Cardiac Autonomic Dysfunction in Euthyroid Hashimoto 191Tohoku J. Exp. Med., 2012, 226, 191-195

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Received January 24, 2012; revision accepted for publication February 5, 2012. doi: 10.1620/tjem.226.191Correspondence: Ayhan Kilic, M.D., Department of Pediatric Cardiology, Gulhane Medical Academy, 06018, Ankara, Turkey.e-mail: akilic@tr.net

Cardiac Autonomic Regulation Is Disturbed in Children with Euthyroid Hashimoto Thyroiditis

Ayhan Kilic,1 Mustafa Gulgun,1 Mehmet Emre Tascilar,2 Erkan Sari2 and Mehmet Yokusoglu3

1Department of Pediatric Cardiology, Gulhane Medical Academy, Ankara, Turkey2Department of Pediatric Endocrinology, Gulhane Medical Academy, Ankara, Turkey3Department of Cardiology, Gulhane Medical Academy, Ankara, Turkey

Hashimoto thyroiditis (chronic autoimmune thyroiditis) is the most common form of thyroiditis in childhood. Previous studies have found autonomic dysfunction of varying magnitude in patients with autoimmune diseases, which is considered a cardiovascular risk factor. We aimed to evaluate the heart rate variability (HRV), a measure of cardiac autonomic modulation, in children with euthyroid Hashimoto thyroiditis (eHT). The study included 32 patients with eHT (27 girls and 5 boys; mean age 11 4.1 years, range 8-16; body mass index 0.47 0.69 kg/m2), as judged by normal or minimally elevated serum TSH levels (normal range: 0.34-5.6 mIU/l) and normal levels of free thyroid hormones (FT4 and FT3) and 38 euthyroid age-matched controls. Patients with eHT and control subjects underwent physical examination and 24-hour ambulatory ECG monitoring. Time-domain parameters of HRV were evaluated for cardiac autonomic functions. Children with eHT displayed significantly lower values of time-domain parameters of SDANN (standard deviation of the averages of NN intervals), RMSSD (square root of the mean of the sum of the squares of differences between adjacent NN intervals), NN50 counts (number of pairs of adjacent NN intervals differing by more than 50 ms) and PNN50 (NN50 count divided by the total number of all NN intervals) for each 5-min interval, compared to healthy controls ( p < 0.05 for each), indicating the decreased beat-to-beat variation of heart rate. In conclusion, eHT is associated with disturbed autonomic regulation of heart rate. Hence, the children with eHT are at higher risk for developing cardiovascular diseases.

Keywords: cardiac autonomic regulation; cardiovascular risk; euthyroid; Hashimoto thyroiditis; heart rate variability.Tohoku J. Exp. Med., 2012, 226 (3), 191-195. 2012 Tohoku University Medical Press

Hashimotos thyroiditis (chronic autoimmune thyroidi-tis), first described by Hakaru Hashimoto in 1912, is the most common form of thyroiditis in childhood and a frequ-ent cause of acquired hypothyroidism (Hashimoto 1912). The natural history of the disease follows the phases of 1) toxic, transient, self-limited thyroiditis; 2) euthyroid goiter; 3) hypothyroidism with/without goiter. However, children may be in any of these phases on the first medical consulta-tion, since there is not a fixed duration for each stage (Radetti et al. 2006; Demirbilek et al. 2007).

Neurological manifestations have been shown to occur in patients with autoimmune diseases such as familial Mediterranean fever or systemic lupus erythematous, often subclinically (Stojanovich et al. 2007).

Heart rate variability (HRV), defined as degree of fluc-tuation of the beat-to-beat differences in cardiac rhythm, is known to be a reliable noninvasive test for investigating the function of the autonomic nervous system and has been used as a predictor of sudden cardiac death, as a marker of the progression of cardiovascular disease in several high-

risk situations (Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology 1996). Clinical studies have shown that reduced HRV correlates with an increased risk of cardiac mortality. Autonomic imbalance, characterized by a hype-ractive sympathetic system and a hypoactive parasympathe-tic system, is associated with various pathological conditi-ons. Detection of such changes, especially for the evaluation of autonomic nervous system functions, may be used as a marker of underlying pathology (Tascilar et al. 2011).

