The scale of the problem is striking. In a landmark cross-sectional study by Brown and colleagues published in Annals of Internal Medicine, biochemically overt autonomous aldosterone production, the hallmark of primary aldosteronism, was detected in 11.3 percent of people with normal blood pressure, 15.7 percent of those with stage 1 hypertension, 21.6 percent of those with stage 2 hypertension, and 22.0 percent of those with resistant hypertension. These figures suggest that primary aldosteronism is not a rare endocrine curiosity but a continuum of renin-independent aldosterone excess that rises steadily in prevalence as blood pressure severity increases. Yet screening rates tell a very different story: among eligible patients with resistant hypertension, the review found that testing for primary aldosteronism was performed in only 1.6 to 2.1 percent of cases.

Primary aldosteronism exemplifies the review’s central thesis, that a limited set of pathophysiological effector pathways maps directly onto specific diagnostic tests and cause-directed treatments. In this condition, the adrenal glands produce aldosterone independently of renin, the usual hormonal regulator, driving sodium retention, potassium loss, and hypertension that often resists conventional drug combinations. Diagnosis begins with measuring the aldosterone-to-renin ratio, followed by confirmatory testing and, when unilateral disease is suspected, adrenal vein sampling to determine which gland is overproducing the hormone. The treatment then follows the mechanism: surgical removal of the overactive adrenal gland in unilateral disease, or mineralocorticoid receptor antagonists in bilateral disease.

The outcomes of that cause-directed approach, however, are more nuanced than the word curative might imply. Drawing on the PASO cohort, an international study of outcomes after adrenalectomy for primary aldosteronism, the review distinguishes complete biochemical success, achieved in 94 percent of patients (656 of 699), from complete clinical success, achieved in only 37 percent (259 of 705), with partial clinical improvement in a further 47 percent. In other words, surgery almost always normalises the hormonal abnormality, but resolving the hypertension itself, and the associated cardiovascular risk profile, is far less predictable, likely because years of aldosterone excess leave lasting vascular and renal changes. This gap between biochemical cure and clinical cure is one of the strongest arguments in the review for earlier diagnosis, before irreversible target-organ damage accumulates.

For patients whose hypertension resists multiple drugs, the review highlights evidence that reshapes fourth-line therapy. The PATHWAY-2 trial established spironolactone, a mineralocorticoid receptor antagonist, as the most effective fourth-line drug for resistant hypertension, outperforming alternatives and reinforcing the central role of aldosterone-mediated sodium retention in treatment resistance. This finding dovetails with the primary aldosteronism data: if roughly one in five patients with resistant hypertension has autonomous aldosterone production, and if blocking aldosterone’s receptor is the single most effective add-on drug in that population, then mechanism-based thinking is not an academic exercise but a practical route to better blood pressure control.

Not every secondary cause benefits from an interventional fix, and the review is candid about where procedures have failed. For atherosclerotic renal-artery stenosis, narrowing of the arteries supplying the kidneys, four major randomised trials, CORAL, ASTRAL, STAR, and DRASTIC, did not support routine revascularisation for stable disease. Despite the intuitive appeal of opening a blocked artery, restoring flow in stable atherosclerotic stenosis does not reliably improve blood pressure or renal outcomes, and medical therapy remains the standard of care for most such patients. The lesson, the review suggests, is that the presence of a plausible mechanism does not automatically justify a procedure; the mechanism must be demonstrated to be the dominant driver of the hypertension before cause-directed intervention is warranted.

At the other end of the diagnostic spectrum sits phaeochromocytoma and paraganglioma, catecholamine-secreting tumours of the adrenal medulla and sympathetic nervous system. Here the review affirms that plasma-free metanephrines, the breakdown products of adrenaline and noradrenaline, remain highly sensitive for detecting these tumours, making the test a cornerstone of mechanism-based diagnosis. Because catecholamine excess can cause paroxysmal hypertension, palpitations, and sweating, and because an unrecognised tumour can precipitate fatal cardiovascular crises during surgery or pregnancy, accurate biochemical subtyping carries direct life-saving value. The contrast with aldosterone screening is instructive: the diagnostic test performs superbly, but the challenge lies in deciding whom to test.

The review’s methodology underscores both its strengths and its limitations. Following PRISMA 2020, with diagnostic accuracy reporting informed by PRISMA-DTA, the authors searched MEDLINE, Embase, CENTRAL, Web of Science, Scopus, ClinicalTrials.gov, and the WHO ICTRP from inception to 30 June 2025, supplemented by citation searching. The formal search identified 580 records; after removing 168 duplicates, 412 records were screened, 106 full-text reports assessed, and 58 included evidence records represented across 63 publications. Risk of bias was appraised with RoB 2, ROBINS-I, QUADAS-2, and AMSTAR 2 as appropriate, and certainty was summarised using GRADE. Notably, the review was not prospectively registered in PROSPERO, and screening, extraction, and structured appraisal were performed by a single reviewer, so no dual-reviewer agreement statistic was applicable, caveats that readers should weigh when interpreting the synthesis.

Looking forward, the review contextualises a new pharmacological frontier through a targeted surveillance update extending to 31 July 2026. Phase 3 trials of selective aldosterone synthase inhibitors, drugs that block the enzyme responsible for aldosterone’s final biosynthetic step, have shown approximately 9 mm Hg placebo-corrected reductions in office systolic blood pressure. These agents promise a more precise way to suppress aldosterone production than receptor blockade, potentially avoiding some of the hormonal side effects of older drugs. But the review is careful: cardiovascular-outcome benefit has not been established for aldosterone synthase inhibitors, and electrolyte and renal monitoring remains necessary, so these drugs should be seen as expanding blood-pressure-lowering options rather than as proven cardiovascular-outcome therapies.

The review’s conclusions converge on a practical prescription for clinical gain. Earlier recognition of high-yield phenotypes, patients with resistant hypertension, hypokalaemia, young-onset hypertension, or suggestive imaging, followed by accurate aetiological subtyping and implementation of established testing pathways, offers the strongest opportunities to improve outcomes with tools that already exist. The problem, as the 1.6 to 2.1 percent screening figure makes painfully clear, is not a shortage of science but a failure of implementation. As mechanism-defined secondary hypertension moves from textbook footnote to precision-medicine framework, the review’s message is that the diagnostic and therapeutic map is largely drawn; what remains is for clinicians to follow it.

Subject of Research: Mechanism-based diagnosis and cause-directed treatment of secondary hypertension

Article Title: Mechanism-defined secondary hypertension enables precision diagnosis and treatment: an evidence review

Article References: Choudhary, A. K., Hait, A., & Baladaniya, M. (2026). Mechanism-defined secondary hypertension enables precision diagnosis and treatment: an evidence review. Frontiers in Cardiovascular Medicine, 13, Article 1958980. https://doi.org/10.3389/fcvm.2026.1958980

Image Credits: AI Generated

DOI: 10.3389/fcvm.2026.1958980

Keywords: secondary hypertension, primary aldosteronism, resistant hypertension, spironolactone, adrenalectomy, renal-artery stenosis, phaeochromocytoma, plasma-free metanephrines, aldosterone synthase inhibitors, PATHWAY-2, systematic review, precision medicine