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(Hypertension. 2003;41:993.)
© 2003 American Heart Association, Inc.
Brief Reviews |
From the MRC Blood Pressure Group, Division of Cardiovascular and Medical Sciences, University of Glasgow, Scotland.
Correspondence to Prof J.M.C. Connell, MRC Blood Pressure Group, Western Infirmary, Glasgow, G11 6NT, UK. E-mail j.connell{at}clinmed.gla.ac.uk
| Abstract |
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Key Words: hypertension, mineralocorticoid adrenal gland aldosterone adrenocorticotropic hormone
| Introduction |
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The same argument can be applied to human hypertension, and it would be naïve to anticipate that the same underlying mechanism was present in all patients with high blood pressure. However, careful study of subgroups might identify common mechanisms that account for the rise in pressure and offer guidance to the best therapeutic option. In this regard, the contribution of adrenal steroids deserves careful review. At a gross level, of course, corticosteroids clearly do have an important role in the development of hypertension. Patients with Addisons disease are hypotensive,3 glucocorticoid excess in patients with Cushings syndrome is associated with high blood pressure,4 and the role of a major excess of aldosterone in classic Conns syndrome due to a solitary adrenal adenoma is clear.5 Recently, however, the straightforward differentiation of these forms of "secondary" hypertension from "essential" hypertension has been obscured by suggestions that primary hyperaldosteronism (PHA) is present in 10% to 15% of unselected patients with hypertension.69 In this article, we will review some of this evidence and consider whether this biochemical abnormality is consistent with other known genetic and physiological mechanisms.
| Definition of PHA |
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First, in hypertensive patients with a high ARR, is there clear evidence of hypermineralocorticoidism? As noted previously, patients with well-defined tumorous primary aldosteronism have a distinct elevation of exchangeable body sodium content.14 It is noteworthy, however, that patients classified as having "idiopathic hyperaldosteronism" had a lesser increase in body sodium (and higher plasma potassium concentrations) than those patients with distinct tumors, consistent with the notion that the 2 diagnoses were not synonomous.15 When older patients (>50 years) with essential hypertension have been studied, body sodium content is certainly higher than in matched normotensive controls16 but to a lesser degree than seen in patients with aldosteronism (either tumorous or idiopathic) who have similar elevations of blood pressure. These careful studies, carried out in the late 1970s, also demonstrated that there was a tendency for young hypertensive patients (<35 years) to have reduced body sodium content.16 However, no long-term studies have been carried out to identify whether body sodium content rises with age in individual hypertensive patients, perhaps due to a chronic resetting of the renal pressure/natriuresis relationship. Furthermore, the relationship between body sodium and the ARR has not been studied. Thus, there has not been a systematic study of body sodium in relation to the ARR in patients (of any age) with hypertension or in patients with presumed primary aldosteronism based on the ARR definition alone. These older data, however, indicate that not all patients with an elevated ARR can be assumed to have the same degree of mineralocorticoid excess. It should be noted that we focus in this review on aldosterone as the key regulator of sodium balance, which is clearly an oversimplification. For example, there is good recent evidence in low-renin hypertension that genetic variation in adducin relates to the phenotype, presumably by altering the pressure-natriuresis relationship.17 Furthermore, it is possible that impairment of renin release in older subjects (perhaps as a consequence of vascular disease) allows potassium to become the principal trophin for aldosterone. Thus, it is important to recognize that altered regulation of aldosterone is likely to interact with other mechanisms to result in a final phenotype of hypertension with a raised ARR.
