Higher cortisol level and reduced circulating triiodothyronine in patients with cardiovascular diseases: A case-control study

Abstract

Background

Thyroid hormone plays a key role in cardiovascular diseases (CVDs), and stress may impact this relationship by affecting cortisol and triiodothyronine (T3) levels. This study explored the association between stress, indicated by cortisol levels, and thyroid function in cardiovascular patients, particularly those with hypertension.

Methods

A cohort of 87 cardiovascular patients (37 females, 50 males) and 60 healthy controls (28 females, 32 males) was analyzed. Patients included those with coronary artery disease, acute myocardial infarction, and a high proportion with anterior wall myocardial infarction (AWMI, 52%). Anthropometric data and blood samples were collected, and cortisol and T3 levels were measured using the radioimmunoassay method. Blood pressure measurements were also recorded to assess associations with cortisol, thyroid function, and hypertension.

Results

Cardiovascular patients had significantly higher cortisol levels (1065.99 ± 700.54 ng/mL vs 768.35 ± 563.10 ng/mL, p < .001) and lower T3 levels (1.25 ± 0.48 ng/mL vs 1.33 ± 0.46 ng/mL) compared to controls. The prevalence of AWMI was 52%. Blood pressure was significantly higher in cardiovascular patients of both sexes (p < .0007). Additionally, 39% of cardiovascular patients had elevated cortisol, and 38% had reduced T3. No sex-based differences in cortisol levels were observed.

Conclusion

This study found significant associations between elevated cortisol and reduced T3 levels in cardiovascular patients, particularly those with hypertension. Although stress-induced thyroid dysfunction remains a hypothesis, these findings suggest a potential link between cortisol, T3, and CVD. Further longitudinal research is needed to explore causal mechanisms.

Introduction

Hypertension, or high blood pressure, is a significant global health concern, impacting around 1.13 billion people worldwide. ¹ High blood pressure is typically diagnosed when the blood pressure reading is at or above 140/90 mmHg. ² Thyroid hormones, specifically T3 and T4, play essential roles in metabolism, growth, and differentiation. Stress can trigger a “fight or flight” response, causing physiological and endocrinological imbalances. Cortisol, a key stress hormone, is known to influence thyroid hormone levels. ³

Research has demonstrated that acute stress can result in a decrease in circulating T3 levels within just 120 min of the stressor. Moreover, studies have identified a positive correlation between thyroid-stimulating hormone (TSH) levels and cortisol levels, indicating an interaction between these hormones. ⁴ In a study published in 2012, TSH levels were found to correlate positively with circulating cortisol levels; higher TSH readings corresponded to higher cortisol levels. ⁵ Critical stress stimulates thyroid function, whereas chronic stress suppresses it. Consequently, hypothyroidism prevalence exceeds 50% in some persistently depressed individuals. ⁶ In other investigations, the rate of depression among severely hypothyroid patients reached as high as 100%. ⁷ Around 50 years ago, thyroid hormones were used to treat depression, ⁸ and some reports have supported the association between thyroid hormone treatment and subsequent depression. ⁹

Liu et al. also explored the relationship between blood pressure and thyroid function. ¹⁰ Some research suggests that hypertensive individuals may have subclinical hypothyroidism, characterized by high serum TSH levels and normal thyroid hormone levels in the blood. ¹¹ Some signs and symptoms of thyroid diseases in the heart and cardiovascular system (CVS) are attributed to thyroid hormones. ¹² Hyperthyroidism and hypothyroidism impact cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance (SVR). ¹³ Current estimates indicate that thyroid dysfunction affects 9% to 15% of the adult female population and a lower percentage of adult males. Low thyroid function predominantly affects the CVS, resulting in reduced cardiac contractility, decreased cardiac output, increased SVR, reduced chronotropy, and cardiac atrophy. ¹⁴ There's also evidence to suggest that thyroid dysfunction serves as an independent risk factor for the development of heart disease leading to heart failure (HF), playing a significant role in patient prognosis and outcomes. ¹⁵

Thyroid hormones, particularly thyroxine (T4) and triiodothyronine (T3), are vital for metabolism and cardiovascular function. While T4 is commonly measured in clinical practice, T3 is the more active hormone with direct effects on cardiovascular health. This study investigates the role of T3 in cardiovascular disease (CVD) and explores the impact of stress-induced cortisol changes on T3 levels. By examining these relationships, we aim to bridge the gap between thyroid function and CVD and enhance understanding of how hormonal fluctuations influence cardiovascular conditions.

