Aldosterone, the brain, and the blood pressure ceiling: a neurological case for aldosterone synthase inhibitors in resistant hypertension.

Hypertension is the leading modifiable risk factor for stroke and a major contributor to cognitive impairment and dementia, with its global burden increasing alongside population aging. Hypertension promotes cerebrovascular damage through endothelial dysfunction, blood-brain barrier disruption, small vessel disease, and accelerated atherosclerosis, all potentially contributing to both ischemic and hemorrhagic stroke risk. These vascular alterations also contribute to neurodegenerative processes, linking hypertension-particularly when present in midlife-to vascular dementia and Alzheimer's disease. Effective blood pressure control (target <130/80 mm Hg) remains central to primary and secondary stroke prevention and is associated with reduced risks of recurrent stroke and cognitive decline. The renin-angiotensin-aldosterone system plays a central role in hypertension-related cerebrovascular injury, with aldosterone excess contributing to vascular inflammation, oxidative stress, and impaired cerebral autoregulation. Resistant hypertension, often driven by aldosterone dysregulation, is associated with increased cardiovascular and neurological risk. Aldosterone synthase inhibitors such as lorundrostat and baxdrostat represent a novel therapeutic approach targeting aldosterone production. Clinical trials demonstrate significant reductions in systolic blood pressure with favorable safety profiles in patients with uncontrolled or resistant hypertension. Although direct evidence for stroke prevention is currently lacking, indirect data suggest that sustained blood pressure reduction and modulation of aldosterone-mediated vascular damage may lower cerebrovascular risk. Aldosterone synthase inhibitors may be particularly relevant in phenotype-driven, personalized treatment strategies for patients with resistant hypertension or suspected aldosterone excess. However, long-term efficacy, safety, and impact on hard outcomes such as stroke and dementia require confirmation in dedicated trials.