, 1.11 ng/dL [14.3 pmol/L], IQR, 1.01-1.22 ng/dL [13.0-15.7 pmol/L]; and TSH, 1.6 mU/L, IQR, 1.1-2.3 mU/L). There were 167 subjects (2.9%) who had subclinical hypothyroidism (median free T4, 0.98 ng/dL [12.6 pmol/L], IQR, 0.89-1.06 ng/dL [11.4-13.6 pmol/L]; and TSH, 6.8 mU/L, IQR, 6.0-8.8). Twenty-three subjects (0.4%) had overt hypothyroidism (median free T4, 0.58 ng/dL [7.5 pmol/L], IQR, 0.45-0.62 ng/dL [5.8-8.0 pmol/L]; and TSH, 40.6 mU/L, IQR, 16.7-52.2). There was a preponderance of women over men in the hyperthyroid (58%) and subclinical hypothyroid (65%) categories (P<.001). Ten subjects fell outside the prespecified diagnostic categories defined in the “Methods” section. Of these 10, 9 had a minor elevation of free T4 (range, 1.56-1.86 ng/dL [20.1-23.9 pmol/L]), with normal free T3 and TSH values, which were low but detectable in 7 (range, 0.2-0.3 mU/L) or undetectable in 2. The remaining subject had low free T4 (0.65 ng/dL [8.4 pmol/L]) and free T3 (201.3 pg/dL [3.1 pmol/L]), with serum TSH lower than 0.1 mU/L. One additional subject had an erroneous free T4 result reflecting familial dysalbuminemic hyperthyroxinemia. These 11 subjects were excluded from analyses based on thyroid status categories but were included in other analyses.

PREVALENCE OF AF ACCORDING TO CATEGORY OF THYROID STATUS

The prevalence of AF evident on resting ECG in the whole cohort was 4.8%, with a prevalence of 3.1% (91/2982) in women and a higher prevalence in men at 6.6% (189/2878) (odds ratio [OR], 2.23; P<.001). Of the cases of AF evident on ECG, 150 (53%) were newly found; a history of AF had been recorded in the remainder. The prevalence of AF according to category of thyroid status is given in Table 1; this indicates little variation in prevalence compared with the numerically dominant euthyroid group, with the exception of the subclinical hyperthyroid group. A comparison of the prevalence of AF between the euthyroid and subclinical hyperthyroid subjects allowing for differences between the sexes was achieved with a logistic regression of AF prevalence against thyroid status and sex. This confirmed the higher prevalence of AF in men (P<.001) and in subclinical hyperthyroid subjects when compared with euthyroid subjects (P = .01). A similar analysis showed no significant difference in AF prevalence between the euthyroid subjects and those in other categories of thyroid status (P = .57). The prevalence of AF in the 126 subjects with subclinical hyperthyroidism was 3.7% (1/27) in those with undetectable TSH and 11.1% (11/99) in those with low but detectable TSH (P = .46).

Table Graphic Jump LocationTable 1. The Prevalence of Atrial Fibrillation (AF) in the Cohort of 5860 Subjects Divided Into Categories of Thyroid Status*

Table 2 gives AF prevalence divided according to age and sex. Logistic regression of AF prevalence against age and sex revealed a significant rise with increasing category of age (P<.001) and higher prevalence in men than in women in all age groups (P<.001). The median ages of subjects with and without AF were 77 and 72 years, respectively (P<.001).

