The thyroid gland and the autonomic nervous system are closely linked by their control center, the hypothalamus, and by their effects on the cardiovascular system ^[1][2][1,2]. Hyperthyroidism is a common global health problem and a risk factor for cardiovascular mortality [3]. One of the main complications of hyperthyroidism is cardiac arrhythmias, most often supraventricular, and may be caused by sympathovagal imbalance. Indeed, the clinical manifestations of hyperthyroidism (tachycardia, palpitation, systolic arterial hypertension) suggest β-adrenergic stimulation and dysautonomia ^[4][5][6][7][4,5,6,7]. Dysautonomia means a change in the function of the autonomic nervous system can negatively affect the health of a person [8]. Sympathovagal imbalance is associated with an increased risk of ventricular arrhythmias and cardiac mortality ^[9][10][9,10], which can be measured by the study of heart rate variability (HRV). HRV is the variation between two consecutive heartbeats related to the continuous interaction between the two arms of the autonomic nervous system, sympathetic and parasympathetic [11]. HRV is a sensitive, quantitative and non-invasive tool for the study of autonomic nerve function ^[12][13][14][12,13,14]. High HRV suggests an adaptable and dynamic autonomic nervous system [15]. Low HRV is a marker of cardiovascular risk and represents an abnormal or restricted ability of the autonomic nervous system to maintain homeostasis ^[16][17][16,17]. Indeed, the degree and type of autonomic imbalance and its contribution to cardiovascular abnormalities in hyperthyroidism are not fully understood [18]. Many studies have shown a tendency for HRV depression with an impaired cholinergic reserve, providing a logical explanation for the increased sympathetic activity in hyperthyroidism. If these results are reproducible, it may contribute to the understanding of the susceptibility to cardiac arrhythmias in hyperthyroidism and indicate possible early therapeutic intervention. In addition, there is no consensus on the decreased levels of HRV parameters in hyperthyroidism. Two biochemical entities are distinguished: overt hyperthyroidism, with a prevalence of 0.5% of the general population [19], and subclinical hyperthyroidism, with 1.8% [20].

The cardiovascular effects of thyroid hormones occur either directly through nuclear receptors [4] or indirectly by the sympathoadrenergic system ^[21][59]. Excess thyroid hormones has a direct chronotropic effect on the sinus node ^[22][23][60,61]. Changes in HRV are not only related to chronotropic effects. For example, propanolol is one of the most effective treatments for heart rate and did not alter HRV parameters ^[24][62]. Hyperthyroidism is characterized by a hyperkinetic state, similar to that induced by catecholamine excess [6], but serum and urine catecholamine levels are normal or decreased in hyperthyroidism ^[25][26][63,64]. The increased density and sensitivity of β-adrenergic receptors to catecholamines in hyperthyroidism may explain the increase in sympathetic activity ^[27][28][29][65,66,67]. More specifically, it showed a sympathovagal imbalance in hyperthyroidism. Vagal inhibition was more intense than increased sympathetic activity, with a greater decrease in HF power than LF power. As expected, TP decreased markedly (cardiac vagal control) as HF is its main contributor—two-thirds—whereas LF and VLF contribute one-third ^[12][30][12,68]. HRV is decreased mainly because of a large decrease in vagal activity ^[12][30][12,68]. Then, RR intervals decreased in patients with subclinical hyperthyroidism, and further decreased in overt hyperthyroidism. Moreover, an increase in fT3 and fT4, and a decrease in TSH, were related to a decrease in RR intervals. HRV parameters may indirectly reflect the severity of hyperthyroidism ^[31][58]. Subclinical hyperthyroidism appears to be an intermediate cardiovascular state between euthyroidism and overt hyperthyroidism, a continuum related to thyroid hormone excess ^[32][33][46,52]. An increase in sympathetic activity seems to be the first modification of the sympathovagal balance, which may be due to the decrease in TSH ^{[33][34][35][36][37][38]}[44,45,50,52,55,57]. However, these results should be treated with caution because those studies only reported some selected HRV parameters. This parasympathetic inhibition may be due to the action of thyroid hormones on centers regulating autonomic functions ^[39][40][69,70] and on cardiac M2-muscarinic receptors ^[28][66], and increased adrenergic reactivity may be due to the main effects of abnormal TSH concentrations ^[41][53].

