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Aldosterone synthase inhibitors for the treatment of cardiovascular disease

Nature Reviews Endocrinology (2026) Cite this article

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Abstract

Aldosterone is essential for maintaining blood pressure during hypovolaemia and/or dehydration through genomic actions mediated by the mineralocorticoid receptor and rapid signalling pathways involving the G-protein-coupled oestrogen receptor. Inappropriate aldosterone secretion contributes to cardiovascular and renal injury in several common disorders, including resistant hypertension, primary aldosteronism and heart failure. Pharmacological blockade of the mineralocorticoid receptor has therefore become a cornerstone in the therapy of cardiovascular disease. Nevertheless, mineralocorticoid receptor antagonism does not address the pathophysiological effects that are mediated by aldosterone, and residual cardiovascular risk remains substantial in many patients. Aldosterone synthase inhibitors are a novel therapeutic strategy that have effectively lowered aldosterone concentrations and reduced blood pressure in randomized clinical trials in patients with resistant or uncontrolled hypertension and patients with chronic kidney disease. Although these findings highlight the potential therapeutic value of aldosterone synthase inhibition, data on long-term safety, effectiveness compared with mineralocorticoid receptor antagonists and effects on cardiovascular outcomes are still lacking.

Key points

  • Excess aldosterone contributes to cardiovascular and renal injury beyond its effects on blood pressure.

  • Mineralocorticoid receptor antagonists improve outcomes in heart failure but do not eliminate risk.

  • Aldosterone synthase inhibitors suppress aldosterone production and reduce blood pressure in resistant hypertension.

  • Early clinical trials with aldosterone synthase inhibitors show promising results on intermediate end points, but long-term cardiovascular outcome data are lacking.

  • Direct comparisons between aldosterone synthase inhibitors and mineralocorticoid receptor antagonists using hard end points are needed to define their clinical role.

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Fig. 1: Systemic effects of aldosterone.
The alternative text for this image may have been generated using AI.
Fig. 2: Genomic (mineralocorticoid receptor-mediated) and non-genomic (G-protein-coupled oestrogen receptor-mediated) actions of aldosterone.
The alternative text for this image may have been generated using AI.
Fig. 3: Mechanisms of vascular mineralocorticoid receptor activation and endothelial dysfunction.
The alternative text for this image may have been generated using AI.
Fig. 4: The feedforward mechanism of aldosterone-induced aldosterone synthesis and secretion in human adrenocortical cells.
The alternative text for this image may have been generated using AI.

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Authors and Affiliations

  1. FORICA ETS - The Foundation for Advanced Research in Hypertension and Cardiovascular Diseases, Padua, Italy

    Gian Paolo Rossi & Federico Bernardo Rossi

  2. ARHYVAB, International PhD Program in Arterial Hypertension and Vascular Biology, Department of Medicine, University of Padova, Padua, Italy

    Federico Bernardo Rossi, Andrea Cignarella & Teresa Maria Seccia

  3. University of Rome ‘La Sapienza’, Rome, Italy

    Federico Bernardo Rossi

  4. Specialized Hypertension Center, Department of Medicine – DIMED, University of Padova, Padua, Italy

    Teresa Maria Seccia

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  1. Gian Paolo Rossi
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  2. Federico Bernardo Rossi
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  3. Andrea Cignarella
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  4. Teresa Maria Seccia
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Contributions

G.P.R. and F.B.R. researched data for the article. G.P.R., A.C. and T.M.S. contributed substantially to discussion of the content. G.P.R. wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Gian Paolo Rossi.

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G.P.R. has given paid seminars sponsored by AstraZeneca. The other authors declare no competing interests.

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Rossi, G.P., Rossi, F.B., Cignarella, A. et al. Aldosterone synthase inhibitors for the treatment of cardiovascular disease. Nat Rev Endocrinol (2026). https://doi.org/10.1038/s41574-026-01259-4

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