Table Graphic Jump LocationTable 2. The Prevalence of Atrial Fibrillation (AF) in the Cohort of 5860 Subjects Divided According to Category of Age and Sex
ASSOCIATION BETWEEN AF AND SERUM FREE T4 CONCENTRATION IN THE WHOLE COHORT

There was a significant difference in serum free T4 concentration between patients with AF and those without in the whole cohort (median free T4, 1.14 ng/dL [14.7 pmol/L], IQR, 0.12-1.27 ng/dL [13.5-16.4 pmol/L] vs 1.10 ng/dL [14.2 pmol/L], IQR, 1.00-1.22 ng/dL [12.9-15.7 pmol/L]; P<.001) but no significant difference in TSH concentration (median TSH, 1.6 mU/L in both groups; P = .82). Figure 1 illustrates the increasing prevalence of AF with increasing serum free T4 concentration for the whole cohort, the smooth curve being derived from logistic regression of the presence of AF vs free T4 level. Figure 2 shows a smoothed plot of the prevalence of AF vs free T4 for different ages and sexes derived from an additive effects logistic regression of the presence of AF vs free T4, sex, and age.

Place holder to copy figure label and caption
Figure 1.

Prevalence of atrial fibrillation (AF) on resting 12-lead electrocardiogram plotted against serum free thyroxine (T4) concentrations in the whole cohort. The plotted points were obtained by rounding each free T4 measurement to the nearest integer; the superimposed curve is that given by a logistic regression on the actual values of free T4 vs presence/absence of AF. To convert free T4 to nanograms per deciliter, divide by 12.87.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Prevalence of atrial fibrillation (AF) on resting 12-lead electrocardiogram plotted against serum free thyroxine (T4) concentrations in the whole cohort subdivided by age and sex (A, men; B, women). To convert free T4 to nanograms per deciliter, divide by 12.87.

Graphic Jump Location

Logistic regression analysis, taking into account risk factors for AF defined previously in the Framingham cohort (smoking, diabetes mellitus, hypertension, heart failure, and ischemic heart disease) (Table 3), showed a persistent association of AF with increasing serum free T4 concentration, subclinical hyperthyroidism, age, and male sex, as well as the expected risk associated with diabetes mellitus, hypertension, and heart failure. Serum TSH, smoking, and ischemic heart disease were not significant independent predictors of AF (P = .94, .33, and .12, respectively). A difference in serum free T4 concentration of 1 pmol/L (0.08 ng/dL) was associated with an OR for the finding of AF of 1.08 (95% CI, 1.03-1.14; P<.001), while larger differences in free T4 concentrations of 2.5 pmol/L (0.19 ng/dL), 5.0 pmol/L (0.39 ng/dL), and 10.0 pmol/L (0.78 ng/dL) were associated with larger ORs of 1.21 (95% CI, 1.06-1.38), 1.47 (95% CI, 1.13-1.91), and 2.17 (95% CI, 1.29-3.63), respectively.

Table Graphic Jump LocationTable 3. Logistic Regression Analyses of the Presence of AF vs Significant Demographic and Diagnosed Risk Factors in the Whole Cohort*
ASSOCIATION BETWEEN THE FINDING OF AF AND SERUM FREE T4 CONCENTRATION IN SUBJECTS WITHOUT THYROID DYSFUNCTION

In view of the well-recognized influence of overt thyroid dysfunction on AF risk,26 further analysis was performed excluding those with previously undiagnosed overt hyperthyroidism and hypothyroidism. The remaining group comprised 5812 subjects, 279 (4.8%) of whom had AF on ECG. Serum free T4 concentration remained higher in those with AF than in those without (median free T4, 1.14 ng/dL [14.7 pmol/L], IQR, 1.05-1.27 ng/dL [13.5-16.4 pmol/L] vs 1.10 ng/dL [14.2 pmol/L], IQR, 1.00-1.22 ng/dL [12.9-15.7 pmol/L]; P<.001). Atrial fibrillation was found more commonly in men than in women (189/2862 [6.6%] vs 90/2950 [3.1%]; adjusted OR, 2.40; P<.001). The median age of those with AF remained higher than in those without (age, 77 vs 72 years; P<.001). Logistic regression analysis of the significant risk factors for this subgroup that excluded those with overt thyroid dysfunction produced similar results to those seen for the whole cohort (Table 4).

