European Journal of Cardiovascular Medicine

Hypothyroidism, both overt and subclinical, is a highly prevalent endocrine disorder worldwide and in India. The prevalence of hypothyroidism is about 4%-5% in Western populations, whereas it is reported to be around 10.95% in the Indian population.^1,2 Studies from India report a prevalence of approximately 8.02% of subclinical hypothyroidism (SCH), with 3.47% undiagnosed cases.^1,3 National data indicate a female predominance (15.9% vs. 5.0% in males) and higher rates in older adults (13.1% vs. 7.5% in younger individuals).¹ A consensus guideline further reports SCH prevalence between 6% and 15% among Indian adults, increasing with age and more common in females (11.4%) than males (6.2%).⁴ Thyroid hormones play critical roles in cardiovascular physiology by regulating cardiac output, vascular resistance, endothelial function, lipid metabolism, and skeletal muscle metabolism.^3,5 Thyroid dysfunction, particularly hypothyroidism, is associated with elevated serum lipids, diastolic hypertension, endothelial impairment, and altered myocardial contractility.^3,5 Even SCH is linked to elevated cardiovascular risk, with increased rates of progression to overt disease and long-term morbidity.^1,4,6

Exercise intolerance is a prominent yet underrecognized consequence of hypothyroidism. Patients often experience reduced maximal oxygen uptake (VO₂ max), early fatigue, and impaired muscle metabolism, mechanistically attributable to diminished peripheral perfusion, substrate utilization imbalance, and altered mitochondrial function.^5,7,8 Moreover, subclinical hypothyroid patients frequently demonstrate slower VO₂ kinetics and persistent exercise inefficiency, even after thyroid hormone replacement.^7,8 Exercise capacity, commonly quantified in metabolic equivalents (METs), is a well-established prognostic indicator. Lower achievements are independently associated with greater cardiovascular and all-cause mortality across populations.^5,9,10

Although cardiovascular risk in hypothyroid patients is well-accepted, most studies focus on static biochemical or imaging markers, such as lipid profiles, carotid intima-media thickness, or endothelial function.^3,5,11 Relatively few studies have directly assessed dynamic cardiac stress responses, such as treadmill stress testing, in hypothyroid populations, and even fewer studies have correlated such responses with exercise tolerance metrics like METs, echocardiographic findings, or present cardiovascular risk. Our study aimed to bridge this gap by evaluating a cohort of hypothyroid patients who underwent standardized treadmill testing.

Study Design and Participants

This was a retrospective observational study conducted using previously collected clinical data of patients diagnosed with hypothyroidism. Data from a total of 109 patients were included in the analysis. Patients were selected based on the availability of complete clinical, biochemical, and treadmill test (TMT) data.

Study Setting and Data Collection

Data were retrieved from institutional databases, medical records, or existing registries in accordance with predefined study data specifications. The data were initially recorded in Microsoft Excel 2007 format (.xlsx), checked for completeness, and verified for consistency and outliers. Only patients fulfilling the inclusion criteria, as evident from complete datasets, were included. Patients were excluded if data were incomplete in key variables.

Variables Analyzed

All data were retrospectively retrieved from existing medical records and categorized into clinically relevant domains. Demographic variables included patient age and gender. Clinical history parameters captured from records included the duration of hypothyroidism and the presence of common cardiovascular risk factors such as diabetes mellitus (DM), hypertension (HTN), and dyslipidemia. In addition, the presence of coronary artery disease (CAD) risk factors and related symptoms-specifically chest pain and dyspnea-were documented where available. Laboratory investigations included markers of glycemic control (HbA1c, %), lipid profile parameters (total cholesterol, low-density lipoprotein [LDL], and triglycerides, all measured in mg/dL), and thyroid function tests (triiodothyronine [T3, µg/dL], thyroxine [T4, ng/dL], and thyroid-stimulating hormone [TSH, µIU/mL]). Cardiovascular fitness was evaluated based on TMT results, which were classified as Positive, Negative, or Inconclusive according to test interpretation criteria documented in the records. Measures of exercise tolerance were also recorded, including metabolic equivalents (METs) achieved, systolic and diastolic blood pressure (SBP and DBP, in mmHg), and maximum heart rate (in beats per minute) during the test. Finally, echocardiographic parameters were extracted where available and included the presence or absence of hypertensive heart disease (HHD), regional wall motion abnormalities (RWMA), and reduced ejection fraction.

