Beta-adrenergic receptors expression in cardiomyocytes with structural and functional myocardial changes in patients with chronic heart failure with preserved ejection fraction

Introduction. Chronic hypersympathicotonia, excessive stimulation of beta-adrenergic receptors (beta-ARs) are key drivers of myocardial remodeling in chronic heart failure (CHF). Beta1-ARs desensitization is a compensatory mechanism limiting catecholamines damaging effects, but its progression exacerbates contractile dysfunction. Beta2-ARs exert predominantly protective effects, attenuating the cardiotoxicity of chronic catecholamine exposure. Of particular interest is the study of these processes in CHF with preserved ejection fraction (HFpEF) in the absence of myocardial infarction, rhythm disturbances, or valvular defects. Aim: To evaluate ADRB1 , ADRB2 genes expression levels and beta1-, beta2-adrenergic receptors myocardial content in HFpEF depending on the presence of structural, functional changes in the myocardium. Material and Methods. A total of 115 patients (65±6.9 years) with coronary artery disease, hypertension, HFpEF were included. ADRB1 , ADRB2 expression (digital droplet PCR), beta1-, beta2-AR levels (ELISA) were determined in right atrial appendage biopsies. Erythrocyte membranes beta-adrenergic reactivity (beta-ARM) was assessed in the blood. Results. Beta-ARM didn't differ between CHF functional classes, in patients with left ventricular (LV) hypertrophy, left atrial (LA) dilation, diastolic dysfunction and without them. With LA dilation, a significant decrease in beta1-AR levels was revealed (2.89 (1.91; 3.75) vs 3.54 (2.88; 4.82) ng/mg protein, p=0.014) with unchanged ADRB1 expression. A direct correlation was established between beta2-AR and end systolic (r=0.363, p=0.045), diastolic volumes (r=0.424, p=0.017), but ADRB2 , beta2-AR levels didn’t depend on the presence of LV hypertrophy or LA dilation. In obesity, beta1-AR higher level was recorded (3.82 (2.89; 4.54) vs 3.25 (2.27; 3.65), p=0.028), in diabetes mellitus 2, the ADRB2 expression was increased (0.017 (0.010; 0.036) vs 0.009 (0.006; 0.013), p=0.005). Conclusion. In patients with HFpEF without myocardial infarction, structural, functional myocardial changes weren’t accompanied by a significant increase in beta-ARM. Decreased beta1-AR level in cardiomyocytes are characteristic of LA dilation, but elevated beta2-AR correlated with increased LV volumes. Obesity was associated with higher beta1-AR level; diabetes mellitus was associated with increased ADRB2 gene expression. The CHF phenotype under study is characterized by a localized pattern of adrenergic dysregulation and divergent changes in the levels of beta-AR subtypes in cardiomyocytes, which are significantly influenced by metabolic disorders.