Second, if we accept that aldosterone is higher than expected from the level of its principal trophin, angiotensin II, why is this so? In other words, why is the relationship between renin and aldosterone altered? Extrapolating from data in older, low-renin hypertensive subjects, we suggest that the prevailing aldosterone level might be higher than predicted from the sodium/volume/renin status and could certainly be seen as "inappropriate," if not necessarily "autonomous."18 Early hypotheses suggested that in low-renin essential hypertension (ie, including patients with a high ARR), aldosterone synthesis is more than normally sensitive to angiotensin II. However, evidence is sparse and inconsistent. There is some evidence of hypersensitivity in patient subgroups, but it does not appear to be a general finding. There remains a second possible explanation: that renin concentration is low because another agonist is exerting a disproportionate effect. One possibility (mentioned previously) is that plasma potassium is sustaining aldosterone secretion in these patients, but there is no evidence that potassium levels are systematically raised in patients with a high ARR. It should, however, be borne in mind that very subtle changes in potassium determine the relationship between angiotensin II and aldosterone and that the role of altered potassium homeostasis in sustaining the raised ARR requires further investigation. One alternative factor that regulates aldosterone secretion is ACTH, and this is addressed later. However, if it is the case that a variable fraction of aldosterone secretion is controlled independently of electrolyte balance and extracellular volume, then this will have possible long-term physiological consequences.
The preceding arguments are, of course, largely semantic. The patients identified by an elevated ARR have an inappropriate level of aldosterone for its principal trophin, angiotensin II. This is likely to have pathophysiological consequences. The adverse cardiovascular effects of aldosterone (on cardiac tissue, the central nervous system, and the kidney) are amplified by sodium loading. Furthermore, McDonald (Lim et al19) has reported that patients with a high ARR show a good hypotensive response with use of the mineralocorticoid receptor antagonist spironolactone. This finding supports the notion that aldosterone is an important contributor to the maintenance of hypertension in this circumstance and that the hormone might be causing cardiovascular damage. Thus, although the true prevalence of primary aldosteronism, as defined by earlier criteria, might be debated, it seems reasonable to concur that a significant proportion (perhaps up to 15%) of patients with hypertension have suppression of renin and altered regulation of aldosterone, so that plasma levels are higher than predicted from the prevailing renin. Such patients might well show an optimum blood pressure response to aldosterone receptor blockade and derive significant benefit in terms of target-organ protection.
It is unclear how these patients (classified now by a high ARR) relate to those with low renin described previously by Laragh (Niarchos et al13) and otherssuch patients were said to respond well to diuretic therapy. Aldosterone responsiveness to perturbations in sodium balance and to exogenous angiotensin II is abnormal in some patients with this phenotype, and there are recent data to show that the trait is heritable.17 Nevertheless, aldosterone concentrations in patients with low-renin hypertension are higher than predicted from the prevailing level of renin, and it seems likely that there is substantial crossover between the groups. If so, it is tempting to speculate that patients with a raised ARR form a substantial proportion of the group of older hypertensive patients categorized as having low-renin essential hypertension and that the prevalence of a raised ratio would be higher in older hypertensive patients compared with younger subjects. If so, the biochemical abnormality may be one that develops with time as part of the evolution of the hypertensive phenotype in individual patients. Studies that compare groups of patients of different ages and that follow up patients over time are clearly indicated.
In summary, although there might remain some uncertainty regarding the exact definition of primary aldosteronism and the significance of a raised ARR, better recognition that a high proportion of patients with hypertension have disproportionate aldosterone production identifies a more targeted therapeutic approach. It might be time to move away from categorizing such patients simply as having primary aldosteronism and to define patients by their response to aldosterone receptor blockade.