As significant autonomic nervous system involvement and cardiovascular risks have been shown in earlier studies in both hypo- and hyperthyroid states, cardiological consul-tation has been part of our follow-up in children with sus-pected or proven thyroid diseases (Inukai et al. 1998; Chen et al. 2006; Galetta et al. 2008). However, to the best of our knowledge, autonomic influence in euthyroid Hashimoto thyroiditis (eHT) has not yet been studied. In this study, we aimed to investigate the cardiac autonomic functions in

A. Kilic et al.192

children with eHT by using time-domain parameters of HRV.

Subjects and MethodsWe retrospectively analyzed the clinical data of 32 children

with euthyroid Hashimoto thyroiditis (27 girls and 5 boys; mean age 11 4.1 years, range: 7-15; body mass index 0.47 0.69 kg/m2), as judged by normal or slightly elevated TSH levels (range 1.1-5.6 mIU/L) and free thyroid hormones within the normal range for age. Thirty-eight age- and sex-matched healthy children served as cont-rols. The study protocol was approved by the institutional ethical committee. All cases were evaluated with a thorough history and physical examination.

The thyroid gland was assessed by palpation and graded accor-ding to the goiter classification system proposed by the World Health Organization (Perez et al. 1960). Serum samples were drawn for measurement of blood biochemistry including cholesterol subtypes, triglycerides, free triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone (TSH), anti-thyroglobulin and anti-thyroid pero-xidase antibody. Overt hypothyroidism was defined as the presence of high basal TSH levels with low T4 levels. Patients with subclinical hypothyroidism had normal T4 and elevated basal TSH levels. The diagnosis of hyperthyroidism was established in the presence of supp-ressed basal TSH level (below 0.5 mIU/mL) with high or normal T4 levels (overt or subclinical hyperthyroidism, respectively) (Surks et al. 1990). Diagnosis of eHT was established in the presence of nor-mal or slightly high TSH and normal free T4 levels (Baskin et al. 2002).

HRV analysisTwenty-four-hour ambulatory electrocardiographic recordings

were obtained from each subject with a Rozinn RZ 152 digital Holter recorder system (Rozinn Electronics, Inc., Glendale, NY, USA), with a sampling frequency of 1024 Hz. All cases were strictly advised to maintain the normal course of their daily life. Their compliance was confirmed again while removing the device from the cases. The recordings were scrutinized for exclusion of beats that were not origi-nated from the sinoatrial node and HRV was determined from normal beats (hence the term NN), using the software of the same device.

The time-domain HRV measures employed in our study include SDNN, SDANN, RMSDD, SDNN index, SDSD, NN50 count and PNN50 and are summarized in Table 1. Among these parameters, RMSSD, NN50 count and PNN50 primarily reflect parasympatheti-cally mediated changes in heart rate. Other time-domain variables reflect a mixture of parasympathetic, sympathetic and other physiolo-gic influences.

Statistical analysisWe used SPSS for Windows, version 15 software (SPSS Inc.,

Chicago, IL, USA) in the analysis. The Shapiro-Wilk test was used to test for normality of variables. The decision to perform parametric testing was based on the result of this test for continuous variables. Comparisons between the groups were carried out with two-tailed Students T test for normally distributed continuous variables. All data were expressed as mean standard deviation. P values below 0.05 were considered significant.

ResultsClinical characteristics

Clinical characteristics and thyroid hormone profiles of children with eHT and controls are summarized in Table 2. The groups of eHT and controls were well matched in terms of age, sex, body mass index, blood pressure, free T4 and TSH levels, lipid profile and heart rate.

All subjects were seen to be in sinus rhythm, without any evidence of conduction abnormalities or ventricular tachyarrhythmias on surface ECG or 24-hour ambulatory ECG monitoring.

HRV analysisHRV indices obtained from the patients and the cont-

rols are illustrated in Table 3, along with statistical compa-rison between the groups. Time domain indices of SDANN, RMSSD, NN50 count and PNN50 recorded from eHT patients were significantly lower than that of controls (p < 0.05 for all). Only SDNN was not significantly altered (p = 0.66). These findings suggested a disturbed sympa-thovagal balance in children with eHT.