Methods

Patients and healthy individuals

The study recruited 87 patients diagnosed with CVD and 60 healthy individuals aged 20–60 years from the Divisional Hospital of Dera Ismail Khan (DHQ-DIK), Khyber Pakhtunkhwa, Pakistan. Both in-patients and out-patients were included to ensure a diverse group representing various clinical presentations. All participants shared similar middle-class socioeconomic backgrounds and dietary habits. Anthropometric data, including body weight (BW) and height, were collected using a specifically designed form. Written informed consent was obtained from the patients or their guardians, and the study was approved by the Research Ethical Committees at PMAS Arid Agriculture University Rawalpindi. The cardiovascular patient group was divided into subgroups based on specific disease entities, including CVD, coronary artery disease (CAD), and myocardial infarction subtypes, such as anterior wall myocardial infarction (AWMI) and inferior wall myocardial infarction (IWMI). CVD was defined as the presence of cardiovascular disorders, including hypertension, CAD, and myocardial infarction. CAD was diagnosed based on clinical history and angiographic evidence of coronary artery narrowing or blockage. AWMI and IWMI were differentiated by the location of infarction, as determined by ECG and clinical imaging. AWMI refers to infarctions in the anterior portion of the left ventricle, while IWMI refers to infarctions in the inferior wall. AWMI was specifically emphasized due to its significant prevalence (52%) in our patient cohort, which provided a larger sample for examining its association with stress-related hormonal changes, particularly cortisol and T3 levels. Although AWMI does not inherently present a unique pathophysiological mechanism compared to other forms of myocardial infarction, its higher incidence in the cohort and its potential link to stress markers made it an important subgroup for further analysis. In addition to the disease entities, the dataset included subgroup analyses for specific clinical features, such as treatment modalities (RAAS inhibitors vs non-RAAS inhibitors), diabetes, and BMI categories.

Inclusion and exclusion criteria

The inclusion criteria for this study comprised male and female individuals diagnosed with hypertension and CVDs. Exclusion criteria included individuals with cerebrovascular and neurological diseases, asthma, chronic renal impairment (an estimated glomerular filtration rate of less than 60 mL/min/1.73 m² or a history of chronic kidney disease stages 3–5), pregnancy, alcohol consumption, advanced hepatic and renal insufficiency, or any other endocrinological disorders among the participants in the study. CVDs defined as conditions affecting the heart or blood vessels, including hypertension, CAD, acute myocardial infarction, AWMI, and IWMI. Endocrinological disorder defined as conditions involving hormonal imbalances, such as hypothyroidism, hyperthyroidism, diabetes mellitus, or adrenal gland dysfunction.

Laboratory analysis

Blood samples (∼1.5 mL) were gently drawn from the antecubital vein of each participant visiting DHQ-DIK, with great care to minimize any discomfort. Blood samples for hormone analysis were obtained during the patients’ hospitalization. Subsequently, the collected samples underwent a 5-min centrifugation at 3000 r/min, effectively separating the serum. These serum samples were promptly frozen and stored at −20°C until they were ready for analysis. To mitigate the potential influence of diurnal variations in cortisol and T3 levels, all blood samples were collected between 10:00 a.m. and 12:00 p.m. The levels of cortisol and T3 were measured using the Radioimmunoassay method (IMMUNOTECH s. r. o. (Radiova 1, 102 27 Prague 10, Czech Republic), allowing for precise quantification of these hormones during a period of acute illness. The assay had a detection range of 5–2000 nmol/L for cortisol and 0.26–12 nmol/L for T3.

