Association of β1- and β2-Adrenergic Receptor Expression with Myocardial Fibrotic Remodeling in Patients with Ischemic Heart Disease and Arterial Hypertension

Background. Chronic ischemic heart disease (IHD) is characterized by progressive myocardial remodeling caused by the combined effects of persistent ischemia and hemodynamic overload. Sustained activation of the sympathetic nervous system leads to alterations in β-adrenergic signaling, which may influence both the extent and spatial distribution of myocardial fibrosis.

Aim: To evaluate the association between β1- and β2-adrenergic receptor expression in cardiomyocytes and topographic patterns of myocardial fibrosis in patients with chronic IHD, and to determine the modifying effect of concomitant arterial hypertension on myocardial remodeling.

Material and Methods. This pilot study included 29 patients with chronic IHD undergoing elective coronary artery bypass grafting. According to the presence of hypertension, patients were stratified into an IHD group (n = 17) and an IHD with hypertension group (n = 12). Right atrial appendage specimens were analyzed. The extent and distribution of fibrosis were assessed using Van Gieson staining. Immunohistochemistry was performed to determine ADRB1 and ADRB2 expression intensity in cardiomyocytes. Associations were evaluated using Spearman’s rank correlation and proportional odds regression adjusted for arterial hypertension.

Results. Myocardial fibrosis was present in all cases. Although the overall burden of fibrosis did not differ between groups, patients with concomitant arterial hypertension demonstrated a distinct distribution of subepicardial fibrosis (p = 0.008). In the pooled cohort, lower ADRB1 expression intensity was significantly associated with greater subendocardial fibrosis severity (ρ = −0.49; p = 0.007), and this relationship remained independent after arterial hypertension (OR = 0.17; p = 0.014). ADRB2 expression intensity showed an inverse correlation with subepicardial fibrosis (ρ = −0.43; p = 0.020); however, statistical significance was attenuated after adjustment for arterial hypertension (p = 0.074).

Conclusions. These findings support the concept of spatial heterogeneity in myocardial fibrotic remodeling in chronic IHD. Reduced β1-adrenergic receptor expression is independently associated with subendocardial remodeling, consistent with an ischemia-driven pattern of injury. In contrast, the relationship between β2-adrenergic receptor expression and subepicardial fibrosis appears less robust and partially influenced by clinical phenotype. Arterial hypertension modifies the topographic distribution of fibrosis without increasing its overall burden.

1. Parichatikanond W., Duangrat R., Kurose H., Mangmool S. Regulation of β-adrenergic receptors in the heart: a review on emerging therapeutic strategies for heart failure. Cells. 2024;13(20):1674. https://doi.org/10.3390/cells13201674

2. Grassi G., Drager L.F. Sympathetic overactivity, hypertension and cardiovascular disease: state of the art. Curr. Med. Res. Opin. 2024;40 (Suppl. 1):5–13. https://doi.org/10.1080/03007995.2024.2305248

3. Maslov L.N., Naryzhnaya N.V., Voronkov N.S. et al. The role of β-adrenergic receptors in the regulation of cardiac tolerance to ischemia/ reperfusion. Why do β-adrenergic receptor agonists and antagonists protect the heart? Fundam. Clin. Pharmacol. 2024;38(4):658–673. https://doi.org/10.1111/fcp.12988

4. Bode C., Preissl S., Hein L., Lother A. Catecholamine treatment induces reversible heart injury and cardiomyocyte gene expression. Intensive Care Med. Exp. 2024;12(1):48. https://doi.org/10.1186/s40635-024-00632-9

5. Manukyan M.A., Falkovskaya A.Yu., Mordovin V.F. et al. Features of beta-adrenergic reactivity of erythrocyte membranes in patients with resistant arterial hypertension combined with type 2 diabetes mellitus. Siberian Journal of Clinical and Experimental Medicine. 2022;37(3):98–107. (In Russ.). https://doi.org/10.29001/2073-8552-2022-37-3-98-107

6. Afanasyev S.A. Adrenergic reactivity of β1-adrenergic receptors of the human myocardium in ischemic heart disease with preserved and reduced left ventricular ejection fraction and its relationship with structural and functional cardiac parameters. Hum. Physiol. 2024;50(5):41–53. (In Russ.). https://doi.org/10.31857/S0131164624050055

7. Xu B., Bahriz S., Salemme V.R. et al. Differential downregulation of β1-adrenergic receptor signaling in the heart. J. Am. Heart Assoc. 2024;13(12):e033733. https://doi.org/10.1161/JAHA.123.033733

8. Skórka P., Piotrowski J., Bakinowska E. et al. The role of signalling pathways in myocardial fibrosis in hypertrophic cardiomyopathy. Rev. Cardiovasc. Med. 2025;26(2):27152. https://doi.org/10.31083/RCM27152

9. Prajapati A.K.K., Shah G.B. The role of TGF-β in cardiac fibrosis and heart failure: a review. IP Int. J. Comprehensive Adv. Pharmacol. 2024;9(1):1–6. https://doi.org/10.18231/j.ijcaap

10. Pitt B., Bakris G.L. Resistant hypertension: cardiorenal protection with mineralocorticoid receptor blockade. Eur. Heart J. 2024;45(2):136–138. https://doi.org/10.1093/eurheartj/ehad299

11. Xie L., Li Y., Luo S., Huang B. Impact of renal denervation on cardiac remodeling in resistant hypertension: a meta-analysis. Clin. Cardiol. 2024;47(2):e24222. https://doi.org/10.1002/clc.24222

12. Matanes F., Siddiqui M., Velasco A. et al. Adverse cardiac remodeling is absent in patients with true controlled resistant hypertension. J. Clin. Hypertens. (Greenwich). 2023;25(5):416–425. https://doi.org/10.1111/jch.14625

13. Mulari S., Eskin A., Lampinen M. et al. Ischemic heart disease selectively modifies the right atrial appendage transcriptome. Front. Cardiovasc. Med. 2021;8:728198. https://doi.org/10.3389/fcvm.2021.728198

14. Li W., Zhu H., Zou X. et al. A brain-to-lung signal from GABAergic neurons to ADRB2+ interstitial macrophages promotes pulmonary inflammatory responses. Immunity. 2025;58(8):2069–2085.e9. https://doi.org/10.1016/j.immuni.2025.05.005

15. Fedchenko N., Reifenrath J. Different approaches for interpretation and reporting of immunohistochemistry analysis results in the bone tissue – a review. Diagn. Pathol. 2014;9:221. https://doi.org/10.1186/s13000-014-0221-9

16. Taylor C.R., Levenson R.M. Quantification of immunohistochemistry-issues concerning methods, utility and semiquantitative assessment II. Histopathology. 2006;49(4):411–424. https://doi.org/10.1111/j.1365-2559.2006.02513.x

17. Detre S., Saclani Jotti G., Dowsett M.A “Quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas. J. Clin. Pathol. 1995;48(9):876–878. https://doi.org/10.1136/jcp.48.9.876