Table Graphic Jump LocationTable 4. Logistic Regression Analyses of the Presence of Atrial Fibrillation vs Significant Demographic and Diagnosed Risk Factors in Subgroups of the Cohort*

Further subgroup analysis confined to those 5519 euthyroid subjects in the cohort with normal serum TSH concentrations (0.4-5.5 mU/L) again revealed higher free T4 concentrations in those with AF compared with those without (median free T4, 1.13 ng/dL [14.6 pmol/L], IQR, 1.05-1.26 ng/dL [13.5-16.2 pmol/L] vs 1.10 ng/dL [14.2 pmol/L], IQR, 1.01-1.21 ng/dL [13.0-15.6 pmol/L]; P = .001). Logistic regression (Table 4) again revealed increasing category of age and male sex to be independent predictors of AF (prevalence of AF, 6.5% [men] vs 2.9% [women]; adjusted OR, 2.44; P<.001). Serum free T4 was again an independent predictor of AF. The final column in Table 4 used a more stringent definition of euthyroidism, namely TSH concentration in the range of 0.4-4.0 mU/L, inclusive. Serum free T4 remained an independent predictor of AF (P = .009), as did other factors significant when the euthyroid range of TSH concentration was defined as 0.4 to 5.5 mU/L.

Because it is well recognized that amiodarone therapy is associated with a rise in serum free T4 concentration (typically within the normal range)27 and this therapy is prescribed in AF, an analysis was repeated excluding results from the 25 subjects in the cohort prescribed this drug, to avoid any potential bias of association. After this exclusion, serum free T4 remained an independent predictor of AF, with a minimal difference in OR (per 1-pmol/L change [0.08 ng/mL] of free T4, 1.07; 95% CI, 1.02-1.13; P = .01), and the association with subclinical hyperthyroidism remained significant (OR, 1.92; 95% CI, 1.03-3.70; P = .04).

The present study has revealed an association between the finding of AF on resting ECG and serum free T4 concentration in a large community-based elderly cohort, even in biochemically euthyroid subjects with normal serum TSH concentrations. As expected, there was an association of AF with increasing age and male sex, as well as other recognized risk factors including hypertension, heart failure, and diabetes mellitus,28 the overall prevalence of AF being similar to that described in other cohorts of similar age.2932 Taking previously recognized risk factors into account, serum free T4 was an independent predictor of the presence of AF in the cohort as a whole, and this association was sustained after exclusion of those with overt thyroid dysfunction. Furthermore, when the analysis was further restricted to those classified as euthyroid (with normal serum TSH concentration), this independent relationship between serum free T4 and AF was still evident.

OVERT AND SUBCLINICAL HYPERTHYROIDISM AND AF RISK

It is well recognized that overt hyperthyroidism is associated with AF, the reported prevalence being 5% to 15%.26,33 This association of AF and overt hyperthyroidism is more common with increasing age and with underlying cardiovascular disease, especially structural heart disease26,34,35 and is known to be associated with complications, especially stroke.34,36 The present study revealed only a low prevalence of previously undiagnosed overt hyperthyroidism detected by screening; none of these subjects had AF.

A topic of considerable debate and importance is the relevance of subclinical hyperthyroidism to AF risk, especially in older age groups. Several studies have indicated an association between subclinical hyperthyroidism and AF prevalence or incidence. Ten years of follow-up of more than 2000 subjects 60 years or older, who were part of the Framingham cohort, revealed an adjusted relative risk of 3.1 (95% CI, 1.7-5.5) for development of AF in the undetectable TSH group and 1.6 (95% CI, 1.0-2.5) in those with low but detectable TSH.7 This cohort was different from the present one in that it included subjects with overt hyperthyroidism and taking thyroid hormones, which may account for the higher prevalence of subclinical thyroid dysfunction than described here. Similar findings have recently been reported by Cappola et al6 investigating incident AF in 3233 US community-dwelling subjects 65 years or older. After exclusion of those with prevalent AF, those with subclinical hyperthyroidism (1.6% of the cohort) had a greater incidence of AF compared with those with normal thyroid function over a period of 12 years (adjusted hazards ratio, 1.98; 95% CI, 1.29-3.03).

