Cushing syndrome (CS) is a clinical condition characterized by chronic exposure to excessive circulating glucocorticoids, either exogenously administered or endogenously produced due to disorders such as pituitary adenomas or adrenal tumors (1). This hypercortisolemic state induces a wide spectrum of systemic manifestations, including central obesity, hypertension, diabetes mellitus, and increased susceptibility to infections (2). Cardiovascular complications remain the leading cause of morbidity and mortality in CS, with growing evidence highlighting the contribution of endothelial dysfunction, atherosclerosis, and myocardial remodeling to these outcomes (3,4).

Among the cardiovascular manifestations, valvular heart disease has received comparatively less attention in the context of CS. Although glucocorticoid excess is known to cause alterations in collagen turnover and myocardial fibrosis, the potential impact on cardiac valve structure and function is not well delineated (5). Simultaneously, CS is associated with a hypercoagulable state that predisposes patients to thromboembolic events, possibly due to increased coagulation factor levels, reduced fibrinolysis, and enhanced platelet activation (6,7). Platelet indices, such as mean platelet volume (MPV) and platelet distribution width (PDW), are simple yet effective markers of platelet activity and have been implicated in various prothrombotic conditions (8).

Additionally, thyroid hormones play a significant role in regulating cardiovascular function and coagulation pathways. Thyroid dysfunction, particularly hypothyroidism, can exacerbate cardiovascular risk through endothelial impairment, dyslipidemia, and altered hemostasis (9). Previous studies have shown altered thyroid profiles in CS patients, possibly mediated by hypothalamic-pituitary-thyroid axis suppression due to excess cortisol (10,11). However, few studies have systematically examined the interaction between thyroid dysfunction, platelet activity, and cardiovascular abnormalities in CS.

This study aims to evaluate the prevalence of cardiac valve dysfunction and hypercoagulability in patients with Cushing syndrome and to explore their associations with thyroid function and platelet biomarkers, thereby providing a comprehensive understanding of cardiovascular risk factors in this endocrine disorder.

A total of 72 adult patients diagnosed with endogenous Cushing syndrome were included in the study. Diagnosis was established based on standard clinical, biochemical, and radiological criteria, including elevated serum cortisol, loss of diurnal variation, and failure of suppression on overnight dexamethasone suppression testing.

Inclusion Criteria

• Patients aged 18 to 65 years
• Confirmed diagnosis of endogenous Cushing syndrome
• Willingness to provide informed consent

Exclusion Criteria

• History of congenital or acquired valvular heart disease unrelated to Cushing syndrome
• Known autoimmune thyroid disorders
• Current use of antiplatelet, anticoagulant, or thyroid medications
• Presence of chronic liver or renal disease

Clinical Assessment

Demographic data, clinical history, and comorbidities were recorded using a structured proforma. Blood pressure, body mass index (BMI), and signs of hypercortisolism such as facial plethora, abdominal striae, and proximal muscle weakness were documented.

Laboratory Investigations

Fasting blood samples were collected for the following assessments:

• Thyroid Function Tests: Serum TSH, free T3 (fT3), and free T4 (fT4) measured using chemiluminescent immunoassay.
• Platelet Parameters: Platelet count, mean platelet volume (MPV), and platelet distribution width (PDW) analyzed via automated hematology analyzer.
• Coagulation Profile: Prothrombin time (PT), activated partial thromboplastin time (aPTT), and plasma D-dimer levels were determined to assess hypercoagulability.

Cardiac Evaluation

Transthoracic echocardiography was performed by a trained cardiologist blinded to laboratory results, using a standardized protocol to assess valvular morphology and function. The presence and severity of regurgitation or stenosis in mitral, aortic, tricuspid, and pulmonary valves were documented.

Statistical Analysis

Data were analyzed using SPSS version 26.0 (IBM Corp., Armonk, NY, USA). Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as frequencies and percentages. Associations between variables were assessed using Pearson’s correlation and chi-square test. Multivariate logistic regression was applied to identify independent predictors of valvular dysfunction and hypercoagulability. A p-value less than 0.05 was considered statistically significant

A total of 72 patients with confirmed Cushing syndrome were included in the study, comprising 54 females (75%) and 18 males (25%), with a mean age of 42.6 ± 10.8 years. The average duration of symptoms prior to diagnosis was 18.3 ± 6.7 months. Clinical features such as truncal obesity (88.9%), facial plethora (72.2%), hypertension (65.3%), and glucose intolerance (58.3%) were commonly observed.

