Decoding Hypertension Through Primary Aldosteronism

HomeCirculationVol. 147, No. 14Decoding Hypertension Through Primary Aldosteronism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDecoding Hypertension Through Primary Aldosteronism Braxton D. Mitchell and Hilary B. Whitlatch Braxton D. MitchellBraxton D. Mitchell Correspondence to: Braxton D. Mitchell, PhD, MPH, University of Maryland Medicine, 670 W Baltimore St, MSTF 302, Baltimore, MD 21201. Email E-mail Address: [email protected] https://orcid.org/0000-0003-4920-4744 Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M., H.B.W.). Geriatrics Research and Education Clinical Center, Baltimore Veterans Administration Medical Center, MD (B.D.M.). Search for more papers by this author and Hilary B. WhitlatchHilary B. Whitlatch https://orcid.org/0000-0002-5770-6544 Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore (B.D.M., H.B.W.). Search for more papers by this author Originally published3 Apr 2023https://doi.org/10.1161/CIRCULATIONAHA.123.064028Circulation. 2023;147:1110–1111This article is a commentary on the followingGenetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association StudiesArticle, see p 1097Primary aldosteronism (PA) is one of the most common causes of secondary hypertension. It is usually caused by idiopathic adrenal hyperplasia or aldosterone-producing adenomas (APAs), and it is a particularly morbid form of secondary hypertension. Compared with those with essential hypertension, patients with PA are at substantially higher risk of stroke, coronary artery disease, atrial fibrillation, and heart failure.1 PA has also been shown to increase the risk of diabetes, metabolic syndrome, and left ventricular hypertrophy.1 Identifying this subgroup of patients with hypertension would allow more aggressive management of their cardiometabolic risk.Genetics provides an important tool for understanding PA pathophysiology. It is recognized that somatic mutations cause up to 80% of aldosterone hypersecretion in those with APAs.2 As a complementary approach for identifying genetic causes of hypertension, in this issue of Circulation, Naito et al3 carried out a cross-ancestry genomewide association study of 816 PA cases from Japan, the United Kingdom, and Finland. Despite this being a very small sample by genomewide association study standards, they identified 5 loci significantly associated with PA. Not surprisingly, all 5 loci were also associated with hypertension, consistent with the notion that PA is a cause of hypertension. The strongest of the loci identified was WNT2B, a key member of the Wnt/β–catenin signaling pathway. β-Catenin is necessary for embryonic development and cell renewal in the adult adrenal cortex.4 Constitutive activation of Wnt/β–catenin expression in animal models resulted in adrenal tumorigenesis and PA.5 Naito et al’s findings in this study further reinforce the role of the Wnt/β–catenin pathway in the pathophysiology of PA. Mutations in multiple ion exchange channel–related genes (eg, KCNJ5, CLCN2, CACNA1D, ATP1A1, and ATP2B3)6,7 have previously been associated with PA or hyperaldosteronism. One can envision that disruption of ion channel homeostasis might also interact with downstream activities related to Wnt/β–catenin signaling. Some of the other loci identified by Naito et al also map to genes with potential ties to the adrenal gland; the challenge now is to understand how the (regulatory) variants identified could lead to elevated aldosterone secretion.Arguably, the most intriguing part of this study was the reverse analysis in which the authors took 42 variants previously associated with blood pressure and asked whether these loci were also associated with PA. Surprisingly, two-thirds (28 of 42) were significantly (although below genomewide thresholds) associated with PA. Moreover, the effect sizes of