2.2. Clinical Implications

Decreased vagal tone and increased sympathetic activity in hyperthyroidism have important clinical implications. Thyroid hormones play a role in arrhythmogenesis with a risk of atrial fibrillation ^[42][71], which may be related to decreased HRV ^[43][72]. For example, a high incidence of supraventricular arrhythmias has been reported in overt hyperthyroidism women with very low HRV ^[31][58]. Increased sympathetic modulation and vagal inhibition were observed before the onset of paroxysmal atrial fibrillation ^[44][73], which may explain the increased prevalence of atrial fibrillation in these patients. A decreased HRV should strengthen the idea of treating subclinical hyperthyroidism ^[45][74]. However, early antithyroid therapy remains contradictory ^[34][45][44,74]. Indeed, if antithyroid treatment allows reversibility of HRV abnormalities, it would constitute an additional argument to treat subclinical hyperthyroidism in order to avoid rhythmic complications in these patients. Patients with decreased vagal tone are more susceptible to cardiovascular disease ^[46][47][75,76] with increased cardiac morbidity and mortality without apparent heart muscle damage ^[48][49]. It has also been shown that decreased TP predicts an increased risk of sudden cardiac death ^[49][77] and total cardiac mortality ^[50][78], that decreased LF is a strong predictor of sudden death independently of other variables ^[45][74], and that decreased VLF is an indicator of increased cardiac mortality in patients after myocardial infarction ^[51][52][79,80]. These data suggest that HRV parameters may be a marker of increased mortality in hyperthyroid patients. Physical activity and hyperthyroidism have the same effects on HRV, i.e., a concomitant sympathetic activation and decreased vagal tone ^[53][81]. Hence, many hyperthyroid patients are intolerant to exercise due to a reduced ability to increase cardiac output ^[54][55][82,83], in addition to the usual musculoskeletal manifestations of hyperthyroidism ^[56][84].

2.3. Other Variables Related to HRV in Hyperthyroidism

Age was associated with higher RR, TP, HFnu, and lower LFnu and LF/HF ratio. Thus, age was linked with an increased HRV in hyperthyroidism. However, in the general population, older age is associated with a decrease in HRV ^[57][58][85,86] due to decreased parasympathetic regulation ^[59][87]. Younger patients had more severe hyperthyroidism and a high prevalence of Graves’ disease ^[60][88]. There is an increase in systolic blood pressure was associated with lower RMSSD, i.e., a decrease in parasympathetic activity. No study has previously evaluated this relationship in hyperthyroidism. Conflicting results have been reported in the general population, with elevated blood pressure associated with either an increase ^[61][89] or a decrease ^[62][90] in HRV. It has also been suggested that decreased autonomic nerve function precedes the development of clinical hypertension ^[63][91]. IWe also demonstrated that increased BMI was associated with higher RR intervals, TP, LF, HF and VLF power, and lower LF/HF ratio, i.e., increasing HRV with increased parasympathetic activity. However, an increase in BMI is associated with lower HRV ^[64][65][92,93]. Hyperthyroid patients often presented a weight loss, resulting in a significantly lower mean BMI than healthy controls. In malnourished subjects, there is a decrease in HFnu with an increase in LFnu and LF/HF ratio ^[66][94]; hence, normalization of BMI may improve HRV. BMI does not distinguish between lean and fat tissue ^[67][68][95,96]. Interestingly, HRV may be more related to body composition than to BMI, and especially to body fat ^[69][70][97,98], which is lowered in hyperthyroid patients ^[71][99].

3. Conclusions

HRV is markedly decreased in hyperthyroid patients. Increased sympathetic and decreased parasympathetic activity may be explained by the deleterious cardiovascular effects of thyroid hormones. The benefits of HRV assessment in the evaluation and monitoring of the severity of hyperthyroidism should be further investigated, given its potential as a noninvasive, reliable, and pain-free measurement.