Statistical Analysis

All statistical analyses were performed using Stata version 13 for Windows. Descriptive statistics were reported as means and standard deviations (SDs) for continuous variables, and counts and percentages for categorical variables. The chi-square test of independence was used to examine associations between categorical variables and TMT results. One-way analysis of variance (ANOVA) was used to compare continuous variables (e.g., laboratory values, METs, heart rate) across the three TMT groups (Positive, Negative, Inconclusive). A p-value ≤ 0.05 was considered statistically significant. Missing values were treated as missing. No imputation methods were employed for the analysis.

Treadmill Test Outcomes

Among the 109 hypothyroid patients included in the analysis, TMT outcomes were positive in 35 patients (32.1%), negative in 64 patients (58.7%), and inconclusive in 10 patients (9.2%). This distribution reflects a substantial proportion of individuals with hypothyroidism demonstrating exercise-induced evidence suggestive of myocardial ischemia.

Association of TMT Outcomes and Patient Demographic Characteristics

The mean age of patients with a positive TMT outcome was significantly higher compared to those with negative or inconclusive outcomes (ANOVA F=11.864, p<0.0001, Table 1).

Data presented as Mean ± SD. p ≤ 0.05 is considered statistically significant. TMT: Treadmill Test.

Detailed age-wise stratification revealed that TMT positivity rates varied substantially by age subgroup (Table 2). Notably, among patients aged 55-65 years, 57.1% had a positive TMT result, the highest proportion across all groups. In the 45-55-year subgroup, 40.0% tested positive. Meanwhile, positivity was markedly lower in younger patients, including just 2.9% in the 35-45-year age group and 0% in those under 35.

Data presented as the number of patients (%). TMT: Treadmill Test.

The cohort included 29 males (26.6%) and 80 females (73.4%). While the majority were female, the rate of positive TMT was higher among males than females, although this difference did not reach statistical significance (Table 3).

Data presented as the number of patients (%). TMT: Treadmill Test.

Association of TMT Outcomes and Cardiovascular Risk Factors and Clinical Symptoms

A significant association was observed between the presence of traditional cardiovascular risk factors and positive TMT outcomes (χ²=7.817, p=0.005, Table 4). Among the patients with diabetes mellitus, 45.7% had a positive TMT result. Similarly, 40.0% of those with dyslipidemia and 29.2% of hypertensive patients showed positive TMT results. Notably, only 18.2% of patients without any identifiable CAD risk factors tested positive, highlighting the additive value of these comorbidities in predicting functional cardiac stress (Table 4).

Data presented as the number of patients (%). p ≤ 0.05 is considered statistically significant. CAD: Coronary Artery Disease; DM: Diabetes Mellitus; HTN: Hypertension; TMT: Treadmill Test.

Association of TMT Outcomes and Symptoms of CAD

Chest pain was the most common presenting symptom, reported by 84.4% patients and was associated with a TMT positivity rate of 35.9% (Table 5). Dyspnea was reported in 17.4% patients, with a TMT positivity rate of 26.3%. Interestingly, the five patients presenting with both chest pain and dyspnea demonstrated an 80.0% TMT positivity rate, suggesting that the combination of symptoms may be a strong clinical marker for inducible ischemia (Table 5).

Data presented as number of patients (%). CAD: Coronary Artery Disease; TMT: Treadmill Test.

Association of TMT Outcomes and Disease Duration

Although no statistically significant associations were identified between the duration of hypothyroidism, hypertension, or diabetes and TMT outcome, trends suggested that patients with longer disease durations (particularly 1-10 years) exhibited higher rates of positive results (Table 6). Among patients with hypothyroidism for 1-10 years, 40.0% tested TMT positive. A similar trend was observed in diabetic and hypertensive subgroups, although these associations did not reach statistical significance.

Data presented as the number of patients (%). p ≤ 0.05 is considered statistically significant. TMT: Treadmill Test.

Association of TMT Outcomes and Laboratory Parameters

Among the biochemical parameters analyzed, serum triglyceride levels differed significantly between TMT groups (F=3.280, p=0.041), with the highest mean observed in the positive TMT group, followed by the inconclusive and negative TMT groups (Table 7). Other lipid parameters, including total cholesterol and LDL levels, as well as thyroid hormone levels (T3, T4, TSH), and HbA1c, showed no statistically significant differences across TMT groups. Although the mean TSH values were elevated in all three groups, as expected in a hypothyroid cohort, no significant variation was detected between groups (F=0.049, p=0.952), suggesting that TSH levels alone were not predictive of exercise-induced ischemia (Table 7).