Data analysis plan

Descriptive and inferential statistics

Before performing any inferential analysis, we summarized the clinical characteristics of the study population using descriptive statistics. This included calculating means, standard deviations, and ranges for continuous variables such as age, cortisol, T3, and BMI. For categorical variables like sex, frequency distributions were determined. Descriptive statistics provide a foundational understanding of the data and help in identifying any initial patterns or anomalies. We employed independent two-sample t-tests to compare mean values of cortisol and T3 between individuals with and without hypertension, and between those with and without CVD. The choice of the t-test was based on its ability to determine if there are statistically significant differences between the means of two independent groups. The test results include t-statistics, degrees of freedom, and p-values, which are used to assess statistical significance. For variables that did not follow a normal distribution, nonparametric alternatives, such as the Mann–Whitney U test, were considered. AWMI was analyzed as a subgroup within the cardiovascular parameters to evaluate its association with key clinical variables. The statistical significance of AWMI compared to other conditions, such as CADs and IWMI, was assessed using chi-square tests.

Logistic regression, assumptions, and model validation

To examine the relationships between clinical parameters (age, cortisol, T3, BMI, and sex) and binary outcomes (hypertension and CVD), we used logistic regression models. Logistic regression was chosen to estimate the probability of a binary outcome based on predictor variables. We included both hypertension and CVD statuses as dependent variables in separate models. Predictors were standardized to facilitate comparison, and categorical variables were converted into dummy variables. Model fitting was performed using the statsmodels.Logit function, and results were interpreted based on coefficients, standard errors, z-values, p-values, and 95% confidence intervals. We verified that the assumptions required for each statistical test were met. For t-tests, this included testing for normality and homogeneity of variances. If these assumptions were not met, appropriate nonparametric tests or data transformations were applied. We assessed the goodness-of-fit of the logistic regression models using the Hosmer–Lemeshow test to evaluate model calibration.

Data visualization, handling of confounders and interpretation

Graphs and Charts: To visually represent differences and relationships in the data, we generated bar plots and scatter plots using seaborn and matplotlib. These visualizations were used to compare mean values and explore the associations between clinical variables and the conditions under study. Potential confounders, such as age and BMI, were controlled for in the logistic regression models to isolate the effects of cortisol and T3 on hypertension and CVD. The inclusion of these variables helps in understanding their independent contributions to the outcomes. Results from statistical tests and models were interpreted in the context of the research hypotheses. Significant findings were discussed in relation to the existing literature, considering both direct and indirect effects of the studied variables on cardiovascular health. All the analyses were considered statistically significant when the p-value was < .05.

Results

Comparative analysis of clinical parameters in hypertension and CVD

This study involved the analysis of clinical parameters in a cohort of 87 patients with CVDs, with 37 females and 50 males, and 60 healthy individuals without CVD diagnoses, of which 28 were females and 32 were males. The comparison of clinical characteristics between individuals with and without hypertension, as well as those with and without CVD, revealed several key findings (Table 1 and Figure 2). The mean age did not show a statistically significant difference in either the hypertension or CVD groups, with p-values of .3659 and .1027, respectively, indicating that age may not be a major independent factor associated with these conditions. However, cortisol levels were significantly elevated in both the hypertension and CVD groups compared to their counterparts without these conditions, with highly significant p-values of .0001 for hypertension and .0001 for CVD. This suggests that elevated cortisol, potentially linked to stress, plays a critical role in both hypertension and CVD. Furthermore, T3 levels were significantly lower in individuals with hypertension and CVD, with p-values of .0001 and .0001, respectively, suggesting that decreased T3 levels might be associated with an increased risk of these conditions. Lastly, BMI was significantly higher in both the hypertension and CVD groups, with p-values of .038 for hypertension and .031 for CVD, highlighting that increased BMI may be an independent risk factor for both conditions. These results suggest that cortisol, T3, and BMI are strongly associated with hypertension and CVD, while age shows less significance in this context. For hypertension, cortisol levels are markedly higher in those with the condition compared to those without, suggesting a strong link between elevated cortisol and hypertension. Conversely, individuals with hypertension have lower T3 levels and slightly higher BMI compared to those without, indicating potential associations. For CVD, the trends are similar: higher cortisol and lower T3 levels are observed in those with the condition, alongside a slightly higher BMI compared to those without CVD. Age shows only minor differences between groups for both conditions. Overall, these visualizations highlight that elevated cortisol and lower T3 levels, along with increased BMI, are associated with both hypertension and CVD, emphasizing their potential roles in these health conditions.

Table 1.

Comparison of clinical characteristics in hypertension and CVD.

