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Searching For Peripheral Proteomic Markers Of Primary Aldosteronism.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.ORCID iD: 0009-0002-7866-677X
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Purpose 

Primary aldosteronism (PA) is prevalent among hypertensive patients, and associated with worsened cardiovascular outcomes compared to primary hypertension (HT). Screening and diagnostics for PA are currently complicated and invasive, why new methods are needed. Unilateral PA (uPA) is best treated surgically, and bilateral PA (bPA) - medically. No validated proteomic diagnostic test has been found yet. Our aim was to explore proteomic markers in peripheral serum to discriminate between HT, PA, uPA and bPA. 

Methods

Eighty-eight hypertensive individuals were evaluated for PA, and diagnosed with HT (n=30); bPA (n=29); and uPA (n=29). Serum samples from these study groups were analyzed by Olink® Explore 384 Cardiometabolic Panel. A machine learning model based on ridge logistic regression with a stratified 5-fold cross-validation was used to identify HT, PA, bPA and uPA.

Results

In the study groups, 56 circulating proteins were significantly different, and some of them specifically: 4 between PA vs. HT;  3 between bPA vs. uPA; 1 between bPA vs. HT; 9 between uPA vs. HT; 1 between HT vs. bPA vs. uPA. Three proteins with strongest differentiation (Coagulation factor IX for PA vs. HT; dipeptidyl peptidase 4 for uPA vs. HT and bPA; heat shock protein B1 for bPA vs. uPA) were validated by enzyme-linked immunosorbent assay. Our machine learning model could successfully identify 95% of HT, bPA, and uPA samples.

Conclusion

Serum protein biomarkers may serve as a tool for discriminating HT, PA, uPA and bPA. Further studies are needed to support our results.

Keywords [en]
Primary aldosteronism; Diagnostics; Proteomics; Proteomic markers; Hypertension; Machine learning
National Category
Surgery
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-554034OAI: oai:DiVA.org:uu-554034DiVA, id: diva2:1950192
Note

Manuskriptet är inskickat till en vetenskaplig tidskrift

Available from: 2025-04-05 Created: 2025-04-05 Last updated: 2025-04-24
In thesis
1. Primary aldosteronism: improving screening-based diagnostics and treatment
Open this publication in new window or tab >>Primary aldosteronism: improving screening-based diagnostics and treatment
2025 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Primary aldosteronism (PA, non-physiologic adrenal overproduction of aldosterone) causes about 10% of arterial hypertension, and substantially elevates morbidity and cardiovascular mortality compared to primary hypertension (HT) alone.  PA often lacks specific clinical traits, and remains mostly undiagnosed. Its diagnosis requires biochemical screening and confirmatory tests - which are quite difficult to perform and/or to interpret correctly. About a quarter of PA cases are lateralized (or unilateral, uPA) – and can be cured or significantly ameliorated by surgery, which gives the best long-term prognosis. Bilateral subtype (bPA) can be controlled by mineralocorticoid receptor antagonists. Even the current lateralizing procedures are technically demand-ing and invasive. The challenge of identifying PA and its subtypes to guide the treatment requires more straightforward and sensitive diagnostic methods.

Our first paper describes the project of screening of 1181 unselected primary care hypertensive patients for PA. The 53 found cases of PA (corresponding to a prevalence of 4,5%) were further evaluated and treated (surgically or medically) according to the current guidelines. The pathophysiologic and clinical aspects of the recommended diagnostic and treatment principles, and the follow-up results after at least 6 months after treatment initiation were presented and analyzed.

Our second and third papers present research of new peripheral blood markers that may support diagnostics of PA among hypertensive individuals, including differentiation between its lateralized and bilateral subtype. MicroRNAs (second paper) and proteomic profile (third paper) were analyzed in groups of well clinically studied patients with HT, bPA and uPA.

MicroRNAs have been shown to regulate both aldosterone production and its effects in the target-tissues. Using machine learning (ML), we demonstrate the potential of both microRNAs (analyzed by NGS) and proteomics (analyzed by Olink® Explore 384 Cardiometabolic Panel based on proximity extension assay) to differentiate PA from HT, and uPA from bPA. Further validating studies are needed to evaluate the constructed ML-models and the clinical utility of both microRNA and proteomic analysis in hypertensive patients.

The theoretic and practical experience of these studies confirms the necessity to actively screen hypertensive patients for PA and to further develop its diagnostic methods as specific treatment ameliorates the long-term prognosis. 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2025. p. 47
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 2159
Keywords
primary aldosteronism, diagnostics, treatment, surgery, screening, primary care, biomarkers, microRNA, proteomics, prevalence
National Category
Surgery
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-554431 (URN)978-91-513-2501-9 (ISBN)
Public defence
2025-06-12, H:son Holmdahlsalen, Akademiska sjukhuset, ingång 100, Uppsala, 13:00 (Swedish)
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Supervisors
Available from: 2025-05-21 Created: 2025-04-24 Last updated: 2025-05-21

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