DiscussionThe purpose of this study was to study the presence of

autonomic dysregulation in young subjects with euthyroid Hashimoto thyroiditis as has been shown in hypothyroid and hyperthyroid Hashimoto thyroiditis. This study has revealed that the time-domain HRV parameters are reduced in children with eHT, which point to the presence of sym-pathovagal imbalance characterized by cardiovascular sym-pathetic and vagal activity in these subjects.

HRV is generated by regulation of blood pressure and respiration through the nucleus tractus solitarii in the mid-brain. Heart rate variability (HRV) is the beat-to-beat varia-

Table 1. Definitions of HRV parameters analyzed in the study.

Variable Unit Definition

SDNN milliseconds Standard deviation of all NN intervalsSDANN milliseconds Standard deviation of the averages of NN intervals in all 5 min segments of the entire recordingRMSSD milliseconds The square root of the mean of the sum of the squares of differences between adjacent NN intervalsSDNN index milliseconds Mean of the standard deviations of all NN intervals for all 5 min segments of the entire recordingSDSD milliseconds Standard deviation of differences between adjacent NN intervalsNN50 count Number of pairs of adjacent NN intervals differing by more than 50 ms in the entire recordingPNN50 percent NN50 count divided by the total number of all NN intervals

Cardiac Autonomic Dysfunction in Euthyroid Hashimoto 193

tion in either heart rate or the duration of the RR interval. Although the exact contributions of the parasympathetic and the sympathetic divisions of the autonomic nervous system to this variability are controversial, both central and peripheral mechanisms can contribute to these beat-to-beat changes in heart rate (Billman 2011). In earlier studies, Hashimoto thyroiditis has been associated with central ner-vous system disturbances, independent of thyroid functions. Leyhe et al. (2008) have reported mild brain dysfunction in patients with Hashimoto thyroiditis even when they are euthyroid. The fact that autoimmune encephalitis can develop in cases with Hashimoto thyroiditis in the presence of normal thyroid hormone levels and elevated antithyroid peroxidase autoantibodies suggest that parts of the brain related to the autonomic nervous system can be affected (Castillo et al. 2006). Besides, Harzheim et al. (2006) have reported a case of Hashimoto thyroiditis with motor neuron disease accompanying encephalitis, suggesting a common autoimmune pathogenesis. Disturbed HRV in eHT might be a consequence of involvement of the central nervous

system.Hashimoto thyroiditis is an autoimmune disorder

capable of affecting various organ systems. Autoimmune disorders are commonly known to mimic or overlap others (Gulcan et al. 2009). Stojanovich et al. (2007) have repor-ted autonomic nervous system dysfunction in autoimmune rheumatic disorders such as systemic lupus erythematosus, rheumatoid arthritis and primary Sjgren syndrome. Various autonomic system disturbances have been noted in patients with other autoimmune rheumatic disorders, inclu-ding ankylosing spondylitis, fibromyalgia and systemic sclerosis (Stojanovic 2009). Canpolat et al. (2011) have also shown disturbed HRV parameters in familial Mediterranean fever, another autoinflammatory disorder. Although altered cardiac autonomic balance has been shown in the hypothyroid and subclinically hypothyroid patients with Hashimoto thyroiditis, there is not any study on the evaluation of cardiac autonomic functions in euthy-roid children with Hashimoto thyroiditis (Galetta et al. 2008).

Table 2. Demographic, clinical and biochemical values in the euthyroid Hashimoto thyroiditis and the control groups (mean s.d.).

Euthyroid Hashimoto thyroiditis group (n = 32)

Control group(n = 38)

Age (range) 11 4.1 (7-16) 11 2.99 (8-15)Sex (male/female) 5/27 10/28BMI SDS 0.047 0.69 0.046 0.83HR (beats/min) 98 32 104 44Total Cholesterol (mg/dL) 174 18.3 166.2 25.2SBP (mmHg) 86 11.2 89 9.1DBP (mmHg) 65 3.1 66 3.4Triglyceride (mg/dL) 85 39.3 81 40.9HDL-cholesterol (mg/dL) 50.8 12 55.4 13LDL-cholesterol (mg/dL) 98.3 30.9 93.3 27.9VLDL-cholesterol (mg/dL) 17.7 6.5 15.4 7.4TSH (mIU/L) 3.5 2.3 3.4 2.1Free T3 (pmol/L) 3.4 1.7 3.3 1.5Free T4 (pmol/L) 0.89 0.18 0.9 0.2

BMI, body mass index; HR, heart rate; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 3. Time-domain HRV parameters of the euthyroid Hashimoto thyroiditis and the control groups.

