Unravelling the complexity of primary aldosteronism: new approaches to study the pathophysiology of aldosterone-producing adenoma

Primary aldosteronism (PA) is one of the most common forms of secondary hypertension characterized by an excessive aldosterone production independent of the renin-angiotensin system and other physiological regulators. Despite its high estimated prevalence, PA is often underdiagnosed, with testing typically occurring after the development of cardiovascular, renal and metabolic complications. It is well-established that high aldosterone circulating levels promote tissue inflammation, fibrosis and injury in multiple organs through inappropriate mineralocorticoid receptor (MR) stimulation. Early detection and targeted therapy with MR antagonist administration and/or adrenalectomy could potentially mitigate the end organ damage typical of PA. This project aimed to provide useful insights into the pathophysiology of PA that could help to improve the diagnostic and therapeutic processes. To achieve this goal, patients with aldosterone-producing adenoma (APA), before and after treatment, and subjects with essential hypertension (EH) were selected for a comparative study divided into two parts. The first section was focused on the transcriptomic analysis of the RNA content of urinary extracellular vesicles, which could reflect specific cellular processes occurring in kidneys and the urogenital tract. The analysis of differentially expressed genes revealed enriched gene ontology terms referring to ion channels and extracellular matrix remodeling, which are potentially linked to well-established hallmarks of PA, namely the dysregulation of ion transport and fibrosis. The second section of this thesis regards the analysis of plasma long- and very-long-chain fatty acids. Compared to subjects with EH, APA patients displayed lower circulating levels of monounsaturated fatty acids and higher levels of ω6 polyunsaturated fatty acids. This difference in the fatty acid distribution was likely related to aldosterone excess, and it could reflect a higher inflammation state of individuals with PA. Moreover, a longitudinal analysis of APA patients undergoing pharmacological and surgical therapy revealed a shift towards a more favorable lipid profile after the treatments, which is associated with a reduced risk of cardiovascular disease and improved metabolic health. Taken together, the results obtained by these two approaches highlighted a more prominent inflammatory state of APA, which is consistent with the information present in the literature. Integrating the outcomes of two different approaches allowed to investigate the pathophysiological processes of PA from different angles, providing new useful elements for risk stratification of this complex condition.