Hyperthyroidism is an endocrine disorder characterized by excessive production and secretion of thyroid hormones, triiodothyronine (T3) and thyroxine (T4), resulting in a hypermetabolic state with widespread systemic effects. The disorder most commonly arises from Graves' disease, toxic multinodular goitre, or toxic adenoma and affects approximately 0.5–2% of the general population, with a higher prevalence among women.[1,2] Clinical manifestations include weight loss despite a normal or increased appetite, heat intolerance, tremor, palpitations, anxiety, excessive sweating, and tachycardia. Many of these features reflect altered autonomic regulation, particularly increased sympathetic activity. The autonomic nervous system (ANS) maintains physiological homeostasis through the coordinated actions of its sympathetic and parasympathetic divisions. Thyroid hormones exert important effects on autonomic cardiovascular regulation by increasing the sensitivity of peripheral tissues to catecholamines. Rather than increasing circulating catecholamine concentrations, excess thyroid hormones enhance β-adrenergic receptor expression and responsiveness, leading to augmented cardiovascular and metabolic responses.[3,4] Cardiovascular involvement is a well-recognized feature of hyperthyroidism. Sinus tachycardia, widened pulse pressure, increased cardiac output, atrial fibrillation, and reduced systemic vascular resistance are frequently observed. These changes have been attributed to enhanced sympathetic activity together with diminished parasympathetic modulation. Studies based on heart rate variability have consistently demonstrated sympathovagal imbalance in untreated hyperthyroid patients, characterized by sympathetic predominance and reduced vagal activity.[5,6] Assessment of sympathetic autonomic function provides an objective means of evaluating these physiological alterations. Standard cardiovascular autonomic function tests described by Ewing and Clarke, including the sustained handgrip test, cold pressor test, and orthostatic blood pressure response, are widely used because they are simple, reproducible, and non-invasive. These tests offer practical information regarding sympathetic cardiovascular reflexes, while heart rate variability analysis provides additional quantitative assessment of autonomic balance.[7,8] Previous studies have shown that autonomic abnormalities improve after successful treatment of hyperthyroidism and restoration of euthyroidism, indicating that these changes are largely reversible.[4,5,9] Evaluation of sympathetic autonomic function may therefore provide useful information regarding cardiovascular involvement, disease severity, and response to therapy. The present study was undertaken to assess sympathetic autonomic function in patients with hyperthyroidism using standard cardiovascular autonomic function tests and to compare the findings with those of healthy age- and sex-matched controls

Study Design and Participants This hospital-based comparative cross-sectional study was carried out in the Department of Physiology, Madhesh Institute of Health Science, Janakpur, Nepal, over a period of 12 months (2025–2026). The study included 60 participants, comprising 30 newly diagnosed patients with hyperthyroidism and 30 age- and sex-matched healthy controls. Participants were recruited consecutively from the outpatient Department of Medicine/Endocrinology after obtaining written informed consent. Inclusion Criteria Patients aged 18–60 years with newly diagnosed hyperthyroidism confirmed by clinical findings together with elevated serum free triiodothyronine (FT3), elevated free thyroxine (FT4), and suppressed thyroid-stimulating hormone (TSH) levels were enrolled. Healthy volunteers with normal thyroid function tests and no history of endocrine, cardiovascular, neurological, or systemic illness served as the control group. Exclusion Criteria Individuals with diabetes mellitus, hypertension, ischaemic heart disease, cardiac arrhythmias, chronic kidney disease, chronic liver disease, pregnancy, smoking, alcohol dependence, autonomic neuropathy, or treatment with medications known to influence autonomic function, including β-blockers and antidepressants, were excluded. Clinical Assessment All participants underwent detailed clinical evaluation, including medical history and physical examination. Age, sex, height, weight, body mass index (BMI), resting pulse rate, and blood pressure were recorded. Thyroid function was assessed by measuring serum FT3, FT4, and TSH concentrations using a chemiluminescent immunoassay. Assessment of Sympathetic Autonomic Function Sympathetic autonomic function was assessed using standardized cardiovascular autonomic function tests. For the sustained handgrip test, maximum voluntary contraction was determined using a handgrip dynamometer. Participants maintained an isometric contraction at 30% of the maximum voluntary contraction for three minutes. Diastolic blood pressure was recorded before the test and during the final minute of contraction, and the increase in diastolic blood pressure was calculated. For the cold pressor test, baseline blood pressure was measured before immersion of one hand in ice-cold water (4–6°C) for one minute. The maximum increase in systolic and diastolic blood pressure during the procedure was recorded. For the orthostatic blood pressure test, blood pressure was measured after 10 minutes of supine rest and again immediately and two minutes after standing. The fall in systolic blood pressure on standing was used to assess sympathetic cardiovascular reflex function. Statistical Analysis Data were entered into Microsoft Excel and analysed using IBM SPSS Statistics version 26.0. Continuous variables are presented as mean ± standard deviation (SD), whereas categorical variables are expressed as frequencies and percentages. Normality was assessed using the Shapiro–Wilk test. Between-group comparisons were performed using the independent Student's t-test or the Mann–Whitney U test, as appropriate. Categorical variables were analysed using the Chi-square test or Fisher's exact test. Correlations between thyroid hormone levels and autonomic function parameters were evaluated using Pearson's or Spearman's correlation coefficients. A two-tailed p value of <0.05 was considered statistically significant