| Does Development of a High ARR Have a Genetic Basis? |
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Polymorphisms in CYP11B2 and Hypertension
Over the last few years, studies have concentrated on 2 common polymorphisms associated with CYP11B2. One is a single-nucleotide polymorphism in the 5' promotor region of the gene at -344 (C-T) that alters a putative recognition site for the transcription factor SF1.25 The immediate biologic importance of this is unclear, as recent reports suggest that, whereas binding of SF1 is reduced 4-fold by the change from C to T, there is no discernible effect on gene transcription studied in in vitro systems.26 The second involves intron 2 of CYP11B2, which is replaced, in part, by the corresponding intron from CYP11B1. The 2 polymorphisms are in close linkage disequilibrium, so that the common haplotypes identified by us and others are T conversion (38%); C wild-type (45%), and T wild-type (16%).27
We initially reported that the T allele of this gene was associated with increased urinary excretion of the aldosterone metabolite tetrahydroaldosterone.27 Subsequent reports have found higher plasma levels of aldosterone,28 although it is important to point out that other findings are not consistent, and some authors have found that the contrasting allele is associated with raised aldosterone levels.29 The T allele and intron 2 conversion have also been found to present more frequently than expected in patients with essential hypertension by us and several other groups27,30; again, however, it should be noted that some authors have failed to find this association. Nevertheless, we have independently verified the association between this locus and blood pressure by demonstrating an epistatic interaction between CYP11B2 and the Y chromosome in a large Scottish population.31 More recently, we have found that the T allele and intron 2 conversion are increased only in hypertensive patients with a high ARR, and that frequencies are normal in subjects with a normal ratio.32 As with the other phenotypes discussed previously, there is also lack of unanimity. Finally, others and we have found an association between the T allele and the diagnosis of tumorous primary aldosteronism.33,34 In summary, therefore, there is a considerable body of data to link the CYP11B2 locus and hypertension, particularly that associated with mineralocorticoid excess. However, the evidence that the polymorphism is associated with significant excess aldosterone responsiveness to trophins in normal subjects is less convincing. In a recent and rigorous investigation of the heritability and genetic basis of low-renin hypertension, Fisher and colleagues17 reported that the variance in renin status attributable to familial factors was
35%; the CYP11B2 SF1 polymorphism was not shown to be a major determinant of this. Furthermore, the association in patients with aldosterone-producing tumors might seem, at first, paradoxical, because there is no a priori reason to suspect that a polymorphism in a gene regulating aldosterone production should predispose to the formation of a benign adenoma. However, we suggest in a subsequent section that this may inform our understanding of the link between low-renin hypertension, bilateral adrenal hyperplasia, and aldosterone-producing tumors.
CYP11B2 and Variation in 11-Hydroxylation
In studying the physiological consequences of the polymorphism in CYP11B2, we have examined not only aldosterone levels but also other adrenal steroids. We have consistently found that the T allele and intron 2 conversion, reported previously to be linked to hypertension in patients with a raised ARR, are also associated with raised basal and ACTH-stimulated levels of the 11-deoxysteroids, DOC and deoxycortisol.35 In addition, urinary excretion of the principal metabolite of deoxycortisol, tetrahydrodeoxycortisol, is increased in comparison with subjects homozygous for the T allele (Kennon et al36). Others have confirmed this unexpected finding.37 Initially, the association appears paradoxical, because the regulation of DOC and deoxycortisol levels reflects 11ß-hydroxylation efficiency, and the finding suggests that this is reduced in subjects carrying the T allele. The molecular mechanism that accounts for this is not understood, but it is possible that the polymorphism in the 5' regulatory region of CYP11B2 is in close linkage disequilibrium with a genetic variant that affects expression or function of the gene encoding 11ß-hydroxylase (CYP11B1). Definitive studies of the pattern of variation across the entire locus are required to clarify this.
| Implications of Altered 11ß-Hydroxylation in Hypertension |
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Clearly, the aforementioned hypothesis focuses on a single genetic polymorphism, and it is accepted that essential hypertension is a polygenic (or oligogenic) condition. Other genes may interact in an epistatic manner to lead to the phenotype of hypertension with an elevated ARR. It is possible that in predisposed subjects, chronic and low-grade activation of the hypothalamic/pituitary/adrenal axis as a result of variation at the CYP11B2 locus leads to a gradual increase in aldosterone production, resulting eventually in suppression of renin and a high ARR. This proposed epistatic interaction is a testable hypothesis that needs to be examined.
| Disordered 11ß-Hydroxylation: A Unifying Hypothesis in Primary Aldosteronism and Hypertension Associated With a Raised ARR |
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| Practical Implications |
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Received November 15, 2002; first decision December 10, 2002; accepted February 18, 2003.
| References |
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2. Bianchi G, Tripodi G, Casari G, Salardi S, Barber BR, Garcia R, Leoni P, Torielli L, Cusi D, Ferrandi M. Two point mutations within the adducin genes are involved in blood pressure variation. Proc Natl Acad Sci U S A. 1994; 91: 39994003.
3. Loriaux DL, McDonald WJ. Adrenal insufficiency. In: DeGroot LJ, Jameson JL, eds. Endocrinology. Philadelphia: WB Saunders Co; 2001: 16831690.