A further large but retrospective cross-sectional study compared the prevalence of AF in 1338 subjects with overt or subclinical hyperthyroidism due to autonomous thyroid nodules or Graves disease with AF prevalence in a control group of 22 300 subjects admitted to a hospital.8 The AF prevalence was 13.8% in patients with overt hyperthyroidism, 12.7% in those with subclinical hyperthyroidism, and 2.3% in euthyroid controls. The relative risk of AF in those with subclinical hyperthyroidism was 5.2 (95% CI, 2.1-8.7) compared with controls. The results of the present study, in terms of the finding of increased AF prevalence in subclinical hyperthyroidism, are similar, but Auer et al8 did not explore any relationship of AF with thyroid hormone concentrations. A further difference is that in the present study, classification of subjects with regard to their thyroid status was restricted to biochemical investigation, and those classified subclinical hyperthyroid were not limited to those with proven underlying thyroid disease.

ASSOCIATION BETWEEN AF WITH SERUM FREE T4 CONCENTRATION

An intriguing and novel finding in the present study is the association between the presence of AF on ECG and serum free T4 concentration, a relationship still evident when those with thyroid dysfunction were excluded and when those prescribed amiodarone were excluded. An expected similar (but negative) association with serum TSH concentration was not evident, despite TSH being considered a more sensitive index of thyroid status than free T4. Circulating TSH reflects the negative feedback effects of T4 and T3 on the pituitary gland, as well as a variety of other influences such as nonthyroidal illnesses and drug therapies.37 It is possible that serum free T4 is a more sensitive index of cardiac “thyroid status” than TSH and that the present findings reflect particular sensitivity of the heart to T4. Several potential mechanisms could be invoked for the effect of T4 on AF risk, including elevation of left atrial pressure secondary to increased left ventricular mass and impaired ventricular relaxation,38 enhanced automaticity and triggered activity in pulmonary vein cardiomyocytes,39 ischemia resulting from raised resting heart rate, and increased atrial ectopic activity.40

Free T4 concentrations may themselves be modulated by “nonthyroidal” factors such as illnesses and drug therapies,37 the typical influence being reduction in free T4 concentration, and these same factors are likely to increase risk of AF. However, we found that low free T4 concentration was associated with the lowest prevalence of AF, arguing against any nonspecific influence of illness state or drug therapies.

The present finding of an association in euthyroid subjects between serum free T4 concentration and AF is consistent with a recent study of 403 ambulatory men aged 73 to 94 years in whom higher free T4 concentration within the reference range was associated with lower physical function, independent of age and illness,41 lending support to the view that variation of free T4 concentration, even within the normal range, may have deleterious physiological consequences.

STRENGTHS AND WEAKNESSES

Major strengths of our study were the recruitment of a large population-based cohort of older subjects that excluded those with current thyroid disease or previous hyperthyroidism and the documentation of major risk factors for AF. The prevalence of AF was determined by resting 12-lead ECG, with interpretation by a single blinded observer. Subgroup analysis was performed after exclusion of those with overt and subclinical thyroid dysfunction, and we performed analyses taking into account age, sex, and known risk factors, as well as category of thyroid status and serum free T4 concentration. A weakness is that incident data for AF and other vascular end points, including mortality, have yet to be recorded for this cohort.

