Evaluation of Autonomic Functions for Assessment of Cardiovascular Risk in Women with Subclinical Hypothyroidism

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INTRODUCTION

Subclinical hypothyroidism (SH), also known as mild thyroid failure, features elevated levels of thyroid-stimulating hormone (TSH) (>4.2 mIU/L to <10 mIU/L) with normal-free thyroid hormone concentrations.^[1] SH affects 4% to 15% of the adult population and has a higher prevalence in women.^[2]

The cardiovascular abnormalities found in SH patients resemble those in overt hypothyroidism, indicating that even mild thyroid dysfunction may affect the cardiovascular system.^[3] Most of the cerebrovascular manifestations observed in primary hypothyroidism are attributable to autonomic dysfunction.^[4] SH persisting for 6–12 months has been associated with the development of an atherogenic lipid profile and hypercoagulable state due to underlying autonomic dysfunction.^[5] As metabolic and vascular alterations progress, the likelihood of cardiovascular complications increases in SH, especially in the presence of autonomic imbalance.

Thyroid hormones affect the autonomic nervous activity, but their manifestations and the extent of impact on autonomic functions are highly variable, and underlying mechanisms remain unclear. Several studies in SH patients have shown a decrease in sympathetic and parasympathetic tone at rest, along with sympatho-vagal imbalance with decreased sympathetic response to postural changes,^[6-9] while others have observed reduced sympathetic tone and increased parasympathetic activity in SH, especially with TSH >10 mIU/L.^[10,11] Previous research also indicates that low thyroid levels are associated with greater sympathetic modulation of cardiovascular autonomic function.^[12,13]

Alterations in the autonomic nervous system due to SH are intermediate between the euthyroid state and overt hypothyroidism. Autonomic disturbances associated with hypothyroidism may result from increased release of plasma adrenaline with decreased receptor sensitivity and elevated thyrotropin-releasing hormone levels that directly influence sympathetic outflow.^[14]

SH typically does not present with notable symptoms in its initial stages, and each year, about 2–5% of cases of SH progress to overt hypothyroidism.^[15] Therefore, early identification of SH and assessing heart rate variability (HRV) and autonomic function tests would help in determining the extent of autonomic dysfunction associated with SH.

Scientific documentation on autonomic functions in SH, particularly among Indian women, is limited and often contradictory. Hence, this study aims to assess autonomic functions in females with SH compared to euthyroid controls.

MATERIALS AND METHODS

RESULTS

This study comprised two groups of female participants between the ages of 18 and 55 years. Group I consisted of 58 women with SH, while Group II included 50 euthyroid women who served as controls. The average age of Group I females was 36.46 ± 7.18 years, and that of Group II was 29.73 ± 7.04 years. Notably, most women in Group I (87%) exhibited TSH levels >10 mIU/L, with a mean TSH value of 12.91 ± 1.92 mIU/L. Additional demographic and metabolic characteristic features for both groups are presented in Table 1.

Analysis of HRV parameters obtained from 5-min ECG recordings presented a decrease in HRV parameters that depict the time domain, i.e., SDNN, RMSDD, and pNN50 in Group I females compared to controls (P < 0.05) [Table 2]. A significant decrease in HF power (P < 0.001) was also observed among women with SH (Group I). These findings are indicative of reduced parasympathetic activity in these females. In addition, a significant reduction in LF power and TP in Group I females was seen as compared to Group II (P < 0.05). These findings suggest that women with SH exhibit diminished HRV and decreased overall autonomic activity, reflecting autonomic dysfunction relative to euthyroid controls.

Analysis of the frequency domain parameters revealed an increase in LF/HF ratio among women with SH (Group I), with a mean value of 1.54±0.09, compared to the control group (Group II), which had a mean LF/HF ratio of 1.22±0.06. An elevated LF/HF ratio in Group I females indicates that these women had a significantly lower parasympathetic tone relative to sympathetic tone, suggesting sympathetic predominance and reflecting decreased parasympathetic modulation of cardiac autonomic activity.

In women with SH, higher levels of TSH significantly correlated with lower HRV parameters. Specifically, TSH showed a negative correlation with RMSSD (r = −0.37, 95% CI, P < 0.001), pNN50 (r = −0.43, P < 0.05), total power (r = −0.67, P < 0.001), and HF power (r = −0.47, P < 0.001). Hence, these findings indicate that the higher the TSH levels, lesser is the vagal or parasympathetic activity.

In addition, the analysis also revealed a strong positive correlation between TSH levels and LF/HF ratio (r = 0.58). This observation suggests that higher values of TSH concentrations are associated with sympathetic dominance, further highlighting the impact of SH on autonomic regulation.

Autonomic functions were evaluated in women with SH using a range of standardized cardiovascular reflex tests [Table 3]. The results indicated distinct patterns of autonomic dysfunction within this group. 29% (n = 17) of females with SH demonstrated abnormal HR responses to DBT and LST, indicative of parasympathetic dysfunction since these tests primarily assess vagal (parasympathetic) activity. Furthermore, 47% (n = 27) of females with SH demonstrated abnormal sympathetic autonomic tests, such as >10 mmHg fall in SBP in response to standing and <10 mmHg rise in DBP during sustained hand grip. In addition, 18% (n = 10) of women with SH displayed both sympathetic and parasympathetic dysfunction, suggesting a combined impairment of autonomic regulation [Figure 1]. Autonomic functions were classified into normal, early, definitive, and severe CAN as per the standard values [Figure 2]. It was found that 66% of women with SH had early CAN characterized by one abnormal HR test or two borderline results, 20% of the women had definitive CAN defined by two abnormal HR tests, and 8% had severe CAN marked by two abnormal HR tests in addition to at least one abnormal BP test.