Baseline Characteristics A total of 60 participants were enrolled in the study, including 30 patients with hyperthyroidism (Group I) and 30 healthy controls (Group II). The mean age of the hyperthyroid group was 36.4 ± 10.2 years, while that of the control group was 35.8 ± 9.6 years. There was no statistically significant difference in age (p = 0.81). Females constituted the majority of participants in both groups, accounting for 73.3% of the hyperthyroid group and 70.0% of the control group (p = 0.78). Table 1. Baseline Characteristics of the Study Population Variable Hyperthyroid (n=30) Controls (n=30) p-value Age (years) 36.4 ± 10.2 35.8 ± 9.6 0.81 Male, n (%) 8 (26.7) 9 (30.0) 0.78 Female, n (%) 22 (73.3) 21 (70.0) BMI (kg/m²) 21.1 ± 2.8 23.6 ± 2.9 0.002* Resting pulse rate (beats/min) 104.6 ± 11.8 76.8 ± 8.4 <0.001* Table 1: The hyperthyroid and control groups were comparable with respect to age and sex (p>0.05). However, patients with hyperthyroidism had a significantly lower body mass index and a significantly higher resting pulse rate than healthy controls (p<0.05). Table 2. Thyroid Function Profile Parameter Hyperthyroid Controls p-value FT3 (pg/mL) 8.6 ± 2.1 3.2 ± 0.6 <0.001* FT4 (ng/dL) 2.9 ± 0.8 1.3 ± 0.2 <0.001* TSH (µIU/mL) 0.04 ± 0.03 2.18 ± 0.92 <0.001* Table 2: Thyroid function tests showed significantly higher mean serum FT3 and FT4 levels and significantly lower TSH levels in the hyperthyroid group compared with the control group (p<0.001), confirming the biochemical diagnosis of hyperthyroidism. Table 3. Blood Pressure Response to Sustained Handgrip Test Parameter Hyperthyroid Controls p-value Rise in DBP (mmHg) 20.8 ± 4.3 15.6 ± 3.2 <0.001* Table 3: The mean rise in diastolic blood pressure during the sustained handgrip test was significantly greater in patients with hyperthyroidism than in healthy controls (p<0.001), indicating enhanced sympathetic autonomic activity. Table 4. Cold Pressor Test Parameter Hyperthyroid Controls p-value Rise in SBP (mmHg) 24.6 ± 5.1 18.2 ± 4.4 <0.001* Rise in DBP (mmHg) 15.8 ± 3.8 11.2 ± 2.9 <0.001* Table 4: During the cold pressor test, both systolic and diastolic blood pressure responses were significantly higher in the hyperthyroid group compared with the control group (p<0.001), suggesting increased sympathetic vasoconstrictor responsiveness. Table 5. Orthostatic Blood Pressure Response Parameter Hyperthyroid Controls p-value Fall in SBP after standing (mmHg) 6.8 ± 3.2 4.5 ± 2.6 0.01* Table 5: The orthostatic blood pressure test demonstrated a significantly greater fall in systolic blood pressure among hyperthyroid patients than controls (p<0.05), reflecting altered autonomic cardiovascular regulation. Table 6. Correlation Between FT3 Levels and Resting Heart Rate Variable Correlation coefficient (r) p-value FT3 vs Resting Pulse Rate 0.64 <0.001* Table 6: A significant positive correlation was observed between serum FT3 levels and resting heart rate (r = 0.64, p<0.001), indicating that increasing thyroid hormone levels were associated with greater sympathetic cardiovascular stimulation