these variants on PA risk were even higher than those for hypertension risk, implying that PA may contribute to the cause of hypertension to a greater degree than previously thought.So, why is this important? As of 2019, the global prevalence of hypertension was 32% in women and 34% in men 30 to 79 years of age.8 Although numerous hypertension susceptibility variants have been identified recently through a large genomewide association study,9 much remains to be learned about how these variants relate to hypertension susceptibility. The study by Naito et al reinforces the emerging view that the prevalence of PA, a potentially curable cause of hypertension, is considerably higher than previous estimates.10,11Despite the prevalence and cardiometabolic consequences of PA, it is underdiagnosed and undertreated. This has substantial clinical implications, given that PA is potentially curable (in the case of APAs) or at least has a targeted medical therapy (in the case of idiopathic adrenal hyperplasia or in those with APAs who are not surgical candidates). A major reason for the underrecognition of PA is the difficulty in diagnosis. Although hypokalemia had been thought to be a hallmark of PA, it is now estimated that <50% of people with PA will present with hypokalemia.12 Current diagnostic guidelines involve a 3-step process that includes a positive screening test, confirmatory provocative biochemical testing, and localization studies. The localization study currently required to distinguish the surgically curable form of PA (APAs) from that best medically managed (idiopathic adrenal hyperplasia) involves adrenal venous sampling, which is a cumbersome interventional radiological procedure requiring technical expertise achieved only at high-volume specialty centers.13 Fortunately, the application of newer functional imaging modalities such as carbon-11 metomidate positron emission computed tomography and galium-68 PentixaFor positron emission tomography14 to noninvasively lateralize APAs is under investigation.15 Our hope is that, as these specialized imaging studies become more widely available, distinguishing APAs from idiopathic adrenal hyperplasia will be more feasible for the clinician. However, the larger public health challenge of ensuring that all medical providers treating the pandemic of hypertension maintain a high clinical suspicion for PA remains. Such a clinical suspicion will lower the threshold for biochemical testing, motivate pursuit of localization studies to determine whether a surgical cure is possible, and, at minimum, allow early initiation of mineralocorticoid receptor blockade.Article InformationDisclosures None.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.For Disclosures, see page 1111.Circulation is available at www.ahajournals.org/journal/circCorrespondence to: Braxton D. Mitchell, PhD, MPH, University of Maryland Medicine, 670 W Baltimore St, MSTF 302, Baltimore, MD 21201. Email bmitchel@som.umaryland.eduReferences1. Monticone S, D’Ascenzo F, Moretti C, Williams TA, Veglio F, Gaita F, Mulatero P. 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)30319-4CrossrefMedlineGoogle Scholar2. Nanba K, Omata K, Else T, Beck PCC, Nanba AT, Turcu AF, Miller BS, Giordano TJ, Tomlins SA, Rainey WE. Targeted molecular characterization of aldosterone-producing adenomas in White Americans.J Clin Endocrinol Metab. 2018; 103:3869–3876. doi: 10.1210/jc.2018-01004CrossrefMedlineGoogle Scholar3. Naito T, Inoue K, Sonehara K, Baba R, Kodama T, Otagaki Y, Okada A, Itcho K, Kobuke K, Kishimoto S, et al. Genetic risk of primary aldosteronism and its contribution to hypertension: a cross-ancestry meta-analysis of genome-wide association study.Circulation. 