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Figure 1:

Type of autonomic dysfunction among women with subclinical hypothyroidism and controls.

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Figure 2:

Severity of autonomic dysfunction among women with subclinical hypothyroidism (Group I) and controls (Group II).

P < 0.002 from Fischer’s exact test; Normal autonomic function: All the tests normal; early cardiac autonomic neuropathy (CAN): One abnormal HR test or 2 borderline tests; definitive CAN: 2 abnormal HR tests; severe CAN: 2 abnormal HR tests in addition to 1 or 2 abnormal BP tests.

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DISCUSSION

The HRV analysis in this study showed that women with SH presented with reduced parameters of pNN50, RMSSD, and HF values, indicating lower parasympathetic activity reflecting a decrease in vagal tone compared to euthyroid women. HRV analysis also showed autonomic imbalance in women with SH, as shown by significantly low values of SDNN representing a decrease in total variation between heartbeats and a reduction in LF values, which reflects a mix of sympathetic and parasympathetic activity. However, LF/HF ratio (which represents sympatho-vagal balance) was found to be high in women with SH, reflecting comparatively higher sympathetic activity than parasympathetic activity. These observations among women with SH highlight significant autonomic dysregulation. These findings are consistent with those of Galetta et al., who observed a higher LF/HF ratio in patients with SH, indicating increased sympathetic activity.^[10] Similarly, Ankitha et al. have also reported an increase in LF/HF ratio with significantly lower SDNN values in SH patients.^[17] Jadav et al. reported decreased vagal activity along with increased sympathetic activity, indicated by a higher LF/HF ratio in SH.^[18] Other studies have similarly reported decreased parasympathetic and increased sympathetic activity in hypothyroid patients^[19,20] as well as altered cardiovascular autonomic functions in SH.^[21-23]

Autonomic disturbances noted in SH may be attributed to heightened catecholamine synthesis, release, and plasma degradation, coupled with reduced beta-adrenergic receptor sensitivity, resulting in sympathetic predominance.^[24] Similarly, reduced parasympathetic activity found in women with SH may be due to reduced thyroid hormone effects on central autonomic pathways and alteration in cardiac parasympathetic neurons leading to decreased muscarinic effects.^[25] Vagal inhibition rather than increased sympathetic activity causes a greater effect on HF than on LF power. TP is decreased as HF accounts for two-thirds, while LF accounts for one-third. Reduced vagal tone in these women may lead to increased susceptibility to cardiovascular diseases such as arrhythmias.

Sahin et al.,^[13] unlike our findings, reported no difference in HRV parameters between subclinical hypothyroid patients and controls. Inukai et al. found no change in parasympathetic functions in a group of patients with masked hypothyroidism.^[26] This controversial trend is noted in hypothyroid patients, too.

Analysis of autonomic functions in this study revealed that majority of the women with SH (47%) have reduced sympathetic reactivity, indicated by abnormal BP response in lying to standing and HGT, which signifies sympathetic dysfunction. The parasympathetic reactivity was found to be decreased in 29% of women with SH, indicated by abnormal HR response to HGT, LST (30:15 ratio) and E:I ratio and combined dysfunction was noted in 18% of women. Jose et al. have reported a similar trend in that sympathetic dysfunction was found in 75% of hypothyroid cases and 66.7% had parasympathetic dysfunction.^[23] Pervin et al. have reported that 28% of the subjects had parasympathetic dysfunction, 22% had sympathetic dysfunction, and 33% exhibited combined autonomic dysfunction.^[27] Mahajan et al. found sympathetic dysfunction in 82% of SH patients,^[5] consistent with findings of Syamsunder et al.^[28] In contrast, Bhat et al. did not find these observations statistically significant.^[29]

Our study found that higher TSH levels were negatively correlated with TP and HF, indicating reduced parasympathetic modulation and autonomic imbalance. These findings prove that SH may impair autonomic regulation even in the absence of overt symptoms. A case– control study by Guidotti et al. further supports this association, having demonstrated clear signs of autonomic hyperarousal in patients with SH using psycho-physiological stress profiling.^[30]

CONCLUSION

Our study underscores that women with SH had autonomic abnormalities with decreased HRV and reduced sympathovagal tone and autonomic reactivity. Among these autonomic disturbances, sympathetic dysfunction emerged as the more dominant feature, although parasympathetic dysfunction was also observed in a significant proportion of the study population. Lifestyle factors may also influence thyroid homeostasis and symptom burden that may be explored in future studies. However, these observations indicate a notable link between impaired thyroid function and autonomic dysfunction. The association is particularly important because autonomic dysfunction in this population may serve as a risk factor for cardiovascular diseases. Hence, timely intervention and appropriate management may help reduce the risk of cardiovascular morbidity and may also prevent the progression from subclinical to overt hypothyroidism.