Thyroid and Platelet Biomarkers

Among the study population, 18 patients (25%) had elevated TSH with normal fT3 and fT4 levels, suggestive of subclinical hypothyroidism. The mean MPV was 11.2 ± 1.4 fL, and PDW was 16.3 ± 2.1%. Elevated MPV (>11 fL) was observed in 48 patients (66.7%), while increased PDW (>15%) was seen in 52 patients (72.2%). These findings are detailed in Table 1.

Table 1. Thyroid Profile and Platelet Indices in CS Patients (n=72)

Coagulation Profile and Echocardiographic Findings

Coagulation markers were abnormal in 44 patients (61.1%), with raised D-dimer in 31 patients (43.1%), and prolonged PT in 21 patients (29.2%). Echocardiographic assessment revealed cardiac valve dysfunction in 29 patients (40.3%), with mitral regurgitation being the most prevalent lesion (22.2%), followed by tricuspid regurgitation (11.1%). Moderate or severe valvular dysfunction was seen in 9 patients (12.5%). These findings are summarized in Table 2.

Table 2. Coagulation and Echocardiographic Parameters (n=72)

Correlation analysis revealed a significant positive association between TSH and MPV (r = 0.41, p = 0.002), and between MPV and the presence of valvular dysfunction (p = 0.01). Multivariate regression identified elevated MPV (OR = 2.74, 95% CI: 1.32–5.88) and TSH (OR = 1.87, 95% CI: 1.10–3.18) as independent predictors of cardiac valve abnormalities (p < 0.05).

These results suggest a strong link between subclinical thyroid dysfunction, platelet activation, and cardiovascular complications in patients with Cushing syndrome (Table 1 and Table 2).

The present study highlights the high prevalence of cardiac valve dysfunction and hypercoagulability in patients with Cushing syndrome, along with their significant association with thyroid abnormalities and platelet activation markers. Our findings support the growing understanding that Cushing syndrome, beyond its classical metabolic and endocrine manifestations, has notable cardiovascular and hematological implications.

The detection of valvular dysfunction in 40.3% of patients, predominantly mitral and tricuspid regurgitation, aligns with prior research that documented structural cardiac changes secondary to prolonged glucocorticoid exposure (1,2). Chronic hypercortisolemia is known to induce myocardial fibrosis and extracellular matrix remodeling, which may extend to the valvular apparatus, contributing to functional valvulopathy (3). The observed association between elevated mean platelet volume (MPV) and valvular dysfunction suggests a possible link between systemic inflammation, platelet activation, and cardiovascular remodeling (4).

Hypercoagulability in Cushing syndrome is a well-established phenomenon and contributes to the increased risk of thromboembolic events, including deep vein thrombosis and pulmonary embolism (5,6). In our cohort, over 60% of patients showed deranged coagulation profiles, with D-dimer elevation being the most frequent finding. These results are comparable to those of van der Pas et al., who reported similar coagulation abnormalities in active Cushing’s disease (7). Elevated MPV and PDW, found in the majority of our patients, further underscore the role of platelet activation in the prothrombotic state seen in CS (8,9).

Interestingly, 25% of the study population exhibited subclinical hypothyroidism, and TSH levels were significantly correlated with both platelet indices and valvular abnormalities. These findings are supported by studies indicating that hypothyroidism contributes to impaired endothelial function, reduced cardiac contractility, and altered hemostatic balance (10,11). Moreover, suppressed hypothalamic-pituitary-thyroid axis activity due to cortisol excess may account for the subtle thyroid dysfunction seen in CS (12). The interaction between thyroid hormones and platelet function has been explored in other endocrine disorders, suggesting that even mild thyroid abnormalities may influence platelet activation and aggregation (13).

Our multivariate regression analysis identified elevated TSH and MPV as independent predictors of valvular involvement, suggesting that these parameters could serve as accessible biomarkers for cardiovascular risk stratification in CS. Similar associations have been reported in non-CS populations with autoimmune thyroiditis and metabolic syndrome, reinforcing the broader relevance of these findings (14,15).

In summary, this study demonstrates that cardiac valve dysfunction and hypercoagulability are common in Cushing syndrome and are significantly associated with thyroid dysfunction and elevated platelet indices. These findings underscore the importance of a multidisciplinary approach in the assessment and monitoring of CS patients, incorporating cardiovascular, hematological, and endocrine parameters.

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