Keywords
cardiovascular diseases
ischemic heart disease
type 2 diabetes mellitus
obesity
post-infarction cardiosclerosis
How to Cite
Abstract
In press
Background. Chronic Heart Failure (CHF) of ischemic origin is a significant medical problem, aggravated by concomitant Type 2 Diabetes Mellitus (T2DM) and obesity. Growth Arrest-Specific protein 6 (GAS6), a ligand for TAM (Tyro3, Axl, Mer) receptors family, is involved in apoptosis and myocardial fibrosis, making it a potential diagnostic marker.
Aim. To assess circulating GAS6 levels and establish correlations with various clinical variants of coronary artery disease in patients with chronic heart failure and concomitant type 2 diabetes mellitus and obesity.
Materials and Methods. The study involved 225 patients with ischemic heart failure, divided into groups according to metabolic disorders: Group 1 – 75 patients with Coronary Artery Disease (CAD), СHF, T2DM and obesity; Group 2 – 50 patients with CAD, CHF and T2DM; Group 3 – 50 patients with CAD, CHF and obesity; Group 4 – 50 patients with CAD and CHF without metabolic disorders. A Control Group included 30 healthy individuals. The patients were sub-divided in accordance with CAD form: stable angina, diffuse cardiosclerosis, and Post-Infarction CardioSclerosis (PICS). GAS6 levels were determined by Enzyme-Linked ImmunoSorbent Assay (ELISA). The data were analyzed using parametric and non-parametric methods via Statistica 14.0 (TIBCO Software Inc., USA). Group comparisons were performed using the Kruskal-Wallis H-test with post-hoc Mann-Whitney U-test with Bonferroni correction. The work was carried out within the framework of the author's dissertation.
Research Ethics. The study was approved by the Bioethics Commission of Kharkiv National Medical University and conducted in accordance with the principles of the World Medical Association Declaration of Helsinki (1964–2024). All patients provided written informed consent to participate.
Results. The most pronounced and significant increase in circulating GAS6 levels was observed in patients of Groups 1 and 3 compared to the controls. The highest GAS6 level ([38.18±2.15] ng/ml) was found in Group 1 patients with PICS, significantly exceeding values in the diffuse cardiosclerosis subgroup (p<0.008). In Groups 2 and 4, GAS6 levels did not differ significantly from the Control Group (p>0.008). Correlation analysis revealed a strong positive correlation between GAS6 and obesity (r=0.77; p<0.05). A moderate significant positive correlation with PICS (r=0.63; p<0.05) and T2DM (r=0.61; p<0.05) was found. The correlation with stable angina was weak and insignificant (r=0.26; p>0.05).
Conclusions. Obesity is a key factor in GAS6 activation, reflecting systemic inflammation and profibrotic processes. Elevated GAS6 levels are reliably associated with post-infarction cardiosclerosis specifically in the presence of obesity, indicating its role in myocardial remodeling and fibrogenesis.
Keywords: therapy, cardiovascular diseases, ischemic heart disease, type 2 diabetes mellitus, obesity, post-infarction cardiosclerosis.
References
Lavalle C, Mariani MV, Severino P, Palombi M, Trivigno S, D'Amato A, et al. Efficacy of Modern Therapies for Heart Failure with Reduced Ejection Fraction in Specific Population Subgroups: A Systematic Review and Network Meta-Analysis. Cardiorenal Med. 2024;14(1):570-80. DOI: 10.1159/000541393. PMID: 39284285.
Piché ME, Tchernof A, Després JP. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ Res. 22;126(11):1477-500. DOI: 10.1161/CIRCRESAHA.120.316101. Erratum in: Circ Res. 2020;127(3):e107. DOI: 10.1161/RES.0000000000000421. PMID: 32437302.
Hahn VS, Petucci C, Kim MS, Bedi KC Jr, Wang H, Mishra S, et al. Myocardial Metabolomics of Human Heart Failure With Preserved Ejection Fraction. Circulation. 2023;147(15):1147-61. DOI: 10.1161/CIRCULATIONAHA.122.061846. PMID: 36856044.
