Sokolova A. Clinical and Immunological Determinants of Heart Failure Development in Young Patients with Diabetes Mellitus

Sokolova A.M. Clinical and immunological features of heart failure development in young patients with diabetes mellitus. – Qualifying scientific work as a manuscript. Dissertation for obtaining the degree of Doctor of Philosophy in specialty 222 “Medicine”, field of knowledge 22 “Health Care”. The aim of the study was to improve approaches to early diagnosis and risk stratification of heart failure in patients with type 1 and type 2 diabetes mellitus based on a comprehensive assessment of clinical, immunological, and biochemical parameters. The study was conducted in 2022–2026 at the Department of Diabetology of the State Institution “V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine”. A total of 492 electronic medical records of patients with diabetes mellitus were analyzed, from which a clinical cohort of 80 patients with confirmed heart failure or metabolic cardiomyopathy was formed. The diagnosis was established based on clinical symptoms (dyspnea, fatigue, palpitations during physical exertion) and a cardiologist’s consultative conclusion using the NYHA functional classification. The control group consisted of 16 practically healthy individuals. All patients underwent a comprehensive examination including clinical, anthropometric, laboratory, immunological, and instrumental methods. Levels of NT-proBNP, glycated hemoglobin, creatinine, albuminuria, as well as immunoinflammatory markers (IL-6, IL-10, IL-17A, IL-4, TGF-β1), lipoprotein(a), and oxidized low-density lipoproteins were assessed. Echocardiography was performed to evaluate systolic and diastolic function of the left ventricle. Statistical analysis included correlation analysis, nonparametric methods, and multiple logistic regression. It was established that in the majority of patients, regardless of diabetes type, the phenotype of heart failure with preserved left ventricular ejection fraction (HFpEF) predominates: 91.3% in type 1 diabetes mellitus and 82.5% in type 2 diabetes mellitus. At the same time, type 2 diabetes mellitus is characterized by greater heterogeneity of systolic function. Elevated NT-proBNP levels (>125 pg/mL) were detected in most patients and showed a statistically significant inverse correlation with left ventricular ejection fraction, confirming its role as an integral marker of myocardial stress. It was found that chronic hyperglycemia is associated with a decrease in systolic cardiac function, especially in type 1 diabetes mellitus, whereas in type 2 diabetes mellitus glycemic parameters reflect cumulative metabolic burden. Albuminuria demonstrated high prognostic significance as an early marker of cardiorenal involvement, being associated with deterioration of renal function and parameters of cardiac remodeling. Immunological analysis showed that in patients with type 2 diabetes mellitus, a pronounced pro-inflammatory and pro-oxidative profile is formed with the involvement of IL-17A, IL-10, and oxLDL, whereas in type 1 diabetes mellitus immune changes are more selective. Increased levels of TGF-β1 and IL-17A were associated with decreased ejection fraction and increased NT-proBNP levels, indicating activation of fibrotic and inflammatory mechanisms of myocardial remodeling. Additionally, it was found that in patients after COVID-19, persistent immunoinflammatory activation is maintained, manifested by increased IL-17A and oxLDL levels, whereas glucose-lowering therapy may have a modulating effect on these parameters. The scientific novelty of the study lies in the first comprehensive assessment of clinical, immunological, and metabolic determinants of heart failure development in diabetes mellitus with the construction of a predictive model of individual risk based on TGF-β1 level, body mass index, age, and metformin use. The results of the study have practical significance for improving early diagnosis of heart failure in patients with diabetes mellitus and can be implemented in clinical practice. Key words: diabetes mellitus; type 1 diabetes mellitus; type 2 diabetes mellitus; heart failure; chronic kidney disease; albuminuria; cardiovascular diseases; cardiovascular complications; cardiovascular risk factors; NT-proBNP; immunoinflammation; IL-17A; TGF-β1.