Parameter	Hypertension (mean ± SD)	CVD (mean ± SD)
Cortisol (ng/mL)	768.35 ± 563.10	1065.99 ± 700.54
T3 (ng/mL)	1.33 ± 0.46	1.25 ± 0.48
SBP (mmHg)	134.68 ± 13.78	142.50 ± 15.33
DBP (mmHg)	89.33 ± 8.63	92.10 ± 9.25
BMI (kg/m²)	26.69 ± 3.46	32.50 ± 4.90

SBP: systolic blood pressure; DBP: diastolic blood pressure; BMI: body mass index; T3: triiodothyronine; cortisol: cortisol levels; CVD: cardiovascular disease.

AWMI was significantly associated with higher prevalence rates compared to CAD and IWMI (67% vs 21.66% and 12%, respectively; p = .0002). RAASi therapy showed a nonsignificant trend toward a higher frequency in AWMI patients (84.21% vs 38%; p > .05). Overweight and normal weight categories were most frequently observed in AWMI cases (55% and 20%, respectively; p = .0079). Statistical significance was observed in terms of age (p < .0441) (Figure 1(A)). Comparison of the weights between the control group and the cardiovascular patients revealed a significant difference, with the latter group having a higher average weight (p = .000) (Figure 1(B)). Furthermore, the body mass index (BMI) of the patients was also significantly higher in comparison to the healthy subjects (p = .035) (Figure 1(C)).

Figure 1.

Comparison of (A) age (years), (B) weight (kg), and (C) body mass index (kg/m²) between “normal” and “cardiovascular diseases patients.” The variables shown were selected based on their clinical relevance and statistically significant differences between the two groups. Statistical significance is indicated as follows: *p < .05, **p < .01, ***p < .001. For consistency, the grouping labels (“normal” and “patients”) match those used in Table 2.

Table 2.

Logistic regression coefficients for hypertension and cardiovascular disease models.

Model	Variable	Coefficient (coef)	Standard error (std err)	z-value	p-value	95% CI Lower	95% CI Upper
Hypertension	Constant	7.5617	2.868	2.637	.008	1.941	13.183
	Age	0.2804	0.493	0.569	.570	−0.686	1.247
	Cortisol	5.3856	2.800	1.923	.054	−0.102	10.873
	T3	0.8878	0.846	1.049	.294	−0.771	2.546
	BMI	0.6100	0.558	1.092	.275	−0.485	1.705
CVD	Constant	3.9348	1.151	3.418	.001	1.678	6.191
	Age	0.5947	0.400	1.486	.137	−0.190	1.379
	Cortisol	5.3199	1.352	3.934	.000	2.670	7.970
	T3	−4.5016	1.105	−4.073	.000	−6.668	−2.335
	BMI	0.0724	0.416	0.174	.862	−0.742	0.887

CVD: cardiovascular disease; BMI: body mass index; T3: triiodothyronine.

Sex and blood pressure: Unmasking the cardiovascular connection

In the context of CVD, blood pressure analysis was conducted in both patients and control subjects. As anticipated, systolic and diastolic pressures in the patient group were significantly higher, confirming the cardiovascular alterations diagnosed in these individuals (Figure 2(A)). Furthermore, we conducted a sex-based comparison of blood pressure between male and female patients participating in the study. While a significant difference was observed in both sexes compared to healthy subjects, no sex-based difference was noted among patients with CVDs (Figure 2(B)). Intriguingly, high blood pressure was evident in all patients, irrespective of their cardiovascular condition.

Figure 2.

Blood pressure was higher in both female and male cardiovascular patients compared to controls. (A) Illustrates the change in systolic blood pressure (BP). (B) Shows the variation in diastolic BP. The data is presented as the average ± standard error of the mean, and statistical significance was determined using the t-test, where *p < .05 indicates significance.

Plasma T3 levels in CVD: An analysis of age-independent trends

This study analyzed plasma triiodothyronine (T3) hormone concentrations in healthy individuals and patients, comparing their respective levels. As depicted in Figure 3(A), our analysis revealed a noticeable decrease in average T3 concentrations in patients diagnosed with CVD. This trend held for both male and female patients, as indicated in Figure 3(B) and (C), with a high degree of statistical significance (r = .46, p < .0001; r = .66, p < .0001; r = .66, p < .0001). Following confirming T3 status, we extended our investigation to cortisol readings in both patient and control groups. The disparity in T3 levels between patients and controls remained consistent across all age groups, as evidenced in Figure 3(C), suggesting that the reduction in T3 levels among cardiovascular patients is not contingent on age or subject. Furthermore, our examination to determine whether T3 levels were associated with any cardiovascular changes revealed that the low T3 levels in patients were independent of their hypertension score.