4. Whitworth JA, Mangos GJ, Kelly JJ. Cushing, cortisol and cardiovascular disease. Hypertension. 2000; 36: 912916.
5. Gordon RD, Stowasser M, Klemm SA, Tunny TJ. Primary aldosteronism and other forms of mineralocorticoid hypertension. In: Swales JD, ed. Textbook of Hypertension. Oxford: Blackwell Scientific Publications; 1994: 865892.
6. Gordon RD, Ziesak MD, Tunny TJ, Stowasser M, Klemm SA. Evidence that primary aldosteronism may not be uncommon: 12% incidence among hypertensive drug trial volunteers. Clin Exp Pharmacol Physiol. 1993; 20: 296298.[Medline] [Order article via Infotrieve]
7. Gordon RD, Stowasser M, Tunny TJ, Klemm SA, Rutherford JC. High incidence of primary aldosteronism in 199 patients referred with hypertension. Clin Exp Pharmacol Physiol. 1994; 21: 315318.[Medline] [Order article via Infotrieve]
8. Lim PO, Rodgers P, Cardale K, Watson AD, MacDonald TM. Potentially high prevalence of primary aldosteronism in a primary-care population. Lancet. 1999; 353: 40. Letter.[Medline] [Order article via Infotrieve]
9. Montori VM, Young WF Jr. Use of plasma aldosterone concentration-to-plasma renin activity ratio as a screening test for primary aldosteronism: a systematic review of the literature. Endocrinol Metab Clin North Am. 2002; 31: 619632.[CrossRef][Medline] [Order article via Infotrieve]
10. Vallotton MB. Primary aldosteronism. I. Diagnosis of primary hyperaldosteronism. Clin Endocrinol. 1996; 45: 4752.[CrossRef][Medline] [Order article via Infotrieve]
11. Vallotton MB. Primary aldosteronism. II. Differential diagnosis of primary hyperaldosteronism and pseudoaldosteronism. Clin Endocrinol. 1996; 45: 5360.[CrossRef][Medline] [Order article via Infotrieve]
12. Padfield PL, Brown JJ, Davies D, Fraser R, Lever AF, Morton JJ, Robertson JI. The myth of idiopathic hyperaldosteronism. Lancet. 1981; 2: 8384.[Medline] [Order article via Infotrieve]
13. Niarchos AP, Weinstein DL, Laragh JH. Comparison of the effects of diuretic therapy and low sodium intake in isolated systolic hypertension. Am J Med. 1984; 77: 10611068.[CrossRef][Medline] [Order article via Infotrieve]
14. Beretta-Piccoli C, Davies DL, Brown JJ, Ferriss B, Fraser R, Lasaridis A, Lever AF, Morton JJ, Robertson JI, Semple PF. Relation of blood pressure with body and plasma electrolytes in Conns syndrome. J Hypertens. 1983; 1: 197205.[Medline] [Order article via Infotrieve]
15. Lasaridis A, Brown JJ, Davies DL, Fraser R, Robertson JI, Lever AF. Arterial blood pressure and plasma and body electrolytes in idiopathic hyperaldosteronism: a comparison with primary hyperaldosteronism (Conns syndrome) and essential hypertension. J Hypertens. 1984; 2: 329336.[Medline] [Order article via Infotrieve]
16. Beretta-Piccoli C, Davies DL, Boddy K, Brown JJ, Cumming AM, East BW, Fraser R, Lever AF, Padfield PL, Semple PF, Robertson JI, Weidmann P, Williams ED. Relation of arterial pressure with body sodium, body potassium and plasma potassium in essential hypertension. Clin Sci. 1982; 63: 257270.[Medline] [Order article via Infotrieve]
17. Fisher NDL, Hurwitz S, Jeunemaitre X, Hopkins PN, Hollenberg N, Williams GH. Familial aggregation of low-renin hypertension. Hypertension. 2002; 39: 914918.