The present study examined a community-based cohort of elderly subjects and specifically excluded those with current thyroid disease and previous hyperthyroidism. The finding of increased likelihood of AF in those with subclinical hyperthyroidism lends support to the small number of studies linking this biochemistry with AF risk.68 We found no association of subclinical hypothyroidism with AF, confirming the results in previous studies.68 The finding that subclinical hyperthyroidism detected as a result of screening is associated with AF contributes to the debate21 about the value of screening at-risk populations, such as elderly subjects, known to have a higher prevalence of undetected (and usually mild) thyroid dysfunction. This debate needs to be informed by evidence from trials investigating whether treatment prevents or reverses AF. In those receiving T4 replacement therapy, the findings add support to recommendations21 to adjust T4 doses until TSH and free T4 concentrations are within the reference range. In euthyroid subjects with normal TSH values, the finding of higher risk of AF in those with high but normal serum free T4 concentrations raises intriguing new questions about reducing risk of this important and common dysrhythmia in the general population.

Correspondence: M. D. Gammage, MD, FRCP, Department of Cardiovascular Medicine, Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, England (m.d.gammage@bham.ac.uk).

Accepted for Publication: December 24, 2006.

Author Contributions: Drs Gammage, Holder, and Franklyn had full access to the data and take responsibility for its integrity and accuracy of analysis. Study concept and design: Gammage, Parle, Holder, Roberts, Hobbs, Wilson, Sheppard, and Franklyn. Acquisition of data: Gammage, Parle, Holder, Roberts, Hobbs, Wilson, Sheppard, and Franklyn. Analysis and interpretation: Gammage, Parle, Holder, Roberts, Hobbs, Wilson, Sheppard, and Franklyn. Drafting and revision of manuscript: Gammage, Parle, Holder, Roberts, Hobbs, Wilson, Sheppard, and Franklyn. Statistical analysis: Holder. Obtained funding: Gammage, Parle, Holder, Roberts, Hobbs, Wilson, Sheppard, and Franklyn. Study supervision: Gammage, Parle, Holder, Roberts, Hobbs, Wilson, Sheppard, and Franklyn.

Financial Disclosure: None reported.

Funding/Support: This study was funded by a project grant from the Health Foundation, with matched support from the Primary Care Research Trust.

Role of the Sponsor: The funding agencies played no part in study design or execution.

Acknowledgment: We are grateful to the participating research nurses and 20 primary care practices and their staff and patients who took part in this study, as well as to all other members of the Birmingham Elderly Thyroid Study Team.