Data presented as Mean ± SD. p ≤ 0.05 is considered statistically significant. HbA1c: Glycosylated hemoglobin; LDL-C: Low-Density Lipoprotein Cholesterol; T3: Triiodothyronine; T4: Thyroxine; TC: Total Cholesterol; TG: Triglycerides; TSH: Thyroid Stimulating Hormone.

Exercise Tolerance

Measures of exercise tolerance varied significantly across TMT groups. The metabolic equivalents (METs) achieved were lowest among patients with inconclusive TMT, intermediate in the positive TMT group, and highest in the negative TMT group, with a statistically significant difference (F=10.648, p<0.0001). Maximum heart rate achieved followed a similar pattern, being significantly lower in the inconclusive group compared to the positive and negative TMT outcome groups (F=19.085, p<0.0001). Systolic blood pressure during exercise was also significantly higher in the TMT positive group than in the inconclusive TMT group (F=6.260, p=0.003), whereas no significant difference was observed in diastolic blood pressure (p=0.313).

Data presented as Mean ± SD. p ≤ 0.05 is considered statistically significant. DBP: Diastolic Blood Pressure; HR: Heart Rate; METs: Metabolic Equivalents; SBP: Systolic Blood Pressure; TMT: Treadmill Test. p ≤ 0.05 considered statistically significant.

Further analysis of METs distribution (Table 7) demonstrated that the majority of patients who achieved 7-9 METs had either a positive (42.9%) or negative (42.2%) TMT result, while 70.0% of those in the 5-7 METs group had inconclusive TMT outcomes. Notably, none of the patients who achieved only 3-5 METs had a positive result. Conversely, in the high-performance group (11-13 METs), only 5.7% had positive TMT results, whereas 85.7% were negative. This trend suggests that lower exercise capacity, as indicated by lower METs achieved, is associated with increased likelihood of a positive or inconclusive TMT, while higher METs are predictive of negative test outcomes.

Echocardiographic Findings

Assessment of echocardiographic data revealed significant structural and functional abnormalities in patients with positive TMT outcomes. Regional wall motion abnormalities (RWMA) and reduced ejection fraction were each observed in 20.0% of the TMT-positive group, but absent in both the negative and inconclusive groups (χ²=15.816, p<0.0001 for both comparisons). Hypertensive heart disease (HHD) did not differ significantly among the groups (p=0.698), although it was present in approximately 38% of the entire cohort.

Data presented as number of patients (%). p ≤ 0.05 is considered statistically significant. TMT: Treadmill Test

In this analysis of retrospectively collected data of hypothyroid patients, we investigated the prevalence of exercise-induced ischemia on treadmill testing and its associations with age, MET-based exercise capacity, traditional cardiovascular risk factors (such as diabetes, hypertension, and dyslipidemia), lipid and thyroid laboratory parameters, and echocardiographic findings. By integrating functional stress testing and structural/biochemical profiling, this study aims to fill a critical gap in risk stratification in hypothyroid populations, where clinical assessment of cardiovascular reserve and susceptibility to ischemia may guide management decisions more effectively than biochemical measures alone.

Previous epidemiological evidence has demonstrated that both overt and subclinical hypothyroidism are independently associated with increased risks of ischemic heart disease (IHD), myocardial infarction, and cardiovascular mortality in large cohort studies.^12,13 In a meta-analysis involving nearly two million participants from 55 cohort studies, the risk of mortality was two times higher in patients with overt and subclinical hypothyroidism (RR ≈ 1.9-2.0, 95% CI 1.38-2.80).¹² In this study, approximately one-third of the patients demonstrated positive TMT results, indicative of exercise-induced myocardial ischemia.

Existing evidence shows that advancing age, particularly when coupled with elevated TSH levels, increases cardiovascular vulnerability in hypothyroid individuals.^12,14 Our study findings also align with this age-related trend. In our study, age was a significant predictor of TMT positivity among hypothyroid patients. Specifically, we observed the highest positivity rate in the 55-65-year age group (57.1%), while younger age groups exhibited minimal or no positivity. Exercise capacity has emerged as a strong determinant of TMT outcomes. In our study, patients with reduced exercise tolerance, achieving 5-7 METs, were more likely to have positive or inconclusive TMT results. In contrast, those who achieved higher exercise levels (11-13 METs) were predominantly TMT-negative. These findings support the well-established role of maximal exercise capacity as a prognostic marker for cardiovascular risk.^7,15,16 The higher incidence of inconclusive tests among low-MET achievers further underscores the association between limited exercise capacity and elevated cardiovascular risk. This study showed that both age and exercise capacity are predictors of TMT positivity.

