Primary aldosteronism (PA) was historically considered a niche disease, but modern-day prevalence studies report that 4%–7% of newly diagnosed hypertension in primary care (1) and up to 20% of resistant hypertension are attributed to PA (2). Importantly, PA leads to a disproportionately higher risk for cardiovascular and kidney diseases compared with essential hypertension, even independent of blood pressure (3, 4). Recent literature is also challenging the dogma of simplifying PA to a categorical disease defined by strict biochemical thresholds in patients with severe hypertension, hypokalemia, or an adrenal nodule (5–7). These studies show that PA spans a broader continuum of dysregulated aldosterone secretion, whereby overt PA is merely the “tip of the iceberg.” In fact, PA pathophysiology has been clearly demonstrated in individuals with mild hypertension and even normotension—populations that are not historically tested for PA (8)—and is associated with inappropriate mineralocorticoid receptor activation, blood pressure elevation, arterial stiffening, and adverse cardiac remodeling.
The latest addition to the literature showcasing PA as a disease that spans a broad continuum of thresholds comes from the recent Repetition of Aldosterone-to-Renin Ratio (ROARR) study (9). This prospective European cohort study followed 184 individuals with an elevated aldosterone-to-renin ratio but a negative confirmatory test for PA (i.e., not meeting the classical thresholds defining PA). At a mean follow-up time of approximately 5 years, PA confirmatory testing was repeated, and one out of every five study participants did meet criteria for PA at that time. One interpretation of these results could be that they simply reflect the inherent challenges in interpreting existing PA confirmatory tests for which the established thresholds are based on very low-quality evidence, leading to poor accuracy and reproducibility among individuals with elevated aldosterone-to-renin ratios and high-probability PA features (10). However, another important finding from the ROARR study is that those participants who transitioned from having a negative to a positive confirmatory test during follow-up also showed worsening blood pressure control and a higher rate of cardiac damage (concentric remodeling or left ventricular hypertrophy) despite similar use of antihypertensive medications (9). This suggests temporal disease progression in these individuals, both clinically and biochemically, along the PA severity continuum to a point at which aldosterone suppressibility was reduced to a level in which it met the classical definition of PA. This underscores the importance of not treating screening and confirmatory testing as a one-time action, especially given the potential for avoiding end-organ damage.
Overall, the mounting evidence showcasing PA as a disease that stretches well beyond its historical confines has reached a point that can no longer be ignored. We need clinical trials to determine whether more expansive use of aldosterone-targeted therapies throughout the PA continuum will serve to improve health outcomes for a much broader patient population.
Footnotes
References
- 1.↑
Xu Z, et al.; Chongqing Primary Aldosteronism Study (CONPASS) Group. Primary aldosteronism in patients in China with recently detected hypertension. J Am Coll Cardiol 2020; 75:1913–1922. doi: 10.1016/j.jacc.2020.02.052
- 2.↑
Brown JM, et al. The unrecognized prevalence of primary aldosteronism: A cross-sectional study. Ann Intern Med 2020; 173:10–20. doi: 10.7326/M20-0065
- 3.↑
Monticone S, et al. Cardiovascular events and target organ damage in primary aldosteronism compared with essential hypertension: A systematic review and meta-analysis. Lancet Diabetes Endocrinol 2018; 6:41–50. doi: 10.1016/S2213-8587(17)30319-4
- 4.↑
Monticone S, et al. Renal damage in primary aldosteronism: A systematic review and meta-analysis. J Hypertens 2020; 38:3–12. doi: 10.1097/HJH.0000000000002216
- 5.↑
Brown JM, et al. The spectrum of subclinical primary aldosteronism and incident hypertension: A cohort study. Ann Intern Med 2017; 167:630–641. doi: 10.7326/M17-0882
- 6.
Parksook WW, et al. The spectrum of dysregulated aldosterone production: An international human physiology study. J Clin Endocrinol Metab (published online March 7, 2024). doi: 10.1210/clinem/dgae145
- 7.↑
Hundemer GL, et al. Subclinical primary aldosteronism and cardiovascular health: A population-based cohort study. Circulation 2024; 149:124–134. doi: 10.1161/CIRCULATIONAHA.123.066389
- 8.↑
Funder JW, et al. The management of primary aldosteronism: Case detection, diagnosis, and treatment: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2016; 101:1889–1916. doi: 10.1210/jc.2015-4061
- 9.↑
Buffolo F, et al. Long-term follow-up of patients with elevated aldosterone-to-renin ratio but negative confirmatory test: The progression of primary aldosteronism phenotypes. Hypertension 2024; 81:340–347. doi: 10.1161/HYPERTENSIONAHA.123.21983
- 10.↑
Leung AA, et al. Performance of confirmatory tests for diagnosing primary aldosteronism: A systematic review and meta-analysis. Hypertension 2022; 79:1835–1844. doi: 10.1161/HYPERTENSIONAHA.122.19377