Tunbridge  WMEvered  DCHall  R  et al.  The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7481- 493
PubMed
Canaris  GJManowitz  NRMayor  GRidgway  EC The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160526- 534
PubMed
Hollowell  JGStaehling  NWFlanders  WD  et al.  Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87489- 499
PubMed
Parle  JVFranklyn  JACross  KWJones  SCSheppard  MC Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;3477- 83
PubMed
Biondi  BPalmieri  EAFazio  S  et al.  Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 2000;854701- 4705
PubMed
Cappola  ARFried  LPArnold  AM  et al.  Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;2951033- 1041
PubMed
Sawin  CTGeller  AWolf  PA  et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;3311249- 1252
PubMed
Auer  JScheibner  PMische  TLangsteger  WEber  OEber  B Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J 2001;142838- 842
PubMed
Wolf  PAAbbott  RDKannel  WB Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22983- 988
PubMed
Parle  JVMaisonneuve  PSheppard  MCBoyle  PFranklyn  JA Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358861- 865
PubMed
Biondi  BPalmieri  EALombardi  GFazio  S Subclinical hypothyroidism and cardiac function. Thyroid 2002;12505- 510
PubMed
Danese  MDLadenson  PWMeinert  CLPowe  NR Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab 2000;852993- 3001
PubMed
Ripoli  APingitore  AFavilli  B  et al.  Does subclinical hypothyroidism affect cardiac pump performance? evidence from a magnetic resonance imaging study. J Am Coll Cardiol 2005;45439- 445
PubMed
Gussekloo  Jvan Exel  Ede Craen  AJMeinders  AEFrolich  MWestendorp  RG Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;2922591- 2599
PubMed
Hak  AEPols  HAVisser  TJDrexhage  HAHofman  AWitteman  JC Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000;132270- 278
PubMed
Lindeman  RDRomero  LJSchade  DSWayne  SBaumgartner  RNGarry  PJ Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey. Thyroid 2003;13595- 600
PubMed
Rodondi  NNewman  ABVittinghoff  E  et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005;1652460- 2466
PubMed
Vanderpump  MPTunbridge  WMFrench  JM  et al.  The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid 1996;6155- 160
PubMed
Walsh  JPBremner  APBulsara  MK  et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005;1652467- 2472
PubMed
Rodondi  NAujesky  DVittinghoff  ECornuz  JBauer  DC Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med 2006;119541- 551
PubMed
Surks  MIOrtiz  EDaniels  GH  et al.  Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291228- 238
PubMed
Wilson  SParle  JVRoberts  LM  et al.  Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community based cross-sectional survey. J Clin Endocrinol Metab 2006;914809- 4816
PubMed
Jick  HJick  SSDerby  LE Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991;302766- 768
PubMed
Jick  SSKaye  JAVasilakis-Scaramozza  C  et al.  Validity of the general practice research database. Pharmacotherapy 2003;23686- 689
PubMed
Boelaert  KHoracek  JHolder  RLWatkinson  JCSheppard  MCFranklyn  JA Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab 2006;914295- 4301
PubMed
Klein  IOjamaa  K Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344501- 509
PubMed
Basaria  SCooper  DS Amiodarone and the thyroid. Am J Med 2005;118706- 714
PubMed
Peters  NSSchilling  RJKanagaratnam  PMarkides  V Atrial fibrillation: strategies to control, combat, and cure. Lancet 2002;359593- 603
PubMed
Heeringa  Jvan der Kuip  DAHofman  A  et al.  Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27949- 953
PubMed
Langenberg  MHellemons  BSvan Ree  JW  et al.  Atrial fibrillation in elderly patients: prevalence and comorbidity in general practice. BMJ 1996;3131534
PubMed
Phillips  SJWhisnant  JPO'Fallon  WMFrye  RL Prevalence of cardiovascular disease and diabetes mellitus in residents of Rochester, Minnesota. Mayo Clin Proc 1990;65344- 359
PubMed
Wolf  PAD'Agostino  RB Secular trends in stroke in the Framingham Study. Ann Epidemiol 1993;3471- 475
PubMed
Frost  LVestergaard  PMosekilde  L Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med 2004;1641675- 1678
PubMed
Petersen  PHansen  JM Stroke in thyrotoxicosis with atrial fibrillation. Stroke 1988;1915- 18
PubMed
Sandler  GWilson  GM The nature and prognosis of heart disease in thyrotoxicosis: a review of 150 patients treated with 131 I. Q J Med 1959;28347- 369
PubMed
Bar-Sela  SEhrenfeld  MEliakim  M Arterial embolism in thyrotoxicosis with atrial fibrillation. Arch Intern Med 1981;1411191- 1192
PubMed
Surks  MISievert  R Drugs and thyroid function. N Engl J Med 1995;3331688- 1694
PubMed
Fazio  SPalmieri  EALombardi  GBiondi  B Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res 2004;5931- 50
PubMed
Chen  YCChen  SAChen  YJChang  MSChan  PLin  CI Effects of thyroid hormone on the arrhythmogenic activity of pulmonary vein cardiomyocytes. J Am Coll Cardiol 2002;39366- 372
PubMed
Sgarbi  JAVillaca  FGGarbeline  BVillar  HERomaldini  JH The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab 2003;881672- 1677
PubMed
van den Beld  AWVisser  TJFeelders  RAGrobbee  DELamberts  SW Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab 2005;906403- 6409
PubMed

Figures

Place holder to copy figure label and caption
Figure 1.

