Association of plasma ADMA, FABP4 levels, and AIP with increased cardiovascular disease risk in Graves’ disease: an exploratory pilot study

BACKGROUND: Graves' disease is an autoimmune disorder characterized by hyperthyroidism and is often associated with diffuse goiter, Graves' ophthalmopathy, antithyroid peroxidase antibodies, TSH receptor antibodies, and high serum thyroxine (T4) and triiodothyronine (T3) levels. Hyperthyroidism causes changes in the cardiovascular system that can be explained by the direct effects of thyroid hormones on vascular smooth muscle cells and cardiomyocytes. On the one hand, heart rate, myocardial contractility, preload, blood volume, and tissue thermogenesis increase, while on the other hand, afterload and systemic vascular resistance decrease. OBJECTIVES: The aim of this exploratory pilot study was to investigate cardiovascular disease risk in patients with Graves' disease by evaluating the relationship between thyroid hormone levels and plasma Asymmetric Dimethylarginine (ADMA), Fatty Acid-Binding Protein 4 (FABP4), Atherogenic Index of Plasma (AIP), and Castelli Risk Index (CRI). METHODS: This study was designed as a cross-sectional study between January 2023 and January 2024 at the Endocrinology and Metabolism Department of Adana City Training and Research Hospital. The study included 30 newly diagnosed patients with Graves' disease, aged 18-65 years, who were recruited from the clinic. The diagnosis was confirmed clinically, biochemically, and through sonographic evaluation. As a control group, 30 euthyroid individuals aged 18-65 years, without thyroid disease, cardiac disease, hypertension, diabetes, or impaired glucose tolerance were selected. Demographic data, including age and gender, were recorded, and Body Mass Index (BMI) was calculated. Blood samples were collected to measure routine parameters such as Thyroid-Stimulating Hormone (TSH), Free Triiodothyronine (fT3), Free Thyroxine (fT4), Thyroid Receptor Antibodies (TRAB), Glucose, Blood Urea Nitrogen (BUN), Creatinine, Aspartate Aminotransferase (AST), Alanine Aminotransferase (ALT), Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), HDL, LDL, Total Cholesterol, and Triglycerides. In addition, the levels of ADMA and FABP4 were analyzed. The Atherogenic Index of Plasma (AIP) and Castelli Risk Index (CRI) were calculated. RESULTS: FABP4 levels were significantly higher in patients compared with the control group (10.03 ± 1.63 vs. 8.99 ± 1.24, p = 0.009). ADMA was significantly correlated with BMI (r = 0.402, p = 0.019), CRP (r = 0.479, p = 0.001), BUN (r = 0.462, p = 0.003), LDL (r = 0.443, p = 0.012), Total Cholesterol (r = 0.508, p = 0.004), and fT4 (r = 0.455, p = 0.005). Notably, ADMA had a strong positive correlation with FABP4 (r = 0.531, p < 0.001), CRI (r = 0.622, p < 0.001), and AIP (r = 0.642, p < 0.001). FABP4 was positively correlated with BMI (r = 0.514, p = 0.002), glucose (r = 0.577, p < 0.001), and TG (r = 0.614, p < 0.001). CRI was positively correlated with gender (Male) (r = 0.548, p = 0.003), BMI (r = 0.621, p < 0.001), glucose (r = 0.578, p < 0.001), and triglycerides (r = 0.949, p < 0.001). AIP showed a strong positive correlation with TG (r = 0.949, p < 0.001), BMI (r = 0.612, p < 0.001), Glucose (r = 0.576, p < 0.001), and Gender (Male) (r = 0.548, p = 0.003). ADMA demonstrated low discriminatory performance AUC of 0.614, with a cut-off value of > 132.9. It had a sensitivity and specificity of 75%, but the p-value was not significant (p = 0.145). FABP4 had a cut-off of > 8.47, with a sensitivity of 86% and specificity of 68% (AUC: 0.690, 95% CI: 0.551-0.829, p = 0.015). CRI had a cut-off value of > 3.27, with a sensitivity of 60% and specificity of 79% (AUC: 0.726, 95% CI: 0.620-0.832, p = 0.001). AIP showed a cut-off value of > 0.66, with sensitivity of 59% and specificity of 73% (AUC: 0.695, 95% CI: 0.587-0.803, p = 0.001). CONCLUSION: The findings suggest that biomarkers like FABP4, AIP, and CRI may provide insights into cardiovascular risk assessment in Graves' disease. However, further studies with larger cohorts are needed to validate these associations.