2023; 147:1097–1109. doi: 10.1161/CIRCULATIONAHA.122.062349LinkGoogle Scholar4. Kim AC, Reuter AL, Zubair M, Else T, Serecky K, Bingham NC, Lavery GG, Parker KL, Hammer GD. Targeted disruption of beta-catenin in Sf1-expressing cells impairs development and maintenance of the adrenal cortex.Development. 2008; 135:2593–2602. doi: 10.1242/dev.021493CrossrefMedlineGoogle Scholar5. Berthon A, Sahut-Barnola I, Lambert-Langlais S, de Joussineau C, Damon-Soubeyrand C, Louiset E, Taketo MM, Tissier F, Bertherat J, Lefrançois-Martinez AM, et al. Constitutive beta-catenin activation induces adrenal hyperplasia and promotes adrenal cancer development.Hum Mol Genet. 2010; 19:1561–1576. doi: 10.1093/hmg/ddq029CrossrefMedlineGoogle Scholar6. Gomez-Sanchez CE, Kuppusamy M, Gomez-Sanchez EP. Somatic mutations of the ATP1A1 gene and aldosterone-producing adenomas.Mol Cell Endocrinol. 2015; 408:213–219. doi: 10.1016/j.mce.2014.12.004CrossrefMedlineGoogle Scholar7. Fernandes-Rosa FL, Daniil G, Orozco IJ, Göppner C, El Zein R, Jain V, Boulkroun S, Jeunemaitre X, Amar L, Lefebvre H, et al. A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.Nat Genet. 2018; 50:355–361. doi: 10.1038/s41588-018-0053-8CrossrefMedlineGoogle Scholar8. NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in hypertension prevalence and progress in treatment and control from 1990 to 2019: a pooled analysis of 1201 population-representative studies with 104 million participants.Lancet. 2021; 398:957–980. doi: 10.1016/S0140-6736(21)01330-1CrossrefMedlineGoogle Scholar9. Evangelou E, Warren HR, Mosen-Ansorena D, Mifsud B, Pazoki R, Gao H, Ntritsos G, Dimou N, Cabrera CP, Karaman I, et al. Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.Nat Genet. 2018; 50:1412–1425. doi: 10.1038/s41588-018-0205-xCrossrefMedlineGoogle Scholar10. Funder JW, Carey RM. Primary aldosteronism: where are we now? Where to from here?Hypertension. 2022; 79:726–735. doi: 10.1161/HYPERTENSIONAHA.121.18761LinkGoogle Scholar11. Brown JM, Siddiqui M, Calhoun DA, Carey RM, Hopkins PN, Williams GH, Vaidya A. The unrecognized prevalence of primary aldosteronism: a cross-sectional study.Ann Intern Med. 2020; 173:10–20. doi: 10.7326/M20-0065CrossrefMedlineGoogle Scholar12. Mulatero P, Stowasser M, Loh KC, Fardella CE, Gordon RD, Mosso L, Gomez-Sanchez CE, Veglio F, Young WF. Increased diagnosis of primary aldosteronism, including surgically correctable forms, in centers from five continents.J Clin Endocrinol Metab. 2004; 89:1045–1050. doi: 10.1210/jc.2003-031337CrossrefMedlineGoogle Scholar13. Williams TA, Reincke M. Non-invasive detection of a common, surgically correctable form of hypertension.Nat Med. 2023; 29:31–32. doi: 10.1038/s41591-022-02083-9CrossrefMedlineGoogle Scholar14. Ding J, Zhang Y, Wen J, Zhang H, Wang H, Luo Y, Pan Q, Zhu W, Wang X, Yao S, et al. Imaging CXCR4 expression in patients with suspected primary hyperaldosteronism.Eur J Nucl Med Mol Imaging. 2020; 47:2656–2665. doi: 10.1007/s00259-020-04722-0CrossrefMedlineGoogle Scholar15. Wu X, Senanayake R, Goodchild E, Bashari WA, Salsbury J, Cabrera CP, Argentesi G, O’Toole SM, Matson M, Koo B, et al. [(11)C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.Nat Med. 2023; 29:190–202. doi: 10.1038/s41591-022-02114-5CrossrefMedlineGoogle Scholar eLetters(0)eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.Sign In to Submit a Response to This Article Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesGenetic Risk of Primary Aldosteronism and Its Contribution to Hypertension: A Cross-Ancestry Meta-Analysis of Genome-Wide Association StudiesTatsuhiko Naito, et al. Circulation. 2023;147:1097-1109 April 4, 2023Vol 147, Issue 14 Advertisement Circulation on the Run: April 4, 2023 April 4, 2023 Article InformationMetrics © 2023 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.123.064028PMID: 37011072 Originally publishedApril 3, 2023 KeywordshyperaldosteronismhypertensionEditorialsPDF download Advertisement SubjectsGenetic, Association StudiesPrecision Medicine