Figure 3.

Triiodothyronine hormone (T3) exhibited a decrease in patients with cardiovascular diseases. The comparison was made between T3 levels in healthy controls (depicted by silver dots) and hypertensive cardiovascular patients (represented by red dots). (A) Illustrates T3 levels in healthy controls compared to CVD patients. (B) Breaks down T3 levels in healthy controls versus patients in both female and male groups. (C) Presents a graph depicting T3 readings across various age groups. The data is presented as the average ± standard error of the mean, and statistical analysis was conducted using the t-test, where *p < .05 indicates significance.

CVD: cardiovascular disease.

Correlation of cortisol levels with blood pressure classifications in cardiovascular patients

In our study, we found that patients with CVD had significantly higher cortisol levels compared to healthy individuals (mean value vs mean value, p < .001), as shown in Figure 4(A). When exploring the impact of sex on cortisol levels within the patient group, our analysis indicated no significant difference between female and male patients (Figure 4(B)). However, a significant variance in cortisol levels was observed across different age groups (Figure 4(C)). Additionally, blood pressure values, categorized into four ranges, were notably associated with cortisol levels. Patients in the G1–G3 blood pressure categories exhibited significantly elevated cortisol levels, whereas those with lower cortisol levels were more commonly associated with the high normal blood pressure range, as illustrated in Figure 4(D).

Figure 4.

In both male and female patients with cardiovascular diseases, cortisol levels were elevated compared to healthy controls. This comparison is depicted with healthy controls (silver dots) and hypertensive cardiovascular patients (red dots). Panel (A) presents a representative graph comparing cortisol levels between these groups. Panel (B) illustrates variations in cortisol readings based on sex, while Panel (C) shows cortisol levels across different age groups. The data are presented as the average ± standard error of the mean, with statistical significance assessed using the t-test where *p < .05 denotes significance.

Logistic regression analysis of hypertension and CVD

The logistic regression analysis for hypertension demonstrated that cortisol levels had a borderline significant positive association (coef = 5.3856, p = .054, 95% CI [−0.102 to 10.873]), while other variables, including age, T3, and BMI, did not show significant associations. For CVD, cortisol levels were strongly and significantly associated with increased risk (coef = 5.3199, p < .001, 95% CI [2.670 to 7.970]), whereas T3 levels exhibited a significant negative association (coef = −4.5016, p < .001, 95% CI [−6.668 to −2.335]). Age and BMI were not significantly associated with CVD. These results highlight cortisol and T3 as potentially relevant biomarkers in the context of hypertension and CVD, warranting further investigation. However, the cross-sectional nature of the study necessitates cautious interpretation, as causality cannot be inferred. In assessing the goodness-of-fit of our logistic regression models, we conducted a Hosmer–Lemeshow test. The test yielded a chi-square value of 0.89 and a p-value of .9989, indicating no significant difference between observed and predicted outcomes. This result suggests that the model adequately fits the data.