Exercise intolerance in hypothyroidism, including SCH, arises from multiple interrelated physiological impairments. These include disrupted muscle energy metabolism, inefficient substrate utilization, reduced vasodilatory capacity, and decreased cardiac output, all of which collectively impair the ability to meet the metabolic demands of exercise.^7,17,18 Werneck et al. highlighted that patients with SCH exhibit significantly slower oxygen uptake (VO₂) kinetics during the onset and recovery phases of constant-load submaximal exercise compared to healthy controls (mean response time: 47 ± 8 sec vs. 40 ± 6 sec; p=0.004), indicating delayed oxygen delivery and utilization even in early stages of thyroid dysfunction.⁸ Additionally, other studies have shown that VO₂_max remains persistently reduced in SCH patients, accompanied by increased lactate accumulation and abnormal fatty acid metabolism, alterations that are not fully corrected even after six months of levothyroxine treatment.^18,19

SCH is known to exacerbate cardiovascular risk associated with arterial hypertension, cardiac dysfunction, atherosclerosis, dyslipidemia, and diabetes mellitus. These comorbidities contribute to a higher risk of CAD, likely due to mechanisms involving lipid abnormalities, endothelial dysfunction, and metabolic disturbances.^12,20 In line with previous findings, our study demonstrated that patients with traditional cardiovascular risk factors, including diabetes, hypertension, and dyslipidemia, had significantly higher rates of TMT positivity. Notably, individuals with multiple CAD risk factors exhibited a markedly increased prevalence of positive TMT results compared to those without it, highlighting the compounding risk profile in hypothyroid patients. Furthermore, the elevated triglycerides in the TMT-positive group also reflect the dyslipidemia milieu inherent to hypothyroid states, which promotes atherosclerosis and endothelial dysfunction.¹²

Hypothyroid-associated myocardial changes, such as reduced contractility, diastolic impairment, and increased systemic vascular resistance, may predispose vulnerable patients to ischemia under hemodynamic stress.^12,15 In our study, we detected RWMA and reduced ejection fraction uniquely in TMT-positive patients, reinforcing the link between functional ischemia and myocardial dysfunction.

Our study reinforces that hypothyroid patients, particularly older adults or those with limited exercise capacity, should be considered high risk for inducible ischemia, especially if they carry traditional cardiovascular comorbidities. Routine assessment of exercise tolerance and cardiovascular risk profiling may be warranted in the clinical evaluation of hypothyroid patients. Moreover, while thyroxine treatment may reverse certain cardiovascular abnormalities, its impact on exercise capacity and stress-induced ischemia needs further exploration.^11,19,21

Strengths, Limitations, and Future Directions

A key strength of this study is the integration of detailed exercise physiology, echocardiographic assessment, risk factor profiling, and MET-based categorization in a real-world hypothyroid cohort. However, limitations of this study include its retrospective design, lack of a euthyroid control group, absence of follow-up cardiovascular outcomes, and no data on thyroid hormone therapy status or titration. TSH values were not correlated longitudinally with TMT results, limiting insights into the effect of thyroid dysfunction severity. Prospective studies are needed to establish a causal relation between hypothyroidism, exercise intolerance, and inducible ischemia and to determine whether normalization of thyroid function reverses exercise intolerance or reduces stress-test positivity. Randomized, controlled trials evaluating whether normalization of euthyroidism improves exercise capacity and reduces TMT positivity would directly address whether intervention mitigates cardiovascular risk in this population.^12,21.

This study highlights that a substantial proportion of hypothyroid patients, particularly older individuals with cardiometabolic risk factors and reduced exercise capacity, are at increased risk of inducible myocardial ischemia. Functional assessments such as treadmill testing and METs estimation offer valuable insights for cardiovascular risk stratification in this population. Future studies should prospectively evaluate whether optimizing thyroid function and addressing modifiable risk factors can improve exercise tolerance and reduce ischemic burden in hypothyroid patients.

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