Prevalence of atrial fibrillation (AF) on resting 12-lead electrocardiogram plotted against serum free thyroxine (T4) concentrations in the whole cohort. The plotted points were obtained by rounding each free T4 measurement to the nearest integer; the superimposed curve is that given by a logistic regression on the actual values of free T4 vs presence/absence of AF. To convert free T4 to nanograms per deciliter, divide by 12.87.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Prevalence of atrial fibrillation (AF) on resting 12-lead electrocardiogram plotted against serum free thyroxine (T4) concentrations in the whole cohort subdivided by age and sex (A, men; B, women). To convert free T4 to nanograms per deciliter, divide by 12.87.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. The Prevalence of Atrial Fibrillation (AF) in the Cohort of 5860 Subjects Divided Into Categories of Thyroid Status*
Table Graphic Jump LocationTable 2. The Prevalence of Atrial Fibrillation (AF) in the Cohort of 5860 Subjects Divided According to Category of Age and Sex
Table Graphic Jump LocationTable 3. Logistic Regression Analyses of the Presence of AF vs Significant Demographic and Diagnosed Risk Factors in the Whole Cohort*
Table Graphic Jump LocationTable 4. Logistic Regression Analyses of the Presence of Atrial Fibrillation vs Significant Demographic and Diagnosed Risk Factors in Subgroups of the Cohort*