18. Padfield PL. Primary aldosteronism, a common entity? The myth persists. J Hum Hypertens. 2002; 16: 159162.[CrossRef][Medline] [Order article via Infotrieve]
19. Lim PO, Jung RT, MacDonald TM. Raised aldosterone to renin ratio predicts antihypertensive efficacy of spironolactone: a prospective cohort follow-up study. Br J Clin Pharmacol. 1999; 48: 756760.[CrossRef][Medline] [Order article via Infotrieve]
20. Jamieson A, Fraser R. Developments in the molecular biology of corticosteroid biosynthesis and action: implications for an understanding of essential hypertension. J Hypertens. 1994; 12: 503509.[Medline] [Order article via Infotrieve]
21. Mornet E, Dupont J, Vitek A, White PC. Characterization of two genes encoding human steroid 11ß-hydroxylase (P-45011ß). J Biol Chem. 1989; 264: 2096120967.
22. White PC. Disorders of aldosterone biosynthesis and action. N Engl J Med. 1994; 331: 250258.
23. Lifton RP, Dluhy RG, Powers M, Rich GM, Gutkin M, Fallo F, Gill JR Jr, Feld L, Ganguly A, Laidlaw JC. A chimaeric 11ß-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension. Nature. 1992; 355: 262265.[CrossRef][Medline] [Order article via Infotrieve]
24. Jamieson A, Slutsker L, Inglis GC, Fraser R, White PC, Connell JMC. Glucocorticoid-suppressible hyperaldosteronism: effects of crossover site and parental origin of chimaeric gene on phenotypic expression. Clin Sci. 1995; 88: 563570.[Medline] [Order article via Infotrieve]
25. White PC, Slutsker L. Haplotype analysis of CYP11B2. Endocr Res. 1995; 21: 437442.[Medline] [Order article via Infotrieve]
26. Bassett MH, Zhang Y, Clyne C, White PC, Rainey WE. Differential regulation of aldosterone synthase and 11ß-hydroxylase transcription by steroidogenic factor-1. J Mol Endocrinol. 2002 28; 125135.[Medline] [Order article via Infotrieve]
27. Davies E, Holloway CD, Ingram MC, Inglis GC, Friel EC, Morrison C, Anderson NH, Fraser R, Connell JM. Aldosterone excretion rate and blood pressure in essential hypertension are related to polymorphic differences in the aldosterone synthase gene CYP11B2. Hypertension. 1999; 33: 703707.
28. Paillard F, Chansel D, Brand E, Benetos A, Thomas F, Czekalski S, Ardaillou R, Soubrier F. Genotype-phenotype relationships for the renin-angiotensin-aldosterone system in a normal population. Hypertension. 1999; 34: 423429.
29. Pojoga L, Gautier S, Blanc H, Guyene TT, Poirier O, Cambien F, Benetos A. Genetic determination of plasma aldosterone levels in essential hypertension. Am J Hypertens. 1998; 11: 856860.[CrossRef][Medline] [Order article via Infotrieve]
30. Brand E, Chatelain N, Mulatero P, Fery I, Curnow K, Jeunemaitre X, Corvol P, Pascoe L, Soubrier F. Structural analysis and evaluation of the aldosterone synthase gene in hypertension. Hypertension. 1998; 32: 198204.
31. Charchar FJ, Tomaszewski M, Padmanabhan S, Lacka B, Upton MN, Inglis GC, Anderson NH, McConnachie A, Zukowska-Szczechowska E, Grzeszczak W, Connell JM, Watt GC, Dominiczak AF. The Y chromosome effect on blood pressure in two European populations. Hypertension. 2002; 39: 353356.
32. Lim PO, Macdonald TM, Holloway C, Friel E, Anderson NH, Dow E, Jung RT, Davies E, Fraser R, Connell JM. Variation at the aldosterone synthase (CYP11B2) locus contributes to hypertension in subjects with a raised aldosterone-to-renin ratio. J Clin Endocrinol Metab. 2002; 87: 43984402.
33. Inglis GC, Plouin PF, Friel EC, Davies E, Fraser R, Connell JMC. Polymorphic differences from normal in the aldosterone synthase gene (CYP11B2) in patients with primary hyperaldosteronism and adrenal tumour (Conns syndrome). Clin Endocrinol. 2001; 54: 725730.[CrossRef][Medline] [Order article via Infotrieve]
34. Mulatero P, Schiavone D, Fallo F, Rabbia F, Pilon C, Chiandussi L, Pascoe L, Veglio F. CYP11B2 gene polymorphisms in idiopathic hyperaldosteronism. Hypertension. 2000; 35: 694698.