Discussion

Our study observed significant findings related to the interplay of cortisol and thyroid hormone levels in patients with CVDs. Among the 87 hypertensive cardiovascular patients, 60 had low plasma triodothyronine (T3) concentrations. This decline in T3 levels has been associated with adverse cardiac effects and myocardial remodeling, especially in severe heart failure cases. Moreover, heart failure patients exhibit low T3 levels, further emphasizing the role of thyroid dysfunction in the severity of cardiac diseases. ¹⁶ Additionally, we identified 62 patients with high cortisol levels, a hormone linked to ischemic heart disease. ¹⁷ Research from others along with our review^18,19 demonstrated that FABP4, ADK, and NDPKs function as a novel regulator of insulin-producing beta cells. Exploring the connections between stress, T3, and the Fabkin complex could provide valuable insights, potentially uncovering new regulatory mechanisms and therapeutic opportunities in diabetes research. Notably, the study revealed no significant sex-based difference in cortisol levels among patients. It is essential to mention that high cortisol levels were significantly associated with blood pressure classifications (G1–G3), while those with lower cortisol levels were associated with high normal blood pressure values. This study also established a connection between cortisol levels and various parameters such as age, weight, BMI, and blood pressure. ²⁰ AWMI demonstrated distinct clinical characteristics, including a higher association with overweight individuals and a nonsignificant trend with RAASi treatment. These findings emphasize the need for targeted management strategies in patients with AWMI. These findings are consistent with previous research linking age, weight, BMI, and blood pressure to hypertension and CVDs.^21–24 Notably, cortisol levels in our patients were significantly higher compared to healthy controls, and cortisol has been identified as an independent predictor of primary cause mortality risk in patients with prolonged heart failure. ²⁵ Substantial evidence suggests that cortisol plays a role in various complications, including obesity, type 2 diabetes, cardiovascular risk factors, and CVD.^26,27 Our study illuminates the intricate relationship between cortisol and hypertension-related CVDs.

Furthermore, we found a negative correlation between cortisol and T3 concentrations in patients. Chronic stress can reduce TSH synthesis due to increased somatostatin levels, leading to suppressed thyrotropin-releasing hormone and TSH production. Glucocorticoids, such as cortisol, have been shown to decrease the activity of 5-deiodinase, an enzyme responsible for converting biologically inactive T4 into potent T3 in peripheral tissues. ²⁸ This decline in T3 concentrations negatively affects cardiac muscle function by inhibiting the enzymes involved in calcium uptake by cardiomyocytes, reducing heart rate and weakening cardiomyocyte contraction and relaxation. In contrast, T3 levels were positively correlated with blood glucose random (BGR) and blood pressure values in the patients, indicating the significance of T3 in these aspects. Research has shown the relationship between low-normal T3 levels and higher glucose concentrations. ²⁹ Our study demonstrated that cortisol levels were positively correlated with BGR, further emphasizing the role of cortisol in glucose metabolism. ³⁰ This study is limited by its cross-sectional design, which restricts the ability to establish causal relationships between cortisol levels, T3, and CVD parameters. The cross-sectional nature of the study only allows for observations at a single point in time, thereby limiting the interpretation of temporal dynamics and causality. Additionally, the relatively small sample size and single-location setting further constrain the generalizability of the findings. While the study suggests an association between elevated cortisol and reduced T3 levels in CVD patients, it does not rule out other potential pathways or direct effects of cortisol on the CVS. The hypothesis that cortisol influences CVD through thyroid dysfunction, rather than through direct cardiovascular effects, is one possible explanation but requires further validation. Other factors such as direct hormonal effects or lifestyle variables could also contribute to the observed relationships. Potential confounders, such as medication use, stress levels, or underlying chronic conditions, may impact both cortisol and thyroid function and should be considered in future research. Addressing these confounders could help clarify the specific mechanisms through which cortisol and thyroid hormones interact and affect CVD. Future research should aim to include larger, more diverse populations and incorporate longitudinal designs to better understand the causal relationships and temporal changes in cortisol, T3, and their impact on CVD. Despite these limitations, this study provides valuable preliminary insights that can inform and guide future investigations in this field.

Conclusion

Among hypertensive cardiovascular patients, a significant proportion exhibited elevated cortisol levels, while a notable percentage had reduced T3 levels. Most of these patients had AWMI, highlighting the diversity of cardiovascular complications in this cohort. Blood pressure analysis confirmed that cardiovascular patients had significantly higher systolic and diastolic blood pressure readings, reinforcing the relationship between hypertension and cardiovascular conditions. Notably, this trend was consistent across sexes within the patient group. Furthermore, reduced T3 levels were observed in cardiovascular patients, irrespective of age, suggesting an age-independent effect. Elevated cortisol levels were significantly higher in cardiovascular patients compared to healthy controls, indicating a potential role for cortisol in cardiovascular pathophysiology. The association between cortisol levels and blood pressure classifications further strengthens the connection between cortisol and hypertension-related CVDs. These findings provide valuable insights into the complex interplay between clinical parameters, sex, hormonal factors, and cardiovascular health, while also highlighting the need for further research to explore causal relationships.