Atrial fibrillation (AF) is the most common cardiac complication of hyperthyroidism, occurring in up to 15% of patients. Hyperthyroidism is defined as a hyper production of triiodothyronine (T3) hormone and an increase in peripheral thyroxine (T4).^[1],^[2] AF in hyperthyroidism is associated with increased thrombo-embolic risk and mortality^[2] and inflammation has been shown to be associated with AF in different patient populations.^[3]–^[11]

The relationship between hyperthyroidism and inflammation is unclear. However, a case study reported that hyperthyroidism was associated with an interstitial inflammation of the atrioventricular node, the His-bundle and its branches at autopsy findings. The authors assumed that death was caused by an arrhythmia due to thyrotoxicosis.^[12] Pearce, et al.^[13] showed that C-reactive protein (CRP) levels were similar among euthyroid, non-goitrous controls and patients with toxic or no-ntoxic, multi-nodular, goiter, or Graves' disease. It has been reported that serum CRP levels did not correlate with thyroid hormone levels in hypothyroid subjects.^[14] However, when compared with euthyroid control subjects, patients with hyperthyroidism had significantly elevated serum levels of interleukin-8 and tumor necrosis factor alpha (TNF-α).^[15] Additionally, the mean serum levels of interleukin-6 (IL-6) and IL-8 were significantly elevated in both Graves' disease and toxic, nodular goiter patients compared with the controls. The elevations in serum levels of IL-1, IL-6 and IL-8 that occur in hyperthyroidism seem to result from the chronic effects of excess thyroid hormone rather than the accompanying autoimmune inflammatory condition produced by Graves' thyroid or eye disease.^[16] However, to the best of our knowledge, no previous studies have evaluated whether there is also a relationship between inflammation and the development of AF in patients with hyperthyroidism. Therefore, the aim of this study was to evaluate the relationship between serum levels of high-sensitivity C-reactive protein (HsCRP), as a marker of inflammation and the development of AF in patients with hyperthyroidism.

A total of 65 patients with hyperthyroidism, 35 of whom in HT-SR group and 30 of whom in HT-AF group and 35 patients in the control group were studied. Patients' characteristics are presented in Table 1. Clinical findings were similar among the three groups (All P values > 0.05, Table 1).

Left atrial diameter was larger in the HT-AF group than the HT-SR group (P < 0.0001) and the control group (P < 0.0001). However, HT-SR and control groups had similar left atrial dia- meters (P = 0.19). LV mass was higher in the HT-AF group than the HT-SR group (P = 0.027) and the control group (P = 0.003). However, HT-SR group and control group had similar LV mass (P = 0.719).

HsCRP levels were higher in the HT-AF group compared to the HT-SR group (P = 0.02) and the control group (P = 0.001). However, similar values were found between the HT- SR and the control groups (P = 0.63).

Free T3 levels were higher in the HT-AF group compared to the HT-SR group (P = 0.04) and the control group (P < 0.0001) although the levels were higher in the HT-SR group as compared to the control group (P = 0.02).

Free T4 levels were higher in the HT-AF group compared to the HT-SR group (P < 0.0001) and the control group (P < 0.0001) and they were higher in the HT-SR group as compared to the control group (P = 0.02).

TSH levels were higher in the control group compared to the HT-AF group (P < 0.0001) and the HT-SR group (P < 0.0001). However, similar values were found between the HT-AF group and the HT-SR group (P = 1).

Medication use was similar among the groups (Table 1). Factors associated with AF in multivariate analysis found in Table 2 included, HsCRP (OR: 11.19; 95% CI: 1.80–69.53; P = 0.003), free T4 (OR: 8.76; 95% CI: 2.09–36.7; P = 0.003) and left atrial diameter (OR: 1.25; 95% CI: 1.06– 1.47; P = 0.008).

The present study suggests that HsCRP, an indicator of inflammation, free T4 and left atrial diameter are associated with the development AF in patients with hyperthyroidism.

Inflammation has been shown to be associated with AF in different patient populations.^[3]–^[11] According to our results, it appears the same association is also present in patients with hyperthyroidism.

Serum freeT4 levels have been found to be an independent predictor of AF.^[18],^[19] The present study is in agreement with previous reports and indicates that free T4 is independently associated with the development of AF in patients with hyperthyroidism.

Iwasaki, et al.^[20] found that patients with toxic nodular goiter had an increased incidence of AF compared to patients with Grave's disease, probably due to their increased age. Subclinical hyperthyroidism is a risk factor for the development of AF.^[21] However, we excluded the patients with subclinical hyperthyroidism and patients with Graves' disease. Therefore, if those patients were included in the present study, our results may have been different.

Iwasaki, et al.^[20] have shown that the majority of patients with hyperthyroidism and AF have an enlarged left atrium. Our study also supports those findings.

Generally, the initiation of AF occurs with premature complexes originating from the pulmonary veins, and the persistence of AF requires re-entry.^[22],^[23] Premature complexes occur secondary to automaticity or triggered activity.^[1],^[24] Increased automaticity and triggered activity in response to elevated T4 levels have been shown in isolated rabbit atrial and pulmonary vein cells.^[24],^[25] Wustmann, et al.^[26] have found increased supraventricular ectopic activity in normal hearts and those of patients with hyperthyroidism. Premature complexes may be secondary to a direct effect of thyroid hormones or their sympathomimetic effects.^[27] Re-entry mostly occurs in patients with structural,^[28],^[29] or electrical remodeling.^[30] It was found that the incidence of abnormal right atrial electrograms was significantly higher in patients with lone paroxysmal AF than in patients without AF or hyperthyroidism. The atrial effective refractory period was significantly shorter in paroxysmal AF and hyperthyroidism than in patients without AF or hyperthyroidism, and patients with lone paroxysmal AF. A substrate in the atrium might not be essential to the genesis of AF in hyperthyroidism.^[31] By shortening the atrial refractory period and atrial action potential duration, thyroid hormones favor re-entry and the persistence of AF.^[1],^[31] The duration of the repolarization was shortened in rabbits given L-thyroxine and was prolonged in thyroidectomized rabbits.^[32] Elevation of left atrial pressure secondary to increased left ventricular mass and impaired ventricular relaxation^[33] and ischemia resulting from raised resting heart rate^[34] and inflammation^[12],^[16] may also play a role in the occurrence of AF in these patients.

However, this was an observational study, and as such, we may will have missed some paroxysmal AF recurrences in the HT-SR group or control group. The data on left atrial area and volume are lacking. Drug treatment was not standardized. We did not include the patients with subclinical hyperthyroidism or Graves' disease that could have an affect on the results.

In conclusion, the present study suggests that high sensitivity C reactive protein, an indicator of inflammation, free T4 and left atrial diameter are associated with the development of AF in patients with hyperthyroidism.