35. Davies E, Holloway CD, Ingram MC, Friel EC, Inglis GC, Swan L, Hillis WS, Fraser R, Connell JM. An influence of variation in the aldosterone synthase gene (CYP11B2) on corticosteroid responses to ACTH in normal human subjects. Clin Endocrinol. 2000; 54: 16.
36. Kennon B, Ingram MC, Friel EC, Davies E, Fraser R, Connell JM. The -T344C polymorphism of the aldosterone synthase gene influences urinary steroid excretion during dietary manipulation of the renin-angiotensin system. Endocr Abs. 2001; 1:P 194. Abstract.
37. Hautanena A, Lankinen L, Kupari M, Janne OA, Adlercreutz H, Nikkila H, White PC. Associations between aldosterone synthase gene polymorphism and the adrenocortical function in males. J Intern Med. 1998; 244: 1118.[CrossRef][Medline] [Order article via Infotrieve]
38. de Simone G, Tommaselli AP, Rossi R, Valentino R, Lauria R, Scopacasa F, Lombardi G. Partial deficiency of adrenal 11ß-hydroxylase: a possible cause of primary hypertension. Hypertension. 1985; 7: 613618.
39. Connell JMC, Jamieson A, Davies E, Ingram MC, Soro A, Fraser R. 11ß-Hydroxylase activity in glucocorticoid suppressible hyperaldosteronism: lessons for essential hypertension? Endocr Res. 1996; 22: 691700.[Medline] [Order article via Infotrieve]
40. Jamieson A, Fraser R, Ingram MC, Connell JMC. Altered 11ß-hydroxylase activity in glucocorticoid suppressible hyperaldosteronism. J Clin Endocrinol Metab. 1996; 81: 22982302.[Abstract]
41. Symington T. The adrenal in hypertension. Functional Pathology of the Adrenal Gland. Edinburgh: E & S Livingstone Ltd; 2002: 7980.
42. Komiya I, Yamada T, Aizawa T, Takasu N, Niwa A, Maruyama Y, Ogawa A. Inappropriate elevation of the aldosterone/plasma renin activity ratio in hypertensive patients with increases of 11-deoxycorticosterone and 18-hydroxy-11-deoxycorticosterone: a subtype of essential hypertension? Cardiology. 1991; 78: 99110.[Medline] [Order article via Infotrieve]
43. Miller WL. Molecular biology of steroid hormone synthesis. Endocr Rev. 1988; 9: 295318.
44. Oelkers W. Prolonged ACTH infusion suppresses aldosterone secretion in spite of high renin activity. Acta Endocrinol. 1985; 108: 9197.[Medline] [Order article via Infotrieve]
45. Yamakita N, Mune T, Morita H, Yasuda K, Miura K, Gomez-Sanchez CE. Plasma 18-oxocortisol levels in the patients with adrenocortical disorders. Clin Endocrinol. 1994; 40: 583587.[Medline] [Order article via Infotrieve]
46. Seifert C, Oelkers W. Aldosterone response to sodium deprivation and angiotensin II in patients with hypopituitarism. Acta Endocrinol. 1981; 96: 6169.
47. Schunkert H, Hense H-W, Andus T, Riegger GAJ, Straub RH. Relation between dehydroepiandrosterone sulfate and blood pressure levels in a population-based sample. Am J Hypertens. 1999; 12: 11401143.[CrossRef][Medline] [Order article via Infotrieve]
48. Hamilton B, Zadik Z, Edwin CM, Hamilton JH, Kowarski AA. Effect of adrenal suppression with dexamethasone in essential hypertension. J Clin Endocrinol Metab. 1079; 48: 848853.
49. Neville AM, MacKay MA. The structure of the adrenal cortex in health and disease. Clin Endocrinol Metab. 1972; 1: 361395.[CrossRef]
50. Rutherford JC, Taylor WL, Stowasser M, Gordon RD. Success of surgery for primary aldosteronism judged by residual autonomous aldosterone production. World J Surg. 1998; 22: 12431245.[CrossRef][Medline] [Order article via Infotrieve]
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