Euthyroid Hashimotos thyroiditis group (n = 32) Control group (n = 38) p value

SDNN (ms) 143.06 38.52 146.89 35.9 0.66SDANN (ms) 32.00 12.51 104.39 40.89 < 0.001RMSDD (ms) 68.06 34.64 89.26 43.40 0.029SDNN index 70.40 24.94 83.78 25.88 0.032SDSD 67.90 34.33 89.26 43.40 0.028NN50 count 21,189 11,073 32709 10606 < 0.001PNN50 (%) 25.39 15.75 32.65 12.10 0.015

Abbreviations as in the text.

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Galetta et al. (2006) have reported abnormalities in cardiac autonomic functions in children with Hashimoto thyroiditis with normal thyroid hormones and elevated TSH levels, ie. subclinical hypothyroidism, and suggested that this could be related to elevation of TSH levels. In our study, the finding of autonomic dysfunction in the absence of significant TSH elevation in children with eHT suggests the presence of other pathogenetic factors. Vascular endo-thelial cells play an important role in cardiovascular regula-tion by secreting various vasoactive compounds like nitric oxide, prostacyclin, endothelium-derived relaxing factor and other hyperpolarizing or vasoconstrictor substances. Endothelial dysfunction plays a role in the pathogenesis of certain cardiovascular disorders, such as hypertension and atherosclerosis, and is known to be related to autonomic imbalance (Harris and Matthews 2004).

Thayer et al. have reviewed the evidence linking HRV to established and emerging modifiable and non-modifiable cardiovascular disease risk factors such as hypertension, obesity, family history and work stress. Substantial evi-dence exists to support the notion that decreased HRV pre-cedes the development of a number of risk factors and that lowering risk profiles is associated with increased HRV. They suggest that autonomic imbalance may be a final com-mon pathway to increased morbidity and mortality from a host of conditions and diseases, including cardiovascular disease (Thayer et al. 2010).

Inflammation can lead to endothelial damage. de la Vega et al. (1998) have shown that IL-10 levels are increased in thyroid tissue samples of patients with Hashimoto thyroiditis and this can lead to stimulation of B cell proliferation and antibody production. Patients with Hashimoto thyroiditis display higher levels of inflammation markers such as TNF- or IFN- (Gulcan et al. 2009). Taddei et al. (2006) have reported low-grade inflammation in subclinically hypothyroid cases with Hashimoto thyroid-itis causing endothelial dysfunction and impairment of nitric oxide availability leading to increased production of oxidative stress. In our study, endothelial dysfunction may have contributed to the development of autonomic dysregu-lation in children with eHT.

According to some researchers, the HRV alterations in hypothyroidism and subclinical hypothyroidism can be reversed by levothyroxine therapy (Galetta et al. 2006, 2008). Padberg et al. (2001) have reported reduction in anti-TPO antibodies and B lymphocyte counts in adults with eHT in response to levothyroxine prophylaxis.

In this study, only the time-domain HRV variables have been utilized. Many time- and frequency-domain variables measured over the entire 24-hour period are strongly correlated with each other. These strong correla-tions exist because of both mathematical and physiological relationships. In addition, the physiological interpretation of the spectral components calculated over 24 hours is diffi-cult. Thus, unless special investigations are performed which use the 24-h HRV signal to extract information other

than the usual frequency components, the results of fre-quency-domain analysis are equivalent to those of time-domain analysis, which is easier to perform (Task Force of the European Society of Cardiology the North American Society of Pacing Electrophysiology 1996). Frequency-domain HRV parameters are more susceptible to changes in respiratory pattern in healthy subjects, as would be expected in children (Billman 2011). Besides, it is usually accepted that time-domain variables better represent vagal activity.

This study shows that the beat-to-beat variability of the cardiac cycle length is decreased in children with eHT. We conclude that cardiac autonomic regulation is impaired in children with Hashimoto thyroiditis regardless of the thyroid hormone status. As these children are at increased risk for developing cardiovascular diseases, they need to be followed for development of autonomic dysfunction even in the absence of any clinical findings. Large-scale pro-spective studies are needed to further address this issue.

Conflict of InterestWe declare no conflict of interest.

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