Aldosterone excess, hypertension, and chromosome 7p22: evidence continues to mount.

In recent years, numerous groups of investigators have reported primary aldosteronism (PAL) to be much more common than previously thought.1–4 This has followed recognition of the aldosterone/renin ratio (ARR) as an improved, more sensitive method of screening for PAL and the application of ARR testing to a wider population, to include normokalemic, as well as hypokalemic, hypertensive subjects. The degree of selectedness of the populations involved in those studies has varied widely, from relatively “unselected” (including subjects randomly selected from general practitioner databases3) to highly selected. Despite this, the great majority of these studies have reported prevalence rates of PAL that have fallen within the range of 5% to 15%, making it the most common specifically treatable and potentially curable form of hypertension. Importantly, clinical responses to specific medical or surgical treatment in patients found in this way to have PAL have been highly gratifying. However, careful steps need to be taken to avoid misdiagnosis. These include controlling posture and avoiding interfering medications during diagnostic testing, performing careful suppression testing to definitively confirm or exclude the diagnosis of PAL, and using adrenal venous sampling to differentiate unilateral from bilateral forms.5 In the wake of these reports, the article by Newton-Cheh et al6 appearing in this edition of Hypertension is highly relevant and should be of great interest to readers of this journal. Following on their recent report describing significant relationships of aldosterone levels with blood pressure progression and hypertension development among Framingham study participants,7 the authors have found similar correlations among this cohort using the ARR. This important finding adds considerable further weight to the argument that disturbed aldosterone production, relatively autonomous of its normal chronic regulator (renin–angiotensin), plays a much greater role in the development of hypertension than has been traditionally recognized. The authors should be congratulated on these results, given the limitations that they faced and that are inherent in any large, longitudinal, observational cohort-based study of this type. They were required to take multiple potential confounders into consideration and to use tailored statistical techniques to demonstrate an independent relation of the ARR with BP progression and hypertension incidence. In the process, they showed expected relationships with age and medication use, which helped to validate their results. Diuretics and angiotensin-converting enzyme inhibitors would be expected to lower the ARR by promoting renin production and are known to be associated with false-negative ARR values in patients with PAL. The negative correlation with -blockers is also as expected as these drugs induce renin suppression and can cause false positive ratios.8,9 The positive relationship of ARR with female gender and with the use of hormone replacement therapy might be explained by an effect of estrogen, stimulating hepatic production of renin substrate (angiotensinogen), which, in turn, would lead to a compensatory lowering in active renin concentration (serving to prevent a rise in plasma renin activity and angiotensin II). A further and very exciting finding was that the authors were able to demonstrate significant heritability of the ARR. This finding is of particular significance given previous reports10–13 describing the occurrence of families with PAL (familial hyperaldosteronism [FH] type II) that is not glucocorticoid suppressible (as it is in FH-I) and 5 times more common than the glucocorticoid-suppressible variety. FH-II, diagnosed when 2 members of a family have PAL (positive fludrocortisone suppression test or consistently raised ARR not because of interfering medications) and lack the hybrid gene mutation of FH-I, is indistinguishable clinically, biochemically, and morphologically from apparently sporadic PAL.12,13 Therefore, mutations underlying FH-II could be responsible for at least some cases of apparently sporadic PAL. The Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals is currently following 39 families with FH-II, which, therefore, may not be rare. Fifteen of them show vertical inheritance. Linkage studies in a large (8 affected) FH-II pedigree excluded linkage with the AT1, CYP11B2, or MEN1 genes but found evidence suggesting linkage to 7p22 (logarithm of odds [LOD] score 3.26).10 Further studies in that family and in 2 additional FH-II families, 1 from Australia and 1 from South America, increased the LOD score to 4.61 and excluded the PRKAR1B gene.11 Sequencing studies on candidate genes, including RBaK,14 PMS2, and GNA12, within the 7p22 locus, have so far not found evidence of mutations responsible for FH-II. Efforts are continuing to identify responsible genes within this locus in the hope that this will lead to new, more streamlined genetic methods of identifying patients with, or predisposed to develop, PAL and to improve our understanding of the pathogenesis of this disorder.14 Currently, reliable screening for FH-II (and PAL in general) by measurement of the ARR and definitive confirmation or exclusion of the diagnosis by suppression testing depend critically on aldosterone and renin assay reliability and require that factors (such The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Greenslopes and Princess Alexandra Hospitals, Brisbane, Australia. Correspondence to Michael Stowasser, Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane 4102, Australia. E-mail [email protected] (Hypertension. 2007;49:761-762.) © 2007 American Heart Association, Inc.