This comparative cross-sectional study evaluated sympathetic autonomic function in patients with hyperthyroidism using standardized cardiovascular autonomic function tests. Compared with healthy controls, patients with hyperthyroidism demonstrated significantly greater sympathetic activity, reflected by an elevated resting pulse rate, exaggerated blood pressure responses during the sustained handgrip and cold pressor tests, and altered orthostatic blood pressure regulation. Resting pulse rate was significantly higher in the hyperthyroid group than in the control group (104.6 ± 11.8 vs. 76.8 ± 8.4 beats/min; p<0.001). Tachycardia is a well-recognized manifestation of hyperthyroidism and is primarily attributed to increased β-adrenergic receptor sensitivity and reduced parasympathetic influence on the heart. Thyroid hormones enhance myocardial responsiveness to catecholamines without increasing their circulating concentrations, thereby producing sustained cardiovascular stimulation. These findings are consistent with those reported by Fazio et al., who observed increased resting heart rate and cardiac output in untreated hyperthyroid patients, both of which improved after restoration of euthyroidism.[5] Similarly, Klein and Ojamaa demonstrated that thyroid hormones directly influence cardiac gene expression and enhance adrenergic responsiveness.[3] The sustained handgrip test showed a significantly greater increase in diastolic blood pressure among patients with hyperthyroidism (20.8 ± 4.3 mmHg) compared with healthy controls (15.6 ± 3.2 mmHg; p<0.001). During isometric exercise, activation of sympathetic efferent pathways produces peripheral vasoconstriction and a rise in diastolic blood pressure. The exaggerated response observed in the present study suggests increased sympathetic vasomotor activity in hyperthyroidism and supports the clinical utility of the sustained handgrip test as an indicator of sympathetic function, as originally described by Ewing and colleagues.[10] A similar pattern was observed during the cold pressor test. Patients with hyperthyroidism exhibited significantly greater increases in both systolic and diastolic blood pressure than healthy controls (p<0.001). The cold pressor test is a well-established measure of sympathetic vasoconstrictor function, and the enhanced pressor response observed in this study is consistent with increased adrenergic responsiveness associated with excess thyroid hormone. Hall has similarly described the amplification of cardiovascular responses in hyperthyroidism as a consequence of increased receptor sensitivity rather than increased catecholamine secretion.[11] The orthostatic blood pressure test demonstrated a significantly greater fall in systolic blood pressure among hyperthyroid patients than among controls (6.8 ± 3.2 vs. 4.5 ± 2.6 mmHg; p=0.01). Although the observed changes remained within physiological limits, they suggest subtle impairment of autonomic cardiovascular regulation and baroreflex adaptation. Comparable findings have been reported by Kahaly and Dillmann, who described alterations in autonomic cardiovascular control associated with excess thyroid hormone that improve following appropriate treatment.[4] As expected, biochemical assessment confirmed significantly elevated FT3 and FT4 levels together with suppressed TSH concentrations in patients with hyperthyroidism. A significant positive correlation was observed between serum FT3 levels and resting pulse rate (r=0.64, p<0.001), indicating that increasing thyroid hormone concentrations are associated with greater sympathetic cardiovascular activation. These observations are in agreement with the findings of Chen et al., who demonstrated increased sympathetic modulation and reduced parasympathetic activity in untreated hyperthyroid patients using heart rate variability analysis.[6] The reversibility of autonomic dysfunction following treatment has important clinical implications. Valcavi et al. reported improvement in heart rate variability and normalization of autonomic balance after successful treatment of hyperthyroidism, suggesting that these functional abnormalities improve with restoration of euthyroidism.[9] This supports the use of autonomic function testing not only for physiological assessment but also for monitoring treatment response. The findings of the present study indicate that hyperthyroidism is associated with increased sympathetic autonomic activity, resulting in measurable alterations in cardiovascular reflex responses. Standard cardiovascular autonomic function tests are simple, non-invasive, and inexpensive methods that can provide useful information regarding autonomic involvement and may complement routine clinical assessment in patients with hyperthyroidism

Patients with hyperthyroidism exhibit significant sympathetic autonomic overactivity, characterized by increased resting heart rate, enhanced blood pressure responses during sustained handgrip and cold pressor tests, and altered orthostatic cardiovascular responses. These findings support the role of excess thyroid hormone in increasing sympathetic cardiovascular responsiveness through enhanced β-adrenergic receptor sensitivity. Standard cardiovascular autonomic function tests offer a practical, non-invasive approach for evaluating autonomic involvement and may be useful in assessing disease severity and monitoring the response to treatment. Further prospective studies with larger sample sizes are warranted to clarify the long-term clinical significance of autonomic dysfunction in hyperthyroidism and its relationship with cardiovascular outcomes. Funding: Nil. Conflict of Interest: None declared. Informed Consent: Written informed consent was obtained from all participants

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