Race and Ancestry in Primary Aldosteronism

Primary aldosteronism (PA) is the most common cause of secondary hypertension and represents a potentially treatable condition, affecting up to 25% of patients with hypertension. ¹ Multiple factors influence disease severity and therapeutic decision‐making, among which race and ethnicity have emerged as important but underrecognized determinants. Growing evidence indicates that the biological and clinical features of PA, including molecular profiles, histopathologic patterns, and response to surgical treatment, vary across populations. ² For example, East Asian patients with unilateral PA more frequently exhibit potassium inwardly rectifying channel subfamily J member 5 (KCNJ5) mutations, whereas patients of African descent tend to present with a higher prevalence of bilateral disease and less favorable surgical outcomes. ³ These observations underscore the importance of explicitly incorporating race and ethnicity into the clinical evaluation and management of PA.

The study by Leung et al., published in this issue of the Journal of the American Heart Association (JAHA), provides compelling evidence demonstrating the potential impact of ethnicity on the clinical presentation of PA. In a 15‐year retrospective analysis of 114 first‐generation Afro‐Caribbean immigrants referred for resistant hypertension in Calgary, Canada, 93% met biochemical criteria for PA, an unprecedented prevalence and approximately double that observed in non‐African patients at the same center (47%). The biochemical phenotypes were severe. Nearly two‐thirds had hypokalemia, 90% had suppressed renin levels (≤8.4 mIU/L), and 87% had aldosterone levels exceeding 277 pmol/L. The median aldosterone/renin ratio was >3.5‐fold above the case‐finding cutoff. Subtype evaluation further reinforced this distinct PA phenotype. Adrenal vein sampling lateralization was observed in only 14% of sampled patients, and none of the 5 patients who underwent adrenalectomy achieved complete biochemical success by Primary Aldosteronism Surgical Outcome (PASO) criteria. ⁴ Post hoc pathologic analysis using cytochrome P450 family 11 subfamily B members 1 and 2 (CYP11B1/B2) immunohistochemistry and histopathology of primary aldosteronism (HISTALDO) consensus criteria identified no solitary aldosterone‐producing adenomas. ⁵ Instead, dominant nodules were cortisol producing, whereas aldosterone excess arose from surrounding micronodules or diffuse zona glomerulosa hyperplasia, which may contribute to poor surgical outcomes. ⁶

In US cohorts, most studies suggest that Black patients with PA are more likely to exhibit bilateral disease and experience less favorable surgical outcomes. ³ Although some studies report a relatively high prevalence of unilateral PA among Black patients based on adrenal vein sampling lateralization, these patients still tend to have poorer postadrenalectomy outcomes. ⁷ Molecular investigations in African American populations have identified specific somatic mutations, including calcium voltage‐gated channel subunit alpha1 D (CACNA1D) mutations, which may contribute to this observation, as these alterations are associated with a higher likelihood of bilateral or multifocal adrenal disease despite an initial classification of unilateral PA. ³ , ⁸ The study by Leung et al., describes an even more extreme phenotype. Their cohort, comprising predominantly first‐generation immigrants from sub‐Saharan African and Caribbean regions, demonstrated an overwhelming predominance of bilateral disease and an absence of surgically curable cases. ⁶ Although genetic data were not available, their findings suggest that differences in ancestry, rather than race alone, may influence the clinical presentation of PA. Further studies are needed to better define this heterogeneous clinical category, and caution is warranted when treating Black patients as a homogeneous group.

The global epidemiology of PA shows substantial variability across populations and study designs. Across major cohorts, the reported prevalence of PA among patients with hypertension ranges from ≈4% to 27%, with higher estimates observed in referral‐based or high‐risk populations, such as those with resistant hypertension. ⁹ In US cohorts, the prevalence of PA is estimated at ≈15% to 20% among patients with hypertension and ≈20% in those with resistant hypertension. ¹⁰ , ¹¹ European cohorts report an overall prevalence of ≈11.2%, increasing to ≈20% among patients with resistant hypertension, ¹¹ , ¹² whereas community‐based studies in East Asia have demonstrated a lower prevalence (4%–7%) in general hypertensive populations. ¹³ Notably, studies applying different screening cutoffs and rigorous confirmatory testing suggest that conventional screening may underestimate the true burden of PA. ¹⁴ Beyond differences in study design, accumulating evidence indicates that PA prevalence and phenotype vary across populations, likely reflecting a complex interplay of regional, environmental, and genetic factors. These differences may contribute not only to variation in overall prevalence but also to heterogeneity in disease subtype and treatment response. In this context, the findings reported by Leung et al., represent an extreme end of this spectrum, with an exceptionally high prevalence of PA (93%) among patients with resistant hypertension and a predominance of bilateral disease. ⁶ Together, these observations underscore that the epidemiology and clinical presentation of PA are not uniform across populations, and further studies are needed to better understand the underlying drivers of this heterogeneity.

Black patients with hypertension more commonly exhibit a low‐renin phenotype, which is associated with increased salt sensitivity and a higher prevalence of resistant hypertension. ¹⁵ Consistent with this physiology, renin–angiotensin–aldosterone system inhibitors are generally less effective, whereas thiazide or thiazide‐like diuretics and calcium channel blockers demonstrate greater antihypertensive efficacy in this population. ¹⁶ Accordingly, the 2020 Nigerian Hypertension Society guideline, applicable to many patients in the study by Leung et al., recommends thiazide or thiazide‐like diuretics and calcium channel blockers as first‐line therapy. ¹⁷ In addition, mineralocorticoid receptor antagonists appear to be effective in this population. ¹⁸ In line with the findings of Leung et al., mineralocorticoid receptor antagonists may represent a reasonable first‐line option for Black patients with low‐renin hypertension. ¹⁹ , ²⁰ However, prospective studies are needed to further establish their effectiveness in this population.

Despite its retrospective, single‐center design, potential referral bias, and absence of somatic mutation profiling, the study by Leung et al., provides important insights into the heterogeneity of PA among Black patients. In summary, their findings highlight that both between‐ and within‐population differences have important clinical implications in PA and emphasize the need for greater clinical awareness and a more individualized approach to evaluation and treatment in this population. ⁶

Disclosures

None.