Science behind the Study: Aldosterone and Treatment-Resistant Hypertension

This Science Behind the Study editorial explores the rationale for targeting aldosterone synthesis in resistant hypertension, contextualizing the recent trial of baxdrostat, a highly selective aldosterone synthase (CYP11B2) inhibitor. The authors detail how excess aldosterone, even in patients without primary aldosteronism, drives sodium retention and blood pressure elevation through activation of the mineralocorticoid receptor. Baxdrostat circumvents limitations of older inhibitors by avoiding cross-reactivity with CYP11B1, preserving cortisol synthesis while lowering aldosterone. Compared to spironolactone, which blocks the receptor but induces hormonal side effects, baxdrostat directly halts synthesis with fewer off-target effects. Emerging therapies, such as nonsteroidal mineralocorticoid receptor antagonists and RNA-based agents are also discussed. A full visual of the renin–angiotensin–aldosterone cascade and aldosterone biosynthesis is included.

This Science Behind the Study editorial explores the rationale for targeting aldosterone synthesis in resistant hypertension, contextualizing the recent trial of baxdrostat, a highly selective aldosterone synthase (CYP11B2) inhibitor. The authors detail how excess aldosterone, even in patients without primary aldosteronism, drives sodium retention and blood pressure elevation through activation of the mineralocorticoid receptor. Baxdrostat circumvents limitations of older inhibitors by avoiding cross-reactivity with CYP11B1, preserving cortisol synthesis while lowering aldosterone. Compared to spironolactone, which blocks the receptor but induces hormonal side effects, baxdrostat directly halts synthesis with fewer off-target effects. Emerging therapies, such as nonsteroidal mineralocorticoid receptor antagonists and RNA-based agents are also discussed. A full visual of the renin–angiotensin–aldosterone cascade and aldosterone biosynthesis is included.