References

Tunbridge  WMEvered  DCHall  R  et al.  The spectrum of thyroid disease in a community: the Whickham survey. Clin Endocrinol (Oxf) 1977;7481- 493
PubMed
Canaris  GJManowitz  NRMayor  GRidgway  EC The Colorado thyroid disease prevalence study. Arch Intern Med 2000;160526- 534
PubMed
Hollowell  JGStaehling  NWFlanders  WD  et al.  Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab 2002;87489- 499
PubMed
Parle  JVFranklyn  JACross  KWJones  SCSheppard  MC Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin Endocrinol (Oxf) 1991;3477- 83
PubMed
Biondi  BPalmieri  EAFazio  S  et al.  Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 2000;854701- 4705
PubMed
Cappola  ARFried  LPArnold  AM  et al.  Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 2006;2951033- 1041
PubMed
Sawin  CTGeller  AWolf  PA  et al.  Low serum thyrotropin concentrations as a risk factor for atrial fibrillation in older persons. N Engl J Med 1994;3311249- 1252
PubMed
Auer  JScheibner  PMische  TLangsteger  WEber  OEber  B Subclinical hyperthyroidism as a risk factor for atrial fibrillation. Am Heart J 2001;142838- 842
PubMed
Wolf  PAAbbott  RDKannel  WB Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22983- 988
PubMed
Parle  JVMaisonneuve  PSheppard  MCBoyle  PFranklyn  JA Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 2001;358861- 865
PubMed
Biondi  BPalmieri  EALombardi  GFazio  S Subclinical hypothyroidism and cardiac function. Thyroid 2002;12505- 510
PubMed
Danese  MDLadenson  PWMeinert  CLPowe  NR Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J Clin Endocrinol Metab 2000;852993- 3001
PubMed
Ripoli  APingitore  AFavilli  B  et al.  Does subclinical hypothyroidism affect cardiac pump performance? evidence from a magnetic resonance imaging study. J Am Coll Cardiol 2005;45439- 445
PubMed
Gussekloo  Jvan Exel  Ede Craen  AJMeinders  AEFrolich  MWestendorp  RG Thyroid status, disability and cognitive function, and survival in old age. JAMA 2004;2922591- 2599
PubMed
Hak  AEPols  HAVisser  TJDrexhage  HAHofman  AWitteman  JC Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann Intern Med 2000;132270- 278
PubMed
Lindeman  RDRomero  LJSchade  DSWayne  SBaumgartner  RNGarry  PJ Impact of subclinical hypothyroidism on serum total homocysteine concentrations, the prevalence of coronary heart disease (CHD), and CHD risk factors in the New Mexico Elder Health Survey. Thyroid 2003;13595- 600
PubMed
Rodondi  NNewman  ABVittinghoff  E  et al.  Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch Intern Med 2005;1652460- 2466
PubMed
Vanderpump  MPTunbridge  WMFrench  JM  et al.  The development of ischemic heart disease in relation to autoimmune thyroid disease in a 20-year follow-up study of an English community. Thyroid 1996;6155- 160
PubMed
Walsh  JPBremner  APBulsara  MK  et al.  Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch Intern Med 2005;1652467- 2472
PubMed
Rodondi  NAujesky  DVittinghoff  ECornuz  JBauer  DC Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis. Am J Med 2006;119541- 551
PubMed
Surks  MIOrtiz  EDaniels  GH  et al.  Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004;291228- 238
PubMed
Wilson  SParle  JVRoberts  LM  et al.  Prevalence of subclinical thyroid dysfunction and its relation to socioeconomic deprivation in the elderly: a community based cross-sectional survey. J Clin Endocrinol Metab 2006;914809- 4816
PubMed
Jick  HJick  SSDerby  LE Validation of information recorded on general practitioner based computerised data resource in the United Kingdom. BMJ 1991;302766- 768
PubMed
Jick  SSKaye  JAVasilakis-Scaramozza  C  et al.  Validity of the general practice research database. Pharmacotherapy 2003;23686- 689
PubMed
Boelaert  KHoracek  JHolder  RLWatkinson  JCSheppard  MCFranklyn  JA Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab 2006;914295- 4301
PubMed
Klein  IOjamaa  K Thyroid hormone and the cardiovascular system. N Engl J Med 2001;344501- 509
PubMed
Basaria  SCooper  DS Amiodarone and the thyroid. Am J Med 2005;118706- 714
PubMed
Peters  NSSchilling  RJKanagaratnam  PMarkides  V Atrial fibrillation: strategies to control, combat, and cure. Lancet 2002;359593- 603
PubMed
Heeringa  Jvan der Kuip  DAHofman  A  et al.  Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur Heart J 2006;27949- 953
PubMed
Langenberg  MHellemons  BSvan Ree  JW  et al.  Atrial fibrillation in elderly patients: prevalence and comorbidity in general practice. BMJ 1996;3131534
PubMed
Phillips  SJWhisnant  JPO'Fallon  WMFrye  RL Prevalence of cardiovascular disease and diabetes mellitus in residents of Rochester, Minnesota. Mayo Clin Proc 1990;65344- 359
PubMed
Wolf  PAD'Agostino  RB Secular trends in stroke in the Framingham Study. Ann Epidemiol 1993;3471- 475
PubMed
Frost  LVestergaard  PMosekilde  L Hyperthyroidism and risk of atrial fibrillation or flutter: a population-based study. Arch Intern Med 2004;1641675- 1678
PubMed
Petersen  PHansen  JM Stroke in thyrotoxicosis with atrial fibrillation. Stroke 1988;1915- 18
PubMed
Sandler  GWilson  GM The nature and prognosis of heart disease in thyrotoxicosis: a review of 150 patients treated with 131 I. Q J Med 1959;28347- 369
PubMed
Bar-Sela  SEhrenfeld  MEliakim  M Arterial embolism in thyrotoxicosis with atrial fibrillation. Arch Intern Med 1981;1411191- 1192
PubMed
Surks  MISievert  R Drugs and thyroid function. N Engl J Med 1995;3331688- 1694
PubMed
Fazio  SPalmieri  EALombardi  GBiondi  B Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res 2004;5931- 50
PubMed
Chen  YCChen  SAChen  YJChang  MSChan  PLin  CI Effects of thyroid hormone on the arrhythmogenic activity of pulmonary vein cardiomyocytes. J Am Coll Cardiol 2002;39366- 372
PubMed
Sgarbi  JAVillaca  FGGarbeline  BVillar  HERomaldini  JH The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J Clin Endocrinol Metab 2003;881672- 1677
PubMed
van den Beld  AWVisser  TJFeelders  RAGrobbee  DELamberts  SW Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J Clin Endocrinol Metab 2005;906403- 6409
PubMed

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