Ng ACT, Delgado V, Borlaug BA, Bax JJ. Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging. Nat Rev Cardiol. 2021;18(4):291-304. DOI: 10.1038/s41569-020-00465-5. PMID: 33188304.
Ma T, Huang R, Xu Y, Lv Y, Liu Y, Pan X, et al. Plasma GAS6 predicts mortality risk in acute heart failure patients: insights from the DRAGON-HF trial. J Transl Med. 2023;21(1):21. DOI: 10.1186/s12967-022-03859-w. PMID: 36635690.
Lu C, Song Y, Wu X, Lei W, Chen J, Zhang X, et al. Pleiotropic role of GAS6 in cardioprotection against ischaemia-reperfusion injury. J Adv Res. 2025;70:481-97. DOI: 10.1016/j.jare.2024.04.020. PMID: 38653371.
Chen J, Wang Y, Li X, Guo X, Tian J, Zheng X, et al. IDHP Mitigates LPS-Induced Cardiomyocyte Injury via the GAS6/Axl-AMPK Axis: A Multi-Target Strategy Counteracting Inflammation, Oxidative Stress, and Apoptosis. Pharmaceuticals (Basel). 2025;18(8):1188. DOI: 10.3390/ph18081188. PMID: 40872581.
Zhao A, Lei W, Tian J, Wu X, Li M, Zhang Y, et al. Mangiferin Attenuates Myocardial Ischemia Reperfusion Injury by Regulating the GAS6/Axl Signalling Pathway. Phytother Res. 2025;39(3):1388-402. DOI: 10.1002/ptr.8423. PMID: 39780746.
Schleh MW, Caslin HL, Garcia JN, Mashayekhi M, Srivastava G, Bradley AB, Hasty AH. Metaflammation in obesity and its therapeutic targeting. Sci Transl Med. 2023;15(723):eadf9382. DOI: 10.1126/scitranslmed.adf9382. PMID: 37992150.
Yang X, Bhowmick K, Rao S, Xiang X, Ohshiro K, Amdur RL, et al. Aldehydes alter TGF-β signalling and induce obesity and cancer. Cell Rep. 2024 Sep 24;43(9):114676. DOI: 10.1016/j.celrep.2024.114676. PMID: 39217614.
Han X, Li W, He X, Lu X, Zhang Y, Li Y, et al. Blockade of TGF-β signalling alleviates human adipose stem cell senescence induced by native ECM in obesity visceral white adipose tissue. Stem Cell Res Ther. 2023;14(1):291. DOI: 10.1186/s13287-023-03525-y. PMID: 37807066.
Xiao H, Chen J, Duan L, Li S. Role of emerging vitamin K‑dependent proteins: Growth arrest‑specific protein 6, Gla‑rich protein and periostin (Review). Int J Mol Med. 2021;47(3):2. DOI: 10.3892/ijmm.2020.4835. PMID: 33448308.
Chen W, Van Beusecum JP, Xiao L, Patrick DM, Ao M, Zhao S, et al. Role of Axl in target organ inflammation and damage due to hypertensive aortic remodelling. Am J Physiol Heart Circ Physiol. 2022;323(5):H917-33. DOI: 10.1152/ajpheart.00253.2022. PMID: 36083796.
Wu KS, Hung YJ, Lee CH, Hsiao FC, Hsieh PS. The Involvement of GAS6 Signaling in the Development of Obesity and Associated Inflammation. Int J Endocrinol. 2015;2015:202513. DOI: 10.1155/2015/202513. PMID: 25954309.
Li YH, Lu CH, Lin FH, Su SC, Liu JS, Hsieh CH, et al. Plasma Growth Arrest-Specific 6 Protein and Genetic Variations in the GAS6 Gene in Patients with Metabolic Syndrome. Metab Syndr Relat Disord. 2019;17(1):22-8. DOI: 10.1089/met.2017.0143. PMID: 30346880.
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